Journal of Bone and Mineral Research

Journal of Bone and Mineral Research

Back Pain‐Inducing Test, a Novel and Sensitive Screening Test for Painful Osteoporotic Vertebral Fractures: A Prospective Clinical Study

04-12-2019 – Huaijian Jin, Xiaoyuan Ma, Yaoyao Liu, Xiang Yin, Jun Zhu, Zhong Wang, Weili Fan, Yufei Jin, Jungang Pu, Jianhua Zhao, Mingyong Liu, Peng Liu

Journal Article

ABSTRACTTo detect painful vertebral fractures (VFs) in back pain populations at risk of osteoporosis, we designed a physical examination test (the Back Pain‐Inducing Test BPIT) that included three movements: lying supine, rolling over, and sitting up. If back pain is induced during any of these movements, the result is defined as positive, thereby establishing a presumptive diagnosis of painful VFs. Pain severity is quantified using a self‐reported numerical rating scale (NRS). The presence or absence of painful VFs is verified by whole‐spine magnetic resonance imaging (MRI), the gold standard for final diagnosis. According to the standards for reporting diagnostic accuracy, a real‐world, prospective, and observational study was performed on 510 back pain patients (enrolled from a single institute) at risk of osteoporosis. The sensitivity, specificity, and accuracy of the BPIT for identifying painful VFs were 99.1% (95% CI, 97.5% to 99.8%), 67.9% (95% CI, 60.4% to 74.5%), and 89.0%, respectively. The positive and negative predictive values were 86.6% (95% CI, 82.9% to 89.6%) and 97.4% (95% CI, 92.6% to 99.3%), respectively. Cutoff NRS scores for lying supine, rolling over, and sitting up were 3, 0, and 2, respectively. The corresponding area under the receiver operating characteristic curves (AUROCs) of each movement was 0.898 (95% CI, 0.868 to 0.922), 0.884 (95% CI, 0.854 to 0.911), and 0.910 (95% CI, 0.882 to 0.933), respectively. Although the high prevalence of VFs in the enrolled cohort partially limits the external validity of the predictive value in the general population, we conclude that the BPIT is potentially effective for detecting painful VFs in back pain populations at risk of osteoporosis. This test may be used as a stratification tool in decision‐making on subsequent imaging procedures: a negative BPIT rules out painful VFs and indicates that an MRI should be spared, whereas a positive BPIT means that an MRI is necessary and is likely to identify painful VFs. © 2019 American Society for Bone and Mineral Research.

Increased expression of FGF‐21 negatively affects bone homeostasis in dystrophin/utrophin double knock‐out mice

04-12-2019 – Hongshuai Li, Hui Sun, Baoli Qian, Wei Feng, Dwayne Carney, Jennifer Miller, MaCalus V. Hogan, Ling Wang

ABSTRACTDuchenne Muscular Dystrophy (DMD) is the most common muscular dystrophy seen in children. In addition to skeletal muscle, DMD also has a significant impact on bone. The pathogenesis of bone abnormalities in DMD is still unknown. Recently, we have identified a novel bone‐regulating cytokine, fibroblast growth factor‐21 (FGF‐21), which is dramatically upregulated in skeletal muscles from DMD animal models. We hypothesize that muscle‐derived FGF‐21 negatively affects bone homeostasis in DMD. Dystrophin/utrophin double‐knockout (d
KO) mice were used in this study. We found the levels of circulating FGF‐21 were significantly higher in d
KO mice than in age‐matched WT controls. Further tests on FGF‐21 expressing tissues revealed that both FGF‐21 m
RNA and protein expression were dramatically upregulated in dystrophic skeletal muscles, while FGF‐21 m
RNA expression was downregulated in liver and white adipose tissue (WAT) compared to WT controls. Neutralization of circulating FGF‐21 by IP injection of anti‐FGF‐21 antibody significantly alleviated progressive bone loss in weight‐bearing (vertebra, femur and tibia) and non‐weight bearing bones (parietal bones) in d
KO mice. We also found that FGF‐21 directly promoted RANKL induced osteoclastogenesis from bone marrow macrophages (BMMs), as well as promoted adipogenesis while concomitantly inhibiting osteogenesis of bone marrow mesenchymal stem cells (BMMSCs). Furthermore, fibroblast growth factor receptors (FGFRs) and co‐receptor β‐klotho (KLB) were expressed in bone cells (BMM derived osteoclasts and BMMSCs) and bone tissues. KLB knockdown by si
RNAs significantly inhibited the effects of FGF21 on osteoclast formation of BMMSs and on adipogenic differentiation of BMMSCs, indicating that FGF‐21 may directly affect dystrophic bone via FGFRs‐β‐klotho complex. In conclusion, this study demonstrates that dystrophic skeletal muscles express and secrete significant levels of FGF‐21, which negatively regulates bone homeostasis and represents an important pathological factor for the development of bone abnormalities in DMD. The current study highlights the importance of muscle/bone cross talk via muscle derived factors (myokines) in the pathogenesis of bone abnormalities in DMD.
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Differential effect of long‐term systemic exposure of TNFα on health of the annulus fibrosus and nucleus pulposus of the intervertebral disc

04-12-2019 – Deborah J. Gorth, Olivia K. Ottone, Irving M. Shapiro, Makarand V. Risbud

ABSTRACTThe inflammatory cytokine tumor necrosis factor alpha (TNFα) is considered to play a key role in the pathogenesis of intervertebral disc disease. To evaluate the importance of this cytokine we examined the inflammatory environment and spinal phenotype of 9‐month‐old h
TNFα overexpressing (h
TNFα‐TG) mice. The mice evidenced increased circulating levels of IL‐1β, IL‐2, KC/GRO, and MCP‐1 along with thinning of the cortical and trabecular vertebral bone. Surprisingly, while the nucleus pulposus (NP) of these mice was intact and healthy, the caudal annulus fibrosus (AF) evidenced robust cell death and immune cell‐infiltration. Despite these differences, there were no obvious alterations in the collagen or aggrecan content in the NP and AF. However, there was a reduction in cartilage oligomeric matrix protein (COMP) suggesting destabilization of the AF matrix. Microarray analysis of the NP from h
TNFα‐TG mice cells revealed minimal changes in global gene expression. These findings lend support to the notion that NP tissue is isolated from systemic inflammation. In contrast, the severe AF phenotype suggests that systemic inflammation interferes with AF health, predisposing discs to herniation as opposed to directly causing NP degeneration.
This article is protected by copyright. All rights reserved.

Effect of Aerobic or Resistance Exercise, or Both, on Bone Mineral Density and Bone Metabolism in Obese Older Adults While Dieting: A Randomized Controlled Trial

04-12-2019 – Reina Armamento‐Villareal, Lina Aguirre, Debra L Waters, Nicola Napoli, Clifford Qualls, Dennis T Villareal

ABSTRACTWeight loss therapy of older adults with obesity is limited by weight loss–induced decrease in bone mineral density (BMD), which could exacerbate ongoing age‐related bone loss and increase the risk for fractures. Therefore, it is recommended that weight loss therapy of older adults with obesity should include an intervention such as regular exercise to reduce the concomitant bone loss. However, the most appropriate exercise types to combine with weight loss therapy in this older population is unknown. In a randomized controlled trial, we performed a head‐to‐head comparison of aerobic or resistance exercise, or both, during matched ~10% weight loss in 160 older adults with obesity. We measured changes in BMD (total hip, femoral neck, trochanter, intertrochanter, one‐third radius, lumbar spine) and bone markers. Changes between groups were analyzed using mixed‐model repeated measures analyses of variance. After 6 months of intensive lifestyle interventions, BMD decreased less in the resistance group (−0.006 g/cm2 −0.7%) and combination group (−0.012 g/cm2 −1.1%) than in the aerobic group (−0.027 g/cm2 −2.6%) (p = 0.001 for between‐group comparisons). Serum C‐telopeptide, procollagen type 1 N‐propeptide, and osteocalcin concentrations increased more in the aerobic group (33%, 16%, and 16%, respectively) than in the resistance group (7%, 2%, and 0%, respectively) and combination group (11%, 2%, and 5%, respectively) (p = 0.004 to 0.048 for between‐group comparisons). Multiple regression analyses revealed that the decline in whole body mass and serum leptin were the independent predictors of the decline in hip BMD (multiple R = 0.45 p < .001). These findings indicate that compared with aerobic exercise, resistance and combined aerobic and resistance exercise are associated with less weight loss–induced decrease in hip BMD and less weight loss–induced increase in bone turnover. Therefore, both resistance and combined aerobic and resistance exercise can be recommended to protect against bone loss during weight loss therapy of older adults with obesity. (LITOE Clinical
Trials.gov number NCT01065636.) © 2019 American Society for Bone and Mineral Research. Published 2019. This article is a U.
S. Government work and is in the public domain in the USA.

Prolonged Effect of Zoledronic Acid on Bone Mineral Density and Turnover in HIV‐Infected Adults on Tenofovir: A Randomized, Open‐Label Study

03-12-2019 – Andrew Carr, Stephen J Kerr, Robyn Richardson, Peter Ebeling, Nicholas Pocock, Jhon Rojas, Esteban Martinez, Jennifer Hoy, ZEST study Investigators

Journal Article

ABSTRACTZoledronic acid (ZOL) 5 mg annually was more effective than tenofovir disoproxil fumarate (TDF) switching at increasing bone mineral density (BMD) over 24 months in HIV‐infected, osteopenic adults. To determine whether the effects of ZOL would persist without further infusions, we compared changes in left hip and spine BMD over 36 months in participants randomized to ZOL 5 mg at baseline and month 12 (and to continue TDF) or to switch TDF (without receiving ZOL). We also compared changes in the plasma bone turnover markers (BTMs) C‐terminal telopeptide of type 1 collagen (CTX; bone resorption), and procollagen type 1 N propeptide (P1NP; bone formation) and determined whether CTX and P1NP changes at month 3 predicted BMD changes at month 36. Changes were compared in the per‐protocol populations, which included 32 (74%) of 43 participants randomized to ZOL and 37 (88%) of 42 participants who switched TDF. Despite not receiving ZOL after month 12, mean hip and spine BMD change from baseline were stable and remained greater with ZOL at month 36 than with TDF switching (spine: 7.5% versus 2.7%, mean difference 4.7%, p < 0.001; hip: 5.5% versus 1.5%, mean difference 4.0%, p < 0.001). CTX and P1NP levels declined in both groups but significantly more with ZOL. Only percent changes in P1NP at month 3 correlated inversely with BMD changes at month 36 (spine: rho = −0.442, p < 0.001; hip: rho = −0.373, p = 0.002). Two infusions of ZOL (in the presence of ongoing TDF) yielded sustained BMD increases through month 36 that remained greater than with TDF switching. © 2019 American Society for Bone and Mineral Research.

Vertebral Fracture Assessment Increases Use of Pharmacologic Therapy for Fracture Prevention in Clinical Practice

03-12-2019 – John T Schousboe, Lisa M Lix, Suzanne N Morin, Sheldon Derkatch, Mark Bryanton, Mashael Alhrbi, William D Leslie

Journal Article

ABSTRACTThe impact of vertebral fracture assessment (VFA) on lateral spine images in clinical practice on subsequent patient use of fracture prevention medication is unknown. Our objective was to determine the association of prevalent vertebral fracture identified on bone density lateral spine images (positive VFA) with subsequent use of fracture prevention therapy in usual clinical practice, using the Manitoba Bone Density Program database prospective observational cohort. Since 2010, targeted VFA imaging has been done at the time of bone densitometry in Manitoba for 21% of women and men meeting criteria based on age, bone mineral density (BMD), height loss, and glucocorticoid use. Among 6652 treatment‐naive individuals with at least 90 days follow‐up who had VFA imaging, 923 (13.9%) had one or more definite vertebral fractures identified using a modified algorithm‐based qualitative (ABQ) method. For those with a positive VFA, their bone density reports stated the patient was at high risk of subsequent fracture and qualified for fracture prevention therapy. Subsequent osteoporosis treatment initiated within the next 12 months was identified using population‐based pharmacy data. Logistic regression models were used to estimate the association of positive VFA with subsequent prescription (Rx), compared to negative VFA. Fracture prevention medication was started by 2127 (32%) individuals, 52.3% with positive versus 28.4% with negative VFA (p value <0.001). This association was substantially stronger in those designated (before VFA results were known) to have low or moderate fracture risk compared to high fracture risk (interaction p value <0.001), and in those with osteopenia (OR 4.51; 95% CI, 3.48 to 5.85) compared to those with osteoporosis by BMD criteria (OR 1.72; 95% CI, 1.43 to 2.08, interaction p value <0.001). Targeted VFA imaging at the time of bone densitometry substantially improves identification of those at high fracture risk and fracture prevention medication use among those with prevalent vertebral fracture. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

Estradiol and Follicle‐Stimulating Hormone as Predictors of Onset of Menopause Transition‐Related Bone Loss in Pre‐ and Perimenopausal Women

03-12-2019 – Albert Shieh, Gail A Greendale, Jane A Cauley, Carrie Karvonen‐Gutierrez, Carolyn J Crandall, Arun S Karlamangla

Journal Article

ABSTRACTThe menopause transition (MT) may be an opportunity for early intervention to prevent rapid bone loss. To intervene early, we need to be able to prospectively identify pre‐ and perimenopausal women who are beginning to lose bone. This study examined whether estradiol (E2), or follicle‐stimulating hormone (FSH), measured in pre‐ and perimenopausal women, can predict significant bone loss by the next year. Bone loss was considered significant if bone mineral density (BMD) decline at the lumbar spine (LS) or femoral neck (FN) from a pre‐ or early perimenopausal baseline to 1 year after the E2 or FSH measurement was greater than the least detectable change. We used data from 1559 participants in the Study of Womens Health Across the Nation and tested E2 and FSH as separate predictors using repeated measures modified Poisson regression. Adjusted for MT stage, age, race/ethnicity, and body mass index, women with lower E2 (and higher FSH) were more likely to lose BMD: At the LS, each halving of E2 and each doubling of FSH were associated with 10% and 39% greater risk of significant bone loss, respectively (p < 0.0001 for each). At the FN, each halving of E2 and each doubling of FSH were associated with 12% (p = 0.01) and 27% (p < 0.001) greater risk of significant bone loss. FSH was more informative than E2 (assessed by the area under the receiver‐operator curve) at identifying women who were more versus less likely to begin losing bone, especially at the LS. Prediction was better when hormones were measured in pre‐ or early perimenopause than in late perimenopause. Tracking within‐individual change in either hormone did not predict onset of bone loss better than a single measure. We conclude that measuring FSH in the MT can help prospectively identify women with imminent or ongoing bone loss at the LS. © 2019 American Society for Bone and Mineral Research.

Hormone‐Independent Sexual Dimorphism in the Regulation of Bone Resorption by Krox20

03-12-2019 – Elias Sabag, Elinor Halperin, Tamar Liron, Sahar Hiram‐Bab, Baruch Frenkel, Yankel Gabet

Journal Article

ABSTRACTKrox20/EGR2 is a zinc finger transcription factor, implicated in the development of the hindbrain, nerve myelination, and tumor suppression. In skeletal biology, we have demonstrated that Krox20 also regulates adult bone metabolism. We and others have characterized several functions of Krox20 in the osteoclast lineage, namely, preosteoclast proliferation and differentiation, and mature osteoclast apoptosis. We have previously reported that systemically Krox20‐haploinsufficient mice have a low bone mass with increased bone resorption. However, new data have now revealed that this phenotype is restricted to females. In addition, we discovered that conditional knockout of Krox20 (c
KO) restricted to osteoclast progenitors is sufficient to induce the same female‐specific bone loss observed in systemic mutants. To test whether this sexual dimorphism results from an interaction between Krox20 and sex hormones, we examined the sex‐ and hormone‐dependent role of Krox20 deficiency on proliferation and apoptosis in osteoclastic cells. Our results indicate that male and female sex hormones (dihydrotestosterone DHT and estradiol E2, respectively) as well as Krox20 inhibit preosteoclast proliferation and augment osteoclast apoptosis. The observation that Krox20 expression is inhibited by DHT and E2 negates the hypothesis that the effect of sex hormones is mediated by an increase in Krox20 expression. Interestingly, the effect of Krox20 deficiency was observed only with cells derived from female animals, regardless of any sex hormones added in vitro. In addition, we have identified sexual dimorphism in the expression of several Krox20‐related genes, including NAB2. This sex‐specific epigenetic profile was established at puberty, maintained in the absence of sex hormones, and explains the female‐specific skeletal importance of Krox20. The findings described in this study emphasize the medical importance of sex differences, which may be determined at the epigenetic level. © 2019 American Society for Bone and Mineral Research.

Osteogenesis Imperfecta: Skeletal Outcomes After Bisphosphonate Discontinuation at Final Height

03-12-2019 – Marie‐Eve Robinson, Pamela Trejo, Telma Palomo, Francis H Glorieux, Frank Rauch

Journal Article

ABSTRACTIntravenous cyclical bisphosphonates are widely used to treat children with moderate to severe osteogenesis imperfecta (OI). Bisphosphonates are often discontinued when growth is completed, but subsequent skeletal changes have not been studied in detail. We assessed 31 patients (22 females) with OI who had started intravenous bisphosphonates (either pamidronate or zoledronic acid) before 13 years of age, were treated for at least 2 years (range 4.7–15.7 years), and discontinued treatment after completion of growth, when their age ranged from 13.4 to 20.0 years (mean 16.4 years). At 4 years after treatment discontinuation, lumbar spine areal bone mineral density (BMD) had increased by 4% (p < 0.05). Peripheral quantitative computed tomography of the radius showed a decrease in trabecular volumetric BMD at the distal metaphysis of 19% but an increase in cortical volumetric BMD of 4% (p < 0.05 for both). None of the patients sustained a new vertebral compression fracture during follow‐up. The proportion of patients with new long‐bone fractures was higher in the 2 years before treatment discontinuation than in the last 2 years of follow‐up (42% and 16%, respectively; p < 0.05). © 2019 American Society for Bone and Mineral Research.

Clinical Performance of the Updated Trabecular Bone Score (TBS) Algorithm, Which Accounts for the Soft Tissue Thickness: The OsteoLaus Study

03-12-2019 – Enisa Shevroja, Bérengère Aubry‐Rozier, Gabriel Hans, Elena Gonzalez Rodriguez, Delphine Stoll, Olivier Lamy, Didier Hans

Journal Article

ABSTRACTRegional soft tissue may have a noise effect on trabecular bone score (TBS) and eventually alter its estimate. The current TBS software (TBS i
Nsight®) is based on an algorithm accounting for body mass index (BMI) (TBSv3.03). We aimed to explore the updated TBS algorithm that accounts for soft tissue thickness (TBSv4.0). This study was embedded in the Osteo
Laus cohort of women in Lausanne, Switzerland. Hip and lumbar spine (LS) dual‐energy X‐ray absorptiometry (DXA) scans were performed using Discovery A System (Hologic). The incident major osteoporotic fractures (MOFs) were assessed from vertebral fracture assessments using Genants method (vertebral MOF) or questionnaires (nonvertebral MOF). We assessed the correlations of bone mineral density (BMD) or TBS with body composition parameters; MOF prediction ability of both versions of TBS; and the differences between Fracture Risk Assessment Tool (FRAX) adjusted for TBSv3.03 or TBSv4.0. In total, 1362 women with mean ± SD age 64.4 ± 7.5 years and mean ± SD BMI 25.9 ± 4.5 kg/m2 were followed for 4.4 years and 132 experienced an MOF. All the anthropometric measurements of our interest were positively correlated with LS, femoral neck, or hip BMD and TBSv4.0; whereas with TBSv3.03 their correlations were negative. In the models adjusted for age, soft tissue thickness, osteoporotic treatment, and LS‐BMD, for each SD decline in TBSv3.03, there was a 43% (OR 1.43; 95% CI, 1.12 to 1.83) increase in the odds of having MOF; whereas for each SD decline in TBSv4.0, there was a 54% (OR 1.54; 95% CI, 1.18 to 2.00) increase in the odds of having an MOF. Both FRAXs were very strongly correlated and the mild differences were present in the already high‐risk women for MOF. This study shows that TBSv4.0 overcomes the debatable residual negative correlation of the current TBS with body size and composition parameters, postulating itself as free from the previously acknowledged technical limitation of TBS. © 2019 American Society for Bone and Mineral Research.

Genetic Screening in a Large Chinese Cohort of Childhood Onset Hypoparathyroidism by Next‐Generation Sequencing Combined with TBX1‐MLPA

03-12-2019 – Yabing Wang, Min Nie, Ou Wang, Yuepeng Li, Yan Jiang, Mei Li, Weibo Xia, Xiaoping Xing

Journal Article

ABSTRACTAt least 15 candidate genes have been implicated in hypoparathyroidism (HP). However, comprehensive screening of causative genes for HP is lacking. Here, we investigated the genotype spectrum in a large group of Chinese patients with childhood onset HP. A total of 173 patients with childhood onset HP were analyzed using targeted next‐generation sequencing (NGS), including 15 candidate genes combined with multiplex ligation‐dependent probe amplification (MLPA) of the TBX1 gene. Twenty‐seven pathogenic or likely pathogenic mutations in five genes (TBX1, AIRE, GATA3, FAM111A, and CASR) including 13 novel variants in 23 patients, and 12 variants of uncertain clinical significance in five genes (GATA3, CASR, FAM111A, GCM2, and PTH) in 11 patients, were identified by NGS. Additionally, an entire gene deletion of TBX1 in 25 patients was found by TBX1‐MLPA. Combined with clinical data, 26 (15.0%) cases of Di
George syndrome (OMIM #188400), nine (5.2%) autoimmune polyglandular syndrome type 1 (OMIM #240300), eight (4.6%) autosomal dominant hypocalcemia type 1 (OMIM #601198), four (2.3%) hypoparathyroidism‐deafness‐renal dysplasia syndrome (OMIM #146255), and one (0.6%) Kenny‐Caffey syndrome type 2 (OMIM #127000) were verified. Among them, 16 of 26 (61.5%) Di
George syndrome cases were undiagnosed due to the lack of obvious clinical clues before genetic testing. The onset age of patients with mutations (median interquartile range, 2.8 0.1, 9.6 years) was significantly earlier than those without mutations (13.0 8.8, 15.0 years) (p < 0.001). Family history, early onset age, especially prior to 5 years old, and extraparathyroid manifestations were clues for hereditary HP. The combined targeted NGS and TBX‐1 MLPA were conveniently and effectively used for comprehensive genetic screening in this large Chinese cohort of childhood onset HP patients. Genetic defects were identified in 27.7% of early‐onset HP patients, including four kinds of syndromic HP and one isolated HP. A total of 13 novel mutations were detected, which expands the mutation spectrum of hypoparathyroidism. © 2019 American Society for Bone and Mineral Research.

Hop2 Interacts with ATF4 to Promote Osteoblast Differentiation

03-12-2019 – Yang Zhang, Tonghui Lin, Na Lian, Huan Tao, Cong Li, Lingzhen Li, Xiangli Yang

Journal Article

ABSTRACTActivating transcription factor 4 (ATF4) is a member of the basic leucine zipper (b
Zip) transcription factor family required for the terminal differentiation of osteoblasts. Despite its critical importance as one of the three main osteoblast differentiation transcription factors, regulators of osteoblast terminal maturation remain poorly defined. Here we report the identification of homologous pairing protein 2 (Hop2) as a dimerization partner of ATF4 in osteoblasts via the yeast two‐hybrid system. Deletional mapping revealed that the Zip domain of Hop2 is necessary and sufficient to bind ATF4 and to enhance ATF4‐dependent transcription. Ectopic Hop2 expression in preosteoblasts increased endogenous ATF4 protein content and accelerated osteoblast differentiation. Mice lacking Hop2 (Hop2−/−) have a normal stature but exhibit an osteopenic phenotype similar to the one observed in Atf4−/− mice, albeit milder, which is associated with decreased Osteocalcin m
RNA expression and reduced type I collagen synthesis. Compound heterozygous mice (Atf4+/−:Hop2+/−) display identical skeletal defects to those found in Hop2−/− mice. These results indicate that Hop2 plays a previous unknown role as a determinant of osteoblast maturation via its regulation of ATF4 transcriptional activity. Our work for the first time reveals a function of Hop2 beyond its role in guiding the alignment of homologous chromosomes. © 2019 American Society for Bone and Mineral Research.

Sclerostin Antibody–Induced Changes in Bone Mass Are Site Specific in Developing Crania

03-12-2019 – Amanda L Scheiber, David K Barton, Basma M Khoury, Joan C Marini, Donald L Swiderski, Michelle S Caird, Kenneth M Kozloff

Journal Article

ABSTRACTSclerostin antibody (Scl‐Ab) is an anabolic bone agent that has been shown to increase bone mass in clinical trials of adult diseases of low bone mass, such as osteoporosis and osteogenesis imperfecta (OI). Its use to decrease bone fragility in pediatric OI has shown efficacy in several growing mouse models, suggesting translational potential to pediatric disorders of low bone mass. However, the effects of pharmacologic inhibition of sclerostin during periods of rapid growth and development have not yet been described with respect to the cranium, where lifelong deficiency of functioning sclerostin leads to patterns of excessive bone growth, cranial compression, and facial palsy. In the present study, we undertook dimensional and volumetric measurements in the skulls of growing Brtl/+ OI mice treated with Scl‐Ab to examine whether therapy‐induced phenotypic changes were similar to those observed clinically in patients with sclerosteosis or Van Buchem disorder. Mice treated between 3 and 14 weeks of age with high doses of Scl‐Ab show significant calvarial thickening capable of rescuing OI‐induced deficiencies in skull thickness. Other changes in cranial morphology, such as lengths and distances between anatomic landmarks, intracranial volume, and suture interdigitation, showed minimal effects of Scl‐Ab when compared with growth‐induced differences over the treatment duration. Treatment‐induced narrowing of foramina was limited to sites of vascular but not neural passage, suggesting patterns of local regulation. Together, these findings reveal a site specificity of Scl‐Ab action in the calvaria with no measurable cranial nerve impingement or brainstem compression. This differentiation from the observed outcomes of lifelong sclerostin deficiency complements reports of Scl‐Ab treatment efficacy at other skeletal sites with the prospect of minimal cranial secondary complications. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

TGFβ Inhibition Stimulates Collagen Maturation to Enhance Bone Repair and Fracture Resistance in a Murine Myeloma Model

03-12-2019 – Alanna C Green, Darren Lath, Katie Hudson, Brant Walkley, Jennifer M Down, Robert Owen, Holly R Evans, Julia Paton‐Hough, Gwendolen C Reilly, Michelle A Lawson, Andrew D Chantry

Journal Article

ABSTRACTMultiple myeloma is a plasma cell malignancy that causes debilitating bone disease and fractures, in which TGFβ plays a central role. Current treatments do not repair existing damage and fractures remain a common occurrence. We developed a novel low tumor phase murine model mimicking the plateau phase in patients as we hypothesized this would be an ideal time to treat with a bone anabolic. Using in vivo μCT we show substantial and rapid bone lesion repair (and prevention) driven by SD‐208 (TGFβ receptor I kinase inhibitor) and chemotherapy (bortezomib and lenalidomide) in mice with human U266‐GFP‐luc myeloma. We discovered that lesion repair occurred via an intramembranous fracture repair‐like mechanism and that SD‐208 enhanced collagen matrix maturation to significantly improve fracture resistance. Lesion healing was associated with VEGFA expression in woven bone, reduced osteocyte‐derived PTHr
P, increased osteoblasts, decreased osteoclasts, and lower serum tartrate‐resistant acid phosphatase 5b (TRACP‐5b). SD‐208 also completely prevented bone lesion development in mice with aggressive JJN3 tumors, and was more effective than an anti‐TGFβ neutralizing antibody (1D11). We also discovered that SD‐208 promoted osteoblastic differentiation (and overcame the TGFβ‐induced block in osteoblastogenesis) in myeloma patient bone marrow stromal cells in vitro, comparable to normal donors. The improved bone quality and fracture‐resistance with SD‐208 provides incentive for clinical translation to improve myeloma patient quality of life by reducing fracture risk and fatality. © 2019 American Society for Bone and Mineral Research.

RANKL Inhibition in Fibrous Dysplasia of Bone: A Preclinical Study in a Mouse Model of the Human Disease

03-12-2019 – Biagio Palmisano, Emanuela Spica, Cristina Remoli, Rossella Labella, Annamaria Di Filippo, Samantha Donsante, Fabiano Bini, Domenico Raimondo, Franco Marinozzi, Alan Boyde, Pamela Robey, Alessandro Corsi, Mara Riminucci

Journal Article

ABSTRACTFibrous dysplasia of bone/McCune‐Albright syndrome (Polyostotic FD/MAS; OMIM#174800) is a crippling skeletal disease caused by gain‐of‐function mutations of Gsα. Enhanced bone resorption is a recurrent histological feature of FD and a major cause of fragility of affected bones. Previous work suggests that increased bone resorption in FD is driven by RANKL and some studies have shown that the anti‐RANKL monoclonal antibody, denosumab, reduces bone turnover and bone pain in FD patients. However, the effect of RANKL inhibition on the histopathology of FD and its impact on the natural history of the disease remain to be assessed. In this study, we treated the EF1α‐GsαR201C mice, which develop an FD‐like phenotype, with an anti‐mouse RANKL monoclonal antibody. We found that the treatment induced marked radiographic and microscopic changes at affected skeletal sites in 2‐month‐old mice. The involved skeletal segments became sclerotic due to the deposition of new, highly mineralized bone within developing FD lesions and showed a higher mechanical resistance compared to affected segments from untreated transgenic mice. Similar changes were also detected in older mice with a full‐blown skeletal phenotype. The administration of anti‐mouse RANKL antibody arrested the growth of established lesions and, in young mice, prevented the appearance of new ones. However, after drug withdrawal, the newly formed bone was remodelled into FD tissue and the disease progression resumed in young mice. Taken together, our results show that the anti‐RANKL antibody significantly affected the bone pathology and natural history of FD in the mouse. Pending further work on the prevention and management of relapse after treatment discontinuation, our preclinical study suggests that RANKL inhibition may be an effective therapeutic option for FD patients. © 2019 American Society for Bone and Mineral Research.

Increased Risk of Bone Fractures in Hemodialysis Patients Treated with Proton Pump Inhibitors in Real World: Results from the Dialysis Outcomes and Practice Patterns Study (DOPPS)

03-12-2019 – “Maria Fusaro, Graziella DArrigo, Annalisa Pitino, Giorgio Iervasi, Francesca Tentori, Bruce Robinson, Andrea Aghi, Brian Bieber, Keith Mccullogh, Fabrizio Fabris, Mario Plebani, Sandro Giannini, Maurizio Gallieni, Giovanni Tripepi”

Journal Article

ABSTRACTLong‐term treatment with proton pump inhibitors (PPIs) is associated with an increased risk of fractures in the general population. PPIs are widely prescribed to dialysis patients but to date no study has specifically tested, by state‐of‐art statistical methods, the relationship between use of PPIs and fractures in this patient population. This study aimed to assess whether use of PPIs is associated with bone fractures (ie, hip fractures and fractures other than hip fractures) in a large international cohort of hemodialysis patients. We considered an observational prospective cohort of 27,097 hemodialysis patients from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Data analysis was performed by the Fine and Gray method, considering the competitive risk of mortality, as well as by a cause‐specific hazards Cox model with death as a censoring event and matching patients according to the prescription time. Of 27,097 hemodialysis patients, 13,283 patients (49%) were on PPI treatment. Across the follow‐up period (median, 19 months), 3.8 bone fractures × 100 person‐years and 1.2 hip fractures × 100 person‐years occurred. In multiple Cox models, considering the competitive risk of mortality, the incidence rate of bone (subdistribution hazard ratio SHR 1.22; 95% CI, 1.10 to 1.36; p < 0.001) and hip fractures (SHR 1.35; 95% CI, 1.13 to 1.62; p = 0.001) was significantly higher in PPI‐treated than in PPI‐untreated patients. These findings also held true in multiple, cause‐specific, hazards Cox models matching patients according to the prescription time (bone fractures: HR 1.47; 95% CI, 1.23 to 1.76; p < 0.001; hip fractures: HR 1.85; 95% CI, 1.37 to 2.50; p < 0.001). The use of PPIs requires caution and a careful evaluation of risks/benefits ratio in hemodialysis patients. © 2019 American Society for Bone and Mineral Research.

Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X‐Linked Hypophosphatemia: A Phase 3, Single‐Arm, International Trial

03-12-2019 – Karl L Insogna, Frank Rauch, Peter Kamenický, Nobuaki Ito, Takuo Kubota, Akie Nakamura, Lin Zhang, Matt Mealiffe, Javier San Martin, Anthony A Portale

Journal Article

ABSTRACTIn adults with X‐linked hypophosphatemia (XLH), excess FGF23 impairs renal phosphate reabsorption and suppresses production of 1,25‐dihydroxyvitamin D, resulting in chronic hypophosphatemia and persistent osteomalacia. Osteomalacia is associated with poor bone quality causing atraumatic fractures, pseudofractures, delayed fracture healing, and bone pain. Burosumab is a fully human monoclonal antibody against FGF23. UX023‐CL304 is an ongoing, open‐label, single‐arm, phase 3 study investigating the efficacy of subcutaneous burosumab, 1.0 mg/kg administered every 4 weeks, in improving osteomalacia in adults with XLH who have not been treated for at least 2 years before enrollment. The primary endpoint was improvement in osteoid volume/bone volume assessed by transiliac bone biopsies obtained at baseline and week 48. Additional assessments included serum phosphorus, markers of bone turnover, fracture/pseudofracture healing, and safety. Fourteen subjects enrolled, 13 completed 48 weeks, and 11 completed paired biopsies. All osteomalacia‐related histomorphometric measures improved significantly at week 48 (mean percent change: osteoid volume/bone volume, –54%, osteoid thickness, –32%, osteoid surface/bone surface, –26%, median mineralization lag time, –83%). Mean serum phosphorus concentration averaged across the mid‐point of the dose cycle between weeks 0 and 24 was 3.3 mg/d
L, a 50% increase from 2.2 mg/d
L at baseline. Markers of bone formation and resorption increased at week 48 (least squares LS mean increase: P1NP, +77%; CTx, +36%; both p < 0.0001). All subjects had one or more treatment‐emergent adverse event (AE). Most AEs were mild to moderate in severity. Two subjects experienced serious AEs (migraine; paresthesia) that were unrelated to treatment and resolved. Eleven subjects had 18 biopsy procedure‐related AEs: 14 for pain, two for itch, and one each for headache and bandage irritation. No deaths or incidents of hyperphosphatemia occurred. In conclusion, by normalizing phosphate homeostasis, burosumab significantly improved osteomalacia in adults with XLH, which likely explains the improved fracture healing and amelioration of skeletal complications. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Fracture and Bone Mineral Density Response by Baseline Risk in Patients Treated With Abaloparatide Followed by Alendronate: Results From the Phase 3 ACTIVExtend Trial

03-12-2019 – Benjamin Z Leder, Carol Zapalowski, Ming‐Yi Hu, Gary Hattersley, Nancy E Lane, Andrea J Singer, Robin K Dore

Journal Article

ABSTRACTIn the randomized, placebo‐controlled, double‐blind phase 3 ACTIVE study (NCT01343004), 18 months of abaloparatide 80 μg daily (subcutaneous injection) in postmenopausal women at risk of osteoporotic fracture significantly reduced the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures and significantly increased bone mineral density (BMD) versus placebo regardless of baseline risk factors. Women from the abaloparatide and placebo groups who completed ACTIVE were eligible for ACTIVExtend (NCT01657162), in which all enrollees received sequential, open‐label monotherapy with alendronate 70 mg once weekly for up to 24 months. This prespecified analysis evaluated whether fracture risk reductions and bone mineral density (BMD) gains associated with abaloparatide during ACTIVE persisted through the full 43‐month ACTIVE–ACTIVExtend study period in nine prespecified baseline risk subgroups. Baseline risk subgroups included BMD T‐score at the lumbar spine, total hip, and femoral neck (≤ − 2.5 versus > − 2.5 and ≤ −3.0 versus > − 3.0), history of nonvertebral fracture (yes/no), prevalent vertebral fracture (yes/no), and age (<65 versus 65 to <75 versus ≥75 years). Forest plots display treatment effect. Treatment‐by‐subgroup interactions were tested using the Breslow‐Day test, Cox proportional hazards model, and ANCOVA model. After the combined ACTIVE–ACTIVExtend study period, reductions in relative risk for new vertebral, nonvertebral, clinical, and major osteoporotic fractures were greater among patients in the abaloparatide/alendronate group than among those in the placebo/alendronate group across all nine baseline risk subgroups. BMD gains at the lumbar spine, total hip, and femoral neck were greater in the abaloparatide/alendronate group versus the placebo/alendronate group. No clinically meaningful interaction between treatment assignment and any baseline risk variable was observed. The sequence of abaloparatide for 18 months followed by alendronate for up to 24 months appears to be an effective treatment option for a wide range of postmenopausal women at risk for osteoporotic fractures. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

Zoledronate for the Prevention of Bone Loss in Women Discontinuing Denosumab Treatment. A Prospective 2‐Year Clinical Trial

03-12-2019 – Athanasios D Anastasilakis, Socrates E Papapoulos, Stergios A Polyzos, Natasha M Appelman‐Dijkstra, Polyzois Makras

Journal Article

ABSTRACTCessation of denosumab treatment is associated with increases in bone turnover above baseline values and rapid bone loss. We investigated the efficacy of zoledronate to prevent this bone loss in women with postmenopausal osteoporosis who were treated with denosumab (mean duration 2.2 years) and discontinued treatment after achieving osteopenia. Women were randomized to receive a single 5‐mg infusion of zoledronate (ZOL) (n = 27) or two additional 60‐mg injections of denosumab (Dmab) (n = 30). Both groups were followed for a total period of 24 months. At 24 months lumbar spine–bone mineral density (LS‐BMD) was not different from baseline in the ZOL group, but decreased in the Dmab group by (mean ± SD) 4.82% ± 0.7% (p < 0.001) from the 12‐month value; the difference in BMD changes between the two groups, the primary endpoint of the study, was statistically significant (p = 0.025). Results of femoral neck (FN)‐BMD changes were similar. ZOL infusion was followed by small but significant increases in serum procollagen type 1 N‐terminal propeptide (P1NP) and C‐terminal telopeptide of type 1 collagen (CTX) during the first year and stabilization thereafter. In the Dmab group, bone turnover marker values did not change during the first 12 months but increased significantly at 15 months and in the majority of women these remained elevated at 24 months. Neither baseline nor 12‐month bone turnover marker values were associated with BMD changes in either group of women. In the Dmab group, three patients sustained vertebral fractures (two patients multiple clinical, one patient morphometric) whereas one patient in the ZOL group sustained clinical vertebral fractures 12 months after the infusion. In conclusion, a single intravenous infusion of ZOL given 6 months after the last Dmab injection prevents bone loss for at least 2 years independently of the rate of bone turnover. Follow‐up is recommended, because in a few patients ZOL treatment might not have the expected effect at 2 years. © 2019 American Society for Bone and Mineral Research.

Cytokine‐Induced and Stretch‐Induced Sphingosine 1‐Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis

03-12-2019 – Alaeddine El Jamal, Anne Briolay, Saida Mebarek, Benoit Le Goff, Frédéric Blanchard, David Magne, Leyre Brizuela, Carole Bougault

Journal Article

ABSTRACTSpondyloarthritis (Sp
A) is a common rheumatic disease characterized by enthesis inflammation (enthesitis) and ectopic ossification (enthesophytes). The current pathogenesis model suggests that inflammation and mechanical stress are both strongly involved in Sp
A pathophysiology. We have previously observed that the levels of sphingosine 1‐phosphate (S1P), a bone anabolic molecule, were particularly high in Sp
A patients serum compared to healthy donors. Therefore, we wondered how this deregulation was related to Sp
A molecular mechanisms. Mouse primary osteoblasts, chondrocytes, and tenocytes were used as cell culture models. The sphingosine kinase 1 (Sphk1) gene expression and S1P secretion were significantly enhanced by cyclic stretch in osteoblasts and chondrocytes. Further, TNF‐α and IL‐17, cytokines implicated in enthesitis, increased Sphk1 m
RNA in chondrocytes in an additive manner when combined to stretch. The immunochemistry on mouse ankles showed that sphingosine kinase 1 (SK1) was localized in some chondrocytes; the addition of a pro‐inflammatory cocktail augmented Sphk1 expression in cultured ankles. Subsequently, fingolimod was used to block S1P metabolism in cell cultures. It inhibited S1P receptors (S1PRs) signaling and SK1 and SK2 activity in both osteoblasts and chondrocytes. Fingolimod also reduced S1PR‐induced activation by Sp
A patients synovial fluid (SF), demonstrating that the stimulation of chondrocytes by SFs from Sp
A patients involves S1P. In addition, when the osteogenic culture medium was supplemented with fingolimod, alkaline phosphatase activity, matrix mineralization, and bone formation markers were significantly reduced in osteoblasts and hypertrophic chondrocytes. Osteogenic differentiation was accompanied by an increase in S1prs m
RNA, especially S1P1/3, but their contribution to S1P‐impact on mineralization seemed limited. Our results suggest that S1P might be overproduced in Sp
A enthesis in response to cytokines and mechanical stress, most likely by chondrocytes. Moreover, S1P could locally favor the abnormal ossification of the enthesis; therefore, blocking the S1P metabolic pathway could be a potential therapeutic approach for the treatment of Sp
A. © 2019 American Society for Bone and Mineral Research.

“Clinical Guidelines on Pagets Disease of Bone”

03-12-2019 – “Stuart H Ralston, Luis Corral‐Gudino, Cyrus Cooper, Roger M Francis, William D Fraser, Luigi Gennari, Nuria Guanabens, M Kassim Javaid, Robert Layfield, Terence W ONeill, Robert Graham G Russell, Michael D Stone, Keith Simpson, Diana Wilkinson, Ruth Wills, M Carola Zillikens, Stephen P Tuck”

Letter

“Reply to Clinical Guidelines on Pagets Disease”

03-12-2019 – Bente Langdahl

Letter

First in Mice: RANKL Neutralization in Fibrous Dysplasia

03-12-2019 – Luis F Castro, PhD, Alison M Boyce, MD, Michael T Collins, MD

Editorial

In Memoriam

03-12-2019 –

Journal Article

Ed Bd, Masthead, Comm List and TOC

03-12-2019 –

Issue Information‐Declaration of Helsinki

03-12-2019 –

JBMR Reviewer List 2019

03-12-2019 –

IRS‐1 Functions as a Molecular Scaffold to Coordinate IGF‐I/IGFBP‐2 Signaling During Osteoblast Differentiation

03-12-2019 – Gang Xi, Xinchun Shen, Clifford J Rosen, David R Clemmons

Published Erratum

Journal of Bone and Mineral Research: Volume 34, Number 12, December 2019

03-12-2019 –

Abaloparatide at the same dose has the same effects on bone as PTH (1‐34) in mice

02-12-2019 – Carole Le Henaff, Florante Ricarte, Brandon Finnie, Zhiming He, Joshua Johnson, Johanna Warshaw, Victoria Kolupaeva, Nicola C. Partridge

Journal Article

Abaloparatide, a novel analog of parathyroid hormone‐related protein (PTHr
P 1‐34) became, in 2017, the second osteoanabolic therapy for the treatment of osteoporosis. This study aims to compare the effects of PTH (1‐34), PTHr
P (1‐36), and abaloparatide on bone remodeling in male mice. Intermittent daily subcutaneous injections of 80 μg/kg/day were administered to four‐month‐old C57Bl/6J male mice for six weeks. During treatment, mice were followed by DEXA‐Piximus to assess changes in bone mineral density (BMD) in the whole body, femur and tibia. At either four or eighteen hours after the final injection, femurs were harvested for μCT analyses and histomorphometry, sera were assayed for bone turnover marker levels, and tibiae were separated into cortical, trabecular, and bone marrow fractions for gene expression analyses. Our results showed that, compared with PTH (1‐34), abaloparatide resulted in a similar increase in BMD at all sites, while no changes were seen with PTHr
P (1‐36). With both PTH (1‐34) and abaloparatide, μCT and histomorphometry analyses revealed similar increases in bone volume associated with an increased trabecular thickness, in bone formation rate as shown by P1NP serum level and in vivo double labeling, and in bone resorption as shown by CTX levels and osteoclast number. Gene expression analyses of trabecular and cortical bone showed that PTH (1‐34) and abaloparatide led to different actions in osteoblast differentiation and activity, with increased Runx2, Col1A1, Alpl, Bsp, Ocn, Sost, Rankl/Opg and c‐fos at different time points. Abaloparatide seems to generate a faster response on osteoblastic gene expression than PTH (1‐34). Taken together, abaloparatide at the same dose is as effective as PTH (1‐34) as an osteoanabolic, with an increase in bone formation but also an increase in bone resorption in male mice.
This article is protected by copyright. All rights reserved.

Direct reprogramming of mouse fibroblasts into functional osteoblasts

02-12-2019 – Hui Zhu, Srilatha Swami, Pinglin Yang, Frederic Shapiro, Joy Wu

Journal Article

Abstract
While induced pluripotent stem cells hold promise as a potential source of osteoblasts for skeletal regeneration, the induction of pluripotency followed by directed differentiation into osteoblasts is time‐consuming and low yield. In contrast, direct lineage reprogramming without an intervening stem/progenitor cell stage would be a more efficient approach to generate osteoblasts. We screened combinations of osteogenic transcription factors and identified four factors, Runx2, Osx, Dlx5, and ATF4, that rapidly and efficiently reprogram mouse fibroblasts derived from 2.3 kb type I collagen promoter‐driven green fluorescent protein (Col2.3GFP) transgenic mice into induced osteoblast cells (i
OBs). i
OBs exhibit osteoblast morphology, form mineralized nodules, and express Col2.3GFP and gene markers of osteoblast differentiation. The global transcriptome profiles validated that i
OBs resemble primary osteoblasts. Genome‐wide DNA methylation analysis demonstrates that within differentially methylated loci, the methylation status of i
OBs more closely resembles primary osteoblasts than mouse fibroblasts. We further demonstrate that Col2.3GFP+ i
OBs have transcriptome profiles similar to GFP+ cells harvested from Col2.3GFP mouse bone chips. Functionally, Col2.3GFP+ i
OBs form mineralized bone structures after subcutaneous implantation in immunodeficient mice and contribute to bone healing in a tibia bone fracture model. These findings provide an approach to derive and study osteoblasts for skeletal regeneration.
This article is protected by copyright. All rights reserved.

PARP1 hinders histone H2B occupancy at the NFATc1 promoter to restrain osteoclast differentiation

02-12-2019 – Chun Wang, Jianqiu Xiao, Kathrin Nowak, Kapila Gunasekera, Yael Alippe, Sheree Speckman, Tong Yang, Dustin Kress, Yousef Abu‐Amer, Michael O. Hottiger, Gabriel Mbalaviele

Journal Article

Abstract
Induction of nuclear factor of activated T cells cytoplasmic 1 (NFATc1) by macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL) is essential for macrophage differentiation into osteoclasts (OCs), but the underlying mechanisms remain unclear. The ability of poly(ADP‐ribose) polymerase 1 (PARP1) to poly‐ADP‐ribosylate NFATc1 in T cells prompted us to investigate the PARP1 and NFATc1 interaction during osteoclastogenesis. However, extensive studies failed to directly link PARP1 to NFATc1. A combination of transcriptomics and proteomics studies was then used to identify PARP1 targets under these conditions. These unbiased approaches in conjunction with site‐directed mutagenesis studies revealed that PARP1 inhibited NFATc1 expression and OC formation by ADP‐ribosylating histone H2B at serine 7 and decreasing the occupancy of this histone variant at the NFATc1 promoter. The anti‐osteoclastogenic function of PARP1 was confirmed in vivo in several mouse models of PARP1 loss‐of‐function or gain‐of‐function, including a novel model in which PARP1 was conditionally ablated in myeloid cells. Thus, PARP1 ADP‐ribosylates H2B to negatively regulate NFATc1 expression and OC differentiation.
This article is protected by copyright. All rights reserved.

Loss‐of‐function mutations in the ALPL gene presenting with adult onset osteoporosis and low serum concentrations of total alkaline phosphatase

02-12-2019 – Nerea Alonso, Beatriz Larraz‐Prieto, Kathryn Berg, Zoe Lambert, Paul Redmond, Sarah E Harris, Ian J Deary, Carys Pugh, James Prendergast, Stuart H Ralston

Journal Article

ABSTRACTHypophosphatasia (HPP) is a rare inherited disorder characterised by rickets and low circulating concentrations of total alkaline phosphatase (ALP) caused by mutations in ALPL. Severe HPP presents in childhood but milder forms can present in adulthood. The prevalence and clinical features of adult HPP are poorly defined. The aim of this study was to evaluate the prevalence and clinical significance of low serum total alkaline phosphatase (ALP) levels in a clinic‐based population of adult osteoporotic patients. We searched for patients with low ALP in a cohort of 3285 patients referred to an osteoporosis clinic over a 10‐year period and performed mutation screening of ALPL in those with low ALP (≤40U/L) on two or more occasions. These individuals were matched with four clinic controls with a normal ALP. We also evaluated the prevalence of low ALP and ALPL mutations in 639 individuals from the general population from the same region. We identified 16/3285 (0.49%) clinic patients with low ALP and 14 (87.5%) had pathogenic variants in ALPL. Ten of these individuals were heterozygous for mutations previously described in HPP and two were heterozygous for novel mutations (p.
Arg301Trp and p.
Tyr101X). These mutations were not found in clinic controls or in the general population. Eight patients with low ALP, including four with ALPL mutations, were treated with bisphosphonates for an average of 6.5 years. In these individuals, the rate of fractures during treatment was comparable to that in normal ALP clinic controls who were treated with bisphosphonates. We conclude that heterozygous loss‐of‐function mutations in ALPL are common in osteoporosis patients with low ALP. Further studies are required to determine how best these individuals should be treated.
This article is protected by copyright. All rights reserved.

Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition

01-12-2019 – Robert B Conley, Gemma Adib, Robert A Adler, Kristina E Åkesson, Ivy M Alexander, Kelly C Amenta, Robert D Blank, William Timothy Brox, Emily E Carmody, Karen Chapman‐Novakofski, Bart L Clarke, Kathleen M Cody, Cyrus Cooper, Carolyn J Crandall, Douglas R Dirschl, Thomas J Eagen, Ann L Elderkin, Masaki Fujita, Susan L Greenspan, Philippe Halbout, Marc C Hochberg, Muhammad Javaid, Kyle J Jeray, Ann E Kearns, Toby King, Thomas F Koinis, Jennifer Scott Koontz, Martin Kužma, Carleen Lindsey, Mattias Lorentzon, George P Lyritis, Laura Boehnke Michaud, Armando Miciano, Suzanne N Morin, Nadia Mujahid, Nicola Napoli, Thomas P Olenginski, J Edward Puzas, Stavroula Rizou, Clifford J Rosen, Kenneth Saag, Elizabeth Thompson, Laura L Tosi, Howard Tracer, Sundeep Khosla, Douglas P Kiel

Journal Article

ABSTRACTOsteoporosis‐related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fracture among people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, and subcutaneous pharmacotherapies are efficacious and can reduce risk of future fracture. Patients need education, however, about the benefits and risks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first‐line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive but may be beneficial for selected patients at high risk. Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the early post‐fracture period, prompt treatment is recommended. Adequate dietary or supplemental vitamin D and calcium intake should be assured. Individuals being treated for osteoporosis should be reevaluated for fracture risk routinely, including via patient education about osteoporosis and fractures and monitoring for adverse treatment effects. Patients should be strongly encouraged to avoid tobacco, consume alcohol in moderation at most, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease). © 2019 American Society for Bone and Mineral Research.

Articular Cartilage Degradation and Aberrant Subchondral Bone Remodeling in Patients with Osteoarthritis and Osteoporosis

22-11-2019 – Linyang Chu, Xuqiang Liu, Zihao He, Xuequan Han, Mengning Yan, Xinhua Qu, Xiaofeng Li, Zhifeng Yu

Journal Article

ABSTRACTOsteoarthritis (OA) and osteoporosis (OP) are two skeletal disorders associated with joint structures. Occasionally, OA and OP occur in the same patient. However, the effect of OP changes on OA progression in patients with osteoporotic OA (OP‐OA) has not been reported, especially the potential association between subchondral bone and articular cartilage. Thus we investigated the alterations in the microstructure, biomechanical properties, and remodeling of subchondral bone as well as their association with cartilage damage in the hip joint of patients with OP‐OA. Thirty‐nine femoral head specimens were obtained from patients who underwent total hip arthroplasty (OA group, n = 19; OP‐OA group, n = 20), and healthy specimens from cadaver donors were used (control group, n = 10). The microstructure and biomechanical properties of subchondral bone were evaluated by micro–computed tomography and micro–finite‐element analysis. Histology, histomorphometric measurements, and immunohistochemistry were used to assess subchondral bone remodeling and cartilage damage. Linear regression analysis was performed to elucidate the relationship between subchondral bone and articular cartilage. In the subchondral bone of the OP‐OA group, compared with that of the OA group, aberrant bone remodeling leads to an inferior microstructure and worsening biomechanical properties, potentially affecting transmission of loading stress from the cartilage to the subchondral bone, and then resulting in accelerated OA progression in patients with OP‐OA. The results indicate that changes in subchondral bone could affect OA development and the improvement in subchondral bone with bone‐metabolism agents may help mitigate OA progression when OP and OA coexist in the same patients. © 2019 American Society for Bone and Mineral Research.

Circulating MicroRNA‐19b Identified From Osteoporotic Vertebral Compression Fracture Patients Increases Bone Formation

22-11-2019 – Mengge Sun, Liqiu Hu, Shang Wang, Tongling Huang, Minyi Zhang, Meng Yang, Wanxin Zhen, Dazhi Yang, William Lu, Min Guan, Songlin Peng

Journal Article

ABSTRACTCirculating micro
RNAs (mi
RNAs) play important roles in regulating gene expression and have been reported to be involved in various metabolic diseases, including osteoporosis. Although the transcriptional regulation of osteoblast differentiation has been well characterized, the role of circulating mi
RNAs in this process is poorly understood. Here we discovered that the level of circulating mi
R‐19b was significantly lower in osteoporotic patients with vertebral compression fractures than that of healthy controls. The expression level of mi
R‐19b was increased during osteoblastic differentiation of human mesenchymal stem cells (h
MSCs) and MC3T3‐E1 cells, and transfection with synthetic mi
R‐19b could promote osteoblastic differentiation of h
MSCs and MC3T3‐E1 cells. PTEN (phosphatase and tensin homolog deleted from chromosome 10) was found to be directly repressed by mi
R‐19b, with a concomitant increase in Runx2 expression and increased phosphorylation of AKT (protein kinase B, PKB). The expression level of circulating mi
R‐19b in aged ovariectomized mice was significantly lower than in young mice. Moreover, the osteoporotic bone phenotype in aged ovariectomized mice was alleviated by the injection of chemically modified mi
R‐19b (agomi
R‐19b). Taken together, our results show that circulating mi
R‐19b plays an important role in enhancing osteoblastogenesis, possibly through regulation of the PTEN/p
AKT/Runx2 pathway, and may be a useful therapeutic target in bone loss disorders, such as osteoporosis. © 2019 American Society for Bone and Mineral Research.

IFT80 Is Required for Fracture Healing Through Controlling the Regulation of TGF‐β Signaling in Chondrocyte Differentiation and Function

22-11-2019 – Min Liu, Mohammed Alharbi, Dana Graves, Shuying Yang

Journal Article

ABSTRACTPrimary cilia are essential cellular organelles that are anchored at the cell surface membrane to sense and transduce signaling. Intraflagellar transport (IFT) proteins are indispensable for cilia formation and function. Although major advances in understanding the roles of these proteins in bone development have been made, the mechanisms by which IFT proteins regulate bone repair have not been identified. We investigated the role of the IFT80 protein in chondrocytes during fracture healing by creating femoral fractures in mice with conditional deletion of IFT80 in chondrocytes utilizing tamoxifen inducible Col2α1‐Cre
ER mice. Col2α1cre
IFT80f/f mice had smaller fracture calluses than IFT80f/f (control) mice. The max‐width and max‐callus area were 31% and 48% smaller than those of the control mice, respectively. Col2α1cre
IFT80f/f mice formed low‐density/porous woven bony tissue with significantly lower ratio of bone volume, Trabecular (Tb) number and Tb thickness, and greater Tb spacing compared to control mice. IFT80 deletion significantly downregulated the expression of angiogenesis markers‐VEGF, PDGF and angiopoietin and inhibited fracture callus vascularization. Mechanistically, loss of IFT80 in chondrocytes resulted in a decrease in cilia formation and chondrocyte proliferation rate in fracture callus compared to the control mice. Meanwhile, IFT80 deletion downregulated the TGF‐β signaling pathway by inhibiting the expression of TGF‐βI, TGF‐βR, and phosphorylation of Smad2/3 in the fracture callus. In primary chondrocyte cultures in vitro, IFT80 deletion dramatically reduced chondrocyte proliferation, cilia assembly, and chondrogenic gene expression and differentiation. Collectively, our findings demonstrate that IFT80 and primary cilia play an essential role in fracture healing, likely through controlling chondrocyte proliferation and differentiation, and the TGF‐β signaling pathway. © 2019 American Society for Bone and Mineral Research.

Bone Marrow and Muscle Fat Infiltration Are Correlated among Postmenopausal Women With Osteoporosis: The AMBERS Cohort Study

20-11-2019 – Andy K Wong, Abinaa Chandrakumar, Rachel Whyte, Shannon Reitsma, Hana Gillick, Anthony Pokhoy, Alexandra Papaioannou, Jonathan D Adachi

Journal Article

ABSTRACTBone and muscle have shown to interact, but little is known about fat within bone and muscle. Clinical studies have isolated fat within bone and muscle using MRI. In this cross‐sectional study, we hypothesized that bone marrow adiposity and muscle adiposity are related and that this relationship is associated with osteoporosis. Postmenopausal women aged 60 to 85 years were recruited as part of the Appendicular Muscle and Bone Extension Research Study (AMBERS). Participants completed dual‐energy X‐ray absorptiometry (DXA) of the hip and spine to diagnose osteoporosis. Muscle adiposity was measured with MRI at the 66% site of the leg. Fat segmentation was achieved using a semi‐automated iterative threshold‐optimizing algorithm (error < 5%). Peripheral quantitative computed tomography measured marrow density of the 4% distal tibia (surrogate for marrow fat) by threshold‐based, edge‐detection segmentations and by examining residuals from trabecular bone density regressed on trabecular tissue mineral density. Muscle adiposity from MRI was regressed on marrow density using linear regression. Models were further examined with an interaction with osteoporosis status. Among 312 women (aged 75.4 ± 5.9 years, body mass index BMI 29.5 ± 5.7 kg/m2), a larger amount of muscle fat was associated with lower marrow density at the 66% mid‐tibia (B = 84.08 27.56, p = 0.002) and at the 4% distal tibia (B = 129.17 55.96, p = 0.022) after accounting for age, height, weight, average daily energy expenditure, hypertension, and diabetes. Interactions of this relationship with osteoporosis status were also significant. Upon probing these interactions, the relationships were significant only in women with osteoporosis but not in those without osteoporosis. Fat from bone marrow and muscle may be related to one another through the same phenomenon, which is likely also responsible for osteoporosis, but independent of hypertension and diabetes. More research should focus on the potential abnormalities in muscle and bone fat metabolism and mesenchymal cell commitment to fat within patients with osteoporosis. © 2019 American Society for Bone and Mineral Research.

High Plasma Erythropoietin Predicts Incident Fractures in Elderly Men with Normal Renal Function: The MrOS Sweden Cohort

20-11-2019 – Hallgerdur Lind Kristjansdottir, Catharina Lewerin, Ulf H. Lerner, Hans Herlitz, Peter Johansson, Helena Johansson, Magnus Karlsson, Mattias Lorentzon, Claes Ohlsson, Östen Ljunggren, Dan Mellström

Journal Article

ABSTRACTPreclinical studies on the role of erythropoietin (EPO) in bone metabolism are contradictory. Regeneration models indicate an anabolic effect on bone healing, whereas models on physiologic bone remodeling indicate a catabolic effect on bone mass. No human studies on EPO and fracture risk are available. It is known that fibroblast growth factor 23 (FGF23) affects bone mineralization and that serum concentration of FGF23 is higher in men with decreased estimated glomerular filtration rate (e
GFR). Recently, a direct association between EPO and FGF23 has been shown. We have explored the potential association between EPO and bone mineral density (BMD), fracture risk, and FGF23 in humans. Plasma levels of EPO were analyzed in 999 men (aged 69 to 81 years), participating in the Gothenburg part of the population‐based Osteoporotic Fractures in Men (Mr
OS) study, Mr
OS Sweden. The mean ± SD EPO was 11.5 ± 9.0 IU/L. Results were stratified by e
GFR 60 m
L/min. For men with e
GFR ≥60 m
L/min (n = 728), EPO was associated with age (r = 0.13, p < 0.001), total hip BMD (r = 0.14, p < 0.001), intact (i)FGF23 (r = 0.11, p = 0.004), and osteocalcin (r = −0.09, p = 0.022). The association between total hip BMD and EPO was independent of age, body mass index (BMI), i
FGF23, and hemoglobin (beta = 0.019, p < 0.001). During the 10‐year follow‐up, 164 men had an X‐ray–verified fracture, including 117 major osteoporotic fractures (MOF), 39 hip fractures, and 64 vertebral fractures. High EPO was associated with higher risk for incident fractures (hazard ratio HR = 1.43 per tertile EPO, 95% confidence interval CI 1.35–1.63), MOF (HR = 1.40 per tertile EPO, 95% CI 1.08–1.82), and vertebral fractures (HR = 1.42 per tertile EPO, 95% CI 1.00–2.01) in a fully adjusted Cox regression model. In men with e
GFR<60 m
L/min, no association was found between EPO and BMD or fracture risk. We here demonstrate that high levels of EPO are associated with increased fracture risk and increased BMD in elderly men with normal renal function. © 2019 American Society for Bone and Mineral Research.

Some Questions About the Article “The Efficacy and Safety of Vertebral Augmentation: A Second ASBMR Task Force Report”

19-11-2019 – Lei Ning, Shuanglin Wan, Shunwu Fan

Letter

Response to: Some Questions About the Article “The Efficacy and Safety of Vertebral Augmentation: A Second ASBMR Task Force Report”

19-11-2019 – Rachelle Buchbinder, Peter R Ebeling, Kristina Akesson, Douglas C Bauer, Richard Eastell, Howard A Fink, Lora Giangregorio, Nuria Guanabens, Deborah Kado, David Kallmes, Wendy Katzman, Alexander Rodriguez, Robert Wermers, H Alexander Wilson, Mary L Bouxsein

Letter

HR‐pQCT Measures of Bone Microarchitecture Predict Fracture: Systematic Review and Meta‐Analysis

19-11-2019 – Nicholas Mikolajewicz, Nick Bishop, Andrew J Burghardt, Lars Folkestad, Anthony Hall, Kenneth M Kozloff, Pauline T Lukey, Michael Molloy‐Bland, Suzanne N Morin, Amaka C Offiah, Jay Shapiro, Bert Rietbergen, Kim Wager, Bettina M Willie, Svetlana V Komarova, Francis H Glorieux

Journal Article

ABSTRACTHigh‐resolution peripheral quantitative computed tomography (HR‐p
QCT) is a noninvasive imaging modality for assessing volumetric bone mineral density (v
BMD) and microarchitecture of cancellous and cortical bone. The objective was to (1) assess fracture‐associated differences in HR‐p
QCT bone parameters; and (2) to determine if HR‐p
QCT is sufficiently precise to reliably detect these differences in individuals. We systematically identified 40 studies that used HR‐p
QCT (39/40 used Xtreme
CT scanners) to assess 1291 to 3253 and 3389 to 10,687 individuals with and without fractures, respectively, ranging in age from 10.9 to 84.7 years with no comorbid conditions. Parameters describing radial and tibial bone density, microarchitecture, and strength were extracted and percentage differences between fracture and control subjects were estimated using a random effects meta‐analysis. An additional meta‐analysis of short‐term in vivo reproducibility of bone parameters assessed by Xtreme
CT was conducted to determine whether fracture‐associated differences exceeded the least significant change (LSC) required to discern measured differences from precision error. Radial and tibial HR‐p
QCT parameters, including failure load, were significantly altered in fracture subjects, with differences ranging from −2.6% (95% confidence interval CI −3.4 to −1.9) in radial cortical v
BMD to −12.6% (95% CI −15.0 to −10.3) in radial trabecular v
BMD. Fracture‐associated differences reported by prospective studies were consistent with those from retrospective studies, indicating that HR‐p
QCT can predict incident fracture. Assessment of study quality, heterogeneity, and publication biases verified the validity of these findings. Finally, we demonstrated that fracture‐associated deficits in total and trabecular v
BMD and certain tibial cortical parameters can be reliably discerned from HR‐p
QCT‐related precision error and can be used to detect fracture‐associated differences in individual patients. Although differences in other HR‐p
QCT measures, including failure load, were significantly associated with fracture, improved reproducibility is needed to ensure reliable individual cross‐sectional screening and longitudinal monitoring. In conclusion, our study supports the use of HR‐p
QCT in clinical fracture prediction. © 2019 American Society for Bone and Mineral Research.

Effect of advanced glycation end‐products (AGE) lowering drug ALT‐711 on biochemical, vascular, and bone parameters in a rat model of CKD‐MBD

19-11-2019 – “Neal X. Chen, Shruthi Srinivasan, Kalisha ONeill, Thomas L. Nickolas, Joseph M. Wallace, Matthew R. Allen, Corinne E. Metzger, Amy Creecy, Keith G. Avin, Sharon M. Moe”

Journal Article

Abstract
Chronic Kidney Disease‐Mineral Bone Disorder (CKD‐MBD) is a systemic disorder that affects blood measures of bone and mineral homeostasis, vascular calcification and bone. We hypothesized that the accumulation of advanced glycation end‐products (AGE) in CKD may be responsible for the vascular and bone pathologies via alteration of collagen. We treated a naturally occurring model of CKD‐MBD, the Cy/+ rat, with a normal and high dose of the AGE crosslink breaker alagebrium (ALT‐711), or with calcium in the drinking water to mimic calcium phosphate binders for 10 weeks. These animals were compared to Normal (NL) untreated animals. The results showed that CKD animals, compared to normal animals, had elevated BUN, PTH, FGF23 and phosphorus. Treatment with ALT‐711 had no effect on kidney function or PTH, but 3 mg/kg lowered FGF23 whereas calcium lowered PTH. Vascular calcification of the aorta assessed biochemically was increased in CKD animals compared to NL, and decreased by the normal, but not high dose of ALT‐711, with parallel decreases in left ventricular hypertrophy. ALT‐711 (3 mg/kg) did not alter aorta AGE content, but reduced aorta expression of receptor for advanced glycation end products (RAGE) and NADPH oxidase 2 (NOX2), suggesting effects related to decreased oxidative stress at the cellular level. The elevated total bone AGE was decreased by 3 mg/kg ALT‐711 and both bone AGE and cortical porosity were decreased by calcium treatment, but only calcium improved bone properties. In summary, treatment of CKD‐MBD with an AGE breaker ALT‐711, decreased FGF23, reduced aorta calcification, and reduced total bone AGE without improvement of bone mechanics. These results suggest little effect of ALT‐711 on collagen, but potential cellular effects. The data also highlights the need to better measure specific types of AGE proteins at the tissue level in order to fully elucidate the impact of AGEs on CKD‐MBD.
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Targeting Bortezomib to Bone Increases Its Bone Anabolic Activity and Reduces Systemic Adverse Effects in Mice

19-11-2019 – Hua Wang, Hengwei Zhang, Venkat Srinivasan, Jianguo Tao, Wen Sun, Xi Lin, Tao Wu, Brendan F Boyce, Frank H Ebetino, Robert K Boeckman, Lianping Xing

Journal Article

ABSTRACTBortezomib (Btz) is a proteasome inhibitor approved by the FDA to treat multiple myeloma. It also increases bone volume by promoting osteoblast differentiation and inhibiting osteoclastogenesis in mice. However, Btz has severe systemic adverse effects, which would limit its use as a bone anabolic agent. Here, we designed and synthesized a bone‐targeted form of Btz by conjugating it to a bisphosphonate (BP) with no antiresorptive activity. We report that BP‐Btz inhibited osteoclast formation and bone resorption and stimulated osteoblast differentiation in vitro similar to Btz. In vivo, BP‐Btz increased bone volume more effectively than Btz in three mouse models: untreated wild‐type mice, mice with ovariectomy, and aged mice with tibial factures. Importantly, BP‐Btz had significantly less systemic side effects than Btz, including less thymic cell death, sympathetic nerve damage, and thrombocytopenia, and it improved survival rates in aged mice. Thus, BP‐Btz represents a novel anabolic agent to treat conditions, such as postmenopausal and age‐related bone loss. Bone targeting is an attractive approach to repurpose approved drugs to treat skeletal diseases. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

Sclerostin antibody treatment increases bone mass and normalizes circulating phosphate levels in growing Hyp mice

19-11-2019 – Kelsey A. Carpenter, Ryan D. Ross

Journal Article

Abstract
X‐linked hypophosphatemia (XLH), caused by a loss‐of‐function mutation in the phosphate regulating gene with homology to endopeptidase located on the X chromosome (PHEX), is the most common form of vitamin D‐resistant rickets. Loss of functional PHEX results in elevated fibroblast growth factor 23 (FGF23) levels, impaired phosphate reabsorption, and inhibited skeletal mineralization. Sclerostin, a protein produced primarily in osteocytes, suppresses bone formation by antagonizing Wnt‐signaling and is reported to be elevated in XLH patients. This study used the Hyp mouse model to investigate sclerostins role in the pathophysiology of XLH by evaluating the use of a monoclonal antibody to sclerostin in a mouse model of XLH, the Hyp mouse.
Male and female wild‐type and Hyp littermates were injected with 25mg/kg of vehicle or sclerostin‐antibody (Scl‐Ab) twice weekly, beginning at 4‐weeks of age and sacrificed at 8‐weeks of age. Scl‐Ab treatment increased serum phosphate levels and suppressed circulating levels of intact FGF23 in treated wild‐type and Hyp mice of both sexes. Cortical area, trabecular bone volume fraction (BV/TV), metaphyseal apparent density, and the peak load increased with Scl‐Ab treatment in both sexes. This short‐term treatment study suggests that Scl‐Ab treatment can effectively improve some of the pathologies associated with XLH, including normalization of phosphate, and that sclerostin may play a role in regulating FGF23 and phosphate metabolism in XLH.

The Accuracy of Prevalent Vertebral Fracture Detection in Children Using Targeted Case Finding Approaches

19-11-2019 – “Jinhui Ma, Kerry Siminoski, Peiyao Wang, Nathalie Alos, Elizabeth A Cummings, Janusz Feber, Jacqueline Halton, Josephine Ho, Kristin Houghton, Bianca Lang, Paivi Miettunen, Rosie Scuccimarri, Jacob L Jaremko, Khaldoun Koujok, Brian Lentle, Mary Ann Matzinger, Nazih Shenouda, Frank Rauch, Leanne M Ward, the Canadian STOPP Consortium, Leanne M. Ward, Josephine Ho, Reinhard Kloiber, Victor Lewis, Julian Midgley, Paivi Miettunen, David Stephure, Brian C. Lentle, Tom Blydt‐Hansen, David Cabral, David B. Dix, Kristin Houghton, Helen R. Nadel, John Hay, Janusz Feber, Jacqueline Halton, Roman Jurencak, Jinhui Ma, MaryAnn Matzinger, Johannes Roth, Nazih Shenouda, Karen Watanabe‐Duffy, Elizabeth Cairney, Cheril Clarson, Guido Filler, Joanne Grimmer, Scott McKillop, Keith Sparrow, Robert Stein, Elizabeth Cummings, Conrad Fernandez, Adam M. Huber, Bianca Lang, Kathy OBrien, Steve Arora, Stephanie Atkinson, Ronald Barr, Craig Coblentz, Peter B. Dent, Maggie Larche, Sharon Abish, Lorraine Bell, Claire LeBlanc, Anne Marie Sbrocchi, Rosie Scuccimarri, David Moher, Monica Taljaard, Frank Rauch, Nathalie Alos, Josee Dubois, Caroline Laverdiere, Veronique Phan, Claire Saint‐Cyr, Julie Barsalou, Robert Couch, Janet Ellsworth, Jacob Jaremko, Kerry Siminoski, Beverly Wilson, Ronald Grant, Martin Charron, Diane Hebert, Isabelle Gaboury, Shayne Taback, Sara Israels, Kiem Oen, Maury Pinsk, Martin Reed, Celia Rodd”

Journal Article

ABSTRACTDue to concerns about cumulative radiation exposure in the pediatric population, it is not standard practice to perform spine radiographs in most conditions that predispose to vertebral fracture (VF). In this study we examined the accuracy of two clinical predictors, back pain and lumbar spine bone mineral density (LS BMD), to derive four case finding paradigms for detection of prevalent VF (PVF). Subjects were 400 children at risk for PVF (leukemia 186, rheumatic disorders 135, nephrotic syndrome 79). Back pain was assessed by patient report, LS BMD was measured by dual‐energy x‐ray absorptiometry, and PVF were quantified on spine radiographs using the modified Genant semi‐quantitative method. Forty‐four patients (11.0%) had PVF. Logistic regression analysis between LS BMD and PVF produced an odds ratio (OR) of 1.9 (95% confidence interval (CI), 1.5‐2.5) per reduction in Z‐score unit, an area under the receiver operating characteristic curve of 0.70 (95% CI, 0.60‐0.79), and an optimal BMD Z‐score cut‐off of ‐1.6. Case identification using either low BMD alone (Z‐score <‐1.6) or back pain alone gave similar results for sensitivity (55%, 52%), specificity (78%, 81%), positive predictive value (PPV; 24%, 25%), and negative predictive value (NPV; 93%, 93%). The paradigm using low BMD plus back pain produced lower sensitivity (32%), higher specificity (96%), higher PPV (47%), and similar NPV (92%). The approach using low BMD or back pain had the highest sensitivity (75%), lowest specificity (64%), lowest PPV (20%), and highest NPV (95%). All paradigms had increased sensitivities for higher fracture grades. Our results show that BMD and back pain history can be used to identify children with the highest risk of PVF so that radiography can be used judiciously. The specific paradigm to be applied will depend on the expected PVF rate and the clinical approach to the use of radiography.
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Nonremission and Recurrent Tumor‐Induced Osteomalacia: A Retrospective Study

15-11-2019 – Xiang Li, Yan Jiang, Li Huo, Huanwen Wu, Yong Liu, Jin Jin, Wei Yu, Wei Lv, Lian Zhou, Yu Xia, Ou Wang, Mei Li, Xiaoping Xing, Yue Chi, Ruizhi Jiajue, Lijia Cui, Xunwu Meng, Weibo Xia

Journal Article

ABSTRACTTumor‐induced osteomalacia (TIO) is a rare paraneoplastic syndrome. It is curable by excision of the causative tumor. However, a few cases may persist or relapse after tumor resection. We aimed to investigate the rate of these events and related factors. We retrospectively studied TIO patients treated with surgery in a tertiary hospital. TIO was established based on a pathologic examination or the reversion of hypophosphatemia. Refractory TIO patients consisted of those with nonremission or recurrent hypophosphatemia after surgery. A total of 230 patients were confirmed as having TIO. After primary surgery, 26 (11.3%) cases persisted, and 16 (7.0%) cases recurred. The overall refractory rate was 18.3%. The median time of recurrence was 33 months. Compared with patients in the recovery group, patients in the refractory group were more likely to be female (59.5% versus 41.0%, p = .029) and have a lower serum phosphate level (0.44 ± 0.13 versus 0.50 ± 0.11 mmol/L, p = .002). The refractory rate was lowest in head/neck tumors (7.5%) and highest in spine tumors (77.8%). Regarding the tissue involved of tumor location, the refractory rate was higher in tumors involving bone than tumors involving soft tissue (32.7% versus 7.0%, p < .001). The outcomes of malignant tumors were worse than those of benign tumors (p < .001): nonremission rate, 21.4% versus 9.7%; recurrence rate, 28.6% versus 6.5%. In the multivariate regression analysis, female sex, spine tumors, bone tissue‐involved tumors, malignancy, and low preoperation serum phosphorus levels were identified as risk factors for refractory outcomes. High preoperative fibroblast growth factor 23 (FGF23) levels were also associated with refractory after adjusting for involving tissue and tumor malignancy. In summary, we are the first to report the rate and clinical characteristics of refractory TIO in a large cohort. For patients with multiple risk factors, especially spine tumors, clinical practitioners should be aware of a poor surgical prognosis. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

The Associations Between Seven Different Types of Physical Activity and the Incidence of Fracture at Seven Sites in Healthy Postmenopausal UK Women

15-11-2019 – Miranda EG Armstrong, Jason Lacombe, Clare J Wotton, Benjamin J Cairns, Jane Green, Sarah Floud, Valerie Beral, Gillian K Reeves, for the Million Women Study Collaborators

Journal Article

ABSTRACTThere is a paucity of information on associations between specific types of physical activity and fracture risk at different sites in otherwise healthy postmenopausal women. Therefore, we examined risk of fracture at seven different sites associated with seven different types of physical activity in the population‐based prospective UK Million Women Study. A total of 371,279 postmenopausal women (mean age 59.8 years), rating their health as good or excellent and reporting participation in walking, cycling, gardening, doing housework, yoga, dance, and sports club activities, were followed for site‐specific incident fracture through record linkage to national databases on day‐case and overnight hospital admissions. Cox regression yielded adjusted relative risks (RRs) and, because of the large number of statistical tests done, 99% confidence intervals (CIs) for fracture at seven different sites in relation to seven different physical activities. During an average follow‐up of 12 years, numbers with a first site‐specific fracture were as follows: humerus (2341), forearm (1238), wrist (7358), hip (4354), femur (not neck) (617), lower leg (1184), and ankle (3629). For upper limb fractures there was significant heterogeneity across the seven activity types (test for heterogeneity p = 0.004), with gardening more than 1 hour/week associated with a lower risk (RR = 0.91; 99% CI, 0.86 to 0.96; p < 0.0001), whereas cycling more than 1 hour/week was associated with an increased risk (RR = 1.11; 99% CI, 1.00 to 1.23; p = 0.008). For fractures of the lower limb (including hip) there was no significant heterogeneity by type of activity, with significant approximately 5% to 15% reductions in risk associated with most activities, except cycling. For hip fractures, there was no significant heterogeneity by type of activity, but with significant 15% to 20% reductions in risk associated with walking for 1 hour/day and participating in yoga and sporting activities. Physical activity is a modifiable risk factor for fracture, but the effects differ between different types of activities and different fracture sites. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Kidney Disease Progression Does Not Decrease Intestinal Phosphorus Absorption in a Rat Model of Chronic Kidney Disease–Mineral Bone Disorder

15-11-2019 – Colby J Vorland, Annabel Biruete, Pamela J Lachcik, Shruthi Srinivasan, Neal X Chen, Sharon M Moe, Kathleen M Hill Gallant

Journal Article

ABSTRACTThe Cy/+ rat has been characterized as a progressive model of chronic kidney disease–mineral bone disorder (CKD‐MBD). We aimed to determine the effect of kidney disease progression on intestinal phosphorus absorption and whole‐body phosphorus balance in this model. A total of 48 Cy/+ (CKD) and 48 normal littermates (NL) rats were studied at two ages: 20 weeks and 30 weeks, to model progressive kidney function decline at approximately 50% and 20% of normal kidney function. Sodium‐dependent and sodium‐independent intestinal phosphorus absorption efficiency were measured by the in situ jejunal ligated loop method using 33P radioisotope. Our results show that CKD rats had slightly higher sodium‐dependent phosphorus absorption compared to NL rats, and absorption decreased from 20 to 30 weeks. These results are in contrast to plasma 1,25OH2D, which was lower in CKD rats. Gene expression of the major intestinal phosphorus transporter, Na
Pi‐2b, was not different between CKD and NL rats in the jejunum but was lower in CKD rats versus NL rats in the duodenum. Jejunal ligated loop phosphorus absorption results are consistent with percent net phosphorus absorption results obtained from metabolic balance: higher net percent phosphorus absorption values in CKD rats compared with NL, and lower values in 30‐week‐olds compared with 20‐week‐olds. Phosphorus balance was negative (below zero) in CKD rats, significantly lower in 30‐week‐old rats compared with 20‐week‐old rats, and lower in CKD rats compared with NL rats at both ages. These results demonstrate no reduction in intestinal phosphorus absorption with progression of CKD despite lower 1,25OH2D status when assessed by an in situ ligated loop test, which is in contrast to the majority of in vitro studies, and if confirmed in further studies, could challenge the physiological relevance of in vitro findings. © 2019 American Society for Bone and Mineral Research.

A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD‐Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis

14-11-2019 – Celia L Gregson, Dylan J. M. Bergen, Paul Leo, Richard B Sessions, Lawrie Wheeler, April Hartley, Scott Youlten, Peter I Croucher, Aideen M McInerney‐Leo, William Fraser, Jonathan CY Tang, Lisa Anderson, Mhairi Marshall, Leon Sergot, Lavinia Paternoster, George Davey Smith, The AOGC Consortium, Matthew A Brown, Chrissy Hammond, John P Kemp, Jon H Tobias, Emma L Duncan

Journal Article

ABSTRACTNovel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.
Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA‐binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z‐scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (p
QCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome‐wide and gene‐based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (PGWAS = 6 × 10−16; PGENE = 8 × 10−17). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone–derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)‐dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss‐of‐function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

The Polycomb Protein Bmi1 Plays a Crucial Role in the Prevention of 1,25(OH)2D Deficiency‐induced Bone Loss

14-11-2019 – Haijian Sun, Wanxin Qiao, Min Cui, Cuicui Yang, Rong Wang, David Goltzman, Jianliang Jin, Dengshun Miao

Journal Article

Abstract
We analyzed the skeletal phenotypes of heterozygous null Cyp27b1 (Cyp27b1+/‐) mice and their wild type (WT) littermates to determine whether haploinsufficiency of Cyp27b1 accelerated bone loss, and to examine potential mechanisms of such loss. We found that serum 1,25‐dihydroxyvitamin D 1,25(OH)2D levels were significantly decreased in aging Cyp27b1+/‐ mice, which displayed an osteoporotic phenotype. This was accompanied by a reduction of expression of the Bmi1 at both gene and protein levels. Using Ch
IP‐PCR, EMSA assays and a luciferase reporter assay, we then demonstrated that 1,25(OH)2D3 up‐regulated Bmi1 expression at a transcriptional level via the VDR. To determine whether Bmi1 overexpression in MSCs could correct bone loss induced by 1,25(OH)2D deficiency, we overexpressed Bmi1 in MSCs using Prx1‐driven Bmi1 transgenic mice (Bmi1Tg) mice. We then compared the bone phenotypes of Bmi1Tg mice on a Cyp27b1+/‐ background, with those of Cyp27b1+/‐ mice and with those of wild‐type mice, all at 8 months of age. We found that overexpression of Bmi1 in MSCs corrected the bone phenotype of Cyp27b1+/‐ mice by increasing osteoblastic bone formation, reducing osteoclastic bone resorption, increasing bone volume and increasing bone mineral density. Bmi1 overexpression in MSCs also corrected 1,25(OH)2D deficiency‐induced oxidative stress and DNA damage, and cellular senescence of Cyp27b1+/‐ mice by reducing levels of reactive oxygen species, elevating serum total superoxide dismutase levels, reducing the percentage of γH2A.
X, p16, IL‐1β and TNF‐α positive cells and decreasing γH2A.
X, p16, p19, p53, p21, IL‐1β and IL‐6 expression levels. Furthermore, 1,25(OH)2D stimulated the osteogenic differentiation of MSCs, both ex vivo and in vitro, from WT mice but not from Bmi1‐/‐ mice and 1,25(OH)2D administration in vivo increased osteoblastic bone formation in WT, but not in Bmi1 ‐/‐ mice. Our results indicate that Bmi1, a key downstream target of 1,25(OH)2D, plays a crucial role in preventing bone loss induced by 1,25(OH)2D deficiency.
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Greater Bone Marrow Adiposity Predicts Bone Loss in Older Women

14-11-2019 – Gina N Woods, Susan K Ewing, Sigurdur Sigurdsson, Deborah M Kado, Gudny Eiriksdottir, Vilmundur Gudnason, Trisha F Hue, Thomas F Lang, Eric Vittinghoff, Tamara B Harris, Clifford Rosen, Kaipin Xu, Xiaojuan Li, Ann V Schwartz

Journal Article

ABSTRACTBone marrow adiposity (BMA) is associated with aging and osteoporosis, but whether BMA can predict bone loss and fractures remains unknown. Using data from the Age Gene/Environment Susceptibility (AGES)‐Reykjavik study, we investigated the associations between 1H‐MRS–based measures of vertebral bone marrow adipose tissue (BMAT), annualized change in bone density/strength by quantitative computed tomography (QCT) and DXA, and secondarily, with incident clinical fractures and radiographic vertebral fractures among older adults. The associations between BMAT and annualized change in bone density/strength were evaluated using linear regression models, adjusted for age, body mass index (BMI), diabetes, estradiol, and testosterone. Cox proportional hazards models were used to evaluate the associations between baseline BMAT and incident clinical fractures, and logistic regression models for incident vertebral fractures. At baseline, mean ± SD age was 80.9 ± 4.2 and 82.6 ± 4.2 years in women (n = 148) and men (n = 150), respectively. Mean baseline BMAT was 55.4% ± 8.1% in women and 54.1% ± 8.2% in men. Incident clinical fractures occurred in 7.4% of women over 2.8 years and in 6.0% of men over 2.2 years. Incident vertebral fractures occurred in 12% of women over 3.3 years and in 17% of men over 2.7 years. Each 1 SD increase in baseline BMAT was associated with a 3.9 mg2/cm4/year greater loss of spine compressive strength index (p value = .003), a 0.9 mg/cm3/year greater loss of spine trabecular BMD (p value = .02), and a 1.2 mg/cm3/year greater loss of femoral neck trabecular BMD (p value = .02) in women. Among men, there were no associations between BMAT and changes in bone density/strength. There were no associations between BMAT and incident fractures in women or men. In conclusion, we found greater BMAT is associated with greater loss of trabecular bone at the spine and femoral neck, and greater loss of spine compressive strength, in older women. © 2019 American Society for Bone and Mineral Research.

Smoking and alcohol intake but not muscle strength in young men increase fracture risk at middle age: a cohort study linked to the Swedish National Patient Registry

12-11-2019 – D Prieto‐Alhambra, A Turkiewicz, C Reyes, S Timpka, B Rosengren, M Englund

Journal Article

ABSTRACTWe aimed to determine the relationship between handgrip strength, smoking and alcohol consumption in young men and fracture risk at middle age. Thus, we carried out a cohort study including young men undergoing conscription examination in Sweden September 1969‐May 1970 at typical age 18 years. Data on muscle strength, height, weight and lifestyle factors were linked to the National Patient Register 1987‐2010.
Handgrip strength was considered the main exposure, and smoking and alcohol consumption as secondary exposures. Outcomes were all fractures (except face, skull, digits), major osteoporotic fractures (thoracic/lumbar spine, proximal humerus, distal forearm or hip) and major traumatic fractures (shaft of humerus, forearm, femur, or lower leg) based on ICD‐9 and 10 codes. We used Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) according to handgrip strength as a continuous variable (per 1 SD), after adjustment for weight, height, parental education, smoking, and alcohol consumption. A total of 40 112 men were included, contributing 892 572 person‐years. Overall, 3974 men fractured in middle age with the incidence rate (95%CI) of 44.5 (43.2‐45.9) per 1000 person‐years. The corresponding rates were12.2 and 5.6per 1000 person‐years for major osteoporotic and traumatic fractures, respectively. Handgrip strength‐adjusted HR (95%CI) was 1.01 (0.98‐1.05), 0.94 (0.88‐1.00) and 0.98 (0.88‐1.08) per SD for all, major osteoporotic, and major traumatic fractures, respectively. Adjusted HR (95%CI) for smokers (>21cigarettes/day):1.44 (1.21, 1.71) for all fractures, while the association between alcohol consumption and hazards of fracture was J‐shaped. Therefore, young adult handgrip strength was not associated with fracture risk in middle‐age men, though smoking and high alcohol consumption did confer an increased risk.
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Temporal trends and factors associated with bisphosphonate discontinuation and restart

12-11-2019 – Giovanni Adami, Ayesha Jaleel, Jeffrey R. Curtis, Elizabeth Delzell, Rui Chen, Huifeng Yun, Shanette Daigle, Tarun Arora, Maria I. Danila, Nicole C. Wright, Suzanne M. Cadarette, Amy Mudano, Jeffrey Foster, Kenneth G. Saag

Journal Article

Abstract
Adverse events related to long‐term use of bisphosphonates have raised interest in temporary drug discontinuation. Trends in bisphosphonate discontinuation and restart, as well factors associated with these decisions are not fully understood at a population level. We investigated temporal trends of bisphosphonate discontinuation from 2010 to 2015, and identified factors associated with discontinuation and restart of osteoporosis therapy. Our cohort consisted of long‐term bisphosphonate users identified from 2010‐2015 Medicare data. We defined discontinuation as ≥ 12 months without bisphosphonate prescription claims. We used conditional logistic regression to compare factors associated with alendronate discontinuation or osteoporosis therapy restart in the 120‐day period preceding discontinuation or restart referent to the 120‐day preceding control periods. Among 73,800 long‐term bisphosphonates users, 59,251 (80.3%) used alendronate, 6,806 (9.2%) risedronate, and 7,743 (10.5%) zoledronic acid, exclusively. Overall 26,281 (35.6%) discontinued bisphosphonates for at least 12 months. Discontinuation of bisphosphonates increased from 1.7% in 2010, reaching a peak of 14% in 2012 with levels plateauing through 2015. The factors most strongly associated with discontinuation of alendronate were: benzodiazepine prescription (a
OR = 2.5, 95% CI 2.1, 3.0), having a dual‐energy X‐ray absorptiometry (DXA) scan (a
OR = 1.8, 95% CI 1.7, 2.0) and skilled nursing facility care utilization (a
OR = 1.8, 95% CI 1.6, 2.1). The factors most strongly associated with restart of osteoporosis therapy were: having a DXA scan (a
OR = 9.9, 95% CI 7.7, 12.6), sustaining a fragility fracture (a
OR = 2.8, 95% CI 1.8, 4.5), and an osteoporosis or osteopenia diagnosis (a
OR = 2.5, 95% CI 2.0, 3.1). Our national evaluation of bisphosphonate discontinuation showed that an increasing proportion of patients on long‐term bisphosphonate therapy discontinue medications. The factors associated with discontinuation of alendronate were primarily related to worsening of overall health status, while traditional factors associated with worsening bone health were associated with restarting osteoporosis medication.
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Acetylcholinesterase inhibitors are associated with reduced fracture risk among older Veterans with dementia

11-11-2019 – Abayomi N. Ogunwale, Cathleen S. Colon‐Emeric, Richard Sloane, Robert A. Adler, Kenneth W. Lyles, Richard H. Lee

Journal Article

Acetylcholinesterase inhibitors (ACh
EIs) have been noted to increase bone density and quality in mice. Human studies are limited but suggest an association with improved bone healing after hip fracture. We examined the relationship between ACh
EIs use and fracture risk in a national cohort of 360,015 male Veterans aged 65‐99 years with dementia but without prior fracture using Veterans Affairs (VA) hospital, Medicare, and Pharmacy records from 2000‐2010. Diagnosis of dementia, any clinical fracture (excluding facial and digital), comorbidities and medications were identified using ICD‐9 and drug class codes. Cox proportional hazard models considering ACh
EIs use as a time‐varying covariate and adjusting for fall and fracture risk factors compared the time‐to‐fracture in ACh
EIs users vs. non‐ACh
EIs users. Potential confounders included demographics (age, race, BMI), comorbidities associated with fracture or falls (diabetes, lung disease, stroke, Parkinsons, seizures, etc.) and medications associated with fracture or falls (bisphosphonates, glucocorticoids, androgen deprivation therapy (ADT), proton pump inhibitors (PPIs), selective serotonin receptors inhibitors (SSRIs), etc.). Competing mortality risk was considered using the methods of Fine and Gray. To account for persistent effects on bone density or quality that might confer protection after stopping the medication, we completed a secondary analysis using the Medication Possession Ratio (MPR) as a continuous variable in logistic regression models, and also compared MPR increments of 10% to minimal/no use (MPR 0 to <0.10). Among older Veterans with diagnosis of dementia, 20.1% suffered a fracture over an average of 4.6 years of follow‐up. Overall, 42.3% of the cohort were prescribed ACh
EIs during the study period. The hazard of any fracture among ACh
EIs users compared to those on other/no dementia medications was significantly lower in fully adjusted models (HR 0.81; 95% CI, 0.75‐0.88). After considering competing mortality risk, fracture risk remained 18% lower in Veterans using ACh
EIs (HR 0.82; 95% CI, 0.76‐0.89).
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Effects of Estrogen Replacement on Bone Geometry and Microarchitecture in Adolescent and Young Adult Oligoamenorrheic Athletes: A Randomized Trial

07-11-2019 – Kathryn E Ackerman, Vibha Singhal, Meghan Slattery, Kamryn T Eddy, Mary L Bouxsein, Hang Lee, Anne Klibanski, Madhusmita Misra

Journal Article

ABSTRACTOligoamenorrheic athletes (OAs) have lower bone mineral density (BMD) and greater impairment of bone microarchitecture, and therefore higher fracture rates compared to eumenorrheic athletes. Although improvements in areal BMD (a
BMD; measured by dual‐energy X‐ray absorptiometry) in OAs have been demonstrated with transdermal estrogen treatment, effects of such treatment on bone microarchitecture are unknown. Here we explore effects of transdermal versus oral estrogen versus no estrogen on bone microarchitecture in OA. Seventy‐five OAs (ages 14 to 25 years) were randomized to (i) a 100‐μg 17β‐estradiol transdermal patch (PATCH) administered continuously with 200 mg cyclic oral micronized progesterone; (ii) a combined 30 μg ethinyl estradiol and 0.15 mg desogestrel pill (PILL); or (iii) no estrogen/progesterone (NONE) and were followed for 12 months. Calcium (≥1200 mg) and vitamin D (800 IU) supplements were provided to all. Bone microarchitecture was assessed using high‐resolution peripheral quantitative CT at the distal tibia and radius at baseline and 1 year. At baseline, randomization groups did not differ by age, body mass index, percent body fat, duration of amenorrhea, vitamin D levels, BMD, or bone microarchitecture measurements. After 1 year of treatment, at the distal tibia there were significantly greater increases in total and trabecular volumetric BMD (v
BMD), cortical area and thickness, and trabecular number in the PATCH versus PILL groups. Trabecular area decreased significantly in the PATCH group versus the PILL and NONE groups. Less robust differences between groups were seen at the distal radius, where percent change in cortical area and thickness was significantly greater in the PATCH versus PILL and NONE groups, and changes in cortical v
BMD were significantly greater in the PATCH versus PILL groups. In conclusion, in young OAs, bone structural parameters show greater improvement after 1 year of treatment with transdermal 17β‐estradiol versus ethinyl estradiol–containing pills, particularly at the tibia. © 2019 American Society for Bone and Mineral Research.

“An Inverse Agonist Ligand of the PTH Receptor Partially Rescues Skeletal Defects in a Mouse Model of Jansens Metaphyseal Chondrodysplasia”

06-11-2019 – Hiroshi Noda, Jun Guo, Ashok Khatri, Thomas Dean, Monica Reyes, Michael Armanini, Daniel J. Brooks, Janaina S. Martins, Ernestina Schipani, Mary L. Bouxsein, Marie B. Demay, John T. Potts, Harald Jüppner, Thomas J. Gardella

Journal Article

ABSTRACTJansens metaphyseal chondrodysplasia (JMC) is a rare disease of bone and mineral ion physiology that is caused by activating mutations in the PTHR1. Ligand‐independent signaling by the mutant receptors in cells of bone and kidney results in abnormal skeletal growth, excessive bone turn‐over, and chronic hypercalcemia and hyperphosphaturia. Clinical features further include short‐stature, limb deformities, nephrocalcinosis and progressive losses in kidney function. There is no effective treatment option available for JMC. In previous cell‐based assays, we found that certain N‐terminally truncated PTH and PTHr
P antagonist peptides function as inverse agonists and thus can reduce the high rates of basal cAMP signaling exhibited by the mutant PTHR1s of JMC in vitro. Here we explored whether one such inverse agonist ligand, Leu11,d
Trp12,Trp23,Tyr36‐PTHr
P(7‐36)NH2 (IA), can be effective in vivo and thus ameliorate the skeletal abnormalities that occur in transgenic mice expressing the PTHR1‐H223R allele of JMC in osteoblastic cells via the collagen‐1α1 promoter (C1HR mice). We observed that after two weeks of twice‐daily injection and relative to vehicle controls, the IA analog resulted in significant improvements in key skeletal parameters that characterize the C1HR mice, as it reduced the excess trabecular bone mass, the bone marrow fibrosis and the levels of bone turnover markers in blood and urine. The overall findings provide proof‐of‐concept support for the notion that inverse agonist ligands targeted to the mutant PTHR1 variants of JMC can have efficacy in vivo. Further studies of such PTHR1 ligand analogs could help open paths towards the first treatment option for this debilitating skeletal disorder.
This article is protected by copyright. All rights reserved.

Early Alendronate Can Be Safe during Fracture Healing?

06-11-2019 – Eugene Fung

Letter

Lactate Efflux from Intervertebral Disc Cells is Required for Maintenance of Spine Health

06-11-2019 – Elizabeth S. Silagi, Emanuel J. Novais, Sara Bisetto, Aristeidis G. Telonis, Joseph Snuggs, Christine L. Le Maitre, Yunping Qiu, Irwin J. Kurland, Irving M. Shapiro, Nancy J. Philp, Makarand V. Risbud

Journal Article

ABSTRACTMaintenance of glycolytic metabolism is postulated to be required for health of the spinal column. In the hypoxic tissues of the intervertebral disc and glycolytic cells of vertebral bone, glucose is metabolized into pyruvate for ATP generation and reduced to lactate to sustain redox balance. The rise in intracellular H+/lactate concentrations are balanced by plasma‐membrane monocarboxylate transporters (MCTs). Using MCT4 null mice and human tissue samples, complimented with genetic and metabolic approaches, we determine that H+/lactate efflux is critical for maintenance of disc and vertebral bone health. Mechanistically, MCT4 maintains glycolytic and TCA cycle flux and intracellular p
H homeostasis in the nucleus pulposus compartment of the disc, where HIF‐1α directly activates an intronic enhancer in SLC16A3. Ultimately, our results provide support for research into lactate as a diagnostic biomarker for chronic, painful disc degeneration.
This article is protected by copyright. All rights reserved.

Effects of Alendronic Acid on Fracture Healing

06-11-2019 – Andrew D Duckworth, Margaret M McQueen, Christopher E Tuck, Jonathan H Tobias, Jeremy Mark Wilkinson, Leela C Biant, Elizabeth Claire Pulford, Stephen Aldridge, Claire Edwards, Chris P Roberts, Manoj Ramachandran, Andrew Richard McAndrew, Kenneth C K Cheng, Phillip Johnston, Nasir H Shah, Philip Mathew, John Harvie, Birgit C Hanusch, Ronnie Harkess, Aryelly Rodriguez, Gordon D Murray, Stuart H Ralston

Letter

“Short Sleep Is Associated With Low Bone Mineral Density and Osteoporosis in the Womens Health Initiative”

06-11-2019 – Heather M Ochs‐Balcom, Kathleen M Hovey, Christopher Andrews, Jane A Cauley, Lauren Hale, Wenjun Li, Jennifer W Bea, Gloria E Sarto, Marcia L Stefanick, Katie L Stone, Nelson B Watts, Oleg Zaslavsky, Jean Wactawski‐Wende

Journal Article

ABSTRACTShort sleep duration, recognized as a public health epidemic, is associated with adverse health conditions, yet little is known about the association between sleep and bone health. We tested the associations of usual sleep behavior and bone mineral density (BMD) and osteoporosis. In a sample of 11,084 postmenopausal women from the Womens Health Initiative (WHI; mean age 63.3 years, SD = 7.4), we performed a cross‐sectional study of the association of self‐reported usual hours of sleep and sleep quality (WHI Insomnia Rating Score) with whole body, total hip, femoral neck, and spine BMD using linear regression models. We also studied the association of sleep duration and quality with dual‐energy X‐ray absorptiometry (DXA)‐defined low bone mass (T‐score < −2.5 to <−1) and osteoporosis (T‐score ≤ −2.5) using multinomial regression models. We adjusted for age, DXA machine, race, menopausal symptoms, education, smoking, physical activity, body mass index, alcohol use, physical function, and sleep medication use. In adjusted linear regression models, women who reported sleeping 5 hours or less per night had on average 0.012 to 0.018 g/cm2 significantly lower BMD at all four sites compared with women who reported sleeping 7 hours per night (reference). In adjusted multinomial models, women reporting 5 hours or less per night had higher odds of low bone mass and osteoporosis of the hip (odds ratio OR = 1.22; 95% confidence interval CI 1.03–1.45, and 1.63; 1.15–2.31, respectively). We observed a similar pattern for spine BMD, where women with 5 hours or less per night had higher odds of osteoporosis (adjusted OR = 1.28; 95% CI 1.02–1.60). Associations of sleep quality and DXA BMD failed to reach statistical significance. Short sleep duration was associated with lower BMD and higher risk of osteoporosis. Longitudinal studies are needed to confirm the cross‐sectional effects of sleep duration on bone health and explore associated mechanisms. © 2019 American Society for Bone and Mineral Research.

Human heterozygous ENPP1 deficiency is associated with early onset osteoporosis, a phenotype recapitulated in a mouse model of Enpp1 deficiency

05-11-2019 – Ralf Oheim, Kristin Zimmerman, Nathan D. Maulding, Julian Stürznickel, Simon Kroge, Dillon Kavanagh, Paul R. Stabach, Uwe Kornak, Steven M. Tommasini, Mark C. Horowitz, Michael Amling, David Thompson, Thorsten Schinke, Björn Busse, Thomas O. Carpenter, Demetrios T. Braddock

ABSTRACTBiallelic ENPP1 deficiency in humans induces Generalized Arterial Calcification of Infancy (GACI) and / or Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2). The latter is characterized by markedly increased circulating FGF23 levels and renal phosphate wasting, but aberrant skeletal manifestations associated with heterozygous ENPP1 deficiency are unknown. Here, we report three adult men with early‐onset osteoporosis who presented with fractures in the thoracic spine and/or left radius, mildly elevated circulating FGF23, and hypophosphatemia. Total hip bone mineral density scans demonstrated osteoporosis (Z‐score < −2.5) and HRp
QCT demonstrated micro‐architectural defects in trabecular and cortical bone. Next generation sequencing revealed heterozygous loss of function mutations in ENPP1 previously observed as biallelic mutations in infants with GACI. In addition, we present bone mass and structure data as well as plasma pyrophosphate PPi data of two siblings suffering from ARHR2 in comparison to their heterozygous and wild type family members indicative of an ENPP1 gene dose effect. The skeletal phenotype in murine Enpp1 deficiency yielded nearly identical findings. 10 week‐old male Enpp1 asj/asj mice exhibited mild elevations in plasma FGF23 and hypophosphatemia, and micro
CT analysis revealed microarchitectural defects in trabecular and cortical bone of similar magnitude to HRp
QCT defects observed in humans. Histomorphometry revealed mild osteomalacia and osteopenia at both 10 and 23 weeks. The biomechanical relevance of these findings was demonstrated by increased bone fragility and ductility in Enpp1 asj/asj mice. In summary, ENPP1 exerts a gene dose effect such that humans with heterozygous ENPP1 deficiency exhibit intermediate levels of plasma analytes associated with bone mineralization disturbance resulting in early onset osteoporosis. ENPP1 deficiency in humans exerts a gene dose effect such that heterozygous ENPP1 deficiency results in early onset osteoporosis, a phenotype recapitulated in a mouse model of Enpp1 deficiency.
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Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells

05-11-2019 – Alexander Loftus, Alfredo Cappariello, Christopher George, Argia Ucci, Kirsty Shefferd, Alice Green, Riccardo Paone, Marco Ponzetti, Simona Delle Monache, Maurizio Muraca, Anna Teti, Nadia Rucci

Journal Article

ABSTRACTExtracellular vesicles (EVs) are emerging as mediators of a range of pathological processes, including cancer. However, their role in bone metastases has been poorly explored. We investigated EV‐mediated effects of osteotropic breast cancer cells (MDA‐MB‐231) on bone resident cells and endothelial cells. Pretreatment of osteoblasts with conditioned medium (CM) of MDA‐MB‐231 (MDA) cells promoted pro‐osteoclastogenic and pro‐angiogenic effects by osteoblast EVs (OB‐EVs), as well as an increase of RANKL‐positive OB‐EVs. Moreover, when treating osteoblasts with MDA‐EVs, we observed a reduction of their number, metabolic activity, and alkaline phosphatase (Alp) activity. MDA‐EVs also reduced transcription of Cyclin D1 and of the osteoblast‐differentiating genes, while enhancing the expression of the pro‐osteoclastogenic factors Rankl, Lcn2, Il1b, and Il6. Interestingly, a cytokine array on CM from osteoblasts treated with MDA‐EVs showed an increase of the cytokines CCL3, CXCL2, Reg3G, and VEGF, while OPG and WISP1 were downregulated. MDA‐EVs contained m
RNAs of genes involved in bone metabolism, as well as cytokines, including PDGF‐BB, CCL3, CCL27, VEGF, and Angiopoietin 2. In line with this profile, MDA‐EVs increased osteoclastogenesis and in vivo angiogenesis. Finally, intraperitoneal injection of MDA‐EVs in mice revealed their ability to reach the bone microenvironment and be integrated by osteoblasts and osteoclasts. In conclusion, we showed a role for osteoblast‐derived EVs and tumor cell–derived EVs in the deregulation of bone and endothelial cell physiology, thus fueling the vicious cycle induced by bone tumors. © 2019 American Society for Bone and Mineral Research.

Denosumab Prevents Early Periprosthetic Bone Loss After Uncemented Total Hip Arthroplasty: Results from a Randomized Placebo‐Controlled Clinical Trial

04-11-2019 – Andreas Nyström, Demostenis Kiritopoulos, Gösta Ullmark, Jens Sörensen, Marianne Petrén‐Mallmin, Jan Milbrink, Nils P Hailer, Hans Mallmin

Journal Article

ABSTRACTImplant loosening is the most common indication for revision surgery after total hip arthroplasty (THA). Although bone resorption around the implants plays a pivotal role in the pathophysiology of loosening, it is unknown whether potent early inhibition of osteoclasts could mitigate this process and thus reduce the need for revision surgery. We performed a randomized, double‐blind, placebo‐controlled phase 2 trial in 64 patients aged 35 to 65 years with unilateral osteoarthritis of the hip. They underwent surgery with an uncemented THA and were randomized to either two subcutaneous doses of denosumab (n = 32) or placebo (n = 32) given 1 to 3 days and 6 months after surgery. Patients were followed for 24 months. Primary outcome was periprosthetic bone mineral density (BMD) of the hip at 12 months as measured by dual‐energy X‐ray absorptiometry (DXA). In addition, 18F sodium fluoride positron emission tomography/CT (F‐PET) was performed in half of the patients for analysis of periprosthetic standardized uptake value (SUV). Analyses were made according to intention‐to‐treat principles. The trial was registered at Clinical
Trials.gov 2011‐001481‐18, NCT01630941. Denosumab potently inhibited early periprosthetic bone loss. After 12 months, BMD in the denosumab group was 32% (95% confidence interval CI 22–44) higher in Gruen zone 7 and 11% (95% CI 8–15) higher in zones 1 to 7. After 24 months, the difference in BMD between groups had decreased to 15% (95% CI 4–27) in zone 7 and 4% (95% CI 0–8) in zones 1 to 7. In both groups, SUV increased after surgery, but the increase was less pronounced in the denosumab group. Biochemical markers of bone metabolism decreased in the denosumab group in the first 12 months, but a rebound effect with marker concentrations above baseline was observed after 24 months. Denosumab potently prevents early periprosthetic bone loss after uncemented THA; however, the effect diminishes after discontinuation of treatment. Further research is needed to determine whether this bone loss will prove to be of clinical importance and, if so, whether the positive effect observed in this study could be preserved by either prolonged treatment with denosumab or additional antiresorptive treatment. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

A Geriatric Exercise Program May Yield Multiple Benefits

31-10-2019 – Jodi Dowthwaite

Editorial

A CTGF‐RUNX2‐RANKL Axis in Breast and Prostate Cancer Cells Promotes Tumor Progression in Bone

31-10-2019 – Bongjun Kim, Haemin Kim, Suhan Jung, Aree Moon, Dong‐Young Noh, Zang Hee Lee, Hyung Joon Kim, Hong‐Hee Kim

Journal Article

ABSTRACTMetastasis to bone is a frequent occurrence in patients with breast and prostate cancers and inevitably threatens the patients quality of life and survival. Identification of cancer‐derived mediators of bone metastasis and osteolysis may lead to novel therapeutic strategies. In this study, we established highly bone‐metastatic PC3 prostate and MDA‐MB‐231 (MDA) breast cancer cell sublines by in vivo selection in mice. In bone‐metastatic cancer cells, the expression and secretion of connective tissue growth factor (CTGF) were highly upregulated. CTGF knockdown in bone‐metastatic cells decreased invasion activity and MMP expression. RUNX2 overexpression in the CTGF knockdown cells restored the invasion activity and MMP expression. In addition, CTGF increased RUNX2 protein stability by inducing its acetylation via p300 acetyl transferase. The integrin αvβ3 receptor mediated these effects of CTGF. Furthermore, CTGF promoted RUNX2 recruitment to the RANKL promoter, resulting in increased RANKL production from the tumor cells and subsequent stimulation of osteoclastogenesis from precursor cells. In addition, animal model with injection of CTGF knocked‐down prostate cancer cells into 6‐week old BALB/c male mice showed reduced osteolytic lesions. More importantly, the expression levels of CTGF and RANKL showed a strong positive correlation in human primary breast tumor tissues and were higher in bone metastases than in other site metastases. These findings indicate that CTGF plays crucial roles for osteolytic bone metastasis both by enhancing invasiveness of tumor cells and by producing RANKL for osteoclastogenesis. Targeting CTGF may lead to the development of effective preventive and therapeutic strategies for osteolytic metastasis. © 2019 American Society for Bone and Mineral Research.

Increased Fracture Risk in Women Treated With Aromatase Inhibitors Versus Tamoxifen: Beneficial Effect of Bisphosphonates

31-10-2019 – Marta Pineda‐Moncusí, Natalia Garcia‐Giralt, Adolfo Diez‐Perez, Sonia Servitja, Ignasi Tusquets, Daniel Prieto‐Alhambra, Xavier Nogués

Journal Article

ABSTRACTAromatase inhibitors have been associated with accelerated bone loss and an increased risk of osteoporotic fractures. Currently, bisphosphonates are recommended to reduce fracture risk in these patients. The aim of this study is to evaluate the fracture risk in breast cancer patients receiving aromatase inhibitors, compared to tamoxifen users, and to assess the effectiveness of oral bisphosphonates in reducing fracture risk. We performed an observational cohort study up to 10 years of follow‐up. Data were extracted from primary care records in a population database. Women diagnosed with breast cancer between 2006 and 2015 and treated with tamoxifen or aromatase inhibitors (n = 36,472) were stratified according to low (without osteoporosis diagnosis nor bisphosphonates exposure) or high (with osteoporosis and/or treated with bisphosphonates) fracture risk. Cox models were used to calculate hazard ratios (HR 95% CI) of fracture from the propensity score–matched patients. Sensitivity analyses account for competing risk of death were performed (subdistribution hazard ratio SHR 95% CI). In postmenopausal women, fracture risk in aromatase inhibitor users showed an HR 1.40 95% CI,1.05 to 1.87 and SHR 1.48 95% CI, 1.11 to 1.98, compared to tamoxifen. Observing aromatase inhibitors patients at high risk of fracture, bisphosphonate‐treated patients had an HR 0.73 95% CI, 0.51 to 1.04 and SHR 0.69 95% CI, 0.48 to 0.98 compared to nontreated. In conclusion, fracture risk in postmenopausal women during aromatase inhibitor treatment, in real‐life conditions, was >40% compared to tamoxifen, corroborating previous randomized controlled trials results. In high‐risk patients, bisphosphonate users had lower significant fracture incidence during aromatase inhibitor therapy than nonbisphosphonate users. Monitoring fracture risk and related risk factors in aromatase inhibitor patients is advisable. © 2019 American Society for Bone and Mineral Research.

Effects of Long‐Duration Spaceflight on Vertebral Strength and Risk of Spine Fracture

31-10-2019 – Katelyn Burkhart, Brett Allaire, Dennis E Anderson, David Lee, Tony M Keaveny, Mary L Bouxsein

Journal Article

ABSTRACTAlthough the negative impact of long‐duration spaceflight on spine BMD has been reported, its impact on vertebral strength and risk of vertebral fracture remains unknown. This study examined 17 crewmembers with long‐duration service on the International Space Station in whom computed tomography (CT) scans of the lumbar spine (L1 and L2) were collected preflight, immediately postflight and 1 to 4 years after return to Earth. We assessed vertebral strength via CT‐based finite element analysis (CT‐FEA) and spinal loading during different activities via subject‐specific musculoskeletal models. Six months of spaceflight reduced vertebral strength by 6.1% (−2.3%, −8.7%) (median interquartile range) compared to preflight (p < 0.05), with 65% of subjects experiencing deficits of greater than 5%, and strengths were not recovered up to 4 years after the mission. This decline in vertebral strength exceeded (p < 0.05) the 2.2% (−1.3%, −6.0%) decline in lumbar spine DXA‐BMD. Further, the subject‐specific changes in vertebral strength were not correlated with the changes in DXA‐BMD. Although spinal loading increased slightly postflight, the ratio of vertebral compressive load to vertebral strength for typical daily activities remained well below a value of 1.0, indicating a low risk of vertebral fracture despite the loss in vertebral strength. However, for more strenuous activity, the postflight load‐to‐strength ratios ranged from 0.3 to 0.7, indicating a moderate risk of vertebral fracture in some individuals. Our findings suggest persistent deficits in vertebral strength following long‐duration spaceflight, and although risk of vertebral fracture remains low for typical activities, the risk of vertebral fracture is notable in some crewmembers for strenuous exercise requiring maximal effort. © 2019 American Society for Bone and Mineral Research.

Association of Mineral Bone Disorder With Decline in Residual Kidney Function in Incident Hemodialysis Patients

30-10-2019 – Yu‐Ji Lee, Yusuke Okuda, John Sy, Yoshitsugu Obi, Duk‐Hee Kang, Steven Nguyen, Jui Ting Hsiung, Christina Park, Connie M Rhee, Csaba P Kovesdy, Elani Streja, Kamyar Kalantar‐Zadeh

Journal Article

ABSTRACTAbnormalities of mineral bone disorder (MBD) parameters have been suggested to be associated with poor renal outcome in predialysis patients. However, the impact of those parameters on decline in residual kidney function (RKF) is uncertain among incident hemodialysis (HD) patients. We performed a retrospective cohort study in 13,772 patients who initiated conventional HD during 2007 to 2011 and survived 6 months of dialysis. We examined the association of baseline serum phosphorus, calcium, intact parathyroid hormone (PTH), and alkaline phosphatase (ALP) with a decline in RKF. Decline in RKF was assessed by estimated slope of renal urea clearance (KRU) over 6 months from HD initiation. Our cohort had a mean ± SD age of 62 ± 15 years; 64% were men, 57% were white, 65% had diabetes, and 51% had hypertension. The median (interquartile range IQR) baseline KRU level was 3.4 (2.0, 5.2) m
L/min/1.73 m2. The median (IQR) estimated 6‐month KRU slope was −1.47 (−2.24, −0.63) m
L/min/1.73 m2 per 6 months. In linear regression models, higher phosphorus categories were associated with a steeper 6‐month KRU slope compared with the reference category (phosphorus 4.0 to <4.5 mg/d
L). Lower calcium and higher intact PTH and ALP categories were also associated with a steeper 6‐month KRU slope compared with their respective reference groups (calcium 9.2 to <9.5 mg/d
L; intact PTH 150 to <250 pg/m
L; ALP <60 U/L). The increased number of parameter abnormalities had an additive effect on decline in RKF. Abnormalities of MBD parameters including higher phosphorus, intact PTH, ALP and lower calcium levels were independently associated with decline in RKF in incident HD patients. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

Zoledronic Acid Improves Muscle Function in Healthy Mice Treated with Chemotherapy

30-10-2019 – Brian A Hain, Baptiste Jude, Haifang Xu, Dallas M Smuin, Edward J Fox, John C Elfar, David L Waning

Journal Article

ABSTRACTCarboplatin is a chemotherapy drug used to treat solid tumors but also causes bone loss and muscle atrophy and weakness. Bone loss contributes to muscle weakness through bone‐muscle crosstalk, which is prevented with the bisphosphonate zoledronic acid (ZA). We treated mice with carboplatin in the presence or absence of ZA to assess the impact of bone resorption on muscle. Carboplatin caused loss of body weight, muscle mass, and bone mass, and also led to muscle weakness as early as 7 days after treatment. Mice treated with carboplatin and ZA lost body weight and muscle mass but did not lose bone mass. In addition, muscle function in mice treated with ZA was similar to control animals. We also used the anti‐TGFβ antibody (1D11) to prevent carboplatin‐induced bone loss and showed similar results to ZA‐treated mice. We found that atrogin‐1 m
RNA expression was increased in muscle from mice treated with carboplatin, which explained muscle atrophy. In mice treated with carboplatin for 1 or 3 days, we did not observe any bone or muscle loss, or muscle weakness. In addition, reduced caloric intake in the carboplatin treated mice did not cause loss of bone or muscle mass, or muscle weakness. Our results show that blocking carboplatin‐induced bone resorption is sufficient to prevent skeletal muscle weakness and suggests another benefit to bone therapy beyond bone in patients receiving chemotherapy. © 2019 American Society for Bone and Mineral Research.

High‐Impact Exercise Increased Femoral Neck Bone Density With No Adverse Effects on Imaging Markers of Knee Osteoarthritis in Postmenopausal Women

29-10-2019 – Chris Hartley, Jonathan P Folland, Robert Kerslake, Katherine Brooke‐Wavell

Journal Article

ABSTRACTHigh‐impact exercise can improve femoral neck bone mass but findings in postmenopausal women have been inconsistent and there may be concern at the effects of high‐impact exercise on joint health. We investigated the effects of a high‐impact exercise intervention on bone mineral density (BMD), bone mineral content (BMC), and section modulus (Z) as well as imaging biomarkers of osteoarthritis (OA) in healthy postmenopausal women. Forty‐two women aged 55 to 70 years who were at least 12 months postmenopausal were recruited. The 6‐month intervention consisted of progressive, unilateral, high‐impact exercise incorporating multidirectional hops on one randomly assigned exercise leg (EL) for comparison with the contralateral control leg (CL). Dual‐energy X‐ray absorptiometry (DXA) was used to measure BMD, BMC, and Z of the femoral neck. Magnetic resonance imaging (MRI) of the knee joint was used to analyze the biochemical composition of articular cartilage using T2 relaxometry and to analyze joint pathology associated with OA using semiquantitative analysis. Thirty‐five participants (61.7 ± 4.3 years) completed the intervention with a mean adherence of 76.8% ± 22.5%. Femoral neck BMD, BMC, and Z all increased in the EL (+0.81%, +0.69%, and +3.18%, respectively) compared to decreases in the CL (−0.57%, −0.71%, and −0.75%: all interaction effects p < 0.05). There was a significant increase in mean T2 relaxation times (main effect of time p = 0.011) but this did not differ between the EL and CL, indicating no global effect. Semiquantitative analysis showed high prevalence of bone marrow lesions (BML) and cartilage defects, especially in the patellofemoral joint (PFJ), with no indication that the intervention caused pathology progression. In conclusion, a high‐impact exercise intervention that requires little time, cost, or specialist equipment improved femoral neck BMD with no negative effects on knee OA imaging biomarkers. Unilateral high‐impact exercise is a feasible intervention to reduce hip fracture risk in healthy postmenopausal women. © 2019 American Society for Bone and Mineral Research.

Osteocalcin Regulates Arterial Calcification Via Altered Wnt Signaling and Glucose Metabolism

29-10-2019 – Nabil A Rashdan, Alisia M Sim, Lin Cui, Kanchan Phadwal, Fiona L Roberts, Roderick Carter, Derya D Ozdemir, Peter Hohenstein, John Hung, Jakub Kaczynski, David E Newby, Andrew H Baker, Gerard Karsenty, Nicholas M Morton, Vicky E MacRae

Journal Article

ABSTRACTArterial calcification is an important hallmark of cardiovascular disease and shares many similarities with skeletal mineralization. The bone‐specific protein osteocalcin (OCN) is an established marker of vascular smooth muscle cell (VSMC) osteochondrogenic transdifferentiation and a known regulator of glucose metabolism. However, the role of OCN in controlling arterial calcification is unclear. We hypothesized that OCN regulates calcification in VSMCs and sought to identify the underpinning signaling pathways. Immunohistochemistry revealed OCN co‐localization with VSMC calcification in human calcified carotid artery plaques. Additionally, 3 m
M phosphate treatment stimulated OCN m
RNA expression in cultured VSMCs (1.72‐fold, p < 0.001). Phosphate‐induced calcification was blunted in VSMCs derived from OCN null mice (Ocn −/−) compared with cells derived from wild‐type (WT) mice (0.37‐fold, p < 0.001). Ocn −/− VSMCs showed reduced m
RNA expression of the osteogenic marker Runx2 (0.51‐fold, p < 0.01) and the sodium‐dependent phosphate transporter, Pi
T1 (0.70‐fold, p < 0.001), with an increase in the calcification inhibitor Mgp (1.42‐fold, p < 0.05) compared with WT. Ocn −/− VSMCs also showed reduced m
RNA expression of Axin2 (0.13‐fold, p < 0.001) and Cyclin D (0.71 fold, p < 0.01), markers of Wnt signaling. CHIR99021 (GSK3β inhibitor) treatment increased calcium deposition in WT and Ocn −/− VSMCs (1 μM, p < 0.001). Ocn −/− VSMCs, however, calcified less than WT cells (1 μM; 0.27‐fold, p < 0.001). Ocn −/− VSMCs showed reduced m
RNA expression of Glut1 (0.78‐fold, p < 0.001), Hex1 (0.77‐fold, p < 0.01), and Pdk4 (0.47‐fold, p < 0.001). This was accompanied by reduced glucose uptake (0.38‐fold, p < 0.05). Subsequent mitochondrial function assessment revealed increased ATP‐linked respiration (1.29‐fold, p < 0.05), spare respiratory capacity (1.59‐fold, p < 0.01), and maximal respiration (1.52‐fold, p < 0.001) in Ocn −/− versus WT VSMCs. Together these data suggest that OCN plays a crucial role in arterial calcification mediated by Wnt/β‐catenin signaling through reduced maximal respiration. Mitochondrial dynamics may therefore represent a novel therapeutic target for clinical intervention. © 2019 American Society for Bone and Mineral Research.

Murine Placental‐Fetal Phosphate Dyshomeostasis Caused by an Xpr1 Deficiency Accelerates Placental Calcification and Restricts Fetal Growth in Late Gestation

25-10-2019 – Xuan Xu, Xiunan Li, Hao Sun, Zhijian Cao, Ruixi Gao, Tingting Niu, Yanli Wang, Tingbin Ma, Rui Chen, Cheng Wang, Zhengang Yang, Jing Yu Liu

Journal Article

ABSTRACTPhosphorus is a necessary component of all living organisms. This nutrient is mainly transported from the maternal blood to the fetus via the placenta, and insufficient phosphorus availability via the placenta disturbs the normal development of the fetus, especially fetal bone formation in late gestation. Key proteins (phosphate transporters and exporters) that are responsible for the maintenance of placental‐fetal phosphorus homeostasis have been identified. A deficiency in the phosphate transporter Pit2 has been shown to result in placental calcification and the retardation of fetal development in mice. What roles does XPR1 (the only known phosphate exporter) play in maintaining placental‐fetal phosphorus homeostasis? In this study, we found that Xpr1 expression is strong in the murine placenta and increases with age during gestation. We generated a global Xpr1 knockout mouse and found that heterozygous (Xpr1+/−) and homozygous (Xpr1−/−) fetuses have lower inorganic phosphate (Pi) levels in amniotic fluid and serum and a decreased skeletal mineral content. Xpr1‐deficient placentas show abnormal Pi exchange during gestation. Therefore, Xpr1 deficiency in the placenta disrupts placental‐fetal Pi homeostasis. We also discovered that the placentas of the Xpr1+/− and Xpr1−/− embryos are severely calcified. Mendelian inheritance statistics for offspring outcomes indicated that Xpr1‐deficient embryos are significantly reduced in late gestation. In addition, Xpr1−/− mice die perinatally and a small proportion of Xpr1+/− mice die neonatally. RNA sequence (RNA‐Seq) analysis of placental m
RNA revealed that many of the transcripts are significantly differentially expressed due to Xpr1 deficiency and are linked to dysfunction of the placenta. This study is the first to reveal that XPR1 plays an important role in maintaining placental‐fetal Pi homeostasis, disruption of which causes severe placental calcification, delays normal placental function, and restricts fetal growth. © 2019 American Society for Bone and Mineral Research.

Oral Iron Replacement Normalizes Fibroblast Growth Factor 23 in Iron‐Deficient Patients With Autosomal Dominant Hypophosphatemic Rickets

25-10-2019 – Erik A Imel, Ziyue Liu, Melissa Coffman, Dena Acton, Rakesh Mehta, Michael J Econs

Journal Article

ABSTRACTAutosomal dominant hypophosphatemic rickets (ADHR) is caused by mutations impairing cleavage of fibroblast growth factor 23 (FGF23). FGF23 gene expression increases during iron deficiency. In humans and mice with the ADHR mutation, iron deficiency results in increased intact FGF23 concentrations and hypophosphatemia. We conducted a prospective open label pilot clinical trial of oral iron replacement over 12 months in ADHR patients to test the hypothesis that oral iron administration would normalize FGF23 concentrations. Eligibility criteria included: FGF23 mutation; and either serum iron <50 μg/d
L; or serum iron 50 to 100 μg/d
L combined with hypophosphatemia and intact FGF23 >30 pg/m
L at screening. Key exclusion criteria were kidney disease and pregnancy. Oral iron supplementation started at 65 mg daily and was titrated based on fasting serum iron concentration. The primary outcome was decrease in fasting intact FGF23 by ≥20% from baseline. Six adults (three male, three female) having the FGF23‐R176Q mutation were enrolled; five completed the 12‐month protocol. At baseline three of five subjects had severely symptomatic hypophosphatemia (phosphorus <2.5 mg/d
L) and received calcitriol with or without phosphate concurrent with oral iron during the trial. The primary outcome was met by 4 of 5 (80%) subjects all by month 4, and 5 of 5 had normal intact FGF23 at month 12. Median (minimum, maximum) intact FGF23 concentration decreased from 172 (20, 192) pg/m
L at baseline to 47 (17, 78) pg/m
L at month 4 and 42 (19, 63) pg/m
L at month 12. Median ferritin increased from 18.6 (7.7, 82.5) ng/m
L at baseline to 78.0 (49.6, 261.0) ng/m
L at month 12. During iron treatment, all three subjects with baseline hypophosphatemia normalized serum phosphorus, had markedly improved symptoms, and were able to discontinue calcitriol and phosphate. Oral iron repletion normalized FGF23 and phosphorus in symptomatic, iron‐deficient ADHR subjects. Thus, the standard approach to ADHR should include recognition, treatment, and prevention of iron deficiency. © 2019 American Society for Bone and Mineral Research.

What Else Do We Need? A Commentary on Zoledronate Effects on Cancer and Cardiac Events

25-10-2019 – Benjamin Z Leder

Editorial

Exercise Degrades Bone in Caloric Restriction, Despite Suppression of Marrow Adipose Tissue (MAT)

25-10-2019 – Cody McGrath, Jeyantt S Sankaran, Negin Misaghian‐Xanthos, Buer Sen, Zhihui Xie, Martin A Styner, Xiaopeng Zong, Janet Rubin, Maya Styner

Journal Article

ABSTRACTMarrow adipose tissue (MAT) and its relevance to skeletal health during caloric restriction (CR) is unknown: It remains unclear whether exercise, which is anabolic to bone in a calorie‐replete state, alters bone or MAT in CR. We hypothesized that response of bone and MAT to exercise in CR differs from the calorie‐replete state. Ten‐week‐old female B6 mice fed a regular diet (RD) or 30% CR diet were allocated to sedentary (RD, CR, n = 10/group) or running exercise (RD‐E, CR‐E, n = 7/group). After 6 weeks, CR mice weighed 20% less than RD, p < 0.001; exercise did not affect weight. Femoral bone volume (BV) via 3D MRI was 20% lower in CR versus RD (p < 0.0001). CR was associated with decreased bone by μCT: Tb.
Th was 16% less in CR versus RD, p < 0.003, Ct.
Th was 5% less, p < 0.07. In CR‐E, Tb.
Th was 40% less than RD‐E, p < 0.0001. Exercise increased Tb.
Th in RD (+23% RD‐E versus RD, p < 0.003) but failed to do so in CR. Cortical porosity increased after exercise in CR (+28%, p = 0.04), suggesting exercise during CR is deleterious to bone. In terms of bone fat, metaphyseal MAT/ BV rose 159% in CR versus RD, p = 0.003 via 3D MRI. Exercise decreased MAT/BV by 52% in RD, p < 0.05, and also suppressed MAT in CR (−121%, p = 0.047). Histomorphometric analysis of adipocyte area correlated with MAT by MRI (R2 = 0.6233, p < 0.0001). With respect to bone, TRAP and Sost m
RNA were reduced in CR. Intriguingly, the repressed Sost in CR rose with exercise and may underlie the failure of CR‐bone quantity to increase in response to exercise. Notably, CD36, a marker of fatty acid uptake, rose 4088% in CR (p < 0.01 versus RD), suggesting that basal increases in MAT during calorie restriction serve to supply local energy needs and are depleted during exercise with a negative impact on bone. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Alveolar Bone Protection by Targeting the SH3BP2‐SYK Axis in Osteoclasts

24-10-2019 – Mizuho Kittaka, Tetsuya Yoshimoto, Collin Schlosser, Robert Rottapel, Mikihito Kajiya, Hidemi Kurihara, Ernst J Reichenberger, Yasuyoshi Ueki

Journal Article

ABSTRACTPeriodontitis is a bacterially induced chronic inflammatory condition of the oral cavity where tooth‐supporting tissues including alveolar bone are destructed. Previously, we have shown that the adaptor protein SH3‐domain binding protein 2 (SH3BP2) plays a critical role in inflammatory response and osteoclastogenesis of myeloid lineage cells through spleen tyrosine kinase (SYK). In this study, we show that SH3BP2 is a novel regulator for alveolar bone resorption in periodontitis. Micro‐CT analysis of SH3BP2‐deficient (Sh3bp2 −/−) mice challenged with ligature‐induced periodontitis revealed that Sh3bp2 −/− mice develop decreased alveolar bone loss (male 14.9% ± 10.2%; female 19.0% ± 6.0%) compared with wild‐type control mice (male 25.3% ± 5.8%; female 30.8% ± 5.8%). Lack of SH3BP2 did not change the inflammatory cytokine expression and osteoclast induction. Conditional knockout of SH3BP2 and SYK in myeloid lineage cells with Lys
M‐Cre mice recapitulated the reduced bone loss without affecting both inflammatory cytokine expression and osteoclast induction, suggesting that the SH3BP2‐SYK axis plays a key role in regulating alveolar bone loss by mechanisms that regulate the bone‐resorbing function of osteoclasts rather than differentiation. Administration of a new SYK inhibitor GS‐9973 before or after periodontitis induction reduced bone resorption without affecting inflammatory reaction in gingival tissues. In vitro, GS‐9973 treatment of bone marrow–derived M‐CSF‐dependent macrophages suppressed tartrate‐resistant acid phosphatase (TRAP)‐positive osteoclast formation with decreased mineral resorption capacity even when GS‐9973 was added after RANKL stimulation. Thus, the data suggest that SH3BP2‐SYK is a novel signaling axis for regulating alveolar bone loss in periodontitis and that SYK can be a potential therapeutic target to suppress alveolar bone resorption in periodontal diseases. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

Effects of a 12‐Month Supervised, Community‐Based, Multimodal Exercise Program Followed by a 6‐Month Research‐to‐Practice Transition on Bone Mineral Density, Trabecular Microarchitecture, and Physical Function in Older Adults: A Randomized Controlled Trial

24-10-2019 – Robin M Daly, Jenny Gianoudis, Mariana E Kersh, Christine A Bailey, Peter R Ebeling, Roland Krug, Caryl A Nowson, Keith Hill, Kerrie M Sanders

Journal Article

ABSTRACTMulticomponent exercise programs are recommended to reduce fracture risk; however, their effectiveness in real‐world community settings remain uncertain. This 18‐month randomized controlled trial investigated the effects of a 12‐month, community‐based, supervised multicomponent exercise program followed by a 6‐month “research‐to‐practice” transition on areal bone mineral density (BMD), trabecular bone microarchitecture, functional performance, and falls in older adults at increased fracture risk. One‐hundred and sixty‐two adults aged ≥60 years with osteopenia or at increased falls risk were randomized to the Osteo‐cise: Strong Bones for Life multicomponent exercise program (n = 81) or a control group (n = 81). Exercise consisted of progressive resistance, weight‐bearing impact, and balance training (3‐days/week) performed at community leisure centers. Overall 148 (91%) participants completed the trial, and mean exercise adherence was 59% after 12 months and 45% during the final 6 months. After 12 months, there were significant net beneficial effects of exercise on lumbar spine and femoral neck BMD (1.0% to 1.1%, p < 0.05), muscle strength (10% to 13%, p < 0.05), and physical function (timed stair climb 5%; four‐square step test 6%; sit‐to‐stand 16%, p ranging <0.05 to <0.001), which persisted after the 6‐month transition. There were no significant effects of the 18‐month intervention on distal femur or proximal tibia trabecular bone microarchitecture or falls incidence, but per protocol analysis (≥66% exercise adherence) revealed there was a significant net benefit of exercise (mean 95% confidence interval 2.8% 0.2, 5,4) on proximal tibia trabecular bone volume fraction (Osteo‐cise 1.5% −1.2, 4.2; controls −1.3% −2.6, 0.1) after 18 months due to changes in trabecular number (Osteo‐cise 1.7% −0.9, 4.3; controls −1.1% −2.4, 0.2) but not trabecular thickness (Osteo‐cise − 0.2% −0.5, 0.2; controls −0.2% −0.4, 0.0). In conclusion, this study supports the effectiveness of the Osteo‐cise: Strong Bones for Life program as a real‐world, pragmatic, evidence‐based community exercise program to improve multiple musculoskeletal health outcomes in older adults at increased fracture risk. © 2019 American Society for Bone and Mineral Research.

CD55 Regulates Bone Mass in Mice by Modulating RANKL‐Mediated Rac Signaling and Osteoclast Function

23-10-2019 – Bongjin Shin, Heeyeon Won, Douglas J Adams, Sun‐Kyeong Lee

Journal Article

ABSTRACTCD55 is a glycosylphosphatidylinositol (GPI)‐anchored protein that regulates complement‐mediated and innate and adaptive immune responses. Although CD55 is expressed in various cell types in the bone marrow, its role in bone has not been investigated. In the current study, trabecular bone volume measured by μCT in the femurs of CD55KO female mice was increased compared to wild type (WT). Paradoxically, osteoclast number was increased in CD55KO with no differences in osteoblast parameters. Osteoclasts from CD55KO mice exhibited abnormal actin‐ring formation and reduced bone‐resorbing activity. Moreover, macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL) treatment failed to activate Rac guanosine triphosphatase (GTPase) in CD55KO bone marrow macrophage (BMM) cells. In addition, apoptotic caspases activity was enhanced in CD55KO, which led to the poor survival of mature osteoclasts. Our results imply that CD55KO mice have increased bone mass due to defective osteoclast resorbing activity resulting from reduced Rac activity in osteoclasts. We conclude that CD55 plays an important role in the survival and bone‐resorption activity of osteoclasts through regulation of Rac activity. © 2019 American Society for Bone and Mineral Research.

Standard Versus Cyclic Teriparatide and Denosumab Treatment for Osteoporosis: A Randomized Trial

23-10-2019 – Felicia Cosman, Donald McMahon, David Dempster, Jeri W Nieves

Journal Article

ABSTRACTIn the absence of an intervening antiresorptive agent, cyclic administration of teriparatide does not increase bone mineral density (BMD) more than standard daily therapy. Because denosumab is a potent antiresorptive agent with a rapid off‐effect, we hypothesized that it might be the optimal agent to help maximize bone gains with cyclic teriparatide. In this 3‐year protocol, 70 postmenopausal women with osteoporosis were randomized to 18 months of teriparatide followed by 18 months of denosumab (standard) or three separate 12‐month cycles of 6 months of teriparatide followed by 6 months of denosumab (cyclic). BMD (dual‐energy X‐ray absorptiometry DXA) measurements of lumbar spine (LS), total hip (TH), femoral neck (FN), and 1/3 radius (RAD) were performed every 6 months and total body bone mineral (TBBM) at 18 and 36 months. Baseline descriptive characteristics did not differ between groups except for a minimal difference in LS BMD but not T‐score (mean age 65 years, mean LS T‐score − 2.7). In the standard group, BMD increments at 36 months were: LS 16%, TH 4%, FN 3%, and TBBM 4.8% (all p < 0.001 versus baseline). In the cyclic group, 36‐month BMD increments were similar: LS 12%, TH 4%, FN 4%, and TBBM 4.1% (all p < 0.001 versus baseline). At 36 months, the LS BMD increase with standard was slightly larger than with cyclic (p = 0.04), but at 18 months, in the cyclic group, there was no decline in RAD or TBBM (p = 0.007 and < 0.001, respectively, versus standard). Although the cyclic regimen did not improve BMD compared with standard at 36 months, there appeared to be a benefit at 18 months, especially in the highly cortical skeletal sites. This could be clinically relevant in patients at high imminent risk of fracture, particularly at nonvertebral sites. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

EZH2 Supports Osteoclast Differentiation and Bone Resorption Via Epigenetic and Cytoplasmic Targets

23-10-2019 – Juraj Adamik, Sree H Pulugulla, Peng Zhang, Quanhong Sun, Konstantinos Lontos, David A Macar, Philip E Auron, Deborah L Galson

Journal Article

ABSTRACTKey osteoclast (OCL) regulatory gene promoters in bone marrow–derived monocytes harbor bivalent histone modifications that combine activating Histone 3 lysine 4 tri‐methyl (H3K4me3) and repressive H3K27me3 marks, which upon RANKL stimulation resolve into repressive or activating architecture. Enhancer of zeste homologue 2 (EZH2) is the histone methyltransferase component of the polycomb repressive complex 2, which catalyzes H3K27me3 modifications. Immunofluorescence microscopy reveals that EZH2 localization during murine osteoclastogenesis is dynamically regulated. Using EZH2 knockdown and small molecule EZH2 inhibitor GSK126, we show that EZH2 plays a critical epigenetic role in OCL precursors (OCLp) during the first 24 hours of RANKL activation. RANKL triggers EZH2 translocation into the nucleus where it represses OCL‐negative regulators Maf
B, Irf8, and Arg1. Consistent with its cytoplasmic localization in OCLp, EZH2 methyltransferase activity is required during early RANKL signaling for phosphorylation of AKT, resulting in downstream activation of the m
TOR complex, which is essential for induction of OCL differentiation. Inhibition of RANKL‐induced pm
TOR‐pS6RP signaling by GSK126 altered the translation ratio of the C/EBPβ‐LAP and C/EBPβ‐LIP isoforms and reduced nuclear translocation of the inhibitory C/EBPβ‐LIP, which is necessary for transcriptional repression of the OCL negative‐regulatory transcription factor Maf
B. EZH2 in multinucleated OCL is primarily cytoplasmic and mature OCL cultured on bone segments in the presence of GSK126 exhibit defective cytoskeletal architecture and reduced resorptive activity. Here we present new evidence that EZH2 plays epigenetic and cytoplasmic roles during OCL differentiation by suppressing Maf
B transcription and regulating early phases of PI3K‐AKT–m
TOR‐mediated RANKL signaling, respectively. Consistent with its cytoplasmic localization, EZH2 is required for cytoskeletal dynamics during resorption by mature OCL. Thus, EZH2 exhibits complex roles in supporting osteoclast differentiation and function. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

High‐Dose TGF‐β1 Impairs Mesenchymal Stem Cell–Mediated Bone Regeneration via Bmp2 Inhibition

22-10-2019 – Jiajia Xu, Jinlong Liu, Yaokai Gan, Kerong Dai, Jingyu Zhao, Mingjian Huang, Yan Huang, Yifu Zhuang, Xiaoling Zhang

Journal Article

ABSTRACTTransforming growth factor‐β1 (TGF‐β1) is a key factor in bone reconstruction. However, its pathophysiological role in non‐union and bone repair remains unclear. Here we demonstrated that TGF‐β1 was highly expressed in both C57BL/6 mice where new bone formation was impaired after autologous bone marrow mesenchymal stem cell (BMMSC) implantation in non‐union patients. High doses of TGF‐β1 inhibited BMMSC osteogenesis and attenuated bone regeneration in vivo. Furthermore, different TGF‐β1 levels exhibited opposite effects on osteogenic differentiation and bone healing. Mechanistically, low TGF‐β1 doses activated smad3, promoted their binding to bone morphogenetic protein 2 (Bmp2) promoter, and upregulated Bmp2 expression in BMMSCs. By contrast, Bmp2 transcription was inhibited by changing smad3 binding sites on its promoter at high TGF‐β1 levels. In addition, high TGF‐β1 doses increased tomoregulin‐1 (Tmeff1) levels, resulting in the repression of Bmp2 and bone formation in mice. Treatment with the TGF‐β1 inhibitor SB431542 significantly rescued BMMSC osteogenesis and accelerated bone regeneration. Our study suggests that high‐dose TGF‐β1 dampens BMMSC‐mediated bone regeneration by activating canonical TGF‐β/smad3 signaling and inhibiting Bmp2 via direct and indirect mechanisms. These data collectively show a previously unrecognized mechanism of TGF‐β1 in bone repair, and TGF‐β1 is an effective therapeutic target for treating bone regeneration disability. © 2019 American Society for Bone and Mineral Research.

Calcium‐Sensing Receptors in Chondrocytes and Osteoblasts Are Required for Callus Maturation and Fracture Healing in Mice

18-10-2019 – Zhiqiang Cheng, Alfred Li, Chia‐Ling Tu, Christian Santa Maria, Nicholas Szeto, Amanda Herberger, Tsui‐Hua Chen, Fuqing Song, Jiali Wang, Xiaodong Liu, Dolores M Shoback, Wenhan Chang

Journal Article

ABSTRACTCalcium and its putative receptor (Ca
SR) control skeletal development by pacing chondrocyte differentiation and mediating osteoblast (OB) function during endochondral bone formation—an essential process recapitulated during fracture repair. Here, we delineated the role of the Ca
SR in mediating transition of callus chondrocytes into the OB lineage and subsequent bone formation at fracture sites and explored targeting Ca
SRs pharmacologically to enhance fracture repair. In chondrocytes cultured from soft calluses at a closed, unfixed fracture site, extracellular Ca2+ and the allosteric Ca
SR agonist (NPS‐R568) promoted terminal differentiation of resident cells and the attainment of an osteoblastic phenotype. Knockout (KO) of the Casr gene in chondrocytes lengthened the chondrogenic phase of fracture repair by increasing cell proliferation in soft calluses but retarded subsequent osteogenic activity in hard calluses. Tracing growth plate (GP) and callus chondrocytes that express Rosa26‐td
Tomato showed reduced chondrocyte transition into OBs (by >80%) in the spongiosa of the metaphysis and in hard calluses. In addition, KO of the Casr gene specifically in mature OBs suppressed osteogenic activity and mineralizing function in bony calluses. Importantly, in experiments using PTH (1‐34) to enhance fracture healing, co‐injection of NPS‐R568 not only normalized the hypercalcemic side effects of intermittent PTH (1‐34) treatment in mice but also produced synergistic osteoanabolic effects in calluses. These data indicate a functional role of Ca
SR in mediating chondrogenesis and osteogenesis in the fracture callus and the potential of Ca
SR agonism to facilitate fracture repair. © 2019 American Society for Bone and Mineral Research.

Secular Trends of Hip Fractures in Lebanon, 2006 to 2017: Implications for Clinical Practice and Public Health Policy in the Middle East Region

14-10-2019 – Randa K Saad, Hilda Harb, Ibrahim R Bou‐Orm, Walid Ammar, Ghada El‐Hajj Fuleihan

Journal Article

ABSTRACTCountry‐specific hip fracture incidence rates (IRs) and longevity allow the Fracture Risk Assessment Tool (FRAX) to be adapted to individual countries. Secular trends can affect tool calibration. Data on hip fracture IRs in the Middle East is scarce, and long‐term secular trend studies are nonexistent. Using the Ministry of Public Health hip fracture registry, we calculated age‐ and sex‐specific hip fracture IRs in Lebanon, from 2006 to 2017, among individuals aged ≥50 years. We used Kendalls tau‐b (τb) test to determine the correlation between time and hip fracture IRs, and calculated both the annual % change in IRs and the % change in IR compared to the baseline period (2006 to 2008). The registry recorded 6985 hip fractures, 74% at the femoral neck, 23% intertrochanteric, and 3% subtrochanteric. Men constituted 32% of the population, and were significantly younger than women (76.5 ± 11.0 years versus 77.7 ± 10.3 years; p < 0.001). Annual overall IRs, per 100,000, ranged from 126.6 in 2014 to 213.2 in 2017 in women, and 61.4 in 2015 to 111.7 in 2017 in men. The average women to men IR ratio was 1.8 (range, 1.5 to 2.1). IRs steadily increased with age, and IR ratios increased in parallel in both sexes, with a steeper and earlier rise (by 5 years) in women. Data showed a consistent decline in hip fracture IRs starting in 2006 in women, and in 2009 in men. There was a significant negative correlation between time (2006 to 2014) and hip fracture IRs in women (τb = −0.611, p = 0.022) but not in men (τb = −0.444, p = 0.095). The steady decrease in IRs reversed after 2015 in both sexes. This long‐term data on secular trends in the Middle East is novel and consistent with worldwide changes in hip fracture rates. The impact of such changes on national FRAX‐derived estimates is unclear, should be assessed, and may necessitate an update in the FRAX Lebanon calculator. © 2019 American Society for Bone and Mineral Research.

YAP and TAZ Mediate Osteocyte Perilacunar/Canalicular Remodeling

14-10-2019 – Christopher D Kegelman, Jennifer C Coulombe, Kelsey M Jordan, Daniel J Horan, Ling Qin, Alexander G Robling, Virginia L Ferguson, Teresita M Bellido, Joel D Boerckel

Journal Article

ABSTRACTBone fragility fractures are caused by low bone mass or impaired bone quality. Osteoblast/osteoclast coordination determines bone mass, but the factors that control bone quality are poorly understood. Osteocytes regulate osteoblast and osteoclast activity on bone surfaces but can also directly reorganize the bone matrix to improve bone quality through perilacunar/canalicular remodeling; however, the molecular mechanisms remain unclear. We previously found that deleting the transcriptional regulators Yes‐associated protein (YAP) and transcriptional co‐activator with PDZ‐motif (TAZ) from osteoblast‐lineage cells caused lethality in mice due to skeletal fragility. Here, we tested the hypothesis that YAP and TAZ regulate osteocyte‐mediated bone remodeling by conditional ablation of both YAP and TAZ from mouse osteocytes using 8 kb‐DMP1‐Cre. Osteocyte‐conditional YAP/TAZ deletion reduced bone mass and dysregulated matrix collagen content and organization, which together decreased bone mechanical properties. Further, YAP/TAZ deletion impaired osteocyte perilacunar/canalicular remodeling by reducing canalicular network density, length, and branching, as well as perilacunar flourochrome‐labeled mineral deposition. Consistent with recent studies identifying TGF‐β as a key inducer of osteocyte expression of matrix‐remodeling enzymes, YAP/TAZ deletion in vivo decreased osteocyte expression of matrix proteases MMP13, MMP14, and CTSK. In vitro, pharmacologic inhibition of YAP/TAZ transcriptional activity in osteocyte‐like cells abrogated TGF‐β‐induced matrix protease gene expression. Together, these data show that YAP and TAZ control bone matrix accrual, organization, and mechanical properties by regulating osteocyte‐mediated bone remodeling. Elucidating the signaling pathways that control perilacunar/canalicular remodeling may enable future therapeutic targeting of bone quality to reverse skeletal fragility. © 2019 American Society for Bone and Mineral Research.

Sex‐Specific Muscular Mediation of the Relationship Between Physical Activity and Cortical Bone in Young Adults

11-10-2019 – Simon Higgins, Chester M Sokolowski, Megha Vishwanathan, Michael D Schmidt, Ellen M Evans, Richard D Lewis

Journal Article

ABSTRACTMuscle mass is a commonly cited mediator of the relationship between physical activity (PA) and bone, representing the mechanical forces generated during PA. However, neuromuscular properties (eg, peak force) also account for unique portions of variance in skeletal outcomes. We used serial multiple mediation to explore the intermediary role of muscle mass and force in the relationships between cortical bone and moderate‐to‐vigorous intensity PA (MVPA). In a cross‐sectional sample of young adults (n = 147, 19.7 ± 0.7 years old, 52.4% female) cortical diaphyseal bone was assessed via peripheral quantitative computed tomography at the mid‐tibia. Peak isokinetic torque in knee extension was assessed via Biodex dynamometer. Thigh fat‐free soft tissue (FFST) mass, assessed via dual‐energy X‐ray absorptiometry, represented the muscular aspect of tibial mechanical forces. Habitual MVPA was assessed objectively over 7 days using Actigraph GT3X+ accelerometers. Participants exceeded MVPA guidelines (89.14 ± 27.29 min/day), with males performing 44.5% more vigorous‐intensity activity relative to females (p < 0.05). Males had greater knee extension torque and thigh FFST mass compared to females (55.3%, and 34.2%, respectively, all p < 0.05). In combined‐sex models, controlling for tibia length and age, MVPA was associated with strength strain index (pSSI) through two indirect pathways: (i) thigh FFST mass (b = 1.11 ± 0.37; 95% CI, 0.47 to 1.93), and (i) thigh FFST mass and knee extensor torque in sequence (b = 0.30 ± 0.16; 95% CI, 0.09 to 0.73). However, in sex‐specific models MVPA was associated with pSSI indirectly through its relationship with knee extensor torque in males (b = 0.78 ± 0.48; 95% CI, 0.04 to 2.02) and thigh FFST mass in females (b = 1.12 ± 0.50; 95% CI, 0.37 to 2.46). Bootstrapped CIs confirmed these mediation pathways. The relationship between MVPA and cortical structure appears to be mediated by muscle in young adults, with potential sex‐differences in the muscular pathway. If confirmed, these findings may highlight novel avenues for the promotion of bone strength in young adults. © 2019 American Society for Bone and Mineral Research.

Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women

11-10-2019 – Ian R Reid, Anne M Horne, Borislav Mihov, Angela Stewart, Elizabeth Garratt, Sonja Bastin, Gregory D Gamble

Journal Article

ABSTRACTWe recently showed that zoledronate prevented fractures in older women with osteopenia (hip T‐scores between −1.0 and −2.5). In addition to fewer fractures, this study also suggested that women randomized to zoledronate had fewer vascular events, a lower incidence of cancer, and a trend to lower mortality. The present analysis provides a more detailed presentation of the adverse event data from that study, a 6‐year, double‐blind trial of 2000 women aged >65 years recruited using electoral rolls. They were randomly assigned to receive four infusions of either zoledronate 5 mg or normal saline at 18‐month intervals. Supplements of vitamin D, but not calcium, were provided. There were 1017 serious adverse events in 443 participants in the placebo group, and 820 events in 400 participants in those randomized to zoledronate (relative risk = 0.90; 95% CI, 0.81 to 1.00). These events included fractures resulting in hospital admission. Myocardial infarction occurred in 39 women (43 events) in the placebo group and in 24 women (25 events) in the zoledronate group (hazard ratio 0.60 95% CI, 0.36 to 1.00; rate ratio 0.58 95% CI, 0.35 to 0.94). For a prespecified composite cardiovascular endpoint (sudden death, myocardial infarction, coronary artery revascularization, or stroke) 69 women had 98 events in the placebo group, and 53 women had 71 events in the zoledronate group (hazard ratio 0.76 95% CI, 0.53 to 1.08; rate ratio 0.72 95% CI, 0.53 to 0.98). Total cancers were significantly reduced with zoledronate (hazard ratio 0.67 95% CI, 0.51 to 0.89; rate ratio 0.68 95% CI, 0.52 to 0.89), and this was significant for both breast cancers and for non‐breast cancers. Eleven women had recurrent or second breast cancers during the study, all in the placebo group. The hazard ratio for death was 0.65 (95% CI, 0.40 to 1.06; p = 0.08), and 0.51 (95% CI, 0.30 to 0.87) in those without incident fragility fracture. These apparent beneficial effects justify further appropriately powered trials of zoledronate with these nonskeletal conditions as primary endpoints. © 2019 American Society for Bone and Mineral Research.

Fracture Risk in Trans Women and Trans Men Using Long‐Term Gender‐Affirming Hormonal Treatment: A Nationwide Cohort Study

07-10-2019 – Chantal M Wiepjes, Christel JM Blok, Annemieke S Staphorsius, Nienke M Nota, Mariska C Vlot, Renate T Jongh, Martin Heijer

Journal Article

ABSTRACTConcerns about bone health in transgender people using gender‐affirming hormonal treatment (HT) exist, but the fracture risk is not known. In this nationwide cohort study, we aimed to compare the fracture incidence in transgender people using long‐term HT with an age‐matched reference population. All adult transgender people who started HT before 2016 at our gender‐identity clinic were included and were linked to a random population‐based sample of 5 age‐matched reference men and 5 age‐matched reference women per person. Fracture incidence was determined using diagnoses from visits to hospital emergency rooms nationwide between 2013 and 2015. A total of 1089 trans women aged <50 years (mean 38 ± 9 years) and 934 trans women aged ≥50 years (mean 60 ± 8 years) using HT for median 8 (interquartile range IQR 3–16) and 19 (IQR 11–29) years, respectively, were included. A total of 2.4% of the trans women aged <50 years had a fracture, whereas 3.0% of the age‐matched reference men (odds ratio OR = 0.78, 95% confidence interval CI 0.51–1.19) and 1.6% of the age‐matched reference women (OR = 1.49, 95% CI 0.96–2.32) experienced a fracture. In trans women aged ≥50 years, 4.4% experienced a fracture compared with 2.4% of the age‐matched reference men (OR = 1.90, 95% CI 1.32–2.74) and 4.2% of the age‐matched reference women (OR = 1.05, 95% CI 0.75–1.49). A total of 1036 trans men (40 ± 14 years) using HT for median 9 (IQR 2–22) years were included. Fractures occurred in 1.7% of the trans men, 3.0% of the age‐matched reference men (OR = 0.57, 95% CI 0.35–0.94), and 2.2% of the age‐matched reference women (OR = 0.79, 95% CI 0.48–1.30). In conclusion, fracture risk was higher in older trans women compared with age‐matched reference men. In young trans women, fracture risk tended to be increased compared with age‐matched reference women. Fracture risk was not increased in young trans men. © 2019 American Society for Bone and Mineral Research. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

American Society for Bone and Mineral Research‐Orthopaedic Research Society Joint Task Force Report on Cell‐Based Therapies

23-09-2019 – “Regis J OKeefe, Rocky S Tuan, Nancy E Lane, Frank Barry, Bruce A Bunnell, Céline Colnot, Matthew T Drake, Hicham Drissi, Lisa A Fortier, Robert E Guldberg, David G Little, Mary F Marshall, Jeremy J Mao, Norimasa Nakamura, Pamela G Robey, Vicki Rosen, David W Rowe, Edward M. Schwarz”

Journal Article

ABSTRACTCell‐based therapies, defined here as the delivery of cells in vivo to treat disease, have recently gained increasing public attention as a potentially promising approach to restore structure and function to musculoskeletal tissues. Although cell‐based therapy has the potential to improve the treatment of disorders of the musculoskeletal system, there is also the possibility of misuse and misrepresentation of the efficacy of such treatments. The medical literature contains anecdotal reports and research studies, along with web‐based marketing and patient testimonials supporting cell‐based therapy. Both the American Society for Bone and Mineral Research (ASBMR) and the Orthopaedic Research Society (ORS) are committed to ensuring that the potential of cell‐based therapies is realized through rigorous, reproducible, and clinically meaningful scientific discovery. The two organizations convened a multidisciplinary and international Task Force composed of physicians, surgeons, and scientists who are recognized experts in the development and use of cell‐based therapies. The Task Force was charged with defining the state‐of‐the art in cell‐based therapies and identifying the gaps in knowledge and methodologies that should guide the research agenda. The efforts of this Task Force are designed to provide researchers and clinicians with a better understanding of the current state of the science and research needed to advance the study and use of cell‐based therapies for skeletal tissues. The design and implementation of rigorous, thorough protocols will be critical to leveraging these innovative treatments and optimizing clinical and functional patient outcomes. In addition to providing specific recommendations and ethical considerations for preclinical and clinical investigations, this report concludes with an outline to address knowledge gaps in how to determine the cell autonomous and nonautonomous effects of a donor population used for bone regeneration. © 2019 American Society for Bone and Mineral Research.

Much‐Needed Clarification and Guidance on Cell‐Based Therapies for Musculoskeletal Disorders

23-09-2019 – Matthew P. Murphy, Derrick C. Wan, Michael T. Longaker

Editorial

Artificial Intelligence in Musculoskeletal Imaging: A Paradigm Shift

12-09-2019 – Joseph E Burns, Jianhua Yao, Ronald M Summers

Journal Article, Review

ABSTRACTArtificial intelligence is upending many of our assumptions about the ability of computers to detect and diagnose diseases on medical images. Deep learning, a recent innovation in artificial intelligence, has shown the ability to interpret medical images with sensitivities and specificities at or near that of skilled clinicians for some applications. In this review, we summarize the history of artificial intelligence, present some recent research advances, and speculate about the potential revolutionary clinical impact of the latest computer techniques for bone and muscle imaging. © 2019 American Society for Bone and Mineral Research. Published 2019. This article is a U.
S. Government work and is in the public domain in the USA.

A New 1,25 Dihydroxy Vitamin D Analog with Strong Bone Anabolic Activity in OVX Rats with Little or no Bone Resorptive Activity

28-08-2019 – Lori A Plum, Julia Zella, Margaret Clagett‐Dame, Hector F DeLuca

Journal Article

ABSTRACTA new 1α,25‐dihydroxy vitamin D3 analog (2‐methylene‐22(E)‐(24R)‐22‐dehydro‐1α,24,25‐trihydroxy‐19‐norvitamin D3 or WT‐51) has been tested as a possible therapeutic for osteoporosis. It is 1/10th as active as 1,25(OH)2D3 in binding affinity for the vitamin D receptor but is at least 200 times more active than 1,25(OH)2D3 and equal to that of 2MD (2‐methylene‐19‐nor‐(20S)‐1α,25(OH)2D3, an analog previously tested in postmenopausal women), in supporting bone formation by isolated osteoblasts in culture. However, in contrast to 2MD, it is virtually inactive on bone resorption in vivo. WT‐51 markedly increased bone mass (lumbar and femur) in ovariectomized (OVX) female rats. Further, bone strength tested by the three‐point bending system is significantly increased by WT‐51. Thus, WT‐51 is an attractive candidate for the treatment of postmenopausal osteoporosis. © 2019 American Society for Bone and Mineral Research.