Journal of Bone and Mineral Research最新文献

Disruption of circadian rhythms predisposes shift workers to many chronic conditions, including osteoporosis. However, the effects of disrupted circadian rhythms on bone remodeling remain largely unknown. Here, we show that one of the core circadian regulators PER1 inhibits osteoclastogenesis by upregulating genes involved in inflammation. The conditional knockout of Per1 in osteoclasts and related cells resulted in decreased bone mass in the femurs of mice, along with increased osteoclasts and decreased osteoblasts. Osteoclastogenesis was also promoted by Per1 depletion in vitro with 16 downregulated inflammatory genes. Seven of these genes were known to promote or inhibit osteoclastogenesis depending on the stage of osteoclastogenesis and the presence or absence of infection. Knockdown of Nlrp3, Tlr8, or Tlr9 in the group of genes promoted osteoclastogenesis, mirroring the effects of Per1 knockout and offering a mechanistic explanation for the Per1-mediated inhibition of osteoclastogenesis. These results were not observed following the knockout of a paralog Per2. Per1 knockout mice maintain general circadian rhythms, unlike arrhythmic Per1;Per2 double knockout mice. This gives credence to Per1 as a selective target for therapeutic interventions without disrupting the circadian rhythms. This study uncovered a molecular link between a circadian regulator and osteoclastogenesis in the broader context of inflammatory reactions. Our findings may be mechanistically relevant to inflammatory bone diseases influenced by circadian rhythms, such as rheumatoid arthritis and osteoarthritis, as well as other bone diseases predisposed by chronic circadian disruption.

The Osteoporotic Fractures in Men study (MrOS) is amongst the largest and longest running prospective cohort studies of older men. MrOS determined how fracture risk was related to bone mass, bone geometry, lifestyle, anthropometric and neuromuscular measures, comorbidity, biomarkers, and fall propensity. The cohort consisted of 5994 community-dwelling, ambulatory U.S. men aged 65 years or older recruited at 6 US academic clinical centers in 2000-2002 and followed through November 2024. After enrollment, men were contacted by mail/phone every 4 months to ascertain information on incident falls, fractures and deaths/loss to follow-up. All fractures were confirmed by imaging reports. Over the 25-year study, 95% of active surviving participants had complete follow-up. The MrOS study had 5 major clinic visits; while an ancillary sleep study had 2 additional clinic visits. MrOS has provided a comprehensive analysis of factors associated with areal (a) and volumetric (v) bone mineral density (BMD) and clinical risk factors for aBMD loss among men. Further analyses identified risk factors for hip, all non-spine, rib, wrist and vertebral fractures. MrOS was the largest single cohort to estimate associations of aBMD with incident fractures in men and results indicated stronger associations in men than women. MrOS also analyzed other structural features from dual x-ray absorptiometry (DXA) and both central and peripheral quantitative computed tomography in relationship to fractures in men. Serum, urine and DNA were collected at clinic visits and extensive analyses have been performed with respect to sex steroid and calciotropic hormones, bone turnover and other novel measures of bone health. Several analyses evaluated the performance of formal tools in estimating the absolute risk of fractures in older men; findings indicated that better fracture prediction tools are needed. MrOS encourages outside investigators to make use of the publicly available data and to access the biospecimen bank. https://mrosonline.ucsf.edu.

Hypoparathyroidism is an endocrine disease caused by insufficient levels of parathyroid hormone (PTH), which acts directly on bone and kidney and indirectly on the intestine to regulate calcium and phosphate balance. In clinical trials, palopegteriparatide (TransCon PTH) treatment enabled independence from conventional therapy (no active vitamin D, ≤500 mg/d calcium) and maintained serum biochemistries within normal ranges. The current analyses describe patterns of change in bone mineral density (BMD), serum bone turnover markers, and serum and urine calcium in adults with chronic hypoparathyroidism treated with palopegteriparatide through 3 yr of the PaTH Forward trial. Baseline BMD Z-scores for the lumbar spine, total hip, femoral neck, and 1/3 distal radius were above zero, indicating bone mass exceeding age-adjusted normative values. BMD decreased from these elevated baseline levels with palopegteriparatide treatment, with larger reductions during the first 26 wk and modest declines thereafter. Mean BMD Z-scores at week 162 remained above zero for all 4 sites. Participants with lower baseline BMD (Z-scores below -1 and T-scores below -2.5) generally exhibited lesser declines in BMD versus those with higher baseline BMD. Palopegteriparatide treatment was associated with early increases in bone resorption (serum C-terminal telopeptide of type I collagen, CTx) and bone formation (serum procollagen type 1 N-terminal propeptide, P1NP) that peaked at weeks 12 and 26, respectively, followed by declines to levels moderately higher than baseline at week 162. Mean CTx and P1NP in the overall population and the subgroup of postmenopausal women were below their upper limits of normal from weeks 58-162. At week 162, mean serum and median urine calcium remained within normal ranges and 91% of participants were independent from conventional therapy. These results suggest that long-term palopegteriparatide therapy in adults with chronic hypoparathyroidism gradually returns the skeleton toward its natural state thereby enhancing the skeleton's contribution to calcium homeostasis.

Lower extremity muscle function has been associated with risk of falls and fractures; however, most studies have examined strength (force), but not power (force*velocity). A jump test on a force plate measures weight-bearing power and allows the dissection of peak power into its components, force and velocity. We investigated the association between jump test power measures and MOF risk in 1841 older men (median age 84 yr). Peak jump power (Watt/kg body weight), force (Newton/kg body weight) at peak power, and velocity (m/s) at peak power were measured by jump tests on a force plate. Fractures were identified by triannual questionnaires, with all self-reported fractures confirmed by medical record. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) by continuous (per one SD increment) and across quartiles of jump test measurements. Participants that were excluded from the jump tests were classified into the "lowest" group (referent; N = 599). A total of 136 incident MOF occurred over 5 yr of follow-up. In the multiply adjusted models, one SD increment of peak power/kg body weight was associated with a lower risk of MOF (HR 0.71, 95% CI 0.54-0.92), with a similar risk reduction observed with velocity at peak power (HR 0.76, 95%CI:0.59-0.98). Further adjustment for femoral neck (FN) bone mineral density (BMD) did not attenuate the association. There was significant trend of decreasing MOF with increasing power and velocity. For force, only the highest quartile was significantly associated with lower risk of MOF, but this was not significant after adjusting for FN BMD. In older men, peak leg power and velocity, but not force, predicted MOF risk independent of FN BMD. Power, which incorporates velocity, may play a more important role than force in reducing the risk of a fracture.

Autosomal dominant osteopetrosis (ADO) is a rare osteosclerotic disorder usually caused by missense variants in the CLCN7 gene, which results in impaired osteoclastic bone resorption. Penetrance is incomplete, and disease severity varies widely, even among relatives within the same family. Although ADO can cause visual loss, osteonecrosis, osteomyelitis, and bone marrow failure, the most common complication of ADO is fracture. We are conducting a natural history study to characterize disease progression and determinants of disease severity. We hypothesized that baseline BMD and bone turnover markers would correlate with self-reported fracture history. We report cross-sectional analysis of baseline data from the natural history study in 54 individuals (42 adults, 12 children). In adults, Z-scores for both volumetric (r = 0.87, p < .001) and areal BMD (aBMD) of the LS, and Z-scores for FN, and TH aBMD (r = 0.77 to 0.78; p < .001) were correlated with lifetime fracture number. Tartrate resistant acid phosphatase, a marker of osteoclast number, correlated positively with fracture (r = 0.52, p = .004) consistent with an adaptive response of higher numbers of osteoclasts among more severely affected individuals. However, fracture number correlated inversely with the bone resorption markers serum C-telopeptide (r = -0.60, p < .001) and urine N-telopeptide/creatinine ratio (r = -0.35, p = .047), suggesting that ADO subjects who have the most reduced osteoclast activity have a greater tendency to fracture. Correlation coefficients between fractures, BMD, and bone turnover markers were similar when limited to the 37 adults with disease-causing CLCN7 variants. There were no statistically significant differences between subjects with the most common CLCN7 variant (G215R), the most common variant in our cohort, compared to other CLCN7 variants with respect to fracture, bone density measures, or biochemical markers of bone turnover. These data demonstrate that bone density and biochemical bone turnover markers are indicators of ADO severity as defined by fracture number.

Monitoring bone health for osteoporosis is typically based on measuring areal BMD. However, widely used fracture risk prediction tools are primarily driven by clinical risk factors and show limited sensitivity to underlying bone changes over time. This study evaluated the ability of the new Microarchitecture Fracture Risk Assessment Calculator ($mu $FRAC) to detect longitudinal changes in fracture risk in relation to bone quality. Our study cohort included 601 participants (70.2% female) from a longitudinal population study. HR-pQCT scans of the distal radius and tibia were acquired at 2 visits, 3-10 years apart. The $mu $FRAC 5-year risk of major osteoporotic fracture was calculated at both time points. Participants were divided into quartiles based on the absolute change in tibia bone strength between study visits to assess the model's sensitivity to changes in bone fragility. Differences between quartiles were assessed using a Mann-Whitney U test and the standardized response mean (SRM). Additionally, changes in fracture risk by decade, were analyzed to investigate age- and sex-specific trends in fracture risk. The average age of participants was 53.8 $pm $ 15.4 years, with an average follow-up of 6.8 $pm $ 1.8 years. The greatest absolute annualized changes in $mu $FRAC risk occurred in individuals with the largest differences in bone strength (SRM = 0.73-0.78), while the least change was observed in individuals with minimal changes (SRM = 0.07-0.21). Age- and sex-specific trends aligned with previously established patterns of bone aging, showing the greatest annualized changes in fracture risk in menopausal females (40-60 years) and older adults (70+ years). We demonstrated $mu $FRAC is sensitive to changes in fracture risk driven by declines in bone quality in aging adults. These results suggest $mu $FRAC is well suited for tracking fracture prediction longitudinally and has potential to monitor osteoporosis disease progression and treatment response.

G protein α-subunit (Gαs), encoded by GNAS, mediates G protein-coupled receptor (GPCR) signaling through the cAMP second messenger pathways, and plays a pivotal role in craniofacial morphogenesis and osteoblast differentiation. Craniosynostosis, one of the most prevalent craniofacial developmental anomalies, is characterized by the premature fusion of cranial sutures. Here, we identify germline heterozygous variants in GNAS as a novel genetic cause of craniosynostosis. Affected individuals presented with multiple-suture synostosis, recognizable dysmorphic features, brachydactyly, short stature, with or without hormone resistance. We identified 3 de novo missense variants (c.286A > G;p.K96E, c.758A > G;p.Y253C, and c.691C > T;p.R231C) and 1 maternally inherited splicing variant (c.1039-2A > G). Functional analyses using bioluminescence resonance energy transfer assays compared these variants to well-characterized activating variants p.R201H and p.Q227L. All tested variants impaired trimeric G protein assembly to varying degrees and exhibited reduced coupling with PTHR1. While the p.R201H and p.Q227L variants induced excessive cAMP production, the craniosynostosis-associated variants either displayed decreased basal cAMP levels or reduced agonist-induced cAMP production compared to WT, suggesting an inactivating nature. In zebrafish models, heterozygous gnas inactivation recapitulated human phenotypes, including multiple-suture synostosis, craniofacial abnormalities, and short stature. Mechanistically, GNAS knockdown in human MSCs promoted osteogenic differentiation through disrupted cAMP-cAMP response element-binding protein signaling, which relieved SMAD6-mediated repression of RUNX2 transcription. This study establishes inactivating GNAS variants as a genetic cause of craniosynostosis, and uncovers a disease mechanism linking G protein inactivation to craniosynostosis through defective GPCR signal transduction.

Fracture risk is commonly assessed by FRAX, a tool that estimates 10-yr risk for major osteoporotic fracture (MOF) and hip fracture. FRAX scores are often refined by including FN BMD measured by DXA as an input. Rho, a novel AI-powered software, estimates FN BMD T-Scores from conventional X-rays, even when FN is not in the image. Whether a FRAX score using this estimate (FRAX-Rho) can improve a FRAX score without a T-Score input (FRAX-NoT) has not been studied. We conducted a retrospective analysis of Canadian Multicentre Osteoporosis Study participants who had X-rays of the lumbar and/or thoracic spine, FRAX risk factors, and DXA T-Scores acquired at the same time point, and follow-up fracture outcomes over 9 yr. In 1361 participants with lumbar X-rays, FRAX-Rho and FRAX with DXA FN T-Scores (FRAX-DXA) had very good agreement in categorizing participants by MOF risk (Cohen's weighted kappa κ = 0.80 [0.77-0.82]), which tended to be better than that between FRAX-NoT and FRAX-DXA (0.76 [0.73-0.79]). Agreement in categorizing participants by hip fracture risk was significantly greater between FRAX-Rho and FRAX-DXA (0.67 [0.63-0.71]) than FRAX-NoT and FRAX-DXA (0.52 [0.48-0.56]). In predicting true incident MOF, FRAX-Rho and FRAX-DXA did not differ in their discriminative power (c-index) (0.76 and 0.77; p = .36); both were significantly greater than that of FRAX-NoT (0.73; p < .004). The accuracy of FRAX-Rho for predicting MOF (Brier Score) was better than FRAX-NoT (p < .05) but not as good as FRAX-DXA. Similar results were observed in participants with thoracic X-rays. In conclusion, FN T-Scores estimated by Rho from lumbar and thoracic X-rays add value to FRAX-NoT estimates and may be useful for risk assessment when DXA is not available.