Microarchitecture and Peripheral BMD are Impaired in Postmenopausal White Women With Fracture Independently of Total Hip T‐Score: An International Multicenter Study

Because single‐center studies have reported conflicting associations between microarchitecture and fracture prevalence, we included high‐resolution peripheral quantitative computed tomography (HR‐pQCT) data from five centers worldwide into a large multicenter analysis of postmenopausal women with and without fracture. Volumetric BMD (vBMD) and microarchitecture were assessed at the distal radius and tibia in 1379 white postmenopausal women (age 67 ± 8 years); 470 (34%) had at least one fracture including 349 with a major fragility fracture. Age, height, weight, and total hip T‐score differed across centers and were employed as covariates in analyses. Women with fracture had higher BMI, were older, and had lower total hip T‐score, but lumbar spine T‐score was similar between groups. At the radius, total and trabecular vBMD and cortical thickness were significantly lower in fractured women in three out of five centers, and trabecular number in two centers. Similar results were found at the tibia. When data from five centers were combined, however, women with fracture had significantly lower total, trabecular, and cortical vBMD (2% to 7%), lower trabecular number (4% to 5%), and thinner cortices (5% to 6%) than women without fracture after adjustment for covariates. Results were similar at the radius and tibia. Similar results were observed with analysis restricted to major fragility fracture, vertebral and hip fractures, and peripheral fracture (at the radius). When focusing on osteopenic women, each SD decrease of total and trabecular vBMD was associated with a significantly increased risk of major fragility fracture (OR = 1.55 to 1.88, p < 0.01) after adjustment for covariates. Moreover, trabecular architecture modestly improved fracture discrimination beyond peripheral total vBMD. In conclusion, we observed differences by center in the magnitude of fracture/nonfracture differences at both the distal radius and tibia. However, when data were pooled across centers and the sample size increased, we observed significant and consistent deficits in vBMD and microarchitecture independent of total hip T‐score in all postmenopausal white women with fracture and in the subgroup of osteopenic women, compared to women who never had a fracture. © 2016 American Society for Bone and Mineral Research.     

Objectively Verified Parental Hip Fracture Is an Independent Risk Factor for Fracture: a Linkage Analysis of 478,792 Parents and 261,705 Offspring

Parental hip fracture (HF) is considered a major risk factor for offspring major osteoporotic fracture (MOF), but all studies to date have relied on self‐reported information of uncertain accuracy. We tested the association of objectively verified parental HF with offspring MOF and HF. We used a population‐based historical cohort study of 261,705 offspring (age ≥40 years) with at least one linked parent (total 478,792 parents) for the province of Manitoba, Canada. Cox proportional hazards models were developed to test hazard ratio (HR) for offspring MOF and HF for 1997 to 2014 according to prior parental HF dating back to 1970. The median age of offspring at study entry was 40 years (range, 40 to 50 years), and 48.3% were women. During 2.9 million person‐years of offspring follow‐up (median per offspring, 12 years), we identified 7323 incident MOF (4.4% versus 2.7% for those with and without a parental HF, p < 0.001), including 331 HF (0.3% versus 0.1%, p < 0.001). Parental HF was independently associated with increased risk of offspring MOF (HR, 1.30; 95% confidence interval [CI], 1.20 to 1.41). The strength of the association decreased with older parental age at HF (p_trend < 0.001), and was no longer significant if parental HF occurred after age 80 years (adjusted HR, 1.07; 95% CI, 0.96 to 1.19). The relationship between parental HF and offspring HF was even stronger than for MOF (adjusted HR, 1.64; 95% CI, 1.21 to 2.23). Associations with MOF or HF were not affected by either the gender of the parent with HF or the gender of the offspring. Parental HF increased the risk for offspring MOF and HF but not when parental HF occurred after age 80 years. This suggests a more nuanced approach for clinicians trying to stratify fracture risk, and illustrates the enormous potential of parent‐offspring record linkage for other familial disorders. © 2016 American Society for Bone and Mineral Research.     

Identification of IDUA and WNT16 Phosphorylation‐Related Non‐Synonymous Polymorphisms for Bone Mineral Density in Meta‐Analyses of Genome‐Wide Association Studies

Protein phosphorylation regulates a wide variety of cellular processes. Thus, we hypothesize that single‐nucleotide polymorphisms (SNPs) that may modulate protein phosphorylation could affect osteoporosis risk. Based on a previous conventional genome‐wide association (GWA) study, we conducted a three‐stage meta‐analysis targeting phosphorylation‐related SNPs (phosSNPs) for femoral neck (FN)‐bone mineral density (BMD), total hip (HIP)‐BMD, and lumbar spine (LS)‐BMD phenotypes. In stage 1, 9593 phosSNPs were meta‐analyzed in 11,140 individuals of various ancestries. Genome‐wide significance (GWS) and suggestive significance were defined by α = 5.21 × 10^–6 (0.05/9593) and 1.00 × 10^–4, respectively. In stage 2, nine stage 1–discovered phosSNPs (based on α = 1.00 × 10^–4) were in silico meta‐analyzed in Dutch, Korean, and Australian cohorts. In stage 3, four phosSNPs that replicated in stage 2 (based on α = 5.56 × 10^–3, 0.05/9) were de novo genotyped in two independent cohorts. IDUA rs3755955 and rs6831280, and WNT16 rs2707466 were associated with BMD phenotypes in each respective stage, and in three stages combined, achieving GWS for both FN‐BMD (p = 8.36 × 10^–10, p = 5.26 × 10^–10, and p = 3.01 × 10^–10, respectively) and HIP‐BMD (p = 3.26 × 10^–6, p = 1.97 × 10^–6, and p = 1.63 × 10^–12, respectively). Although in vitro studies demonstrated no differences in expressions of wild‐type and mutant forms of IDUA and WNT16B proteins, in silico analyses predicts that WNT16 rs2707466 directly abolishes a phosphorylation site, which could cause a deleterious effect on WNT16 protein, and that IDUA phosSNPs rs3755955 and rs6831280 could exert indirect effects on nearby phosphorylation sites. Further studies will be required to determine the detailed and specific molecular effects of these BMD‐associated non‐synonymous variants. © 2015 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

Country-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 Kendall's 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.     

Disruption of BMP Signaling Prevents Hyperthyroidism-Induced Bone Loss in Male Mice

Thyroid hormones (TH) are key regulators of bone health, and TH excess in mice causes high bone turnover–mediated bone loss. However, the underlying molecular mechanisms of TH actions on bone remain poorly defined. Here, we tested the hypothesis whether TH mediate their effects via the pro-osteogenic bone morphogenetic protein (BMP) signaling pathway in vitro and in vivo. Primary murine osteoblasts treated with 3,3′,5-triiodo-L-thyronine (T₃) showed an enhanced differentiation potential, which was associated with activated canonical BMP/SMAD signaling reflected by SMAD1/5/8 phosphorylation. Blocking BMP signaling at the receptor (LDN193189) and ligand level (noggin, anti-BMP2/BMP4 neutralizing antibodies) inhibited T₃-induced osteogenic differentiation. In vivo, TH excess over 4 weeks in male C57BL/6JRj mice led to severe trabecular bone loss with a high bone turnover that was completely prevented by treatment with the BMP ligand scavenger ALK3-Fc. Thus, TH activate the canonical BMP pathway in osteoblasts to promote their differentiation and function. Importantly, this study indicates that blocking the BMP pathway may be an effective strategy to treat hyperthyroidism-induced bone loss. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Metabolomic Pathways to Osteoporosis in Middle‐Aged Women: A Genome‐Metabolome‐Wide Mendelian Randomization Study

The metabolic state of the body can be a major determinant of bone health. We used a Mendelian randomization approach to identify metabolites causally associated with bone mass to better understand the biological mechanisms of osteoporosis. We tested bone phenotypes (femoral neck, total hip, and lumbar spine bone mineral density [BMD]) for association with 280 fasting blood metabolites in 6055 women from TwinsUK cohort with genomewide genotyping scans. Causal associations between metabolites and bone phenotypes were further assessed in a bidirectional Mendelian randomization study using genetic markers/scores as instrumental variables. Significant associations were replicated in 624 participants from the Hong Kong Osteoporosis Study (HKOS). Fifteen metabolites showed direct associations with bone phenotypes after adjusting for covariates and multiple testing. Using genetic instruments, four of these metabolites were found to be causally associated with hip or spine BMD. These included androsterone sulfate, epiandrosterone sulfate, 5alpha‐androstan‐3beta17beta‐diol disulfate (encoded by CYP3A5), and 4‐androsten‐3beta17beta‐diol disulfate (encoded by SULT2A1). In the HKOS population, all four metabolites showed significant associations with hip and spine BMD in the expected directions. No causal reverse association between BMD and any of the metabolites were found. In the first metabolome‐genomewide Mendelian randomization study of human bone mineral density, we identified four novel biomarkers causally associated with BMD. Our findings reveal novel biological pathways involved in the pathogenesis of osteoporosis. © 2017 American Society for Bone and Mineral Research.