Association of Muscle Weakness With Post-Fracture Mortality in Older Men and Women: A 25-Year Prospective Study.

Osteoporotic fracture increases the risk of premature mortality. Muscle weakness is associated with both increased fracture risk and low bone mineral density (BMD). However, the role of muscle strength in post-fracture mortality is not well understood. This study examines the change of muscle strength measured at quadriceps (QS) before and after fracture and defines the relationship between muscle strength and post-fracture mortality. The study involved 889 women and 295 men (who were participating in the Dubbo Osteoporosis Study) who had at least one low-trauma fracture (ascertained from X-ray reports) after the age of 50 years. Median follow-up time was 11 years (range 1 to 24). To determine the change in muscle strength before and after a fracture, we selected a subset of 344 women and 99 men who had had at least two muscle strength measurements before the fracture event and a subset of 407 women and 105 men who had had at least two measurements after the fracture. During the follow-up period, 366 (41.2%) women and 150 (50.9%) men died. The annual rate of decrease in height-adjusted muscle strength before fracture was 0.27 kg/m (1.85%) in women and 0.40 kg/m (1.79%) in men. Strength loss after fracture was not significantly different from that before fracture. In women, after adjusting for baseline age and BMD, each SD (5 kg/m) lower height-adjusted pre- and post-fracture quadriceps strength was associated with a 27% (hazard ratio [HR] = 1.27; 95% confidence interval [CI] 1.07, 1.50) and 18% (HR = 1.18; 95% CI 1.01, 1.38) increase in post-fracture mortality risk, respectively. Similarly, in men, each SD (5 kg/m) lower height-adjusted pre- and post-fracture QS was associated with increased mortality before fracture (HR = 1.33; 95% CI 1.09, 1.63) and after fracture (HR = 1.43; 95% CI 1.16, 1.78). Muscle weakness accounted for 15% (95% CI 0.05, 0.24) of premature deaths after fracture in women and 23% (95% CI 0.11, 0.35) in men. These results indicate that in the older individuals, lower muscle strength is an independent risk factor for post-fracture mortality. © 2017 American Society for Bone and Mineral Research.

Contributions of Caucasian-associated bone mass loci to the variation in bone mineral density in Vietnamese population.

BACKGROUND AND AIM: Bone mineral density (BMD) is under strong genetic regulation, but it is not clear which genes are involved in the regulation, particularly in Asian populations. This study sought to determine the association between 29 genes discovered by Caucasian-based genome-wide association studies and BMD in a Vietnamese population. METHODS: The study involved 564 Vietnamese men and women aged 18 years and over (average age: 47 years) who were randomly sampled from the Ho Chi Minh City. BMD at the femoral neck, lumbar spine, total hip and whole body was measured by DXA (Hologic QDR4500, Bedford, MA, USA). Thirty-two single nucleotide polymorphisms (SNPs) in 29 genes were genotyped using Sequenom MassARRAY technology. The magnitude of association between SNPs and BMD was analyzed by the linear regression model. The Bayesian model average method was used to identify SNPs that are independently associated with BMD. RESULTS: The distribution of genotypes of all, but two, SNPs was consistent with the Hardy-Weinberg equilibrium law. After adjusting for age, gender and weight, 3 SNPs were associated with BMD: rs2016266 (SP7 gene), rs7543680 (ZBTB40 gene), and rs1373004 (MBL2/DKK1 gene). Among the three genetic variants, the SNP rs2016266 had the strongest association, with each minor allele being associated with ~0.02 g/cm(2) increase in BMD at the femoral neck and whole body. Each of these genetic variant explained about 0.2 to 1.1% variance of BMD. All other SNPs were not significantly associated with BMD. CONCLUSION: These results suggest that genetic variants in the SP7, ZBTB40 and MBL2/DKK1 genes are associated with BMD in the Vietnamese population, and that the effect of these genes on BMD is likely to be modest.

Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk.

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or -4.0 to -1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD-associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies.