Obesity and Bone Health Revisited: A Mendelian Randomization Study for Koreans

Epidemiologic studies have replicated positive associations between obesity and bone health, but their mechanisms are still debatable. We aimed to scrutinize an association between bone health and obesity using genetic instrumental variables (IVs) with the distinction of general versus abdominal obesity. We selected independent IVs of body mass index (BMI) and BMI-adjusted waist circumference (aWC, a proxy of a central fat distribution) by combining novel genomewide searches from the Korean Genome Epidemiology Study (KoGES) consortium and existing reports. We evaluated the associations of obesity indices with bone health measures for weight-bearing and non-weight-bearing bones, applying standard Mendelian randomization analyses. The IVs for BMI and aWC selected from KoGES cohort studies (n = 14,389) explained its own trait only, negating the mutual correlation at the phenotypic level. Two-stage least squares analyses using an independent cohort study (n = 2507, mean age = 44.4 years, men = 44.3%) showed that BMI but not aWC was positively associated with bone mineral density (BMD for weight-bearing bones: 0.063 ± 0.016 g/cm² per one standard deviation increase in BMI), implying the fat distribution might be neutral. The association was weaker for non-weight-bearing bones (BMI on BMD: 0.034 ± 0.011 g/cm² ), and for postmenopausal women the association was absent. Obesity increased both bone area and bone mineral content (BMC) to a lesser degree, but the increase in BMC was not evident for menopausal women. When we stratified the weight into lean body mass and fat mass, the increase in BMD was more evident for lean body mass, and fat mass showed a beneficial role only for men and premenopausal women. Our findings suggest that bone health might gain little from obesity, if any, through its added weight, and other means to prevent bone loss would be essential for postmenopausal women. © 2019 American Society for Bone and Mineral Research.