Assessing the causal influence of biomechanical factors on osteoporosis risk: A multivariable Mendelian randomization investigation.

While observational studies indicate correlations between multiple biomechanical traits and osteoporosis, causal inference has been constrained, impeding the clinical application of these measures in risk stratification. This Mendelian randomization (MR) study examines causal associations of ankle spacing width (ASW), height, body mass index (BMI), grip strength, and usual walking pace with bone mineral density (BMD) across skeletal sites and age groups. Genetic proxies for the exposures were derived from the Medical Research Council Integrative Epidemiology Unit and UK Biobank resources. Genetic association estimates for the outcomes were acquired from the Genetic Factors for Osteoporosis Consortium. Two-sample and multivariable MR analyses were applied to infer causality. Genetically proxied ASW (encompassing left, right, and combined measures) and height showed an inverse association with estimated BMD (eBMD; Beta < 0, P. adjusted < .05). In contrast, genetically predicted BMI was associated with an increase in eBMD (Beta > 0, P. adjusted < .05). Moreover, genetically predicted ASW was linked to lower total body BMD, with the inverse association being most pronounced in the 0 to 15 years age group. Multivariable MR analyses confirmed that ASW remained independently associated with both eBMD and total body BMD after adjusting for confounding factors. Our findings offer genetic evidence indicative of a causal detrimental effect of ASW and height on BMD, especially during early life stages, whereas BMI demonstrates a potentially protective causal role.