Soft Tissue Composition, Cardiometabolic Health, and Bone Outcomes During Adolescence and Older Adulthood

Abstract

Adolescence and older adulthood are two critical periods for bone health. Adolescence is a period of rapid bone accrual with bone mass peaking in the second decade of life. Bone is then continuously remodeled throughout adulthood where, with aging, the rate of bone resorption begins to outpace bone formation leading to a net loss in bone. The slow decline in bone mass during adulthood puts older adults at an increased risk for osteoporosis, with women being particularly susceptible to osteoporosis due to 1) having lower peak bone mass compared to men and 2) accelerated bone loss with the onset of menopause. Approximately 60-80% of peak bone mass is genetically determined; however, lifestyle factors (e.g., physical activity, adequate diet) can also influence osteoporosis risk. It is well accepted that being underweight increases the risk for osteoporosis, but the influence of obesity on osteoporosis risk remains controversial. This is significant given the high obesity rates in adolescents and adults. It was previously thought that obesity is protective against osteoporosis due to the additional strain that excess body weight places on the bone, but more recent research suggests that excess adiposity is associated with an increase in fracture risk. The conflicting findings may be due to the use of non-specific measures for obesity, such as body mass index (BMI), which do not directly measure total body fat mass nor account for the physiological differences between adipose tissue depots. Increased visceral adipose tissue (VAT) may be particularly important in explaining the relationship between obesity and osteoporosis due to its role in the development of metabolic dysfunction (e.g., chronic inflammation, insulin resistance). Data from two studies, the Soft Tissue And bone development in young giRls (STAR) study (adolescents) and the UK Biobank (older adults), was used to examine the relationship between soft tissue composition and bone parameters during these two critical periods for bone health. Based on data from direct imaging techniques used to measure body composition and bone, our findings from regression analyses show that total body fat mass and visceral adipose tissue may be independent predictors of bone outcomes; however, the strength and direction of these relationships appears to be dependent on sex, menarcheal status, menopausal status, BMI classification, and bone site. To obtain further insight into the putative causal relationship between adiposity and bone, we used Mendelian Randomization to assess the relationship between metabolically “favorable adiposity” (MFA) (percent body fat increasing genetic variants additionally associated with a more favorable metabolic profile) and aBMD. Genetically-predicted MFA was negatively associated with aBMD for the whole body, lumbar spine, femoral neck, and forearm. These findings were counter to the hypothesis and may be in part explained by the fact that several loci comprising the MFA genetic instrument may function in mesenchymal stem cell differentiation which provides insight into the origins of and connections between bone and fat. In conclusion, the current findings show the complexity of the bone-soft tissue relationship and highlight the importance of accounting for lean mass, sex, menarche/menopause, imaging modality, bone site, and degree/distribution of adiposity when assessing the relationship between obesity and bone.