Life-course adiposity shapes osteoporosis risk, with adult BMI as the key determinant and mediator of early-life influences, and proteomic analyses reveal molecular pathways linking adiposity, hormonal signaling, immune regulation, and bone metabolism.
Low birth weight was associated with increased incident osteoporosis risk in a prospective cohort of 357,903 UK Biobank participants.
Thinner childhood body size was associated with increased risk of incident osteoporosis.
Adult BMI showed the strongest independent effect on incident osteoporosis risk, with underweight individuals at highest risk and obese individuals at lowest risk.
Adult BMI partially mediated the effects of both birth weight and childhood body size on osteoporosis risk.
Developmental mismatch trajectory analyses revealed that consistently lean or downward discordant adiposity trajectories conferred higher osteoporosis risk, while upward discordance and consistently high adiposity were protective.
Proteomic analyses identified 2,413 BMI-associated and 422 osteoporosis-associated plasma proteins, with 95 proteins mediating the BMI-osteoporosis relationship.
Twenty-two core protein mediators of the BMI-osteoporosis relationship were identified, with ADIPOQ and SOST as the top mediators.
This research suggests that body size throughout life — from birth through childhood and into adulthood — plays an important role in determining whether a person develops osteoporosis (a disease that weakens bones and increases fracture risk). Using data from nearly 358,000 UK adults followed for an average of almost 16 years, researchers found that people who were lighter at birth, thinner as children, or had lower body weight as adults were at higher risk of developing osteoporosis. The risk was particularly striking for underweight adults, who were more than twice as likely to develop osteoporosis compared to normal-weight adults, while people with obesity had about half the risk. Importantly, adult body weight appeared to explain a large portion of why early-life body size affects osteoporosis risk — suggesting that being lean early in life matters partly because it predicts being lean in adulthood. The study also found that the pattern of body size across a person's life matters, not just body size at any single point. People who were consistently lean throughout life, or who became leaner over time, faced the greatest osteoporosis risk. Conversely, people who gained weight over the life course or remained heavier throughout life were more protected from osteoporosis. Using advanced protein analysis of blood samples, the researchers identified 95 specific proteins that help explain the biological link between body weight and bone health, with two proteins — adiponectin (a hormone produced by fat tissue) and sclerostin (a protein involved in bone formation) — playing particularly prominent roles in connecting adiposity to bone metabolism. This research suggests that biological pathways involving fat tissue hormones, immune regulation, and bone metabolism connect body composition to osteoporosis risk throughout the life course. The identification of specific proteins as mediators of this relationship points toward potential targets for future therapeutic interventions and could help inform strategies for identifying people at high osteoporosis risk earlier in life, particularly those who are consistently lean or who lose body weight over time.
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Upload Your LabsLiu H, Zhu J, Zhang Q, Chen J, Huang R. (2026). Life course adiposity and risk of incident osteoporosis: a prospective cohort study from the UK Biobank.. Frontiers in endocrinology. https://doi.org/10.3389/fendo.2026.1839419