| Title: | Life course adiposity and risk of incident osteoporosis: a prospective cohort study from the UK Biobank |
| Journal: | Frontiers in Endocrinology |
| Published: | 28 Aug 2026 |
| DOI: | https://doi.org/10.3389/fendo.2026.1839419 |
| URL: | http://dx.doi.org/10.3389/fendo.2026.1839419 |
Publication 20864
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Abstract
Adiposity across the life course may influence osteoporosis (OP) risk, yet the relative contributions of early-life and adult adiposity, their trajectories, and underlying molecular mechanisms remain unclear. We analyzed 357,903 participants from the UK Biobank with a median follow-up of 15.7 years. Life-course adiposity was assessed via birth weight, childhood body size, and adult BMI. Associations with incident OP were evaluated using Cox models, restricted cubic splines, and mediation analyses. Developmental mismatch trajectories were constructed to examine cumulative or discordant effects of adiposity. Plasma proteomics was used to identify molecular mediators of adult BMI on OP risk. During follow-up, 11,905 participants (3.3%) developed OP, predominantly women (82%). Low birth weight, thinner childhood body size, and lower adult BMI were associated with increased incident OP risk, with adult BMI showing the strongest independent effect (underweight HR = 2.41; overweight HR = 0.63; obesity HR = 0.50). Mediation analyses indicated that adult BMI partially accounted for the effects of birth weight (67.1%) and childhood body size (56.1%) on OP. Developmental mismatch analyses revealed that consistently lean or downward discordant trajectories conferred higher OP risk, whereas upward discordance and consistently high adiposity were protective. Proteomic analyses identified 2,413 BMI-associated and 422 OP-associated plasma proteins, with 95 proteins mediating the BMI-OP relationship. Protein-protein interaction and pathway enrichment analyses highlighted 22 core mediators-including ADIPOQ (25.6% mediation) and SOST (16.7%)-involved in metabolic, endocrine, immune, and bone pathways. Life-course adiposity shapes OP risk, with adult BMI as a key determinant and mediator of early-life influences. Proteomic analyses reveal molecular pathways linking adiposity, hormonal signaling, immune regulation, and bone metabolism, offering potential therapeutic targets. These insights advance understanding of OP pathogenesis and may inform early risk stratification and targeted prevention strategies.</p>
5 Authors
- Huimin Liu
- Jicun Zhu
- Qiang Zhang
- Jiajun Chen
- Ruoyao Huang
1 Application
| Application ID | Title |
|---|---|
| 772449 | Integrating Multi-Omics and Imaging Data for Mechanistic Insights and Risk Prediction in Disease Pathogenesis |
Enabling scientific discoveries that improve human health