Legacy effects of randomization to caloric restriction and exercise on bone strength in older adults: a pooled analysis

Over 19 million older Americans have obesity, which is associated with disability and poor clinical outcomes. Clinical trials by our group and others show that diet-induced weight loss interventions, particularly when combined with exercise, improve body composition and physical and metabolic function over the short-term in older adults with obesity. However, clinical recommendations for obesity treatment in older age are controversial, as weight loss can exacerbate bone and muscle loss and the long-term risks have not been extensively studied. Musculoskeletal losses could increase the risk of osteoporotic fractures, which confer significant morbidity and mortality. Osteoporosis is assessed clinically using dual energy X-ray absorptiometry, but bone mineral density (BMD) measured by this method is often inaccurate in those with obesity and weight loss. Quantitative computed tomography (QCT) offers a more robust method that reduces measurement errors. Further, bone strength – a QCT and finite element modeling assessment of 3D bone morphology, volumetric BMD, and cortical thickness – is a stronger predictor of fracture risk than BMD alone. Nonetheless, the legacy effects of caloric restriction (CR) and exercise (EX) on biomechanical bone strength in older adults remain largely unquantified. Our proposed project leverages our unique access to five NIH-supported trials that randomized older adults (baseline age ≥60; BMI≥27 kg/m2) to CR+EX vs. EX alone at Wake Forest from 2005 to 2014, and the Health Outcomes after Participating in Exercise (HOPE) study (R01 AG056418; PI: Houston), which recently completed a follow- up of these participants ~10 years after they completed the intervention. Long-term follow-up QCT scans acquired for 272 HOPE participants will be analyzed to determine the long-term effects of prior randomization to CR+EX vs. EX alone on hip and lumbar spine bone strength [Aim 1]. We hypothesize that randomization to CR+EX will result in lower bone strength at long-term follow-up versus EX alone (controls). Aim 1 will also examine the effect of exercise modality on bone strength following CR, and we hypothesize that participants randomized to CR with aerobic training will have lower bone strength at long-term follow-up compared to participants randomized to CR with resistance training. Leveraging measures acquired at baseline, end of the intervention, and long-term follow-up, we will determine associations between change in lean mass and physical performance with long-term bone strength [Aim 2]. We will also assay stored blood specimens from three time points to explore associations between changes in biomarkers of bone formation (P1NP) and bone resorption (CTX-1) with long-term bone strength [Aim 3]. This work will be the first randomized, controlled design to test the legacy effects of caloric restriction and exercise interventions on bone strength in older adults. Results will inform obesity treatment guidelines for older adults and may identify new early musculoskeletal screening biomarkers and intervention targets to shift clinical paradigms for fracture prevention. Project Number: 1R21AG093631-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Ashley Weaver | Institution: WAKE FOREST UNIVERSITY HEALTH SCIENCES, WINSTON-SALEM, NC | Award Amount: $417,545 | Activity Code: R21 | Study Section: Aging, Injury, Musculoskeletal, and Rheumatologic Disorders Study Section[AIMR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11304203