During median follow-up 6.0 years in 9622 individuals, prior loss in estimated total body lean mass (TBLM), but not total body fat mass loss (TBFM), was associated with increased fracture risk, particularly for hip fracture. INTRODUCTION: Weight loss, and especially muscle loss, adversely affects skeletal health. The FRAX® tool considers baseline body mass index, but not body composition nor changes in its components over time. Our aim was to compare the independent associations between prior loss in DXA-estimated TBLM and TBFM and subsequent fracture risk. METHODS: We identified women and men age 40 years or older with two DXA assessments at least 1 year apart (median interval 3.3 years). TBLM and TBFM were estimated from weight, sex, and DXA of the spine and hip. Incident fractures and deaths were ascertained from linked population-based health service data after the date of the second DXA. Hazard ratios (HRs) from Cox regression models were used to study time to fracture from prior loss in TBLM and TBFM adjusted for FRAX-related covariates. RESULTS: The study population consisted of 9622 individuals (mean age 67 [SD 10] years, 95% female). We identified 692 subjects with incident major osteoporotic fracture [MOF] and 194 with hip fracture. Mean TBLM loss was significantly greater in those with incident MOF and hip fracture (P < 0.001) while TBFM loss was only significantly greater in those with incident hip fracture (P < 0.001). Each SD greater TBLM loss was associated with 10-13% increased MOF risk and 29-38% increased hip fracture risk, adjusted for TBFM loss and other covariates. Prior TBFM loss was not associated with fractures when adjusted for TBLM loss. CONCLUSIONS: Prior loss in total body lean mass, but not in fat mass, is associated with increased fracture risk, particularly hip fracture, independent of other risk factors. This is consistent with the hypothesis that muscle loss (sarcopenia) adversely impacts skeletal health and fracture risk.