Effects of risedronate on bone marrow adipocytes in postmenopausal women

Summary Aminobisphosphonates promote osteoblastogenesis while inhibiting adipogenesis in vitro. Their effect on adipogenesis in vivo remains unknown. In this study, we demonstrate that risedronate prevents marrow fat infiltration in postmenopausal women after 3 years of treatment. Introduction Age-related bone loss is associated with high levels of adipogenesis within the bone marrow at the expense of osteoblast population. Bisphosphonates stimulate osteoblastogenesis while inhibiting adipogenesis in vitro. In the present study, we tested whether the effect of bisphosphonates on marrow adipogenesis in vitro is also seen in vivo. Methods We analyzed transiliac bone biopsies from a randomized, placebo-controlled clinical trial that evaluated the effects of risedronate treatment 5 mg/day on vertebral and non-vertebral fractures in women with postmenopausal osteoporosis. Paired bone biopsies were obtained from a subset of patients at baseline and after treatment with placebo or risedronate for 3 years (n=14 per group). Biopsies were stained with toluidine blue and hematoxylin/ eosin. Adipocyte volume/tissue volume (AV/TV), mean adipocyte number (AD#), and mean adipocyte diameter (ADdiam) were quantified. Finally, expression levels of the adipogenesis transcription factor peroxisome proliferator activator gamma 2 (PPARم2) within the bone marrow were quantified using immunohistochemistry. Results In the placebo group, AV/TV, AD#, and ADdiam significantly increased after 3 years (~15%, p<0.01). In contrast, ADdiam remained unchanged and AV/TV and AD# were significantly reduced (~20%) in the risedronate group at 3 years (p<0.01). These changes were associated with a significant reduction in PPARم2 expression in the bone marrow of risedronate-treated women. Conclusions Risedronate reduces bone marrow fat in postmenopausal women. These findings are the first demonstration of an effect of bisphosphonates on marrow fat in humans in vivo. By regulating the amount of fat within the bone marrow, this effect may contribute to the beneficial effect of bisphosphonates on bone mass.