Skeletal dysplasia and lethality in mice lacking the mid-region, nuclear localization signal and C-terminus of parathyroid hormone-related protein

Introduction: Age-related bone loss is associated with high levels of adipogenesis within the bone marrow. Since osteoblasts and adipocytes share a common marrow stromal cell precursor, it is possible that with aging, there is a preferential “switch” in commitment of this precursor to the adipocyte over the osteoblast lineage. Previously, we have reported a potential anabolic effect of bisphosphonates through the stimulation of osteoblastogenesis and inhibition of adipogenesis in vitro (Alendronate has an anabolic effect on bone through the differentiation of mesenchymal stem cells. Duque G, Rivas D. J Bone Miner Res. 2007, 22:1603–11). In the current study, we tested the hypothesis that the effect of bisphosphonates on marrow adipogenesis in vitro is also present 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 (placebo, n=18, risedronate, n=14). Biopsies were stained with toluidine blue and hematoxylin/eosin. Adipocyte volume/tissue volume (AV/TV) adipocyte number (Ad#) and mean adipocyte size were quantified. Results: In the placebo group AV/TV and Ad# significantly increased (<15%). In contrast, there were significant decreases in these parameters (<28%) in the risedronate group (p<0.01). In addition, mean adipocyte size was significantly reduced (<25%) in the risedronate group (p<0.01) at 3 years. Conclusion: Risedronate reduces marrow adipogenesis in postmenopausal women, independently of its effect on bone mass. These findings are the first demonstration of an effect of bisphosphonates on marrow fat in humans in vivo. This effect may contribute to the beneficial effect of bisphosphonates on bone mass. (1) Alendronate has an anabolic effect on bone through the differentiation of mesenchymal stem cells. Duque G, Rivas D. J Bone Miner Res. 2007, 22:1603–11.