Effects of risedronate on bone marrow adipocytes in postmenopausal women
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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.
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.
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 (PPARγ2) within the bone marrow were quantified using immunohistochemistry.
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 PPARγ2 expression in the bone marrow of risedronate-treated women.
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.
KeywordsAdipocytes Marrow fat Osteoporosis PPARγ Risedronate
This study was supported by a Medical School Grant from Procter and Gamble Pharmaceuticals, USA and by an operating grant from the Nepean Medical Research Foundation. A/Prof. Duque and Dr. Li hold Fellowships from the University of Sydney Medical Research Foundation. The authors would like to thank Mrs. Leigh Bambury for her assistance in the preparation of the manuscript.
Conflicts of interest
A/Prof. Duque is member of the board of speakers for Sanofi Aventis (Australia), Servier (Australia), and Novartis (International). The other authors have no disclosures.
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