Sex-dependent and long-term effects of cisplatin on bone mineral density in juvenile mice.
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BACKGROUND: Cisplatin is an anti-neoplastic treatment widely used to treat pediatric cancers. Negative effects of cisplatin treatment on bone mass have previously been reported; however, long-term effects of cisplatin on skeletal health and potential sex differences have largely been unexplored. METHODS: Four-week-old BALB/c mice were treated with cisplatin (4 mg/kg, intraperitoneally, twice weekly for four weeks). At 13 weeks of age, we assessed structural changes in the tibiofemoral region using microcomputed tomography. We also quantified, using immunohistochemistry and confocal microscopy, the density of tartrate-resistant acid phosphatase+ (TRAcP+) osteoclasts, sclerostin+ osteocytes, and osterix+ (OSX+) osteoblasts, within the femoral metaphysis of female and male mice treated with cisplatin during the juvenile period. RESULTS: At 13 weeks of age, both female and male mice treated with cisplatin showed a significantly greater decrease in trabecular, but not cortical, bone mass in the tibiofemoral region than saline-treated mice. This decrease in trabecular bone mass was significantly greater in females than in males. The density of TRAcP+ osteoclasts on the trabecular surfaces of the femur was higher in mice treated with cisplatin than in those in the saline group, independent of sex. Cisplatin treatment did not alter the density of sclerostin+ osteocytes or OSX+ osteoblasts in the femoral metaphyseal bone marrow compared with the saline group. CONCLUSION: These findings suggest that cisplatin induced sex-dependent and long-term complications in the skeletal system, which may partially explain the greater incidence of fractures in childhood cancer survivors.