Prevention of chemotherapy-induced osteoporosis by cyclophosphamide with a long-acting form of parathyroid hormone.

Abstract

Most chemotherapeutics reduce bone mineral density (BMD) and increase risk for fractures by causing gonadal suppression, which in turn increases bone removal. Cyclophosphamide (CYP) also has a direct effect of inhibiting bone formation and removal, making the resulting bone loss particularly difficult to treat with antiresorptive therapy. We tested whether a single dose of the anabolic agent PTH linked to a collagen binding domain (PTHCBD) could prevent the effects of CYP-induced bone loss. Mice received either buffer alone, CYP, or CYP+ PTH-CBD. BMD and alkaline phosphatase were measured every 2 weeks for a total of 8 weeks. After 6 weeks, mice treated with CYP showed expected reductions in BMD (increase from baseline: 7.4 ± 6.9 vs 24.35 ± 4.86% in mice without chemotherapy, p<0.05) and decrease in alkaline phosphatase levels (42.78 ± 6.06 vs 60.62 ± 6.23 IU/l in mice without chemotherapy, p<0.05), consistent with osteoporosis from impaired bone formation. Administration of a single dose of PTH-CBD (320 μg/kg ip) prior to CYP treatment improved BMD (change from baseline: 23.4 ± 5.4 vs 7.4 ± 6.9%, CYP treatment alone, p<0.05) and increased alkaline phosphatase levels (50.14 ± 4.86 vs 42.78 ± 6.06 IU/l in CYP treatment alone, p<0.05). BMD values and alkaline phosphatase levels were restored to those seen in mice not receiving chemotherapy. A single dose of PTHCBD prior to chemotherapy reversed CYP-induced suppression of bone formation and prevented CYP-induced bone loss in mice.