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

by Ponnapakkam, T.; Katikaneni, R.; Nichols, T.; Tobin, G.; Sakon, J.; Matsushita, O.; Gensure, R. C.

Background: 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. Aim: We tested whether a single dose of the anabolic agent PTH linked to a collagen binding domain (PTH-CBD) could prevent the effects of CYP-induced bone loss. Methods: 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. Results: 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/I in mice without chemotherapy, p<0.05), consistent with osteoporosis from impaired bone formation. Administration of a single dose of PTH-CBD (320 mu g/kg ip) prior to CYP treatment improved BMD (change from baseline: 23.4 +/- 5.4 vs CYP treatment alone, p<0.05) and increased alkaline phosphatase levels (50.14 +/- 4.86 vs 42.78 +/- 6.06 IU/I in CYP treatment alone, p<0.05). BMD values and alkaline phosphatase levels were restored to those seen in mice not receiving chemotherapy. Conclusions: A single dose of PTH-CBD prior to chemotherapy reversed CYP-induced suppression of bone formation and prevented CYP-induced bone loss in mice.

Journal of Endocrinological Investigation
Start Page
1720-8386; 0391-4097