Department of Pediatric Endocrinology, Children's Hospital at Montefiore and Albert Einstein College of Medicine, Bronx, NY, USA.
J Endocrinol Invest. 2011 Dec;34(11):e392-7. doi: 10.3275/7864. Epub 2011 Jul 12.
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.
大多数化疗药物通过引起性腺抑制来降低骨密度（BMD）并增加骨折风险，性腺抑制反过来又会增加骨质流失。环磷酰胺（CYP）还具有直接抑制骨形成和骨吸收的作用，使得由此产生的骨质流失特别难以用抗吸收治疗来治疗。
我们测试了一种与胶原结合域（PTHCBD）连接的合成代谢剂 PTH 是否可以预防 CYP 引起的骨质流失的影响。
小鼠接受缓冲液、CYP 或 CYP+PTH-CBD 治疗。每两周测量一次 BMD 和碱性磷酸酶，总共 8 周。
6 周后，接受 CYP 治疗的小鼠出现预期的 BMD 降低（与无化疗组相比，从基线增加：7.4 ± 6.9%对 24.35 ± 4.86%，p<0.05）和碱性磷酸酶水平降低（42.78 ± 6.06%对 60.62 ± 6.23 IU/l 在无化疗组中，p<0.05），这与骨形成受损导致的骨质疏松一致。在 CYP 治疗前给予单次剂量的 PTH-CBD（320 μg/kg ip）可改善 BMD（与 CYP 单独治疗相比，从基线变化：23.4 ± 5.4%对 7.4 ± 6.9%，p<0.05）和增加碱性磷酸酶水平（50.14 ± 4.86%对 42.78 ± 6.06 IU/l 在 CYP 单独治疗中，p<0.05）。BMD 值和碱性磷酸酶水平恢复到未接受化疗的小鼠的水平。
化疗前单次给予 PTHCBD 逆转了 CYP 对骨形成的抑制作用，并预防了 CYP 引起的小鼠骨质流失。
