Treating osteoporosis by targeting parathyroid hormone to bone.

Osteoporosis is a major public health problem despite widespread use of bisphosphonate therapy. PTH(1-34) is a more effective treatment; but its use has been limited by side effects (hypercalcemia, tumor risk) and inconvenient dosing (daily injection). Long-acting forms of PTH are also effective but cause severe hypercalcemia, presumably from effects in kidney. We hypothesized that targeted delivery of PTH to bone using a collagen binding domain (PTH-CBD) could reduce hypercalcemia. PTH-CBD is cleared from serum within 12hours after subcutaneous administration. In ovariectomized rats, monthly administration of PTH-CBD increased spinal BMD by 14.2% with no associated hypercalcemia. Such bone-targeted anabolic agents may ultimately allow the superior efficacy of anabolic therapy to be obtained with the dosing convenience of bisphosphonates.

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

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 (PTHCBD) 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/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. CONCLUSIONS: A single dose of PTHCBD prior to chemotherapy reversed CYP-induced suppression of bone formation and prevented CYP-induced bone loss in mice.

Monthly administration of a novel PTH-collagen binding domain fusion protein is anabolic in mice.

We synthesized fusion proteins of parathyroid hormone (PTH) (1-33) and the collagen binding domain of ColH (CBD) and tested them for anabolic bone activity in mice. Two fusion proteins were synthesized, linking the carboxy terminus of PTH(1-33) either directly to the amino terminal of the CBD or to the CBD through an adjacent ColH domain (PTH-PKD-CBD). Both PTH-CBD and PTH-PKD-CBD increased cAMP accumulation in cells stably transfected with the PTH/PTHrP receptor, and both peptides bound to type 1 collagen in flow-through assays. Distribution studies indicated that the PTH-CBD was concentrated in the bone and skin, tissues with abundant collagen and blood flow. Administration of 320 µg/kg PTH-CBD either weekly (for 8 weeks) or monthly (for 6 months) to 7-week-old C57BL/6J mice resulted in a sustained increase in bone mineral density (BMD) (15% for weekly studies, 13% for monthly studies; P < 0.05). PTH-PKD-CBD showed only 5% increases in BMD after weekly administration, and, as expected, neither weekly nor monthly PTH(1-34) affected BMD. PTH-CBD increased serum alkaline phosphatase levels. Importantly, there were no significant increases in serum calcium observed. Collectively, the data suggest that PTH-CBD has a sustained anabolic effect in bone with either weekly or monthly administration. This approach of targeted delivery of PTH to bone may show promise for the treatment of disorders of low bone mass, such as postmenopausal osteoporosis.