Intermittent PTH(1–34) does not increase union rates in open rat femoral fractures and exhibits attenuated anabolic effects compared to closed fractures

Abstract

Intermittent Parathyroid Hormone (PTH)(1–34) has an established place in osteoporosis treatment, but also shows promising results in models of bone repair. Previous studies have been dominated by closed fracture models, where union is certain. One of the major clinical needs for anabolic therapies is the treatment of open and high energy fractures at risk of non-union. In the present study we therefore compared PTH(1–34) treatment in models of both open and closed fractures.108 male Wistar rats were randomly assigned to undergo standardized closed fractures or open osteotomies with periosteal stripping. 27 rats in each group were treated s.c. with PTH(1–34) at a dose of 50 μg/kg 5 days a week, the other 27 receiving saline. Specimens were harvested at 6 weeks for mechanical testing (n=17) or histological analysis (n=10).In closed fractures, union by any definition was 100% in both PTH(1–34) and saline groups at 6 weeks. In open fractures, the union rate was significantly lower (p<0.05), regardless of treatment. In open fractures the mechanically defined union rate was 10/16 (63%) in saline and 11/17 (65%) in PTH(1–34) treated fractures. By histology, the union rate was 3/9 (33%) with saline and 5/10 (50%) with PTH(1–34). Radiological union was seen in 13/25 (52%) for saline and 15/26 (58%) with PTH(1–34).Open fractures were associated with decreases in bone mineral content (BMC) and volumetric bone mineral density (vBMD) on quantitative computerized tomography (QCT) analysis compared to closed fractures. PTH(1–34) treatment in both models led to significant increases in callus BMC and volume as well as trabecular bone volume/total volume (BV/TV), as assessed histologically (p<0.01). In closed fractures, PTH(1–34) had a robust effect on callus size and strength, with a 60% increase in peak torque (p<0.05). In the open fractures that united and could be tested, PTH(1–34) treatment also increased peak torque by 49% compared to saline (p<0.05).In conclusion, intermittent PTH(1–34) produced significant increases in callus size and strength in closed fractures, but failed to increase the rate of union in an open fracture model. In the open fractures that did unite, a muted response to PTH was seen compared to closed fractures. Further research is required to determine if PTH(1–34) is an appropriate anabolic treatment for open fractures.