Human parathyroid hormone (1–34) accelerates the fracture healing process of woven to lamellar bone replacement and new cortical shell formation in rat femora
Introduction
Intermittent injections of parathyroid hormone (PTH) have potent anabolic effects on bones [1], [2], [3], [4]. PTH increases vertebral bone mass and mechanical strength in normal rats, both young and old, and reverses ovariectomy-induced decreases in bone mass and mechanical strength of vertebral bodies [5], [6], [7], [8], [9], [10]. Histologically, PTH accelerates bone formation and increases trabecular bone mass by thickening trabeculae [5], [11], [12].
Although many effective anti-resorptive agents are available, PTH is the only anabolic agent for the treatment of osteoporosis. In a recent large-scale clinical trial of postmenopausal women with osteoporosis, recombinant human parathyroid hormone (1–34) reduced vertebral fractures by 65% and non-vertebral fractures by 54% [13]. Since osteoporotic patients are prone to fractures, the clinicians must face the situation of fracture occurring in patient under treatment. Therefore, it is getting important to know the effects of agent for osteoporosis treatment on fracture healing. We have previously reported the effect of anti-resorptive agents such as bisphosphonates and selective estrogen receptor modulator (SERM) on fracture healing [14], [15], [16], [17]. These agents delay callus remodeling although restoration of mechanical strength of fractured bone is not impaired.
Although several studies have reported the effect of intermittent treatment of PTH on fracture healing [18], [19], [20], [21], [22], [23], the durations of these experiments were no longer than 8 weeks. However, our previous studies have demonstrated that the fracture healing process of rat femur is not completed at 6 weeks after fracture, thus longer-term observation is required to evaluate the entire process of fracture healing. Furthermore, no geometrical analyses of fracture callus have ever been performed. The aim of this study was to test whether intermittent treatment of human parathyroid hormone [hPTH(1–34)] disturbs or accelerates the fracture healing process, especially callus remodeling, geometrical changes, and mechanical properties. With respect to clinical relevance, this study may answer the question whether hPTH(1–34) treatment should be stopped or continued when fracture occurs in an osteoporotic patient under PTH treatment.
Section snippets
Materials
Female Sprague–Dawley rats (n = 105; 4 weeks of age; Japan SLC, Inc., Hamamatsu, Japan) were acclimated for 1 week to local vivarium conditions (24 ± 2°C and 12-h light–dark cycle). During the experimental period, animals were housed in cages (988 cm2 in floor area and 18 cm in height) and allowed free access to water and pelleted commercial rodent diet (Oriental Yeast Co., Tokyo, Japan). The experimental protocol was approved by the Kagawa University Animal Study Committee.
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Results
No difference in body weight was observed among all groups during the study period. The animals resumed normal activity within a few days after surgery. Of 105 animals that underwent fracture surgery, 11 were excluded because of technical failure in surgery (poor fracture fixation), death during or after surgery, or post surgical infection. Finally, 31, 31, and 32 animals were evaluated and analyzed at 3, 6, and 12 weeks after surgery, respectively.
Discussion
The primary aim of this study was to examine the effect of intermittent treatment of hPTH(1–34), a potent anabolic agent, on the fracture healing process in a rat fracture model. Our results clearly showed that PTH accelerated the remodeling of woven bone to lamellar bone, the formation of new cortical shell, and the increasing of fractured bone strength.
Many studies have confirmed that the rat fracture model is adequate to investigate the fracture healing mechanism and the effects of
Acknowledgments
The authors thank Mika Kawada and Yoshiko Fukuda for histological preparation and Asahi Kasei Co. for kindly supplying the hPTH(1–34).
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