Efficacy of Locally Delivered Parathyroid Hormone for Treatment of Critical Size Bone Defects

摘要

Large segmental defects in bone (e.g., due to trauma or tumor resection) commonly have complications or fail to heal properly, resulting in delayed or non-union. Around 2.2 million orthopaedic procedures utilize autografts or allografts each year to repair large defects; however, neither is without disadvantages. Disability due to orthopaedic injury has a significant impact on both the patient and the healthcare system. Quality of life for these patients can be severely impacted as healing time may exceed 9 months and multiple treatment attempts may be required if the first is unsuccessful. Research into bone graft substitutes, like InfuseRTM and OP-1 RTM (Bone Morphogenetic Protein and a collagen sponge), has become prominent. PTH is another bioactive molecule that may promote bone regeneration and provide an alternative to autograft and BMP use for treatment of large segmental defects and non-unions. Daily injections of PTH are well known to have an anabolic effect on bone and are presently FDA approved for use as an osteoporosis treatment that results in increases in both bone mineral density and bone volume. Off label PTH 1-84 treatment also resulted in the healing of a non-union fracture that was unresponsive to BMP. Current FDA approval is for daily injections of PTH (intermittent administration), as continuously elevated PTH often has a catabolic effect on bone. However, post-menopausal women with mild primary hyperparathyroidism (PTH levels are not as severely elevated) demonstrate trabecular bone preservation. Low levels of continuous PTH have also been shown to increase bone formation rate and marrow vascularity in mice. Thus, there is some evidence to suggest that low dose continuous PTH could be beneficial as an anabolic therapy in bone and may enhance bone regeneration. Continuously released, locally delivered PTH has been shown to improve healing/formation around dental implants in dogs and drill defects in sheep. However, dose response to local continuously delivered PTH is still unknown. Whether or not the benefits of PTH treatment observed in these models translate to critical size defect models is also unknown. The contribution of the research described in this dissertation increases understanding of the effects of locally delivered PTH on osteoblasts as well as its potential to enhance bone regeneration in a critical size long bone defect. This contribution is significant because presently the effects of low dose continuous PTH are not well understood. Continued development of the approaches described herein could lead to improved therapies for treatment of non-union and critical size defects in bone. Bone regeneration through locally delivered parathyroid hormone has the potential to improve functional restoration, even beyond that of allografts and without the drawbacks of current treatments, which would improve the quality of life for patients.