Bone fractures result in significant morbidity, mortality, and lost productivity worldwide. Little has been done to improve fractures with pharmaceuticals. Current therapeutics have limitations due to invasive administration routes, side effects, or inefficacy. We have developed a potent, nontoxic fracture-targeted bone anabolic agent that, following systemic injection, accumulates selectively on a bone fracture surface and accelerates the rate of fracture repair. The targeted therapy avoids invasive surgery and improves fracture repair rate and quality without promoting ectopic bone growth or altering healthy nontargeted bones. It also allows for repeated administration.
Our targeted anabolic agent is constructed of a bone mineral hydroxyapatite-targeting oligopeptide conjugated to the non-signaling end of an engineered parathyroid hormone-related protein fragment 1-46 with substitutions at Glu22,25, Leu23,28,31, Aib29, and Lys26,30 (ePTHrP). The negatively-charged oligopeptide has been shown to target raw hydroxyapatite with remarkable specificity, while the attached PTHrP induces sustained and accelerated bone growth. We have repeatedly demonstrated the ability of this conjugate to accelerate bone fracture repair in multiple animal models of bone healing. In adult murine midshaft femoral fracture model (n=15), we observed a significant increase in fracture callus size, doubling in callus bone density, and a two-fold increase in callus bone deposition. After three weeks of treatment in the targeted-ePTHrP group over the saline group (P<0.01), we observed an increase in maximum force withstood and a six-fold increase in work-to-fracture. In a bilateral ulnar ostectomy (1cm) in adult beagle studies, we observed a closure of the ostectomy gap seven times as fast as saline controls (P<0.05). Additionally, no significant differences in weight or in a histological evaluation of the organs were observed in the treatment vs. saline controls. Fracture-targeted parathyroid hormone agonist is an effective pharmaceutical for bone repair in both murine and canine models and offers a promising potential therapeutic.