Teriparatide as an alternative treatment modality in nonspontaneous bisphosphonate related osteonecrosis of the jaws (BRONJ): a rat model

Bisphosphonates (BP) are widely used in several metabolic and malignant bone diseases because of their antiresorptive effect on bone. Bisphosphonate related osteonecrosis of the jaws (BRONJ) presents as a serious side effect of nitrogen containing bisphosphonates. Some studies indicated the healing effect of teriparatide (TP) in refractory BRONJ cases, which do not respond conservative treatment. The objective of this study is to establish the role of teriparatide in treatment of bisphosphonate related osteonecrosis of the jaw in a zoledronic acid (ZA) induced rat BRONJ model. Study Design Thirty adult female Sprague-Dawley rats were divided randomly in three groups: I- ZA (n=10), II- ZA+TP (n=10), and III- Control (CON, n=10). BRONJ was induced by administering zoledronic acid 3 times a week for 6 weeks intraperitoneally to groups ZA and ZA+TP. Saline was administered to the CON group intraperitoneally. A week after the injections, rats underwent extraction of the mandibular left first molar teeth. Following a 4 weeks period teriparatide was administered subcutaneously to rats in group ZA+TP for 28 days. Extraction sockets were examined clinically, radiologically and histopathologically. Results Clinical examination revealed mucosal ulceration, sinus tract formation, necrotic bone exposure or apparent infection in the region of extraction socket in none of the animals. In terms of weight measurements, prior to sacrificing, measurements of CON group was greater than ZA group (p<0.05). Radiological examination, performed with micro Computed Tomography (µCT) showed that volumetric bone mineral density (vBMD) of ZA group measured in the extraction sockets, was lower than the vBMD of ZA+TP VI group (p<0.05). Histopathological examination revealed that animals in groups ZA and ZA+TP, which were injected with zoledronic acid developed osteonecrosis, whereas no osteonecrosis developed in the CON group. Histomorphometric measurements of the osteonecrotic bone showed that, in ZA group osteonecrotic bone area was larger compared to ZA+TP group (p<0.05). Tartrate resistant acid phosphatase (TRAcP) enzyme histochemistry, performed to visualize osteoclasts, revealed that in ZA+TP ve CON groups the number of osteoclasts attached to the bone surface and the bone surface area occupied with osteoclasts were greater compared to ZA group (p<0.05). The number of TRAcP positive apoptotic and giant osteoclasts were higher in ZA group (p<0.05). Conclusion Our data suggest that teriparatide might be an effective treatment modality for BRONJ patients. Keywords: Bisphosphonate, Osteonecrosis, Teriparatide, µCT, TRAcP