Zoledronic acid decreases bone formation without causing osteocyte death

Bisphosphonates (BP) have been associated with osteonecrosis of the jaws (ONJ). In biopsy specimens from ONJ patients, empty osteocytes are observed. Objectives: The purpose of this study was to examine the effect of a commonly used potent BP (Zoledronic acid –ZA) on osteocyte viability and bone formation. Methods: C57BL/6 mice (9 experimental, 4 control) were administered ZA (0.01mg/ kg – i.p.) weekly for 9 weeks while control did not receive the drug. A pair of calcein (30 mg/kg) labels was administered 7 days apart, the first being one week after completion of final ZA dose and the second 4 days prior to sacrifice of the 34 week mice. Fresh sections (2 section/site/animal) were obtained to evaluate osteocyte viability from sections of the mandible using the lactate dehydrogenase (LDH) assay. In addition, 2 sections/site/animal from the femur and mandible were prepared for standard histomorphometry in undecalcified unstained sections. The operator was blinded. Data on area of necrosis/total bone area from the mandible LDH sections and bone formation rate (BFR, micron/day) from the femur and mandible were calculated. Mixed models were used to analyze data. Results: The osteocytes were overwhelmingly viable, no necrotic areas were detected in the mandible of both groups. There was a severe suppression (p<0.05) of 93.4% and 92.5% in mean BFR of the femur and mandible respectively, when comparing the ZA with the control group. ZA was not directly cytotoxic to the mouse osteocytes. Development of an animal model for ONJ and understanding effects of ZA on bone modeling and remodeling is crucial. Conclusions: While ZA administration in mice does not produce necrotic osteocytes, it severely suppresses bone formation and such reductions can have a profound effect on bone healing.