Zoledronic acid decreases bone formation without causing osteocyte death in mice

Bisphosphonates have been associated with osteonecrosis of the jaw. The purpose of this study was to examine the effect of a potent bisphosphonate, zoledronic acid (ZA) on osteocyte viability and bone formation. Ten experimental C57BL/6 mice were administered ZA (0.1 mg/kg-i.p.) weekly for 9 weeks while four control mice did not receive the drug. A pair of calcein (30 mg/kg) labels was administered 10 and 3 days prior to sacrifice of the 34-week-old mice. Fresh mandibular and femoral sections were obtained to evaluate osteocyte viability using a lactate dehydrogenase (LDH) assay. In addition, sections from the femur, mandible and maxilla were prepared for standard histomorphometry. The operator was blinded for data collection to eliminate bias. Data on necrotic area/total bone area from the LDH sections were collected. In addition, standard histomorphometric variables including bone formation rate were calculated. Mixed models were used to analyse data. The osteocytes were overwhelmingly viable and no necrotic areas were detected in the mandible and femur of both groups. ZA was not directly cytotoxic to the mouse osteocytes. There was suppression in indices of bone formation at all skeletal sites of the ZA group compared to the control group. While ZA administration in mice does not produce necrotic osteocytes, it severely suppresses bone formation. Such reductions can have a profound effect on bone healing.