Long-term effects of Zoledronic acid on alveolar bone remodeling and quality in the jaw of an oncological rat model

Abstract

Despite great interest in bisphosphonate-induced osteonecrosis of the jaw (ONJ), the underlying pathology remains a matter of debate. In most reports, the etiology of ONJ seems to be ascribed to bisphosphonate-related over suppression of bone remodeling. While suppression of bone remodeling is indeed the prime action mechanism of bisphosphonates, the destructive ONJ effects at the level of the jaw bone are ignored or minimalized when prescribing these drugs. The present study therefore investigated the long-term effects of oncological Zoledronic Acid (ZA) doses on the three factors which may comprise jaw bone:(1) bone quantity, (2) bone structure and (3) bone mineral density (BMD). Twentyfour, healthy, Wistar rats were randomly divided in an experimental group (n = 12) receiving 0.6 mg/kg body weight/month ZA and a control group (n = 12) receiving an equal volume of saline for 5 consecutive months. The ZA doses were equivalent to the doses given to oncologic patients. After animal sacrifice, their mandibles were ex vivo scanned using 1174 micro-CT (Bruker) and the obtained scans were spatially aligned. One mean volume of interest containing only trabecular bone below the apex of the molars was selected, in which 3D quantitative morphometry and BMD were calculated using CT-Analyser (Bruker). Structural-related parameters showed significantly (P < 0.001) increased osteoslerotic characteristics of the alveolar bone (↑ Tb.Pf; ↓ Tb.Sp; ↓Tb.N; ↓ SMI; ↓ Conn.Dn) in ZA-treated rats as compared to the controls. These findings were confirmed by a significantly (P < 0.001) increased bone quantity (↑ BV/TV; ↑ Tb.Th; ↓ BS/TV; ↓ Po[tot]). Finally, the alveolar bone displayed a significantly (P < 0.001) higher BMD after prolonged ZA therapy. These results are strongly supportive for bisphosphonateinduced oversuppression of alveolar bone remodeling. The bone becomes more sclerotic leading to less vascularization and an ONJ prone jaw