Effect of bisphosphonates on periodontitis in a compromised rat model

Abstract

The periodontal benefit of bisphosphonates (BPs) has been reported in some studies, however, the potential benefit and risk of bisphosphonates in immunocompromised patients with periodontal diseases has not been fully investigated. The present study aims to: 1) investigate the development of periodontitis in an immunosuppressed ovariectomized (OVX) rat model; 2) assess the effect of zoledronic acid (ZA) on the process of progressive periodontitis with different dosages in OVX rats; 3) compare the dose-dependent effect of ZA on periodontitis in immunosuppressed OVX rats; 4) evaluate the risk of ZA treatment in causing osteonecrosis in immunosuppressed OVX rats with periodontitis.

In the first experiment, the effect of dexamethasone (DEX), a commonly used immunosuppressive glucocorticoid, on the development of periodontitis was assessed in an OVX Sprague-Dawly (SD) rat model. OVX was performed on all the animals to stimulate intracortical remodeling in jawbones of rats. Periodontitis was induced by ligation at the mandibular molar. After 12-week of DEX or saline injection, all the animals were sacrificed and the whole mandibles were collected for micro-computed tomography (micro-CT) and histological assessments. The extent of alveolar bone loss (ABL) was significantly aggravated, while the bone mineral density (BMD) was improved by DEX treatment. Isolated necrotic bone segments were found only in the DEX treated rats.

In the second study, dose-dependent effect of ZA on periodontitis was investigated using the same periodontitis model. The OVX rats were injected with low dose ZA (84 μg/kg, every four weeks), high dose ZA (67 μg/kg, three times per week) or saline (0.3 ml, three times per week) for 12-week. Micro-CT examination disclosed that high dose ZA exhibited higher inhibition on ABL than low dose ZA, while BMD was largely enhanced in mandibles received low dose ZA treatment. No isolated necrotic bone segment was found in clinical and histological assessment.

To further understand the potential risk and benefit of ZA on periodontitis in immunosuppressed patient, the DEX-treated OVX rat model established in the first study was used. The rats were injected with low dose ZA, high dose ZA or saline for 12 weeks. Micro-CT analysis revealed that the aggravating ABL induced by DEX injection was significantly suppressed by either high dose or low dose ZA treatment, the alveolar BMD was elevated only in high dose ZA treated animals. Histological analysis found isolated necrotic bone in two samples from DEX only group and one sample from low dose ZA group.

In conclusion, 1) the development of periodontitis is aggravated in immunosuppressed OVX rat model; 2) High dose ZA treatment demonstrates higher potential on inhibiting bone loss in OVX rat model with periodontitis than low dose ZA treatment; 3) Both low dose and high dose ZA treatments exhibit suppressive effect on the development of periodontitis in immunosuppressed rat model; 4) The inhibitory effect of ZA treatment on periodontitis is more significant in immunosuppressed rat than in normal rat model; and 5) The risk of osteonecrosis is increased in the immunosuppressed rat model with periodontitis.