Effects of bisphosphonates on bone healing and titanium implant osseointegration

Abstract

Bisphosphonates (BPs) are considered to be the gold standard treatment for metabolic bone diseases and malignant tumors with bone metastasis. Despite their great clinical benefits, a serious adverse event known as medication-related osteonecrosis of the jaws (MRONJ) has been widely reported. While both BPs therapy and dental implants are very common treatments, there is increasing concern regarding the risk of developing MRONJ while place implants in patients taking BPs. It is also unclear whether different surgical approaches of tooth extraction would affect the development of MRONJ. The objectives of this study are 1) to investigate the osseointegration of dental implant in a rabbit model treated with bisphosphonates; and 2) to study the influence of different surgical approaches of tooth extraction on the development of MRONJ. Twenty female New Zealand White rabbits were equally assigned into control and experiment group which received saline or ZA treatment 4 weeks prior to surgeries. Titanium implant was placed on the calvarial bone, after which the mandibular first premolars on both sides were extracted with one side sutured and the other side left open. ZA or saline treatment continued after surgeries for 4 weeks (short term subgroup) or 8 weeks (long term subgroup) until sacrifice. Three different fluorochrome labelling solutions were administrated for assessing bone growth rates. Samples of the calvarial bone and mandible were subjected to micro-computed tomography (micro-CT), confocal microscope and histology analysis. Results showed that ZA treatment significantly reduced bone growth rates in the calvarial bone and mandible, but had no significant influence in bone mineral density and trabecular micro-architecture. Significantly lower bone-to-implant contact ratios were found in ZA-treated animals compared to controls at week 4 but not at week 8. Significantly higher incidence of histological osteonecrosis at week 8 was found in ZA treated animals compared to the controls, while no significant difference was found between the sutured side and the unsutured side. In conclusion, 1) oncologic dose ZA suppresses the bone growth rates of the calvarial bone and mandible; 2) ZA treatment demonstrates similar influence on bone mineral density and bone morphology in calvarial bone and mandible; 3) ZA may have an adverse effect on osseointegration of dental implant in short-term, but this effect tends to diminish in long-term; 4) Closing the wound of tooth extraction does not affect the risk of developing MRONJ.