Histological Analysis of Osteoclastic Activity in Bisphosphonate-Treated Rats

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CONFERENCE: Georgia Undergraduate Research Conference

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Daoudi, Asma
Bisphosphonates; Steonecrosis; Osteoclast; Bone resorption; Zoledronate; Dental extractions; Disease Modeling; Oral and Maxillofacial Surgery; Oral Biology and Oral Pathology
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Bisphosphonates cause osteoclast apoptosis, thus inhibiting bone resorption and reducing bone loss. Despite the overwhelming success of bisphosphonates in the treatment of osteoporosis, hypercalcemia of malignancy, and other bone wasting conditions, the confirmed relationship of long term intravenous bisphosphonate therapy to osteonecrosis of the jaw has raised significant concern in the scientific community. Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) is a devastating and essentially untreatable condition that is characterized by the presence of exposed, non-vital bone in the mouth that persists for over 8 weeks. About 67% of documented occurrences of BRONJ have taken place after invasive dental procedures in patients receiving intravenous zoledronate (ZA), the most potent bisphosphonate. The purpose of this study is to better understand the cellular mechanism of BRONJ by creating a reliable animal model where the animals develop the pathology after dental extractions. We hypothesize that 1) with long-term bisphosphonate therapy, jawbones will have impaired osteoclast activity and 2) the higher doses of bisphosphonates have more profound, direct effects on osteoclasts leading to the diminished attachment. To test these hypotheses, fifty rats were injected with saline, 30 with 80µg/kg Zoledronate (ZA) weekly for 13 weeks, and 20 with 150µg/kg ZA for 16 consecutive days, followed by extraction of the first and second molar teeth. We examined osteoclast and bacterial distribution at one and eight weeks after extraction, using Tartrate-Resistant Acid Phosphatase (TRAP) analysis. The TRAP results indicate a significant decline in osteoclast number (p=0.028), percent attached (p=0.006), and surface ratio (p=0.35) in the 150 treated group compared to controls. This deficiency in osteoclast recruitment and attachment halts the healing process and triggers osteonecrosis. We also saw the expected dose response in the TRAP results, indicating that the higher the dose the more pronounced the decline in percent of osteoclasts attached to bone, p=0.033 and 0.021 for 1 and 8 weeks, respectively. This study validates our hypotheses that bisphosphonate impairs osteoclast activity in a dose dependent manner.