Bisphosphonate Uptake in Areas of Tooth Extraction or Periapical Disease

Abstract

Purpose Bisphosphonates (BPs) are widely used for the management of bone diseases such as osteoporosis and bone malignancy. However, osteonecrosis of the jaws (ONJ) is a serious complication of BP treatment. ONJ lesions mainly occur after extraction of teeth deemed unrestorable or around teeth with active periodontal or periapical disease. Because socket healing or dental disease shows higher bone turnover, the authors hypothesized that preferentially high BP accumulation would be observed in these areas. Materials and Methods The authors tested the uptake of fluorescein-labeled zoledronic acid (5-FAM-ZOL) in sites of tooth extraction or experimental periapical disease in mice. Maxillary molars were extracted or the crowns of mandibular molars were drilled to induce pulp exposure. Animals were injected with 5-FAM-ZOL 200 μg/kg at various times after intervention and fluorescence was measured at healthy versus intervention sites. Fluorescein injections were used as controls. Data were analyzed by t test and mixed effects linear models were constructed because the animals had repeated measurements over time and at the 2 sites. Results A statistically significant (P ≤ .001 to .002) time-dependent uptake of 5-FAM-ZOL was detected in the areas of extraction socket and in the alveolar ridge around teeth with periapical disease compared with the healthy contralateral sites of the same animals. For the 2 conditions, the uptake reached a maximum 3 days after experimental intervention and decreased thereafter. Conclusions These data suggest that sites with increased bone turnover, such as extraction sites or areas of periapical inflammation, are exposed to higher BP doses than the remaining alveolar ridge and could explain, at least in part, the susceptibility of such areas to ONJ.

Rheumatoid Arthritis Exacerbates the Severity of Osteonecrosis of the Jaws (ONJ) in Mice. A Randomized, Prospective, Controlled Animal Study

“…Animal studies can complement clinical findings because they can be designed in a controlled environment, where experimental variables are more predictable and adjustable. Several animal models of ONJ have been reported that provide powerful tools in assessing disease pathophysiology . In the studies presented herein, we employed two mouse ONJ models in animals treated with high levels of ZA in the absence of tooth extractions, but in the presence of either experimental periapical disease or naturally occurring periradicular infection .…”

“…Several animal models of ONJ have been reported that provide powerful tools in assessing disease pathophysiology. (30)(31)(32)(33)59,60) In the studies presented herein, we employed two mouse ONJ models in animals treated with high levels of ZA in the absence of tooth extractions, but in the presence of either experimental periapical disease or naturally occurring periradicular infection. (30)(31)(32) We have reported that these animals develop ONJ-like lesions with clinical bone exposure, and radiographic and histologic features such as periosteal bone formation, bone sclerosis, thickening of lamina dura, empty presence of osteocytic lacunae, and osteonecrosis resembling the human disease.…”

Pathophysiology of Osteonecrosis of the Jaws

“…This is why increased uptake may predispose such sites to higher BP doses and increase susceptibility to BP effects. Although this may not demonstrate a general increase in bone turnover in the jaws, it does show a localized increase in potentially future ONJ sites [25]. The increased bone resorption in the setting of dental disease, coupled with the thin overlying mucosa and a direct pathway through the periodontal ligament with the external environment, make the jaws a suitable breeding ground for ONJ to develop.…”

Design, Synthesis, and Antimicrobial Evaluation of a Novel Bone-Targeting Bisphosphonate-Ciprofloxacin Conjugate for the Treatment of Osteomyelitis Biofilms

“…18–20 BPs form strong bidentate or tridentate bonds with calcium phosphate mineral, and as a result concentrate in hydroxyapatite (HA), particularly at skeletal sites of active metabolism including sites of infection and inflammation. 21 BPs also exhibit exceptional stability against both chemical and biological degradation. 22 BP-fluoroquinolone antimicrobial activity is complex and is related to the specific strain of pathogen tested, the choice of antibiotic and covalently bound BP moiety, the tether length between the two constituents, the bone binding affinity of the BP, the adsorption–desorption equilibria of the BP, and the stability/lability and kinetics of the linkage moiety used for conjugation.…”