Antiresorptive-Type and Discontinuation-Timing Affect ONJ Burden.

Osteonecrosis of the jaws (ONJ), a severe side effect of antiresorptive medications, is characterized by exposed, nonhealing bone in the oral cavity. Treatment options for ONJ range from management of symptomology to surgical resection of the affected area. Antiresorptive discontinuation, often termed a "drug holiday," has been used for managing ONJ patients. Antiresorptives can be discontinued prior to oral surgical procedures, such as tooth extraction, to prevent ONJ development or in patients with established ONJ to accelerate healing. Here, our objective was to test these clinical scenarios using the potent bisphosphonate, zoledronic acid (ZA), and the denosumab surrogate for rodents, OPG-Fc, in a rat model of ONJ. Animals were pretreated with antiresorptives or saline, after which we induced ONJ using periapical disease and tooth extraction. In our first experimental design, antiresorptives were discontinued 1 wk prior to tooth extraction, and animals were evaluated 4 wk later for clinical, radiographic, and histologic features of ONJ. In the second experiment, ONJ was established and antiresorptives were discontinued for 4 wk. Discontinuation of OPG-Fc, but not ZA, prior to tooth extraction ameliorated subsequent ONJ development. In contrast, discontinuation of either ZA or OPG-Fc in rats with established ONJ did not lead to ONJ resolution. In conclusion, our findings suggest that antiresorptive discontinuation is dependent on both the type of antiresorptive and the timing of discontinuation.

Zoledronate Impairs Socket Healing after Extraction of Teeth with Experimental Periodontitis.

Osteonecrosis of the jaws (ONJ) is a rare but severe complication of antiresorptive medications, such as bisphosphonates, used in the treatment of bone malignancy or osteoporosis. Tooth extraction and dental disease have been strongly associated with ONJ development. Here, we investigated molecular and cellular markers of socket healing after extraction of healthy or teeth with experimental periodontitis (EP) in Wistar-Han rats treated with zoledronic acid (ZA). We included 4 experimental groups: vehicle-treated animals with extraction of healthy teeth or teeth with ligature-induced EP and ZA-treated animals with extraction of healthy teeth or teeth with EP. Animals were pretreated with vehicle or ZA for a week, and EP was induced. Four weeks later, the second maxillary molars were extracted; sockets were allowed to heal for 4 wk; animals were euthanized; and maxillae were isolated. Radiographically, extraction sockets in groups 1, 2, and 3 demonstrated normal healing. Contrary incomplete socket healing was noted after extraction of teeth with EP in ZA-treated rats of group 4. Histologically, persistent inflammation and extensive osteonecrosis were seen in group 4. Disorganization of the collagen network, collagen type III predominance, and lack of collagen fiber insertion in the necrotic bone were associated with impaired socket healing. Cells positive for MMP-9, MMP-13, and α-SMA expression were present at the areas of epithelial invagination and adjacent to osteonecrotic bone. Importantly, human biopsies from patients with ONJ showed similar findings. Our data emphasize the importance of dental disease and tooth extraction in ONJ pathogenesis and help delineate an altered profile in wound-healing markers during ONJ development.