Clinically Relevant Doses of Sclerostin Antibody Do Not Induce Osteonecrosis of the Jaw (ONJ) in Rats with Experimental Periodontitis

Abstract

Antiresorptive agents, such as bisphosphonates and denosumab, are frequently used for the management of osteoporosis. Indeed, both medications decrease the risk of osteoporotic fractures; however, these medications are associated with rare but potentially severe side effects, such as osteonecrosis of the jaw (ONJ). ONJ, defined as an area of exposed bone in the maxillofacial region that lasts for 8 weeks, often presents with significant pain and infection and can lead to serious complications. Interestingly, other treatments for osteoporosis have been developed, such as antibodies against the osteocyte-secreted protein, sclerostin. Sclerostin functions to inhibit the Wnt signaling cascade, leading to inhibition of bone formation. In clinical trials, a sclerostin antibody (romosozumab, Amgen Inc., UCB Brussels) increases bone formation and lowers the risk of osteoporotic fractures. However, in conjunction with increased osteoblastic activity, a reduction in bone resorption markers is observed. This antiresorptive effect raises the concern of possible ONJ development in patients treated with sclerostin antibodies. Here, utilizing ligature-induced experimental periodontitis (EP), we evaluated the effects of sclerostin inhibition on the development of ONJ-like lesions in ovariectomized rats. Beginning 8 weeks post-ovariectomy, rats were treated for 22 weeks with weekly injections of vehicle (Veh), 200 μg/kg zoledronic acid (ZA), a potent bisphosphonate at 100-fold the osteoporosis dose, or 5 mg/kg sclerostin antibody (Scl-Ab) at the osteoporotic dose. EP was initiated at week 12 and maintained for the remainder of the study. Scl-Ab treatment transiently increased serum P1NP, a bone formation marker, increased BV/TV, and decreased eroded surfaces in lumbar vertebrae. ZA-treated rats developed histologic features of ONJ, whereas Veh-treated controls did not. Scl-Ab animals lost less periodontal bone in sites with EP. However, these animals presented with no histologic signs of ONJ. In conclusion, sclerostin inhibition enhanced structural bone parameters, without inducing ONJ-like lesions, in ovariectomized rats with EP. © 2018 American Society for Bone and Mineral Research.

Sclerostin antibody stimulates periodontal regeneration in large alveolar bone defects

“…The systemic Scl-Ab group showed significant enhancement of alveolar bone healing after surgery including bone volume, bone fill, and bone mineral density based on μCT analysis. These findings are also consistent with the previous reports about enhancing vertebral structural bone parameters using Scl-Ab in osteoporosis models 32 , and alveolar bone in a molar extraction model 22 . Moreover, histomorphometric analysis confirmed that the percentage area of new bone fill was significantly greater by systemic delivery of Scl-Ab versus control, as well as a tendency for increased cementogenesis and less root resorption.…”

“…Considering the unique characteristics of Scl-Ab for the promotion of bone density in a variety of contexts, several studies have reported the ability of Scl-Ab to address unmet dental needs. Scl-Ab administration has previously shown inhibition of periodontal disease progression 32 , enhancement of the recovery from periodontal disease 21 , and increased osteointegration and bone regeneration around dental implants 23 . Moreover, in two large clinical studies, a single case of osteonecrosis of the jaw (ONJ) bone was reported 17,18,31,32 whereas antiresorptive agents including bisphosphonates and denosumab are associated with an increased risk of ONJ.…”

UV-Photofunctionalization of Titanium Promotes Mechanical Anchorage in A Rat Osteoporosis Model

“…SD rats (8 weeks of age) were randomly divided into two groups: one group of rats was sham-operated, and another group of rats underwent ovariectomy. OVX rats and sham rats were provided by Charles River Laboratories, and the OVX group underwent bilateral OVX using a sterile technique as described previously [48]. Rats in both groups were fed for 4 weeks after surgery.…”

The Osteocyte as a Novel Key Player in Understanding Periodontitis Through its Expression of RANKL and Sclerostin: a Review

“…One of the risk factors for using anti-resorptive treatment using either bisphosphonates or anti-RANKL antibody denosumab is osteonecrosis of the jaw [ 38 ]. In a study comparing the clinically relevant doses of the sclerostin antibody with bisphosphonates in an experimental periodontitis rat model after ovariectomy, no osteonecrosis developed and also less alveolar bone was lost [ 39 ]. Furthermore, all bone anabolic parameters improved after sclerostin antibody treatment [ 39 ].…”

“…In a study comparing the clinically relevant doses of the sclerostin antibody with bisphosphonates in an experimental periodontitis rat model after ovariectomy, no osteonecrosis developed and also less alveolar bone was lost [ 39 ]. Furthermore, all bone anabolic parameters improved after sclerostin antibody treatment [ 39 ]. Progressive periodontitis eventually leads to tooth loss, hereby solving the chronic inflammation.…”