Journal of Evidence Based Dental Practice
Original ArticleAntiresorptives and Osteonecrosis of the Jaw
Introduction
Antiresorptives are drugs that suppress bone resorption by targeting osteoclasts. They are used for the management of osteoporosis, osteopenia, metastatic bone cancer, hypercalcemia of malignancy, and other disease conditions in which elevated osteoclastic bone resorption plays a pathogenic role. Bisphosphonates are currently the major drug in this class. In 2010 the clinical use of denosumab, a monoclonal antibody to RANKL (receptor activator for nuclear factor-kappa B ligand), was approved by US Food and Drug Administration for the treatment of postmenopausal osteoporosis and for the prevention of skeletal-related events in patients with metastatic bone cancer. In 2011, denosumab was approved as a treatment to increase bone mass in patients with breast or prostate cancer who develop osteopenia secondary to androgen deprivation or aromatase inhibitor therapies. RANKL is an essential cytokine that induces osteoclasts and therefore the inactivation of RANKL by denosumab potently suppresses osteoclastogenesis, resulting in an inhibition of bone resorption.1, 2 Although both of these antiresorptives target osteoclasts, their mechanisms are distinct. Bisphosphonates adhere to bone mineral following administration. During osteoclastic bone resorption, matrix-bound bisphosphonates are liberated, internalized, and interfere with cytoskeletal organization and ruffled border integrity, resulting in detachment of resorbing osteoclasts from bone surfaces and eventual osteoclast death.3, 4 On the other hand, denosumab restrains osteoclastogenesis by neutralizing RANKL, which is required for osteoclast precursors to differentiate into mature osteoclasts. Thus, bisphosphonates suppress bone resorption by abolishing mature osteoclasts and denosumab does so by hindering osteoclast formation from precursors. Although bisphosphonates and denosumab are different mechanistically in their antiresorptive actions, recent evidence indicates that both drugs are associated with the development of osteonecrosis of the jaw (ONJ).5, 6 The fact that ONJ is associated with both bisphosphonates and denosumab convincingly suggests that osteoclast suppression is central to the pathophysiology of ONJ. It should be noted that other less potent antiresorptives, such as calcitonin and estrogen, have not been reported to be associated with ONJ, hence the level of resorption inhibition likely affects the development of ONJ. In this review, we focus on ONJ in patients on bisphosphonate therapy and dissect the currently available evidence to establish a clinical approach to assess risk, preventive measures, and management of ONJ.
Section snippets
Mechanisms of Action
Bisphosphonates are the most popular antiresorptive agent for the management of metabolic bone disorders in which elevated osteoclastic bone resorption plays a pathogenic role. Bisphosphonates possess a strong affinity for bone mineral.7 Approximately half of the absorbed dose is excreted in urine and the remaining half binds exclusively to bone with a half-life of greater than 10 years.8, 9 Therefore, the therapeutic effects of bisphosphonates last for years. Likewise, adverse effects of
Bisphosphonates in Dentistry
Periodontal disease is an inflammatory disease that involves local alveolar bone loss in which osteoclasts play a major role. As bisphosphonates suppress osteoclastic bone resorption, the impact of oral bisphosphonates on periodontal status has been evaluated in osteoporotic patients.35, 36, 37 Although conclusions were not solid owing to small sample sizes, in general, there was a trend that patients on bisphosphonates had less clinical attachment loss and probing depth compared with those not
Osteonecrosis of the Jaw
ONJ associated with antiresorptive therapy is a great concern for both dental practitioners and patients on bisphosphonates. ONJ is also termed “bisphosphonate-related osteonecrosis of the jaw” (BRONJ). Although most of the reported ONJ cases thus far are associated with N-BPs, ONJ occurs in patients taking denosumab,6, 78, 79 a newer antiresorptive compound that particularly inhibits osteoclasts. Hence, it is now clear that bisphosphonates are not the only antiresorptives to be associated with
Perspective
Although ONJ is rare, it is a serious complication and is often devastating. The etiology and pathophysiology of ONJ are largely unknown and, therefore, no effective treatment is available to cure ONJ. This is partly because of the extremely low incidence of ONJ in patients on oral antiresorptives (approximately 1:100,000). It seems almost impossible to design meaningful clinical trials to elucidate the etiology and pathophysiology of ONJ; however, findings from recent research indicate a
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2021, International Journal of Oral and Maxillofacial SurgeryCitation Excerpt :It has a poorly understood pathophysiology1,2 with multiple hypotheses postulated to understand the mechanism of this disease affecting the jaw bones30,31. Theories include altered bone remodelling or over-suppression of bone resorption29,32, angiogenesis inhibition29,31,33, constant microtrauma34, suppression of innate or acquired immunity34,35, vitamin D deficiency36, soft tissue bisphosphonate toxicity37, and inflammation or infection38,39,40. Most of this evidence based on animal models suggests the disease process to be multifactorial, contributing to the difficulty in developing effective targeted treatments.