Bone remodeling relies on a balance of osteoclastic (cells that resorb bone) and osteoblastic (cells that build bone) activity.1 Antiresorptive agents suppress bone resorption by binding to active sites of bone remodeling and inhibiting osteoclasts.4
There are three classes of drugs with antiresorbtive properties approved by the U.S. Food and Drug Administration (FDA) for use in osteoporosis: bisphosphonates, RANKL (receptor activator for nuclear factor-kappa B ligand) inhibitors, and sclerostin inhibitors.4 Bisphosphonates (e.g., alendronate sodium,5 ibandronate sodium,6 risendronate sodium,7 and zoledronic acid8) are FDA approved for the treatment or prevention of postmenopausal osteoporosis in women, osteoporosis in men, or osteoporosis that is related to drug therapy (e.g., corticosteroids, Appendix Table 1);9 some are also approved in more intensive, higher-dose, parenteral regimens for treatment of hypercalcemia of metastatic bone disease and Paget’s disease of bone.2 A 2012 Agency for Healthcare Research and Quality comparative effectiveness review10 reported high strength of evidence that alendronate, risendronate, and zoledronic acid reduce the risk of hip and other nonvertebral fractures and that all of the bisphosphonates reduce the risk of vertebral fractures in postmenopausal women with osteoporosis.
Denosumab is a monoclonal antibody against RANKL, a ligand required for osteoclastic precursors to differentiate into mature osteoclasts.4 For osteoporosis indications (Appendix Table 1), the drug is administered every 6 months as a 60-mg subcutaneous injection.11 Denosumab is also approved by the FDA under the trade name Xgeva® for use in solid cancer metastatic to bone, giant cell tumor of bone, and hypercalcemia of malignancy.12 As compared to the dosage/frequency of denosumab (Prolia®) administration for osteoporosis indications, the dosage of denosumab (Xgeva®) for these oncology-related indications is 120 mg subcutaneously every 4 weeks.12
Romosozumab-aqqg (Evenity®) is a sclerostin inhibitor that is FDA approved for treatment of postmenopausal osteoporosis in women at high risk for fracture (i.e., history of osteoporotic fracture or multiple risk factors for fracture) or who have failed or cannot tolerate other drugs for this indication13, 14 (Appendix Table 1). Romosozumab is an anabolic drug, stimulating new bone formation, as well as decreasing bone resorption.13 The drug is administered as 2 monthly subcutaneous injections of 105 mg (total dose 210 mg).14 Because the bone-forming effect of romosozumab wanes after 1 year, therapy is limited to 12 monthly doses; if osteoporosis therapy is needed following that, continued therapy with an antiresorptive drug such as alendronate or denosumab should be considered.13, 14
Other classes of osteoporosis medications, including parathyroid receptor agonists (e.g., teriparatide [Forteo®] or abaloparatide [Tymlos®]), selective estrogen-receptor modulators (e.g., raloxifene), and calcitonin (e.g., Miacalcin®), are not associated with the same risk of development of MRONJ as bisphosphonates, denosumab, and romosozumab.15, 16
Higher-dose parenteral bisphosphonates and denosumab, as well as teriparatide or other antiresorptive or anabolic agents, are also used off-label for the management of osteogenesis imperfecta, a rare inherited metabolic bone disorder resulting in bone fragility (also known as “brittle bone disease”).17, 18 Although treatment with bisphosphonates has shown increases in bone mass, vertebral reshaping, and decreases in long-bone fracture, fractures and scoliosis can still occur.18 No cases of osteonecrosis of the jaw have been reported in persons receiving antiresorptive agents for osteogenesis imperfecta.18-20 A 2014 systematic review21 reviewing 4 retrospective cohort studies and one case series concluded that, “There is no evidence to support hypothesis of causal relationship between bisphosphonates and osteonecrosis of the jaw in children and adolescents with osteogenesis imperfecta.”