Osteoporosis Medications and Medication-Related Osteonecrosis of the Jaw

Key Points

  • Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse effect of bone antiresorptive agents (i.e., bisphosphonates, denosumab) used for osteoporosis.
  • Patients at increased risk of MRONJ include those:
    • receiving the antiresorptive agents at higher dosages and more frequent treatment schedules associated with cancer-related indications, as compared with those for prevention/treatment of osteoporosis;
    • receiving the drugs for more than 2 years;
    • with periodontitis or dentures.
  • Although MRONJ is associated with bone-invasive dental procedures such as tooth extraction, it can also occur without dental intervention.
  • The potential morbidity and mortality associated with osteoporosis-related fracture is considerable and treatment with antiresorptive agents outweighs the low risk of MRONJ in patients with osteoporosis receiving these drugs.
  • A 2011 ADA CSA report developed by an expert panel provides potential treatment management strategies based on expert opinion for patients receiving these drugs for osteoporosis indications and also recommends that “An oral health program consisting of sound hygiene practices and regular dental care may be the optimal approach for lowering [MRONJ] risk” in these patients.

Osteoporosis is the most common bone disease in humans1, 2 and is characterized by low bone mass, disrupted bone architecture, and increased fracture risk.2 Based on data from the National Health and Nutrition Survey III (NHANES III), the National Osteoporosis Foundation in 2014 estimated that more than 9.9 million Americans have osteoporosis.2 Osteoporosis results in 1.5 million fractures per year in the U.S., with the vast majority of these occurring in postmenopausal women.3

Osteoporosis Medications

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.

There are three classes of drugs with antiresorptive 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);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, 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 indication.13, 14 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.”

Medication-Related Osteonecrosis of the Jaw

Osteonecrosis is broadly defined as necrosis of bone due to obstruction of blood supply.22, 23 Osteonecrosis of the jaw (ONJ) is an oral lesion involving exposed mandibular or maxillary bone, which usually manifests with pain and purulent discharge, although it may be asymptomatic.23 ONJ typically occurs following tooth extractions or other dentoalveolar surgeries, but in some cases, it can occur spontaneously.4, 22, 24 ONJ associated with use of drugs such as bisphosphonates, denosumab, or romosozumab is referred to as “medication-related ONJ” or MRONJ.25 The mechanism by which these drugs cause MRONJ has not been clearly elucidated; however, it has been suggested that suppression of bone turnover and remodeling by the drugs impairs the body’s ability to repair microfractures in the maxilla and mandible.25-27 The reported incidence of MRONJ varies, but it is generally considered to be between 1% and 10% of patients taking IV bisphosphonates for the management of bone metastatic disease and between 0.001% and 0.01% in patients taking oral bisphosphonates for the management of osteoporosis.4

The differential diagnosis of MRONJ includes other conditions such as alveolar osteitis, sinusitis, gingivitis/periodontitis, or periapical pathosis.25, 26 According to a 2015 systematic review and international consensus paper,26 patient history and clinical examination remain the most sensitive diagnostic tools for MRONJ. While it is not possible to identify who will develop MRONJ and who will not, research suggests the following as risk factors:4, 9, 24, 25, 27-31

  • age older than 65 years;
  • periodontitis;
  • poor oral hygiene;
  • dentoalveolar surgery, including tooth extraction;
  • high dose and/or prolonged use of antiresorptive agents (more than 2 years);
  • smoking;
  • malignant disease (multiple myeloma, and breast, prostate, and lung cancer);
  • chemotherapy, corticosteroid therapy, or treatment with antiangiogenic agents;
  • denture wearing;
  • diabetes.

The “Warnings and Precautions” sections of the FDA-approved package inserts for bisphosphonate drugs,5-8 as well as denosumab11 and romosozumab,14 state that both MRONJ and atypical femoral fractures have been reported rarely with use of these drugs; however, these are not included as so-called “black box” warnings (which is a specially designated warning designed to call attention to serious or life-threatening risks32). A 2016 consensus task force report,9 based on a literature search, from the American Society for Bone and Mineral Research (ASBMR) concluded that “the risk of atypical femoral fracture, but not osteonecrosis of the jaw, clearly increases with [bisphosphonate] therapy duration, but such rare events are outweighed by vertebral fracture risk reduction in high-risk patients.”

Management of Dental Patients Receiving Antiresorptive Medications for Osteoporosis

In November 2011, the ADA CSA report developed by an expert panel published recommendations for managing the care of patients receiving antiresorptive therapy specifically for prevention and treatment of osteoporosis (i.e., not addressing the care of patients being treated with antiresorptive agents as part of cancer therapy).22, 24 These recommendations were based on a narrative review of the literature from May 2008 (the date of the last search for a 2008 review and statement) through February 2011. Although the 2008 report limited the review to jaw osteonecrosis related to bisphosphonates, the 2011 report expanded the search to include jaw osteonecrosis related to the use of any antiresorptive agent (including denosumab and cathepsin K inhibitors).

The expert panel report found that the highest reliable estimate of MRONJ prevalence is low (approximately 0.10%) in patients receiving drug dosages and regimens intended to treat or prevent osteoporosis. The report concluded that the potential morbidity and mortality associated with osteoporosis-related fracture is considerable and treatment with antiresorptive agents, including bisphosphonates, outweighs the low risk of MRONJ in patients with osteoporosis being treated with these drugs. The report states that “An oral health program consisting of sound hygiene practices and regular dental care may be the optimal approach for lowering [MRONJ] risk” in these patients and that a discussion of the risks and benefits of dental care with patients receiving antiresorptive therapy is appropriate. The report provides the following points that dental practitioners can discuss with patients:

  • Antiresorptive therapy for low bone mass places patients at a low risk of developing drug-related ONJ (highest prevalence estimate of 0.10% in a large sample);
  • The low risk of MRONJ can be minimized, but not eliminated;
  • An oral health program consisting of sound oral hygiene practices and regular dental care may be the optimal approach for lowering the risk of drug-related ONJ;
  • No validated diagnostic technique currently is available to determine which patients are at increased risk of developing drug-related ONJ; and
  • Discontinuing bisphosphonate therapy may not eliminate the risk of developing drug-related ONJ and that discontinuation of bisphosphonate therapy may have a negative impact on the outcomes of treatment for low bone mass.

Because of the paucity of clinical data regarding the dental care of patients receiving antiresorptive therapy, the report22, 24 also describes management recommendations based primarily on expert opinion for general prevention and treatment planning, as well as for specific conditions, such as management of periodontal disease, oral and maxillofacial surgery, endodontics, restorative dentistry and prosthodontics, and orthodontics (summarized in Table 1). There is insufficient evidence to recommend a “holiday” from antiresorptive drug therapy for osteoporosis or waiting periods before performing dental treatment for prevention of MRONJ. There is also insufficient evidence to recommend the use of serum biomarker tests, such as serum C-terminal telopeptide (CTX) as a predictor of MRONJ risk in patients receiving the drugs for osteoporosis indications.

Table 1. Summary of Management Recommendations Based on Expert Opinion from the 2011 Expert Panel Report on Managing the Care of Patients Receiving Antiresorptive Therapy for Prevention and Treatment of Osteoporosis24

Dental Intervention

General Prevention and Treatment Planning

Recommendations Based on Expert Opinion

  • Have a discussion with patients regarding potential risks and benefits
  • Do not modify routine dental treatment solely because of osteoporosis antiresorptive medications
  • A localized clinical approach (e.g., treating a sextant at a time) to dentoalveolar surgery in patients receiving antiresorptive therapy for low bone density may help assess risk (Note, the sextant-by-sextant approach does not apply to emergency cases, even if multiple quadrants are involved)
  • Treat periapical pathoses, sinus tracts, purulent periodontal pockets, severe periodontitis and active abscesses that already involve the medullary bone expeditiously

Dental Intervention

Management of Periodontal Disease

Recommendations Based on Expert Opinion

  • Obtain access to root surfaces using atraumatic techniques that minimize dentoalveolar manipulation whenever possible
  • Use techniques such as guided tissue regeneration or bone grafting judiciously based on patient need
  • Primary soft-tissue closure after periodontal surgical procedures is desirable, when feasible, although extended periosteal bone exposure for the sake of primary closure may increase, rather than decrease, the risk of developing MRONJ

Dental Intervention

Implant Placement and Maintenance

Recommendations Based on Expert Opinion

  • Antiresorptive therapy does not appear to be a contraindication for dental implant placement; however, larger and longer-term studies are needed to determine if implants placed in patients exposed to antiresorptive agents perform as well as those placed in patients who have not been exposed to these agents

Dental Intervention

Oral and Maxillofacial Surgery

Recommendations Based on Expert Opinion

  • If extractions or bone surgery is necessary, dentists should consider a conservative surgical technique with primary tissue closure, when feasible
  • Placement of semipermeable membranes over extraction sites also may be appropriate if primary closure is not possible
  • Before and after any surgical procedures involving bone, the patient should rinse gently with a chlorhexidine-containing rinse until the extraction site has healed

Dental Intervention


Recommendations Based on Expert Opinion

  • In patients with an elevated risk of developing MRONJ, endodontic treatment is preferable to surgical manipulation if a tooth is salvageable
  • Practitioners should use a routine endodontic technique; however, the panel does not recommend manipulation beyond the apex

Dental Intervention

Restorative Dentistry and Prosthodontics

Recommendations Based on Expert Opinion

  • Practitioners should perform all routine restorative procedures with the goal of minimizing the impact on bone, so as not to increase the risk of infection
  • To avoid ulceration and possible bone exposure, practitioners should adjust prosthodontic appliances promptly for fit

Dental Intervention


Recommendations Based on Expert Opinion

  • Inhibited tooth movement in adult patients receiving bisphosphonate therapy has been reported and dentists should advise patients of this potential complication; however, orthodontic procedures have been performed successfully in patients receiving antiresorptive therapy, and it is not necessarily contraindicated
  • Orthognathic surgery and tooth extractions result in more extensive bone healing and remodeling; treatment planning in these cases may require increased vigilance

A 2022 updated position paper on MRONJ by the American Association of Oral and Maxillofacial Surgeons (AAOMS)25 recommends the following MRONJ prevention strategies in people prescribed antiresorptive therapies for nonmalignant disease (e.g., osteoporosis):


  • Educate people about the potential risks associated with long-term antiresorptive therapies.
  • Optimization of dental health can occur concurrent with antiresorptive therapy initiation.

During therapy:

  • No alteration of operative plan for most patients.
  • Considerations include drug schedule, duration of therapy, comorbidities, other medications (especially chemotherapy, steroids, or antiangiogenics), degree of underlying infection/inflammation, and extent of surgery to be performed. Drug holidays are controversial.
  • Markers of bone turnover (e.g., CTX) are not a useful tool to assess MRONJ risk.

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  11. Amgen Inc. Prolia® (denosumab) injection, for subcutaneous use (rev. 1/2023). https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Prolia/prolia_pi.pdf. Accessed April 11, 2023.
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ADA Resources

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ADA Oral Health Topic: Oncology Agents and Medication-Related Osteonecrosis of the Jaw

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For the Patient page: What is MRONJ? (August 2021)

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Topic Last Updated: April 11, 2023

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