Osteoporosis Medications and Medication-Related Osteonecrosis of the Jaw

Osteoporosis is the most common bone disease in humans^{1, 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

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 two classes of antiresorptive drugs approved by the U.S. Food and Drug Administration (FDA) for use in osteoporosis: bisphosphonates and RANKL (receptor activator for nuclear factor-kappa B ligand) 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

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 and denosumab.^{13, 14}

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”).^{15, 16} Although treatment with bisphosphonates has shown increases in bone mass, vertebral reshaping, and decreases in long-bone fracture, fractures and scoliosis can still occur.¹⁶ No cases of osteonecrosis of the jaw have been reported in persons receiving antiresorptive agents for osteogenesis imperfecta.^16-18 A 2014 systematic review¹⁹ 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.”

Osteonecrosis is broadly defined as necrosis of bone due to obstruction of blood supply.^{20, 21} 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.²¹ ONJ typically occurs following tooth extractions or other dentoalveolar surgeries, but in some cases, it can occur spontaneously.^{4, 20, 22} ONJ associated with use of antiresorptive drugs such as bisphosphonates or denosumab is referred to as “medication-related ONJ” or MRONJ.²³ The mechanism by which denosumab and bisphosphonates 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.^23-25 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.^{23, 24} According to a 2015 systematic review and international consensus paper,²⁴ 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, 22, 23, 25-29}

• 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 denosumab,¹¹ 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 risks³⁰). 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.”

NOTE: The recommendations discussed here apply only to patients who are prescribed antiresorptive agents to prevent or treat 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).^{20, 22} 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 report^{20, 22} 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 Osteoporosis²²

Dental Intervention	Recommendations Based on Expert Opinion
General Prevention and Treatment Planning	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
Management of Periodontal Disease	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
Implant Placement and Maintenance	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
Oral and Maxillofacial Surgery	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
Endodontics	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
Restorative Dentistry and Prosthodontics	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
Orthodontics	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

1. Office of the Surgeon General (US). Bone Health and Osteoporosis: A Report of the Surgeon General; 4, The Frequency of Bone Disease. Rockville, MD: Office of the Surgeon General (US) 2004. Accessed March 21, 2019.
2. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int 2014;25(10):2359-81.
3. Black DM, Rosen CJ. Clinical Practice. Postmenopausal Osteoporosis. N Engl J Med 2016;374(3):254-62.
4. Yamashita J, McCauley LK. Antiresorptives and osteonecrosis of the jaw. J Evid Based Dent Pract 2012;12(3 Suppl):233-47.
5. Merck and Co. Inc. Fosamax^® (alendronate sodium) tablets, for oral use, and oral solution (rev. 3/2016). Accessed March 22, 2019.
6. Genentech USA Inc. Boniva^® (ibandronate sodium) tablets for oral use (rev. 12/2016). Accessed March 22, 2019.
7. Warner Chilcott Company L.L.C. Actonel^® (risendronate sodium) tablets (rev. 12/2016). Accessed March 22, 2019.
8. Novartis Pharmaceuticals Corporation. Reclast^® (zoledronic acid) injection (rev. 1/2018). Accessed March 22, 2019.
9. Adler RA, El-Hajj Fuleihan G, Bauer DC, et al. Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res 2016;31(1):16-35.
10. Southern California Evidence-based Practice Center (a Rand Health Center) under Contract No. HHSA 2902007-10062-I for the Agency for Healthcare Research and Quality. Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis: Update of a 2007 Report (Comparative Effectiveness Review Number 53). March 2012. Accessed March 22, 2019.
11. Amgen Inc. Prolia^® (denosumab) injection, for subcutaneous use (rev. 6/2018). Accessed March 22, 2019.
12. Amgen Inc. Xgeva^® (denosumab) injection, for subcutaneous use (rev. 6/2018). Accessed March 21, 2019.
13. Drugs for postmenopausal osteoporosis. Med Lett Drugs Ther 2017;59(1536):203-10.
14. Comparison table: Drugs for postmenopausal osteoporosis. Med Lett Drugs Ther 2017;59(1536):e210-e12.
15. Tournis S, Dede AD. Osteogenesis imperfecta - A clinical update. Metabolism 2018;80:27-37.
16. Palomo T, Vilaca T, Lazaretti-Castro M. Osteogenesis imperfecta: diagnosis and treatment. Curr Opin Endocrinol Diabetes Obes 2017;24(6):381-88.
17. Malmgren B, Astrom E, Soderhall S. No osteonecrosis in jaws of young patients with osteogenesis imperfecta treated with bisphosphonates. J Oral Pathol Med 2008;37(4):196-200.
18. Ierardo G, Bossu M, D'Angeli G, Celli M, Sfasciotti G. Bisphosphonates therapy in children with Osteogenesis imperfecta: clinical experience in oral surgery. Oral Implantol (Rome) 2017;10(3):311-16.
19. Hennedige AA, Jayasinghe J, Khajeh J, Macfarlane TV. Systematic review on the incidence of bisphosphonate related osteonecrosis of the jaw in children diagnosed with osteogenesis imperfecta. J Oral Maxillofac Res 2013;4(4):e1.
20. Hellstein JW, Adler RA, Edwards B, et al. Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: Recommendations from the American Dental Association Council on Scientific Affairs (Narrative review). November 2011. Accessed March 21, 2019.
21. Goodman SB. Osteonecrosis (avascular necrosis; aseptic necrosis; ischemic necrosis of bone). Merck Manual Professional Edition. Accessed March 21, 2019.
22. Hellstein JW, Adler RA, Edwards B, et al. Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc 2011;142(11):1243-51.
23. Ruggiero SL, Dodson TB, Fantasia J, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg 2014;72(10):1938-56.
24. Khan AA, Morrison A, Hanley DA, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 2015;30(1):3-23.
25. Migliorati CA. Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 2003;21(22):4253-4.
26. Khamaisi M, Regev E, Yarom N, et al. Possible association between diabetes and bisphosphonate-related jaw osteonecrosis. J Clin Endocrinol Metab 2007;92(3):1172-5.
27. Mavrokokki T, Cheng A, Stein B, Goss A. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 2007;65(3):415-23.
28. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62(5):527-34.
29. Yarom N, Yahalom R, Shoshani Y, et al. Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome. Osteoporos Int 2007;18(10):1363-70.
30. FDA Consumer Health Information. A Guide to Drug Safety Terms at FDA. U.S. Food and Drug Administration. November 2012. Accessed March 22, 2019.

Professional Resources:
ADA Oral Health Topic: Oncology Agents and Medication-Related Osteonecrosis of the Jaw
Search JADA for articles related to osteoporosis
ADA Library Services
ADA Catalog: Osteoporosis Medications and your Dental Health (Item #W418)

Patient Resources:
For the Dental Patient: Osteoporosis Medications and Your Dental Health (November 2011)
ADA MouthHealthy: Osteoporosis and Oral Health

• U.S. Food & Drug Administration MedWatch Program. If a practitioner suspects a patient to have MRONJ, they may contact the FDA’s MedWatch program online or by calling 800-FDA-1088
• The National Osteonecrosis Foundation
• Mayo Clinic:  Osteoporosis Decision Aid
  
  

Appendix Table 1. Antiresorptive Medications Approved by FDA for Osteoporosis Indications

Drug (trade/generic); Route of Administration	FDA-approved Osteoporosis Indications
Bisphosphonates
Alendronate sodium5 (Fosamax®, Fosamax plus D®, Binosto®, generics); oral	Prevention and treatment of postmenopausal osteoporosis Increase bone mass in men with osteoporosis Treatment of osteoporosis in men and women taking glucocorticoids
Ibandronate sodium6 (Boniva®, generics); oral, IV	Prevention and treatment of postmenopausal osteoporosis
Risendronate sodium7 (Actonel®, Atelvia®, generics); oralRisendronate (Actonel®, Atelvia®, generics); oral	Prevention and treatment of postmenopausal osteoporosis Increase bone mass in men with osteoporosis Prevention and treatment of osteoporosis in men and women initiating or taking glucocorticoids
Zoledronic acid8 (Reclast®); IV	Prevention and treatment of postmenopausal osteoporosis Increase bone mass in men with osteoporosis Prevention and treatment of osteoporosis in men and women expected to be on glucocorticoid therapy for at least 12 months Prevention of new clinical fractures in both men and women who have recently had a low-trauma, osteoporosis-related hip fracture
RANK Ligand Inhibitor
Denosumab11 (Prolia®); SC	Treatment of postmenopausal women with osteoporosis at high risk for fracture Treatment to increase bone mass in men with osteoporosis at high risk for fracture Treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer

IV: intravenous; SC: subcutaneous;