Bisphosphonate use and osteonecrosis of the jaw: association or risk based on evidence?

Apprehension has surfaced as headlines scream Bisphosphonates Tied to High Jaw Necrosis Risk and Study Links Osteoporosis Drugs to Jaw Trouble. According to a recent study, the proportion of people taking widely prescribed oral osteoporosis drugs who develop a "nasty jaw condition" may be much higher than previously thought. Is this excitement and anxiety warranted?

Drug manufacturers and the US Food and Drug Administration have issued warnings about possible bisphosphonate-associated osteonecrosis of the jaw. The American Dental Association (ADA) and the American Association of Oral and Maxillofacial Surgeons (AAOMS) assembled expert panels to formulate treatment guidelines. Both panels differentiated between patients receiving bisphosphonates intravenously and those receiving the drugs orally. However, the recommendations were based on limited data, especially with regard to patients taking oral bisphosphonates. (1) So why all the fuss? Because Fosamax[R] (Merck & Co., Inc.) which is the bisphosphonate alendronate, is the most widely prescribed oral bisphosphonate and has been the 21st most prescribed drug in the United States since 2006. (2)

Bisphosphonates are a class of drugs that inhibit osteoclast action and the resorption of bone. Its indications include the prevention and treatment of osteoporosis, osteitis deformans ("Paget's disease of bone"), bone metastasis (with or without hypercalcaemia), multiple myeloma, osteogenesis imperfecta and other conditions that feature bone fragility. As with any drug, there are side effects that can be beneficial, neutral or harmful. Most commonly, oral bisphosphonates can cause stomach upset and inflammation and erosions of the esophagus, and intravenous bisphosphonates can confer fever and flu-like symptoms after the first infusion. Recent studies have reported bisphosphonate use, specifically zoledronate and alendronate, as a risk factor for atrial fibrillation in women. (3,5)

Bisphosphonates have been associated with osteonecrosis of the jaw (ONJ). ONJ is characterized by pain, soft-tissue swelling, infection, loose teeth and exposed bone. Researchers at the University of Southern California School Of Dentistry recently released results of clinical data that link oral bisphosphonates to increased jaw necrosis. (2) The study is among the first to report that even short-term use of common oral osteoporosis drugs may leave the jaw susceptible to destructive necrosis. However, according to a statement released by Merck & Co., makers of Fosamax, the new study "has material methodological flaws and scientific limitations, making it unreliable as a source for valid scientific conclusions regarding the prevalence of ONJ in patients taking alendronate." (6) The finding of the USC study contradicts claims that the rate of osteonecrosis in alendronate patients is about 0.7 cases per 100,000, or less than 0.00001 percent. (7) In fact, that purported rate is so low that an expert panel selected by the American Dental Association's Council on Scientific Affairs said in December that routine dental treatment should not be altered on the basis of oral bisphosphonate use, the researchers noted. (2)

Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past five years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonates (IVBP) therapy, but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. Data from one study does not support corticosteroid use or oral health as a predictor of risk for ONJ. (8) This study was questioned, as some patients who were not taking bisphosphonates, but were taking antiangiogenic agents, developed ONJ. (9)

High-dose intravenous bisphosphonates have been identified as a risk factor for ONJ in the oncology patient population. Low-dose bisphosphonate use in patients with osteoporosis or other metabolic bone disease has not been causally linked to the development of ONJ. Recommendations from a Canadian Consensus Panel include performing a thorough dental examination including radiographs prior to the initiation of intravenous bisphosphonate therapy. Osteoporosis patients receiving oral or intravenous bisphosphonates do not require a dental examination prior to initiating therapy in the presence of appropriate dental care and good oral hygiene. (10) They also recommend that stopping smoking, limiting alcohol intake, and maintaining good oral hygiene should be emphasized for all patients receiving bisphosphonate therapy. Individuals with established ONJ are most appropriately managed with supportive care including pain control, treatment of secondary infection, and removal of necrotic debris and mobile sequestrate. Aggressive debridement is contraindicated. (10)

Guidelines for treatment of dental patients receiving intravenous bisphosphonate treatments should be different from those for patients taking the oral formulations of these medications. In an implant study, oral bisphosphonate therapy did not appear to significantly affect implant success. (1) Implant surgery on patients receiving bisphosphonate therapy did not result in bisphosphonate-associated osteonecrosis of the jaw. According to the authors, sufficient evidence exists to suggest that all patients undergoing implant placement should be questioned about bisphosphonate therapy including the drug taken, the dosage, and the length of treatment prior to surgery. For patients having a history of oral bisphosphonate treatment exceeding three years and those having concomitant treatment with prednisone, additional testing and alternate treatment options should be considered. (1)

Information available suggests that if these drugs, used at the recommended dose, really do pose a risk, it is probably very small: less than 1 case in 100,000 patient years if taking an oral bisphosphonate such as alendronate. (11) This is significantly less than the risk of fracture in these patients (which may be higher than 1 in 10), and the risk of death following such a fracture. (12) The number of fractures due to osteoporosis is expected to rise to more than 3 million by 2025. (13) The fractures most commonly associated with osteoporosis occur in the hip or spine, and often result in a downward spiral in physical and mental health, which can greatly impair quality of life and can result in death. Indeed, 20 percent of older adults who suffer a hip fracture die within one year. (14,15)

In one study, the cases of osteonecrosis of the jaw were all in cancer patients treated with chemotherapy and high dose bisphosphonates, and all showed histologic evidence of necrosis and concomitant infections, suggesting the actual diagnosis was osteomyelitis. Bone biopsies from affected but macroscopically normal mandibles at the time of surgical debridement for osteonecrosis of the jaw showed normal or increased osteoclastic activity, in contrast to what one would expect if there were oversuppression of bone turnover. (16) Recently, this family of drugs has shown some promise in limiting the progression of alveolar bone loss in periodontal disease (though they are not approved for this indication). (17) Published studies suggest bisphosphonate therapy may even be beneficial in animals and humans with osteonecrosis. (18) As well, bisphosphonate therapy may be beneficial in conditions that mimic osteonecrosis such as SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis and osteitis) of the mandible, in which the histologic appearance may resemble that of osteonecrosis. (19)

The bottom line is that we have a responsibility to weigh the pros and the cons of osteoporosis and its related complications, including death, and the possibility of osteonecrosis of the jaw from bisphosphonate drugs. Risk assessment is vital, and educating patients about the risk/benefit profile of these drugs is essential for them to make informed decisions. The best evidence to date does not support a cause-and-effect relationship between osteonecrosis of the jaw and bisphosphonate therapy, and the risk appears very low in patients without cancer. As ever, prevention is the most successful management strategy because of the significant morbidity associated with and the refractory nature of osteonecrosis of the jaw. And last but not least, communication between patients, their physicians, their dentists and dental hygienists will provide them with the best possible care.

* Updates Resources

Edwards BJ, Hellstein JW, Jacobsen PL et al. Updated recommendations for managing the care of patients receiving oral bisphosphonate therapy: an advisory statement from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc 2008;139; 1674-7. Available at http: / / jada .ada .org/ cgi/ reprint/13 9 /12/1674

American Dental Association. Osteoporosis medications and the risk of developing jaw complications. Patient handout. Available at http://www.ada.org/prof/resources/pubs/jada/ patient/patient_73.pdf

American Dental Association. Obtaining informed consent relating to risks associated with oral bisphosphonate use. Available at http://www.ada.org/prof/resources/topics/topics_osteonecrosis_consent.pdf

References

(1.) Grant BT, Amenedo C, Freeman K, Kraut RA. Outcomes of placing dental implants in patients taking oral bisphosphonates: a review of 115 cases. J Oral Maxillofac Surg 2008; 66(2):223-30.

(2.) Sedghizadeh PP, Stanley K, Caligiuri Met al. Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw: An institutional inquiry. J Am Dent Assoc 2009; 140; 61-6.

(3.) Black DM, Delmas PD, Eastell R et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007; 356 (18): 1809-22. doi:10.1056/NEJMoa067312. PMID 17476007. Available at http://content.nejm.org/cgi/pmidlookup?view=short&pmid=17476007& promo=ONFLNS19.

(4.) Heckbert SR, Li G, Cummings SR et al. Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med 2008; 168 (8): 826-31. doi:10.1001/archinte.168.8.826. PMID 18443257. Available at http:// archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=18443257.

(5.) Cummings SR, Schwartz AV, Black DM. Alendronate and atrial fibrillation. N Engl J Med 2007; 356 (18): 1895-6. doi:10.1056/NEJMc076132. PMID 17476024.

(6.) Garder A. Study links osteoporosis drugs to jaw trouble, KAIT-Jonesboro, Ark. Web site. Available at www.kait8.com/Global/story.asp?S=9604817.

(7.) Smith M. Med Page Today. Osteoporosis drug increases =risk of dental complications. Available at www.medpagetoday.com/Endocrinology/Osteoporosis/ 12288. Accessed Jan. 29, 2009.

(8.) Estilo CL, Van poznak CH, Wiliams T et al. Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy. The Oncologist 2008; 13: 911-20.

(9.) Aragon-Ching JB, Dahut WL. Osteonecrosis of the jaw and the use of antiangiogenic agents: just an association? Oncologist 2008; 13:1314.

(10.) Khan AA, Sandor GK, Dore E et al. Canadian Association of Oral and Maxillofacial Surgeons. Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 20081; 35(7): 1391-7.

(11.) Woo SB, Hellstein JW, Kalmar JR. Narrative review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006; 144: 753-61.

(12.) Bone health and osteoporosis: a report of the Surgeon General. Available at www.surgeongeneral.gov/library/bonehealth/. Accessed Jan. 29, 2009.

(13.) National Osteoporosis Foundation. Fast facts on osteoporososis. Available at www.nof.org/professionals/Fast. Facts_Osteoporosis.pdf. Accessed Jan. 29, 2009.

(14.) Leibson CL, Tosteson AN, Gabriel SE et al. Mortality, disability, and nursing home use for persons with and without hip fracture: A population-based study. J Am Geriatr Soc 2002; Oct; 50(10): 1644-50.

(15.) National action plan for bone health: recommendations from the Summit for a National Action Plan for Bone Health. National Coalition for Osteoporosis and Related Bone Diseases, June 2008. Available at www.nof.org/BoneHealthReport.pdf, p. 1-52. Accessed Jan. 29, 2009

(16.) Carey JL, Palomo L. Bisphosphonates and osteonecrosis of the jaw: innocent association or significant risk? Cleveland Clinic Journal of Medicine 2008; 75(12)871-9.

(17.) Jeffcoat MK, Cizza G, Shih WJ et al. Efficacy of bisphosphonates for the control of alveolar bone loss in periodontitis. J Int Acad Periodontol 2007; 9: 70-6.

(18.) Ramachandran M, Ward K, Brown RR et al. Intravenous bisphosphonate therapy for traumatic osteonecrosis of the femoral head in adolescents. J Bone Joint Surg Am 2007; 89: 27-1734, 1756-8.

(19.) Kopterides P, Pikazis D, Koufos C. Successful treatment of SAPHO syndrome with zoledronic acid. Arthritis Rheum 2004; 50: 2970-73.

By Maria Perno Goldie, RDH, MS

Maria Perno Goldie, RDH, BA, MS is a professional member of the National Speakers Association and president elect of the International Federation of Dental Hygienists (IFDH). She presents seminars nationally and internationally on topics such as women's health and wellness, oral care for the cancer patient, oral cancer, and immunology and periodontal disease. Maria is a member of the International Association for Dental Research (IADR), Oral Health Research Group, and the American Dental Education Association (ADEA). She is a past president of ADHA, and can be reached at [e-mail].