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Should We Be Concerned About Jaw Osteonecrosis with Oral Bisphosphonates?

BRONJ probably occurs rarely with oral bisphosphonate therapy, but the true incidence isn’t clear yet.

Increasingly, patients are asking physicians about bisphosphonate-related osteonecrosis of the jaw (BRONJ). Some patients are researching the topic themselves on the Internet before starting bisphosphonate drugs that are recommended by their physicians. In other cases, dentists are reluctant to perform invasive dental procedures in patients who are taking these drugs. How should primary care physicians respond to these patients or their dentists?

First, some background: BRONJ is defined as exposed, necrotic bone in the maxillofacial region that persists for more than 8 weeks in current or past recipients of bisphosphonate therapy.^1,2 The condition can occur spontaneously or after invasive dental procedures. These lesions often expand — sometimes involving large areas of the alveolar bone — and no treatment has been proven to be effective. Reports of BRONJ first surfaced about 5 years ago, primarily in cancer patients who had received IV bisphosphonates for hypercalcemia and bone metastases. Experts generally accept the association between jaw osteonecrosis and IV bisphosphonates, which are often given repetitively in high doses.^2,3

The data are less compelling for oral bisphosphonates. Based on case reports and surveys, jaw osteonecrosis has been described in relatively few patients who have received oral bisphosphonates to treat osteoporosis. For example, in a recent review of the literature, 11 published reports, comprising 26 cases, were identified.⁴ In a survey mailed to oral surgeons in Australia, 94 clinicians reported 36 cases.⁵ In contrast, no cases of BRONJ were identified in one large New York dental practice where 468 implants were placed in 115 patients who took oral bisphosphonates.⁶ And no cases were reported in the FLEX trial, in which 1099 women took oral alendronate for 5 to 10 years.⁷

Researchers recently attempted an analysis of this problem that was somewhat more population-based: They analyzed medical claims in the database of a large health insurance plan.⁸ No association was found between oral bisphosphonates and jaw osteonecrosis among 180,000 patients with osteoporosis who filled prescriptions for oral bisphosphonates. However, the study had an important limitation: No ICD-9 code exists for jaw osteonecrosis, so the researchers had to use other codes (e.g., diagnostic codes for inflammatory conditions of the jaw and procedure codes for jaw surgery) as surrogate markers for jaw osteonecrosis.

We have spoken to dentists and oral surgeons who occasionally have encountered oral bisphosphonate–treated patients with alveolar bone exposure that arose either after invasive procedures or without apparent trauma. Although these anecdotal unpublished observations hardly prove cause and effect, they should not be dismissed out of hand for at least two reasons. First, if we accept that IV bisphosphonates can cause jaw osteonecrosis, we can reasonably assume that oral therapy occasionally might cause the same complication in highly susceptible people. And second, biopsy-proven severe suppression of bone turnover — resulting in spontaneous fractures of the femur, pelvis, and ribs — has been described in several patients after long-term oral bisphosphonate therapy.⁹

The American Association of Oral and Maxillofacial Surgeons (AAOMS) has published a position paper on BRONJ.¹ The authors recognize limitations in the published data, but they believe that jaw osteonecrosis occasionally occurs in patients who have received oral bisphosphonates. They recommend no alteration to or delay in necessary dental surgery for patients who have taken oral bisphosphonates for fewer than 3 years and have none of the characteristics that are thought to be risk factors (which can be found in the report¹). However, for patients who have taken oral bisphosphonates for longer than 3 years, the statement urges prescribing physicians to stop the drug 3 months before oral surgery and to restart it only after osseous healing has occurred. The authors acknowledge that these recommendations are consensus judgments that are not yet evidence-based.

Now let’s return to our original question: How should primary care physicians respond to patients and dentists who are concerned about BRONJ? In our view, patients who are considering oral bisphosphonate therapy should be told that a small risk — which cannot be quantified yet and which probably emerges only after several years of treatment — is plausible. For most patients with documented osteoporosis and for those with osteopenia plus multiple risk factors for fracture, the potential benefits of bisphosphonate therapy outweigh the risks. However, some clinicians are prescribing bisphosphonates to patients with marginal indications (e.g., to recently postmenopausal healthy women with mild osteopenia). For relatively young patients, delaying bisphosphonate therapy seems prudent: We simply don’t know whether years or decades of exposure to bisphosphonates might result in unanticipated harms.

What about the patient who is already taking an oral bisphosphonate and whose dentist recommends stopping it because an invasive procedure is necessary? Although the AAOMS recommendations admittedly are based on opinion and not hard data, stopping the drug temporarily is reasonable. On the one hand, no proof exists to show that interruption of bisphosphonate therapy will make the dental procedure safer; but, on the other hand, a 6- or 12-month "drug holiday" is unlikely to alter fracture risk substantially in a patient who has already taken a bisphosphonate for several years.² Indeed, the FLEX data suggested that a 5-year drug holiday after 5 years of active treatment is reasonable for many patients.⁷

Practitioners and patients often are forced to make clinical decisions under conditions of uncertainty; the situation with BRONJ is no exception. Although bisphosphonates are extraordinarily valuable drugs with proven benefits, recent developments with cyclooxygenase (COX)-2 inhibitors, recombinant erythropoietins, rosiglitazone, and postmenopausal hormone therapy should remind us to remain open-minded about unexpected effects of drug therapies.

— Allan S. Brett, MD, and Peter B. Lockhart, DDS

Dr. Lockhart is Chair of the Department of Oral Medicine and Director of the Oral Medicine Institute at Carolinas Medical Center in Charlotte, North Carolina.

Published in Journal Watch General Medicine April 8, 2008

Citation(s):

1. Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007 Mar; 65:369. (http://www.aaoms.org/docs/position_papers/osteonecrosis.pdf)

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2. Khosla S et al. Bisphosphonate-associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007 Oct; 22:1479. (http://dx.doi.org/10.1359/JBMR.0707ONJ)

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3. Bilezikian JP. Osteonecrosis of the jaw — Do bisphosphonates pose a risk? N Engl J Med 2006 Nov 30; 355:2278.

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4. Pazianas M et al. A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with oral bisphosphonates: Prevalence, risk factors, and clinical characteristics. Clin Ther 2007 Aug; 29:1548.

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5. Mavrokokki T et al. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 2007 Mar; 65:415.

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6. Grant B-T et al. Outcomes of placing dental implants in patients taking oral bisphosphonates: A review of 115 cases. J Oral Maxillofac Surg 2008 Feb; 66:223.

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7. Black DM et al. Effects of continuing or stopping alendronate after 5 years of treatment. The Fracture Intervention Trial Long-term Extension (FLEX): A randomized trial. JAMA 2006 Dec 27; 296:2927.

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8. Cartsos VM et al. Bisphosphonate use and the risk of adverse jaw outcomes: A medical claims study of 714,217 people. J Am Dent Assoc 2008 Jan; 139:23.

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9. Odvina CV et al. Severely suppressed bone turnover: A potential complication of alendronate therapy. J Clin Endocrinol Metab 2005 Mar; 90:1294.

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• BRONJ
  Mike Moore, 16 Jun 2009 6:06 PM EST
  it has become "fashionable" to have an "NTX Urine" level for patients who are in need of oral surgery, is... [more]