New Details on Osteonecrosis Risk With Bisphosphonates

Cancer Patients Using IV Forms at Greatest Risk

Zosia Chustecka

February 24, 2011

February 24, 2011— More details about osteonecrosis of the jaw (ONJ) associated with bisphosphonate use have been reported in 2 new studies published online February 11 in the Journal of Dental Research.

The largest of the 2 case–control analyses "supports a causal link between bisphosphonates and ONJ," say the authors.

They note that ONJ has been associated with all of the bisphosphonates that are in common use, including intravenous formulations of zoledronic acid and pamidronate — which are used to treat bone metastases in cancer patients — and oral formulations of alendronate, risedronate, and ibandronate — which are used for osteoporosis. The only exception was oral etidronate, but this might be because that drug is not widely used, the researchers explain.

In addition, ONJ has been reported with a nonbisphosphonate drug that acts on bone remodeling — the novel monoclonal anti-RANK antibody denosumab (Xgeva, Amgen).

"ONJ represents a challenging clinical dilemma," according to the journal's editor-in-chief, William Giannobile, DDS, MS, DMSc, director of the Michigan Center for Oral Health Research, University of Michigan, Ann Arbor.

However, because the phenomenon is rare, the literature to date on this subject "has been severely limited; most investigations cannot evaluate sufficient numbers of afflicted individuals to accurately determine the incidence of the disease and associated risk factors," he explained. The 2 new studies represent some of the largest published trials to date on ONJ patients. This work "underscores important clinical implications that will be of value to . . . practicing clinicians," he said.

Risk With All Bisphosphonates

This larger of the 2 studies, led by Andrei Barasch, DMD, MDSc, FAAHD, from the University of Alabama School of Dentistry, Birmingham, investigated 191 ONJ cases (154 [80%] in cancer patients) and 573 matched control subjects from 119 dental practices in the United States.

This team found that bisphosphonate use was strongly associated with ONJ, with an odds ratio of 299.5 for intravenous drugs and of 12.2 for oral drugs.

They also calculated that using bisphosphonates for less than 2 years was associated with a 10-fold risk for ONJ; use for more than 2 years nearly quadrupled that risk.

"This case–control study, conducted in a broad cross-section of dental practices, confirms an elevated risk for ONJ among patients treated with bisphosphonates, with a large effect in the range suggestive of a causal link," the team concludes.

All formulations of bisphosphonates were associated with ONJ, with the exception of oral etidronate — but this drug was used by only 3 participants in the study, the researchers note.

A majority (83%) of the people with ONJ had used bisphosphonates: 48% used intravenous zoledronic acid, 23% used intravenous pamidronate, 38% used oral alendronate, 5% used oral ibandronate, and 8% used oral risedronate.

The risk of developing ONJ was higher for the more potent bisphosphonates, such as intravenous zoledronic acid and pamidronate (both indicated for use in cancer patients), but the risk was also there for weaker oral formulations, such as alendronate (which are used for osteoporosis).

This significant association between the less potent bisphosphonates and ONJ confirms previous reports, and "has significant clinical implications, since millions have been treated with these drugs," the researchers note.

Other Risk Factors

The study also found other factors that were associated with ONJ, including oral suppuration, dental extractions, anemia, and therapeutic radiation for head and neck cancer.

The association between ONJ and radiation to the head and neck region is already well recognized, and has been termed osteoradionecrosis. But this is different from ONJ associated with bisphosphonates, and also different from osteomyelitis, explained Catherine Van Poznak, MD, a breast medical oncologist at the University of Michigan, in an accompanying perspective article.

In fact, she points out that both of the new papers used a broad definition of ONJ, broader than has been proposed by the American Society for Bone and Mineral Research and the American Association of Oral and Maxillofacial Surgeons. Unlike that definition, these studies did not require the ONJ cases to have had bisphosphonate exposure, and they did not exclude patients who had undergone radiation to the head and neck area. As a result, both studies would have included cases of osteoradionecrosis, as well as other diagnoses, Dr. Van Poznak points out.

A clear definition of ONJ is critical.

"These studies highlight the continued need [to reassess] the parameters we use to define the condition that we call ONJ," she writes, adding that going forward, "a clear definition of ONJ is critical."

In an interview with Medscape Medical News, Dr. Van Poznak said that the current definition of ONJ — which stipulates current or previous bisphosphonate exposure — might have to be changed after the recent reports that ONJ is associated with another bone-active drug, denosumab, which is not a bisphosphonate and has a different mechanism of action. "The field needs to revise its vocabulary," she said.

The risk for ONJ with denosumab appears to be comparable to that seen with high-dose intravenous zoledronic acid, Dr. Van Poznak said. An analysis of 3 pivotal clinical trials that compared denosumab with zoledronic acid head to head for the treatment of bone metastases in advanced myeloma patients found that ONJ occurred as an adverse event with both drugs at a rate that was not statistically significantly different. The rates were 1.8% with denosumab and 1.3% with zoledronic acid (P = .13), according to data reported last year at the Cancer and Bone Society 10th International Conference (Brown JE, et al. Abstract OC-9).

Absolute Risk is Low

The second of the 2 studies, led by Jeffrey Fellows, PhD, from the Kaiser Permanente Center for Health Research, in Portland, Oregon, was also a case–control study, but with fewer cases. This team scanned the electronic health records of 2 large health maintenance organizations; from a cohort of 572,606, they found 23 cases of ONJ.

This works out to an incidence of 0.63 per 100,000 patient-years (range, 0.39 to 1.59).

The authors note that this is less than the range of 1 in 10,000 to 1 in 100,000 that has been reported previously (J Bone Miner Res. 2007;22:1479-1491), but is close to the 0.7 per 100,000 that was reported by Merck at the American Association of Oral and Maxillofacial Surgeons 2007 annual meeting.

Among the 23 cases of ONJ that were found in this study, 4 patients had undergone radiation to the head and neck, 6 had taken oral bisphosphonates, and 2 were known to have received intravenous bisphosphonates, although more might have done so, the researchers note.

The absolute risk for ONJ from oral bisphosphonates is low.

When these researchers considered only individuals who had used oral bisphosphonates, the incidence of ONJ went up to 4.1 per 100,000 person-years (range, 3.0 to 6.3).

Patients who had used oral bisphosphonates were 15.5 times more likely to have ONJ than those who had not, they note.

"However, the sparse number of ONJ cases limits firm conclusions and suggests that the absolute risk for ONJ from oral bisphosphonates is low," Dr. Fellows and colleagues conclude.

The authors have disclosed no relevant financial relationships. Dr. Van Poznak reports receiving research funding from Amgen and Novartis.

J Dent Res. Published online February 11, 2011. Abstract

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