Bisphosphonates and osteonecrosis of the jaw: Innocent association or significant risk?

Most cases have been in cancer patients

Most cases of osteonecrosis of the jaw were in patients with cancer (particularly breast cancer and multiple myeloma) receiving potent intravenous bisphosphonates in high doses, most of whom had other documented risk factors, including recent dental procedures such as tooth extraction.^{9–12,15–19,33–38}

One of the most compelling studies supporting causation examined the prevalence of osteonecrosis of the jaw in a cohort of 303 myeloma patients from 1991 to 2003. Osteonecrosis of the jaw developed only in those taking bisphosphonates (28 of 254), and the risk appeared greatest in those treated with both zoledronic acid (Zometa) and thalidomide (Thalomid). The importance of additional chemotherapies, concomitant diseases, and baseline dental pathology was not described.³⁵ Biases, including channeling bias (in which patients who appear at increased risk of this rare condition also appear to be most likely to receive this medication), referral bias, and survivor bias, were not addressed in this paper or in others claiming that the risk is related to the type of bisphosphonate used and the duration of its use.^15,33–38

A review of all cases of osteonecrosis of the jaw over a 5-year period in one institution (N = 163) found that only 17 (10%) were associated with bisphosphonate use, and all 17 patients had other risk factors, such as concomitant therapy for malignancy and recent dental surgery.³⁴ The authors’ concern that longer follow-up may have shown a higher incidence of this problem is supported by the temporal relationship seen in other reports in which cancer patients with osteonecrosis of the jaw appear to have had higher cumulative doses of intravenous bisphosphonates than those without.^{9–12,15,34,35,37,38} Unfortunately, only one study had a control group to highlight the incidence of osteonecrosis of the jaw in similar patients not treated with bisphosphonates.³⁵ The incidence in cancer patients treated with intravenous bisphosphonates has been reported as between 0% and 11%, and the incidence is higher following dental procedures and with a greater duration of drug exposure.^{11,14,15,17,35,38,44}

Interestingly, in a recent survey of oncologists prescribing bisphosphonate medications for metastatic indications, two-thirds said they believe their patients probably have undiagnosed chronic oral conditions that could increase the risk of osteonecrosis of the jaw following bisphosphonate therapy and dental surgery procedures. A similar number reported that their patients receive routine dental care (access to and cost of dental care and the difficulty in physician prescreening are cited as obstacles), but only about one-third actually refer their patients to dentists before starting bisphosphonate therapy.⁴⁵

What recent studies in osteoporosis and Paget disease showed

Controlled scientific studies in osteoporosis and Paget disease of bone have not shown osteonecrosis of the jaw to emerge, even after years of treatment with bisphosphonate drugs.^{24–31,46–49} To date, more than 50,000 patients have been treated with oral bisphosphonates— more than 100,000 patient-years for each drug: alendronate, risedronate (Actonel), and ibandronate (Boniva)—in clinical trials, and there has not been a single case of bisphosphonate-associated osteonecrosis in any of these studies.⁴⁸

Recent publications have addressed the results of clinical trials comparing zoledronic acid (the drug most often associated with this condition in published case series) and risedronate in more than 300 patients with Paget disease of bone,³¹ and with placebo in postmenopausal women with osteoporosis and persons over 50 years of age suffering a hip fracture treated for up to 3 years following their fracture.^29,30

In the largest trial, almost 4,000 osteoporotic women were treated with 5 mg of zoledronic acid annually for 3 years, and a similar number received placebo. Despite a rigorous search for any potential cases of bisphosphonate-associated osteonecrosis of the jaw—adjudicated by a blinded panel of ex on the basis of clinical and dental diagnostic imaging—only two possible cases were found: one in the placebo group and one in the treatment group (a case of osteomyelitis that preceded any treatment with zoledronic acid). Both patients recovered following a course of oral antibiotics and debridement. There was no increase in osteonecrosis at other skeletal sites.^29,49

Observational studies have yielded conflicting results. An Australian postal survey of oral surgeons and dentists combined with drug adverse events data suggested the frequency of osteonecrosis of the jaw was 1:2,260 to 1:8,470 in patients on weekly alendronate treatment for osteoporosis, and 1:56 to 1:380 in patients with Paget disease. Following dental extractions, this rose to 1:296 to 1:1,130 and 1:7.4 to 1:48, respectively. Results in patients with malignancy were similar to those in other studies.⁴⁴ The study raises issues similar to those in other studies: lack of an appropriate control group, reporting bias, and the possibility of multiple reportings of the same patients.

Unpublished information from pharmaceutical companies has suggested the incidence of unconfirmed cases of osteonecrosis of the jaw in persons taking alendronate is 0.7/100,000 person-years.^14,17 One study using administrative claims data did not find evidence of increased bisphosphonate use in patients undergoing jaw surgery (used as a surrogate for osteonecrosis of the jaw),⁵⁰ while another actually found that oral bisphosphonates had a protective effect against osteonecrosis of the jaw, inflammatory conditions of the jaw, and need for major jaw surgery.⁵¹