Risks of bisphosphonate therapy in patients with malignancy

INTRODUCTION — Prolonged therapy with parenteral bisphosphonates in patients with malignancy (eg, breast cancer, prostate cancer, multiple myeloma) is generally well tolerated. However, patients should be periodically monitored for development of a number of potentially serious complications, which are described here.

Unfortunately, the definition of ONJ remains unclear; many patients identified as having ONJ actually have other dental conditions when evaluated by experts in this field.

Multiple factors may contribute to the development of ONJ, which is often seen following dental extraction, local infection, or trauma, although it can occur spontaneously. It is unclear whether ONJ is the primary process that becomes secondarily infected (as interpreted by some authors), or if this disorder could represent primary osteomyelitis. Failure to recognize the signs of ONJ can lead to unnecessary surgical procedures of the jaw, which ultimately may exacerbate the condition and impact the patient's quality of life.

ONJ is increasingly recognized as a complication of bisphosphonate therapy, particularly with chronic intravenous therapy and/or high potency bisphosphonates . It has also been described as a complication among patients with multiple myeloma and other malignancies treated with radiation therapy (ie, osteoradionecrosis) and chemotherapy

In one retrospective review of 90 patients with multiple myeloma who had dental assessments, there were 22 patients with ONJ. On multivariate analysis, the following variables were predictive for the development of ONJ:

• Dental extraction
• Sequential therapy with pamidronate/zoledronic acid
• Longer follow-up time
• Older age at diagnosis

The biology of ONJ and its relationship to treatment with high potency bisphosphonates are unclear:

• Chronic treatment with zoledronic acid has been implicated as a greater contributor to the development of ONJ than pamidronate. This may be due to its greater potency, as demonstrated by larger reductions in collagen type-I degradation products (N-telopeptide).

• Antiangiogenic activity of zoledronic acid that may lead to impairment of blood supply has also been implicated in the development of ONJ. While other antiangiogenic agents (eg, thalidomide) have not been found to be associated with the development of this complication, the use of thalidomide along with a bisphosphonate appears to significantly increase the risk of development of ONJ.

• In a small study, ibandronate, another highly potent bisphosphonate, was reported not to be associated with ONJ.

A web-based survey conducted by the International Myeloma Foundation of 904 patients with multiple myeloma and 299 with breast cancer identified 75 patients with ONJ and an additional 77 with findings suspicious for early ONJ. ONJ developed in 10 and 4 percent of those treated with zoledronic acid or pamidronate, respectively, with a significantly increased risk in those with underlying dental problems (eg, infection, dental extraction). However, there are limitations to this study because the diagnosis of ONJ was based on answers given by the patients. It is not known if this diagnosis was confirmed by dental professionals and whether patients with dental problems might have been more responsive to the survey.

In a prospective series of 252 patients treated with bisphosphonates 17 cases of ONJ were identified (7 percent), including 11 with multiple myeloma and 6 with solid tumors  The incidence was highest among patients with myeloma, and the risk increased with duration of exposure, use of zoledronic acid, and oral trauma (either dental procedures or wearing dentures). The incidence of ONJ was 1.5 percent among patients treated with these agents for 4 to 12 months, rising to 7.7 percent after treatment for 37 to 48 months.

However, these results should be viewed with caution because only limited numbers of patients had long term exposure to these agents. Other factors potentially contributing to the development of ONJ include the heterogeneous nature of patients with dental disease, the degree of oral hygiene undertaken by patients during the study, and the contribution of a variety of concomitant medications (eg, corticosteroids, chemotherapeutic, and biologic agents).

Recommendations — In view of the difficulty in treating this complication, patients should be advised to avoid dental procedures while receiving intravenous bisphosphonates as well as to identify and rectify dental problems prior to treatment with these agents. Patients should be counseled regarding the possible occurrence of ONJ prior to initiating therapy with a bisphosphonate and their oral hygiene status should be closely monitored during treatment with these agents.

Discontinuing or reinitiating bisphosphonate therapy at the time of the diagnosis of ONJ as well as the optimal duration of therapy with bisphosphonates in multiple myeloma are both subjects of debate. These decisions must be based on the clinical effects of the ONJ on the patient compared with the benefits of ongoing bisphosphonate therapy on presenting skeletal complications.

Many patients have been able to continue monthly intravenous bisphosphonate therapy without further exacerbation of this jaw problem, although there have been anecdotal reports of healing and complete resolution after several months of cessation of these agents.

Conservative management with limited debridement, antibiotic therapy, and topical mouth rinses may result in healing, although some cases become chronic with complications; hyperbaric oxygen therapy has had limited efficacy. Surgical resection of necrotic bone, which may lead to disease progression, should be reserved for refractory cases, and should be performed by an experienced oral and maxillofacial surgeon.