Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment
Review of: C.A., Siegel M.A., Elting L.S. Lancet Oncol 2006;7(6): 508–514.
Although bisphosphonates have been used clinically for more than 30 years, complete knowledge of their pharmacokinetics and pharmacodynamics has not yet been presented. The intravenous use of bisphosphonates to treat patients with bone metastasis was first introduced in 1995 and the first cases of bisphosphonate- associated osteonecrosis were described in 2003. Hundreds of cases have now been reported on worldwide.
In this paper, Migliorati and colleagues, summarise the present understanding of bisphosphonate-associated osteonecrosis of the jaw, including its pathogenesis and management options, as well as highlighting several key questions to which the answers still remain unclear. The authors reviewed published work from January, 2003, to Feb 2006, by searching MEDLINE and PubMed with the search terms 'bisphosphonates', 'osteonecrosis', 'oral cavity', 'adverse reactions', and 'long-term complications'.
Bisphosphonate-associated osteonecrosis is characterised by the unexpected appearance of necrotic bone in the oral cavity and it has been reported in patients with cancer on bisphosphonate treatment for multiple myeloma or bone metastasis from breast, prostate, or lung cancer. The incidence is somewhat unclear but in this article the authors refer to a study of 252 patients with multiple myeloma, breast cancer, prostate cancer, or other cancers who received bisphosphonate treatment with pamidronate, zoledronic acid, or both. Overall, (7%) patients had bisphosphonate-associated osteonecrosis and patients with multiple myeloma had the highest risk (10%) while in prostate cancer, three of 46 patients (7%) were identified.
Osteonecrosis can develop spontaneously or after an invasive surgical procedure such as dental extraction. Patients might have constant pain and chronic ulceration or be asymptomatic. Risk factors identified so far comprise intravenous use and the duration of bisphosphonate treatment (i.e., 36 months and longer), although cases are reported after only a few months of adminstration. Additional risk factors are old age in patients with multiple myeloma, and a history of recent dental extraction. Not all types of bisphosphonates have been implicated in osteonecrosis. Intravenous use of compounds containing an aminoterminal group (eg, pamidronate) or a nitrogen- containing side chain (eg, zoledronic acid) seem to present the highest risk. The non-nitrogen-containing bisphosphonate clodronate has a proven record in malignant bone disease, but is not yet linked directly to bisphosphonate-associated osteonecrosis.
The authors also discuss the possible underlying mechanisms for bisphophonate-induced osteonecrosis. Bisphosphonate-induced suppression of remodeling could result in the accumulation of microfractures in the jaws that occur during daily activity. Since osteoclasts are inhibited by bisphosphonates, no bone resorption takes place after the formation of microfractures and accumulation of the non-vital bone is not resorbed by osteoclasts as under normal conditions. Bisphosphonate-associated osteonecrosis has been described to affect the mandible and the maxilla, but recently, avascular necrosis of the hip was reported in patients with multiple myeloma, raising the possibility that bisphosphonate-associated osteonecrosis is a true systemic complication of bone that first manifests in the oral cavity, but it can appear elsewhere if patients live long enough. This is however, still very speculative.
Very sparse recommendations exist today whether to continue bisphosphonate treatment or not when bisphosphonate-related osteonecrosis has been diagnosed. The decision to stop or continue bisphosphonate treatment during invasive dental work is not clear, especially because the balance between other skeletal benefits and the risk of bisphosphonate- associated osteonecrosis will vary from patient to patient. No evidence suggests that discontinuation of bisphosphonate treatment will promote healing of the necrotic process. Alternatively it has been proposed, to either convert to, or begin, treatment with a non-nitrogen-containing bisphosphonate such as clodronate.
Migliorati and colleagues also discuss the importance of collaboration between medical oncologists and dentists in the prevention and management of the disease, and suggest future directions. It is strongly recommended that all patients with cancer who are being considered for bisphosphonate treatment, and those already undergoing treatment, should be referred for dental assessment. Furthermore, a standard letter for dental referral that contains information related to the type of cancer and possible complications of treatment, including risk of bisphosphonateassociated osteonecrosis can be given to each patient. Besides the relatively high costs of giving bisphosphonates to cancer patients, osteonecrosis usually requires surgical debridment and longterm antibiotic treatment at considerable costs and economical aspects should not be forgotten.
In conclusion, the authors underline that the use of bisphosphonate has many proven benefits for patients with cancer and should not be immediately stopped in case of osteonecrosis. New clinical trials of these bisphosphonates should include the routine investigation of the oral cavity also involving a dentist. More research on the pathogenesis is urgently needed.
