Editorial Late Toxicities of Drugs: Bisphosphonates Bruce A. Chabner, M.D., Editor-in-Chief The Oncologist The current issue of The Oncologist contains a series of Letters to the Editor, with responses from authors commenting on recent articles about bisphosphonate, and particularly, zoledronic acid therapy. These letters from a patient advocate [1] and academic physicians [2–5], call attention to drug toxicities as discussed in three recent publications of The Oncologist [6–8]. These comments provide important supplementary information on the renal toxicity of zoledronic acid, and the more general potential of bisphosphonates for causing osteonecrosis of the jaw (ONJ). One of the letters [1] questions why the information on ONJ was not included by the knowledgeable author, who had (appropriately) identified his consulting relationship with the drug’s corporate sponsor, Novartis, in his article. The reader is referred to the letters in this issue, to the authors’ responses, and to the specific publications (on the web at http://www.TheOncologist.com) for more detailed information and discussion about the toxicities in question. Both toxicities deserve careful consideration, as serious complications may arise as their result. For zoledronic acid, the incidence of renal toxicity resulting from standard dosing is still uncertain, but rises in serum creatinine are seen in a small fraction of patients, particularly with infusion times of less than 15 minutes. Deaths have been reported as a consequence of zoledronic acid-induced renal failure [9]. As the letters point out, dose adjustment is recommended for patients with compromised renal function, but simple measurement of serum creatinine may not be sufficient to detect mild renal insufficiency [2]. In the elderly cancer population, or in those previously exposed to nephrotoxic chemotherapy, the potential for renal toxicity is undoubtedly increased. The second toxicity of note, ONJ, is unexpected but equally serious. First reported in chat rooms and in a series of Letters to the Editor in dental surgery journals in the period from 2001–2003, ONJ was brought to the forefront in a study of 63 cases described by Ruggiero and colleagues in June of 2004 [10]. This article appeared after the submission of The Oncologist articles in question. While most (56 of 63) of the patients reported by Ruggiero et al. had received an intravenous bisphosphonate, seven had taken only an oral bisphosphonate (alendronate). Cases presented as a nonhealing extraction socket or an exposed, often infected jawbone. The authors pointed out that conservative debridement and antibiotic therapy were ineffective in many instances, and warned that minor dental procedures in patients with ONJ only exacerbated the problem. The actual incidence and course of ONJ are poorly documented at this point. More than 2 million patients have received zoledronic acid or pamidronate, and even larger numbers have received the less potent, oral bisphosphonates. Thus, the few cases reported so far may indicate a low risk of ONJ of 1 in 10,000 patients treated with intravenous bisphosphonates, and an even lower incidence after oral bisphosphonates. However, as with other late, chronic toxicities, first reports often lead to wider recognition and reporting of cases. Thus the true incidence is not known. At the least, these recent reports will prompt caution in the use of these drugs, particularly in patients who are likely to take them for many years. There is much to learn about bisphosphonates. These agents inhibit bone resorption, kill osteoclasts, and inhibit bone remodeling, and remain bound to bone long after their administration. They have additional properties, including antiangiogenic effects, and the nitrogen-containing bisphosphonates inhibit cholesterol synthesis [11]. Are alternative bisphosphonates safer, as suggested in one of the letters [2], and just as effective as zoledronic acid? To date, no head-to-head comparison of the toxicity profiles of these agents has been performed. Careful metabolic studies are needed to establish the duration and reversibility of the effect on bone remodeling and osteoclast function. Further unresolved questions arise in the light of this new information about toxicity. Which patients are most likely to benefit from bisphosphonate treatment, and for each indication, what is the optimal dose, schedule, and duration of therapy? As clinical studies examine their use in prostate cancer patients with a rising prostate-specific antigen, and in breast cancer patients receiving aromatase inhibitors for adjuvant therapy, these questions assume additional importance but will require careful prospective trials with biochemical, toxicity, and efficacy end points. The objective should be to define the least toxic regimen that provides acceptable efficacy. These letters further highlight several issues of growing general concern in the medical community. Drugs are inherently toxic. Any agent, if used in large populations for a long period of time, can cause problems, as the experience with cox-2 inhibitors [12] so graphically demonstrates. Thus the physician is constantly balancing benefit against risk, and the risk may be unknown, even though the drug is approved. In oncology, because our patients have a potentially fatal disease, physicians and patients have been willing to accept high risk in return for the potential short-term benefits of treatment. However, aggressive and often long-term therapies are now being used to prevent cancer or to prevent its recurrence in otherwise healthy patient populations. In this setting, reporting of low-incidence and long-term toxicities becomes increasingly important. A second concern is the need to maintain impartiality in our journal coverage of new therapies. Here we face a growing problem. Academic physicians, including this author, serve as a source of advice and opinion in the drug development process. Experts who write about certain drugs have often played a significant advisory role to companies, and thus are vulnerable to accusations of bias and conflict of interest. The rapid global expansion of the cancer drug industry has drawn increasing numbers of academic physicians into consulting relationships. How can we assure that the medical community and its patients are receiving accurate and complete information? Disclosure of these industrial relationships is mandatory, but not sufficient. As the patient advocate points out, "The challenging issue of commercial bias in CME content is a timely one with a recent ‘perspective’ piece by Robert Steinbrook, M.D., in the February 10, 2005, issue of the New England Journal of Medicine that discusses the updated ACCME standards for CME commercial conflicts-of-interest. [5, 6]" [1]. The Oncologist CME Online is jointly sponsored by AlphaMed Press and the National Institutes of Health/Foundation for Advanced Education in the Sciences (NIH/FAES), which is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians and is responsible for general oversight of the educational objectives and adherence to the accreditation criteria. In our continued effort to better address the needs of our CME users, The Oncologist CME Online conducts quality assurance reviews of each course posted on our website. The two-phase process consists of a statistical and a medical review. Further, The Oncologist CME is already in compliance with the ACCME updated standards that will become effective in May 2005. Peer review of published information is also necessary. In this instance, the papers in question were subjected to multiple reviews and to further evaluation by a section editor. Like the authors, reviewers are neither infallible nor clairvoyant. The best we can do as authors and editors is to know our field, disclose our ties to industry, subject our work to peer review, and do what is best for the patient. Thus, upon receipt of the Food and Drug Administration warning about ONJ on February 7, 2005, The Oncologist immediately pulled our articles from the CME website and provided this new information in cross-links with previously published articles on bisphosphonates on the journal website. Further, in response to the aforementioned Letters to the Editor, we planned this unusual issue of The Oncologist to give our readership full access to information about bisphosphonates. We look forward to your comments, and invite additional commentaries or proffered papers that will further illuminate our handling of this issue. The Oncologist, Vol. 10, No. 5, 301-303, May 2005; doi:10.1634/theoncologist.10-5-301 Remember we are NOT Doctors and have NO medical training. 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