Tuesday, January 22, 2008

Bisphosphonate issues

Serious toxicities of bisphosphonates, including the oral bisphosphonates indicated for the prevention of osteoporosis, have recently been reported.

Atrial fibrillation
The first was in an article and related letter in NEJM, calling attention to a puzzling association between infusional zoledronic acid (Zometa) (once yearly for prevention of osteoporosis) and atrial fibrillation. A study of alendronate (Fosamax) (oral) was also cited. The FDA followed up with an “Early Communication.”

Severe musculoskeletal pain
More recently—Jan 7, 2008—the FDA issued an “Alert” for health care professionals related to otherwise unexplained severe and “incapacitating” musculoskeletal pain associated with any form of bisphosphonate. In the cases cited, response to stopping the bisphosphonate ranged from immediate cessation of pain to “slow or incomplete resolution.” The FDA Alert points out that the prescribing information for bisphosphonates includes information on this issue in the Precautions section. I have abstracted the pertinent statement from the alendronate package insert (I’m not picking on alendronate; this seems to be a class effect):

Musculoskeletal Pain
In post marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the prevention and treatment of osteoporosis (see ADVERSE REACTIONS). However, such reports have been infrequent. This category of drugs includes FOSAMAX (alendronate). Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.
In placebo-controlled clinical studies of FOSAMAX, the percentages of patients with these symptoms were similar in the FOSAMAX and placebo groups.

Osteonecrosis of the jaws (and other sites)
Almost all of us (in oncology-related settings, anyway) are aware of the phenomenon of osteonecrosis of the jaws associated with pamidronate (Aredia) and zoledronic acid (Zometa), first reported in 2003. These two bisphosphonates are used to treat bony disease in multiple myeloma and metastatic cancer. However, most of the literature on bisphosphonate-related osteonecrosis of the jaws appears in journals that most of us don’t regularly read.

I’m going to report on a new article, an excellent review of bisphosphonate-related osteonecrosis of the jaws (BRONJ) (the preferred terminology adopted last year in a position statement by the American Association of Oral and Maxillofacial Surgeons). The review begins with a discussion of the actions of bisphosphonates that make them so valuable in cancer therapy and supportive/palliative care: they treat/prevent pain & hypercalcemia, and “skeletal-related events” such as pathologic fractures, are tumoricidal, and may also be antiangiogenic. Bisphosphonates are cytotoxic to osteoclasts, resulting in reduction of bone resorption. Amazingly, the half-life of bisphosphonates is 10 years.

Incidence and prevalence data are weak, but certainly in the single digits for intravenous bisphosphonates, and ranges from 1 in 100,000 patient years to 1 in 2260-8470 patients for oral bisphosphonates. More and more case reports are being published, however. Sites are generally in the mandible or maxilla, probably because the thin mucosa and bacteria-rich environment predispose to injury and infection. There is a long discussion, with plenty of pictures and radiographs, of diagnosis and clinical presentation. Pain may be a presenting symptom, usually because of infection/inflammation, but exposed necrotic bone may be asymptomatic. History and oral examination lead to the diagnosis. A staging system has been proposed, but is yet to be extensively tested.

Proposed risk factors

  1. Zoledronic acid has a much higher incidence than pamidronate. A single patient who took only an oral bisphosphonate has been reported to have BRONJ.
  2. Cumulative dose of bisphosphonate. Cancer patients receive significantly higher doses than patients treated for prevention of osteoporosis and constitute the preponderance of cases.
  3. Risk of developing BRONJ increases significantly with length of time treated.
  4. Tooth extraction or other oral surgery
  5. Oral trauma

Guidelines for management tend to be conservative, because early experience suggests surgical intervention makes things worse. Goals of therapy are to preserve/improve quality of life by treating pain, preventing infection, and preventing new areas of necrosis. Prevention includes instruction to patients on good oral hygiene, increased frequency of professional oral exams, instruction on the risks of developing BRONJ, and informed consent prior to oral procedures. Whenever possible, dental exams and necessary procedures should be completed prior to commencement of bisphosphonate therapy, especially intravenously. Weighing risks and benefits of alternative, less invasive procedures, should be considered. Optimizing oral health through exemplary self care and professional prophylaxis is emphasized.

Management of later stage BRONJ is not well defined, and prospective trials have not been completed. In addition to surgery, interventions under consideration include hyperbaric oxygen, topical application of autologous platelet rich plasma, laser biostimulation, and systemic administration of teriparatide, a synthetic parathormone.

A major patient-level question, of course, is whether bisphosphonates should be discontinued. This paper recommends consultation between the treating oncologist and treating dental specialist, with risk and benefits thoroughly explored and discussed with the patient. There is general acceptance of the major therapeutic benefits of bisphosphonates. I am unaware of any systematic approaches to adjusting current dose or scheduling of bisphosphonates in an attempt to ameliorate risk. Without a new round of clinical trials with long-term follow up, any changes in current practice will be a shot in the dark and could expose patients to increased risk of the very conditions that bisphosphonate therapy is intended to prevent.

I should also point out that this month alone there are several articles in various journals, mostly from the dental literature, on various facets this topic. An example is a first-of-its kind study of aseptic osteonecrosis (of any site) as a potential adverse outcome of oral bisphosphonates. This was done as a retrospective case control study of a large group of elders in a Quebec data base. The results showed an overall incidence of avascular osteonecrosis (AON) (sites undefined) of approximately 2.7/10,000. Ten matched controls were identified for each AON case. The adjusted rate ratio for oral bisphosphonate users was 2.87. Prior corticosteroid use may have been a risk factor.

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