Bisphosphonates Linked to Severe Side Effects, including Osteonecrosis of the Jaw
Although prescribed to 30 million Americans each year, the bisphosphonates, a class of FDA-approved pharmaceuticals for the treatment of numerous disorders affecting bone (including osteoporosis, cancer metastases to bone, hypercalcemia of malignancy, and multiple myeloma), have now been linked to significantly increased risk of osteonecrosis of the jaw (ONJ).
This follows an FDA warning, issued January 2008, that all bisphosphonate drugs may cause “severe and sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain…[which] may occur within days, months or years” after starting the medication, and in some patients, may not resolve even after discontinuing the drug.1
Osteolytic lesion in the lower jaw of patient treated with Zometa for 12 months (59 years old, female, breast cancer).
Therapeutics and Clinical Risk Management 2009:5 217–227. © 2009 Borgioli et al, publisher and licensee Dove Medical Press Ltd.
Numerous other adverse effects have also been noted during the 16-year period since bisphosphonates’ FDA approval, including gastrointestinal tract intolerability, symptomatic hypocalcemia, bone stress fractures, influenza-like illness, myalgia, deterioration of renal function (especially in patients on nephrotoxic drugs), renal failure, acute tubular necrosis, esophageal erosions and ulcerations, and anti-angiogenic effects.
Despite this long list of adverse side-effects, their prevalence has been low. Of growing concern, however, is the fact that since 2003, more than 2,000 cases of bisphosphonate-induced ONJ have been reported, most of which have occurred in patients given nitrogen-containing rather than non-nitrogenous bisphosphonates (discussed below, see Table 1).
Prevalence of ONJ in cancer patients receiving intravenous bisphosphonate therapy has always been high (6-10%), but until recently, was thought to be much lower (< 1%) in patients on oral bisphosphonate therapy. In the January 2009 issue of the Journal of the American Dental Association, however, Sedghizadeh et al. report seeing two to three new patients a week with bisphosphonate-related ONJ, which translates to ONJ incidence of 4% in patients taking oral bisphosphonates.2
Even short term oral bisphosphonate therapy significantly increases risk of ONJ following dental therapy, particularly surgical dental procedures, such as root canals or extractions. Sixty percent of all cases of ONJ have been reported to occur after dentoalveolar surgery to treat infections, with the remaining 40% related to infection, denture trauma, or other physical trauma.
A Cochrane Review noted that age = or > 60 years, female sex and previous invasive dental treatment were the most common characteristics of patients taking bisphosphonates who developed ONJ.3 Considering that the primary target population for bisphosphonate use is postmenopausal women, many of whom are = or >60, and as they age, may become more likely to need some kind of invasive dental procedure, these risk traits for ONJ with bisphosphonate use are far too common for comfort, so common that the ADA is warning dentists to avoid “invasive dental producures” in patients on IV bisphosphonates and to take a “conservative” approach to dental procedures for patients taking oral bisphosphonates. ADA’s updated recommendations for managing patients on oral bisphosphonates, released December 2008,4 now include a recommendation to dentists to consult with an attorney to develop an informed consent form that will be certain to satisfy the criteria of the state in which they practice. Concerned dentists are becoming increasingly reluctant to perform any type of dental surgery on women taking these drugs.5
A key reason for dentists’ concern is that bisphosphonate-related ONJ is extremely difficult to treat. Affected individuals are usually asymptomatic until necrotic bone is secondarily infected. Initial symptoms include numbness, heaviness, swelling, pain and infection in the jaw, and loosening of the teeth, after which lesions are often persistent and unresponsive to conventional treatments, including debridement, antibiotic therapy, and hyperbaric oxygen therapy.
Bisphosphonates may also contribute to chronic oral infections. In research published in the Journal of Oral Maxillofacial Surgery in April 2008, Sedghizadeh’s team found a direct correlation between bisphosphonate use and the development of microbial biofilms (bacterial colonies that cause chronic infections) in affected bone.6
Other recent studies have reported that bisphosphonate use is a risk factor for atrial fibrillation in women. One study estimates that 3% of atrial fibrillation cases might have been due to bisphosphonate (specifically, alendronate) therapy, and warns that bisphosphonate use should be closely monitored in populations at high risk of serious adverse effects from atrial fibrillation (such as patients with heart failure, coronary artery disease or diabetes). In other words, those at risk for serious side effects from bisphosphonates include not only women aged 60 and older, but also anyone with heart disease or diabetes, a significant percentage of the U.S. population.7
Bisphosphonates Subclasses and Mechanisms of Action
There are two types of bisphosphonates, one of which contains nitrogen, while the other does not. Both types concentrate selectively in bone where they form strong bonds with hydroxyapatite crystals and potently inhibit osteoclastic activity, suppressing osteoclast-mediated bone resorption. Highly persistent drugs, bisphosphonates accumulate and remain in the mineralized bone matrix for years; e.g., alendronate has an estimated half-life of ~12 years. ONJ secondary to bisphosphonate therapy is thought to be time- and dose-dependent due to bisphosphonates’ long half-life in bone, so risk factors include duration of treatment and the patient’s level of compliance.
|Table 1: FDA-approved Bisphosphonates|
|Generic Name||Brand Name||Formulation||Nitrogen-containing||Manufacturer|
|Alendronate||Fosamax®||Oral||Yes||Merck & Co.|
|Etidronate||Didronel®||Oral/IV||No||Procter & Gamble|
|Risedronate||Actonel®||Oral||Yes||Procter & Gamble|
|Adapted from Sedghizadeh PP, et al. 2008|
Increased risk of ONJ has been seen more frequently in the nitrogen-containing drugs, most likely due to their differing mechanisms of action. The non-nitrogen containing bisphosphonates are metabolized by osteoclasts intracellularly into inactive non-hydrolyzable ATP analogues, which are directly cytotoxic and induce apoptosis. The nitrogen-containing versions inhibit critical enzymes in the mevalonate pathway, thus suppressing prenylation of small GTPases essential for many cellular functions.8
GTPases are a large family of regulatory proteins involved in signal transduction. Their ability to switch between two distinct conformations, one in which they bind to guanosine triphosphate (GTP) and the other in which they bind to guanosine diphosphate (GDP), allows GTPases to serve as molecular switches that regulate important cellular processes, including growth, motility and protein trafficking. GTP also plays a role of as a source of energy or an activator of substrates in metabolic reactions, like that of ATP, but more specific: GTP is used as a source of energy for protein synthesis.9 10
Possible Explanations for Bisphosphonates’ Inducing ONJ
Bisphosphonates’ strong suppression of osteoclasts is thought to contribute to the pathogenesis of ONJ. Both types inhibit osteoclastic activity by several mechanisms: preventing the differentiation of precursor monocytes into osteoclasts, blocking the activity of mature osteoclasts, and inducing osteoclastic apoptosis. Suppression of osteoclastic activity allows damaged bone to be left in place rather than resorbed, so the amount of compromised tissue accumulates until it reaches a level where any trauma or insult will result in extremely poor healing, the exposure of necrotic bone to the oral environment, and increased risk of microbial infection—precisely what is seen in bisphosphonate-associated cases of ONJ.
Why ONJ secondary to bisphosphonate treatment almost exclusively affects the jaw remains poorly understood, though several hypotheses have been suggested. The most promising is that bisphosphonates concentrate in the jaw bones due to their different properties from other bones in the body. The maxilla and mandible form primarily through intramembranous ossification, in contrast to long bones, which form through endochondral ossification. The jaw bones also have a greater blood supply than other bones and a faster bone turnover rate, due both to their daily activity and the presence of teeth, which makes daily bone remodeling around the periodontal ligament necessary. When combined with chronic invasive dental diseases and their treatment, these factors provide conditions for ischemic bone necrosis, which would then allow secondary infection.
Increasing patients’ risk of ONJ by prescribing bisphosphonates is far from trivial since, currently, no definitive cure exists. Most treatment is palliative, and the condition is associated with significant oral dysfunction, impaired eating ability, pain and disfigurement, resulting in compromised quality of life.11
Interestingly, the majority of patients seen by Sedghizadeh et al., who had developed ONJ (69.2%) were on oral alendronate, which, until now, has had a relatively lower incidence of ONJ reported in the literature. One explanation for this sudden increase in alendronate-associated ONJ is that the risk of bisphosphonate-associated ONJ is time- and dose-dependent. Large numbers of menopausal and postmenopausal women have now been on alendronate long enough that sufficient amounts of the drug (and its corollary, conserved, yet compromised, bone tissue) have accumulated, such that any trauma will provoke only an extremely poor healing response.
The increasing risk of ONJ secondary to alendronate use is of special concern because several million women take this medication for prevention of postmenopausal osteoporosis, and as the aging population continues to grow, these numbers, along with attendant risk of ONJ, will increase.
Bisphosphonates May Increase Fracture Risk
As noted by Neustadt and Pieczenik in their excellent review of osteoporosis published in Integrative Medicine: A Clinician’s Journal,12 several recently published retrospective analyses suggest bisphosphonates’ suppression of normal bone remodeling may actually increase fracture risk in some patients within as little as 2.5 years of use.
A case series reported 9 patients who, after 3 to 8 years on alendronate, experienced spinal fractures “while performing normal daily activities such as walking, standing, or turning around.” In 6 of these patients, all of whom continued on alendronate after their fracture, healing was delayed from the normal healing time after the fracture for 3 months to 2 years.13
A retrospective analysis of patients admitted to a Level 1 trauma center over a 5-year period found that low-energy fractures of the femoral shaft with a simple, transverse pattern are associated with alendronate use. Reviewers identified 70 patients with low-energy femoral shaft fractures (59 women, 11 men, median age 74.7 years). Of these, 25 patients were taking alendronate, 19 of whom suffered low energy femoral shaft fractures exhibiting this specific simple, transverse pattern. In contrast, only 1 patient not being treated with alendronate had this fracture pattern. This translates to an astronomically high odds ratio of 139.33 for low-energy simple, transverse femoral shaft fracture in patients taking alendronate.
It should be noted that average duration of alendronate use in patients experiencing this fracture pattern was significantly longer than in those taking alendronate who did not experience this type of fracture: 6.9 years versus 2.5 years of use, respectively, which again confirms the impact of treatment duration on fracture risk. However, one patient with this fracture pattern had been taking alendronate for less than 4 years. Researchers hypothesized the increased risk of low-energy simple, transverse femoral fracture seen with alendronate use results from the accumulation of stress fractures whose healing has been retarded by the diminished osteoclast activity and impaired microdamage repair resulting from prolonged bisphosphonate therapy.14
A third recent report from 2 hospitals noted 13 women (mean age 66.9 years) suffered subtrochanteric fractures with minimal or no trauma during a 10-month period (May 2005 to February 2006). Nine of these women had been taking alendronate, with duration of therapy ranging from as few as 2.5 years to 5 years.15
The far from negligible risks associated with bisphosphonates, and their questionable efficacy in the treatment of osteopenia/osteoporosis, offer sufficient reasons to question the advisability of their use as first-line therapy for these conditions.
A substantial amount of peer-reviewed research indicates that the balance between osteoclastic demolition and osteoblastic reconstruction can be restored by addressing the causes of excessive osteoclast activity and providing an adequate supply of the materials necessary to build new bone. Considerations involved in developing such an individualized integrative medicine protocol for bone health will be the topic discussed in Part II of this review.
http://www.fda.gov/cder/drug/infopage/bisphosphonates/default.htm (Accessed 2/27/09).↑
Sedghizadeh PP, Stanley K, Caligiuri M, Hofkes S, Lowry B, Shuler CF. Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw: An institutional inquiry. J Am Dent Assoc. 2009;140:61-66. ↑
Pazianas M, Miller P, Blumentals WA, et al. A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with oral bisphosphonates: prevalence, risk factors, and clinical characteristics. Clin Ther. 2007 Aug;29(8):1548-58. ↑
http://www.ada.org/prof/resources/topics/osteonecrosis.asp (Accessed 2/27/09) .↑
Parker Waichman Alonso LLP. Breaking News, Osteonecrosis of the Jaw. ↑
Sedghizadeh PP, Kumar SK, Gorur A, et al.. Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy. J Oral Maxillofac Surg. 2008 Apr;66(4):767-75. ↑
Pereira-Leal JB, Seabra MC. The mammalian Rab family of small GTPases: definition of family and subfamily sequence motifs suggests a mechanism for functional specificity in the Ras superfamily. J Mol Biol. 2000 Aug 25;301(4):1077-87. ↑
Neustadt J, Pieczenki S. Osteoporosis: beyond bone mineral density, Part II. IMCJ. Dec2008/Jan2009;7(6):44-48. ↑