Bisphosphonates and osteonecrosis of the jaw: Innocent association or significant risk?

Bisphosphonates are widely used

Today, oral and intravenous bisphosphonates are widely prescribed for several skeletal disorders, including metastatic disease, malignant hypercalcemia, Paget disease of bone, and prevention and treatment of osteoporosis.^21–23

More than 10 million Americans and more than 200 million people worldwide may have osteoporosis, which results in more than 1 million fractures each year. The lifetime risk of fracture for a postmenopausal white woman today is approximately 40% (approximately 15% for a 50-year-old man), and her annual risk of fracture is greater than her combined risk of stroke, heart attack, and breast cancer.²² Several bisphosphonates have been shown to safely and significantly reduce the risk of fracture in patients with osteoporosis and to be effective therapies for Paget disease of bone.^24–31

Bisphosphonates are the most widely prescribed drugs for osteoporosis,^22,23,29 with almost 200 million prescriptions for oral bisphosphonates worldwide. As of 2004, exposure to alendronate (Fosamax) was estimated to be about 20 million patient-years.³² Noncompliance limits their effectiveness in practice, due in part to concerns about adverse effects.

Since bisphosphonates are so widely prescribed, concern has been raised that they may be causing a new epidemic of osteonecrosis of the jaw.⁹ However, most reported cases have been in cancer patients, who are known to be at increased risk of this condition and who receive doses of bisphosphonates up to 12 times higher than in patients with osteoporosis or Paget disease of bone.^{9–12,33–38}

The optimal duration of bisphosphonate therapy for these diseases to obtain the maximum benefit and minimize cost and harm remains unclear. Although a recent report suggests a bisphosphonate “drug holiday” may be an option when treating postmenopausal osteoporosis, larger, more robust studies of longer duration are needed.³⁹ Outcomes of osteonecrosis of the jaw related to drug holidays have not been investigated.

‘IF I TAKE THIS TO STOP BONE LOSS, WILL IT HURT MY JAWS?’

The recently described association between bisphosphonates and osteonecrosis of the jaw has received considerable attention. Guidelines have been drawn up, some based on the assumption that bisphosphonates cause the osteonecrosis, but not based on scientific research.^14–18 More than 90% of reported cases have been in cancer patients, a group known to be at increased risk of osteonecrosis of the jaw and other skeletal sites, for reasons that include radiation therapy, chemotherapy, corticosteroid use, and increased risk of infections.^{4,6,9–12,33–38} Nevertheless, it has been assumed that these patients are the same as osteoporosis patients, and sometimes that causation is beyond dispute. This is problematic for two main reasons:

• Since noncompliance and lack of adherence (due to lack of knowledge about the dangers posed by osteoporosis, cost of the drugs, difficulty with dosing regimens, and fear of adverse effects) limit the effectiveness of these therapies in clinical practice, such attention has already persuaded patients to discontinue or refuse therapy (J.J. Carey, personal experience and communications from colleagues); and
• Patients with osteoporosis and osteoporotic fractures have increased rates of morbidity and mortality and significantly higher fracture risk, which can be prevented with these agents if they are willing to take them.

Association does not prove causation

However, association does not prove causation. A relationship between a drug and a disease may be due to chance alone or to confounding factors.⁴⁰ To judge the exact nature of this relationship, several issues need to be considered when reviewing the available evidence.

Substantiating that an agent causes a disease requires careful consideration of several aspects of their relationship: temporality, strength, dose-response, reversibility, consistency, biologic plausibility, and specificity.⁴¹ Correct interpretation of the strength of the evidence should also incorporate an evaluation of the study design, size, and reporting mechanism. Accordingly, case reports and case series are considered to constitute the weakest evidence, while randomized controlled trials and meta-analyses are usually considered the strongest.

When a true cause-and-effect relationship does exist, the situation can be a simple one in which only a single agent is involved. However, the issue can be decidedly more complex when the cause is an effect-modifier, requiring the interaction of additional factors.

When a cause has been assumed, demonstration of the dose-response relationship is also important: whether the risk is related in a continuous fashion to dose and duration of therapy (all patients), is seen only with particular doses or regimens (such as frequent use of high doses of potent bisphosphonates), or exists only in people who have passed a certain threshold value (for example, it may only occur in those who have received 0.5 g of an intravenous or 10 g of an oral bisphosphonate). Bearing in mind these considerations, the nature of the relationship between an agent and a disease can be better understood.^40–43

A cause-and-effect relationship has not been established

A cause-and-effect relationship between bisphosphonates and osteonecrosis of the jaw has not been clearly established.^14,17 Although case series highlight a relationship between the two, large controlled trials evaluating the occurrence of osteonecrosis of the jaw as the primary outcome have not been conducted. To date, most cases have been reported as uncontrolled case series, generally considered the weakest form of evidence.⁴³