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

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ABSTRACTPublished case series and systematic reviews have documented an association between bisphosphonates and osteonecrosis of the jaw. However, a cause-and-effect relationship has not been established, and most of the reported cases have been in patients with cancer who were receiving much higher doses than those used to treat osteoporosis or Paget disease of bone. The risk, if any, to patients with these latter conditions receiving these drugs appears to be very small.


  • Recently published data do not support the hypothesis that these drugs cause osteonecrosis of the jaw.
  • There is no evidence to support routine dental examinations for all patients before starting bisphosphonate therapy for osteoporosis or Paget disease, but heightened concern seems warranted for cancer patients.
  • Clinical experience suggests that dental work by experienced dentists and surgeons can be carried out safely with very little risk to patients taking bisphosphonates.



Recent case reports have linked bisphosphonate drugs to osteonecrosis of the jaw, and these reports have been widely publicized. Many patients receiving these drugs are asking their dentists and doctors whether the drugs do more harm than good, and some have even stopped taking them against medical advice. Health care professionals may be unsure what to tell patients and may be fearful of litigation.

However, most of the cases reported were in cancer patients, who are at significantly higher risk of osteonecrosis of the jaw for several reasons, and who receive much higher doses of bisphosphonates than do patients with osteoporosis or Paget disease of bone.

Moreover, although case reports have clearly documented an association between these drugs and osteonecrosis of the jaw, there is a lack of robust scientific evidence to support a cause-and-effect relationship. In fact, wellcontrolled clinical studies have not shown an increased risk of this complication in patients with osteoporosis or Paget disease of bone who were exposed to these agents, nor have they elucidated definite pathogenic mechanisms by which it might occur.

For these reasons, we believe that patients with osteoporosis should be advised of:

  • Their risk of fracture
  • The significant risk of morbidity and death following such a fracture
  • The effectiveness and excellent safety of bisphosphonate therapy in preventing fractures
  • The evidence that such therapy for osteoporosis and Paget disease poses little or no risk of osteonecrosis of the jaw
  • The need for further research.


Osteonecrosis—a general loss of bone tissue as a result of cell death1—can occur at any skeletal site, but it typically involves the long bones, ie, the femur, tibia, and humerus.

Osteonecrosis of the jaw is a rare disorder characterized by exposure and loss of bone in the maxillofacial complex. It can result in significant morbidity and can be resistant or refractory to conventional therapy.

This condition is not new, having been described in 19th century factory workers exposed to white phosphorus used in matchstick manufacturing. Known then as “phossy jaw,” it was associated with poor dentition and often resulted in severe disfigurement, disease, and death. Use of white phosphorus, and matches containing it, were subsequently banned in many countries.2

In the early 20th century, radiation therapy for cancers of the head and neck area came into vogue, but its side effects included damage to the skeleton, or osteoradionecrosis.3 In 1950, LaDow4 described a case of osteoradionecrosis of the jaw and reviewed the literature available at that time. He concluded that there were three main causes of osteonecrosis of the jaw, namely, radiation therapy, trauma, and infection.

Although many such cases have since been reported in association with radiation therapy, chemotherapy, or both, and involvement of other skeletal sites is well described,5–8 the actual incidence of osteoradionecrosis in the general population remains unclear because no large epidemiologic studies to elucidate accurate numbers have been published.


Bisphosphonate-associated osteonecrosis of the jaw is a relatively new condition, having been first reported in three case series9–11 published in 2003 and 2004. The patients had exposure of areas of alveolar bone, mostly after oral surgery, eg, mucogingival flap elevation procedures (such as tooth extraction), that did not respond or were refractory to conventional treatment. All had received a bisphosphonate drug.

After these articles were published, the number of reported cases rose dramatically, including a case presented by one of us.12 By the end of January 2008, more than 500 papers on this condition were listed in PubMed. More than 60% had been printed since 2003, and approximately 85% concerned the association between osteonecrosis of the jaw and bisphosphonate use (search terms: “osteonecrosis of the jaw” and “bisphosphonate”).13

Although some dentists and oral surgeons claim to have seen many patients with this disorder, physicians who specialize in osteoporosis and metabolic bone disease do not. The medical literature and popular press have suggested that bisphosphonates are the cause of this malady. However, such articles are more perspective than evidence, as they are not scientific studies but rather reports of cases or series, or reviews of these. High-impact journals have given such articles prominent positions, highlighting the issue further, rather than balancing what is known and what is not known.

Thus, medicine safety boards, physicians, dentists, and oral surgeons have become increasingly concerned about the possible risk of this disorder in their patients on long-term bisphosphonate therapy, prompting organizations to issue management guidelines for this disorder and regulatory bodies to mandate warning labels on all drugs in this class about the possible risk.14–18 Funding agencies have highlighted this as an area in need of further investigation.17

However, robust evidence of a causal relationship is lacking. Contributing to the problem, other disorders can have similar presentations.

As a result, the diagnosis requires a dental examination and dental imaging, which are often impossible or impractical in a medical setting. Well-designed studies have relied on blinded panels of dental specialists using clinical and imaging data to adjudicate cases as osteonecrosis of the jaw before including them in published reports; case reports, however, often do not.


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