The adverse event of jaw osteonecrosis has been reported most commonly with the use of intravenous bisphosphonates (zoledronate and pamidronate) in cancer patients, but has also been reported with the use of oral bisphosphonates in osteoporosis and Paget’s patients. There have been 78 cases associated with alendronate therapy in 20 million patient years of exposure (Fosamax, Merck & Co) and there have also been a number of cases associated with risedronate (Actonel, Procter & Gamble).

What is it?

A number of conditions including “dry sockets” are currently grouped under the name of “jaw osteonecrosis’. In the worst case, individuals develop a deformity around or at a tooth socket. A painful and gaping hole may occur in the jaw. The deforming area around dead bone may fail to heal which may result in chronic dental problems.

Why does it occur? Why is the jaw affected?

The cause is not understood, nor is it clear why some patients get the more severe condition. However bone normally undergoes renewal on a continuous basis. This remodelling process involves osteoclasts resorbing old, possibly damaged bone and osteoblasts building new bone. Jaw osteonecrosis may stem from the mechanism of action of bisphosphonates. These drugs work by preventing the resorption of old bone, since bisphosphonates are toxic to the osteoclasts. This leads to a reduction in bone turnover that may be more critical in the jaw.

Bone in the jaw has a faster turnover than bone elsewhere in the body, both because it is subjected to constant stress from activities such as talking and chewing and also because of the presence of teeth, which mandates daily bone remodeling at the periodontal ligament. Also the jaw can often be damaged during dental surgery such as extractions. The potential concentration of these drugs in the jaw bones, when coupled with chronic invasive dental diseases/treatments and the thin mucosa over the bone, may predispose to the condition being manifest in the jaw.

Who is at risk?

Jaw osteonecrosis has usually been observed after patients have been taking therapy for five or more years. However it has been reported to occur earlier in the presence of certain risk factors. For example, of the 78 cases with alendronate, most developed after an invasive dental procedure, such as a tooth extraction. Other risk factors include oral infections, use of steroid therapy and radiotherapy.

How common is this problem?

Jaw osteonecrosis is rare, occurring in perhaps one out of 1,000 to 10,000 patients. At the US Federal Drug Administration hearing on this subject in March 2005, Novartis reported 875 possible cases of jaw osteonecrosis associated with the two intravenous products, zoledronate and pamidronate. The majority of these cases occurred in patients with cancer treated with doses ranging up to 20 times higher than used in osteoporosis. As of June 2005, Merck had received 78 reports of jaw osteonecrosis associated with alendronate. However, the company saw no cases of jaw osteonecrosis during preclinical studies, in which alendronate was used at far higher doses than are approved for osteoporosis, and also no cases were seen in controlled clinical trials, which involved more than 17,000 patients. Alendronate has been on the market for 10 years now, during which time total exposure to the drug is estimated at around 20 million patient-years. Moreover these case reports have not all been carefully evaluated and some may represent relatively mild problems, such as dry socket that have been reported long before bisphosphonates were in use.

Prevention is better than cure.

Despite its rarity, physicians who prescribe bisphosphonates should be aware of this side effect and should discuss it with patients. It is important to ask about dental hygiene before starting therapy. The best strategy is prevention, as most cases appear to follow a dental procedure. If the patient’s dental fitness is in doubt, it may be prudent to send them for these procedures before they start on a course of bisphosphonate therapy and to encourage thorough dental hygiene at all times. Once on the drug, patients should be advised to let their dentist know they are taking such medication and, in general, invasive dental procedures should be avoided. It may be prudent to temporarily withdraw bisphosphonate therapy before such procedures although it is recognised that these drugs remain in bone long term – for example, alendronate has a half-life of about 10 years.

Summary

In osteoporosis, the bisphosphonates have been shown to increase bone mineral density and significantly reduce the risk of fractures. The very small potential absolute risk of jaw osteonecrosis with doses used to treat osteoporosis must be kept in perspective and considered in relation to their demonstrated benefit.

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