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Bisphosphonates and jaw osteonecrosis

Systematic review [1]
Results
Incidence of jaw surgery
Comment

Rare adverse events are now often reported in the media as well as in medical journals. It makes for a good story, after all, because it is easier to scare than to reassure. It seems humans are hard wired to believe the worst.

So it has been for bisphosphonates and osteonecrosis of the jaw. A quick look for news items confirms headlines like ' Are drugs for bones a threat to jaws?' , followed by the information that lawyers are looking for patients who want to sue a drug company. Adverse events get particularly to the financial pages.

For the many older women and men who take bisphosphonates to strengthen bones, this is a potential worry. It is also difficult for professionals to get a handle on, especially when it comes to reassuring or informing patients. A systematic review often helps.


Systematic review [1]

The systematic review used searches to the end of January 2006, making it current. It used two electronic databases for studies linking jaw osteonecrosis with bisphosphonates. It reviewed all the case reports and case series, and included those with acceptable documentation of disease and use of bisphosphonates. They were particular about including only one report per patient, as this is an area replete with multiple publications.


Results

There were 368 cases of bisphosphonate-associated osteonecrosis of the jaw (Table 1). Almost all of them (95%) occurred in people being treated for cancer (where larger intravenous doses of bisphosphonates are used), and only 15 cases occurred in people treated for osteoporosis (involving lower, oral, doses). Intravenous palmidronate or zoledronic acid were most often used in cancer patients.



Table 1: Cases of osteonecrosis of the jaw associated with bisphosphonates from a systematic literature review



Diagnosis
Number of cases
Percent of total
Multiple myeloma
171
47
Metastatic breast cancer
143
39
Metastatic prostate cancer
23
6
Other metastatic disease
13
3
All malignancy
350
95
Osteoporosis
15
4
Paget disease of bone
3
1


Tooth extraction or oral surgery was a factor in 60% of the cases, and the 40% that did not often involved people using dentures, or who had some other oral health problem.

The most important risk factors for developing bisphosphonate-associated osteonecrosis of the jaw were type and total dose of bisphosphonate and history of trauma, dental surgery, or dental infection.

A closer look at incidence studies in cancer patients can be helpful to give more background. For instance, a retrospective examination [2] of 252 cancer patients receiving at least six bisphosphonate infusions and followed up for at least two years recorded 17 cases (7%) of osteonecrosis of the jaw. There was a higher incidence in multiple myeloma (10%), with lower rates for breast and other cancers. Patients developing osteonecrosis had received more bisphosphonate infusions (35 vs 15 in those not developing osteonecrosis) and had longer exposure (39 months vs 19 months). There is a suggestion that incidence of jaw osteonecrosis could be very significant in long term users with many infusions (Figure 1), though with small numbers.



Figure 1: Incidence of osteonecrosis of the jaw with duration of exposure to intravenous bisphosphonates in cancer patients






Incidence of jaw surgery

Another way of looking at the effects of bisphosphonates might be to use a surrogate to diagnosis of osteonecrosis, like jaw surgery. A database analysis of 256,000 patients with breast, lung, or prostate cancer was analysed for jaw surgery [3].

There were 224 cases of jaw surgery. Of these 185 cases occurred in 229,000 who never used bisphosphonates, while 39 occurred in 26,000 patients given bisphosphonates. Table 2 shows the event rates for jaw surgery according to bisphosphonate use. Oral use was not significantly different from non-use, but with intravenous use jaw surgery was about four times more frequent.



Table 2: Cases of jaw surgery associated with bisphosphonates in an observational study in cancer patients



Bisphosphonate use
Number with jaw surgery
Total number
Rate
(1 in )
None
185
229,470
1240
Intravenous
20
5,850
293
Oral
19
20,438
1076



Comment

The bulk of the reported cases are in patients being treated for cancer, where bisphosphonates reduce bone pain, and significantly reduce bone problems. There are clear risk factors, and newer guidance places great emphasis on oral examinations before starting treatment with bisphosphonates in cancer patients, and maintaining good oral health.

Cancer patients receive high doses of bisphosphonates intravenously. Osteoporosis patients receive much lower doses orally. Here the risk is much lower, with only 15 reported cases.

The problem, of course, is that not all cases get reported in the literature. A quick scan of the Internet suggests that many more have been reported using established yellow card systems. Most of these appear, again, to be cancer patients. Few reports relate to oral bisphosphonates, with perhaps 150 cases in the USA, and fewer than 10 in the UK. Given the millions of people taking oral bisphosphonates, the risk is negligible. Maintaining good oral health in older people still makes sense, as does exchange of information on drugs by dentists and patients.

References:

  1. SB Woo et al. Systematic review: bisphosphonates and osteonecrosis of the jaws. Annals of Internal Medicine 2006 144: 753-761.
  2. A Bamias et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. Journal of Clinical Oncology 2005 23: 8580-8587.
  3. AI Zavras, S Zhu. Bisphosphonates are associated with increased risk for jaw surgery in medical claims data: is it osteonecrosis? Journal of Oral and Maxillofacial Surgery 2006 64: 917-923.

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