Bisphosphonates and jaw osteonecrosis
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 | ||
| Multiple myeloma | ||
| Metastatic breast cancer | ||
| Metastatic prostate cancer | ||
| Other metastatic disease | ||
| All malignancy | ||
| Osteoporosis | ||
| Paget disease of bone |
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 | (1 in ) |
||
| None | |||
| Intravenous | |||
| Oral |
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:
- SB Woo et al. Systematic review: bisphosphonates and osteonecrosis of the jaws. Annals of Internal Medicine 2006 144: 753-761.
- 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.
- 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.