PeteFree.comOral Bisphosphonates Used Long-Term Increase Risk of Esophageal Cancer, but Absolute Risk Remains Small ─ an Illustration of the Need to Evaluate Absolute as Well as Relative Risk
© 2010 Peter Free
16 October 2010
Oral bisphosphonates, used long-term, can increase the patient’s risk for esophageal cancer
Oral bisphosphonates are often used to treat osteopenia and osteoporosis. As with all drugs, long-term safety is a concern.
The United Kingdom’s General Practice Research Database lends itself to important epidemiological research in this regard. Recently, Jane Green et al., writing in the British Medical Journal reported that extended use of oral bisphosphonates increased the risk of developing esophageal cancer by 1.3 times in people with one or more prescriptions, as compared with people not on the drug.
The relative risk increased 1.93 times for people who had had 10 or more prescriptions.
Importantly:
Risk of oesophageal cancer did not differ significantly by bisphosphonate type, and risk in those with 10 or more bisphosphonate prescriptions did not vary by age, sex, smoking, alcohol intake, or body mass index; by diagnosis of osteoporosis, fracture, or upper gastrointestinal disease; or by prescription of acid suppressants, non-steroidal anti-inflammatory drugs, or corticosteroids.
© 2010 Jane Green et al., Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort, BMJ 341: c4444 (02 September 2010)
What does this medical language mean?
A relative risk of 1.30 means that risk has been elevated by 30 percent, as compared to the non-treatment, normal baseline.
Similarly, a 1.93 relative risk (as in the ten or more bisphosphonate prescription group) means that risk for esophageal cancer rose 93 percent (almost double the “normal” risk), as compared to the non-treated patient baseline.
“Oh my goodness, that sounds bad!” ─ Maybe not so much
All drugs have negative side-effects (as does life, generally speaking). So it is important to make a knowledgeable balancing of risks and benefits to any medical intervention.
Here, Jane Green’s group sensibly assessed what the increased risk for esophageal cancer meant in absolute terms. In medicine, “absolute risk” simply compares the number of people who have bad things happen to them compared to a set population size. This allows one to make a real world assessment of just how dangerous the medical intervention might statistically be.
Green wrote in this regard:
In Europe and North America, the incidence of oesophageal cancer at age 60-79 is typically 1 per 1000 population over five years, and this is estimated to increase to about 2 per 1000 with five years’ use of oral bisphosphonates.
© 2010 Jane Green et al., Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort, BMJ 341: c4444 (02 September 2010)
Notice the relatively older age group cited in assessing absolute risk. If you are younger, the authors do not address your risk.
Questions that patients should discuss with their doctors are
(1) How much additional benefit am I getting from taking my oral bisphosphonate for an extended period?
(2) How afraid should I be of getting esophageal cancer, as compared to the risk of worsening my osteoporosis, if I discontinue using my oral bisphosphonate?
Hard answers will probably not be available (at least as of this writing)
Clinical trials of bisphosphonates have not exceeded five years. See Paul S. Mueller, Oral Bisphosphonate Use Is Associated with Esophageal Cancer, JournalWatch 30(19): 151 (01 October 2010).
No one knows what benefits and risks they bring with them when used for longer periods.
That’s why having a conversation with your doctor is important. The two of you can weigh risks and benefits of both avenues.
One possible successful balancing might include a drug “holiday”
Drug holidays (cessation of taking a drug) are often used to limit habituation or lower the risks of bad outcomes.
This idea is incompletely similar to giving over-used musculoskeletal components a rest after too much exercise.
“Incompletely” because some pharmaceuticals (and some other medical treatments) can very occasionally cause cellular conversions that can’t be reversed. An example would include a chromosomal (genetic) mutation that thereafter affected the patient’s well being. One-time genetic mutations of this kind are how some cancers start.
No one yet knows why bisphosphonates can (apparently) cause esophageal cancer. My suspicion is that the phenomenon parallels the cellular events that cause the same thing after too many episodes of gastroesphageal reflux disease. In some people, reflux leads to Barrett’s Esophagus, which (in turn) can rarely lead to esophageal cancer via transitioned esophageal cell types.
In the case of bisphosphonates, even before the cancer risk was revealed, some physicians recommended considering giving their patients a holiday in using them. Data had already emerged that the drugs have rarely caused:
(i) osteonecrosis of the jaw
(ii) atypical femur fractures
(British J of Medical Practitioners)
(iii) musculoskeletal pain
Consequently, physicians Nelson Watts and Dima Diab said that:
Because [bisphosphonates] accumulate in bone and provide some residual antifracture reduction when treatment is stopped, we recommend a drug holiday after 5–10 yr of bisphosphonate treatment. The duration of treatment and length of the holiday are based on fracture risk and pharmacokinetics of the bisphosphonate used.
Patients at mild risk might stop treatment after 5 yr and remain off as long as bone mineral density is stable and no fractures occur. Higher risk patients should be treated for 10 yr, have a holiday of no more than a year or two, and perhaps be on a nonbisphosphonate treatment during that time.
© 2010 Nelson B. Watts & Dima L. Diab, Long-Term Use of Bisphosphonates in Osteoporosis, Journal of Clinical Endocrinology & Metabolism 95(4): 1555-1565 (April 2010) (paragraphs split)
So talk to your physician
And keep in mind that the absolute risk of esophageal cancer happening to you, as a result of using bisphosophonates, is probably still comparatively low.