NPC Archive Item: Are oral bisphosphonates associated with an increased risk of oesophageal cancer?

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7 October 2010

A UK case-control study suggests a small increased risk of oesophageal cancer (but not stomach or colorectal cancer) in people with previous prescriptions for oral bisphosphonates. The increased risk equates to about one extra case of oesophageal cancer for every 1000 people aged 60–79 years who take bisphosphonates for five years. However, in view of the limitations of the study and evidence from other studies, the findings are not strong enough to suggest a definite association between oral bisphosphonates and oesophageal cancer.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

The MHRA have previously issued detailed guidance on this safety issue and prescribers should continue to follow this advice. It is important that patients who are prescribed bisphosphonates are advised to carefully follow the instructions in the Patient Information Leaflet on how to take the medicine, and to report any signs of oesophageal irritation such as difficulties or pain on swallowing, chest pain or heartburn to their doctor. The safety of all bisphosphonates will continue to be monitored closely by the MHRA.

What is the background to this?
Bisphosphonates are widely prescribed for the prevention and treatment of bone-related conditions, in particular osteoporosis (see NICE Technology Appraisal Guidance 160 and 161). Among other side effects, oral formulations of bisphosphonates (alendronate, ibandronate and risedronate) are associated with serious oesophageal adverse reaction including oesophagitis and oesophageal ulcers, strictures, and erosions. Warnings about these risks and clear instructions on how to take these medicines are provided in their product information.

Following post-marketing reports of oesophageal cancer in association with oral bisphosphonate use the MHRA, in conjunction with the Cancer Epidemiology Unit at the University of Oxford, conducted this study to examine this issue. They also examined the risk of cancers of the stomach and colorectum.

What does this study claim?
This nested case control study used a large cohort of men and women, aged 40 years or older, identified from the UK General Practice Research Database (GPRD). It identified patients who had been diagnosed with oesophageal, stomach or colorectal cancer during a 10-year period and whether they had also received a prescription for bisphosphonates. Taking into account a number of confounding factors, the study identified a statistically significantly increased risk of oesophageal cancer (but not stomach or colorectal cancers) in individuals with prior prescriptions for oral bisphosphonates compared with those who had not received bisphosphonates (relative risk [RR] 1.30, 95% confidence interval [CI] 1.02 to 1.66; P=0.02]. The risk was significantly higher for those patients who used bisphosphonates for more than 3 years (on average about 5 years; RR 2.24, 95%CI 1.47 to 3.43 compared with no use) and for those who had more than 10 prescriptions for bisphosphonates. The incidence of oesophageal cancer in Europe and North America in people aged 60–79 years is about 0.5 cases per 1000 women and 1.5 cases per 1000 men over a period of five years. If these study results were true, these rates would be approximately doubled in users of bisphosphonates to 1 case per 1000 women aged 60–79 years and 3 cases per 1000 men over 5 years.

How does this relate to other studies?
Several other studies have examined the relationship between oral bisphosphonates and oesophageal cancer and have not identified a significantly increased risk of cancer with bisphosphonates. In correspondence to the New England Journal of Medicine in 2009, Abrahamson et al, and Solomon et al report analyses that do not show an increased risk of oesophageal cancer with the use of bisphosphonates. However, the value of these studies is difficult to assess as full details are not published. More recently, a study by Cardwell et al, also using data extracted from the UK GPRD, found no significant increase in the incidence of oesophageal and gastric cancer between patients treated with oral bisphosphonates and non-users (between January 1996 and December 2006, about 40,000 in each cohort). The incidence of oesophageal cancer alone in the bisphosphonate and control cohorts was 0.48 and 0.44 per 1000 person-years of risk, respectively (adjusted hazard ratio1.07, 95%CI 0.77 to1.49).

The results of the Cardwell study were considered by the authors of the present study. Although the Cardwell study used the same database as the present study, the observation time was considerably shorter (average 4.5 vs. 7.7 years) and the study had less statistical power to detect an effect. When broadly equivalent exposures were compared the confidence intervals for the relative risks in both studies overlap, and the results of the two studies cannot be considered significantly different.

So what?
The MHRA presented the findings of this study, together with available evidence (not including the Cardwell study) to the Commission of Human Medicines (CHM) who reviewed all the evidence. Although there were strengths to the study, notably the large sample size, long follow up and attempts to account for confounding factors, the CHM considered that the study had a number of limitations. These were due to the limited amount of information available in the GPRD database, and other factors unrecorded in the database that may have influenced the results. In view of the limitations and lack of supporting evidence the MHRA consider that there is insufficient evidence to suggest a definite association between oral bisphosphonates and oesophageal cancer. The benefits of bisphosphonates are still considered to outweigh the risk, although as with all medicines the safety of bisphosphonates will continue to be monitored.

There is a specific MHRA webpage which provides information for patients and healthcare professions about the safety issues around the use of bisphosphonates. This includes links to previously issued MHRA advice.

Study details
Green J, et al. Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. BMJ 2010; 341:c4444

Nested case-control analysis within a primary care cohort of about 6 million people in the UK, with prospectively recorded information on prescribing of bisphosphonates.

UK General Practice Research Database cohort. Men and women aged 40 years or over — 2,954 with oesophageal cancer, 2,018 with gastric cancer, and 10,641 with colorectal cancer, diagnosed in 1995–2005; five controls per case matched for age, sex, general practice, and observation time.

Intervention and comparison
Relative risks for incident invasive cancers of the oesophagous, stomach, and colorectum, adjusted for smoking, alcohol, and body mass index.

Outcomes and results
The incidence of oesophageal cancer was increased in people with one or more previous prescriptions for oral bisphosphonates compared with those with no such prescriptions (RR 1.30, 95%CI 1.02 to1.66; P=0.02). Risk of oesophageal cancer was significantly higher for 10 or more prescriptions (RR 1.93, 95%CI 1.37 to 2.70) than for one to nine prescriptions (RR 0.93, 95%CI 0.66 to 1.31), and for use for over 3 years (on average, about five years: RR vs. no prescription 2.24, 95%CI 1.47 to 3.43). 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. Cancers of the stomach and colorectum were not associated with prescription of bisphosphonates — one or more vs. no prescriptions: RR 0.87 (95%CI 0.64 to 1.19) and RR 0.87 (95%CI 0.77 to 1.00), respectively.

Sponsorship: Cancer Research UK provided funding for the study.

More information on the treatment of osteoporosis can be found on the osteoporosis section of NPC and in the MeReC Bulletin on the management of osteoporosis in a post-menopausal woman.

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