This nested case control analysis found a significantly increased risk of oesophageal cancer in people with previous exposure to oral bisphosphonates. The risk of oesophageal cancer increased with 10 or more prescriptions for oral bisphosphonates and with prescriptions over approximately a five year period. For example, the results found prescribing of bisphosphonates over a period of about five years was associated with a doubling of the risk of oesophageal cancer.
The analysis was based on primary care data obtained from the United Kingdom General Practice Research Database (UK GPRD), a database covering a cohort of around 6 million people in the UK. The database provided prospectively recorded information on bisphosphonate prescribing for the purpose of the study. Cases were defined as men and women aged at least 40 years with a diagnosis of oesophageal cancer (n= 2954), gastric cancer (n= 2018) or colorectal cancer (n = 10,641). The cases were diagnosed between 1995 and 2005. Five controls were selected for each case (n= 77,750), with no record of gastrointestinal cancer before the index date (defined as the date of diagnosis of the case). The controls were matched for age, sex, general practice, and observation time. The frequency of oral bisphosphonate exposure in cases versus matched non-cases was compared. Patients were defined as being exposed to bisphosphonates if they had a record within the observation period of at least one prescription for any oral bisphosphonate preparation licensed in the UK for use in osteoporosis. The study excluded patients with prescriptions for bisphosphonates licensed to treat Paget’s disease or bone metastases. The main outcome measures considered were the relative risks for incident invasive cancers of the oesophagus, stomach, and colorectum, adjusted for smoking, alcohol, and body mass index (BMI). The results found (direct from source):
• 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 (relative risk 1.30, 95% confidence interval 1.02 to1.66; P=0.02).
• Risk of oesophageal cancer was significantly higher for 10 or more prescriptions (1.93, 1.37 to 2.70) than for one to nine prescriptions (0.93, 0.66 to 1.31) (P for heterogeneity=0.002), and for use for over 3 years (on average, about 5 years: relative risk vs. no prescription, 2.24, 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 bisphosphonate: relative risks for one or more versus no prescriptions were 0.87 (0.64 to 1.19) and 0.87 (0.77 to 1.00).
• The specificity of the association for oesophageal cancer argues against methodological problems in the selection of cases and controls or in the analysis.
The researchers discuss the strengths and limitations of their study, with the size of the study (almost 3,000 oesophageal cancer cases) being highlighted as a strength. The limitations include that fact that the UK GPRD does not provide information on what the drugs were actually used for, patient compliance or whether special instructions for taking the drugs were adhered to. They note, “On the basis of incidences for Europe and North America published by the World Health Organisation in 2007, a doubling of risk of oesophageal cancer associated with about five years’ use of oral bisphosphonates would mean an estimated overall increase in incidence of oesophageal cancer in people aged 60-79 years from 1 case per 1000 population over five years in both sexes combined (in women 0.5 and in men 1.5 per 1000) in non-users to 2 cases per 1000 over five years (in women 1 case and in men 3 cases per 1000) in users.”
The researchers conclude that further research is required in this area “to confirm or refute” the findings and to investigate differences between types and formulations of bisphosphonates and risk of the different histological types of oesophageal cancer.
The author of an accompanying editorial says that the evidence is inconclusive, but advises cautious prescribing and active follow-up. A spokesperson for the National Osteoporosis Society told BBC News, "It is a case of balancing the reduced risk of fractures against the side effects of treatment. When you consider the fact that there are 230,000 osteoporotic fractures every year in the UK and 1,150 hip-fracture-related deaths every month, the case for treatment is strong."