Exposure to bisphosphonates and risk of cancer: a protocol for nested case–control studies using the QResearch primary care database

Abstract

IntroductionBisphosphonates are becoming a common treatment for osteoporosis particularly after discovery of the association between hormone replacement therapy and increased risk of breast cancer. As osteoporosis develops with age, treatment is a long-term intervention. Randomised control trials typically have limited follow-up times, which restricts investigation of the effects of the drugs on risk of primary cancers. A few observational studies have demonstrated a reduced risk of breast cancer and possibly of endometrial cancer in bisphosphonate users. Two epidemiological studies have studied the effect of the drugs on oesophageal cancer but did not reach any definite conclusions. So far, no effects on colorectal and stomach cancer have been shown. This study will investigate the association of bisphosphonates with risks of the 10 most common primary cancers.Methods and analysisA series of nested case–control studies will be based on the general population using records from 660 UK general practices within the QResearch Database. Cases will be patients with primary cancers diagnosed between 1996 and 2011. Each case will be matched by age, sex, practice and calendar year to five controls, who are alive and registered with the practice at the time of diagnosis of the case. Exposure to bisphosphonates will be defined as at least one prescription during the study period. For the most common cancers with substantial numbers of observations, the effect of the duration of the treatment and different types of bisphosphonates will be studied. Conditional logistic regression will be applied to produce ORs adjusted for smoking status, socioeconomic status, ethnicity, cancer-specific co-morbidities and use of other medications.

Meta‐analysis: oral bisphosphonates and the risk of oesophageal cancer

“…We are aware of an upcoming study by Vinogradova et al, 32 for which a protocol has been published. This study will also use data from the UK, and it will be interesting to see what results the investigators will report, considering the relative inconsistency of the current two studies from the UK, Cardwell et al 16 and…”

Exposure to bisphosphonates and risk of common non-gastrointestinal cancers: series of nested case–control studies using two primary-care databases

“…Both are representative of the general population in the United Kingdom, have been rigorously validated using other sources of information (Jick et al , 2003; Hippisley-Cox et al , 2004) and have been used for a range of safety studies involving commonly prescribed medications (Green et al , 2010; Hippisley-Cox and Coupland, 2010; Parker et al , 2010; Walker et al , 2011). The protocol for this study was published in Vinogradova et al (2012) and, although originally based on QResearch, a replicate study has also been conducted using CPRD to examine any possible differences between the two and further increase in the statistical power by running analyses to derive combined results from both data sources.…”

“…If they were diagnosed at least a year before the index date, comorbidities, which affect risks of cancer, were also included: rheumatoid arthritis (Thomas et al , 2000) for any cancer; benign breast disease for breast cancer; diabetes for pancreatic (Vincent et al , 2011) and uterine (Burbos et al , 2010) cancers; hypertension for uterine cancer (Bangalore et al , 2011); and gastrointestinal disorders for pancreatic cancer (Vinogradova et al , 2012). The results were also adjusted for cancer-specific family histories of cancer (Mai et al , 2011) (to reduce recall bias in cases only if recorded at least 6 months before the index date; Chang et al , 2006).…”

“…Although sample size calculations were carried out and presented in the protocol (Vinogradova et al , 2012), all available data were used in the analyses. We considered a 1% level as statistically significant to allow for multiple comparisons, but have presented 95% CIs in our results to create parity with other studies.…”

The identification of incident cancers in UK primary care databases: a systematic review

“…In total, only 5 of the 84 studies (6%) described methods used to create study code lists (Table ). Five studies (6%) included details directly in the publication, 2 (2%) included the list itself as an appendix, and 3 (4%) by stating which Read code chapters and sections were used; a further 6 (7%) stated that the list was ‘available on request’ …”