1. Exposure to bisphosphonates and risk of non-gastrointestinal cancers: nested case-control studies SAPC 2013, Nottingham Yana Vinogradova, Carol Coupland, Julia Hippisley-Cox

2. Background  Bone loss and bisphosphonates  Laboratory linkages with reduced cancer risk Anti-tumor properties, accumulation in different organs  Treatment for osteoporosis and cancer risk  Reduced risk of breast cancer Chlebowski (2010) 1993-1998 Newcomb (2010) 2003-2006 Rennert (2010) 2000-2006 Vestergaard (2011) 1996-2006  No associations for other cancers Cardwell (2011) 1996-2006

3. QResearch –EMIS –660 GP practices Clinical Practice Research Datalink –Main (EHR)-IT –643 GP practices Patient level data from GP clinical records Anonymised Longitudinal data for 20+ years Validated externally and internally Industry independent

4. Methods: Study design Nested case control study Study period Jan 1997 – July 2011 Aged 50 – 100 At least 2 years of records Up to 5 controls matched by –Age –Sex –Practice –Calendar year

5. Methods: Assessment of Exposure excluding 6 months before the index date use: at least 1 script short-term (<12m), long-term users different types of bisphosphonates

6. Methods: Confounding factors BMI, ethnicity, smoking, alcohol Osteoporosis Morbidities (rheumatoid arthritis, diabetes, benign breast disease, GI disorders, hypertension) Family history of cancers Other medications (NSAIDs, corticosteroids, acid-lowering drugs, vitamin D, HRT)

7. Methods: Statistical analysis Multiple imputations Conditional logistic regression Combined analysis –Odds ratios + 95% CI –1% significance level

8. QRESEARCH Cases: exposed total Breast 130424,489 Prostate 46026,554 Lung 103517,961 Bladder 274 7,464 Melanoma 241 4,998 Ovary 204 3,427 Pancreas 178 3,593 Uterus 99 2,248 Cervix 32 822 4.2% users CPRD Cases: exposed total Breast 132425,444 Prostate 37623,176 Lung 111419,059 Bladder 280 7,084 Melanoma 178 4,621 Ovary 170 3,088 Pancreas 196 3,485 Uterus 96 2,149 Cervix 35 739 4.2% users

10. Any use of bisphosphonates and risk of cancer QResearch CPRD

11. Any use of bisphosphonates and risk of cancer, combined analysis P-trend=0.2 P-trend=0.005 P-trend=0.02 P=0.004 P=0.003

12. Prostate cancer: long-term use of bisphosphonates

13. Prostate cancer: types of bisphosphonates QResearch CPRD P=0.004 Ptrend=0.009

14. Summary of findings Use of bisphosphonates is not associated with increased risk of any of the most common cancers Decreased risk of breast, prostate and pancreatic cancers had no duration relationship in either database Decreased risk of prostate cancer associated with alendronate use only in QResearch

15. Residual confounding as no information –on stage of cancer –on any cancer-related tests –on bone density test Information on prescriptions only Missing data Large sample size and representative population Data electronically collected – unlikely misclassification bias Data collected before diagnosis – no recall bias All cases used – no selection bias Data in the last 6 months before the diagnosis was excluded as might be misleading Based on the most recent data Limitations and Strengths

16. Thank you Questions?