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Exposure to bisphosphonates and risk of non-gastrointestinal cancers:
nested case-control studies
SAPC 2013 , Nottingham
Yana Vinogradova, Carol Coupland, Julia Hippisley-Cox
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
• 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
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
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
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)
Methods: Statistical analysis
• Multiple imputations• Conditional logistic regression• Combined analysis
– Odds ratios + 95% CI – 1% significance level
QRESEARCH
Cases: exposed total
Breast 1304 24,489
Prostate 460 26,554
Lung 1035 17,961
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 1324 25,444
Prostate 376 23,176
Lung 1114 19,059
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
1
2
3
4
5
6
7
8
1998 2001 2004 2007 2010 1998 2001 2004 2007 2010
QResearch CPRD
controls bisphosphonates cases
controls etidronate cases
controls alendronate cases
controls risedronate cases
%
Index year
© QRESEARCH 2011 version 31, CPRD March 2012
Proportion of cases and controls exposed to bisphosphonates by index year
Cervix, 0.78 (0.48 to 1.27)
Uterus, 1.07 (0.79 to 1.44)
Ovary, 1.19 (0.96 to 1.47)
Pancreas, 0.81 (0.64 to 1.01)
Melanoma, 1.05 (0.87 to 1.28)
Bladder, 0.96 (0.80 to 1.14)
Lung, 0.97 (0.88 to 1.08)
Prostate, 0.90 (0.79 to 1.02)
Breast, 0.89 (0.82 to 0.97)
Cancer site, OR (95%CI)
.5 .75 1 1.25 1.5
OR and 95% CI
Cervix, 1.21 (0.76 to 1.93)
Uterus, 0.95 (0.71 to 1.27)
Ovary, 0.84 (0.67 to 1.04)
Pancreas, 0.78 (0.63 to 0.97)
Melanoma, 0.95 (0.77 to 1.19)
Bladder, 0.94 (0.79 to 1.12)
Lung, 1.12 (1.01 to 1.23)
Prostate, 0.84 (0.73 to 0.96)
Breast, 0.95 (0.88 to 1.03)
Cancer site, OR (95%CI)
.5 .75 1 1.25 1.5
OR and 95% CI
Any use of bisphosphonates and risk of cancer
QResearch CPRD
Cervix (1560) 0.98 (0.70 to 1.37)
Uterus (4393) 1.00 (0.81 to 1.24)
Ovary (6516) 1.00 (0.86 to 1.16)
Pancreas (7079) 0.79 (0.68 to 0.93)
Melanoma (9620) 1.01 (0.87 to 1.17)
Bladder (14548) 0.95 (0.84 to 1.08)
Lung (37020) 1.04 (0.97 to 1.12)
Prostate (49730) 0.87 (0.79 to 0.96)
Breast (49933) 0.92 (0.87 to 0.97)
Cancer site (N of cases) OR (95%CI)
.5 .75 1 1.25 1.5
Adjusted OR's and 95% CI's
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
P=0.003
6years+ 0.89 (0.59 to 1.33)
3yrs < 6yrs 0.77 (0.60 to 1.00)
7mths < 3yrs 0.85 (0.72 to 1.00)
up to 6 mths 1.11 (0.90 to 1.36)
QResearch OR (95%CI)
.5 .75 1 1.25
OR and 95%CI
6years+ 0.77 (0.49 to 1.22)
3yrs < 6yrs 0.87 (0.66 to 1.14)
7mths < 3yrs 0.83 (0.69 to 0.99)
up to 6 mths 0.86 (0.68 to 1.08)
CPRD OR (95%CI)
.5 .75 1 1.25
OR and 95%CI
Prostate cancer: long-term use of bisphosphonates
1yr or more, 1.09 (0.81 to 1.46)
overall use, 0.98 (0.77 to 1.23)
Risedronate
1yr or more, 1.04 (0.81 to 1.33)
overall use, 1.06 (0.87 to 1.30)
Etidronate
1yr or more, 0.75 (0.62 to 0.92)
overall use, 0.81 (0.70 to 0.93)
Alendronate
.75 1 1.25 1.5
OR and 95%CI
1yr or more, 0.83 (0.58 to 1.19)
overall use, 0.87 (0.66 to 1.13)
Risedronate
1yr or more, 1.02 (0.77 to 1.34)
overall use, 0.88 (0.70 to 1.10)
Etidronate
1yr or more, 0.86 (0.70 to 1.05)
overall use, 0.88 (0.75 to 1.03)
Alendronate
.75 1 1.25 1.5
OR and 95%CI
Prostate cancer: types of bisphosphonates
QResearch CPRD
P=0.004 Ptrend=0.009
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
• 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
Thank you
Questions?
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