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% usersCPRD

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?