Table 1.

Characteristics of Studies Included in the Final Analysis (N = 11)

StudyCountry; Study Design or SettingStudy YearsOutcome and AscertainmentAgent and ComparisonAdjusted OR or RR (95% CI)Adjustment VariablesExposed and Unexposed Case/Control, n
BMI = body mass index; CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease; CRF = chronic renal failure; DMARD=disease-modifying anti-rheumatic drug; GPRD = General Practice Research Database; HCC = hospital-based case-control; ICD=International Classification of Diseases; H2RA=histamine 2 receptor antagonist; HRT = hormone replacement therapy; MI = myocardial infarction; MrOS = Osteoporotic Fractures in Men study; na = not available; NCC = nested case-control; NSAID=nonsteroidal anti-inflammatory drug; OR = odds ratio; PCC = population-based case-control; PPI = proton pump inhibitor; RA = rheumatoid arthritis; RR=relative risk; SOF = Study of Osteoporotic Fractures.
aCombined OR with 95% CI calculated from data set.
Grisso et al,49 1997USA; HCC; Kaiser Permanente, northern California; men aged ≥45 y1991–1993Outcome: hip fracture
 Ascertainment: radiologically confirmed diagnosisAgent: cimetidine
 Comparison: ever use vs never use2.00 (1.0–4.4)Age category, zip code or telephone exchange, age as a continuous variable, and BMIExposed: 39/26
 Unexposed: 317/376
Vestergaard et al,39 2006Denmark; PCC; whole population2000Outcome: hip fracture, spine fracture, forearm fracture, any fracture
 Ascertainment: insurance code using ICD systemAgent: PPIs, H2RA, other antacids, antihistamines, and NSAIDs
 Comparison: last use <1 y ago vs nonusePPIs
 Total: 1.18 (1.1–1.4)
 Hip: 1.45 (1.3–1.7)
 Spine: 1.60 (1.3–2.0) Forearm: 0.95 (0.8–1.1)
 Total: 0.88 (0.8–0.95)
 Hip: 0.69 (0.6–0.8)
 Spine: 1.00 (0.7–1.4)
 Forearm: 0.90 (0.7–1.1)Alcoholism; working or not; Charlson index; ever use of antiepileptic drugs, anxiolytics or sedatives, antidepressants, neuroleptics, corticosteroids; number of bed-days in 1999; number of contacts to general practitioner or specialist in 1999; living with someone or alone; prior fracture; education level; and income in 1999Exposed: PPIs: 14,557/29,784
 H2RAs: 11,202/26,333
 Unexposed: PPIs: 10,098/344,178
 H2RAs: 113,453/347,629
Yang et al,22 2006UK; NCC; GPRD; patients aged ≥50 y1987–2003Outcome: hip fracture
 Ascertainment: confirmed by general practitionersAgent: PPIs and H2RAs
 Comparison: user (>1 y) vs nonuserPPIs: 1.44 (1.3–1.6)
 H2RAs: 1.23 (1.1–1.4)Age, sex, BMI, medication use, and health conditionExposed: PPIs: 571/3,351
 H2RAs: 732/4,478
 Unexposed: PPIs: 12,985/132,035
 H2RA: 12,824/130,908
Kaye and Jick,42 2008UK; NCC; GPRD; patients aged 50–79 y1995–2005Outcome: hip fracture
 Ascertainment: computerized medical records (Oxford Medical Information System or Read codes)Agent: PPIs
 Comparison: any PPI prescription vs no prescription0.90 (0.7–1.1)Age, sex, smoking, and BMIExposed: 132/1,428
 Unexposed: 966/9,495
Targownik et al,23 2008Canada; PCC; patients aged ≥50 y1996–2004Outcome: fractures of hip, vertebra, and wrist
 Ascertainment: physician or hospital admission with a diagnosis of osteoporosis-related fractures (ICD system)Agent: PPIs
 Comparison: user vs nonuserExposure ≥7 y
 Hip+vertebra+wrist: 1.92 (1.2–3.2)
 Hip+vertebra: 2.47 (1.2–5.1)
 Hip: 4.55 (1.7–12.3)Area of residence, income, comorbidity, home care services, medications that might have affected the risk of osteoporosis or fractureExposed: 415/872
 Unexposed: 12,963/39,176
Yu et al,40 2008USA; cohort; men and women aged ≥65 y1986–2007Outcome: nonspine and hip fracture
 Ascertainment: review of radiographic reports or radiologistAgent: PPIs and H2RAs
 Comparison: user vs nonuserPPIs
 Nonspine: 1.3 (1.1–1.53)a
 Hip: 1.05 (0.8–1.5)a
 Nonspine: 1.04 (0.9–1.2)a
 Hip: 1.26 (0.9–1.7)aAge, clinic, race, BMI, alcohol, exercise, corticosteroids, NSAIDs, calcium supplement, osteoporosis medication, self-reported health, initial total hip BMD, weight change, (SOF; caffeine, estrogen), (MrOS; smoking, history of stomach surgery)na
Roux et al,41 2009France; cohort; women aged 55–79 y1999–2007Outcome: vertebral fracture
 Ascertainment: 2 radiologistsAgent: omeprazole
 Comparison: user vs nonuser3.10 (1.1–8.4)BMI, history of clinical low-trauma fracture, steroids, thiazide, thyroid hormone, calcium, vitamin D, smoking, alcohol, self-reported falls and health poor to fair, baseline lumbar spine T score, spine and/or hip T score ≤2.5Exposed: risk among exposed=14/61
 Unexposed: risk among unexposed=128/1,150
Gray et al,51 2010USA; cohort; Women’s
 Health Initiative; women aged 50–79 y1993–2005Outcome: hip, spine, forearm, or wrist fracture
 Ascertainment: review of radiology reportsAgent: PPIs and H2RAs
 Comparison: user vs nonuserPPIs
 Total: 1.25 (1.2–1.4)
 Hip: 1.00 (0.7–1.4)
 Spine: 1.47 (1.2–1.8)
 Forearm or wrist: 1.26 (1.1–1.5)
 Total: 1.08 (1.0–1.1)
 Hip: 1.07 (0.9–1.3)
 Spine: 1.02 (0.9–1.2)
 Forearm or wrist: 1.05 (0.9–1.2)Age, race/ethnicity, BMI, enrollment in clinical trial status, indicator for cohort, smoking, physical activity, self-reported health, having a parent who broke a hip after age 40 y, treated diabetes mellitus, history of fracture at 55 y or older, corticosteroid use, physical function score, history of MI or angina, asthma or emphysema, arthritis, stomach or duodenal ulcer, moderate or severe heart-burn, osteoporosis, number of psychoactive medications, use of HRT and bisphosphonatesna
Corley et al,50 2010USA; NCC; Kaiser Permanente, northern California1995–2007Outcome: hip/femur fracture
 Ascertainment: electronic codingAgent: PPIs and H2RAs
 Comparison: user vs nonuserPPIs
 Hip: 1.30 (1.21–1.39)
 Hip: 1.18 (1.08–1.29)Age, sex, smoking, alcohol abuse, diabetes, arthritis, kidney disease, ethnicity, medicationsExposed: PPIs: 1,558/4,806
 H2RAs: 875/3,061
 Unexposed: PPIs: 32,194/125,665
 H2RAs: 32,877/127,410
Chiu et al,53 2010Taiwan; PCC; patients aged ≥50 y2005–2006Outcome: hip fracture
 Ascertainment: ICD code for National Health InsuranceAgent: PPIs
 Comparison: user vs nonuser2.11 (1.45–3.07)Age, sex, hypertension, diabetes, stroke, asthma, COPD, CHF, MI, dementia, depression, CRF, NSAID, corticosteroids, anticoagulants, diuretics, antipsychotics, thyroxine, HRT, statins, antihypertensive medications, sedatives, bisphosphonatesna
Pouwels et al,52 2011Netherlands; PCC1991–2002Outcome: hip/femur fracture
 Ascertainment: ICD codeAgent: PPIs and H2RAs
 Comparison: current use vs never usePPIs
 Hip: 1.20 (1.04–1.4)
 Hip: 1.19 (1.00–1.4)Use of other antacids, average daily dose of oral corticosteroids, anxiolytics/hypnotics, short- or long-acting benzodiazepines, HRT, anticonvulsants, antipsychotics, antidepressants, β-blockers, antidiabetics, ≥2 NSAIDs, DMARDs, a history of digestive system disorders, anemia, mental disorders, cerebrovascular disease, CHF, endocrine disorders, RA, diabetes mellitus, COPD and inflammatory bowel disease. Furthermore, the PPI analysis was adjusted for the use of H2RAs and the H2RA analysis for the use of PPIsExposed: PPIs: 305/773
 H2RAs: 196/520
 Unexposed: PPIs: 5,810/23,430
 H2RAs: 5,624/22,545