Characteristics of Studies Included in the Final Analysis (N = 11)
| Study | Country; Study Design or Setting | Study Years | Outcome and Ascertainment | Agent and Comparison | Adjusted OR or RR (95% CI) | Adjustment Variables | Exposed 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 1997 | USA; HCC; Kaiser Permanente, northern California; men aged ≥45 y | 1991–1993 | Outcome: hip fracture Ascertainment: radiologically confirmed diagnosis | Agent: cimetidine Comparison: ever use vs never use | 2.00 (1.0–4.4) | Age category, zip code or telephone exchange, age as a continuous variable, and BMI | Exposed: 39/26 Unexposed: 317/376 |
| Vestergaard et al,39 2006 | Denmark; PCC; whole population | 2000 | Outcome: hip fracture, spine fracture, forearm fracture, any fracture Ascertainment: insurance code using ICD system | Agent: PPIs, H2RA, other antacids, antihistamines, and NSAIDs Comparison: last use <1 y ago vs nonuse | PPIs 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) H2RAs 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 1999 | Exposed: 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 2006 | UK; NCC; GPRD; patients aged ≥50 y | 1987–2003 | Outcome: hip fracture Ascertainment: confirmed by general practitioners | Agent: PPIs and H2RAs Comparison: user (>1 y) vs nonuser | PPIs: 1.44 (1.3–1.6) H2RAs: 1.23 (1.1–1.4) | Age, sex, BMI, medication use, and health condition | Exposed: PPIs: 571/3,351 H2RAs: 732/4,478 Unexposed: PPIs: 12,985/132,035 H2RA: 12,824/130,908 |
| Kaye and Jick,42 2008 | UK; NCC; GPRD; patients aged 50–79 y | 1995–2005 | Outcome: hip fracture Ascertainment: computerized medical records (Oxford Medical Information System or Read codes) | Agent: PPIs Comparison: any PPI prescription vs no prescription | 0.90 (0.7–1.1) | Age, sex, smoking, and BMI | Exposed: 132/1,428 Unexposed: 966/9,495 |
| Targownik et al,23 2008 | Canada; PCC; patients aged ≥50 y | 1996–2004 | Outcome: 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 nonuser | Exposure ≥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 fracture | Exposed: 415/872 Unexposed: 12,963/39,176 |
| Yu et al,40 2008 | USA; cohort; men and women aged ≥65 y | 1986–2007 | Outcome: nonspine and hip fracture Ascertainment: review of radiographic reports or radiologist | Agent: PPIs and H2RAs Comparison: user vs nonuser | PPIs Nonspine: 1.3 (1.1–1.53)a Hip: 1.05 (0.8–1.5)a H2RAs Nonspine: 1.04 (0.9–1.2)a Hip: 1.26 (0.9–1.7)a | Age, 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 2009 | France; cohort; women aged 55–79 y | 1999–2007 | Outcome: vertebral fracture Ascertainment: 2 radiologists | Agent: omeprazole Comparison: user vs nonuser | 3.10 (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 ≤2.5 | Exposed: risk among exposed=14/61 Unexposed: risk among unexposed=128/1,150 |
| Gray et al,51 2010 | USA; cohort; Women’s Health Initiative; women aged 50–79 y | 1993–2005 | Outcome: hip, spine, forearm, or wrist fracture Ascertainment: review of radiology reports | Agent: PPIs and H2RAs Comparison: user vs nonuser | PPIs 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) H2RAs 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 bisphosphonates | na |
| Corley et al,50 2010 | USA; NCC; Kaiser Permanente, northern California | 1995–2007 | Outcome: hip/femur fracture Ascertainment: electronic coding | Agent: PPIs and H2RAs Comparison: user vs nonuser | PPIs Hip: 1.30 (1.21–1.39) H2RAs Hip: 1.18 (1.08–1.29) | Age, sex, smoking, alcohol abuse, diabetes, arthritis, kidney disease, ethnicity, medications | Exposed: PPIs: 1,558/4,806 H2RAs: 875/3,061 Unexposed: PPIs: 32,194/125,665 H2RAs: 32,877/127,410 |
| Chiu et al,53 2010 | Taiwan; PCC; patients aged ≥50 y | 2005–2006 | Outcome: hip fracture Ascertainment: ICD code for National Health Insurance | Agent: PPIs Comparison: user vs nonuser | 2.11 (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, bisphosphonates | na |
| Pouwels et al,52 2011 | Netherlands; PCC | 1991–2002 | Outcome: hip/femur fracture Ascertainment: ICD code | Agent: PPIs and H2RAs Comparison: current use vs never use | PPIs Hip: 1.20 (1.04–1.4) H2RAs 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 PPIs | Exposed: PPIs: 305/773 H2RAs: 196/520 Unexposed: PPIs: 5,810/23,430 H2RAs: 5,624/22,545 |