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 |