Introduction
Methods
Study population
Exposure
Fracture outcomes
Assessment of risk markers
Statistical analyses
Prospective cohort analyses
Systematic review and meta-analysis
Results
Baseline characteristics
Overall (N = 1743) Mean (SD), median (IQR), or n (%) | Without fracture (N = 1540) Mean (SD), median (IQR), or n (%) | With fracture (N = 203) Mean (SD), median (IQR), or n (%) |
P value* | |
---|---|---|---|---|
Questionnaire/prevalent conditions
| ||||
Age at survey (years) | 62.9 (6.5) | 62.5 (6.4) | 65.2 (6.4) | <0.0001 |
Males | 830 (47.6) | 763 (50.0) | 67 (33.0) | <0.001 |
Alcohol consumption (g/week) | 48.2 (100.4) | 48.5 (101.6) | 46.2 (91.2) | 0.755 |
Socioeconomic status | 10.9 (4.7) | 10.8 (4.7) | 11.4 (4.6) | 0.081 |
History of diabetes | 140 (8.0) | 123 (8.0) | 17 (8.4) | 0.849 |
Smoking status | 228 (13.1) | 203 (13.2) | 25 (12.3) | 0.731 |
History of hypertension | 722 (41.4) | 637 (41.4) | 85 (41.9) | 0.890 |
History of CHD | 488 (28.0) | 418 (27.1) | 70 (34.5) | 0.029 |
History of heart failure | 129 (7.4) | 108 (7.0) | 21 (10.3) | 0.088 |
Use of medication
| ||||
Antihypertensives | 736 (42.2) | 643 (41.8) | 93 (45.8) | 0.271 |
Beta-blockers | 457 (26.2) | 396 (25.7) | 61 (30.1) | 0.187 |
CCBs | 210 (12.1) | 182 (11.8) | 28 (13.8) | 0.417 |
Diuretics | 172 (9.9) | 146 (9.5) | 26 (12.8) | 0.135 |
Statins | 78 (4.5) | 74 (4.8) | 4 (2.0) | 0.066 |
ACEIs and/or ARBs | 249 (14.3) | 222 (14.4) | 27 (13.3) | 0.670 |
Physical measurements
| ||||
BMI (kg/m2) | 27.9 (4.5) | 27.8 (4.4) | 28.1 (4.7) | 0.445 |
WHR | 0.91 (0.09) | 0.91 (0.09) | 0.89 (0.09) | 0.034 |
SBP (mmHg) | 135.9 (17.3) | 135.8 (17.3) | 136.3 (17.0) | 0.694 |
DBP (mmHg) | 81.1 (9.0) | 81.4 (9.0) | 79.4 (8.3) | 0.004 |
Physical activity (kj/day) | 477.6 (402.1) | 482.5 (408.7) | 441.0 (346.8) | 0.166 |
Blood biomarkers
| ||||
Total cholesterol (mmol/l) | 5.48 (0.96) | 5.48 (0.95) | 5.46 (1.05) | 0.735 |
HDL-C (mmol/l) | 1.25 (0.31) | 1.25 (0.31) | 1.28 (0.33) | 0.192 |
Triglycerides (mmol/l)** | 1.12 (0.83–1.54) | 1.12 (0.82–1.54) | 1.13 (0.83–1.55) | 0.554 |
Fasting plasma glucose (mmol/l) | 5.08 (1.21) | 5.07 (1.18) | 5.11 (1.39) | 0.667 |
RAS inhibitors and risk of fractures
Prospective cohort analysis
Events/total | Model 1 | Model 2 | Model 3 | ||||
---|---|---|---|---|---|---|---|
HR (95% CI) |
P value | HR (95% CI) |
P value | HR (95% CI) |
P value | ||
Total fractures
| |||||||
No use | 121/1093 | ref | ref | ref | |||
Diuretic use | 3/50 | 0.36 (0.11–1.14) | 0.083 | 0.34 (0.10–1.10) | 0.072 | 0.35 (0.11–1.13) | 0.080 |
β-blocker use | 52/351 | 1.11 (0.79–1.54) | 0.547 | 1.06 (0.71–1.59) | 0.771 | 1.07 (0.72–1.61) | 0.729 |
ACEI or ARB use | 27/249 | 1.00 (0.66–1.52) | 0.992 | 1.00 (0.59–1.69) | 0.997 | 1.00 (0.59–1.69) | 0.988 |
Hip fractures
| |||||||
No use | 39/1093 | ref | ref | ref | |||
Diuretic use | 1/50 | 0.31 (0.04–2.28) | 0.250 | 0.31 (0.04–2.36) | 0.258 | 0.33 (0.04–2.50) | 0.281 |
β-blockers use | 24/351 | 1.39 (0.83–2.34) | 0.209 | 1.76 (0.91–3.39) | 0.093 | 1.81 (0.94–3.49) | 0.078 |
ACEI or ARB use | 6/249 | 0.66 (0.28–1.55) | 0.338 | 0.89 (0.32–2.47) | 0.820 | 0.89 (0.32–2.47) | 0.819 |
Wrist fractures
| |||||||
No use | 30/1093 | ref | ref | ref | |||
Diuretic use | 1/50 | 0.51 (0.07–3.81) | 0.513 | 0.72 (0.09–5.78) | 0.755 | 0.73 (0.09–5.88) | 0.769 |
β-blocker use | 5/351 | 0.47 (0.18–1.22) | 0.120 | 0.52 (0.18–1.54) | 0.239 | 0.53 (0.18–1.57) | 0.251 |
ACEI or ARB use | 6/249 | 0.95 (0.39–2.28) | 0.905 | 1.19 (0.39–3.64) | 0.764 | 1.20 (0.39–3.68) | 0.749 |
Meta-analysis of published cohort studies
References | Name of study/source of participants | Location of study | Year(s) of baseline survey | Baseline age range (years) | % male | Mean/median duration of follow-up (years) | Total no. of participants | Fracture types | No. of fracture cases | Covariates adjusted for | Study quality |
---|---|---|---|---|---|---|---|---|---|---|---|
Solomon et al. [44] | Medicare beneficiaries | USA | NR | ≥65 | 22.9 | 1.0 | 376,061 | Composite, hip, wrist, humerus, and pelvic | 6418 | Age, gender, race, Charlson comorbidity score, number of physician visits, acute-care hospitalizations, number of different medications, osteoporosis diagnoses and medications, prior fractures, BMD testing, use of medications with fracture associations (e.g., oral steroids, anticonvulsants, benzodiazepines, selective serotonin reuptake inhibitors, and proton pump inhibitors), diagnoses associated with falls (e.g., Parkinson disease and Alzheimer disease), and prior history of falls | 6 |
Song et al. [45] | KHIRAS database | Korea | 2005–2006 | ≥65 | 35.0 | 1.0 | 501,924 | Composite, hip, and vertebral | NR | Age, confounding comorbidities (osteoporosis, diabetes mellitus, hyperthyroidism, Cushing’s syndrome, COPD, asthma, chronic liver disease, chronic renal failure, congestive heart failure, dementia, stroke), and confounding medications (warfarin, antidepressants, benzodiazepines, anti-Parkinson drug, thiazolidinediones, bisphosphonates) | 5 |
Thorell et al. [46] | CDWO | Sweden | 2006 | ≥75 | 39.0 | 1.0 | 38,407 | Hip | 795 | Age, gender, and multimorbidity level | 5 |
Choi et al. [29] | HIRAS database | South Korea | 2007–2011 | ≥50 | 48.6 | 1.9 | 528,522 | Composite, vertebral, and non-vertebral | 16,805 | Age, gender, comorbidity score, diabetes, osteoporosis, osteoporosis treatment, and osteoporosis related diseases | 6 |
Ruths et al. [47] | Norwegian Prescription Database; Norwegian Hip Fracture Registry; Central Population Registry | Norway | 2005–2010 | 72.8* | 44.0 | 5.2 | 906,422 | Hip | 39,938 | NR | 6 |
Torstensson et al. [48] | Danish Nation-wide Register | Denmark | 1999–2012 | ≥65 | 81.2 | 6.7 | 1586,554 | Composite | 255,936 | Age, gender, calendar year, comorbidities and exposure to the other classes of CVD-drugs | 7 |
Yamamoto et al. [22] | MBD-5D Study | Japan | 2008–2011 | 63.0* | 61.5 | 2.7 | 3276 | Composite | 178 | Age, sex, duration of dialysis, causes of end-stage kidney disease, BMI; Kt/V; comorbidity of cardiovascular disease and/or DM; smoking; history of parathyroidectomy; prescriptions of anticoagulants, vitamin D receptor activators, and phosphate binders; and serum levels of albumin, calcium, phosphorus, intact parathyroid hormone, alkaline phosphatase, and blood hemoglobin, in addition to systolic and diastolic blood pressure and the use of antihypertensive drugs (β-blockers, CCB, diuretics, and others) | 6 |
Corrao et al. [49] | NHS | Italy | 2005–2009 | 70–90 | NR | 5.0 | 81,617 | Hip | 2153 | Use of antidepressants, neuroleptics, hypoglycemic agents, statins, digoxin, benzodiazepines, anti-arrhythmics, and anti-epileptics; Charlson comorbidity index | 6 |
Kwok et al. [50] | MrOS | USA | 2000–2002 | ≥65 | 100.0 | 6.8 | 2573 | Non-vertebral and hip or wrist | 801 | Age, tricyclic antidepressants, thiazide use, previous fracture, inability to complete a narrow walk trial, falls in previous year, depressed mood, hip BMD, DM, cardiac failure, hypertension, duration of use of loop diuretic, statin, beta blocker and ARB (or ACEI) | 7 |
Chen et al. [28] | TBNHI | Taiwan | 2002–2012 | 65–80 | 43.6 | 11.0 | 1144 | Composite | 128 | Age, sex, comorbidities, concurrent medication | |
Current study | KIHD | Finland | 1998–2001 | 53–74 | 47.6 | 14.8 | 1743 | Composite, hip, and wrist | 203 | Age, sex, body mass index, smoking, history of diabetes, systolic blood pressure, prevalent hypertension, prevalent coronary heart disease, prevalent heart failure, alcohol consumption, statin use, calcium channel blocker use, socioeconomic status, and physical activity | 8 |