Appendix Table D3Primary Prevention Randomized Controlled Trials

Author yearStudy design/durationInclusion criteriaPopulationInterventionsRoutine lumbar radiography to identify new fracturesFracturesAdverse events and withdrawalsComments
Ascott-Evans et al, 2003139Double-blind, randomized PCT
1 year
Postmenopausal aged <80 years; previous use of HRT for at least 1 year; baseline T-score −3.5 to −1.5n=144
aged <65 years: 85%
mean T-score: −2.3
previous fractures: excluded
Alendronate 10 mg qd vs. placeboNoAlendronate vs. placebo
Any fracture: 0/95 (0%) vs. 0/47 (0%)
Alendronate vs. placebo
Withdrawals: 25/144 (17.3%); 12/95 (13%) vs. 13/49 (26%)
Withdrawals due to AEs: 10/95 (10%) vs. 10/49 (20%)
Fracture incidence was not an efficacy outcome
Chesnut et al,1995140Double-blind, randomized PCT
2 years
At least 5 years postmenopausal aged 43–75 years; lumbar spine BMD ≤0.88 g/cm2 (~−2.0 SD below normal)n=188
mean age: 63 years
mean hip T-score: −1.1
previous fractures: excluded
Alendronate 10 mg qd vs. placeboYesAlendronate vs. placebo
Vertebral fracture: 0/30 (0%) vs. 0/31 (0%)
Non-vertebral fracture: 13 total, results not stratified by treatment group
Withdrawals: 34/188 (18%) overall (not stratified by treatment group) Other adverse events not stratified by treatment group
Cummings et al, 199850
Fracture Intervention Trial (FIT)
Double-blind, randomized PCT
4 years
At least 2 years postmenopausal age 55–80 years; femoral neck BMD ≤0.68 g/cm2 (~−1.6 SD below normal)n=4,432
mean age: 67.7 years
mean T-score: −2.2
previous fractures: excluded
Alendronate 5 mg qd for 2 years, then 10 mg qd for 1 year vs. placeboYesAlendronate vs. placebo
Vertebral fracture - first fracture: 43/2214 (1.9%) vs. 78/2218 (3.5%); RR 0.56 (CI 0.39–0.80; p=0.002)
Nonvertebral fracture: 261/2214 (11.8%) vs. 294/2218 (13.3%) placebo; RR 0.88 (CI 0.74 to 1.04; p=0.13)
Hip fracture: 19/2214 (0.9%) vs. 24/2218 (1.1%)
Wrist fracture: 83/2214 (3.7%) vs. 70/2218 (3.2%)
Alendronate vs. placebo
Withdrawals due to AEs: 221/2214 (9.9%) vs. 227/2218 (10.2%)
All-cause mortality: 37/2214 (1.7%) vs. 40/2218 (1.8%)
Any upper GI event: 1052/2214 (48%) vs. 1047/2218 (47%)
Abdominal pain: 322/2214 (14%) vs. 325/2218 (15%)
Esophagitis: 19/2214 (0.9%) vs. 10/2218 (0.5%)
Esophageal ulcer: 4/2214 (0.2%) vs. 4/2218 (0.2%)
Other esophageal: 44/2214 (2.0%) vs. 41/2218 (1.8%)
Acid regurgitation/reflux: 204/2214 (9.2%) vs. 194/2218 (8.7%)
Dursun et al, 2001141Randomized PCT
1 year
Postmenopausal with BMD ≤ −2.0 SD below mean at lumbar spine or femoral neckn=151
mean age: 61.2 years
mean T-score: −1.5
previous fractures: unknown
Alendronate 10 mg + calcium 1000 mg qd vs. calcium 1000 mg qdYesAlendronate vs. placebo
Vertebral fracture: 12/51 (24%) vs. 14/50 (28%)
Nonvertebral fracture: not reported
Withdrawals due to AEs: none in either treatment group
Greenspan et al, 2007151Double-blind, randomized PCT 18 monthsPostmenopausal age 45–54 years with T-score ≤ 3.0 below mean for young women with no prevalent vertebral fracture or T-score −2.5 with 1–4 vertebral fracturesn=2532 (n=2061 without baseline fracture)
mean age: 64.4 years
mean T-score: −2.2
previous fractures: 19%
PTH 100μg qd vs. placeboYesPTH vs. placebo. Vertebral fracture (results for participants without baseline fracture): PTH 7/1050 (0.7%) vs. placebo 21/1011 (2.1%) Nonvertebral fracture (results not stratified by baseline fracture status): 72/1286 (5.6%) vs. 72/1246 (5.8%)Parathyroid hormone vs. placeboWithdrawals: 831/2532 (32.8%) Withdrawals dues to AEs: 154/1286 (12%) vs. 76/1246 (6.1%) All-cause mortality: 1/1286 (0.08%) vs. 2/1246 (0.16%) Arthralgia: 282/1286 (22%) vs. 276/1246 (22%) Myalgia: 64/1286 (5.0%) vs. 62/1246 (5.0%)
Herd et al, 1997144Double-blind, randomized PCT
2 years
1–10 years postmenopausaln=152
mean age 54.8 years
mean T-score: −1.3
prior fractures: excluded
Cyclical etidronate 400 mg qd vs. placeboYesEtidronate vs. placebo
Any fracture: 0/75 (0%) vs. placebo 0/77 (0%)
Etidronate vs. placebo
Withdrawals: 11/75 (14.7%) vs. 6/77 (7.8%)
Withdrawals due to AEs: 5/75 (6.7%) vs. 0/77 (0%)
Back pain: 12/74 (16%) vs. 14/76 (18%)
Fracture incidence not an efficacy outcome
Hooper et al, 2005147Double-blind, randomized PCT
2 years
6–36 months postmenopausaln=383
mean age: 53 years
mean T-score: −0.7
previous fractures: unknown
Risedronate 2.5 to 5.0mg qd vs. placeboYesRisedronate 2.5 mg vs. 5 mg vs. placebo
Vertebral fractures: 11/127 (8.7%) vs. 10/129 (7.8%) vs. 10/125 (8.0%)
Nonvertebral fractures: 3/127 (2.4%) vs. 5/129 (3.9%) vs. 6/125 (4.8%)
Risedronate vs. placebo
Withdrawals: 52/256 (20%) vs. 32/125 (26%)
Withdrawals due to AEs: 19/256 (7.4%) vs. 8/125 (6.4%)
Abdominal pain: 18/256 (7.0%) vs. 6/125 (4.8%)
Hosking et al, 1998142Double-blind, randomized PCT
2 years
≥6 months postmenopausal with no clinical or laboratory evidence of systemic diseasen= 1609
mean age 53.3 years
mean T-score: −0.1
previous fractures: unknown
Alendronate 5 mg qd vs. placeboNoAlendronate vs. placebo
Vertebral fracture: 0/498 (0%) vs. 0/502 (0%)
Nonvertebral fracture: alendronate 2.5 mg 22/499 (4.4%) vs. alendronate 5 mg 22/498 (4.4%) vs. placebo 14/502 (2.8%)
Withdrawals: 139/1609 (8.6%); 89/997 (8.9%) alendronate vs. 46/503 (9.2%) placebo vs. 4/110 (3.4%) estrogen-progestin
Withdrawals due to AEs: 67/997 (6.7%) alendronate vs. 27/503 (5.4%) placebo vs. 15/110 (13.6%) estrogen-progestin
Upper GI AEs, any type: 300/997 (30%) alendronate vs. 148/502 (29%) placebo vs. 31/110 (28%) estrogen-progestin
CV AEs: 99/997 (10%) alendronate vs. 47/502 (9.4%) placebo vs. 15/110 (14%)
Baseline data and efficacy outcomes assessment included only women with baseline LS BMD and at least one on-treatment measurement; safety data included all randomized patients
Liberman et al, 199547Double-blind, randomized PCT
3 years
Age 45–80 years, ≥5 years postmenopausal with BMD T-score worse than −2.5n=637 (no prior fracture)
mean age: 64 years (with or without prior fracture)
mean T-score: −2.2
previous fracture: 21%
Alendronate 5 or 10 mg qd for 3 years or 20 mg qd for 2 years followed by 5 mg qd for 1 year vs. placeboYesAlendronate (all doses) vs. placebo
Vertebral fracture (in women without prior vertebral fracture) 4/384 (1.0%) vs. 5/253 (2.0%)
Alendronate 10 mg vs. placebo (with or without vertebral fracture at baseline)
Withdrawals: 26/196 (13.3%) vs. 65/397 (16.4%)
Withdrawals due to AEs: 35/597 (5.8%; all doses of alendronate) vs. 24/397 (6.0%)
Withdrawals due to upper GI AEs: 2/196 (1.0%) vs. 8/397 (2.0%)
Abdominal pain: 13/196 (6.6%) vs. 19/397 (4.8%)
Musculoskeletal pain: 8/196 (4.1%) vs. 10/397 (2.5%) Nausea: 7/196 (3.6%) vs. 16/397
(4.0%) Dyspepsia: 7/196 (3.6%) vs. 14/397 (3.5%)
Constipation: 6/196 (3.1%) vs. 7/397 (1.8%) Diarrhea: 6/196 (3.1%) vs. 7/397 (1.8%)
Non-vertebral fractures not reported in subgroup of women without baseline fracture
McClung et al, 200141Double-blind, randomized PCT
3 years
Women 70–79 years with BMD T-score worse than −4 or worse than −3 with non-skeletal risk factors for falln=2648 (no prior fracture)
mean age: 74 years (with or without prior fracture)
mean T-score: −3.7 (with or without prior fracture)
previous fractures: results of subgroup with no previous fractures reported
Risedronate 2.5 or 5 mg qd vs. placeboNoRisedronate 2.5 or 5 mg vs. placebo
Hip fracture (in women without prior vertebral fracture): 14/1773 (1.0%) vs. 12/875 (1.6%)
Risedronate 5 mg vs. placebo (with or without vertebral fracture at baseline)
Withdrawal due to AEs: 550/3104 (18%) vs. 564/3134 (18%)
Serious AEs: 943/3104 (30%) vs. 973/3134 (31%)
Any AEs: 2786/3104 (89.8%) vs. 2805/3134 (89.5%)
Any upper GI AEs: 657/3104 (21%) vs. 684/3134 (22%)
Moderate to severe upper GI AEs: 279/3104 (9.0%) vs. 258/3134 (8.3%)
Abdominal pain: 250/3104 (8.1%) vs. 288/3134 (9.2%)
Dyspepsia: 255/3104 (8.2%) vs. 254/3134 (8.1%) Esophagitis: 54/3104 (1.7%) vs. 59/3134
(1.9%) Esophageal ulcer: 9/3104 (0.3%) vs. 14/3134 (0.4%)
Hip fractures reported in subgroup of women without baseline fracture
Meunier et al, 1997145Double-blind, randomized PCT
2 years
6–60 months postmenopausal women within 15% of normal BMI, normal BMD (+/− 2SD expected value)n=54
mean age: 52.7 years
mean T-score: −1.1
previous fractures: not reported
Cyclical etidronate 400 mg qd vs. placeboYesEtidronate vs. placebo
Vertebral fracture: 1/27 (3.7%) vs. 0/27 (0%)
Non-vertebral fracture: 2/27 (7.4%) vs. 3/27 (11%)
Etidronate vs. placebo Withdrawals: 2/27 (7.4%) vs. 3/27 (11%)
Withdrawals due to AEs: 0/27 (0%) vs. 2/27 (7.4%) Pain: 5/27 (18%) vs. 5/27 (18%)
Abdominal pain: 4.27 (15%) vs. 1/27 (3.7%)
All reported fractures described as traumatic
Mortensen et al, 1998148Double-blind, randomized PCT
2 years treatment, outcomes assessed through 3 years
6–60 months postmenopause, weight 45–90kg, within 25% of normal weight and heightn=111
mean age: 51.5 years
mean T-score: −1.1
previous fractures: not reported
Risedronate 5 mg (daily or 2-week cyclical dosing) vs. placeboYesRisedronate daily vs. risedronate cyclic vs. placebo
Vertebral fractures: 1/37 (2.7%) vs. 1/38 (2.6%) vs. 0/36 (0%)
Nonvertebral fractures: 0/37 (0%) vs. 3/38 (7.9%) vs. 3/36 (8.3%)
Risedronate vs. placebo
Withdrawals: 15/111 (13.5%) overall
Withdrawals due to AEs: 5/75 (6.7%) vs. 3/36 (8.3%)
Abdominal pain: 8/75 (11%) vs. 4/36 (11%)
Nonvertebral fractures were all described as traumatic Withdrawals reported through year 1 - continuation in study beyond that point was at patient's discretion
Orwoll et al, 2003159Double blind, randomized PCT planned for 2 years, study stopped after median 11 monthsMen age 30–85 years, ambulatory, free of chronic, disabling conditions other than osteoporosis, lumbar spine of proximal femur BMD ≥ −2 SD below mean for healthy young menn=437
mean age: 59 years
mean T-score −2.7
previous fractures: unknown
Teriparatide 20 or 40 μg subcutaneous injection qd vs. placeboYesTeriparatide 20 ug vs. 40 ug vs. placebo
Vertebral fractures: not reported
Nonvertebral fracture: 2/151 (1.3%) vs. 1/139 (0.7%) vs. 3/147 (2.0%)
Teriparatide vs. placebo
Withdrawals due to AEs: 32/290 (11.0%) vs. 7/147 (4.8%)
Nausea: 34/290 (11.7%) vs. 5/147 (3.4%)
Pols et al, 1999143Double-blind, randomized PCT 1 year≤ 3 years postmenopause, ≥ 85 years, BMD of Lumbar spine (L2–4)
≥ −2 SD below the average for mature, menopausal women. Between > 20% and < 50% ideal body weight.
n = 1908
mean age: 63.0 years
mean T-score: −2.0
previous fractures: unknown
Alendronate 10 mg qd vs. placeboNoAlendronate vs. placebo
Vertebral fractures: not evaluated
Nonvertebral fractures: 19/950 (2.0%) vs. 37/958 (3.9%) placebo
Hip fracture: 2/950 (0.2%) vs. 3/958 (0.3%)
Wrist fracture: 6/950 (0.6%) vs. 15/958 (1.6%)
Ankle/lower leg fracture: 2/950 (0.2%) vs. 5/958 (0.5%)
Alendronate vs. placebo
Withdrawals due to AEs: 61/950 (6.4%) vs. 54/958 (5.6%)
Pouilles et al, 1997146Double-blind, randomized PCT 2 years6–60 months postmenopause women aged 45–60 years, within 20% of normal BMIn=109
mean age: 53.8 years
mean T-score: −0.8
previous fractures: unknown
Cyclical etidronate 400 mg qd vs. placeboNoEtidronate vs. placebo
Vertebral fracture: 1/54 (1.9%) vs. 0/55 (0%)
Nonvertebral fracture: 3/54 (5.6%) vs. 6/55 (11%)
Etidronate vs. placebo
Withdrawals: 9/54 (17%) vs. 9/55 (16%)
Withdrawals due to AEs: 1/54 (1.9%) vs. 0/55 (0%)
Abdominal pain: 7/54 (13%) vs. 6/55 (11%)
9/10 fractures described as traumatic (1 non-traumatic, non-vertebral fracture)
Reid et al, 2002150Double-blind, randomized PCT 1 yearAge 45–80 years, ≥5 years postmenopause, lumbar spine BMD ≤2.0 SD below the mean value for young adults; no more than one vertebral fracture at baselinen=351
mean age: 64.2 years
mean T-score: −1.2
previous fractures: excluded
Zoledronic acid 4 mg intravenous annually in 1 to 4 doses vs. placeboYesZoledronic acid 4 mg/year vs. placebo
Vertebral fractures: 0/174 (0%) vs. 0/59 (0%)
Nonvertebral fractures: 4/174 (2.3%) vs. 1/59 (1.7%)
Zoledronic acid (any dose) vs. placebo
Withdrawals: 35/351 (9.8%) overall
Withdrawals due to AEs: 13/292 (4.6%) vs. 1/59 (1.7%)
Myalgia: 41/292 (14%) vs. 1/59 (1.7%)
Arthralgia: 46/292 (16%) vs. 9/59 (15%)
No patients had baseline vertebral fractures
Valimaki et al, 2007149Double-blind, randomized PCT 2 years≥5 years postmenopause, ≥osteoporosis risk factor or the presence of hip osteopenian=171
mean age: 65.9 years
mean T-score: −1.2
previous fractures: unknown
Risedronate 5mg qd vs. placeboNoRisedronate vs. placebo
Vertebral fracture: 0/114 (0%) vs. 0/56 (0%)
Nonvertebral fracture: 2/114 (1.8%) vs. 2/53 (3.8%)
Hip fracture: 0/114 (0%) vs. 0/56 (0%)
Wrist fracture: 0/114 (0%) vs. 1/56 (1.8%)
Ankle fracture: 0/114 (0%) vs. 1/56 (1.8%)
All-cause mortality: 0/114 (0%) vs. 0/56 (0%)
Risedronate vs. placebo
Withdrawals: Not reported
Withdrawals due to AEs: 10/115 (8.7%) vs. 9/55 (16%) placebo

Abbreviations: AE = adverse events; BMD = bone mineral density; BMI = body mass index; CI = confidence interval; CV = cardiovascular; GI = gastrointestinal; HRT = hormone replacement therapy; LS = lumbar spine; PCT = placebo controlled trial; PTH = parathyroid hormone; RR = relative risk; SD = standard deviation.

*

BMD T-scores are based on femoral neck measurements and calculated using the FRAX Patch instrument, unless otherwise stated.

From: Appendix D, Appendix Tables

Cover of Screening for Osteoporosis
Screening for Osteoporosis: Systematic Review to Update the 2002 U.S. Preventive Services Task Force Recommendation [Internet].
Evidence Syntheses, No. 77.
Nelson HD, Haney EM, Chou R, et al.

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