Table 1.
Summary of studies.
| Study Information | Study participants (safety population) | Treatment | Published fracture outcomes - fracture | Meta-analysis | Factors | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ID | Study name Author, year (ref) | Design | Country | Data source | Median follow-up duration | Age (Years)a | Post-menopausal (%) | Prior tamoxifen b (duration) | No. | Arms | Duration | Type | Participants with fractures No. | Fracture events per 1000 PY | Risk measure (95% CI) | Risk Measure used in meta-analysis (95% CI) | Adjusted |
| Tamoxifen vs. Control / placebo (reference) | |||||||||||||||||
| 1 | Kristense, 199428 | RCT | Denmark | Self-report | 44 M | 57 (NR, 65) | 100 | N | 20 23 |
Tam Control |
24 M | Osteo-porotic | 0 / – 0 / – |
– | – | – | – |
| 2 | Love, 199429 | RCT | USA | Self-report | Mean 60.5 M |
58 ± 4 | 100 | N | 70 70 |
Tam Placebo | 24 M | Any | 6 / 7 8 / 10 |
– | – | Calculated RR 0.75 (0.27, 2.05) |
– |
| 3 | Sacco, 200330 | RCT | Italy | Self-report | 52 M | 61 ± 6 | 95 | Y (24 M) | 943 958 |
Tam Control | 36 M | Any | 8 / – 10 / – |
– | – | Calculated RR 0.81 (0.32, 2.05) |
- |
| Aromatase inhibitors (AIs) vs. Control / placebo (reference) | |||||||||||||||||
| 4 | Mincey, 200631 | Cohort | US | Data-linkage | Range 1998- 2005 |
66 ± 11 64 ± 13 |
<100c | N | 1354 11,014 |
AIs Control |
– | Any | 183 / – 1132 / – |
86 / – 63.6 / – |
aHR 1.21 (1.03, 1.43) IRR 1.35 (1.16, 1.58) |
Published aHR 1.21 (1.03, 1.43) |
Age, 1, 2, 3, 4 |
| 5 |
MA 17
Goss, 200332; DeGrendele, 200333 |
RCT | Multiple, 9 | Self-report | 2.4 Y | 62 (NR) | 100 | Y (60 M) | 2154 2145 | AIs (Let) Placebo |
60 Months | Any | 77 / – 63 / – |
– | – | – | – |
| 6 |
MA 17
Goss, 200534 |
30 M | 2572 2577 | AIs (Let) Placebo | 137 / – 119 / – |
– | – | Calculated RR 1.15 (0.94, 1.41) | – | ||||||||
| 7 |
MA 17
Goss, 200835 |
1.1 Yd (after unblinding) | 1579e 804 | AIs (Let) Placebo |
82 / – 25 / – |
– | – | – | – | ||||||||
| 8 |
Norwegian
Lonning, 200536 |
RCT | Norway | Self-report | 24 M | 59 (46–73) | 100 | N | 73 74 |
AIs (Exe) Placebo |
24 months | Any | 4 / – 5 / – |
– | – | – | – |
| 9 |
Norwegian
Geisler, 200637 |
36 M | 73 74 |
AIs (Exe) Placebo |
4 / – 5 / – |
– | – | Calculated RR 0.81 (0.23, 2.90) |
– | ||||||||
| 10 |
NSABP (B-33)
Mamounas, 2008 38 |
RCT | USA / Canada | Self-report | Till April 2004 |
60 (NR) | 100 | Y (57–66 M) | 783 779 |
AIs (Exe) Placebo |
60 months | Any | 28 / – 20 / – |
– | – | Calculated RR 1.39 (0.79, 2.45) |
– |
| Aromatase inhibitors (AIs) vs. Tamoxifen (reference) | |||||||||||||||||
| 11 | Koopal, 201539 |
Cohort | Netherland | Charts + X-ray |
Post-Tam/AI (3.1 Y) |
52 ± 7 (pre-m) 71 ± 10 (post-m) |
0 | N | 39 92 |
AIs Tam |
5.7 – 6 years |
Any | 4 / – 24 / – |
– | – | Calculated RR 0.39 (0.15, 1.06) |
– |
| 12 |
ABCSG – 8 /
ARNO 95 Jakesz, 200523 |
RCT | Germany / Austria, | Self-report | 28 M | 62 (41–80) | 100 | Y (24 M) | 1602 1597 | AIs (Ana) Tam |
36 months | Any | 34 / – 16 / – |
– | OR 2.14 (1.14, 4.17) |
– | |
| 13 |
ABCSG-12
Grant, 200940 |
RCT | Austria | Self-report | 47.8 M | 45 (26–57) | 0 | N | 903 900 | AIs (Ana) Tam |
36 months | Any | 12 / – 12 / – |
– | – | Calculated RR 1.00 (0.45, 2.21) |
– |
| 14 |
ABCSG-12
Grant, 201141 |
62 M | 903 900 |
AIs (Ana) Tam |
13 / – 12 / – |
– | – | Calculated RR 1.08 (0.50-2.35) |
– | ||||||||
| Aromatase inhibitors (AIs) vs. Tamoxifen (reference) | |||||||||||||||||
| 15 |
ARNO 95
Kaufmann, 200742 |
RCT | Germany | Self-report | 30.1 M | 61 (46–74) | 100 | Y (24 M) | 445 452 | AIs (Ana) Tam |
36 months | Any | 10 / – 10 / – |
– | – | Calculated RR 1.02 (0.43, 2.42) |
– |
| 16 |
ATAC
Buzdar, 200243; Fisher, 200244; Baum, 200245 |
RCT | Multiple, 21 | Self-report | 33.3 M | 64 ± 9 | 100 | N | 3092 3094 |
AIs (Ana) Tam |
60 months | Any | 183 / – 115 / – |
– | – | Calculated RR 1.59 (1.27,2.00) |
– |
| 17 |
ATAC
Baum, 200346 |
42 M | 3092 3093 | AIs (Ana) Tam |
219 / – 137 / – |
– | – | Calculated RR 1.60 (1.30, 1.97) |
– | ||||||||
| 18 |
ATAC
Howell, 200547; Cuzick, 200748 |
68 M | 3092 3094 | AIs (Ana) Tam |
340 / – 237 / – |
22.6 / – 15.6 / – |
OR 1.49 (1.25, 1.77) HR 1.44 (1.21, 1.68) |
Calculated RR 1.44 (1.23, 1.68) |
– | ||||||||
| 19 |
ATAC
Arimidex, 200849 |
100 M | 3092 3094 | AIs (Ana) Tam |
– | – | – | – | – | ||||||||
| On Tam/AI | 3092 3094 |
AIs (Ana) Tam |
– / 375 – / 234 |
– / 29.3 – / 19 |
IRR 1.55 (1.31-1.83) |
– | – | ||||||||||
| Post Tam/AI | 2496 2419 |
AIs (Ana) Tam |
– / 146 – / 143 |
– / 15.6 – / 15.1 |
IRR 1.03 (0.81, 1.31) |
– | – | ||||||||||
| 20 |
ATAC
Cuzick, 201014 |
120 M | 3092 3094 | AIs (Ana) Tam |
– | – | – | – | – | ||||||||
| On Tam/AI | 3092 3094 |
451 / – 351 / – |
– | – | Calculated RR 1.29 (1.13, 1.46) |
– | |||||||||||
| Post-Tam/AI | 2223 2246 |
110 / – 112 / – |
– | – | Calculated RR 0.99 (0.77, 1.28) |
– | |||||||||||
| 21 |
BIG 1-98
Thurlimann, 200550; Monnier, 200551 |
RCT | Multiple, 27 | Self-report | 25.8 M | 61 (38–90) | 100 | N | 3975 3988 |
AIs (Let) Tam |
60 M | Any | 225 / – 159 / – |
22 / – 15 / – |
OR 1.44 |
Calculated RR 1.42 (1.16, 1.73) |
– |
| 22 |
BIG 1-98
Crivellari, 200852 |
40.4 M | 2448 2447 |
AIs (Let) Tam |
196 / – 132 / – |
– | – | – | – | ||||||||
| 23 |
BIG 1-98
Coates, 200753 |
51 M | 2448 2447 |
AIs (Let) Tam |
211 / – 141 / – |
– | – | Calculated RR 1.50 (1.22, 1.84) |
– | ||||||||
| 24 |
BIG 1-98
Rabaglio, 2009,15 |
On Tam/AI 60.3 Mf | 2448 2447 |
AIs (Let) Tam |
228 / – 160 / – |
25.2 / 27.1 18.1 / 18.7 |
HR 1.38 (1.13, 1.69) aHR 1.40 (1.14, 1.71) |
Calculated RR 1.42 (1.17, 1.73) |
Age, 5, 6, 7, 8, 9, 10 | ||||||||
| 25 |
BIG 1-98
Mouridsen, 200954 |
71 M | 1540 1534 | AIs (Let) Tam |
– | – | – | – | – | ||||||||
| on Tam/AI (Y1–2) | 1540 1534 |
AIs (Let) Tam |
65 / – 50 / – |
– | – | – | – | ||||||||||
| on Tam/AI (Y 3–5)g | 1540 1534 | AIs (Let) Tam |
90 / – 67 / – |
– | – | – | – | ||||||||||
| on Tam/AI (Y 1–5) |
1540 1534 | AIs (Let) Tam |
150 / – 112 / – |
– | – | – | – | ||||||||||
| 26 |
BIG 1-98
Colleoni, 201155 |
74 M | 2448 2447 | AIs (Let) Tam |
244 / – 165 / – |
– | – | Calculated RR 1.48 (1.22, 1.79) |
– | ||||||||
| 27 |
HOBOE
Nuzzo, 201256 |
RCT | Italy | Self-report | 12 M | 50 (29–80) | 46 | N | 148 152 |
AIs (Let) Tam |
60 M | Any | 0 / 0 0 / 0 |
– | – | – | – |
| 28 |
IES
Coombes, 200457 |
RCT | Multiple, 37 | Self-report | 30.6 M | 64 ± 8 | 100 | Y ( 2.4 Y) | 2305 2329 |
AIs (Exe) Tam |
2-3 Y | Any | 72 / – 53 / – |
– | – | Calculated RR 1.37 (0.97, 1.95) |
– |
| 29 |
IES
Coleman, 200758 |
58 M | 2320 2338 |
AIs (Exe) Tam |
162 / 188 115 / 143 |
17.6 / 20.1 13.2 / 16.0 |
OR 1.45 (1.13-1.87) |
Calculated RR 1.42 (1.13, 1.79) |
– | ||||||||
| 30 |
IES
Bliss, 201259; Clomean, 20109 |
91 M | 2319 2338 | AIs (Exe) Tam |
249 / 280 190 / 214 |
– | ORh
1.36 (1.04, 1.76) |
Calculated RR 1.32 (1.10, 1.58) |
– | ||||||||
| On Tam/AI | 2319 2338 |
AIs (Exe) Tam |
113 / 117 86 / 83 |
– / 21 – / 12.3 |
ORh
1.39 (0.94, 2.06) HRh 1.39 (0.96, 2.01) |
Calculated RR 1.37 (1.04, 1.81) |
– | ||||||||||
| Post Tam/AI | 2105 2036 |
AIs (Exe) Tam |
144 / 163 117 / 128 |
– / 20.3 – / 20.6 |
ORh
1.20 (0.86, 1.69) HRh 1.20 (0.89, 1.63) |
Calculated RR 1.19 (0.94, 1.51) | – | ||||||||||
| 31 |
ITA
Boccardo. 200560 |
RCT | Italy | Self-report | 36 M | 63 (38–77) | 100 | Y (28 M) | 223 225 |
AIs (Ana) Tam |
2-3 Y | Any | 2 / – 2 / – |
– | – | Calculated RR 1.01 (0.14, 7.10) |
– |
| 32 |
ITA
Boccardo, 201361 |
128 M | 223 225 |
AIs (Ana) Tam |
Hospital events, |
4 / – 4 / – |
– | – | Calculated RR 1.01 (0.26, 3.98) |
– | |||||||
| 33 |
N-SAS BC03
Aihara, 201062 |
RCT | Japan | Self-report | 42 M | 60 ± 7 | 100 | Y (1-4 Y) | 347 349 |
AIs (Ana) Tam |
1-4 Y | Any | 5 / – 9 / – |
– | – | Calculated RR 0.56 (0.19, 1.65) |
– |
| 34 |
TEXT / SOFT (IBCSG)
Pagani, 201424 |
RCT | Multiple | Self-report | 68 M | 43 ± NR | 0 | N | 2318 2325 |
AIs (Exe) Tam |
60 M | Any | 158 / – 120 / – |
– | – | – | – |
| Multiple treatment arms | |||||||||||||||||
| 35 | Ligibel, 201263 | Cohort | US | Data linkage | 30 M | 67 ± NR | <100 c | N | Total 44,026 | Tam Control |
– | Any | – | 26.8 / – 38.1 / – |
aHR 0.93 (0.82-1.06) |
Published aHR 0.93 (0.82-1.06) |
Age, 1, 2, 3, 11, 12, 13, 14, 15 |
| Total 44,026 | AIs Control |
33.3 / – 38.1 / – |
aHR 1.13 (1.02-1.25) |
Published aHR 1.13 (1.02-1.25) |
|||||||||||||
| Total 44,026 | AIs Tam |
33.3 / – 26.8 / – |
– | ||||||||||||||
| 36 | Robinson, 201464 | Cohort | Australia | Self-report | Mean 5.7 Y |
57 (27–87) | 35 | N | 393 252 |
Tam Control |
– | Minimal trauma | 56 / – 30 / – |
– | – | Calculated RR 1.20 (0.79-1.81) |
– |
| 306 252 |
AIs Control |
46 / – 30 / – |
OR 1.31 (0.80, 2.14) |
Calculated RR 1.26 (0.82-1.94) |
– | ||||||||||||
| 306 393 |
AIs Tam |
46 / – 56 / – |
Calculated RR 1.05 (0.74, 1.51) |
– | |||||||||||||
| 37 | Xu, 201465 | Cohort | China | Self-report | 32.5 M | 56 ± 8 61 ± 9 |
76–88 | N | 52 89 |
Tam Control |
– | Any | 1 / – 1 / – |
– | aHR 2.64 (0.14, 48.73) |
Published aHR 2.64 (0.14, 48.73) |
10, 16, 17 |
| 61 ± 7 61 ± 9 |
70 89 |
AIs Control |
9 / – 1 / – |
aHR 20.08 (1.7, 234.1) |
Published aHR 20.08 (1.7, 234.1) |
||||||||||||
| 61 ± 7 56 ± 8 |
70 52 |
AIs Tam |
9 / – 1 / – |
– | Calculated RR 6.69 (0.87, 51.14) |
||||||||||||
a
Mean ± SD or median (range)
b
Tamoxifen treatment prior to the study
c
Menopausal status was determined based on age range
d
Information of fracture outcome was collected for 1.1 years after unblinding on October 2003
e
1579 participants crossed over from placebo group after unblinding
f
Fracture data obtained from participants on medications only
g
25.2% crossover
h
99% confidence intervals
Abbreviations: aHR adjusted hazard ratio, AIs Aromatase inhibitors, Ana anatrozole, CI confidence interval, Exe Exemestane, HR hazard ratio, IRR incidence rate ratio, Let letrozole, M month, No number, NR not recorded, OR odds ratio, pre-m pre-menopausal, post-m post-menopausal, ref reference, RCT randomized controlled trail, RR risk ratio, SD standardized deviation, Tam Tamoxifen, Y year,
Study abbreviations: ABCSG Austrian Breast & Colorectal Cancer Study Group, ARNO Arimidex-Nolvadex, ATAC Arimidex, Tamoxifen, Alone or in Combination, BIG Breast International Group, HOBOE Hormonal Bone Effects, IES Intergroup Exemestane Study, ITA Italian Tamoxifen Anastrozole, NSABP National Surgical Adjuvant Breast and Bowel Project, SOFT Suppression of Ovarian Function Trial, TEXT Tamoxifen and Exemestane
Adjusted factor: 1 Charlson Comorbidity Index, 2 residential regions, 3 health plan, 4 income, 5 body mass index, 6 smoking, 7 osteoporosis, 8 fracture history, 9 hormonal replacement therapy, 10 bisphosphonates, 11 index year, 12 urban/rural status, 13 drug class, 14 education, 15 % of black, 16 age of diagnosis, 17 age of menopause