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. 2022 Oct 4;25(6):454–472. doi: 10.4048/jbc.2022.25.e39

Table 2. The included studies’ characteristics.

# Author Year Country Study design The regimen of control group Type of BP Type of breast cancer Mean age Menstruation Case (n) Control (n) F/U (mon) Duration of BP use (mon) HER2 PR ER
1 Korde et al. [28] 2017 USA Cohort study Hormone therapy Alendronate, risedronate, zoledronate AJCC stage 64.2 Post: 1,527, Pre: 191 302 1,511 11.8 41.2 - BP: PR+: 238, PR−: 56 BP: ER+: 257, ER−: 37
BP: I: 172, IIA: 57, IIB: 15, IIIA: 23, IIIB: 6 Post: 266 Post: 1,261 Control: PR+: 1,131, PR−: 345 Control: ER+: 1,269, ER−: 209
Control: I: 788, IIA: 299, IIB: 154, IIIA: 114, IIIB: 38
2 Rack et al. [22] 2010 Germany Non-randomized phase II trial Cytostatic treatment, hormone therapy Zoledronate G1–G3 53.1–54.2 Post: 107, Pre: 49 31 141 39 6 - - -
Post: 89 Post: 18
3 Hadji et al. [20] 2013 Germany Retrospective Endocrine therapy - chemotherapy Alendronate, clodronate, ibandronate, zoledronic acid Stage 59.5–64.9 - 937 630 12–24 3 ≤ Case: 125, Control: 75 Case: 937, Control: 630 Case: 937, Control: 630
T1: BP: 620, control: 401
Zoledronic acid 4 mg IV two to three times per year; ibandronate 50 mg/day PO, 150 mg/month PO, or 4 mg to 6 mg IV every 3 months; clodronate 1,600 mg/day PO; or alendronate 70 mg/week PO. T2, 3, or 4: BP: 317, control: 229 HER2−: BP: 750, Control: 517
Nodal
N0: BP: 537, control: 413
N+: BP: 400, control: 217
Histologic grade
BP: G1,G2: 662, G3: 275
Control: G1,G2: 421, G3: 209
4 Gnant et al. [26] 2014 Italy RCT Goserelin, tamoxifen, anastrozole Zoledronic acid, 4 mg given intravenously every 6 months) T1–T3 45–45.5 Post: 5, Pre: 1,798 900 903 94.4 36 - Case: 803, Control: 804 Case: 835, Control: 848
Post: 2 Post: 3
5 Coleman et al. [31] 2018 UK Randomized controlled, phase 3 Standard adjuvant systemic therapy Zoledronic acid, 4 mg zoledronic acid given intravenously every 3–4 weeks for the first six doses, every 3 months for eight doses, and every 6 months for five doses to complete 5 years of treatment Grade 18 ≤ Pre: 1,503, Post: 1,532 1,681 1,678 117 60 BP: HER2+: 192, HER2−: 648 BP: PR+: 725, PR−: 382 BP: ER+: 1,318, ER−: 350
BP: I: 146, II: 731, III: 765 Post: 766 Post: 765 Control: HER2+: 223, HER2−: 604 Control: PR+: 699, PR−: 424 Control: ER+: 1,315, ER−: 356
Control: I: 141, II: 708, III: 787
Node
BP: 0: 30, 1–3: 1,042, ≥4: 604
Control: 0: 32, 1–3: 1,033, ≥4: 607
Stage
BP: I: 542, II: 850, III: 228, IV: 58
Control: I: 523, II: 867, III: 228, IV: 59
6 Paterson et al. [29] 2012 USA Multicentre, placebo-controlled, randomised trial Endocrine therapy - chemotherapy Clodronate, 1,600 mg daily for 3 years Nodal 49 ≥ to 50 ≤ - 1,656 1,655 90.7 36 - - -
1–3: BP: 18, control: 295
4 or more: BP: 7, control: 114
7 Perrone et al. [30] 2019 Italy Phase 3 randomised trial Letrozole, tamoxifen Zoledronic acid G1–G3 44.7–45.2 Pre: 1,065 355 710 64 60 Case: 47, Control: 98 Case: 346, Control: 685 -
8 Banys et al. [24] 2013 Germany Controlled randomized open-label multi-center study Endocrine treatment chemotherapy Zoledronic acid, intravenous zoledronic acid every 4 weeks for 24 months Grading - Pre: 55, Post: 31 40 46 88 24 BP: HER2+: 5, HER2−: 30 BP: PR+: 24, PR−: 11 BP: ER+: 30, ER−: 5
BP: I/II: 33, III: 5 Post: 26 Post: 29 Control: HER2+: 5, HER2−: 28 Control: PR+: 23, PR−: 11 Control: ER+: 30, ER−: 4
Control: I/II: 35, III: 5
Nodal+: BP: 4, control: 6
Nodal−: BP: 35, control: 35
9 Ishikawa et al. [27] 2017 Japan Randomized phase II trial FEC100 Paclitaxel Zoledronic acid, (4 mg) 3–4 times weekly for 7 weeks IIA–IIIB 20–70 - 93 95 36 36–60 Case: 0, Control: 0 - -
(T ≥ 3.0 cm and node negative, or T ≥ 2.0 cm and cytologically or pathologically defined as node positive) Zoledronic acid (4 mg) 3–4 times weekly for 7 weeks
10 Powles et al. [34] 2006 UK Randomized double-blind, placebo-controlled trial Chemotherapy tamoxifen Clodronate, 1,600 mg/day during a 2 year Stage 1–3 52.8 ± 10.6 Pre: 530, Post: 539 530 539 67.2 24 - BP: PR+: 112, PR−: 79 BP: ER+: 245, ER−: 136
BP: TI: 137, TII: 304, TIII: 48 52.7 ± 10.5 Post: 265 Post: 274 Control: PR+: 116, PR−: 75 Control: ER+: 240, ER−: 136
Control: TI: 143, TII: 305, TIII: 52
11 Aft et al. [32] 2010 USA Open label, randomised, phase 2 trial Epirubicin, docetaxel Zoledronic acid, 4mg intravenous ZOL every 3 weeks for 1 year (total 17 doses) BP: GI: 7, GII: 20, GIII: 33 18–56 Pre: 64, Post: 55 60 59 60 12 Case: 13, Control: 10 BP: PR+: 24, PR−: BP: ER+: 32, ER−: 28
Control: GI: 2, GII: 28, GIII: 29 Post: 29 Post: 26 Control: PR+: 31, PR−: Control: ER+: 34, ER−: 28
12 Kristensen et al. [38] 2008 Sweden Randomized Clinical trial CMF, CEF Pamidronate, 150 mg twice daily for 4 years BP: GI: 35, GII: 181, GIII: 151 39 ≥ to 69 Pre: 634, Post: 318 460 493 120 ≤ 36 - BP: PR+: 51, PR−: 135 BP: ER+: 62, ER−: 278
Control: GI: 23, GII: 202, GIII: 168 Post: 152 Post: 166 Control: PR+: 54, PR−: 136 Control: ER+: 85, ER−: 261
13 Body et al. [37] 2003 USA Double-blind, placebo-controlled, parallel-group, multicentre, phase III study Endocrine treatment chemotherapy Gp1: Ibandronate (2 mg) (n = 154), Gp2: Ibandronate (6 mg) (n = 154), every 3–4 weeks for up to 2 years - 55.3 - Gp1: 154 158 12.67 19.5 - - -
Gp2: 154
14 Delmas et al. [19] 1997 UK Double-Blind, Placebo-Controlled Placebo Risedronate, eight cycles oral risedronate 30 mg/d daily for 2 weeks followed by 10 weeks of no drug (12 weeks per cycle) - 36–55 Pre: 0, Post: 53 27 26 36 36 - - -
Post: 27 Post: 0
15 Eidtmann et al. [25] 2010 UK Open-label, multicenter, randomized study Letrozole Zoledronic acid, immediate zoledronic acid (ZOL; 4 mg every 6 months) or delayed ZOL (initiated only for fracture or high risk thereof) Stage I–IIIa 58 Post: 884, Pre: 176 524 536 36 11.84 - - -
Post: 438 Post: 448
16 Diel et al. [33] 1998 Germany Prospective, randomized, non–placebo-controlled study Tamoxifen, CMF, CEF Clodronate, 1,600 mg of oral clodronate per day for two years BP: T1: 59, T2: 71, T3: 17, T4: 10 51 Post: 189, Pre: 113 157 145 36 24 - BP: PR+: 85, PR−: 51 BP: ER+: 104, ER−: 35
Control: T1: 54, T2: 67, T3: 18, T4: 6 Post: 101 Post: 88 Control: PR+: 72, PR−: 42 Control: ER+: 84, ER−: 34
Nodal
BP: N0: 77, N1 or N2: 80
Control: N0: 66, N1 or N2: 79
G1, or II: BP: 93, control: 92
GIII: BP: 44, control: 34
17 Saarto et al. [35] 2003 Finland Randomized Controlled Trial CMF Clodronate, 1,600 mg daily for 3 years BP: T1: 71, T2: 59, T3: 9 52 Post: 134, Pre: 148 139 143 120 36 - BP: PR+: 70, PR−: 62 BP: ER+: 85, ER−: 48
Control: T1: 66, T2: 65, T3: 9 Post: 72 Post: 62 Control: PR+: 86, PR−: 44 Control: ER+: 97, ER−: 33
18 Ahn et al. [23] 2014 Korea Retrospective Aromatase inhibitors Zoledronic acid, 4 mg of ZA was administered intravenously every 3 to 6 months Histologic grade 56–57 Post: 235 77 158 68 45 Case: 13, Control: 30 Case: 64, Control: 132 Case: HER+: 74, HER−: 3
BP: I or II: 61, III: 8 Post: 77 Post: 158 Control: HER+: 148, HER−: 10
Control: I or II: 130, III: 19
T stage
BP: T1: 57, T2: 19, T3: 1
Control: T1: 101, T2: 55, T3: 2
N stage
BP: N0: 50, N1: 20, N2: 7, N3: 0
Control: N0: 90, N1: 55, N2: 9, N3: 4
Stage
BP: SI: 39, SII: 31, SIII: 7
Control: SI: 59, SII: 85, SIII: 14
19 Jallouk et al. [21] 2021 USA Randomized placebo-controlled phase II clinical trial in Chemotherapy Zoledronic acid, 4 mg intravenous ZOL every 3 weeks for 1 year (17 total doses) Stage II–III (≥T2 and/or ≥N1) 47–49 Post: 55, Pre: 64 60 59 172.8 12 Case: 13, Control: 10 Case: 24, Control: 31 Case: 32, Control: 34
Grade Post: 29 Post: 26
BP: GI: 7, GII: 20, GIII: 33
Control: GI: 2, GII: 28, GIII: 29
20 Aft et al. [39] 2012 USA Randomized clinical trial Chemotherapy Zoledronic acid, 4 mg intravenous ZOL every 3 weeks for 1 year (total 17 doses) Stage II–III 49–50 Post: 55, Pre: 64 59 60 61.9 12 Case: 13, Control: 10 - Case: 32, Control: 34
Grade I: 7 in BP; 2 in control Post: 26 Post: 29 ER+/HER2+: 6 in BP; 5 in control
Grade II: 20 in BP; 28 in control ER+/HER2−: 26 in BP; 29 in control
Grade III: 33 in BP; 29 in control ER−/HER2+: 7 in BP; 5 in control
ER−/HER2−: 21 in BP; 19 in control
21 von Minckwitz et al. [36] 2013 Germany Open-label, randomized, controlled phase III trial Observation Ibandronate Tumor stage 40–60 Post: 1,549, Pre: 1,431 1996 998 38.7 24 BP: HER2+: 415, HER2−: 1,467 - -
BP: pT1: 635, pT2: 1,112, pT3: 202, pT4: 41 Post: 1,023 Post: 526
Control: pT1: 320, pT2: 557, pT3: 103, pT4: 14
Grade
BP: G1: 63, G2: 987, G3: 943
Control: G1: 33, G2: 520, G3: 442
Node
BP: N1: 7,361, N2: 696, N3: 539
Control: N1: 370, N2: 362, N3: 266

BP = bisphosphonate; F/U = follow-up; HER2 = human epidermal growth factor receptor 2; PR = progesterone receptor; ER = estrogen receptor; AJCC = American Joint Committee on Cancer; PO = per os; RCT = randomized controlled trial; CMF = cyclophosphamide, methotrexate, fluorouracil; CEF = cyclophosphamide, epirubicin, and fluorouracil.