Bisphosphonates and primary breast cancer risk: an updated systematic review and meta-analysis involving 963,995 women

Figures & data

Figure 1 Flow diagram of study selection.

Abbreviations: BCa, breast cancer; BPs, bisphosphonates; CBCa, contralateral breast cancer.

Figure 2 Forest plot for the association between bisphosphonates and primary breast cancer risk. Square markers indicate effect sizes of each study; horizontal lines, the 95% CI. The diamond data marker indicates the summarized effect size. The vertical solid line indicates the overall pooled effect. Note that the studies are ranked in order of their relative weights from random effects analysis.

Table 1 The pooled association between bisphosphonates and breast cancer risk

Subgroups	No. of studies	Models^a	Effect estimate (95% CI)	Heterogeneity between studies		Heterogeneity between models^a	E-values^b for
				I^2 (%)	P-value	P-value	Point estimate	Upper CI limit
Total	10	R	0.879 (0.826–0.936)	35.53	0.124	0.695	1.533	1.339
		F	0.892 (0.858–0.927)				1.490	1.370
Study design
Case-control study	3	R	0.834 (0.711–0.979)	61.79	0.073	0.354	1.688	1.170
		F	0.903 (0.857–0.951)				1.452	1.284
Cohort study	5	R	0.874 (0.803–0.951)	33.18	0.200	0.948	1.550	1.284
		F	0.871 (0.822–0.924)				1.148	1.381
RCT	2	R	1.127 (0.808–1.573)	0.00	0.918	1.000	1.505	1.000
		F	1.127 (0.808–1.573)				1.505	1.000
Invasive BCa	6	R	0.829 (0.692–0.994)	59.54	0.030	0.902	1.705	1.084
		F	0.840 (0.757–0.932)				1.667	1.353
Postmenopausal	7	R	0.888 (0.798–0.989)	30.50	0.195	1.000	1.503	1.117
		F	0.888 (0.817–0.964)				1.503	1.234
Duration of BPs use (year)
<1	5	R	0.904 (0.842–0.970)	0.00	0.522	1.000	1.449	1.210
		F	0.904 (0.842–0.970)				1.449	1.210
≥1 (including 1–2, 2–3, 3–4, and >4)	19	R	0.745 (0.658–0.844)	74.61	<0.001	0.143	2.020	1.653
		F	0.823 (0.785–0.864)				1.726	1.584
1–2	5	R	0.690 (0.534–0.893)	87.00	<0.001	0.103	2.256	1.486
		F	0.859 (0.811–0.909)				1.601	1.432
2–3	4	R	0.732 (0.554–0.967)	72.82	0.012	0.973	2.073	1.222
		F	0.728 (0.632–0.838)				2.090	1.674
3–4	6	R	0.862 (0.682–1.090)	59.40	0.031	0.638	1.591	1.000
		F	0.807 (0.699–0.932)				1.784	1.353
>4	4	R	0.678 (0.525–0.875)	38.45	0.181	0.899	2.312	1.547
		F	0.664 (0.546–0.809)				2.379	1.776

Notes: ^aWe used the summarized effect estimates with a random-effects model in the primary meta-analyses, and performed a sensitivity analysis using a fixed-effects model. The homogeneity between the results from a random-effects model and a fixed-effects model was evaluated with the heterogeneity between models. ^bE-value shows the minimum strength of association that a hypothetical residual confounding factor would need to have with both the use of bisphosphonates and the risk of primary BCa to fully explain an association between bisphosphonates and primary BCa risk. Note that these calculations assumed an optimal frequency for the hypothetical confounder. For an infrequent confounder, the strength of the associations between the confounder and bisphosphonate use and between the confounder and primary BCa risk needs to be much stronger.

Abbreviations: BCa, breast cancer; BPs, bisphosphonates; F, a fixed-effects model; R, a random-effects model.