Breast cancer remains the most common cancer in US women1 and is associated with substantial morbidity, including increased fracture risk attributed in part to estrogen deficiency, aromatase inhibitors, frailty, and skeletal metastases. While fractures associated with these factors have been examined, epidemiologic studies often lack detail regarding pathologic (ie, cancer-related) fractures. We examined the extent to which pathologic fractures are associated with major osteoporotic fracture events in women with invasive breast cancer who received endocrine therapy.
This cohort study was approved by the institutional review board at Kaiser Permanente Northern California (KPNC). All study participants provided written informed consent for the Pathways or Research Program on Genes, Environment, and Health (RPGEH) studies. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.
The Pathways Study2 enrolled women with newly diagnosed invasive breast cancer (ie, diagnosed from 2005 to 2013) at KPNC, of whom 3312 received endocrine therapy.3 The RPGEH4 identified 1698 women at KPNC with invasive breast cancer that was diagnosed from 1996 to 2014 who received endocrine therapy. This yielded 5010 women who received endocrine therapy followed up from invasive breast cancer diagnosis up to 10 years or until September 30, 2015, for incident fracture.
Breast cancer stage at initial diagnosis was obtained from the KPNC Cancer Registry. International Classification of Diseases, Ninth Revision (ICD-9) diagnoses of femur fractures (ie, principal hospital diagnoses) and vertebral, humerus, or wrist fractures (ie, hospital, emergency, ambulatory, and institutional-stay diagnoses), including pathologic-coded fractures, were identified from KPNC databases (Table 1). The first fracture per site was adjudicated using clinical, histopathology, and radiology reports to determine incident vs prevalent and pathologic vs nonpathologic fracture. Major osteoporotic fractures were fractures at 1 of these 4 sites. Fracture incidence was calculated with 95% CIs using Poisson distributions. Data were analyzed from 2018 to 2021 using the statistical package SAS version 9.4 (SAS Institute). Statistical significance was set at P < .05, and tests were 2-tailed.
Among 5010 women (mean [SD] age, 60.2 [11.5] years, 543 [10.8%] Asian women, 244 [4.9%] Black women, 473 [9.4%] Hispanic women, 3672 [73.3%] non-Hispanic White women, 78 [1.6%] women of other or unknown ethnicity; 4542 [90.7%] stage I to stage II at initial diagnosis), 340 (6.8%) had incident fracture(s) during follow-up (median [IQR], 6.7 [4.1-9.1] years), including 46 hip, 104 vertebral, 78 humerus, and 137 wrist fractures. These excluded prevalent fractures, which accounted for 46 of 150 (30.7%) identified vertebral fractures. Clinical characteristics by fracture type are shown in Table 2. Among women with hip fracture, 20 (43.5%) were age 80 years or older, compared with less than 25% for women with vertebral (23 [22.1%]), humerus (15 [19.2%]), or wrist fracture (21 [15.3%]) (P < .01).
Pathologic fractures accounted for 22 of 104 (21.2%) of incident vertebral fractures and fewer than 5 of 46 (8.7%) of incident hip fractures (Table 2); the latter is consistent with 10% reported among 752 KPNC women with breast cancer history and hip fracture.5 Few humerus and wrist fractures were pathologic. By tumor stage, 15 of 87 (17.2%) vs 7 of 17 (41.2%) vertebral fractures in women with initial stage I and stage II vs stage III to stage IV breast cancer were pathologic (P < .05). The incidence of nonpathologic fracture was highest for the wrist, followed by vertebral and humerus fractures, and lowest for hip fractures (Table 2).
This report highlights vertebral fracture considerations among women with breast cancer, where a subset of the sample is prevalent and/or pathologic fractures. Among women with initial stage III or stage IV breast cancer, pathologic fractures comprised at least 1 in 3 subsequent incident vertebral fractures. As the axial skeleton is a common site for breast cancer metastasis and vertebrae a common site for pathologic fracture,6 primary care physicians should consider the possibility of pathologic fracture in women with higher risk based on advanced-stage cancer history. Limitations of this study are that our analyses did not account for fracture risk factors, treatment, and chemotherapy and included only clinically diagnosed fractures (asymptomatic vertebral fractures were missed). However, a strength of this study is the large nonreferral population size and comprehensive approach to fracture ascertainment.
Overall, these data support clinicopathologic adjudication of high-risk vertebral fractures and differentiation of prevalent vertebral fractures in studies of women with breast cancer. Examination of nonpathologic fracture risk by treatment type (eg, aromatase inhibitors, cytotoxic chemotherapy) may determine which women benefit from aggressive osteoporotic fracture prevention care.
Accepted for Publication: September 11, 2021.
Published: November 17, 2021. doi:10.1001/jamanetworkopen.2021.33861
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Lo JC et al. JAMA Network Open.
Corresponding Author: Marilyn L. Kwan, PhD, Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94507 (Marilyn.L.Kwan@kp.org).
Author Contributions: Dr Kwan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Lo, Yao, Kwan.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Lo, Lee.
Critical revision of the manuscript for important intellectual content: Lo, Laurent, Roh, Chandra, Yao, Kwan.
Statistical analysis: Laurent, Chandra, Kwan.
Obtained funding: Yao, Kwan.
Administrative, technical, or material support: Lo, Roh, Kwan.
Supervision: Lo, Kwan.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by grants R01 CA166701, R01 CA105274, and U01 CA195565 from the National Cancer Institute, National Institutes of Health, and the Research Program on Genes, Environment and Health of Kaiser Permanente Northern California.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, Kaiser Permanente, or The Permanente Medical Group.