Beyond direct carcinogenicity: does skeletal biology mediate the host effects of hormonal contraception on colorectal cancer?

Source Summary

Agreement: I Agree Body: Dear Editor Lange and colleagues have provided clinically important reassurance. In a nationwide Danish cohort of 1,956,948 premenopausal women followed for 24.5 million person-years, contemporary hormonal contraception was not materially associated with colorectal cancer (CRC). The analysis went beyond a simple ever-versus-never comparison and examined recency, duration, and major contemporary formulations. Within contemporary prescribing patterns, hormonal contraception does not appear to be a major direct determinant of premenopausal CRC risk. That null result, however, need not close the biological discussion. Earlier literature on oral contraceptives often suggested a modest inverse association with CRC1, whereas Lange et al found neither substantial protection nor harm under contemporary exposure patterns. This discrepancy raises a critical scientific question: Does the simple classification of hormonal prescriptions mask complex, heterogeneous downstream biological effects? A more precise interpretation is not that endocrine exposure is biologically irrelevant, but that prescription categories may be an incomplete proxy for the host states created by hormonal exposure. Here, bone represents one such critical yet often overlooked target system. Given the high prevalence of bone loss among women exposed to hormonal fluctuations2, the skeletal system warrants greater clinical attention and may represent a clinically relevant window into host physiological states associated with CRC susceptibility. It is highly responsive to sex steroids, and its biology extends beyond skeletal maintenance to interactions with metabolism, immunity, and hematopoiesis. Importantly, hormonal contraceptive methods are not skeletally equivalent: adolescent use of combined hormonal contraceptives after menarche may attenuate physiological bone accrual, whereas depot medroxyprogesterone acetate is associated with bone mineral density (BMD) loss; in contrast, levonorgestrel intrauterine devices do not appear to adversely affect BMD3. If endocrine exposures leave distinct skeletal, metabolic, or immune phenotypes, these secondary physiological shifts may drive variation in CRC risk that cannot be captured by analyzing broad drug labels alone. Epidemiological signals are beginning to point in this direction. In a Korean nationwide population-based cohort, osteoporosis was associated with increased colorectal neoplasm risk regardless of sex, including both adenoma and invasive CRC4. Although these findings do not establish causality, the observed association may still be influenced by residual confounding from age, metabolic factors, vitamin D status, or frailty. Even so, skeletal phenotype may capture aspects of host biology relevant to CRC susceptibility. Mechanistic data also justify continued attention, although they currently speak more strongly to tumor progression and immune context. In CRC models, downregulation of osteoprotegerin (OPG) promoted liver metastasis through tumor-associated macrophage activity, and anti-RANKL blockade suppressed metastatic spread5. In parallel, TGF-β/BMP-family signaling provides a second plausible bridge: bone resorption releases matrix-sequestered growth factors, while BMP signaling is deeply involved in intestinal epithelial homeostasis, adenoma restraint, and CRC growth programs6. More broadly, Cheng and colleagues showed in Cancer Cell that osteopontin-producing osteoclasts in bone lesions can release circulating signals that reprogram extraosseous tumor microenvironments, impair T-cell recruitment, and blunt checkpoint blockade efficacy7. These findings support biological plausibility for a potential bone-gut-cancer axis, even if its role in disease initiation remains unproved. A constructive next step would be to test this question in biologically enriched settings rather than in the overall population alone. Women with inflammatory bowel disease (IBD) merit particular attention because they have increased CRC risk and are also vulnerable to low BMD through chronic inflammation, corticosteroid exposure, and malabsorption. Longitudinal studies integrating contraceptive formulation, age at exposure, repeated bone measures (including BMD, bone turnover markers, and bone-derived mediators), IBD status, and colorectal precursor lesions would be especially informative. A null overall association should reassure patients. It should not close investigation of a bone-gut-cancer axis that may still matter in susceptible subgroups. References 1. Bosetti C, Bravi F, Negri E, et al. Oral contraceptives and colorectal cancer risk: a systematic review and meta-analysis. Hum Reprod Update 2009; 15(5): 489-498. doi: 10.1093/humupd/dmp017 2. Duralde ER, Sobel TH, Manson JE. Management of perimenopausal and menopausal symptoms. BMJ 2023; 382: e072612. doi: 10.1136/bmj-2022-072612 3. Bachrach LK. Hormonal Contraception and Bone Health in Adolescents. Front Endocrinol (Lausanne) 2020; 11: 603. doi: 10.3389/fendo.2020.00603 4. Yoo SH, Nam JH, Oh DJ, et al. Osteoporosis Is Associated with an Increased Risk of Colorectal Neoplasms Regardless of Sex: Nationwide Population-Based Cohort Study. Diagnostics (Basel) 2024; 14(6): 666. doi: 10.3390/diagnostics14060666 5. Hirata W, Itatani Y, Masui H, et al. Downregulation of osteoprotegerin in colorectal cancer cells promotes liver metastasis via activating tumor-associated macrophage. Sci Rep 2023; 13(1): 22217. doi: 10.1038/s41598-023-49312-w 6. Kodach LL, Bleuming SA, Musler AR, et al. The bone morphogenetic protein pathway is active in human colon adenomas and inactivated in colorectal cancer. Cancer 2008; 112(2): 300-306. doi: 10.1002/cncr.23160 7. Cheng JN, Jin Z, Su C, et al. Bone metastases diminish extraosseous response to checkpoint blockade immunotherapy through osteopontin-producing osteoclasts. Cancer Cell 2025; 43(6): 1093-1107 e9. doi: 10.1016/j.ccell.2025.03.036 No competing Interests: Yes The following competing Interests: Electronic Publication Date: Sunday, July 19, 2026 - 19:35 AI use: No, I have not used AI Highwire Comment Subject: Contemporary hormonal contraception and colorectal cancer in premenopausal women: nationwide cohort study Workflow State: Released Full Title: Beyond direct carcinogenicity: does skeletal biology mediate the host effects of hormonal contraception on colorectal cancer? Highwire Comment Response to: Contemporary hormonal contraception and colorectal cancer in premenopausal women: nationwide cohort study Check this box if you would like your letter to appear anonymously:: Last Name: Cui First name and middle initial: Jiarui Email: [email protected] Address: Longhua Hospital, Shanghai University of Traditional Chinese Medicine. 725#, Wan-Ping South Road, Xuhui District, Shanghai, 200032, China Occupation: Postdoctoral Researcher Other Authors: Dr. Chunchun Yuan and Prof. Yongjun Wang BMJ: Additional Article Info: Rapid response