Breast safety and efficacy of genistein aglycone for postmenopausal bone loss: a follow-up study
Abstract
Context: Genistein aglycone improves bone metabolism in women. However, questions about the long-term safety of genistein on breast as well as its continued efficacy still remain. Objective: We assessed the continued safety profile of genistein aglycone on breast and endometrium and its effects on bone after 3 yr of therapy. Design: The parent study was a randomized, double-blind, placebo-controlled trial involving 389 osteopenic, postmenopausal women for 24-months. Subsequently, a subcohort (138 patients) continued therapy for an additional year. Patients and Interventions: Participants received 54 mg of genistein aglycone daily (n = 71) or placebo (n = 67). Both treatment arms received calcium and vitamin D3 in therapeutic doses. Main Outcomes: Mammographic density was assessed at baseline, 24 and 36 months by visual classification scale and digitized quantification. BRCA1 and BRCA2, sister chromatid exchange, and endometrial thickness were also evaluated. Lumbar spine and femoral neck bone mineral density were also assessed. Secondary outcomes were biochemical levels of bone markers. Results: After 36 months, genistein did not significantly change mammographic breast density or endometrial thickness, BRCA1 and BRCA2 expression was preserved, whereas sister chromatid exchange was reduced compared with placebo. Bone mineral density increases were greater with genistein for both femoral neck and lumbar spine compared to placebo. Genistein also significantly reduced pyridinoline, as well as serum carboxy-terminal cross-linking telopeptide and soluble receptor activator of NF-κB ligand while increasing bone-specific alkaline phosphatase, IGF-I, and osteoprotegerin levels. There were no differences in discomfort or adverse events between groups. Conclusions: After 3 yr of treatment, genistein exhibited a promising safety profile with positive effects on bone formation in a cohort of osteopenic, postmenopausal women.
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The most common adverse event associated with soy consumption was mild to moderate gastrointestinal discomfort, usually occurring with comparable frequency in soy and placebo groups.
“The most common adverse event associated with soy consumption was mild to moderate gastrointestinal discomfort, but this usually occurred with comparable frequency in both the soy and the placebo groups [128,130,131,136,142,147,150]; only in one study was there considerable difference in the frequency of GI upset, 47% in the soy group compared to 22% in the control group [130].”
From Soy, Red Clover, and Isoflavones and Breast Cancer: A Systematic Review (2013) · cites this paper as [136]
None of the RCTs assessing endometrial thickness, mammographic density or changes, nipple aspirate volume, PAP results and uterine fibroid growth, or vaginal cytology found any evidence of negative impact from soy compared to control.
“None of the studies assessing endometrial thickness [132,136,155], mammographic density or mammographic changes [66,132,136,137,144,146], nipple aspirate volume [134], PAP results and uterine fibroid growth [132], or vaginal cytology [155] found any evidence of negative impact from soy compared to the control group.”
From Soy, Red Clover, and Isoflavones and Breast Cancer: A Systematic Review (2013) · cites this paper as [136]
One RCT found no change in BRCA 1 and 2 mRNA level due to soy consumption, but there was a decrease over time in the placebo group, yielding a significant difference between groups (p<0.001).
“One study found no change in BRCA 1 and 2 mRNA level due to soy consumption, however there was a decrease over time in the placebo group, yielding a significant difference between groups (p<0.001) [136].”
From Soy, Red Clover, and Isoflavones and Breast Cancer: A Systematic Review (2013) · cites this paper as [136]
Cites
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BRCA1 and BRCA2 and the genetics of breast and ovarian cancer
Welcsh, P. L. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.7.705 · Cited by 648 · see citing works
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Soy and Health Update: Evaluation of the Clinical and Epidemiologic Literature
Messina, M. (2016) · Nutrients · doi:10.3390/nu8120754 · Cited by 537 · see citing works
Soy, Red Clover, and Isoflavones and Breast Cancer: A Systematic Review
Fritz, H., Seely, D., Flower, G., Skidmore, B., Fernandes, R., Vadeboncoeur, S., Kennedy, D., Cooley, K., Wong, R., Sagar, S., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0081968 · Cited by 188 · see citing works
- Authors
- Marini, H., Bitto, A., Altavilla, D., Burnett, B. P., Polito, F., Di Stefano, V., Minutoli, L., Atteritano, M., Levy, R. M., D'Anna, R., Frisina, N., Mazzaferro, S., Cancellieri, F., Cannata, M. L., Corrado, F., Frisina, A., Adamo, V., Lubrano, C., Sansotta, C., Marini, R., Adamo, E. B., & Squadrito, F.
- Affiliations
- University of Messina (IT)
- Primus Pharmaceuticals, Inc. (United States) (US)
- Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology (A.B., D.A., F.P., V.D.S., L.M., F.S.), University of Messina, 98125 Messina, Italy
- Obstetrical and Gynecological Sciences (R.D., F.Ca., M.L.C., F.Co.), University of Messina, 98125 Messina, Italy
- Sapienza University of Rome (IT)
- Corresponding author
- Squadrito, Francesco
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2008-12-01
- Volume
- 93
- Issue
- 12
- Pages
- 4787-4796
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2144921993
- Cited by
- 167
- References
- 2
- Citations by year
- 2026: 1 · 2025: 10 · 2024: 6 · 2023: 9 · 2022: 7 · 2021: 14 · 2020: 3 · 2019: 10 · 2018: 8 · 2017: 12 · 2016: 11 · 2015: 11 · 2014: 7 · 2013: 13 · 2012: 12
- FWCI
- 7.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Phytoestrogen effects and research
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- postmenopausal bone loss, breast cancer risk, breast density, endometrial thickness, BRCA1, BRCA2, sister chromatid exchange, bone mineral density, bone turnover markers, isoflavones, long-term safety, osteopenia
- MeSH terms
- Aged, Bone Diseases, Metabolic, Breast Neoplasms, Double-Blind Method, Endometrium, Female, Humans, Mammography, Middle Aged, RNA, Messenger, Sister Chromatid Exchange, Biomarkers, Bone Density, Osteoporosis, Postmenopausal, BRCA1 Protein, Genistein, BRCA2 Protein, Phytoestrogens
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