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Breast Safety and Efficacy of Genistein Aglycone for Postmenopausal Bone Loss: A Follow-Up Study

Department of Biochemical, Physiological and Nutritional Sciences, Section of Physiology and Human Nutrition (H.M., R.M., E.B.A.), and 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; Primus Pharmaceuticals, Inc. (B.P.B., R.M.L.), Scottsdale, Arizona 85251; Departments of Internal Medicine (M.A., N.F., S.M., A.F.), Obstetrical and Gynecological Sciences (R.D., F.Ca., M.L.C., F.Co.), and Human Pathology, Section of Clinical Oncology (V.A.), University of Messina, 98125 Messina, Italy; Department of Medical Physiopathology (C.L.), "La Sapienza" University, 00161 Rome, Italy; and Department of Environmental, Sanitary, Social and Industrial Protection (C.S.), University of Messina, 98125 Messina, Italy

Address all correspondence and requests for reprints to: Prof. Francesco Squadrito, M.D., Department of Experimental and Clinical Medicine and Pharmacology, Section of Pharmacology, Torre Biologica 5th floor, Policlinico "G. Martino," Via C. Valeria, 98125 Messina, Italy. E-mail: Francesco.Squadrito{at}unime.it.

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-B 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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