Third Year Evaluation on Genistein Efficacy and Safety

Safety Profile and Bone Efficacy of the Phytoestrogen Genistein in a Cohort of Osteopenic, Postmenopausal Women After Three Years of Treatment: a Follow-up Study

BACKGROUND: Recent evidences showed that the phytoestrogen genistein positively affects bone metabolism with no clinically significant adverse effects in a cohort of osteopenic, postmenopausal women. However, there is still a knowledge gap regarding the long-term safety of genistein on the breast, the uterus, the thyroid gland and its efficacy in postmenopausal women.

OBJECTIVE: To assess the safety profile of genistein on mammary and thyroid glands and endometrium and cardiovascular apparatus and its effects on bone metabolism after a 3-year therapy with pure, standardized genistein (54 mg/day).

Study Overview

• Status: Completed
• Conditions: Menopause; Osteopenia
• Intervention / Treatment: Dietary supplement: aglycone genistein; Dietary supplement: placebo

Detailed Description

DESIGN: The parent study was a randomized, double-blind, placebo-controlled trial involving 389 osteopenic, postmenopausal women for 24 months. After the 24-month visit, a sub-population (138 patients) accepted to continue the intervention until 36 months, thus generating a follow-up study.

SETTING: 3 Italian university medical centers. INTERVENTIONS: Participants received 54 mg of genistein, daily, (n=71) or placebo (n=67). Both intervention and placebo contained calcium and vitamin D3. All patients also received dietary instruction in an isocaloric fat-reduced diet.

MEASUREMENTS: Mammographic breast density at baseline and after 24 and 36 months was assessed by visual classification scale and by digitized quantification. BRCA1 and BRCA2 molecular message, sister chromatid exchanges and endometrial thickness were also evaluated at the same time points. Measurements of lumbar spine and femoral neck BMD and QUS t-score were assayed in our patients. Secondary outcomes were serum levels of B-ALP, IGF-I, sRANKL, osteoprotegerin and urinary excretion of CTX, pyridinoline and deoxypyridinoline. Furthermore insulin resistance (HOMA-IR), glucose levels, homocysteine and hot flushes were also evaluated. In addition for thyroid safety TSH, fT3, fT4, thyroid autoantibodies, and mRNA for thyroid and retinoid receptors were evaluated.

• Study Type: Observational
• Enrollment (Actual): 138

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 49 years to 67 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Postmenopausal women (age 49-67 yrs)

Description

Inclusion Criteria:

• Good general health
• Have not had a menstrual period in the preceding year
• Had not undergone surgically induced menopause
• Had a follicle-stimulating hormone level > 50 IU/liter and a serum 17 beta-estradiol level ≤ 100 pmol/liter
• Established osteopenia (-1<T-score<-2.5 SD)

Exclusion Criteria:

• Clinical or laboratory evidence of confounding systemic diseases, such as cardiovascular, hepatic, or renal disorders
• Coagulopathy, use of oral or transdermal estrogen, progestin, androgen or other steroids
• Biphosphonates, cholesterol-lowering therapy or cardiovascular medications in the preceding six months
• Smoking habit of more than two cigarettes per day
• Previous treatment with any drug that could affect the skeleton in the preceding year
• A family history of estrogen-dependent cancer
• BMD at femoral neck > 0.795 g/cm2; this BMD value corresponds to a T score of -1 standard deviation

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
1; Postmenopausal women with established osteopenia receiving aglycone genistein 54 mg/day for 3 years	Dietary supplement: aglycone genistein; 2 capsules per day containing 27 mg of aglycone genistein, calcium carbonate (500 mg) and vitamin D (400 IU), for a 3-year period.; Other Names: Genivis; Fosteum
2; Postmenopausal women with established osteopenia receiving placebo (Calcium and vitD) for 3 years	Dietary supplement: placebo; 2 capsules per day containing calcium carbonate (500 mg) and vitamin D (400 IU), for a 3-year period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Bone Mineral Density	basal and after 1 year
Mammographic breast density	basal and after 3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Bone-specific alkaline phosphatase (B-ALP)	basal and after 1 year
Insulin-like growth factor 1 (IGF-1)	basal and after 1 year
Pyridinium cross-links (pyridinoline and deoxypyridinoline)	basal and after 1 year
carboxy-terminal cross-linking telopeptide (CTX)	basal and after 1 year
Osteoprotegerin and soluble receptor activator of NF-kB ligand (s-RANKL)	basal and after 1 year
BRCA1 and BRCA2 mRNA levels	basal and after 3 years
Sister Chromatid exchanges	basal and after 3 years
Endometrial thickness	basal and after 3 years
Insulin resistance	basal and after 3 years
hot flushes	basal and after 3 years
Thyroid status	basal and after 3 years

Collaborators and Investigators

• Sponsor: University of Messina
• Collaborators: Primus Pharmaceuticals
• Investigators: Principal Investigator: Francesco Squadrito, MD, University of Messina; Study Director: Rosario D'Anna, MD, University of Messina

Publications and helpful links

General Publications

• Marini H, Minutoli L, Polito F, Bitto A, Altavilla D, Atteritano M, Gaudio A, Mazzaferro S, Frisina A, Frisina N, Lubrano C, Bonaiuto M, D'Anna R, Cannata ML, Corrado F, Adamo EB, Wilson S, Squadrito F. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern Med. 2007 Jun 19;146(12):839-47. doi: 10.7326/0003-4819-146-12-200706190-00005.
• Bitto A, Polito F, Atteritano M, Altavilla D, Mazzaferro S, Marini H, Adamo EB, D'Anna R, Granese R, Corrado F, Russo S, Minutoli L, Squadrito F. Genistein aglycone does not affect thyroid function: results from a three-year, randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2010 Jun;95(6):3067-72. doi: 10.1210/jc.2009-2779. Epub 2010 Mar 31.
• Marini H, Bitto A, Altavilla D, Burnett BP, Polito F, Di Stefano V, Minutoli L, Atteritano M, Levy RM, D'Anna R, Frisina N, Mazzaferro S, Cancellieri F, Cannata ML, Corrado F, Frisina A, Adamo V, Lubrano C, Sansotta C, Marini R, Adamo EB, Squadrito F. Breast safety and efficacy of genistein aglycone for postmenopausal bone loss: a follow-up study. J Clin Endocrinol Metab. 2008 Dec;93(12):4787-96. doi: 10.1210/jc.2008-1087. Epub 2008 Sep 16.

Study record dates

Study Major Dates

• Study Start: July 1, 2005
• Primary Completion (Actual): July 1, 2006
• Study Completion (Actual): September 1, 2006

Study Registration Dates

• First Submitted: February 19, 2008
• First Submitted That Met QC Criteria: February 28, 2008
• First Posted (Estimate): February 29, 2008

Study Record Updates

• Last Update Posted (Estimate): May 19, 2009
• Last Update Submitted That Met QC Criteria: May 18, 2009
• Last Verified: May 1, 2009

More Information

Terms related to this study

• Keywords: safety; Genistein; Bone mineral density; digital mammography
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protective Agents; Estrogens, Non-Steroidal; Estrogens; Protein Kinase Inhibitors; Anticarcinogenic Agents; Phytoestrogens; Genistein
• Other Study ID Numbers: 2005-07