Clinical trial NCT00626769: Third Year Evaluation on Genistein Efficacy and Safety
Official title: 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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Menopause
Osteopenia
Keywords: Genistein
Bone mineral density
digital mammography
safety
Lead sponsor: University of Messina
Sponsor class: OTHER
Collaborators: name: Primus Pharmaceuticals
First posted: 2008-02-29
Enrollment: 138
Sex: FEMALE
Minimum age (years): 49
Maximum age (years): 67
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Postmenopausal women (age 49-67 yrs)

Brief summary: 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).

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.

Eligibility criteria: 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

Primary outcomes:
measure: Bone Mineral Density
timeFrame: basal and after 1 year
measure: Mammographic breast density
timeFrame: basal and after 3 years
Secondary outcomes:
measure: Bone-specific alkaline phosphatase (B-ALP)
timeFrame: basal and after 1 year
measure: Insulin-like growth factor 1 (IGF-1)
timeFrame: basal and after 1 year
measure: Pyridinium cross-links (pyridinoline and deoxypyridinoline)
timeFrame: basal and after 1 year
measure: carboxy-terminal cross-linking telopeptide (CTX)
timeFrame: basal and after 1 year
measure: Osteoprotegerin and soluble receptor activator of NF-kB ligand (s-RANKL)
timeFrame: basal and after 1 year
measure: BRCA1 and BRCA2 mRNA levels
timeFrame: basal and after 3 years
measure: Sister Chromatid exchanges
timeFrame: basal and after 3 years
measure: Endometrial thickness
timeFrame: basal and after 3 years
measure: Insulin resistance
timeFrame: basal and after 3 years
measure: hot flushes
timeFrame: basal and after 3 years
measure: Thyroid status
timeFrame: basal and after 3 years
Other outcomes:
Locations:
Study officials:
affiliation: University of Messina
name: Francesco Squadrito, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Messina
name: Rosario D'Anna, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.