Effects of Genistein Aglycone in Glucocorticoid Induced Osteoporosis

Metabolic, Endocrine, and Central Effects of Genistein Aglycone in Glucocorticoid Induced Osteoporosis

Prolonged glucocorticoid therapy affects bone fragility, cardiovascular health, glucidic and lipidic metabolism, thyroid and brain function. Glucocorticoid-induced osteoporosis is characterized by low bone turnover and fractures, which occur in 30-50% of patients. Glucocorticoids affect predominantly cancellous or trabecular bone, increasing the risk of vertebral fractures, which may be asymptomatic and occur early during the first months of glucocorticoid treatment. Genistein exerts biological effects by several potential mechanisms. Besides protective effects on bone loss, genistein reduces cardiovascular risk markers, improves endothelial function and ameliorates glucose and lipid metabolism. This study is aimed at demonstrating genistein efficacy in glucocorticoid-induced osteoporosis in a cohort of caucasian post-menopausal women.

Study Overview

• Status: Unknown
• Conditions: Osteoporosis, Steroid Induced
• Intervention / Treatment: Dietary supplement: Genistein aglycone; Drug: Alendronate Oral Tablet; Dietary supplement: Calcium + vitamin D3 tablet

Detailed Description

Glucocorticoid-induced osteoporosis (GIOP) is one of the primary side effects of glucocorticoid use resulting in increased risk of fractures. Glucocorticoid therapy affects bone mass, glucidic and lipidic metabolism, thyroid function and is also responsible for a decline in cognitive function. In this study a natural approach will be used, a soy-derived isoflavone, namely genistein. Genistein has been proven effective in preserving bone mineral density in post-menopausal women, and has an high safety profile. Genistein was also able in improving cardiovascular markers, as well as lipidic and glucidic metabolism markers without interfering with thyroid function.

Treatment guidelines for the use of glucocorticoids have been established which advise that if prednisolone is administered at 5 mg per day for three months or longer requires regular monitoring of bone mineral density (BMD) and treatment to prevent osteoporosis must be initiated (American college of Rheumatology). Vitamin D and calcium are also recommended for the management of all patients treated with glucocorticoids. Bisphosphonates should be considered for the prevention and treatment of this disorder, because they can prevent the initial loss of bone mass from glucocorticoids. Alendronate, risedronate, and zoledronic acid were shown to prevent and reverse the loss of BMD in glucocorticoid-induced osteoporosis with greater effects than those observed with vitamin D and calcium. In fact, bisphosphonates induce improvement of BMD that is 2-fold greater than that observed during vitamin D treatment alone (4.6% vs. 2.0%, respectively). Anabolic therapy is also used for the treatment of glucocorticoid-induced osteoporosis. Teriparatide causes a greater increase in BMD than alendronate and greater reduction in the risk of vertebral fractures. Even with these evidentiary clinical trials and guidelines, patient bone loss is, in general, poorly managed. In glucocorticoid-induced osteoporosis, fractures also occur at higher BMDs than in postmenopausal osteoporosis in untreated women. Consequently, guidelines for the treatment of postmenopausal osteoporosis are not applicable to glucocorticoid-induced osteoporosis, and patients should be treated at BMD T-scores of -1.0 to -1.5 standard deviations. In addition, vertebral fractures may be asymptomatic and often require radiological diagnosis before treatment.

During the initial phases of glucocorticoid exposure bone resorption is increased. Glucocorticoids inhibit the formation of mature osteoblasts, but also activate an activate apoptosis in these cell types. Osteoprotegrin (OPG) expression, a key factor involved in modulating maturation of osteoclasts, is reduced also by glucocorticoids resulting in increased osteoclastogenesis. Therefore, the combination of reduced osteoblast formation, increased osteoclast maturation leads to accelerated bone loss while on glucocorticoid therapy. Therapies are needed which modulate osteoclast as well as osteoblast activity to restore a more normal balance to the bone remodeling process in glucocorticoid treated patients.

A rational treatment for glucocorticoid-induced osteoporosis should combine a significant anti-osteoporotic and anti-fracture activity with positive actions on the several undesirable effects of this therapy including alteration in glucose and lipid metabolism, amplification of the cardiovascular risk, impairment in thyroid and cognitive function.

Genistein aglycone represents an innovative therapeutic bullet to challenge the metabolic derangements induced by glucocorticoids. Among the anabolic compounds tested in recent years genistein aglycone seems a promising agent able to stimulate bone formation and to reduce bone resorption, acting via a genomic as well as a non-genomic pathways. Genistein is an isoflavone found in small quantities in certain legumes throughout the plant kingdom. Genistein has both ER agonist and antagonist activity in different cell types and works in a promoter specific manner in gene activation via ERs. Effects of genistein on bone metabolism derived from direct and indirect actions on bone cells and can be summarized in stimulation of osteoblastic bone formation and inhibition of osteoclastic bone resorption.

It has been demonstrated that genistein inhibits glucocorticoid receptor transactivation and may also induce a proteosomal degradation of the glucocorticoid receptor complex via the p53 and ubiquitin pathways. Another mechanism might involve genistein activity as a tyrosine kinase inhibitor via the limitation of the subcellular nuclear transport and the recycling of the glucocorticoid receptors, inhibiting in turn the effects of glucocorticoids on bone. In a rat model, we studied genistein preservative effects on methylprednisolone-induced bone loss and osteonecrosis of the femoral head. In our study genistein succeeded in preventing osteoporosis and osteonecrosis of the femoral head when co-administered with the glucocorticoid. The isoflavone statistically maintained bone mineral density and content over the methylprednisolone-treated group and showed comparable efficacy with the vehicle group. Genistein co-administered with methylprednisolone also statistically maintained femoral bone's resistance to rupture compared with the methylprednisolone group and preserved the normal architecture of cartilage as well as both cortical and trabecular bones with a well-organized matrix in femoral head.

Besides the protective effects on osteoporosis, genistein has been shown to positively affects the cardiovascular system reducing predictors of cardiovascular risk, improving endothelial function and ameliorating glucose and lipid metabolism. In addition genistein possesses beneficial activity in the central nervous system and protects the hippocampus from injury.

Regarding the effects of genistein on thyroid function that may be impaired by glucocorticoids a recent clinical trial evaluated the effects of three year administration of pure genistein aglycone (54 mg/day) on thyroid-related markers, in postmenopausal women. Specifically, changes in thyroid hormone receptors and thyroid hormone enzymes, blood levels of thyroid hormones and thyroid auto-antibodies were assessed. The results of this research showed that daily consumption of genistein aglycone did not modified circulating fT4 (free thyroxine), fT3 (free triiodothyronine), and TSH (thyroid-stimulating hormone) levels; further, genistein aglycone administration over 3 yr did not affect the enzymes involved in thyroid hormone production, the thyroid hormone auto-antibodies, and the expression of thyroid hormone receptors then confirming that genistein does not appear to alter thyroid function in postmenopausal women.

Taken together this clinical and pre-clinical observations lead the investigators to hypothesize a role for genistein in the management of glucocorticoid-related side effects.

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Francesco Squadrito, MD; Phone Number: +390902213648; Email: fsquadrito@unime.it

Study Locations

• Italy
  • Messina, Italy, 98123
    • Recruiting
    • University of Messina
    • Principal Investigator: Francesco Squadrito, MD
  • Messina, Italy, 98125
    • Recruiting
    • University Hospital
    • Contact: Francesco Squadrito, MD; Phone Number: +390902213648; Email: fsquadrito@unime.it
    • Principal Investigator: Marco Atteritano, MD
    • Sub-Investigator: Alessandra Bitto, MD/PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 54 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• being treated with glucocorticoids (5 mg of prednisone equivalents) for the preceding 3 months or less, and expect to continue the therapy for at least 12 months;
• being post-menopausal;

Exclusion Criteria:

• use of other steroids or osteoporosis medications;
• have been diagnosed with metabolic bone diseases (other than glucocorticoid osteoporosis)
• previous (1 year) or current use of HRT (hormone replacement therapy)
• other diseases that may affect participation (i.e. mental illness)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Genistein; Each tablet will contain 27 mg of 98% pure genistein + 500mg Calcium + 200 IU Vit. D3. Subjects will receive 2 tablets per day 6 days/week for all the duration of the study. Once a week subjects will receive a tablet containing only 500mg Calcium + 200 IU Vit. D3.	Dietary supplement: Genistein aglycone; 27mg bid in tablets; Other Names: fosteum
Active Comparator: Alendronate; Each tablet will contain 500mg Calcium + 200 IU Vit. D3. Subjects will receive 2 tablets per day 6 days/week for all the duration of the study. Once a week subjects will take one tablet containing 70mg alendronate.	Drug: Alendronate Oral Tablet; 70 mg/week in tablets; Other Names: Fosamax; Dietary supplement: Calcium + vitamin D3 tablet; 500mg Calcium + 200 IU Vitamin D3 bid in tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Bone mineral density	BMD of lumbar spine and femoral will be measured by DEXA (dual energy x-ray absorptiometry)	24 months
Bone fracture	Xrays of the lumbar spine (T4-L4) will be taken to evaluate the presence of fractures	24 months
Change in Bone quality	pQCT (peripheral quantitative computed tomography) will be used for bone quality evaluation	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Bone markers	bone turnover markers will be evaluated on peripheral blood	24 months
Change in Cardiovascular markers	Markers of cardiovascular risk will be evaluated on peripheral blood	24 months
Change in Glucose and lipid metabolism	Glycaemia and blood lipids will be evaluated on peripheral blood	24 months
Change in Quality of life	European Quality of Life Questionnaire will be administered to subjects	24 months
Chage in skin elasticity	skin elasticity will be tested in subjects taking glucocorticoids	24 months
Change in thyroid markers	markers of thyroid function will be evaluated on peripheral blood	24 months
Change in inflammatory markers	markers of inflammation will be evaluated on peripheral blood	24 months
Polymorphisms of estrogen receptor	Estrogen receptor polymorphisms will be evaluated on white blood cells	24 months

Collaborators and Investigators

• Sponsor: University of Messina
• Collaborators: Ministry of Health, Italy
• Investigators: Study Director: Francesco Squadrito, MD, University of Messina

Study record dates

Study Major Dates

• Study Start (Actual): January 19, 2017
• Primary Completion (Anticipated): June 30, 2018
• Study Completion (Anticipated): December 30, 2018

Study Registration Dates

• First Submitted: January 30, 2017
• First Submitted That Met QC Criteria: January 31, 2017
• First Posted (Estimate): February 2, 2017

Study Record Updates

• Last Update Posted (Actual): March 3, 2017
• Last Update Submitted That Met QC Criteria: March 1, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: glucocorticoid; genistein; alendronate
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis; 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; Micronutrients; Protein Kinase Inhibitors; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Anticarcinogenic Agents; Phytoestrogens; Vitamin D; Cholecalciferol; Calcium; Alendronate; Genistein
• Other Study ID Numbers: 45/16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No