Effects of Genistein Aglycone in Glucocorticoid Induced Osteoporosis

• ClinicalTrials.gov Identifier: NCT03040531
• Recruitment Status: Unknown
• First Posted: February 2, 2017
• Last Update Posted: March 3, 2017
• Sponsor: University of Messina
• Collaborator: Ministry of Health, Italy
• Information provided by (Responsible Party): Francesco Squadrito, University of Messina

Tracking Information

• First Submitted Date: January 30, 2017
• First Posted Date: February 2, 2017
• Last Update Posted Date: March 3, 2017
• Actual Study Start Date: January 19, 2017
• Estimated Primary Completion Date: June 30, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 2, 2017)

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

Original Primary Outcome Measures (submitted: January 31, 2017)

• Change in Bone mineral density [ Time Frame: 24 months ]
  BMD of lumbar spine and femoral will be measured by DEXA
• Bone fracture [ Time Frame: 24 months ]
  Xrays of the lumbar spine (T4-L4) will be taken to evaluate the presence of fractures
• Change in Bone quality [ Time Frame: 24 months ]
  pQCT will be used for bone quality evaluation

Current Secondary Outcome Measures (submitted: March 1, 2017)

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

Original Secondary Outcome Measures (submitted: January 31, 2017)

• Change in Bone markers [ Time Frame: 24 months ]
  bone turnover markers will be evaluated on peripheral blood
• Change in Cardiovascular markers [ Time Frame: 24 months ]
  Markers of cardiovascular risk will be evaluated on peripheral blood
• Change in Glucose and lipid metabolism [ Time Frame: 24 months ]
  Glycaemia and blood lipids will be evaluated on peripheral blood
• Change in Quality of life [ Time Frame: 24 months ]
  European Quality of Life Questionnaire will be administered to subjects

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Effects of Genistein Aglycone in Glucocorticoid Induced Osteoporosis
• Official Title: Metabolic, Endocrine, and Central Effects of Genistein Aglycone in Glucocorticoid Induced Osteoporosis
• Brief Summary: 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.

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
• Study Phase: Phase 2; Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:

Drugs will be labelled as "A" and "B" and so will be the groups. Patients and doctors involved will not be aware of the treatment.

Primary Purpose: Prevention

• Condition: Osteoporosis, Steroid Induced

Intervention

• Dietary Supplement: Genistein aglycone
  27mg bid in tablets
  Other Name: fosteum
• Drug: Alendronate Oral Tablet
  70 mg/week in tablets
  Other Name: Fosamax
• Dietary Supplement: Calcium + vitamin D3 tablet
  500mg Calcium + 200 IU Vitamin D3 bid in tablets

Study Arms

• 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.

  Intervention: Dietary Supplement: Genistein aglycone
• 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.

  Interventions:

  • Drug: Alendronate Oral Tablet
  • Dietary Supplement: Calcium + vitamin D3 tablet

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: January 31, 2017): 200
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 30, 2018
• Estimated Primary Completion Date: June 30, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Only female XX patients will be included, to avoid interactions with other steroid drugs.

• Ages: 54 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT03040531
• Other Study ID Numbers: 45/16
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Francesco Squadrito, University of Messina
• Study Sponsor: University of Messina
• Collaborators: Ministry of Health, Italy

Investigators

• Study Director: Francesco Squadrito, MD; University of Messina

• PRS Account: University of Messina
• Verification Date: March 2017