Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03040531 |
| Other study ID # |
45/16 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 2/Phase 3
|
| First received |
January 30, 2017 |
| Last updated |
March 1, 2017 |
| Start date |
January 19, 2017 |
| Est. completion date |
December 30, 2018 |
Study information
| Verified date |
March 2017 |
| Source |
University of Messina |
| Contact |
Francesco Squadrito, MD |
| Phone |
+390902213648 |
| Email |
fsquadrito[@]unime.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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.
