Osteoporosis Clinical Trial
Official title:
A Randomized, Open-label Therapeutic Trial Evaluating the Efficacy and Safety of Neridronate (Nerixia®) in the Treatment of Osteoporosis in Patients With Thalassemia Major and Severe Thalassemia Intermedia.
An Italian Multicentric randomized, open-label therapeutic trial evaluating the efficacy and
safety of Neridronate in the treatment of Osteoporosis in patients with Thalassemia Major and
Severe Thalassemia Intermedia.
Efficacy and safety of the drug will be evaluated measuring at every visit this parameters:
- haematological: Haemochrome
- blood chemistry: creatinine, BUN, AST, ALT, Ca, P, proteins electrophoresis, total
proteins.
The prevalence of ectopic calcification and pseudoxantoma elasticum (PXE)-like syndrome and
their follow-up will be evaluated at the beginning of the study vs 24 months through physical
examination, abdominal echography and fundus oculi examination.
During the trial other known risks factors for osteoporosis will be recorded, including
prevalence and incidence of bone fractures and, if executed, Polimorphisms COLIA1.
At the beginning of the study and at months 12 and 24 morphometry DXA will be performed to
evaluate of the presence of bone deformities.
Furthermore data regarding QOL and symptom pain will be evaluated trough administration of
scale SF-36.
At 12 months an intratrial analisis will be performed on efficacy and safety parameters in
order to introduce possible amendments to the study design and to decide the prosecution of
the trial
During the trial all adverse events will be recorded
Aim of the Study At present, due to the global therapeutic approach, the prognosis of
Thalassemia Major and Severe Thalassemia Intermedia is open-ended. Regular transfusional
regimens from childhood and early iron chelation therapy prevent bone deformities that in the
past characterized this disease even though according to several authors a high percentage of
patients suffers from osteopenia-osteoporosis. This persistent complication may be explained
by one or more coexistent factors such as anaemia, genetic factors, sex hormones involved in
the bone metabolism, iron and chelation therapy, hypothiroidism, low or subnormal
concentrations of serum vitamin D, etc.
Pain resulted to be the only parameter that may be considered to distinguish patients with
Thalassemia Major from healthy patients of the same age through a survey about Quality of
Life performed in the Center of Genoa. More frequently pain is localized in the lumbar
vertebrae, it is often described with invalidant pictures and it has to be referred to
osteoporosis of vertebral bodies.
The incidence of spontaneous fractures observed in the specialistic centers treating these
pathologies is increasing.
Thalassemia Intermedia is an eterogeneous clinical entity including a wide range of
phenotypes from mild to severe forms. In the mild forms hemoglobin levels range between 8-9
g/dl, which is stable without the need for regular transfusion therapy unless an intercurrent
episode aggravates anemia; no expansion of the bone marrow is observed. By contrast, there
are forms in which anemia is persistently more severe (6.5- 7.5 g/dl) with marked ineffective
erythropoiesis. In these cases, especially when the diagnosis is made in childhood, patients
should receive a transfusional regimen similar to Major forms with similar complications such
as osteoporosis.
For these reasons in patients affected with Severe Thalassemia Intermedia and with
Thalassemia Major prevention and early diagnosis of osteoporosis are important as well as
treatment of the established disease in order both to improve quality of life and life
expectancy.
In therapeutical trials previously described bisphosphonates have been shown to be effective
because of their ability to inhibit bone resorption and their relatively few side effects
resulting in an increase bone density. Since all the previous trials were conducted on a
small number of patients, we propose a randomized, open label large multicentric trial to
test the efficacy of Neridronate. The possibility to administrate this drug every 90 days
intravenous makes dosing regimens simple and reduces the frequency of administration. These
are important factors to improve adherence to therapy in patients already subjected to an
heavy daily therapeutic load.
Primary Objectives The primary objective of this study is to evaluate the efficacy of
Neridronate (an aminobisphosfonate of third generation that has been proved in several
clinical trials to have the ability to inhibit osteoclast-mediated bone resorption) to
increase Bone Mass Density (BMD) measured through Double X-ray densitometry (DXA). Bone
densitometry will be performed at basal screening and then at 6, 12, 18, 24 months from the
beginning of the treatment.
Secondary objectives The effect of Neridronate on bone turn over will be evaluated through
bone alcaline phosphatase (BALP) and telopeptide C-terminal of type 1 seric collagen (CTX-s),
at screening and then at 6, 12, 18, 24 months from the beginning of the treatment.
The dosage of the markers will be centralized. Study design An Italian Multicentric
randomized, open-label therapeutic trial evaluating the efficacy and safety of Neridronate in
the treatment of Osteoporosis in patients with Thalassemia Major and Severe Thalassemia
Intermedia.
Efficacy and safety of the drug will be evaluated measuring at every visit this parameters:
- haematological: Haemochrome
- blood chemistry: creatinine, BUN, AST, ALT, Ca, P, proteins electrophoresis, total
proteins.
The prevalence of ectopic calcification and pseudoxantoma elasticum (PXE)-like syndrome and
their follow-up will be evaluated at the beginning of the study vs 24 months through physical
examination, abdominal echography and fundus oculi examination.
During the trial other known risks factors for osteoporosis will be recorded, including
prevalence and incidence of bone fractures and, if executed, Polimorphisms COLIA1 At the
beginning of the study and at months 12 and 24 morphometry DXA for the evaluation of the
presence of bone deformities Furthermore data regarding QOL and symptom pain will be
evaluated trough administration of scale SF-36.
During the trial all adverse events will be recorded
Extension study:
Objectives of the extension study
1. In vitro analysis of the effects of iron overload and chelating molecules on mesenchymal
stem cells growth and osteogenic differentiation
2. Evaluation of the effects of neridronate on normal and thalassemic MSCs'proliferation
and differentiation.
3. Phenotypical characterization of MSCs prepared from thalassemic patients treated with or
without neridronate Study design A. In vitro analysis of the effects of iron overload
and chelating molecules on MSCs growth and osteogenic differentiation B. Evaluation of
the effects of neridronate on normal and thalassemic MSCs'proliferation and
differentiation.
C. Phenotypical characterization of MSCs prepared from thalassemic patients treated with or
without neridronate A. In vitro analysis of the effects of iron overload and chelating
molecules on MSCs growth and osteogenic differentiation
1. Preparation of a collection of bone marrow mesenchymal stem cells from normal subjects
To isolate and prepare MSCs, we will utilize the protocol described in detail in Oliva
et. al. (Molec. and Cell. Biochem., 2003, 247:55-60). The details of MSCs preparation
are reported in annexes.
The cells expressed specific surface markers, such as CD13, CD29, CD44, CD105, CD166,
and were negative for hematopoietic cell markers CD14, CD34 and CD45.
In this way, we are preparing a normal MSCs'bank, on which perform the experimentation.
At present, we have already available more than 10 preparations of MSCs from normal
subjects.
2. Analysis of the effects of iron overload on proliferation and differentiation of MSCs
Although it is well known that thalassemic subjects undergo iron overload, no data are
available in Literature on the effects of this metal on proliferation and
differentiation of MSCs. To this aim we will proceed as indicated below. We will
evaluate the proliferation rate and iron and ferritin intracellular levels in MSCs in
logarithmic phase incubated with increasing concentrations of iron, starting from
physiological hematic amounts, i.e. 2-18 microg/ml, until reaching values 10-fold
higher, similar to those occurring in thalassemic patients. We will analyze the effect
on growth rate by direct cell count, MTT vitality assay, and 3H-thymidine incorporation
(DNA synthesis).
Successively we will analyze the effects of iron overload on the levels of the main
proteic product of MSCs, namely type I collagen, following the protocol reported.
Confluent cultures of early passages (0-3) of MSCs, nontreated and treated with iron
overload, are tripsinized, counted and centrifuged at 800xg. The pellets are resuspended
in 0.5 M acetic acid containing 250 microg/ml pepsin.
After 16 hours of gentle shaking at 4°C, the insoluble residue is pelleted at 20.000xg
for 1 hour, solubilized in run buffer and analyzed by 6% SDS-PAGE. Afterwards, proteins
are blotted to a nitrocellulose membrane and incubated with rabbit monoclonal antibodies
specific for human type I collagen. The immunoreactive bands are then incubated with
horse radish peroxidase conjugated secondary antibodies and detected by means of
enhanced chemoluminescent technique (ECL).
The effects on differentiation will be evaluated analyzing the expression of specific
markers of osteoblastic phenotype, namely alkaline phosphatase activity and osteocalcin
production. In addition, we will evaluate the osteogenic capacity of MSCs expressed by
extracellular matrix mineralization. Confluent cultures are incubated with an osteogenic
medium composed of dexametasone 100 nM and beta-glycerophosphate 10 mM. If osteogenic
capacity is present, calcification noduli appear within 2-4 weeks. To further confirm
the matrix mineralization we will measure calcium levels and finally carry out a
specific stain by von Kossa method.
3. Analysis of effects of iron chelating molecules on proliferation and differentiation of
MSCs We will evaluate the effects of DFO, which represents so far the most used
chelating molecule in the therapy of thalassemia in spite of the well known
disadvantages and toxicity. MSCs cultures, nontreated or treated with iron overload,
will be added with DFO at concentrations similar to those obtained in vivo following
drug administration to thalassemic patients. We will analyze the effect of the treatment
on growth rate, collagen type I levels, alkaline phosphatase activity, osteocalcin
production, as well as the osteogenic capacity.
4. Characterization of cell cycle components in MSCs subjected to iron overload and/or DFO
It is well known that characterization of cell cycle components represents the basis for
the comprehension of pivotal events of proliferation and differentiation processes.
Thus, cell extracts obtained from both MSCs cell populations treated as described above (i.e.
iron, DFO or iron overload and/or desferrioxamine) will be analyzed by immunoblotting
employing antibodies against several cycle proteic components. Among them in particular:
cyclin D1, D2, and D3, cyclin E, cyclin A; CDK4, CDK6, CDK2 and CDK1; p16, p14, p15, p21, and
p27. Moreover, the phosphorylation of the retinoblastoma protein and the cdk activities will
be analyzed.
B. Evaluation of the effects of neridronate on normal and thalassemic MSCs'proliferation and
differentiation.
The objective of this study will be the in vitro analysis of the effects of the neridronate
on normal and thalassemic human MSCs. In particular, we will evaluate if the drug, tested at
concentrations between 10(-4) M and 10(-6) M being 10(-5) M the therapeutic dose, affect the
viability, proliferation, and cellular activity of MSCs. The effects on proliferation will be
assessed in terms of 3H-thymidine incorporation, MTT test and cell cycle engine modulation.
The action on differentiation will be evaluated analyzing the expression of specific markers,
namely type I collagen levels, alkaline phosphatase activity and osteocalcin production. In
addition, we will evaluate the osteogenic capacity of MSCs expressed by extracellular matrix
mineralization, by the measure of calcium levels and by von Kossa staining.
C. Phenotypical characterization of MSCs prepared from thalassemic patients treated with or
without neridronate The aim of this study will be to investigate whether the treatment of
thalassemic patients with neridronate might positively affect the osteoporotic condition and,
at the same time, improve the osteogenic capacity of MSCs. Therefore, we will prepare MSCs
from thalassemic patients treated or not with neridronate and cultivate them according to
standard method. In particular, we will analyze the growth rate, the cell cycle machinery,
the collagen levels, the AP activity and the osteocalcin synthesis. Most importantly we will
evaluate the extracellular matrix mineralization.
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