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DENOSUMAB INCREASES BONE MINERAL DENSITY IN PATIENTS WITH THALASSEMIA MAJOR AND OSTEOPOROSIS: RESULTS OF A RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE BLIND, PHASE 2B CLINICAL TRIAL
Author(s): ,
Ersi Voskaridou
Affiliations:
Thalassemia and Sickle Cell Disease Center,'Laiko' General Hospital,Athens,Greece
,
Athanasios Papaefstathiou
Affiliations:
Endocrine Unit, 2nd Department of Internal Medicine-Propaedeutic, Research Institute and Diabetes Center,National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital,Athens,Greece
,
Dimitrios Christoulas
Affiliations:
Department of Hematology,251 General Air-Force Hospital,Athens,Greece
,
Maria Dimopoulou
Affiliations:
Thalassemia and Sickle Cell Disease Center,'Laiko' General Hospital,Athens,Greece
,
Konstantina Repa
Affiliations:
Thalassemia and Sickle Cell Disease Center,'Laiko' General Hospital,Athens,Greece
,
Athanasios Papatheodorou
Affiliations:
Department of Biomedical Research,251 General Air-Force Hospital,Athens,Greece
,
Melpomeni Peppa
Affiliations:
Endocrine Unit, 2nd Department of Internal Medicine-Propaedeutic, Research Institute and Diabetes Center,National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital,Athens,Greece
Evangelos Terpos
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens, School of Medicine,Athens,Greece
(Abstract release date: 05/18/17) EHA Library. Voskaridou E. 06/23/17; 181417; S130
Dr. Ersi Voskaridou
Dr. Ersi Voskaridou
Contributions
Abstract

Abstract: S130

Type: Oral Presentation

Presentation during EHA22: On Friday, June 23, 2017 from 12:00 - 12:15

Location: Room N105

Background

Osteoporosis is a common complication of thalassemia major (TM) with a complex pathophysiology. We have previously shown that RANKL, the most potent osteoclast activator, is elevated in the serum of TM patients and correlates with reduced bone mineral density (BMD). Denosumab (DMB) is a human monoclonal antibody that targets and binds to RANKL and has been licensed for patients with different types of osteoporosis. However, there are no prospective data for the effects of DMB on TM-induced osteoporosis.

Aims
The primary objective of this study was to evaluate the results of DMB on lumbar spine (L1-L4) BMD in patients with TM and osteoporosis as compared to placebo at 12 months. Secondary endpoints included the evaluation of the effects of DMB on femoral neck (FN) and wrist (WR) BMD at 12 months, the safety profile of DMB as well as its effects on bone turnover.

Methods
This was a single-site, randomized, placebo-controlled, double blind phase 2b clinical trial. Main inclusion criteria included adult patients (>30 years of age) with TM and BMD T-score between -2.5 and - 4.0 in at least one of the examined sites (L1-L4, FN, WR). Main exclusion criteria included: impaired renal function (eGFR of ≤30 mL/min); elevated ALT and/or AST >2 fold the upper limit of normal (UNL), or elevated direct bilirubin >1.5xUNL; heart failure (NYHA above 2); administration of bisphosphonates within one year of study enrolment; presence of any other disorder that affects bone metabolism. Patients were assigned into two treatment groups: in group A, 60 mg DMB was administered sc, every 6 months for 12 months for a total of 2 doses (day 0 and day 180); in group B, placebo was administered sc, at the same time. All patients received calcium and vitamin D supplementation. Measurement of BMD with dual energy X-ray absorptiometry at three body sites (L1-L4, FN, WR) was performed during the screening period and at the end of the study.

Results
Sixty-three patients with TM and osteoporosis participated in the study (group A, n=31; group B, n=32). Patients of groups A and B showed no differences in BMD of all evaluated sites at baseline. Patients of group A (DMB arm) achieved an increase in both L1-L4 BMD (mean±SD: 0.811±0.105 g/cm2 vs. 0.772±0.098, p<0.001) and FN BMD (0.653±0.121 g/cm2 vs. 0.631±0.103, p=0.022), while there were no changes in WR BMD. Patients of group B (placebo arm) achieved a slight increase in their L1-L4 BMD (0.801±0.097 g/cm2 vs. 0.775±0.080, p=0.004) and a significant decrease in their WR BMD (0.520±0.099 g/cm2 vs. 0.549±0.098, p=0.008). The percentage increase of L1-L4 BMD was higher in DMB arm than in placebo arm (6.02±5.30 % vs. 3.11±5.46 %, respectively; p=0.03), while the advantage of DMB regarding WR BMD was much higher compared to placebo (-0.22±5.40 % vs. -4.15±8.58 %, respectively; p=0.02) as well as in FN BMD (p<0.001). No grade 3 or 4 toxicity was observed in this study.

Conclusion
This first analysis of our phase 2B study regarding the effects of DMB on BMD of different sites (the results of bone markers will be presented in the conference), suggests that DMB, given twice per year, increases the BMD of the L1-L4 more efficiently than placebo (in combination with vitamin D and calcium), after 12 months, in patients with TM and osteoporosis, with excellent safety profile. Furthermore, DMB increased the FN BMD, which was not increased in the placebo arm, while DMB has also a positive effect on WR BMD compared to placebo. These data support the use of DMB for the management of TM-induced osteoporosis.

Session topic: 26. Thalassemias

Keyword(s): Treatment, Thalassemia, Osteoporosis, Beta thalassemia

Abstract: S130

Type: Oral Presentation

Presentation during EHA22: On Friday, June 23, 2017 from 12:00 - 12:15

Location: Room N105

Background

Osteoporosis is a common complication of thalassemia major (TM) with a complex pathophysiology. We have previously shown that RANKL, the most potent osteoclast activator, is elevated in the serum of TM patients and correlates with reduced bone mineral density (BMD). Denosumab (DMB) is a human monoclonal antibody that targets and binds to RANKL and has been licensed for patients with different types of osteoporosis. However, there are no prospective data for the effects of DMB on TM-induced osteoporosis.

Aims
The primary objective of this study was to evaluate the results of DMB on lumbar spine (L1-L4) BMD in patients with TM and osteoporosis as compared to placebo at 12 months. Secondary endpoints included the evaluation of the effects of DMB on femoral neck (FN) and wrist (WR) BMD at 12 months, the safety profile of DMB as well as its effects on bone turnover.

Methods
This was a single-site, randomized, placebo-controlled, double blind phase 2b clinical trial. Main inclusion criteria included adult patients (>30 years of age) with TM and BMD T-score between -2.5 and - 4.0 in at least one of the examined sites (L1-L4, FN, WR). Main exclusion criteria included: impaired renal function (eGFR of ≤30 mL/min); elevated ALT and/or AST >2 fold the upper limit of normal (UNL), or elevated direct bilirubin >1.5xUNL; heart failure (NYHA above 2); administration of bisphosphonates within one year of study enrolment; presence of any other disorder that affects bone metabolism. Patients were assigned into two treatment groups: in group A, 60 mg DMB was administered sc, every 6 months for 12 months for a total of 2 doses (day 0 and day 180); in group B, placebo was administered sc, at the same time. All patients received calcium and vitamin D supplementation. Measurement of BMD with dual energy X-ray absorptiometry at three body sites (L1-L4, FN, WR) was performed during the screening period and at the end of the study.

Results
Sixty-three patients with TM and osteoporosis participated in the study (group A, n=31; group B, n=32). Patients of groups A and B showed no differences in BMD of all evaluated sites at baseline. Patients of group A (DMB arm) achieved an increase in both L1-L4 BMD (mean±SD: 0.811±0.105 g/cm2 vs. 0.772±0.098, p<0.001) and FN BMD (0.653±0.121 g/cm2 vs. 0.631±0.103, p=0.022), while there were no changes in WR BMD. Patients of group B (placebo arm) achieved a slight increase in their L1-L4 BMD (0.801±0.097 g/cm2 vs. 0.775±0.080, p=0.004) and a significant decrease in their WR BMD (0.520±0.099 g/cm2 vs. 0.549±0.098, p=0.008). The percentage increase of L1-L4 BMD was higher in DMB arm than in placebo arm (6.02±5.30 % vs. 3.11±5.46 %, respectively; p=0.03), while the advantage of DMB regarding WR BMD was much higher compared to placebo (-0.22±5.40 % vs. -4.15±8.58 %, respectively; p=0.02) as well as in FN BMD (p<0.001). No grade 3 or 4 toxicity was observed in this study.

Conclusion
This first analysis of our phase 2B study regarding the effects of DMB on BMD of different sites (the results of bone markers will be presented in the conference), suggests that DMB, given twice per year, increases the BMD of the L1-L4 more efficiently than placebo (in combination with vitamin D and calcium), after 12 months, in patients with TM and osteoporosis, with excellent safety profile. Furthermore, DMB increased the FN BMD, which was not increased in the placebo arm, while DMB has also a positive effect on WR BMD compared to placebo. These data support the use of DMB for the management of TM-induced osteoporosis.

Session topic: 26. Thalassemias

Keyword(s): Treatment, Thalassemia, Osteoporosis, Beta thalassemia

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