Impact of Denosumab in the Prevention of Bone Loss in Non-menopausal Women With Anorexia Nervosa

Study Overview
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Brief Summary
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The drastic reduction of nutritional intake in anorexia nervosa(AN) alters many hormonal factors that regulate the activity of bone cells. This alteration of bone remodeling is characterized by increased bone resorption and decreased bone formation, leading to a marked reduction of bone mineral density, osteoporosis and an increased risk of fracture. To date, there is a paucity of studies and no consensus on the management of bone loss in patients with AN. The few previous studies were performed with small samples and using short follow-up periods. Denosumab is a fully human monoclonal antibody that binds with high specificity to human RANKL (6, 7), thereby reducing the number and activity of osteoclasts and therefore decreasing bone resorption that was found increased in patients AN. Denosumab may transiently protect bone whilst psychonutritional management will induce a weight restoration

Detailed Description
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The project propose to assess, with a double-blind multicentric randomized clinical trial, the effects of Denosumab on bone mineral density (BMD) change at lumbar spine over 12 months among patients suffering from an acute anorexia nervosa (AN). 84 patients suffering from a current anorexia nervosa with an evidence of low BMD determined by a Z-score value < -2 DS at least one site (lumbar spine or total proximal femur) will be recruit . Eligible patients will be randomized into two groups: denosumab versus placebo. Each patient will attend a total of 8 scheduled visits, which will be completed over a period of 24 months +/- 15days from screening visit to end of study (inclusion, 10 days, and 3, 6, 12, 15, 18, & 24 months).

Official Title
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Impact of Denosumab in the Prevention of Bone Loss in Non-menopausal Women With Anorexia Nervosa

Conditions
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Anorexia Nervosa

Intervention / Treatment
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* Drug: Denosumab subcutaneous injections
* Drug: Placebo subcutaneous injections


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients with a current AN defined by DSM-V criteria Being female Age over or equal to 18 years and less or equal to 40 years . For patients under 20 years of age, effective bone maturation (attested by a radiography of the hip) Agree to take contraception up to five months after the last injection of denosumab . Absence of pregnancy evidenced by an interview and a negative assay of human chorionic gonadotropin (ßhCG). Evidence of low BMD determined by Z-score value < -2 DS (at least one site (lumbar spine or total proximal femur) Signing an informed consent. Exclusion criteria: Not affiliated to a social security scheme or not being the beneficiary of such a scheme. Severe hepatic cytolysis with transaminase up to 5 times normal. Severe dental problems: in case of doubt an assessment by a dentist will be required before inclusion. Desire of pregnancy during the two years of follow-up study. Disease or treatment potentially responsible for secondary osteoporosis. Participant already treated with a molecule known to have an effect on bone Diabetes. Current hypocalcemia. Immunodeficiency. Cancer with bone lesions Patient on protectice measures (guardianship or trusteeship) Hypersensitivity to the active substance or to any of the excipients of Prolia® Unable to read and / or write and understand the methodology of the study Reporting relationship to the investigator Anticipate a long stay outside the region that would prevent compliance with the schedule of visits Participation to other biomedical research on health products Deprived of liberty Breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Denosumab subcutaneous injections<br>The treated group (n = 42) will receive Denosumab (60 mg, two subcutaneous injections at M0 and M6) associated with a daily treatment of vitamin D (800 IU) + calcium (1000 mg). | Drug: Denosumab subcutaneous injections<br>* Subcutaneous injection of Denosumab 60 mg, one injection at baseline and another injection at 6 months<br>* Other names: Treated group;|
| Placebo Comparator: Placebo subcutaneous injections<br>The control group (n = 42) will received a placebo injection (two subcutaneous injections at M0 and M6) with daily treatment of vitamin D (800 IU) +calcium (1000 mg). | Drug: Placebo subcutaneous injections<br>* Subcutaneous injection of Placebo, one injection at baseline and another injection at 6 months<br>* Other names: Control group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Value of bone mineral density in lumbar spine (g/cm2) | Comparison of bone mineral density changes in the lumbar spine at M12 between groups with Denosumab and placebo after two injections either of Denosumab or placebo. Bone mineral density is objectified by the Z-score obtained by bone mineral density. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| value of bone mineral density in the whole body, the total proximal femur and the radius (g/cm2) | Comparison of bone mineral density changes in the whole body, the total proximal femur and the radius between groups at M12 after two injections of Denosumab. | 12 months | 
| values of bone mineral density at 24 months | Comparison of the levels of bone mineral density at 24 months | 24 months | 
| values of bone remodeling markers at 24 months | Comparison of the values of bone remodeling markers at 24 months | 24 months | 
| links between ESR1 genotype and bone minéral density at Baseline and response to Denosunab | Assess the links between ESR1 genotype and BMD at baseline and response to Denosunab (variation of BMD between baseline and 12 months). | 12 months |