Therapy of the Skeletal Disease of Type 2 Diabetes With Denosumab

Study Overview
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Brief Summary
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The goal of the study is to characterize the effect of Prolia® (denosumab) on indices of bone strength in type 2 diabetes (T2D). The investigational plan involves administration of Prolia® or identical placebo for 12 months as a randomized double-blind placebo-controlled trial in 66 T2D postmenopausal women assigned to Prolia® or placebo. The study will include assessment of different measures of bone quality: skeletal microarchitecture, including measurement of skeletal cortical pores; bone mineral density; bone material quality, and accumulation of advanced glycation endproducts (AGEs) in collagen. This information will help to determine whether Prolia® treatment in type 2 diabetes has skeletal benefits.

Detailed Description
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Type 2 Diabetes Mellitus (T2DM) has become one of the most important diseases of our time. Recent research shows that diabetes has negative effects on bones and that people with diabetes might be more likely to break a bone. We don't know the reasons for this, but we suspect that normal bone replacement is slowed down in diabetes and this could slow down the growth of new bone. It is possible that the normal bone material becomes weaker because sugar-related components (Advanced Glycation Endproducts) are making the bone more brittle. The investigators have shown in past research that people who have type 2 diabetes are more likely to have both weaker bone with lower bone material strength and also higher levels of sugar-related components (Advanced Glycation Endproducts). This study will focus on attempting to lower the sugar-related components (Advanced Glycation Endproducts) by treating a group of patients with type 2 diabetes with a medication Prolia® or denosumab for one year. The investigators will compare postmenopausal women both before and after denosumab use and study them in terms of different bone features based on blood tests, bone imaging, a bone indentation test and a measurement of sugar-related components in the skin. This study will help to clarify if using this medication helps improve bone strength in women with diabetes.

Official Title
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Therapy of the Skeletal Disease of Type 2 Diabetes With Denosumab

Conditions
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Diabetes Mellitus, Type 2, Osteoporosis

Intervention / Treatment
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* Drug: Denosumab 60 mg/ml [Prolia]
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: An understanding, ability and willingness to fully comply with study procedures and restrictions. Ability to voluntarily provide written, signed and dated informed consent as applicable to participate in the study. Postmenopausal women age ≥ 50 and ≤ 90 years at time of consent. Diagnosis of T2D for ≥ 2 years. Upon review of patient's medical history, patient will be confirmed to currently have reasonably controlled T2D as assessed by the investigator, with HbA1c ≤ 8.4%. If HbA1c is ≥ 8.5%, re-screening will be allowed after approximately 3 months following adjustment of diabetes therapy. DXA T-score ≤ -1.0 at one or more sites (lumbar spine, femoral neck, total hip or distal 1/3 radius). Normal albumin-adjusted serum calcium level. Exclusion Criteria: Hormone replacement treatment use (to avoid the influence of estrogen). Fractures (excluding skull, facial bones, metacarpals, fingers, toes, and fractures associated with severe trauma) within 12 months. A history of pathological fractures (eg, due to Paget's disease, myeloma, metastatic malignancy). Type 1 diabetes. Disorders associated with altered skeletal structure or function (chronic renal disease stage 4 or worse, chronic liver disease, malignancy, hypoparathyroidism or hyperparathyroidism, acromegaly, Cushing's syndrome, hypopituitarism, chronic obstructive pulmonary disease, alcohol intake > 3 units/day). Treatment with any of the following drugs in past year: anticonvulsant therapy, pharmacological doses of thyroid hormone (TSH<normal is permitted if subject has normal T4, clinical euthyroidism and is in steady-state), adrenal or anabolic steroids, calcitonin, estrogen or selective estrogen receptor modulator, sodium fluoride (other than dental treatment), teriparatide, denosumab, abaloparatide, strontium or aromatase inhibitors; any history of bisphosphonate treatment. Corticosteroid use permitted if subject is in steady-state. Serum 25(OH)D levels < 20 ng/ml. If 25(OH)D levels are < 20 ng/ml, rescreening will be allowed following a vitamin D loading regimen of 50,000 IU/week for 4 weeks. If serum 25(OH)D levels are ≥ 20 ng/ml after supplementation, the subject will be allowed to enroll. Clinically significant hypersensitivity to denosumab or any components of denosumab 60 mg. Known sensitivity to any of the products to be administered during the study (e.g., calcium or vitamin D). Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after the end of treatment. Female subject of child bearing potential and is not willing to use, in combination with her partner, highly effective contraception during treatment and for 5 months after the end of treatment. Significant dental/oral disease, including prior history or current evidence of osteonecrosis/osteomyelitis of the jaw, or the following: Active dental or jaw condition which requires oral surgery Non-healed dental/oral surgery Planned invasive dental procedures for the course of the study DXA T-score of ≤ -3.5 at any site.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study is a 12 month randomized (2:1 assignment) double-blind placebo-controlled trial of T2D postmenopausal women assigned to either Denosumab 60 mg subcutaneously (SC) at baseline and 6 months (n=44) or placebo (n=22); total study n=66.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Group<br>Denosumab 60 mg/ml [Prolia] SC at baseline and 6 months. | Drug: Denosumab 60 mg/ml [Prolia]<br>* Denosumab 60 mg will be administered subcutaneously in the upper arm at the Baseline and 6 Month Visits<br>* Other names: Prolia®;|
| Placebo Comparator: Control Group<br>Placebo SC at Baseline and 6 months. | Other: Placebo<br>* Placebo will be administered subcutaneously in the upper arm at the Baseline and 6 Month Visits<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cortical Porosity (Ct.Po) (%) by High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT) Imaging From Baseline to 6 and 12 Months. | The primary outcome is the 12 months change in Ct.Po and the primary intent-to-treat analysis is a one-way ANCOVA with the fixed effect of treatment (treated vs. placebo), and baseline Ct.Po as a continuous covariate. | Baseline, 6 months and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Serum Collagen Type I C-Telopeptide (s-CTX) (ng/ml) and Tartrate-resistant Acid Phosphatase 5b (TRAP 5b) (ng/ml) by Blood Test From Baseline to 3, 6 and 12 Months. | Secondary outcomes will be analyzed using ANCOVA models with P-value adjustment for multiple endpoint comparisons. | Baseline, 3 months, 6 months and 12 months | 
| Change in Dual-energy X-ray Absorptiometry (DXA) (gm/cm2) at Lumbar Spine, Femoral Neck, Total Hip and Radius From Baseline to 6 and 12 Months. | Secondary outcomes will be analyzed using ANCOVA models with P-value adjustment for multiple endpoint comparisons. | Screening visit, 6 months and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prolia, Denosumab, Diabetes