The Effect of Oral Semaglutide on Bone Turnover in Patients With T2D: a Randomized Placebo-controlled Clinical Trial

Study Overview
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Brief Summary
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The hypothesis for this study is that oral Semaglutide, a GLP-1Ra, has a positive effect on the balance between build-up and degradation as well as the strength of the bones in men and women aged 50-85 years with type 2 diabetes and an increased risk of bone fractures. Treatment involves once daily oral GLP-1Ra semaglutide or matching placebo for 52 weeks. The effect will be measured by bone markers in blood samples, bone scans, bone tissue and bone marrow tests (bone marrow aspiration and biopsy), physical activity assessed by a questionnaire, and direct bone strength measured by microindentation at the start and end of the study.

Official Title
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The Effect of Oral Semaglutide on Bone Turnover in Patients With Type 2 Diabetes: a Randomized Placebo-controlled Clinical Trial - (SOBER II)

Conditions
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Type 2 Diabetes, Osteopenia

Intervention / Treatment
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* Drug: oral Semaglutide/Rybelsus
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Type 2 diabetes and glycosylated haemoglobin (HbA1C) of 48-91 mmol/mol (6.5-10.5%) and T-score <-1 in hip or lower back, assessed by DXA scan and / or Low-energy fracture within the last 3 years Exclusion criteria T-score <-2.5 in hip or lower back, assessed by DXA scan, although these individuals may be included if they are not candidates for conventional osteoporosis therapy, e.g., due to allergies and renal impairment, or if they prefer to participate in the trial. Type 1 diabetes mellitus Severe NPDR (non-proliferative diabetic retinopathy) or PDR (proliferative diabetic retinopathy) assessed within the last year. If a recent assessment is unavailable, a new retinal photo test will be performed. Congestive heart failure (NYHA Class IV) Primary hyperparathyroidism Vitamin D deficiency (<25 nM) (re-test after substitution acceptable) Known disorders affecting bone metabolism, e.g., uncontrolled thyrotoxicosis, severe renal impairment (eGFR <30) or liver dysfunction (baseline phosphatase higher than twice upper limit (105 U/L)), rheumatism, celiac disease, hypogonadism, severe COPD, hypopituitarism, Cushing's disease Clinically significant concomitant diseases or disorders (e.g., cancer) or clinically significant abnormal values in laboratory screening tests, including increased Choriogonadotropin (hCG) in women. History of gastrointestinal surgery (except uncomplicated surgical procedures such as hernia surgery and appendectomy) Antiresorptive or bone anabolic drugs for the last 12 months Use of anabolic steroids in the previous year Use of GLP-1Ras within 90 days Stable therapy with DPP4 inhibitors (unless the patient is willing to discontinue the treatment) History of pancreatitis Allergy or hypersensitivity to the active substance or to any of the ingredients Inability to give informed consent Previous bariatric surgery BMI <20 kg/m2 or BMI>37 kg/m2

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: oral Semaglutide/Rybelsus<br>oral Semaglutide 7-14 mg (or highest tolerated dose) once daily for 52 weeks (incl. titration) | Drug: oral Semaglutide/Rybelsus<br>* Weeks 1-4: 3 mg of oral semaglutide once daily. Weeks 5-52: 7 mg of semaglutide once daily as maintenance dose. Dose may be increased to 14 mg of semaglutide once daily as maintenance dose after 2 months if glucose levels are out of range.<br>|
| Placebo Comparator: oral Placebo<br>oral Placebo 7-14 mg (or highest tolerated dose) once daily for 52 weeks (incl. titration) | Drug: Placebo<br>* Weeks 1-4: 3 mg of oral placebo once daily. Weeks 5-52: 7 mg of placebo once daily as maintenance dose. Dose may be increased to 14 mg of placebo once daily as maintenance dose after 2 months if glucose levels are out of range.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Procollagen type 1 N-terminal propeptide (P1NP) | Percentage changes in bone formation marker P1NP from baseline and after 12 months | Baseline and 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Collagen 1 cross link C-terminal telopeptide (CTX) | Changes in bone resorption marker CTX from baseline and after 12 months | Baseline and 52 weeks | 
| Osteocalcin | Changes in bone formation marker osteocalcin from baseline and after 12 months | Baseline and 52 weeks | 
| Bone specific alkaline phosphatase (BALP) | Changes in bone formation marker BALP from baseline and after 12 months | Baseline and 52 weeks | 
| BMSi | Changes in direct bone strength measured by microindentation from baseline and after 12 months | Baseline and 52 weeks | 
| Bone mineral density (BMD) | Changes in BMD (total hip, femoral neck and lumbar spine (L1-4)) assessed by DXA scans from baseline and after 12 months | Baseline and 52 weeks | 
| Estimated bone strength | Changes in estimated bone strength assessed by finite elemental analysis (HR-pQCT scan) from baseline and after 12 months | Baseline and 52 weeks | 
| Total volumetric BMD | Changes in total volumetric BMD (mg/cm^3) assessed by HR-pQCT scan of distal tibia and radius | Baseline and 52 weeks | 
| Trabecular volumetric BMD | Changes in trabecular volumetric BMD (mg/cm^3) assessed by HR-pQCT scan of distal tibia and radius | Baseline and 52 weeks | 
| Cortical volumetric BMD | Changes in cortical volumetric BMD (mg/cm^3) assessed by HR-pQCT scan of distal tibia and radius | Baseline and 52 weeks | 
| Bone volume | Changes in trabecular bone volume pr total volume (BV/TV) assessed by HR-pQCT scan of distal tibia and radius | Baseline and 52 weeks | 
| Trabecular thickness | Changes in trabecular thickness (mm) assessed by HR-pQCT scan of distal tibia and radius | Baseline and 52 weeks | 
| Cortical thickness | Changes in cortical thickness (mm) assessed by HR-pQCT scan of distal tibia and radius | Baseline and 52 weeks | 
| Cortical porosity | Changes in cortical porosity assessed by HR-pQCT scan of tibia and radius | Baseline and 52 weeks | 
| Bone formation rate | Changes in bone formation rate (BRF/BS, µm^3/µm^2 per day), the volume of mineralized bone made per unit surface of bone per year, based on dynamic histomorphometry of bone tissue | 52 weeks | 
| Fat tissue distribution | Change in fat tissue distribution, assessed by DXA | Baseline and 52 weeks | 
| Lean tissue distribution | Change in lean tissue distribution, assessed by DXA | Baseline and 52 weeks | 
| Glycosylated haemoglobin (HbA1C) | Change in HbA1c from baseline and after 12 months | Baseline and 52 weeks | 
| Physical activity | Change in physical activity based on analysis of International Physical Activity Questionnaire Short Form (IPAQ-SF) from baseline and after 12 months | Baseline and 52 weeks | 
| Body mass index (BMI) | Change in BMI from baseline and after 12 months | Baseline and 52 weeks |