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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Type 2 Diabetes; Osteopenia
• Intervention / Treatment: Drug: oral Semaglutide/Rybelsus; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 64
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Morten Frost, MD; Email: mmfnielsen@health.sdu.dk
• Study Contact Backup: Name: Julie Bjerrelund, MD; Phone Number: +4529849154; Email: julie.bjerrelund@rsyd.dk

Study Locations

• Denmark
  • Odense, Denmark, 5000
    • Odense University Hospital
    • Principal Investigator: Morten Frost, MD
    • Contact: Julie Bjerrelund, MD; Phone Number: +4529849154; Email: julie.bjerrelund@rsyd.dk
    • Sub-Investigator: Julie Bjerrelund, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: oral Semaglutide/Rybelsus; oral Semaglutide 7-14 mg (or highest tolerated dose) once daily for 52 weeks (incl. titration)	Drug: oral Semaglutide/Rybelsus; 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.
Placebo Comparator: oral Placebo; oral Placebo 7-14 mg (or highest tolerated dose) once daily for 52 weeks (incl. titration)	Drug: Placebo; 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Osteogenic potential	Change in osteogenic potential, i.e., ability to form new bone, assessed using spatial transcriptomics and single-cell RNA sequencing.	52 weeks

Collaborators and Investigators

• Sponsor: Odense University Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2023
• Primary Completion (Estimated): November 1, 2025
• Study Completion (Estimated): November 1, 2025

Study Registration Dates

• First Submitted: September 8, 2023
• First Submitted That Met QC Criteria: September 21, 2023
• First Posted (Actual): September 22, 2023

Study Record Updates

• Last Update Posted (Actual): September 22, 2023
• Last Update Submitted That Met QC Criteria: September 21, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Musculoskeletal Diseases; Bone Diseases; Diabetes Mellitus, Type 2; Bone Diseases, Metabolic
• Other Study ID Numbers: EU CT: 2023-505959-45-00

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No