RANK-ligand Inhibition to Combat Sarcopenia with Underlying Osteoporosis

RANK-ligand Inhibition to Combat Sarcopenia with Underlying Osteoporosis: a Randomized, Double-blind, Double-dummy, Active-Controlled Trial

The objective of this study was to conduct a randomized, double-blind, double-dummy active controlled trial to determine the efficacy of denosumab in treating sarcopenia with underlying osteoporosis.

Study Overview

• Status: Recruiting
• Conditions: Sarcopenia in Elderly
• Intervention / Treatment: Drug: Denosumab; Drug: Zolendronic Acid

Detailed Description

Aims:

1. To assess whether receptor activator of nuclear factor-kB ligand (RANKL)-inhibition can treat sarcopenia in osteosarcopenic patients, in terms of appendicular skeletal muscle mass (ASM), handgrip strength, and physical performance.
2. To assess whether RANKL-inhibition improves quality of life, and decreases falls, fractures, hospital admissions and mortality in osteosarcopenic patients.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ronald Man Yeung Wong; Phone Number: 852 3505 1654; Email: ronald.wong@cuhk.edu.hk

Study Locations

• China
  • Hong Kong, China
    • Recruiting
    • The Chinese University of Hong Kong
    • Contact: Ronald Man Yeung Wong; Phone Number: 852 3505 1654; Email: ronald.wong@cuhk.edu.hk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Elderly males or females aged 65 years or older
• diagnosed with osteosarcopenia (sarcopenia diagnosis based on AWGS 2019 guidelines - low appendicular skeletal muscle mass (ASM) by Dual-energy X-ray absorptiometry (DXA) (M:<7.0kg/m2, F:<5.4kg/m2) AND low handgrip strength (M:<28kg, F:<18kg) OR low physical performance (6-metre walk: <1.0m/s or 5-time chair stand test ≥ 12 s); osteoporosis diagnosed based on World Health Organization (WHO) criteria with DXA scan T-score ≤ -2.5)
• Willing and able to comply with study protocol including follow-up evaluations.

Exclusion Criteria:

• history of recent fracture i.e., within 3 months
• history of prior anti-osteoporotic drug
• disease or medication affecting bone or muscle metabolism
• Chairbound or bedbound
• Unable to agree for consent
• contraindication to drug i.e., Denosumab or Zoledronic Acid
• Underlying malignancy or disease known to cause cachexia
• severe renal impairment e.g., Creatinine Clearance (CrCl) < 35ml/min
• moderate to severe liver failure (Child-Pugh Class B or C).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Denosumab group; 60mg subcutaneous Denosumab (1mL solution) every 6 months and intravenous placebo (100mL normal saline) once yearly	Drug: Denosumab; 60mg subcutaneous Denosumab (1mL solution) every 6 months and intravenous placebo (100mL normal saline) once yearly
Placebo Comparator: Zolendronic acid group; 5mg intravenous Zoledronic Acid (100mL solution) once yearly and subcutaneous placebo (1mL normal saline) every 6 months	Drug: Zolendronic Acid; 5mg intravenous Zoledronic Acid (100mL solution) once yearly and subcutaneous placebo (1mL normal saline) every 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-metre walk	The time taken to walk 6 metres without deceleration. Average result of 2 trials is recorded. Slow speed is defined as <1.0m/s.	From enrollment to the end of treatment at 52 weeks
5-time chair stand test	The time to rise from a chair 5 times is recorded. The cut-off for is taken at >=12 seconds.	From enrollment to the end of treatment at 8 weeks
Appendicular skeletal muscle mass (ASM)	Determined with Dual-energy X-ray absorptiometry (Horizon®, DXA system, Hologic, USA). Total ASM by DXA is evaluated by segmented measurement of muscle mass at four limbs by operator-defined cutlines at specific anatomical landmarks. ASM is adjusted to square of height to calculate ASMI (kg/m2). Low ASMI by DXA is < 7 kg/m2 for men and 5.4 kg/m2 for women.	From enrollment to the end of treatment at 52 weeks
Handgrip strength	Assessed by spring-type hand dynamometer (JAMAR Hand Dynamometer 5030JO). Cut-off for men is < 28kg, and female is <18kg. Maximum reading of 3 trials using dominant hand in a maximum-effort isometric contraction	From enrollment to the end of treatment at 52 weeks
Quadriceps muscle strength	Measured on affected limb with isometric dynamometer (Baseline, Genova, Italy). Subject will sit on a chair with both feet above ground, while raising the affected leg 45° forwards. The dynamometer is placed above the ankle and the subject will push the leg forward with maximum force. Measurements will be repeated 3 times and maximum value will be used for evaluation	From enrollment to the end of treatment at 52 weeks
Balancing ability	The Basic Balance Master System (NeuroCom International Inc, USA) is used to measure static and dynamic ability of subjects to maintain center of balance. Subjects will stand barefoot on force plate and control location of their center-of-gravity by weight-shifting to eight different targets. Measured parameters of limits of stability test includes directional control (%).	From enrollment to the end of treatment at 52 weeks
Balancing ability	The Basic Balance Master System (NeuroCom International Inc, USA) is used to measure static and dynamic ability of subjects to maintain center of balance. Subjects will stand barefoot on force plate and control location of their center-of-gravity by weight-shifting to eight different targets. Measured parameters of limits of stability test includes movement velocity (degrees/s)	From enrollment to the end of treatment at 52 weeks
Balancing ability	The Basic Balance Master System (NeuroCom International Inc, USA) is used to measure static and dynamic ability of subjects to maintain center of balance. Subjects will stand barefoot on force plate and control location of their center-of-gravity by weight-shifting to eight different targets. Measured parameters of limits of stability test includes endpoint excursion (%)	From enrollment to the end of treatment at 52 weeks
Balancing ability	The Basic Balance Master System (NeuroCom International Inc, USA) is used to measure static and dynamic ability of subjects to maintain center of balance. Subjects will stand barefoot on force plate and control location of their center-of-gravity by weight-shifting to eight different targets. Measured parameters of limits of stability test includes maximum excursion (%)	From enrollment to the end of treatment at 52 weeks
Balancing ability	The Basic Balance Master System (NeuroCom International Inc, USA) is used to measure static and dynamic ability of subjects to maintain center of balance. Subjects will stand barefoot on force plate and control location of their center-of-gravity by weight-shifting to eight different targets. Measured parameters of limits of stability test includes reaction time(s)	From enrollment to the end of treatment at 52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Falls	To assess the occurrence of falls, patients are required to self-report via a fall calendar, which will be returned at 1-year	From enrollment to the end of treatment at 52 weeks
Fracture	Assess occurrence of a fracture within a year of study period.	From enrollment to the end of treatment at 52 weeks
Quality of life Short Form-36 (SF-36)	The highest score is 900, and the lowest score is 0. Highest score indicates a better quality of life.	From enrollment to the end of treatment at 52 weeks
Physical activity scale for elderly (PASE)	It assesses the types of activities typically chosen by older adults, ranging from 0 to 793, with higher scores indicating greater physical activity	From enrollment to the end of treatment at 52 weeks
Food frequency questionnaire	Daily and weekly intake of 280 food items will be performed using a validated food frequency questionnaire developed in a local population survey. Mean nutrient quantitation and energy intake per day will be calculated referring to food composition tables derived from the Chinese Medical Sciences Institute and Centre for Food Safety in Hong Kong.	From enrollment to the end of treatment at 52 weeks
Hospital admissions	Number and cause of emergency hospital admission within 1 year of study period are documented.	From enrollment to the end of treatment at 52 weeks
Mortality	Mortality within 1-year of study period is documented.	From enrollment to the end of treatment at 52 weeks

Collaborators and Investigators

• Sponsor: Prince of Wales Hospital, Shatin, Hong Kong
• Collaborators: Chinese University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2024
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: September 15, 2024
• First Submitted That Met QC Criteria: October 13, 2024
• First Posted (Actual): October 16, 2024

Study Record Updates

• Last Update Posted (Actual): October 16, 2024
• Last Update Submitted That Met QC Criteria: October 13, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Neurologic Manifestations; Musculoskeletal Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Bone Diseases; Muscular Atrophy; Atrophy; Bone Diseases, Metabolic; Sarcopenia; Osteoporosis; Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: 2022.555

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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.: Yes