To Test the Effect of Calcifediol Hy.D Supplementation on Muscle Function and Bone Quality in Younger Postmenopausal Women With Osteopenia

To Test the Effect of Calcifediol Hy.D Supplementation on Muscle Function and Bone Quality in Younger Postmenopausal Women With Osteopenia: a Double-blind Randomized Placebo-controlled Trial

Young postmenopausal women with osteopenia / or women with osteoporosis and a FRAX score below pharmacologic treatment indication have limited treatment options in the prevention of osteoporosis/treatment of osteopenia. Further, there is a concern about long-term side effects of bisphosphonate treatment among young postmenopausal women, and hormone replacement therapy has been controversial. In a pilot study 20 microgram Calcifediol Hy.D improved several muscle related function in this target population within 4 months of treatment, which can help to prevent falls and associated bone fractures. Thus the main aim of this study is to test whether Calcifediol Hy.D at a daily dose of 20 μg / day improves muscle function (lower extremity test battery) compared with (1) placebo and compared with (2) 3200 Vitamin D3 IU per day, at 3 and 6 month follow-up. As a secondary and exploratory objective of this study, the investigators will compare the beforementioned doses on muscle strength and the quality of the bones, beside muscle mass, body composition and systolic and diastolic blood pressure measurements.

Study Overview

• Status: Completed
• Conditions: Osteopenia/Osteoporosis
• Intervention / Treatment: Dietary supplement: Calcifediol; Dietary supplement: Vitamin D3; Other: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Phase 2

Contacts and Locations

Study Locations

• Switzerland
  • Zurich, Switzerland, 8091
    • Center on Aging and Mobility, Klinik für Geriatrie, UniversitätsSpital Zürich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Women age 50 to 70
• Post-menopausal (defined as: at least 1 year after the last menstrual period)
• community-dwelling and ambulatory without help
• with documented osteopenia (BMD by DEXA t-score: < -1.0 and > -2.5 at the spine or hip) in the 6 months prior to enrolment or with documented osteoporosis (BMD by DEXA t-score: ≤ -2.5 at the spine or hip) and a FRAX score (online calculation tool of absolute 10 year fracture risk) below the Swiss age-dependent indication threshold for pharmacologic treatment for the 10-year risk of major osteoporotic fractures - at the screening visit and including DEXA (in the 6 months prior to enrolment) as part of the calculation
• body mass index > 18.5 and < 30 kg/m2
• 25(OH)D level < 24 µg/l (< 60 nmol/l)
• understands German in reading and writing plus able to read, understand, and complete questionnaires and tests
• willingness to limit additional vitamin D3 intake to 800 IU per day
• willingness to limit calcium supplement intake to 500 mg/day
• willingness to stop active vitamin D metabolites
• participant understands the study procedures, alternative treatments available and risks involved with the study and voluntarily agrees to participate by giving a written informed consent
• participant meets the routine clinical laboratory safety screening tests performed at screening visit
• participant is able and willing to perform all study tests, attend all required office visits, and provide blood and urine samples
• participant is able to swallow the study medication

Exclusion Criteria:

• Consumption of more than 1'000 IU vitamin D on any day in the 4 weeks prior to enrollment.
• Elevated serum calcium > 2.60 mmol/l adjusted for albumin if albumin ≤ 35 or ≥ 45g/l
• estimated creatinine clearance < 30 ml/min (Cockcroft and Gault = 140 - age(yr)*weight(kg)/ serum Cr(mmol/l))×(1.04 for women)
• severe visual or hearing impairment
• malabsorption syndrome (celiac diseases, inflammatory bowel disease).
• Pathologic fracture (excl. fractures due to osteoporosis) in the last year
• Fracture due to osteoporosis in the last 10 years
• Chemo therapy / Radiation due to cancer in the last year
• Treatment which has an effect on calcium metabolism (e.g. PTH, calcitonin, chronic cortisone intake > 5mg/day for more than 4 weeks in the last 12 months (except for inhalation and sporadic infiltration))
• Current treatment with a bisphosphonate
• For participants of the ancillary study "Muscle Biopsy" only: Treatment which has an effect on blood coagulation (e.g. factor X inhibitor, thrombin inhibitor, NSAR, low-molecular heparin, inhibitor for platelet aggregation, vitamin K antagonist) and/or abnormal blood coagulation status .
• Unwilling or unable to take study medication
• Diseases with a risk of recurrent falling (e.g. Parkinson's disease/syndrome, Hemiplegia after stroke, symptomatic stenosis of the spinal canal, polyneuropathy, epilepsy, recurring vertigo, recurring syncope)
• History of or current diseases that may enhance serum calcium: sarcoidosis, lymphoma, primary hyperparathyroidism
• Individual that heavily consumes alcohol containing products defined as greater than (>) 3 drinks (beer, wine, or distilled spirits) of alcoholic beverages per day.
• Individual is unlikely to adhere to the study procedures, to keep appointments, or is planning to relocate during the study.
• Individuals who are planning a stay in a "sunny" location (e.g. winter sun resort) for more than one month during the course of the study
• Medication which has an effect on 25-hydroxyvitamin D level (e.g. certain anticonvulsants (e.g. Phenobarbital, Carbamazepin, Phenytoin))
• M. Paget (Ostitis deformans)
• Inflammatory arthritis (e.g. rheumatoid arthritis, Reiter syndrome, psoriasis arthritis)
• Participation in a study in the last 6 months, except for studies without drug-application, or any influence of the study-medication can be excluded

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Calcifediol Hy.D (25-hydroxyvitamin D); 20 μg Calcifediol Hy.D (25-hydroxyvitamin D) (one capsule) per day for 6 months	Dietary supplement: Calcifediol; One capsule orally of Calcifediol (20 µg) per day with a meal for a duration of 6 months; Other Names: 25-hydroxyvitamin D (Hy.D)
Active Comparator: Vitamin D3 (cholecalciferol); 3200 IU Vitamin D3 (cholecalciferol) (one capsule) per day for 6 months	Dietary supplement: Vitamin D3; One capsule orally of Cholecalciferol (3200 IU) per day with a meal for a duration of 6 months; Other Names: Cholecalciferol
Placebo Comparator: Placebo; 1 Placebo capsule per day for 6 months	Other: Placebo; One capsule orally of a Placebo capsule per day with a meal for a duration of 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall assessment of the "lower extremity function" test battery (difference in proportion of those who improved or maintained function compared to those who declined in function by treatment group)	The "lower extremity function" test battery consists of: 8-meter walk test, repeated sit-to-stand test and knee flexion and extension strength test). A repeated measures analysis across all four test battery components simultaneously documenting the difference in proportion of those who improved or maintained function compared to those who declined in function by treatment group (comprised endpoint on lower extremity function) will be performed. Calcifediol Hy.D will be compared with (1) placebo and compared with (2) 3200 Vitamin D3 IU per day -for the time points baseline 3 and 6 months. Outcomes of the individual tests are subject to the secondary outcome measures.	Baseline, 3 months, 6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Gait speed measurement (8-meter walk)	Baseline, 3 months, 6 months
Knee flexion and extension strength test	Baseline, 3 months, 6 months
Repeated sit-to-stand test (reaction time)	Baseline, 3 months, 6 months
Systolic and diastolic blood pressure	Baseline, 3 months, 6 months
Timed up and go test (functional mobility)	Baseline, 3 months, 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bone mineral density (DXA)	spine, hip (both sides at baseline, side with lowest total femur BMD only at follow-up), radius	Baseline and 6 months
Muscle mass (DXA)	Upper and lower extremity, body composition	Baseline and 6 months
Bone quality (Xtreme CT):	Tibia (funding is pending), radius (funding is pending)	Baseline and 6 months
Cognition (MoCa test score)	MoCa: Montreal Cognitive Assessment	Baseline and 6 months
Quality of life questionnaire	EuroQol country specific TTM Index	Baseline, 3 months, 6 months
Upper extremity test (grip strength)		Baseline, 3 months, 6 months
Cardiovascular fitness (6-minute walking test)		Baseline, 3 months, 6 months
Cardio vascular risk marker (NT-BNP)		Baseline, 3 months, 6 months
Bone marker: P1NP		Baseline, 3 months, 6 months
Bone marker: Osteocalcin		Baseline, 3 months, 6 months
Bone marker: Sclerostin		Baseline, 3 months, 6 months
Muscle marker: myostatin		Baseline, 3 months, 6 months
Safety: Serum calcium adjusted for albumin		Screening, 3 months, 6 months
Safety: Serum creatinine		Screening, 3 months, 6 months
Safety: Urinary calcium/creatinine Ratio		Screening, 3 months, 6 months
Safety: Blood pressure		Screening, 3 months, 6 months
Safety: Pulse rate		Screening, 3 months, 6 months
Ancillary studies: Analysis of expression of the vitamin D receptor (VDR) in skeletal muscle	18 of 50 participants in active group I, active group II and control will be enrolled in the muscle biopsy ancillary study. The muscle biopsies (about 0.2 g) will be taken from mid-thigh at baseline and at 6 months follow-up. Biopsies will be taken at the Zurich site, frozen and send to the Tufts University Boston, USA for analysis. Analysis: Expression of the vitamin D receptor (VDR) in skeletal muscle	Baseline, 6 months
Ancillary studies: Analysis of total cross-sectional area (CSA) of muscle fibers	18 of 50 participants in active group I, active group II and control will be enrolled in the muscle biopsy ancillary study. The muscle biopsies (about 0.2 g) will be taken from mid-thigh at baseline and at 6 months follow-up. Biopsies will be taken at the Zurich site, frozen and send to the Tufts University Boston, USA for analysis. Analysis: Total cross-sectional area (CSA) of muscle fibers	Baseline, 6 months
Ancillary studies: Dried blood spot	Among all 150 participants, we compare 25(OH)D content in arterial finger tip blood and venous blood at baseline and at 3 months	Baseline, 3 months

Collaborators and Investigators

• Sponsor: DSM Nutritional Products, Inc.
• Collaborators: University of Zurich; Tufts University
• Investigators: Principal Investigator: Heike Bischoff-Ferrari, Prof, Dr.PH, Center on Aging and Mobility, Klinik für Geriatrie, UniversitätsSpital Zürich

Publications and helpful links

General Publications

• Ceglia L, Rivas DA, Schlogl M, Fielding GB, Egli A, Bischoff-Ferrari HA, Dawson-Hughes B. Effect of vitamin D3 vs. calcifediol on VDR concentration and fiber size in skeletal muscle. J Bone Miner Metab. 2022 Nov 16. doi: 10.1007/s00774-022-01374-y. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2015
• Primary Completion (Actual): September 1, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: August 14, 2015
• First Submitted That Met QC Criteria: August 17, 2015
• First Posted (Estimate): August 19, 2015

Study Record Updates

• Last Update Posted (Actual): April 30, 2019
• Last Update Submitted That Met QC Criteria: April 29, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Osteoporosis; Bone Diseases, Metabolic; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol; Calcifediol; Hydroxycholecalciferols
• Other Study ID Numbers: 2013-11-25-HyD-O; 000000198 (Other Identifier: SNCTP No.)