ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12617000570381

Ethics application status

Approved

Date submitted

12/04/2017

Date registered

24/04/2017

Date last updated

28/10/2021

Date data sharing statement initially provided

28/10/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

Building bone from blood: The effect of vitamin D on circulating bone-forming cells

Scientific title

A randomised, double blind, placebo-controlled trial to determine the effect of vitamin D supplementation on the number of Circulating Osteo-Progenitor (COP) cells in vitamin D-deficient individuals

Secondary ID [1]

None

Universal Trial Number (UTN)

U1111-1195-4316

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Vitamin D deficiency

Condition category

Condition code

Musculoskeletal

Other muscular and skeletal disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

After randomisation, on day 1 of the 3 month dosing period, participants will be given either loading dose of one tablet containing 50000IU of vitamin D orally (treated group - Arm 1) or a tablet containing placebo (placebo group - Arm 2). Both groups will also receive 1000IU/day of vitamin D for 3 months starting on day 1 post-loading dose for both groups. Participants will be required to return every 4 weeks for a total of 3 monthly visits. During each monthly visit, adherence will be monitored by asking the participants to bring their empty bottles of vitamin D tablets. At their monthly visits, participants will receive enough vitamin D tablets (1,000 IU/tablet) for a month. In addition, a monthly blood test (40ml) will be performed.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Arm 2 will consist of placebo (tablets containing microcrystalin cellulose) followed by 1000IU/day of vitamin D for 3 months, which will be started on day 1 post-loading dose.

Control group

Placebo

Outcomes

Primary outcome [1]

The primary outcome of the intervention will be the proportion of participants with an increase in number of circulating osteoprogenitor cells (COP) cells (as a percentage), measure by flow cytometry, at the end of the first month post-loading dose.

Timepoint [1]

One month post-loading dose (50,000 IU) of vitamin D

Secondary outcome [1]

The secondary outcome would be to observe the rate of increase (monthly) of COP cells for three months. Percentage of COP cells in the circulation will be mesured monthly by flow cytometry.

Timepoint [1]

At 1, 2 and 3 months post-loading dose

Eligibility

Key inclusion criteria

1- Age > 55yo
2- Both male and females
3- Independent in Activities of Daily Living (ADL) (Barthel > 60%)
4- Vitamin D deficient < 35 nmol/L
5- Normal Bone Mineral Density (BMD) (>-1 SD)

Minimum age

55 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1- Current smoker
2- High Body Mass Index (>30)
3- Diabetics
4- Hematopoietic / Hematological diseases
5- Current or prior use of drugs that could interfere with bone mass (ie Glucocorticosteroids, anti-resorptive drugs, Hormone Replacement Therapy, Teriparatide)
6- History of recent / traumatic fractures in the last 3 months
7- History of bone tumours
8- Aortic valve calcification
9- HyperPTH (>6.8pmol/L)
10- Abnormal thyroid function (Thyroid Stimulating Hormone (TSH) > 10mIU/L)
11- Estimated Glomerular Filtration rate (eGFR) < 35 ml/min

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Randomisation is achieved at the pharmacy through central randomisation by computer.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Parallel

Other design features

Phase

Phase 4

Type of endpoint/s

Efficacy

Statistical methods / analysis

Sample size calculations were based on COP levels observed in healthy populations from previous unpublished datasets. Since COP cells are not normally distributed, the mean and SD of logarithmic transformation will be used (mean -0.9, SD 0.9). It is expected that the intervention group will reach normal COP values within 1 month, while the placebo group will be 50% lower in value. Based on this estimate and assuming a two-tailed significance level of 0.05 and power of 80%, 42 patients per group will be required. Sample size calculations were obtained using STATA 13.0.
Withdrawn participants will not be replaced in the study. Every patient will be contacted and reminded prior to their monthly visits, therefore the drop-out is not expected to exceed 5%. The total number of patients recruited will therefore be 84
All the results will be presented following CONSORT guidelines. Baseline characteristics will be presented as frequencies with percentages and median values with interquartile ranges. The outcome variable will be transformed to follow normal distribution if required. Primary outcome (the difference in COP levels at 1 month) will be analysed on intention to treat principle with case-wise deletion of those patients with missing primary outcome. Statistical test used will be 2-samples independent t-test with no adjustment for covariates (two-tailed level of significance at 5%). Secondary outcomes (the difference in COP levels at 2 and 3 months) will be analysed in similar manner. As part of sensitivity analysis for primary and secondary outcomes, the ‘per-protocol’ analysis will be performed as well as adjustment for unbalanced baseline covariates using linear regression. Missing data imputation will not be attempted unless a large proportion of missing data or its non-random nature is observed during the study and at analysis stage in which case missing data imputation may be performed and results presented as part of sensitivity analysis.

Recruitment

Recruitment status

Stopped early

Data analysis

Data analysis is complete

Reason for early stopping/withdrawal

Participant recruitment difficulties
Other reasons/comments

Other reasons

COVID-19

Date of first participant enrolment

Anticipated

1/07/2018

Actual

1/07/2019

Date of last participant enrolment

Anticipated

28/02/2019

Actual

3/02/2020

Date of last data collection

Anticipated

31/05/2019

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Footscray Hospital - Footscray

Recruitment hospital [2]

Sunshine Hospital - St Albans

Recruitment hospital [3]

Williamstown Hospital - Williamstown

Recruitment postcode(s) [1]

3011 - Footscray

Recruitment postcode(s) [2]

3021 - St Albans

Recruitment postcode(s) [3]

3016 - Williamstown

Funding & Sponsors

Funding source category [1]

University

Name [1]

The University of Melbourne

Address [1]

176 Furlong Road
St. Albans VIC 3021

Country [1]

Australia

Primary sponsor type

Hospital

Name

Western Health

Address

176 Furlong Road
St. Albans VIC 3021

Country

Australia

Secondary sponsor category [1]

None

Name [1]

None

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

MELBOURNE HEALTH HUMAN RESEARCH ETHICS COMMITTEE

Ethics committee address [1]

Office for Research
The Royal Melbourne Hospital
Level 2 South West
300 Grattan Street
Parkville VIC 3050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

09/12/2016

Approval date [1]

10/02/2017

Ethics approval number [1]

HREC/16/MH/348

Summary

Brief summary

Bone remodelling involves a process of continuous bone resorption and formation through the co-ordinated recruitment of osteoclasts (bone resorbing cells) and osteoblasts (bone forming cells), and it is well recognised that the bone marrow provides the progenitor cells (mesenchymal and hematopoietic stem cells) needed for such processes to occur. Mesenchymal stem cells (MSCs) give rise to bone (including osteoblasts), adipose tissue and muscle, while the hematopoietic stem cells (HSCs) give rise to the blood cells (including osteoclasts). Many studies have attempted to investigate factors that regulate the bone remodeling process, with vitamin D as a popular choice due to its known beneficial effects in bone conditions such as osteoporosis in the elderly. Although its effect on osteoblasts, osteoclasts and myocytes are well known, the effects on the progenitor cells are not. 
Currently, the origin of osteoblastic cells is not as well understood as osteoclastic cells. With ageing, there is a significant reduction in the number and quality of the osteogenic precursors within the bone marrow, which is more prominent in osteoporotic bone. This has allowed researchers to hypothesise that increasing the number of osteoblast precursors in bone could be used as a new approach to osteoporosis. However, one of those potential therapeutic options involves an invasive and complex technique of bone biopsy with aspiration to obtain such progenitor cells for ex-vivo culturing and re-implantation for treatment in osteoporotic patients. This has led to the research of less invasive techniques that aim to assess the quality and quantity of such progenitor cells without the need of invasive procedures, with one such development being the discovery of circulating osteogenic progenitor (COP) cells within peripheral blood.
COP cells are considered as a surrogate of MSC population in the bone marrow and are implicated in processes such as the pubertal growth spurt and frailty. Presently, there are few interventional studies regarding COP cells described in the literature. As such, more should be done in an attempt to explore and further characterise the biology of COP cells and their exact role in bone formation. In addition, COP cells could become a biomarker for diseases that affect MSC population, such as sarcopenia and osteoporosis, and also as an indicator of the therapeutic response to treatments that induce bone formation.
There have been many studies recognising various compounds that affect bone. Vitamin D is one of those compounds with an anabolic effect on bone and also as an inhibitor of bone marrow adipogenesis. In this study, we hypothesise that individuals who are deficient in vitamin D will have a relatively lower number of COP cells as compared to healthy individuals. Secondly, we also hypothesise that the beneficial effect of vitamin D supplementation on human bone is associated with increasing numbers of  COP cells.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Gustavo Duque

Address

Level 3 WCHRE, Sunshine Hospital
176 Furlong Road
St. Albans VIC 3021

Country

Australia

Phone

+61 3 83958121

Fax

gustavo.duque@unimelb.edu.au

Contact person for public queries

Name

Elizabeth Liberts

Address

Level 3 WCHRE, Sunshine Hospital
176 Furlong Road
St. Albans VIC 3021

Country

Australia

Phone

+61 3 83958121

Fax

liz.liberts@unimelb.edu.au

Contact person for scientific queries

Name

Karin du Plessis

Address

Level 3 WCHRE, Sunshine Hospital
176 Furlong Road
St. Albans VIC 3021

Country

Australia

Phone

+61 3 83958121

Fax

karin.du@unimelb.edu.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

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