W22 - Vitamin D Levels in 6% Blood Subsample of CaD
This site provides study documentation for the W22 Core Study. Datasets for this study are contained within the existing WHI datasets, located on the Data site (a completed Data Distribution Agreement is required; see details on the Data site).
Investigator Names and Contact Information
Core study approved by WHI Steering Committee
Introduction/Intent
In the CaD trial, CaD supplementation was associated with a non-significant 12% reduction in hip fractures and no significant effect of total fractures or colorectal cancer. Biomarker studies of pre-randomization 25(OH) vitamin D levels have not demonstrated an association with a CaD on hip fracture reduction. Meta-analyses of CaD on osteoporosis and fracture however suggest that post-intervention vitamin D levels may need to exceed a specific threshold to achieve a beneficial intervention effect. To determine the true magnitude of change in 25(OH) vitamin D in response to the WHI CaD intervention to begin to place the WHI CaD trial results in context with other major CaD supplementation trials, we propose to measure CaD baseline (year 01) and post-intervention (year 03) 25(OH) vitamin D levels in a cohort of CaD randomized participants and CaD control participants from the 6% subsample of the CaD trial, not specifically selected on basis of adherence status (N~2200).
The calcium plus vitamin D (CaD) clinical trial tested the primary hypothesis that CaD supplementation would decrease the risk of hip fractures in healthy, community-dwelling postmenopausal women and secondarily, that CaD would decrease the risk of colorectal cancer and total fractures. In analyses reported in the primary papers, CaD was shown to be associated with a 1.06% greater bone mass in participants receiving CaD than placebo and a non-significant 12% decrease in hip fractures in the intention-to-treat analyses with no significant effect on total fractures or colorectal cancer. Secondary analyses further revealed a significant reduction in hip fractures in woman over 60 and those who were adherent to study medication. There was also a suggestion of interaction with HT randomization (P=0.07).
To examine the role of vitamin D sufficiency in the reduction of fractures, a case-control study was also performed. Initial analyses showed that the CaD effect on hip and total fractures did not vary based on pre-randomization 25-hydroxy vitamin D levels. However, the case-control study performed could not examine whether the 25 hydroxy- vitamin D levels had reached current targeted goals and due to the lack of post-CaD intervention biospecimen in all WHI participants, a case-control analysis of the change in vitamin D levels (or the proportion of women who reached levels defined a sufficient) on specific outcomes could not be explored. The lack of this information has limited further interpretation of the CaD intervention effects particularly as related to the ongoing interest in attempting to determine the level of serum 25-hydroxy vitamin D associated with fracture reduction.
To attempt to place the magnitude of the change in vitamin D levels in response to CaD intervention in context, in the early years of the CaD trial, a small cross-sectional pilot study was performed in a sub-sample. No specific details regarding this assay done at GSK have been made available to WHI. Although the results of this pilot had some limited utility in demonstrating that participants who received active calcium- vitamin D in the CaD trial did have higher 25(OH) vitamin D levels, the techniques for measuring vitamin D have subsequently been refined and the result from these original assays cannot be used effectively to further analyses on intervention effect.
In addition, Rowan Chlebowski showed that the baseline 25(OH)D levels were influenced by body weight and physical activity (the latter may be a proxy for sun exposure). Thus, based upon the concerns raised regarding interpretation of the results and the great need for an estimate of the magnitude of treatment response to facilitate inclusion of WHI CaD trial results, we are proposing a core study to elucidate the magnitude of change in 25(OH) vitamin D in response to CaD within 200 participants in the CaD trial(100 active CaD and 100 placebo).
Specific Aims
The objectives of the proposed core study are:
a) To assess the magnitude of change in 25(OH) vitamin D in response to the CaD intervention.
b) To determine whether the magnitude of changes differs by important sub-groups including age, BMI, HT randomization status, race/ethnicity, and adherence.
The CaD trial is unique relative to the other WHI clinical trials in that the blood sampling intervals at baseline and Yr 01 do not allow us to examine the change in vitamin D levels in a case-control design since the second pre-specified phlebotomy time is the randomization period for the CaD trial. To allow us to address the objective of this study, we propose to examine the Yr 1 (as baseline of the CaD trial) and Yr 03 25 hydroxy-vitamin D levels from participants in the 6% sub-sample who had blood draws at 3 year intervals.
Samples will be drawn from the 6% sub-sample from both active and placebo in a 1:1 proportion. All African-American (~200) and Hispanic (~100) women will be included, as well as a random sample of 300 white women for a total sample size of 600. Although we would exclude subjects who discontinued the study during the two years (drop outs), subjects will not be excluded for non-adherence.
The 25(OH)D levels will be measured using the DiaSorin LIAISON 25(OH)Vitamin D Chemiluminescent immunoassay system. Where possible samples previously measured using this method will be included in the sampling frame, which will lower overall costs.