Methods
The WHI program includes 4 clinical trials (2 hormone therapy trials [HT], a dietary modification trial [DM], and a calcium plus vitamin D supplementation trial [CaD]) and an observational study. For the WHI clinical trials, postmenopausal women 50-79 years of age with life expectancy ≥ three years, no personal breast cancer history and no other cancer within 10 years were eligible. The HT and DM trials had additional eligibility requirements largely based on medical history. Women participating in the WHI hormone therapy trials (13, 14) or WHI dietary modification (15) trial were invited to enroll in an additional randomized, placebo-controlled trial evaluating calcium plus vitamin D supplementation at their first or second annual follow-up main trial visit (16, 17). For the calcium plus vitamin D trial, additional exclusions included hypercalcemia, history of kidney stones and current corticosteroid or calcitriol use. Personal use of calcium (no upper limit) and vitamin D was allowed while on study. The upper limit for allowed personal vitamin D initially was 600 International Units (IU) daily which was subsequently increased to 1,000 IU daily during the study course (17).
Eligible women who entered the calcium and vitamin D trial were randomly assigned, in a double-blind fashion, to receive active supplement or placebo stratified according to clinical center and calcium and vitamin D supplement containing calcium carbonate (500 mg as elemental calcium) with vitamin D3 (200 IU) or matching placebo was taken twice daily (GlaxoSmithKline Consumer Healthcare, Parsippany, NJ). Study pills were discontinued after development of kidney stones, hypercalcemia, kidney dialysis, and calcitriol use, which causes a greater hypercalcemia risk than other vitamin D compounds.
Details of the eligibility and conduct of the HT and DM trials have been reported (13, 14, 15). We now report on joint symptom outcomes in a subset of calcium and vitamin D trial participants. The participant flow through the WHI CT to arrive at the current study population with joint symptom assessment is outlined in Figure 1.
From the 36,282 calcium and vitamin D supplementation clinical trial participants, a 6% sub-sample of 2185 participants for the current study was randomly identified from those who were randomized at their first annual visit for the main trial and who had information collected during follow-up on joint symptoms. The sampling was done on the entire clinical trial population (n= 68,132) with 6-fold higher odds of selection for non-White participants, and a sampling rate of 8.6% in the HT trials and 4.3% in the DM trial, resulting in a 6% overall sample. There was not a specific sampling target for the calcium and vitamin D supplementation trial since the women in that trial were also in a HT and/or DM trial (16). It was planned to assess joint symptoms at baseline and after 2 years in the identified subgroup. Among these 2185 women, 242 had missing information on joint symptoms or for other variables at year 2, 32 (1.5%) died or dropped out resulting in a study population of 1911.
Details of the eligibility and conduct of the calcium plus vitamin D trial have also been reported (12, 17). The trial completed the planned intervention duration of 7 years (mean) of follow-up and calcium and vitamin D supplement effects on hip fracture as primary study endpoint (17, 18) and colorectal cancer (18) and breast cancer (19, 20), as secondary endpoints, have been published.
The described clinical trial had institutional review board approval from all participating institutions and written informed consent was obtained from all participants. Statistical analyses and data management were conducted at the WHI Clinical Coordinating Center. Dietary supplement data was collected during in-person clinic visits. Women brought their supplement bottles to the baseline clinic visit and annually thereafter. A standardized interviewer-administered form was used to collect information on multivitamins and single supplements. Staff members directly transcribed the ingredients for each supplement and asked participants about frequency and duration of use. A validity study of these procedures found correlations with photocopied labels ranged from 0.8 to 1.0 (21, 22). Prescription medication use was similarly determined by in-person review of medication containers. All reported medications were matched to the Master Drug Data Base (MDDB; Medi-Span, Indianapolis, IN).
A self-assessment food frequency questionnaire (FFQ) specifically designed for WHI (23) was used to assess dietary intake over the previous 3 months at entry into the WHI HT or DM trials (23). DM trial participants also had the FFQ administered at year 1, coinciding with entry into the CaD trial. For non-DM participants, the baseline vitamin D intake at entry into the HT trials, which was 1 year before entry into the CaD trial, was used for baseline analyses. For DM participants, dietary vitamin D at baseline was correlated to year 1 values (correlation coefficient, P<0.0001). Total daily calcium intake at baseline was defined as the sum of the dietary intake (assessed with the use of a modified Block food frequency questionnaire) (23) and the average daily self-reported intake of elemental calcium from supplements and from prescription medications in the previous two weeks. Total vitamin D intake was similarly determined reflecting not only dietary vitamin D intake (largely from fortified dairy products and fatty fish) but also vitamins D supplement use. Information on physical activity was collected by questionnaire regarding walking outside the house and recreational physical activity including frequency, duration and intensity. This information was used to generate metabolic equivalent (MET) values (24). Measurements of height and weight were made in the clinic to permit body mass index (BMI) determinations.
Clinical outcomes were determined at annual clinic visits and semi-annual contacts. Annual clinic visits included counting or weighing returned pills as an adherence measure. Joint pain and swelling was assessed by questionnaire collected at initial WHI clinical trial entry (one year prior to the calcium vitamin D supplement trial randomization), one year after entry and again after 2 years on the calcium and vitamin D supplement study. Joint pain was assessed as: (yes/no), severity was assessed as none=0, mild=1, moderate=2, severe=3 and joint swelling was assessed similarly.