This trial was a pilot to assess the feasibility of a community trial (not subsequently conducted owing to lack of funding) in 20
000 men and women. We recruited men and women aged 65-85 from the British doctors study register at the Clinical Trials Studies Unit, Oxford,8
and the age-sex register of a general practice in Ipswich, Suffolk. Cambridge local ethics committee approved the study.
Recruitment and randomisation
We recruited participants by using a mailed letter and information sheet. We excluded people who were already taking vitamin D supplements and people with conditions that were contraindications to vitamin D supplementation—for example, a history of renal stones, sarcoidosis, or malignancy.
We sent invitations to 11
120 people (9582 from the British doctors study and 1538 from general practice), and 3504 (31.5%) of them (2907 from British doctors study and 597 from general practice) initially agreed to participate. From June 1996 to March 1997 we randomised 2686 (77.5%) people who were eligible and gave informed consent, after stratification by age and sex, to receive either treatment with vitamin D or a placebo. Participants and investigators were blinded to the treatment until the study ended, when Ipswich Pharmacy revealed the coding.
We conducted the study by post. Participants completed an initial questionnaire. We assessed prevalence of disease with the question “Do you have the following conditions?” followed by a checklist. We used a modified food frequency questionnaire at four years to estimate dietary calcium intake.
We sent one capsule containing 100
000 IU vitamin D3
(cholecalciferol) or matching placebo by post every four months for five years (15 doses in total). We asked participants to take the capsule immediately on receipt, complete a form indicating that they had done so, and return the form by Freepost.
The dose had previously been shown to be safe, to raise blood 25-hydroxyvitamin D concentrations to physiological levels achievable by lifestyle means, and to have a measurable impact on concentrations of parathyroid hormone over several weeks.9
The expected differences in blood concentrations of 25-hydroxyvitamin D and parathyroid hormone are associated with differences in bone density and fracture risk.10,11
Participants continued any usual drug treatment and any new drugs that were advised during routine care. If they were advised to start vitamin D supplements of more than 200 IU daily they discontinued the trial intervention but continued to be followed for endpoints.
On receiving the capsule, participants filled in a checklist of events (fracture or major illness) and returned the form by Freepost. All participants were flagged at the Office for National Statistics for mortality and followed until 31 March 2002. A nosologist blind to the intervention coded death certificates by using ICD-9 (international classification of diseases, 9th revision). We ascertained incidences of fracture, cardiovascular disease, and cancer by using events identified from questionnaires or death certification by cause.
Serum 25-hydroxyvitamin D, parathyroid hormone, and heel sonometry
After four years we invited 235 participants from general practice who had taken at least 10 capsules to a clinic for measurement of serum vitamin D and parathyroid hormone concentrations. The visit took place in September and October, about three weeks after a dose. We assessed heel bone sonometry with CUBA equipment (McCue Ultrasonics, Winchester).
We included all participants randomised to active vitamin D or placebo in the analyses, according to intention to treat. We compared relative risks for incidence of fracture, mortality by cause, and incidence of cardiovascular disease and cancer for active vitamin D versus placebo by using crude rates and then, after adjustment for age, with the Cox regression method,12
by using SPSS software, version 10.0.