Study design and participants
This study is a post-hoc analysis of a multicenter, randomized, double-blind, placebo-controlled trial, the Vitamin D Effect on Osteoarthritis (VIDEO) study, aimed to evaluate the effect of vitamin D supplementation in patients with symptomatic knee OA and vitamin D deficiency19. Participants were allocated to either the treatment or placebo arm at a ratio of 1:1, and received a capsule containing 50,000IU (1.25mg) vitamin D3 (cholecalciferol) or placebo monthly for 24 months19. In this current study, both treatment and placebo groups were combined together as a cohort, which adheres to STROBE statement and include a completed STROBE checklist in the supplementary file.
Participants who suffered from symptomatic knee OA (American College of Rheumatology criteria) for at least 6 months in Tasmania and Victoria (Australia) were enrolled19 20. Exclusion criteria were detailedly described in the protocol19. The important exclusion criteria were participants with the severe radiographic changes (grade 3 on the Altman and Gold atlas) and/or severe knee pain on standing (>80 mm on a 100-mm VAS)19.
Anthropometrics and social demographic characteristics
Height and weight were measured to the nearest 0.1 cm and 0.1 kg (with shoes and bulky clothing removed) using electronic scales (Heine S-7307, Heine, New Hampshire, USA) and stadiometer (Leicester Height Measure, Invicta Plastics Ltd, Leicester, UK) at baseline. Body mass index (BMI, in kg/m2) was calculated19. The participants’ information of education history, work status/types, current smoking and concomitant medication usage were collected by the questionnaire at baseline.
Depression severity was measured using the patient health questionnaire (PHQ-9) at baseline and 24 month. PHQ-9 is a validly, reliably and commonly used instrument in diagnosing and assessing the severity of depression21. It contains nine items with a score range of 0 to 27, with each item being scored from 0 (not at all) to 3 (nearly every day). In this current study, the cut-off point of ≥5 for PHQ-9 score at baseline was defined as prevalent depression (no depression or depression), and PHQ-9 score of ≥5 at follow-up in those without depression (PHQ-9 score<5) was defined as incident depression. Besides, based on the generally recommended criterion, a cut-off point of ≥5 has a sensitivity of 81.5% and a specificity of 80.6% for mild depression and a cut-off point of ≥10 has a sensitivity of 54.3% and a specificity of 91.1% for moderate or severe depression22. The severity of depression (none, mild and moderate, severe) was used to explore the association between baseline depressive severity and change in knee symptoms over 24 months.
Knee joint symptoms
The Western Ontario and McMaster Universities OA Index (WOMAC) was used to evaluate knee joint symptoms at baseline and 24 month. The index is widely used to assess the joint functional capacity in clinical trials23. Three subscales (pain, stiffness, and physical function) and 24 questions (5 related to pain, 2 to stiffness and 17 to physical function) constitutes the index, with scores from 0 (none) to 100 (severe). The sum of three subscales scores was calculated as the total WOMAC score (0-2400). The WOMAC score was used in the analyses as a continuous variable.
Knee joint radiographic structures
Radiographic OA was assessed at baseline using a standing semi-flexed anterior-posterior radiograph as per the Altman atlas24. Radiographs were assessed simultaneously by two observers using the Altman atlas to score osteophytes and joint space narrowing on a four-point scale (0 to 3) at medial tibial, lateral tibial, medial femoral and lateral femoral sites. The presence of radiographic OA was defined as any score of ³ 1 for JSN or osteophytes.
Participants were asked whether they experienced (yes/no) neck, lower back, hands, shoulders and others pain at baseline. The total number of painful locations (range 0 to 5) was categorized into three groups (no pain, one painful site, two or more painful sites).
Self-reported medical conditions
Participants were asked whether they have been diagnosed (yes/no) by a doctor or a nurse with any of the following conditions: depression, angina, high blood pressure, heart attack, stroke, high cholesterol, diabetes, osteoporosis, asthma, bronchitis and emphysema, and whether they had these conditions currently. The total number of current comorbidities, except for depression, was categorized into three groups (no comorbidity, one comorbidity and two or more comorbidities).
Baseline characteristics are described as mean ± standard deviation (SD) or numbers of participants (percentage). Univariable and multivariable log-binomial regressions were used to explore risk factors associated with the prevalence of depression at baseline and incidence of depression over time. If the log binomial model failed to converge, it was estimated by using a poisson distribution and robust standard errors. Multivariable models for prevalent depression were adjusted for age, sex, BMI and baseline vitamin D level. Multivariable models for incident depression were adjusted for age, sex, BMI, baseline 25-hydroxyvitamin D level and treatment arms (vitamin D treatment versus placebo). Univariable and multivariable linear regressions were used to examine the temporal relationship between baseline depressive severity and change in knee symptoms over 24 months before and after adjustment for age, sex, BMI, baseline 25-hydroxyvitamin D level, treatment arms and baseline WOMAC score. All tests were two-sided and a P value of <0.05 was considered as statistically significant. Stata version 12.0 was used to perform statistical analyses.