Table 1:
Overview of major RCTs examining the effect of vitamin D supplementation on bone and cardiovascular outcomes in the general population and people with CKD.
| Study | N, participants | Intervention/follow-up | Outcome: fractures | Outcome: MACE | Outcome: all-cause mortality |
|---|---|---|---|---|---|
| General population | |||||
| WHI 2006 [62, 63] | 36 282 post-menopausal women, aged 50–79 years | Calcium 1000 mg + vitamin D3 400 IU daily vs placebo 7 years | • Hip fractures: HR 0.88 (0.72 to 1.08)a • Vertebral fractures: HR 0.90 (0.74–1.10) • Forearm/wrist fractures: HR 1.01 (0.90–1.14) • Total fractures: HR 0.96 (0.91–1.02) | • Composite MACE (MI, CV death, CABG or PCI): HR 1.08 (0.99–1.19) • Hospitalized HF: HR 0.96 (0.83–1.10) • Stroke: HR 0.95 (0.82–1.10) | HR 0.91 (0.83–1.01) |
| VITAL 2019 [64, 65] | 25 871 older adults (men >50 years, women >55 years) | Vitamin D3 2000 IU daily vs placebo 5.3 years | • Total fractures: HR 0.98 (0.89–1.08) • Non-vertebral fractures: HR 0.97 (0.87–1.07) • Hip fractures HR 1.01 (0.70–1.47) | Composite MACE (MI, stroke or cardiovascular death): HR 0.97 (95% CI 0.85–1.12)a | HR 0.99 (0.87–1.12) |
| D-Health 2022 [30, 66, 67] | 21 315 older adults, aged 60–84 years | Vitamin D3 60 000 IU monthly vs placebo 5 years | • Total fractures: HR 0.94 (0.84–1.06) • Non-vertebral fractures: HR 0.96 (0.85–1.08)• Major osteoporotic fractures: HR 1.00 (0.85–1.18)• Hip fractures: HR 1.11 (0.86–1.45) | Composite MACE (MI, stroke or coronary revascularization): HR 0.91 (0.81–1.01) | HR 1.04 (0.93–1.18)a |
| RECORD 2005 [68] | 5292 older adults (age >70 years) with a low-trauma, osteoporotic fracture in past 10 years | 2 × 2 factorial design: Vitamin D3 800 IU daily vs D3 800 IU plus calcium 1000 mg daily vs placebo 3.8 years | • Low-trauma fractures: HR 1.02 (0.88–1.19)a • Any new fracture: HR 1.01 (0.88–1.17) | • Composite MACE (fatal and non-fatal HF, MI, stroke): HR 0.92 (0.80–1.08) • Composite fatal CVD (HF, MI and stroke): HR 0.87 (0.73–1.03) | HR 0.92 (0.80–1.05) |
| VIDA 2017 [69, 70] | 5110 community-dwelling adults, aged 50–84 years 3.3 years | Vitamin D3 200 000 IU then 100 000 IU monthly vs placebo | Non-vertebral fractures: HR 1.19 (0.94–1.50) | • Incident CVD and death: HR 1.02 (0.87–1.20)a • MI: HR 0.90 (0.54–1.50) • Heart failure: HR 1.19 (0.84–1.68) • Stroke: HR 0.95 (0.55–1.62) | HR 1.12 (0.79–1.58) |
| Vital D 2010 [71] | 2256 community-dwelling women ≥70 years with high fracture risk | Vitamin D3 500 000 IU yearly vs placebo 2.96 years | • Any new fracture: RR 1.26 (1.00–1.59)† • Non-vertebral fracture: RR 1.28 (1.00–1.65) | • Not reported | No difference between vitamin D (40/1131) and placebo group (47/1125) |
| CKD population | |||||
| J-DAVID 2018 [26] | 976 haemodialysis patients with serum iPTH ≤180 pg/mL | Alfacalcidol 0.5 µg daily vs no treatment 4.0 years | No difference in fractures between alfacalcidol (9/488) and control (12/476) groups | • Composite MACE (fatal and non-fatal MI, HF hospitalizations, stroke, aortic dissection/rupture, amputation of lower limb due to ischaemia, sudden cardiac death; coronary revascularization; and leg artery revascularization): HR 1.25 (0.94–1.67)a | HR 1.12 (0.83–1.52) |
| Morrone 2022 [27] | 284 haemodialysis patients (age ≥18 years) with serum PTH 2–9× ULN and 25(OH)D <30 ng/mL | Calcifediol 40 mcg thrice weekly after dialysis vs no treatment 2.0 years | Not reported | • Composite MACE (non-fatal MI, non-fatal stroke, all-cause death): HR 1.03 (0.63–1.67)a • Cardiovascular death: HR 1.06 (0.41–2.74) | HR 1.11 (0.67–1.83) |
| PRIMO 2011 [28] | 227 patients with eGFR 15–60 mL/min/1.73 m2, serum iPTH 50–300 pg/mL | Paricalcitol 2 µg daily vs placebo 48 weeks | No difference in fractures between paricalcitol (1/115) and placebo group (2/112) | Fewer hospitalizations for CVD events in paricalcitol group (1/115 vs 7/112, P = .03) | No deaths during study period |
| FLUID 2022 [44] | 65 peritoneal dialysis patients (age ≥18 years) | Cholecalciferol 50 000 IU weekly for 8 weeks followed by 10 000 IU weekly for 44 weeks vs placebo 52 weeks | No difference in fractures between vitamin D (1/43) or placebo groups (2/31), P = .5 | • Fewer cardiovascular deaths in vitamin D group (1/34 vs 6/31, P = .03) • No difference in MACE (MI, HF hospitalization, coronary revascularization, stroke, limb amputation or peripheral revascularization): 5/34 vs 7/31 (P = .4) | Fewer deaths in vitamin D group (4/34 vs 12/31, P = .004) |
| OPERA 2014 [29] | 60 patients with non-dialysis CKD (eGFR <60 mL/min/1.73 m2), serum iPTH >55 pg/mL | Paricalcitol 1 µg daily (if iPTH <500 pg/mL) or 2 µg daily (if iPTH ≥500 pg/mL) vs placebo 52 weeks | Not reported | • Fewer cardiovascular events (0/30 vs 6/30) in paricalcitol group • Fewer cardiovascular-related hospitalizations (0/30 vs 5/30) in paricalcitol group | No deaths during study period |
aPrimary study outcome.
iPTH, intact PTH; ULN, upper limit of normal; IU, international units; MI, myocardial infarction; CV, cardiovascular; CVD, cardiovascular disease; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; HF, heart failure; VITAL, Vitamin D and Omega-3 trial; WHI, Women's Health Initiative; RECORD, Randomised Evaluation of Calcium or Vitamin D; VIDA, Vitamin D Assessment.