The Effect of Vitamin D Supplementation for Bone Healing in Fracture Patients: A Systematic Review

Table 1

Study design characteristics and main findings.

Author	Country	Study design	Patient cohort	Cohort size	Intervention	Outcomes assessed	Summary of results
Haines et al. [14]	USA	Double blind RCT	18 yr+; tibia, humerus, femur diaphyseal fractures	100	Deficient patients given either 100,000 IU oral D3 or placebo	Clinical and radiological union	No difference between union rates between treatment and control ()
Slobogean et al. [24]	USA/Canada	Double blinded pilot trial for FAITH2	18–60 yr; NOF part of the FAITH2 trial; randomized to either CS or SHS	86	D3 drops 2000 IU BD for 6 months vs. placebo	Orthopaedic complications including reoperation, head osteonecrosis, malunion, and radiological nonunion	Rate of nonunion was 8.7% (n = 4) vs. 7.5% (n = 3) when comparing supplementation to placebo, respectively
							For overall complications, the hazard ratio was 0.96 for supplementation (95% CI 0.42–2.18) () and this study was underpowered
Slobogean et al. [34]	USA	Double blind RCT (vita shock trial)	18–55 yr; tibia or femoral shaft fracture for intramedullary nail	102	Three month supplementation across four treatment groups; 150,000 IU loading at injury and 6 weeks vs. 4000 IU daily vs. 600 IU daily vs. placebo	Clinical and radiological union (FIX-IT and RUST scores)	No differences between clinical or radiological union between loading doses vs. high daily dosing; high dose vs. low dose groups or between low dose vs. placebo at 3 or 12 months
							Post-hoc comparison of high dose vs. placebo showed improved clinical union () but not radiological union ()
Behrouzi et al. [33]	Iran	Nonrandomised, double blind trial	60 yr+; intertrochanteric fractures	100	Participants were divided into two groups based on vitamin D status. All patients given 50000 D3 IM bolus, but deficient patients were supplemented with 50,000 IU oral weekly for 12 weeks	Clinical and radiological union	No significant difference in radiological union rate at 2, 4, 8, or 12 weeks ()
							There was significant difference in clinical union at 4 () and 8 weeks () favouring vitamin D supplementation
Ko et al. [27]	Korea	Prospective cohort	Osteoporotic vertebral fractures	130	Groups weredivided into supplemented (n = 65) and nonsupplemented (n = 65). Supplementation was 300,000 IU D3 SC for deficient or 100,000 IU for insufficient	Radiological union, functional outcome scores (ODI, RMDQ), and QoL scores (SF-36)	Fracture union in all patients regardless of vitamin D level. No significant difference in functional outcomes (ODI, ; RMDQ, or QoL scores (SF-36 PC,), ) between the supplemented and nonsupplemented group
Gorter et al. [31]	Netherlands	Retrospective cohort	18 yr+; upper or lower extremity fracture	617	Deficient patients were supplemented with 1200 IU oral D3 daily	Clinical and radiological union	Patients remaining vitamin D deficient despite supplementation had a higher rate of delayed clinical union () but not radiological union. ()
Ingstad et al. [28]	Norway	Retrospective cohort	18 yr+; hip fractures for operation	407	100,000 IU oral D3 loading dose	Orthopaedic complications (incl nonunion, SSI < dislocation and peri-implant fractures)	Decrease in early (<30 days) orthopaedic complications only, with loading dose. ()
Bodendorfer et al. [32]	USA	Retrospective cohort	18 yr+; fracture type unknown	201	1000 IU D3 and 1500 mg Ca for all patients. Deficient or insufficient patients were given 50000 D2 weekly until normal D levels or healing demonstrated	Healing complications; nonunion, malunion, delayed union, wound problems, or infection	No significant difference between initial () or repeat () vitamin D in patients who developed fracture complications
Mak et al. [26]	Australia	Double blind RCT	65 yr+; NOF for surgery	218	All patients had oral 800 IU and 500 mg. Supplementation groups had oral loading 250,000 IU D3 vs. placebo	Gait velocity, grip strength, and BI, (EguroQol EQ5D)	No significant differences in gait velocity between both groups. No significant differences for BI () and grip strength () at 4 weeks between the groups
							EuroQoL scores were higher in treatment group but not significant. ( 0.092) pain scores at week 26 were significant higher in treatment group ()
Renerts et al. [25]	Switzerland	Double blind RCT	65 yr+; NOF surgery	173	Patients had baseline 800 IU D3 and 1 g Ca. Then, supplementation group was given D3 2000 IU/dly + -HE vs. no further supplementation + -HE	Health-related quality of life (EuroQol-EQ5D)	No difference in quality of life between two interventions over time (); however, high dose vitamin D slowed health-related quality of life decline after 6 months ()
Heyer et al. [29]	Netherlands	Single blind RCT	50 yr+; females with conservative distal radius fractures	32	Three groups given either high dose (1800 IU daily), low dose (700 IU daily), and no treatment. Liquid vitamin D was administered at 2 boluses on weeks 1 and 6	BMD using HRpQCT; PRWE scores	No difference in total BMD between control vs. low dose ( 0.26) or high dose vs. control ()
							No difference in PRWE scores between control vs. low dose () or high dose vs. control ()
Sprague et al. [23]	Multiple	Retrospective cohort	50 yr+; NOF fractures (FAITH trial cohort)	573	1000 U daily to all patients then divided the groups by compliance (consistent, inconsistent, and no vit D use)	Short Form-12 Physical Component Score	Consistent vitamin D supplementation after fracture improved 1 year SF-12 Physical Component Scores. ()
Harwood et al. [30]	UK	Nonblinded RCT	60 yr+; NOF admitted to orthogeriatric rehab ward	97	Four groups; 300,000 IU D2 injected vs. 300,000 IU D2 injected + 1 g/day Ca vs. 800 u/day D3 and 1 g/day Ca vs. no treatment	28 day BMD	Vitamin D had a small but statistically significant effect on total hip BMD at 28 days. Mean difference of 0.013 (95% CI interval; 0.003; 0.023). Mean difference increased when calcium was added. No differences for spine BMD
Hoikka et al. [10]	Finland	NRCT	50 yr+; NOF fracture	37	1 mcg daily alfacalcidol and 2.5 g caco3 vs. placebo and 2.5 g caco3	BMD and grip strength	No change in BMD or grip strength after 3 or 6 months

BI, barthel index; BD, bis in die; BMD, bone mineral density; CS, cannualted screws; HE, home exercise therapy; FIX-IT, function index for trauma; IM, intramuscular; HRpQCT, high resolution peripheral computed topography; NRT, nonrandomised control trial; NOF, neck of femur; ODI, Owestry Disability Index; PRWE, Patient-Rated Wrist Evaluation; RCT, randomised control trial; RMDQ, Roland Morris Disability Questionnaire; RUST, radiograph union scale in tibial fractures; SHS, sliding hip screws; SC, subcutaneous; SF, short form.