Vitamin D and bone fracture healing

Table 1 Diverse vitamin D terminology and modes of assessment in the related literature and related source

Serum 25(OH)D, 24R,25(OH)2D, 1,25(OH)2D[10]

Vitamin D2[25]

24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3], and 1 α,25-dihydroxyvitamin D3[1 α, 25(OH)2D3] hormonally active vitamin D metabolites[24]

Plasma 1,25-dihydroxyvitamin D3 25(OH)2D3[28]

24R,25-dihydroxyvitamin D3[29]

25OHD concentration[36]

Serum 25-hydroxyvitamin D[37]

Serum 25(OH)D3[38]

Serum 25-hydroxyvitamin D (25-OH-D3, 24,25 dihydroxyvitamin D3 [24,25(OH)2D3], 1,25 dihydroxyvitamin D3 [1,25(OH)2D3][44]

Serum 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D3, 24,25 dihydroxyvitamin D3 metabolites[46]

25-hydroxyvitamin D [25(OH)2D3], 1,25 dihydroxyvitamin D3 [1,25(OH)2D3], and 24,25 dihydroxycholecaciferol; 24,25(OH)2D3-active metabolites of vitamin D3[30]

1,25 dihydroxyvitamin D [1,25(OH)2D]-biologically active metabolite of vitamin D; 24,25(OH)2D3-a metabolite of vitamin D[54]

1,25(OH)D[58]

Vitamin D 25(OH)D[63]

Vitamin D refers to an inactive compound ingested from the diet or produced after exposure of skin to sunlight. 25-hydroxyvitamin D [25-(OH)D] is an inactive metabolite produced in the liver that is hydroxylated in the kidney to form 1-alpha,25-dihydroxyvitamin D [1,25(OH)₂D] is the active form of vitamin D that binds to vitamin D receptor or VDR on target tissues[11]. 24R,25-dihydroxyvitamin D3 [24R,25(OH)₂D₃] is an essential vitamin D metabolite[24,29].

Table 2 Sample of studies using animal models to examine vitamin D influence on bone healing

Researchers	Model	Finding
Andreen et al[27]	Rat	Low doses 1,25(OH)2D3 increased early callus mineralization
Blahos et al[14]	Rat tibia	1,25(OH)2D3 may produce a general response
Brumbaugh et al[45]	Chick	Chicks without 1 α, 25 dihydroxy D3 supplementation showed prolonged fracture healing; 1 α, 25 dihydroxyvitamin D3 promotes bone repair in the absence vitamin D3, 25 hydroxyvitamin D3, and 24, 25 dihydroxyvitamin D3
Dekel et al[30]	Chick	24,25(OH)2D3, as well as 1,25(OH)2D3 are essential for bone formation after fracture
Fu et al[19]	Rat	Vitamin D affected fracture healing positively for up to 12 wk compared to controls both biomechanically and histologically
Lindgren et al[49]	Adult rat	Rats given 1,25(OH)2D3 had stronger fracture callus
Lindgren et al[26]	Rabbit	1,25(OH)2D3 impairs fracture healing
Lidor et al[12]	Chick	Active metabolites of vitamin D3 are involved directly in fracture repair
Melhus et al[16]	Rat	Vitamin D deficiency does not impact fracture healing
Omeroğlu et al[15]	Rabbit	A single high dose of vitamin D3 had Positive mechanical effects on fractured bone
Seo et al[29]	Chicken	24,25(OH)D2 levels increased during fracture repair
Steier et al[23]	Rat	Vitamin D2 accelerated initial mineralization in the fracture healing region

Table 3 Sample of human studies designed to examine vitamin D influence on bone healing

Ref.	Type of Study	Finding
Briggs et al[10]	Examined vitamin D levels in 28 patents with diaphyseal long bone fractures at 48 h, 1 wk and 6 wk	Serum 1,25-dihydroxyvitamin D decreased from baseline, but serum 24R,25(OH)2D levels did not change
Delgado-Martínez et al[22]	Investigated 25-OH-vitamin D effect in elderly with fractures	The addition of the vitamin D supplement improved strength of the fractured bone
Sun et al[25]	Examined effect of vitamin D3 on the differentiation of mesenchymal stem cells from a human fracture site	Vitamin D3 was able to modulate the the differentiation towards osteoblastic phenotype of the cells derived from fracture sites
Doetsch et al[32]	Quantified impact of vitamin D3 + calcium on healing of osteoporotic fracture	Bone mineral density at 6 wk was higher in actively treated group suggesting vitamin D3 had a positive effect 6 wk post fracture, but this was not maintained at 12 wk
Parchi et al[33]	Case report of child post-fracture	Hypovitaminosis D is a possible cause of inadequate fracture healing and refracture in children Vitamin D has a clear effect on callus formation
Boszczyk et al[36]	35 patients with inexplicable fracture healing impairments and controls were studied with regard to vitamin D	No impact of vitamin D deficiency noted
Ettehad et al[37]	Determined serum levels of vitamin D during fracture healing of 73 patients	Serum levels of vitamin D were reduced in curative period, suggesting vitamin D plays a role in the formation and mineralization of callus
Alkalay et al[44]	Assessed vitamin D metabolite levels in 28 patients after fracture, and 27 undergoing surgery	Serum 1,25-dihydroxyvitamin D3 was significantly reduced in the fracture cases
Tauber et al[50]	Determined active metabolites of vitamin D3 in 7 fracture patients	24,25(OH)2D3 levels showed a relative decrease, and a decrease in 1,25(OH)2D3 in 2 cases, suggesting these metabolites are consumed at fracture site during healing
Meller et al[51]	Levels of 25(OH)D3 + 24,25(OH)2D3 were determined in 13 young patients with long bone fractures on admission and after 6-8 wk	Plasma 24,25(OH)2,-D3 levels rose over the 6 wk period, but no changes in 25(OH)D3 levels occurred
Hoikka et al[52]	Treated 37 osteoporotic fracture cases with 1 α, OHD3– dosage 1 ug per day, plus 2.5 gm calcium	1 α-OHD3 impacts fracture healing although 5/19 cases developed hypercalcemia

Table 4 Rationale for hypothesizing vitamin D as beneficial in fracture healing

Plays an essential role in bone formation and maintenance[1,58]

Has positive benefits on muscle strength[5,58]

Is involved in calcium and bone metabolism[1,29,37,54,57,58,64]

Deficiency is associated with fractures[58]

Can modulate cell growth and neuromuscular function[57,65]

May influence the inflammation stage of bone healing positively, as well as the callus formation stage[31]

Can help regulate inflammation and bone marrow and intramuscular fat deposits[58]

Protects older people from osteoporosis[58]

Enhance fixation of implants[58]

Deficiency may be associated with refrature[33]

Deficiency is associated with non union[34,35,67,69]