title: Differential Responses to Vitamin D2 and Vitamin D3 Are Associated With Variations in Free 25-Hydroxyvitamin D.
abstract: 25-Hydroxyvitamin D (25D) circulates bound primarily to serum vitamin D binding protein (DBP), with DBP showing higher binding affinity for 25D3 than 25D2. We therefore hypothesized that vitamin D2 (D2) promotes higher serum levels of unbound 25D (free 25D), with different functional responses, relative to vitamin D3 (D3). Week 3 C56BL/6 mice were placed on diets containing either D2 or D3 alone (both 1000 IU/kg). At week 8 and week 16, D2 mice had only 25D2 in circulation (26.6 ± 1.9 and 33.3 ± 4.4 ng/mL), and D3 mice had only 25D3 (28.3 ± 2.0 and 31.7 ± 2.1 ng/mL). At week 8 (44.5 ± 6.4 vs 62.4 ± 11.6 pg/mL, P < .05) and week 16 (78.4 ± 12.6 vs 95.5 ± 11.6), D2 mice had lower serum 1,25-dihydroxyvitamin D relative to D3 mice. By contrast, measured free 25D was significantly higher in D2 mice at week 8 (16.8 ± 0.65 vs 8.4 ± 0.63 pg/mL, P < .001) and week 16 (17.4 ± 0.43 vs 8.4 ± 0.44, P < .001). A two-way ANOVA of bone histomorphometry showed that week 8 D2 mice had significantly higher osteoclast surface/bone surface, eroded surface/bone surface, and mineral apposition rate compared with D3 mice. Osteoblast surface/bone surface was higher in week 8 D2 females but not week 8 D2 males. At week 16, D2 mice had significantly higher bone volume/total volume and trabecular number compared with D3 mice. Differences in bone phenotype were observed despite D2 mice reaching similar serum 25D levels and lower 1,25D levels compared with D3 mice. These data indicate that 25D2 binds less well to DBP than 25D3, with resulting higher levels of free 25D promoting differential effects on bone in mice exposed to D2 alone.
authors.affiliation: Departments of Orthopaedic Surgery (R.F.C., R.Z., N.Q.L., A.S., J.S.A., M.H.), and Pediatric Nephrology (R.P.), David Geffen School of Medicine at University of California, Los Angeles, and Section of Oral and Maxillofacial Radiology (M.G., S.M.M.), UCLA School of Dentistry, Los Angeles, California 90095; and Institute of Metabolism and Systems Research (I.H., M.H.), The University of Birmingham, and Centre for Endocrinology, Diabetes, and Metabolism (M.H.), Birmingham Health Partners, Birmingham B15 2TT, United Kingdom; and Future Diagnostics (L.S., T.H.), Wijchen 6603 BN, The Netherlands.
authors.forename: Rene F
authors.initials: RF
authors.lastname: Chun
authors.affiliation: Departments of Orthopaedic Surgery (R.F.C., R.Z., N.Q.L., A.S., J.S.A., M.H.), and Pediatric Nephrology (R.P.), David Geffen School of Medicine at University of California, Los Angeles, and Section of Oral and Maxillofacial Radiology (M.G., S.M.M.), UCLA School of Dentistry, Los Angeles, California 90095; and Institute of Metabolism and Systems Research (I.H., M.H.), The University of Birmingham, and Centre for Endocrinology, Diabetes, and Metabolism (M.H.), Birmingham Health Partners, Birmingham B15 2TT, United Kingdom; and Future Diagnostics (L.S., T.H.), Wijchen 6603 BN, The Netherlands.
authors.forename: Ivan
authors.initials: I
authors.lastname: Hernandez
authors.affiliation: Departments of Orthopaedic Surgery (R.F.C., R.Z., N.Q.L., A.S., J.S.A., M.H.), and Pediatric Nephrology (R.P.), David Geffen School of Medicine at University of California, Los Angeles, and Section of Oral and Maxillofacial Radiology (M.G., S.M.M.), UCLA School of Dentistry, Los Angeles, California 90095; and Institute of Metabolism and Systems Research (I.H., M.H.), The University of Birmingham, and Centre for Endocrinology, Diabetes, and Metabolism (M.H.), Birmingham Health Partners, Birmingham B15 2TT, United Kingdom; and Future Diagnostics (L.S., T.H.), Wijchen 6603 BN, The Netherlands.
authors.forename: Renata
authors.initials: R
authors.lastname: Pereira
authors.affiliation: Departments of Orthopaedic Surgery (R.F.C., R.Z., N.Q.L., A.S., J.S.A., M.H.), and Pediatric Nephrology (R.P.), David Geffen School of Medicine at University of California, Los Angeles, and Section of Oral and Maxillofacial Radiology (M.G., S.M.M.), UCLA School of Dentistry, Los Angeles, California 90095; and Institute of Metabolism and Systems Research (I.H., M.H.), The University of Birmingham, and Centre for Endocrinology, Diabetes, and Metabolism (M.H.), Birmingham Health Partners, Birmingham B15 2TT, United Kingdom; and Future Diagnostics (L.S., T.H.), Wijchen 6603 BN, The Netherlands.
authors.forename: Leon
authors.initials: L
authors.lastname: Swinkles
authors.affiliation: Departments of Orthopaedic Surgery (R.F.C., R.Z., N.Q.L., A.S., J.S.A., M.H.), and Pediatric Nephrology (R.P.), David Geffen School of Medicine at University of California, Los Angeles, and Section of Oral and Maxillofacial Radiology (M.G., S.M.M.), UCLA School of Dentistry, Los Angeles, California 90095; and Institute of Metabolism and Systems Research (I.H., M.H.), The University of Birmingham, and Centre for Endocrinology, Diabetes, and Metabolism (M.H.), Birmingham Health Partners, Birmingham B15 2TT, United Kingdom; and Future Diagnostics (L.S., T.H.), Wijchen 6603 BN, The Netherlands.
authors.forename: Tonnie
authors.initials: T
authors.lastname: Huijs
authors.affiliation: Departments of Orthopaedic Surgery (R.F.C., R.Z., N.Q.L., A.S., J.S.A., M.H.), and Pediatric Nephrology (R.P.), David Geffen School of Medicine at University of California, Los Angeles, and Section of Oral and Maxillofacial Radiology (M.G., S.M.M.), UCLA School of Dentistry, Los Angeles, California 90095; and Institute of Metabolism and Systems Research (I.H., M.H.), The University of Birmingham, and Centre for Endocrinology, Diabetes, and Metabolism (M.H.), Birmingham Health Partners, Birmingham B15 2TT, United Kingdom; and Future Diagnostics (L.S., T.H.), Wijchen 6603 BN, The Netherlands.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Departments of Orthopaedic Surgery (R.F.C., R.Z., N.Q.L., A.S., J.S.A., M.H.), and Pediatric Nephrology (R.P.), David Geffen School of Medicine at University of California, Los Angeles, and Section of Oral and Maxillofacial Radiology (M.G., S.M.M.), UCLA School of Dentistry, Los Angeles, California 90095; and Institute of Metabolism and Systems Research (I.H., M.H.), The University of Birmingham, and Centre for Endocrinology, Diabetes, and Metabolism (M.H.), Birmingham Health Partners, Birmingham B15 2TT, United Kingdom; and Future Diagnostics (L.S., T.H.), Wijchen 6603 BN, The Netherlands.
authors.forename: Nancy Q
authors.initials: NQ
authors.lastname: Liu
authors.affiliation: Departments of Orthopaedic Surgery (R.F.C., R.Z., N.Q.L., A.S., J.S.A., M.H.), and Pediatric Nephrology (R.P.), David Geffen School of Medicine at University of California, Los Angeles, and Section of Oral and Maxillofacial Radiology (M.G., S.M.M.), UCLA School of Dentistry, Los Angeles, California 90095; and Institute of Metabolism and Systems Research (I.H., M.H.), The University of Birmingham, and Centre for Endocrinology, Diabetes, and Metabolism (M.H.), Birmingham Health Partners, Birmingham B15 2TT, United Kingdom; and Future Diagnostics (L.S., T.H.), Wijchen 6603 BN, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Shieh
authors.affiliation: Departments of Orthopaedic Surgery (R.F.C., R.Z., N.Q.L., A.S., J.S.A., M.H.), and Pediatric Nephrology (R.P.), David Geffen School of Medicine at University of California, Los Angeles, and Section of Oral and Maxillofacial Radiology (M.G., S.M.M.), UCLA School of Dentistry, Los Angeles, California 90095; and Institute of Metabolism and Systems Research (I.H., M.H.), The University of Birmingham, and Centre for Endocrinology, Diabetes, and Metabolism (M.H.), Birmingham Health Partners, Birmingham B15 2TT, United Kingdom; and Future Diagnostics (L.S., T.H.), Wijchen 6603 BN, The Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Guemes
authors.affiliation: Departments of Orthopaedic Surgery (R.F.C., R.Z., N.Q.L., A.S., J.S.A., M.H.), and Pediatric Nephrology (R.P.), David Geffen School of Medicine at University of California, Los Angeles, and Section of Oral and Maxillofacial Radiology (M.G., S.M.M.), UCLA School of Dentistry, Los Angeles, California 90095; and Institute of Metabolism and Systems Research (I.H., M.H.), The University of Birmingham, and Centre for Endocrinology, Diabetes, and Metabolism (M.H.), Birmingham Health Partners, Birmingham B15 2TT, United Kingdom; and Future Diagnostics (L.S., T.H.), Wijchen 6603 BN, The Netherlands.
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Mallya
authors.affiliation: Departments of Orthopaedic Surgery (R.F.C., R.Z., N.Q.L., A.S., J.S.A., M.H.), and Pediatric Nephrology (R.P.), David Geffen School of Medicine at University of California, Los Angeles, and Section of Oral and Maxillofacial Radiology (M.G., S.M.M.), UCLA School of Dentistry, Los Angeles, California 90095; and Institute of Metabolism and Systems Research (I.H., M.H.), The University of Birmingham, and Centre for Endocrinology, Diabetes, and Metabolism (M.H.), Birmingham Health Partners, Birmingham B15 2TT, United Kingdom; and Future Diagnostics (L.S., T.H.), Wijchen 6603 BN, The Netherlands.
authors.forename: John S
authors.initials: JS
authors.lastname: Adams
authors.affiliation: Departments of Orthopaedic Surgery (R.F.C., R.Z., N.Q.L., A.S., J.S.A., M.H.), and Pediatric Nephrology (R.P.), David Geffen School of Medicine at University of California, Los Angeles, and Section of Oral and Maxillofacial Radiology (M.G., S.M.M.), UCLA School of Dentistry, Los Angeles, California 90095; and Institute of Metabolism and Systems Research (I.H., M.H.), The University of Birmingham, and Centre for Endocrinology, Diabetes, and Metabolism (M.H.), Birmingham Health Partners, Birmingham B15 2TT, United Kingdom; and Future Diagnostics (L.S., T.H.), Wijchen 6603 BN, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Hewison
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000033:anatomy & histology; D002460:Cell Line; D002762:Cholecalciferol / Q000493:pharmacokinetics*; D004872:Ergocalciferols / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D004872:Ergocalciferols; D014807:Vitamin D; D002762:Cholecalciferol; C104450:25-hydroxyvitamin D