It has been suggested that early postmenopausal women and patients treated with
steroids should receive preventive
therapy (
calcium,
vitamin D,
vitamin D analogs,
estrogens, or
bisphosphonates) to preserve their bone mineral density (BMD) and to avoid fragility fractures. We designed the present study to compare the effects of native
vitamin D to its hydroxylated analogs
alfacalcidol 1-alpha(OH)D and
calcitriol 1,25(OH)(2)D. All randomized, controlled, double-blinded trials comparing oral native
vitamin D and its analogs,
alfacalcidol or
calcitriol, to placebo or head-to-head trials in primary or
corticosteroids-induced
osteoporosis were included in the meta-analysis. Sources included the Cochrane Controlled Trials Register, EMBASE, MEDLINE, and a hand search of abstracts and references lists. The study period January 1985 to January 2003. Data were abstracted by two investigators, and methodological quality was assessed in a similar manner. Heterogeneity was extensively investigated. Results were expressed as effect-size (ES) for bone loss and as rate difference (RD) for fracture while allocated to active treatment or control. Publication bias was investigated. Fourteen studies of native
vitamin D, nine of
alfacalcidol, and ten of
calcitriol fit the inclusion criteria. The two
vitamin D analogs appeared to exert a higher preventive effect on bone loss and fracture rates in patients not exposed to
glucocorticoids. With respect to BMD,
vitamin D analogs versus placebo studies had an ES of 0.36 (P < 0.0001), whereas native
vitamin D versus placebo had an ES of 0.17 (P = 0.0005), the interclass difference being highly significant (ANOVA-1, P < 0.05). When restricted to the lumbar spine, this intertreatment difference remained significant: ES = 0.43 (P = 0.0002) for
vitamin D analogs and ES = 0.21 (P = 0.001) for native
vitamin D (analysis of variance [ANOVA-1], P = 0.047). There were no significant differences regarding their efficacies on other measurement sites (ANOVA-1, P = 0.36). When comparing the adjusted global relative risks for fracture when allocated to
vitamin D analogs or native
vitamin D,
alfacalcidol and
calcitriol provided a more marked preventive efficacy against fractures: RD = 10% (95% Confidence interval [CI-2] to 17) compared to RD = 2% (95% CI, 1 to 2), respectively. The analysis of the spinal and nonspinal showed that fracture rates differed between the two classes, thereby confirming the benefits of
vitamin D analogs, with significant 13.4% (95% CI 7.7 to 19.8) and. 6% (95% CI 1 to 12) lower fracture rates for
vitamin D analogs, respectively. In patients receiving
corticosteroid therapy, both treatments provided similar global ESs for BMD: ES = 0.38 for
vitamin D analogs and ES = 0.41 for native
vitamin D (ANOVA-1, P = 0.88). When restriced to spinal BMD, D analogs provided significant effects, whereas native
vitamin D did not: ES = 0.43 (P < 0.0001) and ES = 0.33 (P = 0.21), respectively. The intertreatment difference was nonsignificant (ANOVA-1, P = 0.52). Neither D analogs for native
vitamin D significantly prevented fractures in this subcategory of patients: RD = 2.6 (95%CI, -9.5 to 4.3) and RD = 6.4 (95%CI, -2.3 to 10), respectively. In head-to-head studies comparing D analogs and native
vitamin D in patients receiving
corticosteroids, significant effects favoring D analogs were found for femoral neck BMD: ES = 0.31 at P = 0.02 and
spinal fractures: RD = 15% (95%CI, 6.5 to 25). Publication bias was not significant. Our analysis demonstrates a superiority of the D analogs atfacalcidol and
calcitriol in preventing bone loss and
spinal fractures in primary
osteoporosis, including postmenopausal women. In
corticosteroid-induced
osteoporosis, the efficacy of D analogs differed depending on the comparative approach: indirect comparisons led to nonsignificant differences, whereas direct comparison did provide significant differences. In this setting, D analogs seem to prevent
spinal fractures to a greater extent than do native
vitamin D, but this assumption should be confirmed on a comprehensive basis in multiarm studies including an inactive comparator.