title: Comparison of effects of alfacalcidol and alendronate on mechanical properties and bone collagen cross-links of callus in the fracture repair rat model.
abstract: Both bone density and quality are important determinants of bone strength. Bone quality is prescribed by matrix characteristic including collagen cross-linking and bone structural characteristics and is important in reinforcement of bone strength. We investigated the effects of alfacalcidol (ALF), a prodrug of calcitriol, and alendronate (ALN), a bisphosphanate, on the mechanical properties and content of enzymatic cross-links in femoral bone using a fracture repair rat model. Forty 3-month-old female Wistar-Imamichi rats were randomized into 4 groups: SHAM (sham-operated+vehicle), OVX (ovariectomy+vehicle), ALF (ovariectomy+ALF, 0.1 microg/kg/d, p.o.) and ALN (ovariectomy+ALN, 10 microg/kg/d, s.c.). Treatment began immediately after SHAM or OVX surgery. Three weeks later, all animals underwent transverse osteotomies at the midshaft of the left femur. Treatment was continued and rats were sacrificed at 12 weeks post-fracture for evaluation by X-ray radiography, micro-CT, pQCT, biomechanical testing and bone histomorphometry. In the ALN group, no new cortical shell appeared and the callus diameter was significantly larger than in the OVX group (p<0.05). Stiffness of fractured callus in the ALF group, but not in the ALN group, was significantly higher than in the OVX group. Young's modulus in the ALN group was significantly decreased compared to the OVX group. Moreover, micro-CT analysis showed that ALN treatment increased the lowly mineralized bone in the callus by, resulting in the highest content of woven bone area and lowest content of lamellar bone. The total amount of enzymatic cross-links in both the ALF and ALN groups was significantly higher than in the OVX control group. Of particular interest, the Pyr-to-Dpyr ratio was significantly decreased by ALF administration, suggesting that ALF but not ALN normalized the enzymatic cross-link patterns in fractured bone to the control level. In conclusion, ALN and ALF treatment increased bone strength via the distinctive effect on bone mass and quality. ALN formed larger calluses and increased enzymatic cross-links despite delayed woven bone remodeling into lamellar bone, whereas ALF treatment induced lamellar bone formation coincided with increasing in the enzymatic cross-linking and normalizing the cross-link pattern in callus to native bone pattern.
authors.affiliation: Department of Orthopaedic Surgery, Jikei University School of Medicine 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.forename: Ayako
authors.initials: A
authors.lastname: Shiraishi
authors.forename: Masako
authors.initials: M
authors.lastname: Ito
authors.forename: Sadaoki
authors.initials: S
authors.lastname: Sakai
authors.forename: Naohiko
authors.initials: N
authors.lastname: Hayakawa
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mihara
authors.forename: Keishi
authors.initials: K
authors.lastname: Marumo
mesh_terms: D019386:Alendronate / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D016723:Bone Remodeling / Q000187:drug effects; D002146:Bony Callus / Q000000981:diagnostic imaging / Q000187:drug effects*; D005260:Female; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy*; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects; D017102:Fracture Healing / Q000187:drug effects*; D006887:Hydroxycholecalciferols / Q000494:pharmacology*; D011859:Radiography; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
chemical_list: D050071:Bone Density Conservation Agents; D006887:Hydroxycholecalciferols; C008088:alfacalcidol; D019386:Alendronate