title: Loss of vertebral bone and mechanical strength in estrogen-deficient rats is prevented by long-term administration of zoledronic acid.
abstract: This study investigated the protective effect of long-term treatment with the bisphosphonate zoledronic acid on bone mass, structure, and strength in adult, estrogen-deficient rats. Rats were ovariectomized (OVX) at the age of 4 months and divided into four groups of 20 rats: one group of saline-treated OVX controls, and three groups of OVX rats treated with 0.3, 1.5, or 7.5 microg/kg/week s.c. zoledronic acid (ZOL). An additional group of sham-operated, saline-treated rats served as normal controls. Biochemical assays were performed after 16 and 51 weeks, respectively, and bone mineral density (BMD) determinations after 17 and 52 weeks, respectively. Before the end of the experiment animals were injected with tetracyclines for the determination of dynamic bone indexes. Finally, animals were sacrificed after 52 weeks, and vertebral bones (LV5) were subjected to mechanical compression testing. LV4 were used for histology and LV2 for microcomputed tomography. ZOL treatment abolished the rise of osteocalcin and reduced urinary deoxypyridinoline excretion. BMD was reduced in the OVX group in comparison to sham controls, and the decline was dose-dependently prevented by ZOL treatment. Tetracycline labeling showed a significant increase in bone formation rate (BFR) in OVX rats which was abolished by ZOL treatment. The same was observed for osteoid perimeter (Os.Pm) suggesting that ZOL diminished the high bone turnover associated with estrogen deficiency. Architectural parameters (BV/TV, Tb.Th*, Tb.N*, Tb.Sp*, SMI, CD) underwent the expected changes toward structural deterioration which was completely prevented by ZOL administration at doses of 1.5 and 7.5 microg/kg/week s.c. Similar results were obtained in compression testing: maximum stress fell significantly after OVX, and this effect was effectively prevented by ZOL treatment. Regression analysis suggests that in this rat model, SMI and Tb.Th* significantly contribute to compressive strength, albeit to a smaller degree than total cross-sectional area. The data further suggest that in the aged OVX rat, SMI and TB.Th* change in an interdependent way. ZOL prevents this process by inhibiting plate thinning and the transition into rod-shaped trabeculae.
authors.affiliation: Bone Metabolism Unit, WKL-125.9, Novartis Pharma, CH 4002, Basel, Switzerland. markus.glatt@pharma.novartis.com
authors.forename: Markus
authors.initials: M
authors.lastname: Glatt
authors.forename: Alexander
authors.initials: A
authors.lastname: Pataki
authors.forename: G Paul
authors.initials: GP
authors.lastname: Evans
authors.forename: Simon B
authors.initials: SB
authors.lastname: Hornby
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Green
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D015519:Bone Density / Q000502:physiology; D001862:Bone Resorption / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D019245:Compressive Strength / Q000187:drug effects / Q000502:physiology; D004164:Diphosphonates / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage*; D008159:Lumbar Vertebrae / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D015675:Osteocalcin / Q000032:analysis; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014054:Tomography / Q000379:methods; D000077211:Zoledronic Acid
chemical_list: D015415:Biomarkers; D004164:Diphosphonates; D004967:Estrogens; D007093:Imidazoles; D015675:Osteocalcin; D000077211:Zoledronic Acid