title: Reductions in bone mass, structure, and strength in axial and appendicular skeletons associated with increased turnover after ovariectomy in mature cynomolgus monkeys and preventive effects of clodronate.
abstract: Over 16 months, we evaluated the effects of ovariectomy (OVX) and bisphosphonate clodronate (CLO) on bone in 48 cynomolgus monkeys (9-15 years old) fed a normal calcium diet. We established three OVX groups (oral CLO at 0 [OVX control], 12, or 60 mg/kg per day) and one sham-operated (SHAM) group. At 16 months, the bone mineral density (BMD) values (percentage of group baseline; OVX control vs. SHAM) for lumbar bone (L3-L5), proximal femur, midfemur, radius, and tibia were -2.6% versus 11.2%, -3.5% versus 8.9%, -3.0% versus 9.0%, -5.5% versus 15.7%, and -6.7% versus 13.9%, respectively. In OVX control (i) tibia showed significant loss of bone mineral content (BMC; vs. baseline), (ii) urinary deoxypyridinoline (DPD) and serum osteocalcin (OC) levels increased (peak = 182% and 168%, respectively, of SHAM), (iii) in lumbar bone and midfemur, ultimate load (UL) was reduced (vs. SHAM), (iv) in lumbar bone, trabecular bone-formation rates (BFRs) were not changed significantly, but tibial endocortical and intracortical bone formation rates were significantly raised (vs. SHAM), (v) the volumetric BMD (vBMD) and geometry of the tibial cortex (measured by peripheral quantitative computed tomography [pQCT]) were significantly reduced (vs. SHAM). CLO, 60 mg/kg per day but not 12 mg/kg per day, significantly inhibited OVX-induced changes, age-dependent increases in bone mass, and ability to maintain structure. Thus, in OVX mature cynomolgus monkeys (possibly, a unique model of the cortical bone loss secondary to estrogen deficiency), the post-OVX increases in systemic bone markers were slight, but stimulation of local turnover in the cortical envelope was enough to cause bone loss (more so in tibia than in lumbar trabecular bone). High-dose CLO prevented these changes.
authors.affiliation: Pharmacology Research, R & D, Kissei Pharmaceutical Company, Ltd., Nagano, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Itoh
authors.forename: Masami
authors.initials: M
authors.lastname: Kojima
authors.forename: Hanako
authors.initials: H
authors.lastname: Furihata-Komatsu
authors.forename: Shigemi
authors.initials: S
authors.lastname: Aoyagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kusama
authors.forename: Hidetada
authors.initials: H
authors.lastname: Komatsu
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000596:Amino Acids / Q000652:urine; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects; D004002:Clodronic Acid / Q000494:pharmacology*; D005260:Female; D005269:Femur / Q000187:drug effects / Q000502:physiology; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000502:physiology; D008252:Macaca fascicularis; D010052:Ovariectomy; D013997:Time Factors
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D004002:Clodronic Acid; C036020:deoxypyridinoline