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 boneformation 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. (J Bone Miner Res 2002;17:534 -543)

Influence of Ovariectomy on Bone Turnover and Trabecular Bone Mass in Mature Cynomolgus Monkeys

“…Because bone loss at the skeletal site rich in trabecular bone after OVX appears to be more pronounced than that at the skeletal site rich in cortical bone in cynomolgus monkeys,9 a statistically significant loss of trabecular bone mass could be detected at the above described 3 sites even with a smaller sample size. From the point of research and development (R&D) view, it is important to establish the influence of OVX on the clinically important skeletal sites in mature monkeys.…”

“…The procedure used for scanning was based on the method previously described 9. After anesthesia with an intramuscular injection of a mixed solution of ketamine hydrochloride and xylazine, the lumbar spine (L1-L7) was scanned by DXA using a DPX-alpha (Lunar Ltd., Madison, WI, USA), with the animals supine on a Styrofoam board together with tap water 10 cm deep.…”

Surface-specific Bone Formation Effects of Osteoporosis Pharmacological Treatments

“…Pre-clinical models consistently document reductions in intracortical remodeling with bisphosphonates. In ovariectomized non-human primates clodronate suppressed tibia intracortical bone formation to control levels [46] while ibandronate reduced intracortical remodeling in the rib and central radius, but not the femoral neck, compared to controls [47]. Suppression of intracortical turnover with bisphosphonates has also been shown in ovariohysterectomized beagles [22], intact beagles [19,21,48], and intact minipigs [23].…”

“…These reductions in remodeling with bisphosphonate treatment are associated with prevention of the normal loss of bone volume and architecture in placebo-treated patients [43,44,55,71,72]. Pre-clinical models similarly show that bisphosphonates suppress remodeling and increase bone volume in ovariectomized non-human primates [46,47,73], ovariectomized beagles [22,74], intact minipigs [23], and intact beagles [17,21,48,73,[75][76][77][78][79].…”

Hormonal Therapies and Osteoporosis

“…The greater ability of ibandronate to preserve BMD at trabecular versus cortical sites was attributed to the higher incorporation of ibandronate in trabecular bone, which has a higher surface area available for drug binding (Smith et al 2003). However, treatment of cynomolgus macaques for 16 mo with clodronate was most effective in preventing cortical bone loss (e.g., tibia) secondary to estrogen deficiency (Itoh et al 2002). Spinal BMD was dramatically increased in ovariectomized cynomolgus monkeys treated for 54 wk with MCC-565, a bone selective 17␤-estradiol-bisphosphonate conjugate (Akihito et al 2000).…”