The bisphosphonate, alendronate, prevents bone loss in ovariectomized baboons

Thompson, David D.; Seedor, J.G.; Quartuccio, H.; Solomon, Howard F.; Fioravanti, Christine; Davidson, James S.; Klein, Hilton J.; Jackson, Rebecca D.; Clair, James St.; Frankenfield, D.; Brown, E.; Simmons, Hollis A.; Rodan, Gideon A.

doi:10.1002/jbmr.5650070812

Cited by 94 publications

(17 citation statements)

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“…Strong and positive effects of ALN on bone density, bone strength, and fracture risk in human and other species have been widely acknowledged 26–29. Interestingly, these studies demonstrated that a higher dose of ALN (200 to 600 µg/kg/week s.c.) was needed to protect against OVX‐induced bone loss in the rabbit than in rat and other species 30, 31. However, we selected doses of ODN (4 and 9 µM/day), which provided steady‐state exposure similar to the estimated daily clinical dose (7.2 µM/day).…”

Section: Discussionsupporting

confidence: 64%

Cathepsin K inhibitors prevent bone loss in estrogen-deficient rabbits

Pennypacker

Duong

Cusick

et al. 2010

Journal of Bone and Mineral Research

104

115

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Two cathepsin K inhibitors (CatKIs) were compared with alendronate (ALN) for their effects on bone resorption and formation in ovariectomized (OVX) rabbits. The OVX model was validated by demonstrating significant loss (9.8% to 12.8%) in lumbar vertebral bone mineral density (LV BMD) in rabbits at 13-weeks after surgery, which was prevented by estrogen or ALN. A potent CatKI, L-006235 (L-235), dosed at 10 mg/kg per day for 27 weeks, significantly decreased LV BMD loss ( p < .01) versus OVX-vehicle control. ALN reduced spine cancellous mineralizing surface by 70%, whereas L-235 had no effect. Similarly, endocortical bone-formation rate and the number of double-labeled Haversian canals in the femoral diaphysis were not affected by L-235. To confirm the sparing effects of CatKI on bone formation, odanacatib (ODN) was dosed in food to achieve steady-state exposures of 4 or 9 mM/day in OVX rabbits for 27 weeks. ODN at both doses prevented LV BMD loss ( p < .05 and p < .001, respectively) versus OVX-vehicle control to levels comparable with sham or ALN. ODN also dose-dependently increased BMD at the proximal femur, femoral neck, and trochanter. Similar to L-235, ODN did not reduce bone formation at any bone sites studied. The positive and highly correlative relationship of peak load to bone mineral content in the central femur and spine suggested that ODN treatment preserved normal biomechanical properties of relevant skeletal sites. Although CatKIs had similar efficacy to ALN in preventing bone loss in adult OVX rabbits, this novel class of antiresorptives differs from ALN by sparing bone formation, potentially via uncoupling bone formation from resorption. ß

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Section: Discussionsupporting

confidence: 64%

Cathepsin K inhibitors prevent bone loss in estrogen-deficient rabbits

Pennypacker

Duong

Cusick

et al. 2010

Journal of Bone and Mineral Research

104

115

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“…This reduction in BMD occurred earlier in the axial than in the peripheral skeleton, and in trabecular than in cortical bone [24], presumably because of the larger surface to volume ratio in trabecular bone. Similar to our data, other investigators [4, 10] also found recovery after early spinal bone loss in untreated OVX baboons, and spinal BMD gain in non‐OVX baboons.…”

Section: Discussionsupporting

confidence: 92%

“…The rise in serum calcium (sCa) and phosphate (sPi) in our OVX animals is in keeping with similar findings in OVX baboons by Thompson [4] and Balena [10]. This change may be attributable to estrogen deficiency since estrogen replacement therapy in OVX monkeys was associated with lower levels of sCa and sPi than in untreated OVX monkeys [11].…”

Section: Discussionsupporting

confidence: 88%

“…Bone loss following acute oestrogen deficiency in women takes about 5 years to plateau [2]. Non‐human primates undergo decreased bone mass and bone strength with increased bone turnover after ovariectomy (OVX) [3, 4], with advancing age [5] and after prolonged immobilization [6]. Bone histomorphometric studies in human and non‐human primates show similar characteristics [7–9] since non‐human primates also undergo bone remodeling.…”

Section: Introductionmentioning

confidence: 99%

“…

Ovariectomy has been associated with systemic bone loss in several animal models including non-human and human primates [1][2][3][4]. Bone loss following acute oestrogen deficiency in women takes about 5 years to plateau [2].

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mentioning

confidence: 99%

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Bone loss in the ovariectomized baboonPapio ursinus: densitometry, histomorphometry and biochemistry

Mas

Biscardi

Schnitzler

et al. 2007

J Cellular Molecular Medi

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To develop a non-human primate model of systemic bone loss after ovariectomy, 24 ovariectomized (OVX) and eight control (non-OVX) female baboons Papio ursinus were investigated over a period of 48 months using bone mineral density (BMD), iliac crest bone histomorphometry, bone turnover markers, and variables of calcium metabolism. Lumbar spine (L1–L4) BMD measured by dual energy X-ray absorptiometry (DXA) decreased in OVX animals in the first 12 months (−7.6%) and showed a slow trend towards recovery after 24 months. Controls showed a slow increase in spinal BMD over 4 years (+9.7%). Total hip BMD decreased slowly up to 48 months in all animals (OVX −12.6%versus controls −10%); this indicated that OVX had a limited effect on total hip BMD. Forearm BMD did not change. The significant decrease in trabecular bone volume (TBV) of the iliac crest from baseline to 12 months was followed by some recovery. Microarchitectural deterioration of trabecular bone in OVX animals was demonstrated by a decline in trabecular number and an increase in trabecular spacing. These changes were also evident on sections of whole vertebrae, proximal femora and iliac crests. Changes in iliac TBV reflected spinal but not hip BMD changes in the OVX animals. Static and dynamic histomorphometric variables indicated that bone turnover was increased for 36 months following OVX. Controls showed no changes in histomorphometric variables. Bone specific alkaline phosphatase (ALPs) in OVX animals remained elevated throughout the study; osteocalcin (OC) was significantly elevated only at 6 and 12 months, and deoxypyridinoline (Pyr-D) was elevated at 12 months but declined after 24 months. ALPs was thus more sensitive to the long-term effects of OVX than were OC or Pyr-D. Controls showed no changes in bone turnover markers. This study showed consistent deleterious changes in lumbar BMD, bone histomorphometry with microarchitectural deterioration together with altered biochemical markers of bone turnover in the first 12 months after OVX. Since these changes resemble those in post-menopausal women, the non-human primate Papio ursinus is suitable for the study of bone loss in post-menopausal women.

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