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RANKL inhibition with osteoprotegerin increases bone strength by improving cortical and trabecular bone architecture in ovariectomized rats.
J Bone Miner Res. 2008 May; 23(5):672-82.JB

Abstract

INTRODUCTION

Ovariectomy (OVX) results in bone loss caused by increased bone resorption. RANKL is an essential mediator of bone resorption. We examined whether the RANKL inhibitor osteoprotegerin (OPG) would preserve bone volume, density, and strength in OVX rats.

MATERIALS AND METHODS

Rats were OVX or sham-operated at 3 mo of age. Sham controls were treated for 6 wk with vehicle (Veh, PBS). OVX rats were treated with Veh or human OPG-Fc (10 mg/kg, 2/wk). Serum RANKL and TRACP5b was measured by ELISA. BMD of lumbar vertebrae (L(1)-L(5)) and distal femur was measured by DXA. Right distal femurs were processed for bone histomorphometry. Left femurs and the fifth lumbar vertebra (L(5)) were analyzed by muCT and biomechanical testing, and L(6) was analyzed for ash weight.

RESULTS

OVX was associated with significantly greater serum RANKL and osteoclast surface and with reduced areal and volumetric BMD. OPG markedly reduced osteoclast surface and serum TRACP5b while completely preventing OVX-associated bone loss in the lumbar vertebrae, distal femur, and femur neck. Vertebrae from OPG-treated rats had increased dry and ash weight, with no significant differences in tissue mineralization versus OVX controls. muCT showed that trabecular compartments in OVX-OPG rats had significantly greater bone volume fraction, vBMD, bone area, trabecular thickness, and number, whereas their cortical compartments had significantly greater bone area (p < 0.05 versus OVX-Veh). OPG improved cortical area in L(5) and the femur neck to levels that were significantly greater than OVX or sham controls (p < 0.05). Biomechanical testing of L(5) and femur necks showed significantly greater maximum load values in the OVX-OPG group (p < 0.05 versus OVX-Veh). Bone strength at both sites was linearly correlated with total bone area (r(2) = 0.54-0.74, p < 0.0001), which was also significantly increased by OPG (p < 0.05 versus OVX).

CONCLUSIONS

OPG treatment prevented bone loss, preserved trabecular architecture, and increased cortical area and bone strength in OVX rats.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Ominsky MS
Metabolic Disorders Research, Amgen, Thousand Oaks, California, USA.
Li X
No affiliation info available
Asuncion FJ
No affiliation info available
Barrero M
No affiliation info available
Warmington KS
No affiliation info available
Dwyer D
No affiliation info available
Stolina M
No affiliation info available
Geng Z
No affiliation info available
Grisanti M
No affiliation info available
Tan HL
No affiliation info available
Corbin T
No affiliation info available
McCabe J
No affiliation info available
Simonet WS
No affiliation info available
Ke HZ
No affiliation info available
Kostenuik PJ
No affiliation info available

MeSH

AnimalsBone and BonesFemaleOsteoprotegerinOvariectomyRANK LigandRatsRats, Sprague-Dawley

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18433301

Citation

Ominsky, Michael S., et al. "RANKL Inhibition With Osteoprotegerin Increases Bone Strength By Improving Cortical and Trabecular Bone Architecture in Ovariectomized Rats." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 23, no. 5, 2008, pp. 672-82.
Ominsky MS, Li X, Asuncion FJ, et al. RANKL inhibition with osteoprotegerin increases bone strength by improving cortical and trabecular bone architecture in ovariectomized rats. J Bone Miner Res. 2008;23(5):672-82.
Ominsky, M. S., Li, X., Asuncion, F. J., Barrero, M., Warmington, K. S., Dwyer, D., Stolina, M., Geng, Z., Grisanti, M., Tan, H. L., Corbin, T., McCabe, J., Simonet, W. S., Ke, H. Z., & Kostenuik, P. J. (2008). RANKL inhibition with osteoprotegerin increases bone strength by improving cortical and trabecular bone architecture in ovariectomized rats. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 23(5), 672-82. https://doi.org/10.1359/jbmr.080109
Ominsky MS, et al. RANKL Inhibition With Osteoprotegerin Increases Bone Strength By Improving Cortical and Trabecular Bone Architecture in Ovariectomized Rats. J Bone Miner Res. 2008;23(5):672-82. PubMed PMID: 18433301.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RANKL inhibition with osteoprotegerin increases bone strength by improving cortical and trabecular bone architecture in ovariectomized rats. AU - Ominsky,Michael S, AU - Li,Xiaodong, AU - Asuncion,Frank J, AU - Barrero,Mauricio, AU - Warmington,Kelly S, AU - Dwyer,Denise, AU - Stolina,Marina, AU - Geng,Zhaopo, AU - Grisanti,Mario, AU - Tan,Hong-Lin, AU - Corbin,Timothy, AU - McCabe,James, AU - Simonet,William S, AU - Ke,Hua Z, AU - Kostenuik,Paul J, PY - 2008/4/25/pubmed PY - 2008/8/9/medline PY - 2008/4/25/entrez SP - 672 EP - 82 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J Bone Miner Res VL - 23 IS - 5 N2 - INTRODUCTION: Ovariectomy (OVX) results in bone loss caused by increased bone resorption. RANKL is an essential mediator of bone resorption. We examined whether the RANKL inhibitor osteoprotegerin (OPG) would preserve bone volume, density, and strength in OVX rats. MATERIALS AND METHODS: Rats were OVX or sham-operated at 3 mo of age. Sham controls were treated for 6 wk with vehicle (Veh, PBS). OVX rats were treated with Veh or human OPG-Fc (10 mg/kg, 2/wk). Serum RANKL and TRACP5b was measured by ELISA. BMD of lumbar vertebrae (L(1)-L(5)) and distal femur was measured by DXA. Right distal femurs were processed for bone histomorphometry. Left femurs and the fifth lumbar vertebra (L(5)) were analyzed by muCT and biomechanical testing, and L(6) was analyzed for ash weight. RESULTS: OVX was associated with significantly greater serum RANKL and osteoclast surface and with reduced areal and volumetric BMD. OPG markedly reduced osteoclast surface and serum TRACP5b while completely preventing OVX-associated bone loss in the lumbar vertebrae, distal femur, and femur neck. Vertebrae from OPG-treated rats had increased dry and ash weight, with no significant differences in tissue mineralization versus OVX controls. muCT showed that trabecular compartments in OVX-OPG rats had significantly greater bone volume fraction, vBMD, bone area, trabecular thickness, and number, whereas their cortical compartments had significantly greater bone area (p < 0.05 versus OVX-Veh). OPG improved cortical area in L(5) and the femur neck to levels that were significantly greater than OVX or sham controls (p < 0.05). Biomechanical testing of L(5) and femur necks showed significantly greater maximum load values in the OVX-OPG group (p < 0.05 versus OVX-Veh). Bone strength at both sites was linearly correlated with total bone area (r(2) = 0.54-0.74, p < 0.0001), which was also significantly increased by OPG (p < 0.05 versus OVX). CONCLUSIONS: OPG treatment prevented bone loss, preserved trabecular architecture, and increased cortical area and bone strength in OVX rats. SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/18433301/RANKL_inhibition_with_osteoprotegerin_increases_bone_strength_by_improving_cortical_and_trabecular_bone_architecture_in_ovariectomized_rats_ DB - PRIME DP - Unbound Medicine ER -