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Biosynthetic Human Parathyroid Hormone (1–34) Effects on Bone Quality in Aged Ovariectomized Rats

Department of Endocrine Research (M.S., G.Q.Z.), Lilly Research Laboratories, Indianapolis, Indiana 46285; and Department of Orthopaedic Surgery (C.H.T.), and The Biomechanics and Biomaterials Research Center, Indiana University Medical Center, Indianapolis, Indiana 46202

Address all correspondence and requests for reprints to: Dr. Masahiko Sato, MC 797, Department of Endocrine Research, Lilly Corporate Center, Indianapolis, Indiana 46285. E-mail: sato-masahiko{at}lilly.com

For the first time, PTH (1–34) was found to significantly affect bone quality, femora length, and body weight of aged, ovariectomized rats. Specifically, we examined the effects of biosynthetic human PTH (1–34) in 9 month-old rats that were ovariectomized and dosed for the ensuing 6 months with 8 or 40 µg/kg PTH. Bone content, architecture, and quality of axial and appendicular skeletal sites were analyzed by computed tomography (QCT), histomorphometry, and biomechanical testing. The large sample size (n = 26–35) of this study was useful in confirming the anabolic, dose-dependent effects of PTH at trabecular and cortical bone sites. Longitudinal analysis of tibias by QCT confirmed a small age-dependent reduction in bone density, with further reductions observed for ovariectomized controls (OVX). Subtle but deleterious effects of ovariectomy on bone quality are described. Additionally, the strength of the femoral neck was shown not to differ between baseline, sham-operated controls, or OVX in this model, suggesting limited utility of this measurement in aged rats. Both doses of PTH induced substantial gains above OVX, in bone mass and connectivity for the proximal tibia, distal femur, proximal femur, and spine. Ovariectomy significantly decreased the toughness of vertebral bone. However, PTH at 8 µg/kg reversed this deleterious effect on bone quality, while 40 µg/kg PTH significantly improved both toughness and brittleness beyond baseline controls. Cortical bone analyses at the femoral or tibial diaphysis confirmed the PTH stimulation of endosteal and periosteal bone formation with resulting increase in cortical thickness, moment of inertia, strength, and stiffness of the femur. PTH treatment significantly improved the intrinsic properties, Young’s modulus and toughness, of the femur compared with OVX. At 40 µg/kg PTH, bone mass and strength were typically greater than sham or baseline controls, confirming that PTH is functionally anabolic at trabecular and cortical bone sites. Interestingly, PTH dose-dependently increased the femora length, in the absence of differences between baseline, sham, and OVX controls. PTH slightly increased body weight above OVX. In addition, PTH did not interfere with the beneficial effects of ovariectomy on rat longevity.

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