Elsevier

Bone

Volume 28, Issue 5, May 2001, Pages 538-547
Bone

Original article
Effects of human parathyroid hormone (1-34), LY333334, on bone mass, remodeling, and mechanical properties of cortical bone during the first remodeling cycle in rabbits

https://doi.org/10.1016/S8756-3282(01)00433-1Get rights and content

Abstract

We have previously shown that parathyroid hormone (PTH) increases cortical bone mass and mechanical strength of female rabbits after 140 days of treatment. However, cortical porosity was also shown to increase. If cortical porosity increases prior to the change in geometry, there may be a transient decrease in cortical bone strength that could make the bone more susceptible to fracture in the early phase of treatment. The purpose of this study is to examine the effects of PTH on the remodeling dynamics and mechanical properties of cortical bone in rabbits, which exhibit haversian remodeling, during the first remodeling cycle after the initiation of treatment. Fifty 9-month-old intact female New Zealand white rabbits were randomized into five groups. A baseline control group was killed at the start of the experiment. The two PTH-treated groups were given human PTH(1-34) at 10 μg/kg daily subcutaneously for 35 (P35) or 70 (P70) days. Two respective age-matched control groups (V35, V70) were injected with vehicle. Histomorphometry of the cortical bone in the tibial midshaft showed that, although intracortical activation frequency was significantly increased by PTH at 35 days, there was no significant increase of cortical porosity in the first remodeling cycle (70 days). Moreover, stimulation of cortical surface bone formation in the treated animals led to significantly greater cortical area and greater bone strength in both P35 and P70. We conclude that, although intracortical remodeling increases within the first remodeling period (70 days) in animals treated with 10 μg/kg PTH, the greater cortical area due to acceleration of bone formation on cortical surfaces increases cortical bone strength. There is no mechanical risk during the first remodeling cycle associated with intermittent PTH treatment in animals with normal bone mass.

Introduction

Intermittent administration of human parathyroid hormone (hPTH) has great potential as a treatment for patients with osteoporosis. Numerous studies have demonstrated that PTH has a pronounced anabolic effect on cancellous bone as a result of stimulation of bone formation in several animal models,2, 4, 5, 9, 14, 15, 17, 19, 23, 26, 28, 29, 33, 37, 38, 39, 44, 45, 47, 51, 53 and some anabolic effects of PTH on cancellous bone have also been shown in humans.10, 11, 16, 22, 30, 34, 35, 36, 41, 43 However, the effect of PTH on cortical bone in humans remains controversial. Some early clinical studies showed that cortical bone densities were reduced after PTH treatment, while cancellous bone mass increased.11, 16, 34, 41 These findings led to the speculation that the cancellous bone anabolic effect of PTH is obtained at the expense of cortical bone.

We previously showed that PTH, at both 10 and 40 μg/kg per day for 140 days (two remodeling periods), increases cortical porosity of the tibia in female rabbits, which exhibit haversian remodeling, by stimulating intracortical remodeling.13 The increased cortical porosity was compensated by periosteal and endocortical apposition so that bone mass and mechanical strength were increased. However, there is the concern that, if porosity increases during the first remodeling period prior to compensatory apposition of bone to the cortical surfaces, there may be a transient decrease in cortical bone strength that could make the bone more susceptible to fracture.

The purpose of this study is to examine the effects of PTH on the remodeling dynamics and mechanical properties of cortical bone in rabbits during the first remodeling cycle after the initiation of treatment. We used 10 μg/kg per day of PTH in this study because, in our previous study,13 a higher dose (40 μg/kg per day) resulted in mild hypercalcemia, and the rabbits did not gain weight normally compared with controls. In humans, this hypercalcemia would have skeletal effects similar to those seen in hyperparathyroidism. The lower dose is more like the dose that would be used in clinical treatment. Use of the lower dose also increased cortical porosity in our previous study.

Section snippets

Experimental design

Fifty intact female New Zealand white rabbits were purchased from Myrtle’s Rabbitry, Inc. (Thompson Station, TN). They were acclimated for a period of 1 month and housed individually in rooms maintained at 20°C on a 12 h light/12 h dark cycle and fed lab rabbit chow containing 0.5% calcium, 0.41% phosphorus, and 2.2 IU/g vitamin D3 (Diet #5736C-Y, PMI, Richmond, IN). The amount of food served was 105 g/day per animal, and water was available at all times. The rabbits were 9 months old at the

General condition

There were no significant body weight differences among groups at the beginning of the experiment (Table 1). Rabbits treated with vehicle or PTH had normal body weight gain and there were no significant differences between PTH-treated animals and respective age-matched controls at any timepoint during the study. There were no treatment-related physical signs.

Blood chemistry

There were no significant differences between PTH-treated animals and age-matched controls in any biochemical parameter (Table 2).

Discussion

This study was undertaken to evaluate the effects of hPTH(1-34) on intracortical porosity and bone strength during the first remodeling cycle (70 days) following initiation of treatment. Because it is known that PTH increases intracortical remodeling rates, the aim was to determine if there is a transient decrease in mechanical strength of cortical bone within the first remodeling cycle after the initiation of PTH treatment. The results show that, although intracortical remodeling was

Acknowledgements

The authors thank Mary Hooser, Diana Jacob, and Thurman Alvey for performing all histological procedures. This study was funded by Eli Lilly and Co., which also provided the hPTH(1-34).

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