Effects of separate and combined therapy with growth hormone and parathyroid hormone on lumbar vertebral bone in aged ovariectomized osteopenic rats

doi:10.1016/S8756-3282(00)00416-6

Bone

Volume 28, Issue 2, February 2001, Pages 202-207

https://doi.org/10.1016/S8756-3282(00)00416-6 Get rights and content

Abstract

Previous studies have demonstrated that growth hormone (GH) has a marked anabolic effect on cortical bone, and parathyroid hormone (PTH) has been shown to increase cancellous bone markedly and cortical bone to some extent in ovariectomized (ovx) rats. Combined therapies mostly focused on combining a bone anabolic agent with an antiresorptive agent. The following study was carried out to examine the efficacy of combined therapy with GH and PTH, two bone anabolic agents in rebuilding bone after loss due to ovariectomy in lumbar vertebrae, which contain both cortical and cancellous bones. Twelve-month-old female F344 rats were divided into five groups: sham + solvent vehicle, ovx + solvent vehicle, ovx + GH (2.5 mg/kg/day), ovx + PTH (80 μg/kg/day), and ovx + GH (2.5 mg/kg/day) + PTH (80 μg/kg/day). After surgery, animals were left for 4 months to become osteopenic before the beginning of therapy. Hormone administrations were given 5 days per week for 2 months and the animals were killed. The L3 vertebra was removed and examined by pQCT densitometry and by histomorphometry. Compared with age-matched, sham-operated controls, there was a 21% decrease in total bone mineral content (BMC) (p < 0.0001), 17.0% decrease in total bone mineral density (BMD) (p < 0.0001), 25.4% decrease in cortical BMC (p < 0.001), 3.1% decrease in cortical BMD (p < 0.05), 50.5% decrease in cancellous BMC (p < 0.01), 47.3% decrease in cancellous BMD (p < 0.01), and 14.5% decrease in cancellous bone volume (BV/TV) (p < 0.05) in the vehicle-treated ovx rats. Compared with age-matched, vehicle-treated ovx controls, GH, PTH, and GH + PTH increased total BMC by 22.8% (p < 0.001), 32.4% (p < 0.0001), and 72.7% (p < 0.0001), respectively; total BMD by 9.7% (p > 0.05), 22.6% (p < 0.001), and 38.8% (p < 0.0001), respectively; cortical BMC by 28.8% (p < 0.01), 50.8% (p < 0.0001), and 98.4% (p < 0.0001), respectively; and cortical BMD by 4.5% (p < 0.01), 2.9% (p < 0.05), and 6.3% (p < 0.0001), respectively. PTH and GH + PTH significantly increased cancellous BMC by 95.3% (p < 0.01) and 255.8% (p < 0.0001), respectively; cancellous BMD by 77.6% (p < 0.05) and 181% (p < 0.0001), respectively; cancellous BV/TV by 38.6% (p < 0.0001) and 55.9% (p < 0.0001), respectively; and trabecular thickness by 48% (p < 0.0001) and 68.3% (p < 0.0001), respectively. Note that GH by itself had no significant effect on vertebral cancellous BMC, cancellous BMD, and cancellous BV/TV. In conclusion, the effect of PTH was mostly more marked than that of GH. GH acted mainly by increasing cortical bone with less effect on cancellous bone, while PTH acted by increasing both cortical and cancellous bones. Combined therapy with GH and PTH was more effective in rebuilding bone after ovariectomy than either therapy alone. The effects of combined therapy with GH and PTH were additive in vertebral bone in the aged osteopenic rats.

Introduction

Osteoporosis due to estrogen deficiency is characterized by increased bone turnover with bone resorption exceeding bone formation especially in trabecular and endocortical bone surfaces.18, 22, 48, 49 Increase in bone turnover results in decreased bone mass in many bone sites including the vertebra,46, 47, 51 femoral neck,3, 25 and the metaphyses of long bones,21, 44, 51, 52 where cancellous bone and cortical bone are lost in varying degrees. Most previous combined therapies were a combination of parathyroid hormone (PTH) with estrogen, bisphosphonate, or calcitonin,7, 23, 34, 35, 37, 38, 50 but these therapies did not appear to be more effective in increasing bone mass than treatment with PTH alone.23, 34, 38, 50 An ideal therapy in established osteoporosis would aim to rebuild bone mass by restoring the lost cancellous and cortical bones.

Previous studies have demonstrated both growth hormone (GH) and PTH are anabolic agents on bone.1, 2, 12, 21, 38, 39 GH administration stimulates cortical bone formation in rats by mainly increasing subperiosteal bone formation.1, 2 Intermittent administration of PTH acts mainly to increase cancellous bone mass, but it also stimulates cortical bone formation to some extent.5, 12, 21, 38, 39, 53 Therefore, we hypothesized that combining a cortical bone formation-stimulating therapy such as GH with a mainly cancellous bone formation-stimulating therapy such as PTH in the treatment of established osteoporosis would optimize bone accretion more than either therapy alone. In a separate report of the same study, such combined therapy with GH and PTH was found to be more effective in rebuilding a more mechanically competent bone than either therapy alone.30 Vertebral bodies contain both cancellous and cortical bones, which are clinically relevant, as these are the sites that undergo bone loss and are prone to fractures in humans.19 The rat vertebra is of interest as a sample site due to its relatively slow rate of longitudinal bone growth and the presence of, at least, some remodeling activity similar to that of adult human bone.6 So we have chosen to focus on the lumbar vertebrae in the aged ovariectomized (ovx) rats in this study.

To test the hypothesis of this project, we employed the aged osteopenic ovx rat model of postmenopausal bone loss.15, 16 After the establishment of osteopenia, the ovx animals were treated with GH, PTH, and GH + PTH for 2 months and killed. The L3 vertebral bones were harvested and examined by peripheral quantitative computed tomography (pQCT) and by static and dynamic histomorphometry.

Section snippets

Materials and methods

Ten-month-old female Fisher 344 rats were bought from the National Institute on Aging rodent colony at Harlan Sprague Inc. (Indianapolis, IN). When they arrived in our institution, they were housed in a room maintained at 26°C with 14-h light and 10-h dark cycles. When the animals were 12 month old, 10 rats were sham operated (sham) and 55 rats were bilaterally ovariectomized (ovx) after the groups were weight matched (body weight/group). After surgery, all animals were maintained without

Uterine weights

At the termination of the study, the expected decrease in uterine weight occurred in the ovx rats. Compared with vehicle-treated ovx rats, GH, PTH and GH + PTH increased the uterine weight slightly but not significantly (sham, 0.553 ± 0.073 g; ovx, 0.157 ± 0.008 g, ovx + GH, 0.172 ± 0.008 g; ovx + PTH, 0.171 ± 0.009 g; ovx + GH + PTH, 0.200 ± 0.007 g).

pQCT measurements of the L3 vertebra

After a 2-month treatment, compared with the age-matched sham controls, in the vehicle-treated ovx rats there was a 21.0% decrease in total BMC,

Discussion

This study was designed to investigate whether combination therapy with two bone anabolic agents that stimulate the formation of cancellous and cortical bone will be more effective in rebuilding bone mass in ovx rats with established cancellous and cortical osteopenia than either therapy alone. At the termination of the study, the animals were 18 months old and the ovx animals had lost a significant amount of cancellous and cortical bone, as expected. The decrease in cortical bone was

Acknowledgements

This study was supported in part by grants from the National Institutes of Health (AG-13309) and the Texas Higher Education Co-ordinating Board and by a University Grant program for osteoporosis from Procter and Gamble Pharmaceuticals (Cincinnati, OH). The authors thank Genentech Inc. (South San Francisco, CA) for providing the recombinant human growth hormone (rhGH) used in this study.

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Taking the bone specific properties of PTH and the bone and muscle specific properties of GH into consideration, a combination treatment using these agents may counteract immobilization-induced osteopenia and sarcopenia and seems a rational therapeutic approach. The effect of PTH and GH combination treatment on the skeleton have previously been studied in ovariectomized [35–38] and hypophysectomized rats [39], whereas this treatment regime has not previously been investigated in disuse osteopenic animals. Therefore, the aim of the present study was to investigate whether PTH and GH alone, or in combination, can prevent immobilization-induced osteopenia and sarcopenia.
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Original articleEffects of separate and combined therapy with growth hormone and parathyroid hormone on lumbar vertebral bone in aged ovariectomized osteopenic rats

Abstract

Introduction

Section snippets

Materials and methods

Uterine weights

pQCT measurements of the L3 vertebra

Discussion

Acknowledgements

Bone

Bone

Bone

Lancet

Mech Ageing Dev

Bone

Bone

Bone

Bone

Bone

Bone

Bone

Bone

Bone

Bone

Bone

Bone

The influence of growth hormone on cancellous and cortical bone of the vertebral body in aged rats

J Bone Miner Res

Effect of estrogen deficiency on cancellous and cortical bone structure and strength of the femoral neck in rats

Calcif Tissue Int

Evidence of sequential remodeling in rat trabecular bonemorphology, dynamic histomorphometry, and changes during skeletal maturation

Anat Rec

Treatment of osteoporosis with parathyroid peptide (hPTH 1-34) and oestrogenincrease in volumetric density of iliac cancellous bone may depend on reduced trabecular spacing as well as increased thickness of packets of newly formed bone

Clin Endocrinol

Anabolic actions of parathyroid hormone on bone

Endocrine Rev

Peripheral quantitative computed tomography (pQCT) for evaluating structural and mechanical properties of small bone

The Design of Experiments

Assessing bone quantity by pQCT

Bone

Original article
Effects of separate and combined therapy with growth hormone and parathyroid hormone on lumbar vertebral bone in aged ovariectomized osteopenic rats