Maintenance of cancellous bone in ovariectomized, human parathyroid hormone [hPTH(1-84)]-treated rats by estrogen, risedronate, or reduced hPTH

doi:10.1016/S8756-3282(01)00582-8

Bone

Volume 29, Issue 4, October 2001, Pages 352-360

https://doi.org/10.1016/S8756-3282(01)00582-8 Get rights and content

Abstract

This study compares effects of maintenance doses of human parathyroid hormone [hPTH(1-84)], 17β-estradiol (E₂), and risedronate on distal femur bone mineral density and proximal tibia cancellous bone histomorphometry in ovariectomized (ovx), osteopenic rats previously administered a higher dose of hPTH. Nine groups (n = 8) of 3.5-month-old ovx or intact Sprague-Dawley rats were left untreated for 11 weeks to allow for the development of cancellous osteopenia in the ovx groups. Next, the ovx rats received subcutaneous injections of hPTH (75 μg/kg per day, three times per week) or vehicle for 12 weeks. Treatments were then changed to E₂ (10 μg/kg per day, two times per week), risedronate (Ris; 3 μg/kg per day, three times per week), low-dose hPTH(1-84) (LowPTH; 25 μg/kg per day, three times per week), or vehicle, and administered for 36 weeks. The intact control group remained untreated for the duration of study. Femora and tibiae were collected at weeks −11 (baseline); 0 (ovx effect); 12 (hPTH effect), and 24, 36, and 48 (maintenance effects). Endpoints evaluated included distal femur bone mineral density (BMD) and proximal tibia cancellous bone volume (BV/TV), osteoclast surface (Oc.S), mineralizing surface (MS), mineral apposition rate (MAR), and bone formation rate (BFR). Ovariectomy had a negative effect on distal femur BMD and proximal tibia BV/TV. Treatment of ovx rats with hPTH for 12 weeks resulted in higher BMD in comparison to intact controls, and higher cancellous BV/TV in comparison to ovx controls. Discontinuation of hPTH resulted in loss of gained BMD within 24 weeks and loss of gained BV/TV within 12 weeks. Treatment of ovx rats with hPTH for 12 weeks followed by E₂ treatment left BMD and BV/TV similar to vehicle-treated ovx rats by week 48 (36 weeks after commencement of the E₂ maintenance treatment). Maintenance treatment with risedronate resulted in BMD and BV/TV similar to that of intact controls. Maintenance treatment with low-dose hPTH resulted in greater BMD and similar BV/TV in comparison to intact controls. MS and BFR were highest after low-dose hPTH administration. MS and BFR were lowest after E₂ or risedronate, whereas Oc.S was lowest after risedronate administration. Thus, in osteopenic rats, the increment in distal femur BMD and proximal tibia BV/TV gained by 12 weeks of hPTH treatment was lost within 24 and 12 weeks of treatment termination, respectively. Low-dose hPTH maintained BMD and BV/TV after hPTH treatment by stimulating bone formation, whereas risedronate maintained BMD and BV/TV by reducing bone resorption. E₂ in a maintenance dose failed to maintain BMD and BV/TV after withdrawal of hPTH treatment.

Introduction

The intermittent administration of parathyroid hormone (PTH) or its peptide fragments increases bone mass and/or strength in various animals, including normal and osteopenic rats,24, 36 and may prove therapeutic in the treatment of osteoporosis in humans.4, 5, 19 PTH is, however, currently effective only by parenteral administration and termination of treatment results in loss of gained bone.8, 33, 39 Antiresorptive agents that maintain existing bone tissue by decreasing the rate of bone turnover include estrogen and the bisphosphonates. Estrogen replacement therapy and bisphosphonate therapy, especially if initiated during the early stages of estrogen deficiency, preserve bone mass in rats,15, 16, 38 and preserve bone mass and reduce the incidence of bone fractures in postmenopausal women.7, 23, 30 Consequently, one strategy for treating osteopenia may be to induce bone gain with an anabolic agent like PTH and subsequently provide treatment with a maintenance agent such as estrogen or a bisphosphonate, or possibly with a reduced dose of PTH to retain the bone gained. The purpose of the current investigation was to determine whether this therapeutic strategy was effective in reversing cancellous bone osteopenia and maintaining gained bone mass in ovariectomized rats. Results of treatment effects on cortical bone and vertebral strength have been presented elsewhere.28, 29

Section snippets

Materials and methods

Two hundred sixty-seven, 3.5-month-old, virgin, intact (n = 48) and ovariectomized (ovx; n = 219) female Sprague-Dawley rats (Sasco, Omaha, NE), initially weighing 250 ± 13 g, were used in the experiment. The animals were housed individually in hanging wire cages and maintained on a regular laboratory rat diet. Food and water were provided ad libitum to the intact animals. Food consumption for the ovx animals was restricted to that of the intact controls to minimize weight gain associated with

Results

The survival rate over the 59 week course of the study was remarkably high with only 6 of 267 (2%) rats lost to early death. Three rats died of pneumonia, two of unknown causes, and one was killed because of convulsions. No overt adverse health effects were noted in the remainder of the rats. Successful ovariectomy (lack of ovarian tissue and atrophied uterine horns) was confirmed in all ovx animals. Body weight did not differ among treatment groups at baseline (week −11, data not shown). In

Discussion

The current investigation compared the long-term efficacy of 17β-estradiol, risedronate, and a reduced dose of hPTH(1-84) in maintaining bone mass in estrogen-depleted (ovx) rats treated previously with a higher dose of hPTH(1-84). Estrogen depletion in 3.5-month-old rats caused a persistent relative osteopenia in the proximal tibia. Six-month-old rats appeared to have achieved peak bone mass, perhaps making this the age of choice when relative cancellous osteopenia after estrogen depletion

Acknowledgements

The authors thank Toni Howard, Susan Bare, Dwayne Belongia, Jennifer Matula, Julia Westrich, Nina Veccio, and Michelle Hunke-Daffer for their technical assistance, and Allelix Biopharmaceuticals, Ltd., for supplying the hPTH(1-84) used in this experiment. The editorial comments of Dr. T. Wronski are also greatly appreciated. This work was supported by NIH Grant AR39221-09.

References (39)

B.D. Baumann et al.
Response of cortical bone to antiresorptive agents and parathyroid hormone in aged ovariectomized rats
Bone
(1995)
M. Gunness-Hey et al.
Loss of the anabolic effect of parathyroid hormone on bone after discontinuation of hormone in rats
Bone
(1989)
A.B. Hodsman et al.
Assessment of maintenance therapy with reduced doses of PTH(1-34) in combination with a raloxifene analogue (LY117018) following anabolic therapy in the ovariectomized rat
Bone
(1999)
W.S.S. Jee et al.
Maintaining restored bone with bisphosphonate in the ovariectomized rat skeletonDynamic histomorphometry of changes in bone mass
Bone
(1993)
K. Kippo et al.
Effect of clodronate treatment on established bone loss in ovariectomized rats
Bone
(1998)
M. Li et al.
Parathyroid hormone monotherapy and cotherapy with antiresorptive agents restore vertebral bone mass and strength in aged ovariectomized rats
Bone
(1995)
R. Lindsay et al.
Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis
Lancet
(1997)
T.J. Wronski et al.
Anabolic effects of parathyroid hormone on cortical bone in ovariectomized rats
Bone
(1994)
N. Yamamoto et al.
Maintenance of bone mass by physical exercise after discontinuation of intermittent hPTH (1-34) administration
Bone Miner
(1993)
P.T. Cheng et al.
Estrogen dose required to maintain parathyroid hormone mediated bone gain in osteopenic ovariectomized rats is probably higher than in preventive treatment with estrogen
Bone
(1995)

W.J. Conover

Practical Nonparametric Statistics

(1980)

F. Cosman et al.

Is parathyroid hormone a therapeutic option for osteoporosis? A review of the clinical evidence

Calcif Tissue Int

(1998)

D. Dempster et al.

Anabolic actions of parathyroid hormone on bone

Endocrine Rev

(1993)

E. Eskandar et al.

Rapid determination of cancellous bone mineral loss in ovariectomized rats by a subtraction technique

Anat Rec

(1991)

J.C. Gallagher

EstrogenPrevention and treatment of osteoporosis

J.M. Hock et al.

Human parathyroid hormone-(1-34) increases bone mass in ovariectomized and orchidectomized rats

Endocrinology

(1988)

J.M. Hock et al.

Resorption is not essential for the stimulation of bone growth by hPTH-(1-34) in rats in vivo

J Bone Miner Res

(1989)

U.T. Iwaniec et al.

Effects of nicotine on bone and calciotropic hormones in growing female rats

Calcif Tissue Int

(2000)

D.B. Kimmel et al.

The effect of recombinant human (1-84) or synthetic human (1-34) parathyroid hormone on the skeleton of adult osteopenic ovariectomized rats

Endocrinology

(1993)

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Sequential treatment with zoledronic acid followed by teriparatide or vice versa increases bone mineral density and bone strength in ovariectomized rats
2017, Bone Reports
Citation Excerpt :
The results that we obtained after sequential use of TPTD followed by ZOL were similar to those of previous studies that used other BP agents. The phenomenon of BMD decreases after termination of TPTD treatment has been reported in clinical and nonclinical studies (Kaufman et al., 2005; Kurland et al., 2004; Sugimoto et al., 2013; Prince et al., 2005; Ejersted et al., 1998; Shahnazari et al., 2011) and prevention of bone loss by BP administration after withdrawal of TPTD has also been reported (Kurland et al., 2004; Sugimoto et al., 2013; Prince et al., 2005; Ejersted et al., 1998; Iwaniec et al., 2001; Samnegard et al., 2001a; Samnegard et al., 2001b). In the present study, the use of ZOL following TPTD treatment increased the BMD of the proximal tibia by approximately 2.9% over 4 months (Fig. 6b), which is similar to the 2.3% increase in lumbar spine BMD over a 1-year period reported in a clinical study of the sequential use of once-weekly TPTD followed by a BP (Sugimoto et al., 2013).
Bisphosphonates (BPs) and teriparatide (TPTD) are both effective treatments for osteoporosis, but BP treatment prior to daily TPTD treatment has been shown to impair the effect of TPTD in some clinical studies. In contrast, the loss of bone mineral density (BMD) that occurs after withdrawal of TPTD can be prevented by BP treatment. Although various studies have investigated the combination and/or sequential use of BP and TPTD, there have been no clinical studies investigating sequential treatment with zoledronic acid (ZOL) and TPTD (or vice versa). In this study, we evaluated the effects of sequential treatment with TPTD followed by ZOL, and ZOL followed by TPTD, using ovariectomized (OVX) rats.
Two months after OVX, osteopenic rats were treated with ZOL, TPTD, or vehicle for a period of 4 months (first treatment period), and then the treatments were switched and administered for another 4 months (second treatment period).
The group treated with ZOL followed by TPTD showed an immediate increase in BMD of the proximal tibia and greater BMD and bone strength of the lumbar vertebral body, femoral diaphysis, and proximal femur than the group treated with ZOL followed by vehicle. Serum osteocalcin, a marker of bone formation, increased rapidly after switching to TPTD from ZOL.
The group treated with TPTD followed by ZOL did not lose BMD in the proximal tibia after TPTD was stopped, while the group treated with TPTD followed by vehicle did lose BMD. The BMD and bone strength of the lumbar vertebral body, femoral diaphysis, and proximal femur were greater in the group treated with TPTD followed by ZOL than in the group treated with TPTD followed by vehicle. The increase in serum osteocalcin and urinary CTX after withdrawal of TPTD was prevented by the switch from TPTD to ZOL.
In conclusion, our results demonstrate that switching from ZOL to TPTD resulted in a non-attenuated anabolic response in the lumbar spine and femur of OVX rats. In addition, switching from TPTD to ZOL caused BMD to be maintained or further increased. If these results can be reproduced in a clinical setting, the sequential use of ZOL followed by TPTD or vice versa in the treatment of osteoporosis patients would contribute to increases in BMD that, hopefully, would translate into a corresponding decrease in the incidence of vertebral and non-vertebral fractures.
Sequential treatment of ovariectomized mice with bFGF and risedronate restored trabecular bone microarchitecture and mineralization
2006, Bone
Basic fibroblast growth factor (bFGF), a potent mitogen, has been found to restore trabecular bone mass and connectivity in osteopenic rats. The purpose of this study was to determine how sequential treatment of ovariectomized (OVXed) mice with bFGF followed by risedronate would restore trabecular microarchitecture and improve bone strength through alterations in bone mineralization. Six-month old female Swiss–Webster mice were OVXed or sham-operated and left untreated for 4 weeks to develop osteopenia. At week 5, a group of Sham and OVXed mice were treated with vehicle, and 3 other groups of OVXed mice were treated with bFGF (1 mg/kg daily, s.c., 5×/week) for 3 weeks. At week 8, one group of bFGF-treated mice was sacrificed and the other two bFGF-treated groups were treated with vehicle or risedronate (Ris, 5 μg/kg, s.c., 3×/week) for an additional 6 weeks. Study endpoints included trabecular microarchitecture by microCT, histomorphometry, bone turnover, degree of bone mineralization (DBM), and whole bone strength for the lumbar vertebral body. Compared to sham-operated animals, OVXed mice had significant reductions in trabecular bone volume, connectivity density, DBM, and bone biomechanical properties (P < 0.05). Treatment with bFGF resulted in higher trabecular bone structure and bone strength compared to pre-treatment sham control (P < 0.05). Treatment of OVXed mice with bFGF for 3 weeks followed by 6 weeks Ris maintained the trabecular microarchitecture gained by bFGF treatment, and DBM and bone strength were restored to baseline control levels. Also compared to Sham-operated animals, serum TGF-β1 was transiently increased after OVX, increased an additional 100% after bFGF withdrawal, and decreased by 30% with risedronate. In addition, DBM was the strongest predictor for bone biomechanical properties (R² > 0.7, P < 0.001). Serum TGF-β1 correlated with bone turnover (DPD/Cr, osteocalcin) and was negatively correlated to DBM. Thus, in osteopenic mice, sequential treatment with bFGF followed by risedronate increased trabecular bone microarchitecture, DBM, and bone strength. In addition, suppression of the serum TGF-β1 with risedronate was associated with increased DBM. Therefore, sequential treatment with bFGF and Ris restores trabecular architecture and allows mineralization of bone to increase, which appears to be beneficial to bone strength.
Developments in parathyroid hormone and related peptides as bone-formation agents
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Osteoporosis is a major and growing healthcare concern. When administered by daily injection, parathyroid hormone (PTH) and its N-terminal fragments and analogs are potent bone-formation agents. Teriparatide, recombinant human PTH(1–34), is likely to be the first anabolic agent approved for treating osteoporosis, despite inducing osteosarcomas in rats. Native PTH and other PTH fragments and analogs are also in development. N-terminal fragments sometimes differ in activity from the native hormone, however, and the C-terminal region of PTH, acting through a receptor different from the classical PTH-1 receptor, initiates a variety of distinct biological activities. In particular, the C-terminal region of PTH, by promoting bone-cell apoptosis, may be important in opposing the anti-apoptotic effects of teriparatide in these cells, thereby maintaining normal bone-cell turnover. Because of these differences, care must be taken to consider the effects of native PTH and N-terminal PTH fragments and analogs separately.
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Maintenance of cancellous bone in ovariectomized, human parathyroid hormone [hPTH(1-84)]-treated rats by estrogen, risedronate, or reduced hPTH

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Bone

Bone

Bone

Bone

Bone

Bone

Lancet

Bone

Bone Miner

Estrogen dose required to maintain parathyroid hormone mediated bone gain in osteopenic ovariectomized rats is probably higher than in preventive treatment with estrogen

Bone

Practical Nonparametric Statistics

Is parathyroid hormone a therapeutic option for osteoporosis? A review of the clinical evidence

Calcif Tissue Int

Anabolic actions of parathyroid hormone on bone

Endocrine Rev

Rapid determination of cancellous bone mineral loss in ovariectomized rats by a subtraction technique

Anat Rec

EstrogenPrevention and treatment of osteoporosis

Human parathyroid hormone-(1-34) increases bone mass in ovariectomized and orchidectomized rats

Endocrinology

Resorption is not essential for the stimulation of bone growth by hPTH-(1-34) in rats in vivo

J Bone Miner Res

Effects of nicotine on bone and calciotropic hormones in growing female rats

Calcif Tissue Int

The effect of recombinant human (1-84) or synthetic human (1-34) parathyroid hormone on the skeleton of adult osteopenic ovariectomized rats

Endocrinology