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Rhee, Youn, Won, Baek, and Lim: Effect of Sequential Therapy with Incadronate after Withdrawal of Recombinant Human Parathyroid Hormone (1-84) on Bone Quantity and Quality in Ovariectomized Rats
Original Article
Journal of Korean Society of Endocrinology

Journal of Korean Society of Endocrinology 2005; 20(4): 334-343.

Published online: 31 August 2005

DOI: https://doi.org/10.3803/jkes.2005.20.4.334

Effect of Sequential Therapy with Incadronate after Withdrawal of Recombinant Human Parathyroid Hormone (1-84) on Bone Quantity and Quality in Ovariectomized Rats

Yumie Rhee1, Jong Chan Youn1, Ye-Yeon Won2, Myong-Hyun Baek2, Sung-Kil Lim1

1Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea.

2Department of Orthopaedic Surgery, College of Medicine, Ajou University, Suwon, Korea.

Received 18 January 2005       Accepted 24 May 2005

Copyright © 2005 Korean Endocrine Society

Abstract

Background

Human parathyroid hormone (hPTH) is a promising anabolic agent. However, since hPTH (1-34) is available only via injection, and has a critical side effect of causing bone tumors during life-long administration in the rat, it would be practical to use PTH for the shortest possible duration to obtain the maximal effect. In addition, acquired bone mass due to hPTH tend to decrease after drug cessation. To determine the effectiveness of the osteoporosis-reversing concept of lose, restore, and maintain (LRM), recombinant human PTH(1-84) [rhPTH(1-84)] and the respective anti-resorptive agents were sequentially studied.

Methods

Thirty six, 20-week-old, Sprague-Dawley rats were used in this study. Treatment was started on the 25th week after an ovariectomy, which had been performed at 20 weeks of age, with 5 weeks of rhPTH (1-84) 100 (µg/kg/d), 5 days/wk, followed by the respective sequential therapies for 5 weeks as follows: 1) Ovariectomized rats (OVX, n=6), 2) Sham operated rats (SHAM, n=6), 3) OVX rats with PTH maintenance (PTH-M, n=6), 4) OVX rats treated with PTH then withdrawn (PTH-W, n=6), 5) PTH-treated OVX rats then treated with 17β-estradiol (PTH-E, 10 µg/d, SQ, 5 days/wk, n=6), 6) PTH-treated OVX rats then treated with incadronate (PTH-I, 3 mg/kg, per os 5 days/wk, n=6). The bone mineral density (BMD) of the right femurs was measured using dual χ-ray absorptiometry (DXA). Microcomputed tomography (µCT) was used to measure the structural parameters of the 2nd lumbar vertebrae. A three-point bending test of the femur and compressive tests of vertebrae were also performed.

Results

Bone quantity data showed that the femoral BMD was significantly higher in the PTH-M and PTH-I groups than in the OVX and PTH-W groups (P < 0.05). Measurement of the cortical thickness revealed that only the PTH-M group had a significant increase (P = 0.001). The ultimate force (Fu) at the midshaft of the femur was stronger in the PTH-M group than in the OVX group (P < 0.001). However, no significant difference was found among the treated groups.

Conclusion

PTH withdrawal resulted in the loss of the acquired BMD, but sequential therapy with the anti-resorptive, incadronate, prevented further bone loss. The use of incadronate after rhPTH(1-84), as a sequential regimen, was significantly effective on the maintenance in the bone mass, but further clarification in the improvement in the bone quality is needed.

Keywords: Osteoporosis, Sequential therapy, rhPTH(1-84), Incadronate, Microcomputed tomography

Figures and Tables

Fig. 1
Bone mineral density (BMD, g/cm2) of the right femur. *: P < 0.003 vs. OVX, PTH-W & PTH-E, †: P < 0.05 vs. OVX.
jkse-20-334-g001
Fig. 2
Three-dimensional trabecular microstructures of L2 vertebral body from each group.
jkse-20-334-g002
Fig. 3
Cortical thickness of the mid-diaphysis of the femur. *: P = 0.001 vs. OVX
jkse-20-334-g003
Fig. 4
Fmax of right femur. *: P < 0.005 vs. all other groups, †: P = 0.03 vs. SHAM, P = 0.089 vs. PTH-I
jkse-20-334-g004
Table 1
jkse-20-334-i001

Footnote: sac (sacrifice), small dotted line (no treatment), bold line (rhPTH(1-84) treatment), large dotted line (vehicle treatment), broken line with one dot (17β-estradiol treatment), broken line with two dots (incadronate treatment)

Table 2
Effects of Sequential Therapy After RhPTH(1-84) Treatment on the Microstructural Parameters of L2 Vertebrae
jkse-20-334-i002

Footnote:

Results are presented as the mean ± SD.

BV (Bone Volume, mm2), Vol. F (Volume Fraction, %), Surface/volume (1/mm), Tb.Th (Trabecular Thickness, mm), Tb.Sp (Trabecular Separation, mm), Tb.N (Trabecular Node Number), DOA (Degree of Anisotropy), SMI (Structure Model Index)

o: P < 0.001 vs. OVX, w: P < 0.01 vs. PTH-W, e: P < 0.05 vs. PTH-E, s: P < 0.001 vs. SHAM, o': P < 0.05 vs. OVX, s': P < 0.05 vs. SHAM

Table 3
Changes in the Biomechanical Parameters of the Femur after Various Treatment Modality
jkse-20-334-i003

Footnote:

Data are shown as the mean ± SD.

The cortical bones of the femora diaphysis were examined using the three-point bending test to measure the ultimate force (Fu), ultimate stress (οu), stiffness (S), Young's modulus (E) and ultimate strain (εu). I denotes the moment of inertia.

o: P < 0.0001 vs. OVX, s: P < 0.05 vs SHAM, o': P < 0.05 vs. OVX

Table 4
Changes in the Biomechanical Parameters of the Lumbar Vertebrae after Various Treatment Modality
jkse-20-334-i004

Footnote:

Data are shown as the mean ± SD.

L2 vertebrae were loaded to failure in compression, to measure the ultimate force (Fu), ultimate stress (οu), stiffness (S), Young's modulus (E) and ultimate strain (εu)

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