Intermittent Ibandronate Maintains Bone Mass, Bone Structure, and Biomechanical Strength of Trabecular and Cortical Bone After Discontinuation of Parathyroid Hormone Treatment in Ovariectomized Rats

Abstract

Although parathyroid hormone (PTH) expresses an anabolic effect on bone mass, the increased bone mass disappears once PTH treatment is withdrawn. Therefore, sequential treatment with anti-bone-resorptive agents is required to maintain bone mass after PTH treatment. We examined the effect of sequential treatment with ibandronate (IBN), a nitrogen-containing bisphosphonate, following PTH in ovariectomized (OVX) rats. Wistar-Imamichi rats (27 weeks old) were ovariectomized and treated with PTH (10 µg/kg, s.c.; 5 times/week; PTH group) for 8 weeks from 8 weeks after OVX. Thereafter, PTH was withdrawn and rats were administered IBN (10 µg/kg, s.c.; every 4 weeks; PTH-IBN group) or vehicle (PTH-Veh group) for another 8 weeks. PTH increased bone mineral density (BMD) measured by dual-energy X-ray absorptiometry and biomechanical strength in the lumbar spine and femur as compared to the disease control rats. BMD and biomechanical strength in the PTH-Veh group were lower than in the PTH group, whereas in the PTH-IBN group they were maintained at the level of the PTH group. Microstructure of the trabecular and cortical bone in the PTH-IBN group was not significantly different from that in the PTH group. In histomorphometric analysis of the lumbar vertebra, eroded surface and osteoclast surface in the PTH-Veh group were no different from those in the PTH group, whereas they were lower in the PTH-IBN group. Osteoid surface, osteoblast surface, and mineralize surface decreased in both PTH-IBN and PTH-Veh groups compared to the PTH group, and these parameters in the PTH-IBN group were lower than in the PTH-Veh group. These results indicated that intermittent IBN after PTH treatment suppressed bone turnover and maintained BMD, biomechanical strength, and microstructure in the lumbar spine and femur of OVX rats.

Sequential Treatment with Eldecalcitol After PTH Improves Bone Mechanical Properties of Lumbar Spine and Femur in Aged Ovariectomized Rats

“…Although the dosage of PTH in this study was lower than that of other groups [27,28], we select this dose as a suitable dose to evaluate the bone volume or strength in OVX rats. Indeed, our previous studies using same PTH doses with this study, BV/TV in PTH group were almost same as Sham group [13,29]. The difference of age of rats or experimental condition might influence to the anabolic effects of PTH.…”

“…Several reports have demonstrated the usefulness of sequential treatment with anti-bone-resorptive agents such as SERMs or bisphosphonate after PTH treatment in animal models [11,12]. We also reported that ibandronate, a nitrogen-containing bisphosphonate, suppressed bone turnover and maintained BMD in ovariectomized (OVX) rats that had been pretreated with PTH [13].…”

“…ELD dissolved in medium-chain fatty acid was administered orally at a dose of 20 ng/kg, five times a week. The doses of PTH and ELD were determined by previous reports as a suitable dose to evaluate the bone volume or strength in OVX rats [13,19]. Animals were euthanized by exsanguination under isoflurane anesthesia and their lower limbs and lumbar spines were collected at time points of Pre (Sham-Pre group; N = 7, OVX-Pre group; N = 8), Wk 4 (Sham; N = 8, OVX; N = 10, and PTH; N = 10 groups), and Wk 8 (PTH-PTH; N = 11, PTH-ELD; N = 11, and PTH-Veh; N = 11 groups).…”

Histological Effects of the Combined Administration of Eldecalcitol and a Parathyroid Hormone in the Metaphyseal Trabeculae of Ovariectomized Rats

“…Nine-week-old female Wistar rats either underwent an ovariectomy (OVX) or Sham operation. The rats were divided into the following groups with eight to nine animals each and treated from 4 weeks after operation (13 weeks old): Sham group (Sham operated), OVX group, PTH group (OVX administered 10 µg/kg/day of hPTH(1-34) five times per week; the dosage of the drug was decided according to the previous reports [20][21] ) (Peptide Institute Inc., Osaka, Japan), eldecalcitol group (OVX administered 20 ng/kg/day of eldecalcitol five times per week, as reported by Takeda et al 22 ), or a combined group (OVX administered 10 μg/kg/day of hPTH(1-34) and 20 ng/kg/day of eldecalcitol for 4 or 8 weeks). This study was performed according to the experimental protocol approved by the Institutional Animal Care and Use Committee at Chugai Pharmaceutical Co., Ltd.…”

Effect of osteoporosis treatment agents on the cortical bone osteocyte microenvironment in adult estrogen-deficient, osteopenic rats

“…Osteoporosis treatment agents may alter cortical bone matrix. This can be inferred from measurements of ultimate stress ( Ardawi et al, 2016 ; Wang et al, 2011 ; Bahar et al, 2016 ; Takeda et al, 2017 ), a whole bone biomechanical strength endpoint that indirectly reflects bone material properties including those of bone matrix, and more direct methods such as nanoindentation testing ( Yang et al, 2013 ; Brennan et al, 2009a ) and FTIRI (Fourier transform infrared imaging) ( Gamsjaeger et al, 2011 ). Separate studies report that osteoporosis treatment agents can also alter the bone response to mechanical loading ( Roberts et al, 2009 ; Hagino et al, 2001 ).…”