Bone Responses at Various Skeletal Sites to Human Parathyroid Hormone in Ovariectomized Rats: Effects of Long-term Administration, Withdrawal, and Readministration

Kishi, Takahiro; Hagino, Hiroshi; Kishimoto, Hiroyuki; Nagashima, Hideki

doi:10.1016/s8756-3282(98)00045-3

Cited by 42 publications

(40 citation statements)

References 23 publications

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“…In contrast to the results from lumbar vertebrae, trabecular architecture in caudal vertebrae did not change in response to OVX and ZOL. Our results concur with previous reports on nonresponsiveness to OVX in caudal vertebrae [11,[15][16][17]. It has been suggested that differences in marrow composition between lumbar and caudal vertebrae play a role in responsiveness to OVX [11].…”

Section: Discussionsupporting

confidence: 92%

Influence of Early and Late Zoledronic Acid Administration on Vertebral Structure and Strength in Ovariectomized Rats

2008

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An annual infusion of zoledronic acid (ZOL) reduces fracture risk in osteoporotic patients. Previously, we showed that a single ZOL injection inhibited changes in bone microstructure and strength in rat tibiae after ovariectomy. Here, we determined the effects of a single ZOL injection as preventive and restorative treatment on the bone microstructure and strength in lumbar and caudal vertebrae of ovariectomized (OVX) rats. Twenty-nine female 35-weekold Wistar rats were divided into four groups: SHAM-OVX (n = 9), OVX (n = 5), OVX and early ZOL (n = 8), and OVX and late ZOL (n = 7). ZOL was given once (20 lg/kg body weight s.c.) at OVX in the early ZOL group and 8 weeks later in the late ZOL group; rats were killed 16 weeks after OVX. Trabecular and cortical bone microarchitecture were measured in lumbar (L3) and caudal (Cd6) vertebrae using micro-computed tomography, and compressive mechanical properties were determined in L3 vertebrae. Compared to SHAM-OVX, OVX rats had significantly lower BV/TV; SMI, Tb.N, Tb.Sp, and Conn.D tended to be deteriorated in lumbar vertebrae, while both ZOL groups did not differ from the SHAM-OVX group. Both ZOL groups had significantly higher BV/TV than OVX; the early ZOL group also had significantly lower SMI and higher Tb.Th. OVX tended to decrease mechanical properties, while early and late ZOL treatment inhibited OVX-induced degeneration. Neither OVX nor ZOL induced changes in the trabecular microarchitecture of caudal vertebrae. In summary, in adult rats a single ZOL injection inhibited OVX-induced changes in lumbar vertebral bone microarchitecture and strength.Keywords Bisphosphonate Á Bone architecture/ structure Á Osteoporosis Á Animal model Bisphosphonates inhibit bone resorption and are commonly used to treat osteoporotic patients. They slow the process of bone loss and reduce the risk of fracture by maintaining bone mass and microstructure [1][2][3]. Zoledronic acid (ZOL) is a potent bisphosphonate that has recently been shown to significantly reduce fracture risk in osteoporotic patients who received once-yearly doses [4,5]. As the number and depth of in vivo analyses in patients are limited, animal research is ongoing to further elucidate the effects of ZOL on skeletal fragility [6][7][8][9]. Previously, we showed in a longitudinal study of adult rats that a single injection of ZOL at the time of ovariectomy (OVX) inhibited OVX-induced deterioration of bone microstructure and strength in the proximal tibiae for up to 16 weeks [10]. Furthermore, a single injection of ZOL 8 weeks after OVX inhibited further deterioration of the bone microstructure and strength in rat tibiae compared to untreated OVX rats. Other studies have shown that weekly injections of ZOL inhibit changes in bone microstructure and strength in rat vertebrae after OVX [8,9]. However, it is not known to what extent a single dose of ZOL is able to inhibit and restore OVX-induced loss of bone mass, structure, and strength in rat vertebrae.

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Section: Discussionsupporting

confidence: 92%

Influence of Early and Late Zoledronic Acid Administration on Vertebral Structure and Strength in Ovariectomized Rats

2008

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“…In a study of 9-month-old Sprague-Dawley ovariectomized rats (Sato et al, 1997), equivalent doses of PTH (8 and 40 g/kg) increased femoral midshaft BMD (30 and 47%), BMC (36 and 51%), ultimate load (50 and 74%), stiffness (49 and 74%), strength (24 and 33%), and Young's modulus (21 and 30%), respectively, compared with Ovx. In another study, 6-monthold Wistar rats were ovariectomized for 1 month before PTH treatment for 6 months (Kishi et al, 1998). DXA analysis showed about a 25% increase in BMD for the mid-diaphysis of femora after 6 months of PTH treatment (Kishi et al, 1998), which is comparable with our midshaft BMD data (Fig.…”

Section: Discussionsupporting

confidence: 87%

“…In rats, a single administration of PTH was shown to activate bone cells within minutes by regulation of gene expression, and to increase bone-forming surfaces within 6 to 24 h (Hock et al, 1994;Onyia et al, 1995). PTH skeletal efficacy did not seem to be dependent on rat age because 3-, 6-, and 15-month-old ovariectomized females and aged males responded to PTH by increasing bone mass, architecture, and quality in the spine, femoral neck, and long bones after treatment for 12 days to 9 months (Gasser and Jerome, 1992;Dempster et al, 1993;Sato et al, 1997;Kishi et al, 1998;Kneissel et al, 2001).…”

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confidence: 99%

“…For example, only five studies have evaluated the long-term effects of PTH between 6 to 9 months of treatment (Mosekilde et al, 1994a;Sato et al, 1997;Kishi et al, 1998;Stewart et al, 2000;Kneissel et al, 2001). In addition, previous studies have generally lacked sufficient statistical power with which to evaluate the pathology of PTH on target tissues, with the possible exception of one study (Sato et al, 1997).…”

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confidence: 99%

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Skeletal Efficacy with Parathyroid Hormone in Rats Was Not Entirely Beneficial with Long-Term Treatment

Sato

L²,

Hock³

et al. 2002

J Pharmacol Exp Ther

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We report the consequences of prolonged treatment with recombinant human parathyroid hormone (1-34) (PTH) in male and ovariectomized female rats with mature skeletons. Intact male and osteopenic, ovariectomized, female F-344 rats were evaluated after 1 year of treatment with 0, 8, or 40 g/kg/day s.c. PTH. Males and females were about 6 months of age at study initiation; females were ovariectomized (Ovx) for 5 weeks before initiation of PTH treatment. PTH did not affect the survival of either intact males or ovariectomized females. Qualitative histopathology showed expected changes associated with aging in kidneys and proximal tibiae, with no treatment-related anomalies after 1 year of PTH administration. PTH slightly increased the femoral length of ovariectomized females but not that of males. No significant differences in femoral length were observed between sham and Ovx controls. Proximal femora of the males and ovariectomized females given the high dose of 40 g/kg showed 211 and 186% greater trabecular bone area, 118 and 94% greater cortical thickness, 170 and 189% greater trabecular number, and 321 and 404% greater connectivity (node-to-node struts) compared with respective vehicle controls. Increased trabecular and endocortical surface apposition coincided with a 78 and 70% loss of marrow space for males and females treated with PTH, respectively. Biomechanical strength (ultimate load) of the femoral neck increased by 73 and 76%, respectively, in males and ovariectomized females. Cortical bone analyses of the femoral midshaft showed 105 and 72% increases in bone mineral content, 67 and 55% increases in bone mineral density, and 22 and 10% increases in crosssectional area for males and ovariectomized females, respectively, with altered shape of femora. Biomechanical analyses of the midshaft showed substantial increases in strength and stiffness but a reduction in ultimate strain, which was likely due to the altered geometry of the midshaft for PTH groups. Aging effects on strength of vertebra and femoral midshaft were reversed by PTH treatment. In summary, the 1-year treatment duration, which represents about 50% of lifetime, did not affect survival and was not associated with any treatment-related anomalies in the kidney or skeleton. PTH reversed the aging process in bones but not kidneys and substantially increased bone mass and strength to well beyond normally attained levels. However, compared with short-term studies reported previously, there seemed to be no advantages to extending PTH treatment to 12 months in rat bones.Once daily, subcutaneous administration of human PTH (1-34) stimulates new bone formation in rats, monkeys, and humans (Gasser and Jerome, 1992;Dempster et al

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“…By contrast, an intermittent injection of low-dose parathyroid hormone-derived peptide (TPTD) can effectively stimulate bone formation by increasing osteoblast number and activity via the promotion of the differentiation and survival of osteoblasts, thereby increasing trabecular bone mass and strength (13)(14)(15)(16)(17). In fact, clinical trials show that TPTD increases bone mineral density (BMD) and decreases the fracture risk in females with postmenopausal osteoporosis (18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Effects of the combination of vitamin K and teriparatide on the bone metabolism in ovariectomized rats

et al. 2015

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Abstract. The purpose of the present study was to evaluate the combined effects of vitamin K (VK) and teriparatide (TPTD) on bone mineral density (BMD), mechanical strength and other parameters for bone metabolism using a rat ovariectomized osteoporosis model. Ovariectomized female Sprague-Dawley rats were administered with VK (an oral dose of 30 mg/kg/day), TPTD (a subcutaneous dose of 30 µg/kg, three times a week) or a combination for 8 weeks. Thereafter, serum levels of γ-carboxylated osteocalcin (Gla-OC) were quantitated by ELISA; BMD and mechanical strength were measured by computed tomography and biomechanical testing, respectively at the femoral metaphysis. Additionally, histomorphometry was performed using the toluidine blue-stained coronal sections of distal femur. The combination of VK and TPTD clearly increased the serum levels of Gla-OC (a specific marker for bone formation) and osteoblast surface (the number of osteoblasts attaching with the surface of cancellous bone), compared to VK or TPTD alone. In addition, the combination of the two agents improved the BMD and bone strength of the femur in the ovariectomized rats, compared to VK or TPTD alone. Taken together, these findings suggest that the treatment with VK and TPTD may have a therapeutic advantage over VK or TPTD monotherapy for postmenopausal osteoporosis, possibly by enhancing the bone formation through the actions on OC and osteoblasts.

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Bone Responses at Various Skeletal Sites to Human Parathyroid Hormone in Ovariectomized Rats: Effects of Long-term Administration, Withdrawal, and Readministration

Cited by 42 publications

References 23 publications

Influence of Early and Late Zoledronic Acid Administration on Vertebral Structure and Strength in Ovariectomized Rats

Influence of Early and Late Zoledronic Acid Administration on Vertebral Structure and Strength in Ovariectomized Rats

Skeletal Efficacy with Parathyroid Hormone in Rats Was Not Entirely Beneficial with Long-Term Treatment

Effects of the combination of vitamin K and teriparatide on the bone metabolism in ovariectomized rats

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