Effect of intermittent administration of human parathyroid hormone on bone mineral density and arthritis in rats with collagen‐induced arthritis

Fukata, Satoru; Hagino, Hiroshi; Okano, T.; Yamane, Itsuro; Kameyama, Yasuhiro; Teshima, Ryota

doi:10.1002/art.20728

Cited by 20 publications

(16 citation statements)

References 38 publications

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“…On the other hand, intermittent daily injection with the N-terminal 1-34 fragment of human PTH (hPTH1-34) is an approved anabolic therapy for the treatment of osteoporosis (Reeve et al 1980, Lindsay et al 1997, Duan et al 1999, Cosman et al 2001, Chen et al 2003, Finkelstein et al 2003, Fukata et al 2004, Dobnig 2004. Infusion of hPTH1-34 (0·55 U/kg per h or 25 µg/24 h) to normal and osteoporotic women suppressed endogenous intact human PTH (hPTH1-84) secretion, decreased bone formation and increased boneresorption markers (Cosman et al 1991).…”

Section: Introductionmentioning

confidence: 99%

“…Regarding the anabolic action, it has been well established that intermittent treatment with PTH, both N-terminal 1-34 fragment and intact 1-84 peptide, is anabolic in a range of species including mice (Jilka et al 1999, Alexander et al 2001, Andersson et al 2001, Iida-Klein et al 2002, Fukata et al 2004, Rhee et al 2004, Seebach et al 2004. However, there are very few studies that demonstrate the catabolic effects of continuously elevated PTH on bone in mice.…”

Section: Introductionmentioning

confidence: 99%

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Short-term continuous infusion of human parathyroid hormone 1–34 fragment is catabolic with decreased trabecular connectivity density accompanied by hypercalcemia in C57BL/J6 mice

Iida-Klein

Lu²,

Kapadia³

et al. 2005

Journal of Endocrinology

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Parathyroid hormone (PTH) stimulates bone resorption as well as bone formation in vivo and in organ culture. The catabolic actions of PTH have been recognized in patients with hyperparathyroidism, or with acute infusion of the N-terminal 1-34 fragment of human PTH (hPTH1-34). Whereas the anabolic actions of daily injection with PTH have been well studied in both humans and mice, the catabolic actions of PTH on murine bone remain to be defined. To do this we sought to create a model with short-term, sustained hyperparathyroidism using osmotic infusion pumps. We treated 10-week-old female C57BL/J6 mice with continuous infusion of hPTH1-34 (8·1 pmol/0·25 µl per h, equivalent to 40 µg/kg per day) or vehicle for 2 weeks, using Alzet osmotic pumps. Bone mineral density (BMD), serum total calcium, hPTH1-34, mouse intact PTH (mPTH1-84), osteocalcin and mouse tartrate-resistant acid phosphatase (mTRAP) activity, and microarchitectural variables of the distal femur were measured. Separately, we compared the effects of intermittent daily injection of hPTH1-34 (40 µg/kg per day) with continuous infusion of hPTH1-34 on BMD and bone markers. Exogenous hPTH1-34 was detected only in the PTH-infused mice. Both intermittent and continuous treatment with hPTH1-34 markedly suppressed endogenous mPTH1-84, but only the latter induced hypercalcemia. Daily PTH injection significantly increased both serum osteocalcin and mTRAP, while continuous PTH infusion showed a strong trend to stimulate mTRAP, with a slight but non-significant increase in osteocalcin. There were significant differences in BMD at all sites between animals treated with the same daily dose of intermittent and continuous hPTH1-34. Microcomputed tomography (µCT) analysis of the distal femurs revealed that hPTH1-34 infusion significantly decreased trabecular connectivity density (P<0·05). Thus, the murine bone response to continuous PTH infusion was quite different from that seen with daily PTH injection. Short-term infusion of hPTH1-34 appears to be a good model to study the mechanisms underlying the catabolic action of PTH in mice.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Short-term continuous infusion of human parathyroid hormone 1–34 fragment is catabolic with decreased trabecular connectivity density accompanied by hypercalcemia in C57BL/J6 mice

Iida-Klein

Lu²,

Kapadia³

et al. 2005

Journal of Endocrinology

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“…Continuous PTH infusion, similar to the condition of hyperparathyroidism, initiates bone catabolism by enhancing resorption and decreasing formation. In contrast, when administered intermittently (by daily injection), PTH promotes bone formation, as measured by increased bone mass and enhanced mechanical properties [1][2][3][4][5] abstract. The anabolic effect of intermittent PTH on bone is variable depending on the species studied, duration/mode of administration, and location of skeletal response investigated.…”

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confidence: 99%

Short-term intermittent PTH 1-34 administration enhances bone formation in SCID/Beige mice

et al. 2010

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Parathyroid hormone (Pth) is an 84 amino acid polypeptide secreted by parathyroid glands in response to low serum calcium. The exogenous administration of PTH can induce both anabolic and catabolic actions in bone; however, such consequences depend upon how PTH is administered. Continuous PTH infusion, similar to the condition of hyperparathyroidism, initiates bone catabolism by enhancing resorption and decreasing formation. In contrast, when administered intermittently (by daily injection), PTH promotes bone formation, as measured by increased bone mass and enhanced mechanical properties [1][2][3][4][5] abstract. The anabolic effect of intermittent PTH on bone is variable depending on the species studied, duration/mode of administration, and location of skeletal response investigated. We tested the hypothesis that low dose, short term, intermittent PTH 1-34 administration is sufficient to enhance bone formation without altering bone resorption. To test our hypothesis, mice were treated intermittently with one of three concentrations of PTH 1-34 (1 μg/kg, low; 10 μg/kg or 20 μg/kg, high) for three weeks. The skeletal response was identified by quantifying: serum markers of bone turnover, cancellous bone parameters in distal femur, proximal tibia, and lumbar vertebrae by µCT, and number of osteoblasts and osteoclasts in distal femur. Mice receiving 20 μg/kg of PTH 1-34 demonstrated a 30% increase in serum osteocalcin, but no differences in serum calcium, type I collagen teleopeptides, or TRACP 5b. For all bones, µCT analysis suggested mice receiving 20 μg/kg of PTH 1-34 had increased cancellous bone mineral density, trabecular thickness and spacing, but decreased trabecular number. A 60% increase in the number of alkaline phosphatase positive osteoblasts in the distal femur was also observed in tissue sections; however, the number of TRAP positive osteoclasts was not different between test and control groups. While animals administered 10 μg/kg demonstrated similar trends for all bone turnover indices, such alterations were not observed in animals administered PTH 1-34 at 1 μg/kg per day. Thus, PTH 1-34, administered intermittently for three weeks at 20 μg/kg is sufficient to enhance bone formation without enhancing resorption.Key words: Parathyroid hormone, Bone turnover, SCID/Beige mouse, Microcomputed tomography full length peptide, the first 34 amino acids (1-34) are sufficient for its biological activity in bone [3,[6][7][8].Daily PTH 1-34 administration, similar to the full length peptide, is thought to increase bone formation primarily by enhancing the number of bone forming osteoblasts [9]. The anabolic action of intermittent PTH 1-34 on the skeleton has been studied widely in rodent models [10][11][12][13][14][15][16][17]. Studies employing murine models suggest the skeletal response to exogenous PTH 1-34 varies depending on the dose and duration of administration, as well as the mouse strain, age, and skeletal site investigated. Investigations of PTH 1-34 action on bone have employed doses ranging from ...

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“…263910; Difco, Detroit, MI, USA) were injected subcutaneously at three sites on the back of each rat. For additional sensitization, 0.5 ml of the same emulsion was injected subcutaneously at two sites on the posterior aspects of both hip joints 1 week after the initial sensitization [8][9][10][11][12]. In the CONT group, physiologic saline was injected subcutaneously, using the same volume and methods applied for the other two groups.…”

Section: Animalsmentioning

confidence: 99%

“…The parameters of measurement were determined as follows: Contmode 2, peelmode 20, cortmode 1, and threshold 0.63 for cancellous BMD (mg/cm 3 ) and 0.93 for cortical BMD (mg/cm 3 ) [8,12,13]. Coefficients of variation (CVs) for this measurement with repositioning were 2.8% for cancellous bone and 3.3% for cortical bone [8,12,13].…”

Section: Measurement Of Bone Mineral Densitymentioning

confidence: 99%

Effect of estrogen replacement therapy on arthritis and bone mineral density in estrogen-replete rats with collagen-induced arthritis

Yoshioka¹,

Hagino²,

Yamasaki³

et al. 2007

Mod Rheumatol

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The influence of estrogen therapy on changes in arthritis and bone mineral density (BMD) was evaluated using an estrogen-replete collagen-induced arthritis (CIA) rat model. Seven-month-old female Sprague-Dawley rats (n = 30) were divided into the three groups; control (CONT), collagen sensitization (CIA), and CIA + 17beta-estradiol administration for 7 weeks (CIA + E). BMD was measured by peripheral quantitative computed tomography in the proximal tibia every 2 weeks. Eight weeks after the initial sensitization the rats were killed and histomorphometry of tibia was performed. The hind paw thickness increased with time in CIA rats and there was a significant difference between CONT and CIA at 8 weeks after the initial sensitization. Estrogen tended to make the development of arthritis milder. In CIA, BMD at metaphyseal cancellous bone began to decrease with the onset of arthritis and became significantly lower than in CONT after 8 weeks. Compared with the CIA, the deterioration in BMD was inhibited in CIA + E. Histomorphometrical parameters of bone resorption were increased in CIA compared with CONT, and those elevations were reduced by estrogen treatment, but estrogen had no effect on bone formation parameters. In conclusion, estrogen could partially suppress arthritis and bone loss in estrogen-replete rats as well as estrogen-deplete ones.

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Effect of intermittent administration of human parathyroid hormone on bone mineral density and arthritis in rats with collagen‐induced arthritis

Abstract: Our findings indicate that, in an animal model of arthritis, intermittent PTH administration activates bone formation, resulting in increased BMD and preventing deterioration of mechanical properties. However, PTH has no effect on the arthritis itself.

Cited by 20 publications

References 38 publications

Short-term continuous infusion of human parathyroid hormone 1–34 fragment is catabolic with decreased trabecular connectivity density accompanied by hypercalcemia in C57BL/J6 mice

Short-term continuous infusion of human parathyroid hormone 1–34 fragment is catabolic with decreased trabecular connectivity density accompanied by hypercalcemia in C57BL/J6 mice

Short-term intermittent PTH 1-34 administration enhances bone formation in SCID/Beige mice

Effect of estrogen replacement therapy on arthritis and bone mineral density in estrogen-replete rats with collagen-induced arthritis

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