Effects of Two Treatment Regimes with Synthetic Human Parathyroid Hormone Fragment on Bone Formation and the Tissue Balance of Trabecular Bone in Greyhounds

Abstract

The adult greyhound was found to be similar to adult man with respect to kinetic and histomorphometric indices of calcium metabolism. The relationship between trabecular bone tissue balance and the pattern of human PTH fragment 1-34 (hPTH 1-34) administration by daily injections or continuous sc infusions was investigated in this model and the results compared to those from a clinical trial of hPTH 1-34 in involutional osteoporosis (peptide administration by single daily injections). In the dogs, the daily injection regime elevated plasma levels of immunoreactive hPTH 1-34 for no more than 4 h/day. The greyhounds so treated showed significantly increased indices of bone formation (surface osteoid, plasma alkaline phosphatase activity, and skeletal accretion rate of calcium) and resorption (number of osteoclasts, resorption surfaces). Iliac trabecular bone volume increased significantly, as it did in the patients. The infusions did not significantly increase the trabecular bone volume or the 47Ca accretion rate, two parameters which increased in parallel in dogs and patients treated successfully by daily injections. The osteoclastic surfaces, however, were clearly increased by continuous infusions, while the increases in the osteoblastic surfaces were less statistically significant. Since hPTH 1-34 may inhibit osteogenesis in Friedenstein chambers, it is possible that the increased osteoblastic activity induced by the daily injection regime in trabecular bone is dependent on the noncontinuous nature of the PTH stimulus.

Stimulation of cell proliferation in skeletal tissues of the rat by defined parathyroid hormone fragments

“…The increases are dose-and time-dependent, as shown previously using in vitro models of chondrocytes [32] and both osteoblast-enriched calvaria cell cultures and ROS 17/2.8 osteoblast-like cells [33]. These results are in accord with data in vivo for stimulation of proliferation by bPTH-(1-84) and bPTH-(1-34) in ovariectomized rats [38] and intact rats [30,38,39], dogs [4] and humans [30]. The fact that the mid-region fragments hPTH-(28-48) and hPTH-(25-39) can induce bone cell proliferation is of particular interest, since they do not stimulate cyclic AMP formation [32,33], which serves as an intracellular messenger for the osteolytic response to PTH [40].…”

“…Parathyroid hormone (PTH) has been shown to stimulate both formation [1] and resorption [2] of bone; the result of prolonged PTH treatment in vivo is an increase in bone turnover [3,4]. However, specific binding of PTH can be demonstrated only in osteoblasts [5] and osteoclast precursor cells [6], but not in mature osteoclasts.…”

Stimulation of creatine kinase activity in rat skeletal tissue in vivo and in vitro by protease-resistant variants of parathyroid hormone fragments

“…Parathyroid hormone (PTH) acts by different pathways in skeletal tissues to stimulate bone turnover [1,2] leading to either net bone formation [3][4][5][6] (for a review see ref. [7]) or net bone resorption [8][9][10] depending on cell type, dose and schedule of administration.…”

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

“…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].…”

“…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].…”