A comparison of parathyroid hormone-related protein (1-36) and parathyroid hormone (1-34) on markers of bone turnover and bone density in postmenopausal women: The PrOP study

Horwitz, Mara J.; Augustine, Marilyn; Kahn, Leila; Martin, E Alavez; Oakley, Christine C; Carneiro, R C G; Tedesco, Mary Beth; Laslavic, Angela; Sereika, Susan M.; Bisello, Alessandro; Garcı́a-Ocaña, Adolfo; Gundberg, Caren M.; Cauley, Jane A.; Stewart, Andrew F.

doi:10.1002/jbmr.1978

Cited by 63 publications

(47 citation statements)

References 37 publications

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“…Whereas constant application acted catabolically on bone, an intermittent application (eg, once daily) provided anabolic effects, resulting in a net increase in bone mass [22,23]. Similar effects were reported for PTHrP [24][25][26] and first clinical trials are conducted to evaluate the benefit of intermittent PTHrP administration for the treatment of osteoporosis [27].…”

mentioning

confidence: 65%

Intermittent PTHrP(1–34) Exposure Augments Chondrogenesis and Reduces Hypertrophy of Mesenchymal Stromal Cells

Fischer

Aulmann

Dexheimer

et al. 2014

Stem Cells and Development

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Phenotype instability and premature hypertrophy prevent the use of human mesenchymal stromal cells (MSCs) for cartilage regeneration. Aim of this study was to investigate whether intermittent supplementation of parathyroid hormone-related protein (PTHrP), as opposed to constant treatment, can beneficially influence MSC chondrogenesis and to explore molecular mechanisms below catabolic and anabolic responses. Human MSCs subjected to chondrogenic induction in high-density culture received PTHrP(1-34), forskolin, dbcAMP, or PTHrP(7-34) either constantly or via 6-h pulses (three times weekly), before proteoglycan, collagen type II, and X deposition; gene expression; and alkaline phosphatase (ALP) activity were assessed. While constant application of PTHrP(1-34) suppressed chondrogenesis of MSCs, pulsed application significantly increased collagen type 2 (COL2A1) gene expression and the collagen type II, proteoglycan, and DNA content of pellets after 6 weeks. Collagen type 10 (COL10A1) gene expression was little affected but Indian hedgehog (IHH) expression and ALP activity were significantly downregulated by pulsed PTHrP. A faster response to PTHrP exposure was recorded for ALP activity over COL2A1 regulation, suggesting that signal duration is critical for catabolic versus anabolic reactions. Stimulation of cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling by forskolin reproduced major effects of both treatment modes, whereas application of PTHrP(7-34) capable of protein kinase C (PKC) signaling was ineffective. Pulsed PTHrP exposure of MSCs stimulated chondrogenesis and reduced endochondral differentiation apparently uncoupling chondrogenic matrix deposition from hypertrophic marker expression. cAMP/PKA was the major signaling pathway triggering the opposing effects of both treatment modes. Intermittent application of PTHrP represents an important novel means to improve chondrogenesis of MSCs and may be considered as a supporting clinical-treatment mode for MSCbased cartilage defect regeneration.

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confidence: 65%

Intermittent PTHrP(1–34) Exposure Augments Chondrogenesis and Reduces Hypertrophy of Mesenchymal Stromal Cells

Fischer

Aulmann

Dexheimer

et al. 2014

Stem Cells and Development

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“…This therapy increases bone formation as opposed to antiresorptive drugs that reduce bone resorption, but the efficacy of this anabolic therapy in terms of fracture reduction has been the same as that of antiresorptive drugs (4). Multiple newer and more potent anabolic agents are currently being evaluated in clinical trials (5)(6)(7), but none of these entities appear to have the potential to rejuvenate the osteoporotic skeleton back to one with normal bone density and strength.…”

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confidence: 99%

PDGFB-based stem cell gene therapy increases bone strength in the mouse

Chen

Baylink

Brier-Jones

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Substantial advances have been made in the past two decades in the management of osteoporosis. However, none of the current medications can eliminate the risk of fracture and rejuvenate the skeleton. To this end, we recently reported that transplantation of hematopoietic stem/progenitor cells (HSCs) or Sca1 + cells engineered to overexpress FGF2 results in a significant increase in lamellar bone matrix formation at the endosteum; but this increase was attended by the development of secondary hyperparathyroidism and severe osteomalacia. Here we switch the therapeutic gene to PDGFB, another potent mitogen for mesenchymal stem cells (MSCs) but potentially safer than FGF2. We found that modest overexpression of PDGFB using a relatively weak phosphoglycerate kinase (PGK) promoter completely avoided osteomalacia and secondary hyperparathyroidism, and simultaneously increased trabecular bone formation and trabecular connectivity, and decreased cortical porosity. These effects led to a 45% increase in the bone strength. Transplantation of PGK-PDGFB-transduced Sca1 + cells increased MSC proliferation, raising the possibility that PDGF-BB enhances expansion of MSC in the vicinity of the hematopoietic niche where the osteogenic milieu propels the differentiation of MSCs toward an osteogenic destination. Our therapy should have potential clinical applications for patients undergoing HSC transplantation, who are at high risk for osteoporosis and bone fractures after total body irradiation preconditioning. It could eventually have wider application once the therapy can be applied without the preconditioning.PDGFB | hematopoietic stem cells | bone formation | gene therapy

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“…A more recent 3-month study carried out on postmenopausal osteoporotic women compared daily subcutaneous injections of synthetic human PTHrP 1-36 (at 400 and 600 μg doses) with PTH 1-34. While PTH induced a greater increase in bone markers, there was no significant difference in BMD changes between groups at any site (11). However, the fact that the PTH 1-36 needs to be administered at a much higher dosage compared to teriparatide and produces an increased number of episodes of hypercalcemia, has moved the interest of researchers towards a novel synthetic analog of human PTHrP 1-34 (BA058 or abaloparatide) which is currently being assessed as a new treatment for osteoporosis.…”

Section: Pthrp Analogs and Bonementioning

confidence: 77%

Abaloparatide

Gonnelli¹

2016

ccmbm

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SummaryAbaloparatide is an investigational analog of human PTHrP (1-34) being developed for the treatment of osteoporosis. The amino-acid sequence of abaloparatide is identical to that of PTHrP in the first 20 amino-acids, while over half of the remaining amino-acids are different. Some studies in animals and in humans reported that abaloparatide presented a potent anabolic activity with reduced effects on bone resorption as compared to that observed with teriparatide. This may be due to a more transient signaling response of abaloparatide related to differing affinities of the two drugs to the specific conformations of the PTH1 receptor. In the ACTIVE study, a phase 3 fracture prevention trial, 2460 postmenopausal osteoporotic women at high risk for fracture were randomized to receive 18-months of either daily abaloparatide 80 μg s.c., placebo or teriparatide 20 μg s.c. The reduction in vertebral fracture rate with respect to placebo was 86% in the abaloparatide group and 80% in the teriparatide group. Abaloparatide also produced a significant 43% reduction in the rate of nonvertebral fractures (2.7 vs 4.0% with placebo, p=0.04) whereas teriparatide determined a 28% reduction (2.9 vs 4.0% with placebo, p=NS). Abaloparatide or teriparatide showed similar increases in BMD at lumbar spine, while the patients of the abaloparatide group showed significantly greater increases in BMD at both total hip (4.18 vs 3.26%) and femoral neck (3.60 vs 2.66%). Therefore, if the preliminary data of the AC-TIVE study is confirmed, abaloparatide may become an important option for the anabolic treatment of postmenopausal osteoporosis.

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A comparison of parathyroid hormone-related protein (1-36) and parathyroid hormone (1-34) on markers of bone turnover and bone density in postmenopausal women: The PrOP study

Cited by 63 publications

References 37 publications

Intermittent PTHrP(1–34) Exposure Augments Chondrogenesis and Reduces Hypertrophy of Mesenchymal Stromal Cells

Intermittent PTHrP(1–34) Exposure Augments Chondrogenesis and Reduces Hypertrophy of Mesenchymal Stromal Cells

PDGFB-based stem cell gene therapy increases bone strength in the mouse

Abaloparatide

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