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Biochemical Pharmacology Oct 2021Parathyroid hormone (PTH) is an 84-amino-acid peptide hormone that is secreted by the parathyroid gland. It has different administration modes in bone tissue through... (Review)
Review
Parathyroid hormone (PTH) is an 84-amino-acid peptide hormone that is secreted by the parathyroid gland. It has different administration modes in bone tissue through which it promotes bone formation (intermittent administration) and bone resorption (continuous administration) and has great potential for application in sbone defect repair. PTH regulates bone metabolism by binding to PTH1R. PTH plays an osteogenic role by acting directly on mesenchymal stem cells, cells with an osteoblastic lineage, osteocytes, and T cells. It also participates as an osteoclast by indirectly acting on osteoclast precursor cells and osteoclasts and directly acting on T cells. In these cells, PTH activates the Wnt signaling, cAMP/PKA, cAMP/PKC, and RANKL/RANK/OPG pathways and other signaling pathways. Although PTH(1-34), also known as teriparatide, has been used clinically, it still has some disadvantages. Developing improved PTH-related peptides is a potential solution to teriparatide's shortcomings. The action mechanism of these PTH-related peptides is not exactly the same as that of PTH. Thus, the mechanisms of PTH and PTH-related peptides in bone metabolism were reviewed in this paper.
Topics: Animals; Bone Density; Bone Resorption; Humans; Osteoclasts; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Receptor, Parathyroid Hormone, Type 1; Teriparatide
PubMed: 34224692
DOI: 10.1016/j.bcp.2021.114669 -
Current Osteoporosis Reports Apr 2017The purpose is to review the efficacy and optimal use of parathyroid hormone and parathyroid hormone-related protein analogs in osteoporosis treatment. (Review)
Review
PURPOSE OF REVIEW
The purpose is to review the efficacy and optimal use of parathyroid hormone and parathyroid hormone-related protein analogs in osteoporosis treatment.
RECENT FINDINGS
The parathyroid hormone analog teriparatide, a potent stimulator of bone remodeling, increases hip and spine bone mineral density and reduces the risk of vertebral and non-vertebral fractures in postmenopausal osteoporotic women. The parathyroid hormone-related protein analog, abaloparatide, also reduces fracture incidence but has pharmacological effects that differ from teriparatide, particularly in cortical bone. These analogs provide maximal benefit when their use is followed by a potent antiresorptive medication. Moreover, studies have shown that the combination of teriparatide and the RANK-ligand inhibitor, denosumab, increase bone density and estimated strength more than monotherapy and more than any currently available regimen. Parathyroid hormone and parathyroid hormone-related protein analogs, whether as monotherapy, in combination with antiresorptive agents or in sequence with antiresorptive agents, will likely play an expanding role in osteoporosis management.
Topics: Bone Density; Bone Density Conservation Agents; Denosumab; Drug Therapy, Combination; Humans; Osteoporosis; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Spinal Fractures; Teriparatide
PubMed: 28303448
DOI: 10.1007/s11914-017-0353-4 -
Journal of Orthopaedic Research :... Oct 2018Delayed healing and/or non-union occur in approximately 5-10% of the fractures that occur annually in the United States. Segmental bone loss increases the probability of... (Review)
Review
Delayed healing and/or non-union occur in approximately 5-10% of the fractures that occur annually in the United States. Segmental bone loss increases the probability of non-union. Though grafting can be an effective treatment for segmental bone loss, autografting is limited for large defects since a limited amount of bone is available for harvest. Parathyroid hormone (PTH) is a key regulator of calcium homeostasis in the body and plays an important role in bone metabolism. Presently PTH is FDA approved for use as an anabolic treatment for osteoporosis. The anabolic effect PTH has on bone has led to research on its use for bone regeneration applications. Numerous studies in animal models have indicated enhanced fracture healing as a result of once daily injections of PTH. Similarly, in a human case study, non-union persisted despite treatment attempts with internal fixation, external fixation, and autograft in combination with BMP-7, until off label use of PTH1-84 was utilized. Use of a biomaterial scaffold to locally deliver PTH to a defect site has also been shown to improve bone formation and healing around dental implants in dogs and drill defects in sheep. Thus, PTH may be used to promote bone regeneration and provide an alternative to autograft and BMP for the treatment of large segmental defects and non-unions. This review briefly summarizes the unmet clinical need for improved bone regeneration techniques and how PTH may help fill that void by both systemically and locally delivered PTH for bone regeneration applications. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2586-2594, 2018.
Topics: Bone Regeneration; Fractures, Ununited; Humans; Parathyroid Hormone
PubMed: 29926970
DOI: 10.1002/jor.24075 -
Rheumatic Diseases Clinics of North... Nov 2006PTH is an exciting new treatment option for postmenopausal women and hypogonadal men who have osteoporosis. As an anabolic agent that affects bone metabolism, it... (Review)
Review
PTH is an exciting new treatment option for postmenopausal women and hypogonadal men who have osteoporosis. As an anabolic agent that affects bone metabolism, it represents an entirely new class of medication for osteoporosis and a novel approach to reducing fracture risk. Numerous clinical trials have demonstrated increases in trabecular and cortical BMD (trabecular more than cortical) in men and women, and reduction in vertebral and nonvertebral fractures in postmenopausal women. Studies suggest that it is safe for use for up to 2 years, but further studies are needed to tes longer intervals of use. Although the combination of PTH and bisphosphonates does not seem to be additive, sequential therapy of PTH followed by bisphosphonate yields maximum gains in BMD compared with combined use or monotherapy with antiresorptive agents. As our knowledge of PTH grows, this is an exciting time for researchers, clinicians, and patients who study, treat, and live with the devastating consequences of progressive osteoporosis.
Topics: Female; Humans; Male; Osteoporosis; Parathyroid Hormone
PubMed: 17288973
DOI: 10.1016/j.rdc.2006.07.005 -
Molecular Metabolism Jun 2022Late in the nineteenth century, it was theorized that a circulating product produced by the parathyroid glands could negatively impact skeletal homeostasis. A century... (Review)
Review
BACKGROUND
Late in the nineteenth century, it was theorized that a circulating product produced by the parathyroid glands could negatively impact skeletal homeostasis. A century later, intermittent administration of that protein, namely parathyroid hormone (PTH), was approved by the FDA and EMA as the first anabolic agent to treat osteoporosis. Yet, several unanswered but important questions remain about the skeletal actions of PTH.
SCOPE OF REVIEW
Current research efforts have focused on improving the efficacy of PTH treatment by designing structural analogs and identifying other targets (e.g., the PTH or the calcium sensing receptor). A unique but only recently described aspect of PTH action is its regulation of cellular bioenergetics and metabolism, namely in bone and adipose tissue but also in other tissues. The current review aims to provide a brief background on PTH's previously described actions on bone and highlights how PTH regulates osteoblast bioenergetics, contributing to greater bone formation. It will also shed light on how PTH could alter metabolic homeostasis through its actions in other cells and tissues, thereby impacting the skeleton in a cell non-autonomous manner.
MAJOR CONCLUSIONS
PTH administration enhances bone formation by targeting the osteoblast through transcriptional changes in several pathways; the most prominent is via adenyl cyclase and PKA. PTH and its related protein, PTHrP, also induce glycolysis and fatty acid oxidation in bone cells and drive lipolysis and thermogenic programming in adipocytes; the latter may indirectly but positively influence skeletal metabolism. While much work remains, alterations in cellular metabolism may also provide a novel mechanism related to PTH's temporal actions. Thus, the bioenergetic impact of PTH can be considered another of the myriad anabolic effects of PTH on the skeleton. Just as importantly from a translational perspective, the non-skeletal metabolic effects may lead to a better understanding of whole-body homeostasis along with new and improved therapies to treat musculoskeletal conditions.
Topics: Bone and Bones; Homeostasis; Osteoblasts; Parathyroid Glands; Parathyroid Hormone
PubMed: 35338013
DOI: 10.1016/j.molmet.2022.101480 -
Annual Review of Physiology 1967
Review
Topics: Animals; Humans; Parathyroid Glands; Parathyroid Hormone
PubMed: 5335437
DOI: 10.1146/annurev.ph.29.030167.002025 -
Science Translational Medicine Nov 2023Low back pain (LBP) is one of the most prevalent diseases affecting quality of life, with no disease-modifying therapy. During aging and spinal degeneration, the balance...
Low back pain (LBP) is one of the most prevalent diseases affecting quality of life, with no disease-modifying therapy. During aging and spinal degeneration, the balance between the normal endplate (EP) bilayers of cartilage and bone shifts to more bone. The aged/degenerated bony EP has increased porosity because of osteoclastic remodeling activity and may be a source of LBP due to aberrant sensory innervation within the pores. We used two mouse models of spinal degeneration to show that parathyroid hormone (PTH) treatment induced osteogenesis and angiogenesis and reduced the porosity of bony EPs. PTH increased the cartilaginous volume and improved the mechanical properties of EPs, which was accompanied by a reduction of the inflammatory factors cyclooxygenase-2 and prostaglandin E. PTH treatment furthermore partially reversed the innervation of porous EPs and reversed LBP-related behaviors. Conditional knockout of PTH 1 receptors in the nucleus pulposus (NP) did not abolish the treatment effects of PTH, suggesting that the NP is not the primary source of LBP in our mouse models. Last, we showed that aged rhesus macaques with spontaneous spinal degeneration also had decreased EP porosity and sensory innervation when treated with PTH, demonstrating a similar mechanism of PTH action on EP sclerosis between mice and macaques. In summary, our results suggest that PTH treatment could partially reverse EP restructuring during spinal regeneration and support further investigation into this potentially disease-modifying treatment strategy for LBP.
Topics: Mice; Animals; Parathyroid Hormone; Low Back Pain; Macaca mulatta; Quality of Life; Disease Models, Animal
PubMed: 37967203
DOI: 10.1126/scitranslmed.adg8982 -
Medicina (Kaunas, Lithuania) 2004Parathyroid hormone naturally secreted by the parathyroid glands is a potent anabolic agent for bone. Parathyroid hormone is primarily thought of as a catabolic protein... (Review)
Review
Parathyroid hormone naturally secreted by the parathyroid glands is a potent anabolic agent for bone. Parathyroid hormone is primarily thought of as a catabolic protein involved in the physiologic release of calcium from bone. Whereas during recent years, a number of animal studies and clinical trials have demonstrated that intermittent parathyroid hormone administration induces anabolic effects on both cancellous and cortical bone, enhances bone mass and increases mechanical strength of the bones. Most of the studies, both animal and human, have addressed the treatment of osteoporosis and parathyroid hormone represents an important new advance in the therapy of osteoporosis. Few studies have investigated the effect of intermittent parathyroid hormone treatment in the field of orthopedics on fracture healing and fixation of orthopedic implants. The results of those studies indicated an enhancement of fracture healing, faster bone repair and better fixation of the implant. Recently there were few animal studies started to investigate the effects of parathyroid hormone treatment on bone formation in regenerated and surrounding bone of distracted callus during limb lengthening. Distraction osteogenesis is a technique for bone lengthening that is widely used clinically and experimentally. Newly forming bone during distraction osteogenesis is expected to be an appropriate pattern for parathyroid hormone anabolic effect. Preclinical studies as well as clinical trials suggest that parathyroid hormone might be useful as a stimulator of bone formation whereas a lot of questions regarding parathyroid hormone therapy remain unanswered and require further experimental studies and investigations.
Topics: Animals; Bone Lengthening; Bony Callus; Controlled Clinical Trials as Topic; Disease Models, Animal; Dogs; Female; Forecasting; Fracture Healing; Haplorhini; Humans; Leg Length Inequality; Orthopedics; Osteogenesis; Osteoporosis; Parathyroid Hormone; Rabbits; Rats; Time Factors
PubMed: 15456969
DOI: No ID Found -
Archives of Internal Medicine Nov 2002Osteoporosis is a common condition associated with multiple deleterious consequences. No therapy entirely abolishes fracture risk. (Review)
Review
BACKGROUND
Osteoporosis is a common condition associated with multiple deleterious consequences. No therapy entirely abolishes fracture risk.
METHODS
A MEDLINE database (1966 to the present) search was performed for randomized controlled trials in humans using the keywords osteoporosis and parathyroid hormone (PTH) or parathyroid hormone and fracture. The Cochrane database was searched using the search terms osteoporosis and parathyroid hormone.
RESULTS
Parathyroid hormone (usually subcutaneous) dosages varied markedly across the 20 randomized controlled trial studies retrieved. In the range of 50 to 100 micro g/d, effects may be dose-related. Results of larger trials (up to 1637 patients) were conflicting as to whether effects were limited to the spine and suggested detrimental effects on radius bone mineral density. Little data analyzed the effects of PTH in older vs younger subjects or directly compared the effects by sex. Increases in spine bone mineral density are induced by PTH in postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, and idiopathic osteoporosis. Parathyroid hormone may protect against gonadotropin-releasing hormone agonist-related bone loss. Effects are less clear at nonspine sites when PTH is used as part of combination or sequential therapies or for treatment of glucocorticoid-induced osteoporosis. Parathyroid hormone decreased the incidence of radiographically detected spinal fractures. The numbers of nonvertebral fractures were too low to be broken down by individual site. Parathyroid hormone injections were difficult for some patients to comply with. Occasionally, PTH-associated hypercalcemia may be dose-dependent, often manifesting early in treatment. An increase in cancer risk from PTH is not reported in humans.
CONCLUSIONS
Parathyroid hormone decreases vertebral fractures and increases spinal bone density in postmenopausal osteoporosis and glucocorticoid-induced osteoporosis, but at the expense of a decrease in radius bone density. The long-term safety and nonvertebral fracture efficacy are unknown.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Osteoporosis; Parathyroid Hormone
PubMed: 12418944
DOI: 10.1001/archinte.162.20.2297 -
Current Osteoporosis Reports Dec 2013Osteoporotic fractures result in significant morbidity and mortality. Anabolic agents reverse the negative skeletal balance that characterizes osteoporosis by... (Review)
Review
Osteoporotic fractures result in significant morbidity and mortality. Anabolic agents reverse the negative skeletal balance that characterizes osteoporosis by stimulating osteoblast-dependent bone formation to a greater degree than osteoclast-dependent bone resorption. Parathyroid hormone (PTH) and parathyroid hormone- related protein (PTHrP) are peptide hormones, which have anabolic actions when administered intermittently. The only FDA-approved anabolic bone agent for the treatment of osteoporosis in the United States is PTH 1-34, or teriparatide, administered by daily subcutaneous injections. However, PTH 1-84 is also available in Europe. Synthetic human PTHrP 1-36 and a PTHrP 1-34 analog, BA058, have also been shown to increase lumbar spine bone density. These agents and several other PTH and PTHrP analogs, including some which are not administered as injections, continue to be investigated as potential anabolic therapies for osteoporosis.
Topics: Anabolic Agents; Animals; Bone Resorption; Disease Models, Animal; Humans; Osteogenesis; Osteoporosis; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Teriparatide; Treatment Outcome
PubMed: 24078470
DOI: 10.1007/s11914-013-0171-2