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British Journal of Hospital Medicine... Jun 2022Hypercalcaemia is a common metabolic abnormality and its differential diagnosis is vast. Immobility is an uncommon cause of hypercalcaemia. Immobilisation hypercalcaemia... (Review)
Review
Hypercalcaemia is a common metabolic abnormality and its differential diagnosis is vast. Immobility is an uncommon cause of hypercalcaemia. Immobilisation hypercalcaemia is independent of parathyroid hormone and is associated with low levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. In addition, it is characterised by elevated levels of markers of bone resorption and low levels of bone-specific alkaline phosphatase, highlighting an imbalance of bone remodelling favouring osteoclastic bone resorption. Although immobilisation hypercalcaemia is a diagnosis of exclusion, physicians need to be aware of this condition to avoid excessive and invasive investigations when all other causes of parathyroid hormone-independent hypercalcaemia have been excluded. Management of immobilisation hypercalcaemia revolves around early mobilisation and rehabilitation together with pharmacotherapeutic agents such as intravenous isotonic saline, calcitonin and bisphosphonates. Denosumab may be a potential alternative yet off-label treatment for immobility hypercalcaemia in patients with renal insufficiency.
Topics: Bone Resorption; Diagnosis, Differential; Diphosphonates; Humans; Hypercalcemia; Parathyroid Hormone
PubMed: 35787163
DOI: 10.12968/hmed.2021.0624 -
Frontiers in Endocrinology 2023Osteoporosis is an age-related disease of bone metabolism marked by reduced bone mineral density and impaired bone strength. The disease causes the bones to weaken and... (Review)
Review
Osteoporosis is an age-related disease of bone metabolism marked by reduced bone mineral density and impaired bone strength. The disease causes the bones to weaken and break more easily. Osteoclasts participate in bone resorption more than osteoblasts participate in bone formation, disrupting bone homeostasis and leading to osteoporosis. Currently, drug therapy for osteoporosis includes calcium supplements, vitamin D, parathyroid hormone, estrogen, calcitonin, bisphosphates, and other medications. These medications are effective in treating osteoporosis but have side effects. Copper is a necessary trace element in the human body, and studies have shown that it links to the development of osteoporosis. Cuproptosis is a recently proposed new type of cell death. Copper-induced cell death regulates by lipoylated components mediated mitochondrial ferredoxin 1; that is, copper binds directly to the lipoylated components of the tricarboxylic acid cycle, resulting in lipoylated protein accumulation and subsequent loss of iron-sulfur cluster proteins, leading to proteotoxic stress and eventually cell death. Therapeutic options for tumor disorders include targeting the intracellular toxicity of copper and cuproptosis. The hypoxic environment in bone and the metabolic pathway of glycolysis to provide energy in cells can inhibit cuproptosis, which may promote the survival and proliferation of various cells, including osteoblasts, osteoclasts, effector T cells, and macrophages, thereby mediating the osteoporosis process. As a result, our group tried to explain the relationship between the role of cuproptosis and its essential regulatory genes, as well as the pathological mechanism of osteoporosis and its effects on various cells. This study intends to investigate a new treatment approach for the clinical treatment of osteoporosis that is beneficial to the treatment of osteoporosis.
Topics: Humans; Bone Resorption; Copper; Osteoclasts; Osteoporosis; Parathyroid Hormone; Apoptosis
PubMed: 37214253
DOI: 10.3389/fendo.2023.1135181 -
Vitamins and Hormones 2022The number of the patients with chronic kidney disease is now increasing in the world. The pathophysiology of renal hyperparathyroidism is closely associated with...
The number of the patients with chronic kidney disease is now increasing in the world. The pathophysiology of renal hyperparathyroidism is closely associated with Klotho-FGF-endocrine axes, which must be solved definitively as early as possible. It was revealed that the expression of fgf23 is activated by calciprotein particles, which induces vascular ossification. And it is well known that phosphorus overload directly increases parathyroid hormone and hyperparathyroid bone disease develops in those subjects. On the other hand, low turnover bone disease is often recently. Both the patients with chronic kidney disease suffering from hyperparathyroid bone disease or low turnover bone disease are associated with increased fracture risk. Micropetrosis may be one of the causes of increased fracture risk in the subjects with low turnover bone disease. In this chapter, we now describe the diagnosis, pathophysiology and treatments of renal hyperparathyroidism.
Topics: Bone Diseases; Calcium; Humans; Hyperparathyroidism; Parathyroid Hormone; Renal Insufficiency, Chronic
PubMed: 35953115
DOI: 10.1016/bs.vh.2022.04.010 -
Molecular and Cellular Endocrinology Jul 2021Parathyroid hormone (PTH), which is primarily regulated by extracellular calcium changes, controls calcium and phosphate homeostasis. Different diseases are derived from...
Parathyroid hormone (PTH), which is primarily regulated by extracellular calcium changes, controls calcium and phosphate homeostasis. Different diseases are derived from PTH deficiency (hypoparathyroidism), excess (hyperparathyroidism) and resistance (pseudohypoparathyroidism, PHP). Pseudohypoparathyroidism was historically classified into subtypes according to the presence or not of inherited PTH resistance associated or not with features of Albright's hereditary osteodystrophy and deep and progressive ectopic ossifications. The growing knowledge on the PTH/PTHrP signaling pathway showed that molecular defects affecting different members of this pathway determined distinct, yet clinically related disorders, leading to the proposal of a new nomenclature and classification encompassing all disorders, collectively termed inactivating PTH/PTHrP signaling disorders (iPPSD).
Topics: Calcium; Humans; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Pseudohypoparathyroidism; Signal Transduction
PubMed: 33989717
DOI: 10.1016/j.mce.2021.111311 -
American Journal of Kidney Diseases :... Feb 2024Maintaining normal calcium and phosphate homeostasis is essential for optimal cellular, metabolic, and organ function. Parathyroid hormone, fibroblast growth factor 23,... (Review)
Review
Maintaining normal calcium and phosphate homeostasis is essential for optimal cellular, metabolic, and organ function. Parathyroid hormone, fibroblast growth factor 23, and 1,25-dihydroxyvitamin D regulate calcium and phosphate homeostasis via multiple interlinked feedback loops, receptors, ion channels, and transporters. Following an initial overview of the stimuli and effects of the different hormonal regulators, this installment of AJKD's Core Curriculum in Nephrology reviews the physiology and pathophysiology of calcium and phosphate disorders through the lens of a series of illustrative cases. The cases span clinical conundrums commonly encountered by nephrologists in their daily clinical practice and other less common disorders. Some of the cases present in the outpatient clinic setting and others in the inpatient hospital setting. Patients with normal kidney function, chronic kidney disease, kidney failure, and acute kidney injury are all represented. Some of the disorders are iatrogenic, and some are due to native disease. All demonstrate key aspects of pathophysiology that are essential knowledge for nephrology clinicians of all career stages.
Topics: Humans; Calcium; Phosphates; Parathyroid Hormone; Renal Insufficiency, Chronic; Curriculum; Fibroblast Growth Factors
PubMed: 38099870
DOI: 10.1053/j.ajkd.2023.04.017 -
Frontiers in Endocrinology 2021Regulation of the serum calcium level in humans is achieved by the endocrine action of parathyroid glands working in concert with vitamin D and a set of critical target... (Review)
Review
Regulation of the serum calcium level in humans is achieved by the endocrine action of parathyroid glands working in concert with vitamin D and a set of critical target cells and tissues including osteoblasts, osteoclasts, the renal tubules, and the small intestine. The parathyroid glands, small highly vascularized endocrine organs located behind the thyroid gland, secrete parathyroid hormone (PTH) into the systemic circulation as is needed to keep the serum free calcium concentration within a tight physiologic range. Primary hyperparathyroidism (HPT), a disorder of mineral metabolism usually associated with abnormally elevated serum calcium, results from the uncontrolled release of PTH from one or several abnormal parathyroid glands. Although in the vast majority of cases HPT is a sporadic disease, it can also present as a manifestation of a familial syndrome. Many benign and malignant sporadic parathyroid neoplasms are caused by loss-of-function mutations in tumor suppressor genes that were initially identified by the study of genomic DNA from patients who developed HPT as a manifestation of an inherited syndrome. Somatic and inherited mutations in certain proto-oncogenes can also result in the development of parathyroid tumors. The clinical and genetic investigation of familial HPT in kindreds found to lack germline variants in the already known HPT-predisposition genes represents a promising future direction for the discovery of novel genes relevant to parathyroid tumor development.
Topics: Calcium; Genetic Predisposition to Disease; Humans; Hyperparathyroidism; Mutation; Parathyroid Glands; Parathyroid Hormone
PubMed: 33716975
DOI: 10.3389/fendo.2021.623667 -
Endocrinology and Metabolism Clinics of... Dec 2021Extracellular calcium is normally tightly regulated by parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, as well as by calcium ion (Ca) itself. Dysregulated PTH... (Review)
Review
Extracellular calcium is normally tightly regulated by parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, as well as by calcium ion (Ca) itself. Dysregulated PTH production leading to hypercalcemia occurs most commonly in sporadic primary hyperparathryoidism (PHPT) but may also result from select genetic mutations in familial disorders. Parathyroid hormone-related protein shares molecular mechanisms of action with PTH and is the most common cause of hypercalcemia of malignancy. Other cytokines and mediators may also cause resorptive hypercalcemia once bone metastases have occurred. Less commonly, extrarenal production of calcitriol can occur in malignancies and in infectious and noninfectious inflammatory conditions and can cause hypercalcemia.
Topics: Bone Neoplasms; Calcitriol; Calcium; Calcium, Dietary; Humans; Hypercalcemia; Parathyroid Hormone
PubMed: 34774236
DOI: 10.1016/j.ecl.2021.07.008 -
Archives of Disease in Childhood. Fetal... Sep 2019Metabolic bone disease of prematurity (MBDP) is characterised by skeletal demineralisation, and in severe cases it can result in fragility fractures of long bones and... (Review)
Review
Metabolic bone disease of prematurity (MBDP) is characterised by skeletal demineralisation, and in severe cases it can result in fragility fractures of long bones and ribs during routine handling. MBDP arises from prenatal and postnatal factors. Infants who are born preterm are deprived of fetal mineral accumulation, 80% of which occurs in the third trimester. Postnatally, it is difficult to maintain a comparable intake of minerals, and medications, such as corticosteroids and diuretic therapy, lead to bone resorption. With improvements in neonatal care and nutrition, the incidence of MBDP in preterm infants appears to have decreased, although the recent practice of administering phosphate supplements alone will result in secondary hyperparathyroidism and associated bone loss, worsening MBDP. Postnatal immobilisation and loss of placental supply of oestrogen also contribute to skeletal demineralisation. There is no single diagnostic or screening test for MBDP, with pitfalls existing for most radiological and biochemical investigations. By reviewing the pathophysiology of calcium and phosphate homeostasis, one can establish that plasma parathyroid hormone is important in determining the aetiology of MBDP - primarily calcipaenia or phosphopaenia. This will then direct treatment with the appropriate supplements while considering optimal physiological calcium to phosphate ratios.
Topics: Bone Diseases, Metabolic; Calcium; Disease Management; Humans; Infant, Newborn; Infant, Premature; Parathyroid Hormone; Phosphates
PubMed: 31079069
DOI: 10.1136/archdischild-2018-316330 -
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 -
The Journal of Clinical Endocrinology... Jan 2022Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the treatment of hypoparathyroidism.
OBJECTIVE
This work aimed to investigate the safety, tolerability, and efficacy of daily TransCon PTH in adults with hypoparathyroidism.
METHODS
This phase 2, randomized, double-blind, placebo-controlled 4-week trial with open-label extension enrolled 59 individuals with hypoparathyroidism. Interventions included TransCon PTH 15, 18, or 21 µg PTH(1-34)/day or placebo for 4 weeks, followed by a 22-week extension during which TransCon PTH dose was titrated (6-60 µg PTH[1-34]/day).
RESULTS
By Week 26, 91% of participants treated with TransCon PTH achieved independence from standard of care (SoC, defined as active vitamin D = 0 μg/day and calcium [Ca] ≤ 500 mg/day). Mean 24-hour urine Ca (uCa) decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while normal serum Ca (sCa) was maintained and serum phosphate and serum calcium-phosphate product fell within the normal range. By Week 26, mean scores on the generic 36-Item Short Form Health Survey domains increased from below normal at baseline to within the normal range. The Hypoparathyroidism Patient Experience Scale symptom and impact scores improved through 26 weeks. TransCon PTH was well tolerated with no treatment-related serious or severe adverse events.
CONCLUSION
TransCon PTH enabled independence from oral active vitamin D and reduced Ca supplements (≤ 500 mg/day) for most participants, achieving normal sCa, serum phosphate, uCa, serum calcium-phosphate product, and demonstrating improved health-related quality of life. These results support TransCon PTH as a potential hormone replacement therapy for adults with hypoparathyroidism.
Topics: Adult; Aged; Calcium; Delayed-Action Preparations; Double-Blind Method; Drug Administration Schedule; Female; Hormone Replacement Therapy; Humans; Hypoparathyroidism; Male; Middle Aged; Parathyroid Hormone; Patient Reported Outcome Measures; Placebos; Prodrugs; Quality of Life; Treatment Outcome; Vitamin D
PubMed: 34347093
DOI: 10.1210/clinem/dgab577