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JAMA Oct 2022Hypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of... (Review)
Review
IMPORTANCE
Hypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma.
OBSERVATIONS
Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (<20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival.
CONCLUSIONS AND RELEVANCE
Mild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.
Topics: Humans; Calcium; Coma; COVID-19; Dehydration; Denosumab; Hypercalcemia; Hyperparathyroidism, Primary; Immune Checkpoint Inhibitors; Nausea; Neoplasms; Pamidronate; Parathyroid Hormone; SARS-CoV-2; Sleepiness; Sodium Chloride Symporter Inhibitors; Vitamin A; Vitamin D; Vomiting; Zoledronic Acid
PubMed: 36282253
DOI: 10.1001/jama.2022.18331 -
Current Opinion in Nephrology and... Jul 2017In the United States, the number of parathyroidectomies among patients with chronic dialysis has remained stable in the last decade. A fall in serum calcium... (Review)
Review
PURPOSE OF REVIEW
In the United States, the number of parathyroidectomies among patients with chronic dialysis has remained stable in the last decade. A fall in serum calcium concentration is common postparathyroidectomy in patients with hyperparathyroidism, which usually resolves in 2-4 days. A severe drop in serum total calcium concentration less than 2.1 mmol/L and/or prolonged hypocalcemia for more than 4 days postparathyroidectomy is called hungry bone syndrome (HBS). Concomitant hypophosphatemia, hypomagnesemia, and hyperkalemia can be seen. Hypocalcemia and hypophosphatemia can persist for months to years. In contemporary clinical practice, HBS may be more commonly seen in patients with secondary compared to primary hyperparathyroidism. Preoperative radiological changes in bone, elevated serum alkaline phosphatase and parathyroid hormone (PTH) levels, and high numbers of osteoclasts on bone biopsy may identify patients at risk. Treatment consists of high-dose oral calcium and calcitriol supplementation. A low-dose pamidronate infusion 1-2 days prior to surgery may prevent HBS.
RECENT FINDINGS
Recent in-vitro studies reported net calcium movement into bone because of a sudden fall in serum PTH level after a prolonged period of elevation. This supports a previous hypothesis that a sudden drop in serum PTH level after surgery results in the unopposed action of osteoblasts and influx of calcium into bone.
SUMMARY
Incidence of HBS and its association with morbidity and mortality remains unclear in contemporary clinical practice. It is more common to encounter HBS in chronic dialysis patients with secondary hyperparathyroidism than those with primary hyperparathyroidism that undergo parathyroidectomies. Use of bisphosphonates to prevent HBS should be explored in future studies.
Topics: Bone Density Conservation Agents; Bone Diseases, Metabolic; Calcitriol; Calcium; Diphosphonates; Humans; Hyperparathyroidism; Hyperparathyroidism, Secondary; Hypocalcemia; Kidney Failure, Chronic; Pamidronate; Parathyroidectomy; Renal Dialysis; Syndrome
PubMed: 28375869
DOI: 10.1097/MNH.0000000000000327 -
Endocrinology and Metabolism (Seoul,... Oct 2022Paget's disease of the bone is a prevalent bone disease characterized by disorganized bone remodeling; however, it is comparatively uncommon in East Asian countries,...
Paget's disease of the bone is a prevalent bone disease characterized by disorganized bone remodeling; however, it is comparatively uncommon in East Asian countries, including China, Japan, and Korea. The exact cause still remains unknown. In genetically susceptible individuals, environmental triggers such as paramyxoviral infections are likely to cause the disease. Increased osteoclast activity results in increased bone resorption, which attracts osteoblasts and generates new bone matrix. Fast bone resorption and formation lead to the development of disorganized bone tissue. Increasing serum alkaline phosphatase or unique radiographic lesions may serve as the diagnostic indicators. Common symptoms include bone pain, bowing of the long bones, an enlarged skull, and hearing loss. The diagnosis is frequently confirmed by radiographic and nuclear scintigraphy of the bone. Further, bisphosphonates such as zoledronic acid and pamidronate are effective for its treatment. Moreover, biochemical monitoring is superior to the symptoms as a recurrence indicator. This article discusses the updates of Paget's disease of bone with a clinical case.
Topics: Humans; Osteitis Deformans; Diphosphonates; Pamidronate; Bone and Bones; Bone Resorption
PubMed: 36327984
DOI: 10.3803/EnM.2022.1575 -
The American Journal of Medicine Nov 2018Paget's disease of bone is a common bone disorder characterized by disorganized bone remodeling. The most likely etiology is a slow paramyxoviral infection in... (Review)
Review
Paget's disease of bone is a common bone disorder characterized by disorganized bone remodeling. The most likely etiology is a slow paramyxoviral infection in genetically susceptible individuals; however, the exact cause is unknown. Enhanced bone resorption due to an increased activity of osteoclasts recruits numerous osteoblasts to resorption sites, with large quantities of new bone matrix produced as a result. The accelerated bone resorption and formation are not as closely coupled as in a healthy bone; a disorganized bone tissue is formed. Many patients are asymptomatic; rising serum alkaline phosphatase or incidental finding of characteristic radiographic lesions are often the only diagnostic clues. Common clinical manifestations include bone pain, bowing of long bones, enlarged skull, and hearing loss. An elevated serum alkaline phosphatase level correlates with the disease activity. The diagnosis is confirmed by characteristic radiographic findings and by nuclear scintigraphy of the bone (the most sensitive test). Bisphosphonates, such as zoledronic acid, pamidronate, alendronate, and risedronate, are the mainstay of treatment. Patients who do not tolerate bisphosphonates can be treated with calcitonin.
Topics: Diphosphonates; Humans; Osteitis Deformans
PubMed: 29752905
DOI: 10.1016/j.amjmed.2018.04.028 -
Bone Aug 2023Osteopetrosis (OPT) denotes the consequences from failure of osteoclasts to resorb bone and chondroclasts to remove calcified physeal cartilage throughout growth....
Osteopetrosis (OPT) denotes the consequences from failure of osteoclasts to resorb bone and chondroclasts to remove calcified physeal cartilage throughout growth. Resulting impairment of skeletal modeling, remodeling, and growth compromises widening of medullary spaces, formation of the skull, and expansion of cranial foramina. Thus, myelophthisic anemia, raised intracranial pressure, and cranial nerve palsies complicate OPT when severe. Osteopetrotic bones fracture due to misshaping, failure of remodeling to weave the collagenous matrix of cortical osteons and trabeculae, persistence of mineralized growth plate cartilage, "hardening" of hydroxyapatite crystals, and delayed healing of skeletal microcracks. Teeth may fail to erupt. Now it is widely appreciated that OPT is caused by germline loss-of-function mutation(s) usually of genes involved in osteoclast function, but especially rarely of genes necessary for osteoclast formation. Additionally, however, in 2003 we published a case report demonstrating that prolonged excessive dosing during childhood of the antiresorptive aminobisphosphonate pamidronate can sufficiently block osteoclast and chondroclast activity to recapitulate the skeletal features of OPT. Herein, we include further evidence of drug-induced OPT by illustrating osteopetrotic skeletal changes from repeated administration of high doses of the aminobisphosphonate zoledronic acid (zoledronate) given to children with osteogenesis imperfecta.
Topics: Child; Humans; Osteopetrosis; Osteoclasts; Zoledronic Acid; Fractures, Bone; Skull
PubMed: 37172883
DOI: 10.1016/j.bone.2023.116788 -
Molecules (Basel, Switzerland) Nov 2022[F]sodium fluoride ([F]NaF) is recognised to be superior to [mTc]-methyl diphosphate ([Tc]Tc-MDP) and ([F]FDG) in bone imaging. However, there is concern that [F]NaF...
[F]sodium fluoride ([F]NaF) is recognised to be superior to [mTc]-methyl diphosphate ([Tc]Tc-MDP) and ([F]FDG) in bone imaging. However, there is concern that [F]NaF uptake is not cancer-specific, leading to a higher number of false-positive interpretations. Therefore, in this work, [F]AlF-NOTA-pamidronic acid was prepared, optimised, and tested for its in vitro uptake. NOTA-pamidronic acid was prepared by an Hydroxysuccinimide (NHS) ester strategy and validated by liquid chromatography-mass spectrometry analysis (LC-MS/MS). Radiolabeling of [F]AlF-NOTA-pamidronic acid was optimised, and it was ensured that all quality control analysis requirements for the radiopharmaceuticals were met prior to the in vitro cell uptake studies. NOTA-pamidronic acid was successfully prepared and radiolabeled with F. The radiolabel was prepared in a 1:1 molar ratio of aluminium chloride (AlCl) to NOTA-pamidronic acid and heated at 100 °C for 15 min in the presence of 50% ethanol (/), which proved to be optimal. The preliminary in vitro results of the binding of the hydroxyapatite showed that [F]AlF-NOTA-pamidronic acid was as sensitive as [F]sodium fluoride ([F]NaF). Normal human osteoblast cell lines (hFOB 1.19) and human osteosarcoma cell lines (Saos-2) were used for the in vitro cellular uptake studies. It was found that [F]NaF was higher in both cell lines, but [F]AlF-NOTA-pamidronic acid showed promising cellular uptake in Saos-2. The preliminary results suggest that further preclinical studies of [F]AlF-NOTA-pamidronic acid are needed before it is transferred to clinical research.
Topics: Humans; Fluorine Radioisotopes; Pamidronate; Sodium Fluoride; Chromatography, Liquid; Heterocyclic Compounds; Oligopeptides; Tandem Mass Spectrometry; Positron-Emission Tomography
PubMed: 36432069
DOI: 10.3390/molecules27227969 -
CMAJ : Canadian Medical Association... Mar 2024
Topics: Humans; Scleritis; Pamidronate; Uveitis, Anterior; Acute Disease
PubMed: 38527748
DOI: 10.1503/cmaj.230859-f -
Molecules (Basel, Switzerland) Jun 2020Early diagnosis of bone metastases is crucial to prevent skeletal-related events, and for that, the non-invasive techniques to diagnose bone metastases that make use of...
Early diagnosis of bone metastases is crucial to prevent skeletal-related events, and for that, the non-invasive techniques to diagnose bone metastases that make use of image-guided radiopharmaceuticals are being employed as an alternative to traditional biopsies. Hence, in the present work, we tested the efficacy of a gallium-68 (Ga)-based compound as a radiopharmaceutical agent towards the bone imaging in positron emitting tomography (PET). For that, we prepared, thoroughly characterized, and radiolabeled [Ga]Ga-NODAGA-pamidronic acid radiopharmaceutical, a Ga precursor for PET bone cancer imaging applications. The preparation of NODAGA-pamidronic acid was performed via the -Hydroxysuccinimide (NHS) ester strategy and was characterized using liquid chromatography-mass spectrometry (LC-MS) and tandem mass spectrometry (MS). The unreacted NODAGA chelator was separated using the ion-suppression reverse phase-high performance liquid chromatography (RP-HPLC) method, and the freeze-dried NODAGA-pamidronic acid was radiolabeled with Ga. The radiolabeling condition was found to be most optimum at a pH ranging from 4 to 4.5 and a temperature of above 60 °C. From previous work, we found that the pamidronic acid itself has a good bone binding affinity. Moreover, from the analysis of the results, the ionic structure of radiolabeled [Ga]Ga-NODAGA-pamidronic acid has the ability to improve the blood clearance and may exert good renal excretion, enhance the bone-to-background ratio, and consequently the final image quality. This was reflected by both the in vitro bone binding assay and in vivo animal biodistribution presented in this research.
Topics: Acetates; Animals; Bone and Bones; Chromatography, High Pressure Liquid; Gallium Radioisotopes; Heterocyclic Compounds, 1-Ring; Male; Mass Spectrometry; Pamidronate; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Tissue Distribution
PubMed: 32526838
DOI: 10.3390/molecules25112668