Review

Authors: Heidi Horns, Rika Draenert, Markus Nistal...

Topics: Biomarkers; Calcitonin; Calcitonin Gene-Related Peptide; Humans; Procalcitonin

PubMed: 34086237
DOI: 10.1007/s15006-021-9959-7

Review

Authors: Akash Srinivasan, Felyx K Wong, Dimitrios Karponis...

Calcitonin regulates blood calcium levels and possesses certain clinically useful anti-fracture properties. Specifically, it reduces vertebral fractures in postmenopausal osteoporotic women significantly compared to a placebo. Nevertheless, the use of calcitonin has declined over the years and salmon calcitonin is no longer the first-line treatment for many of its indications. Commercial calcitonin only exists in intranasal or injectable preparations, which are less preferable for patients. Efficacy of a potential oral formulation has been under investigation but achieving adequate bioavailability remains a conundrum and the latest phase III trials have not shown promising evidence justifying its use. Associations with cancer have also derailed this treatment option. Furthermore, the rise of bisphosphonates and, more recently, monoclonal antibodies (such as denosumab), has revolutionised the treatment of osteoporotic fractures. Therefore, we are posed with an interesting question: is calcitonin a treatment of the past? This review aims to explore the reasons behind this paradigm shift and outline the potential role of calcitonin in the management of fractures and other conditions in the years to come.

Topics: Animals; Calcitonin; Humans; Osteoporotic Fractures

PubMed: 33265089
DOI: No ID Found

Review

Authors: Philipp Schuetz

OBJECTIVES

Procalcitonin (PCT) is a host-response biomarker that has shown clinical value for assessing the likelihood of bacterial infections and guiding antibiotic treatment. Identifying situations where PCT can improve clinical care is therefore highly important.

METHODS

The aim of this narrative review is to discuss strategies for the usage and integration of PCT into clinical routine, based on the most recent clinical evidence.

RESULTS

Although PCT should not be viewed as a traditional diagnostic marker, it can help differentiate bacterial from non-bacterial infections and inflammation states - particularly in respiratory illness. Several trials have found that PCT-guided antibiotic stewardship reduces antibiotic exposure and associated side-effects among patients with respiratory infection and sepsis. Studies have demonstrated that patient-specific decisions regarding antibiotic usage is highly complex. Factors to consider include: the clinical situation (with a focus on the pretest probability for bacterial infection), the acuity and severity of presentation, as well as PCT test results. Low PCT levels help rule out bacterial infection in patients with both low pretest probability for bacterial infection and low-risk general condition. In high-risk individuals and/or high pretest probability for infection, empiric antibiotic treatment is mandatory. Subsequent monitoring of PCT helps track the resolution of infection and guide decisions regarding early termination of antibiotic treatment.

CONCLUSIONS

PCT possesses high potential to improve decision-making regarding antibiotic treatment - when combined with careful patient assessment, evidence-based clinical algorithms, and continuous notification and regular feedback from all antibiotic stewardship stakeholders. Medical Journals such as () have played a critical role in reviewing and dissemination the high-quality evidence about assays for PCT measurement, observational research regarding association with outcomes among different populations, and interventional research proofing its effectiveness for patient care.

Topics: Humans; Procalcitonin; Calcitonin; Bacterial Infections; Sepsis; Anti-Bacterial Agents; Biomarkers

PubMed: 36317790
DOI: 10.1515/cclm-2022-1072

Authors: Philipp Schuetz, Albertus Beishuizen, Michael Broyles...

Background Procalcitonin (PCT)-guided antibiotic stewardship (ABS) has been shown to reduce antibiotics (ABxs), with lower side-effects and an improvement in clinical outcomes. The aim of this experts workshop was to derive a PCT algorithm ABS for easier implementation into clinical routine across different clinical settings. Methods Clinical evidence and practical experience with PCT-guided ABS was analyzed and discussed, with a focus on optimal PCT use in the clinical context and increased adherence to PCT protocols. Using a Delphi process, the experts group reached consensus on different PCT algorithms based on clinical severity of the patient and probability of bacterial infection. Results The group agreed that there is strong evidence that PCT-guided ABS supports individual decisions on initiation and duration of ABx treatment in patients with acute respiratory infections and sepsis from any source, thereby reducing overall ABx exposure and associated side effects, and improving clinical outcomes. To simplify practical application, the expert group refined the established PCT algorithms by incorporating severity of illness and probability of bacterial infection and reducing the fixed cut-offs to only one for mild to moderate and one for severe disease (0.25 μg/L and 0.5 μg/L, respectively). Further, guidance on interpretation of PCT results to initiate, withhold or discontinue ABx treatment was included. Conclusions A combination of clinical patient assessment with PCT levels in well-defined ABS algorithms, in context with continuous education and regular feedback to all ABS stakeholders, has the potential to improve the diagnostic and therapeutic management of patients suspected of bacterial infection, thereby improving ABS effectiveness.

Topics: Adult; Algorithms; Anti-Bacterial Agents; Antimicrobial Stewardship; Bacterial Infections; Biomarkers; Calcitonin; Consensus; Female; Humans; Male; Middle Aged; Procalcitonin; Sepsis

PubMed: 30721141
DOI: 10.1515/cclm-2018-1181

Comparative Study

Authors: Madeleine M Fletcher, Peter Keov, Tin T Truong...

Obesity and associated comorbidities are a major health burden, and novel therapeutics to help treat obesity are urgently needed. There is increasing evidence that targeting the amylin receptors (AMYRs), heterodimers of the calcitonin G protein-coupled receptor (CTR) and receptor activity-modifying proteins, improves weight control and has the potential to act additively with other treatments such as glucagon-like peptide-1 receptor agonists. Recent data indicate that AMYR agonists, which can also independently activate the CTR, may have improved efficacy for treating obesity, even though selective activation of CTRs is not efficacious. AM833 (cagrilintide) is a novel lipidated amylin analog that is undergoing clinical trials as a nonselective AMYR and CTR agonist. In the current study, we have investigated the pharmacology of AM833 across 25 endpoints and compared this peptide with AMYR selective and nonselective lipidated analogs (AM1213 and AM1784), and the clinically used peptide agonists pramlintide (AMYR selective) and salmon CT (nonselective). We also profiled human CT and rat amylin as prototypical selective agonists of CTR and AMYRs, respectively. Our results demonstrate that AM833 has a unique pharmacological profile across diverse measures of receptor binding, activation, and regulation. SIGNIFICANCE STATEMENT: AM833 is a novel nonselective agonist of calcitonin family receptors that has demonstrated efficacy for the treatment of obesity in phase 2 clinical trials. This study demonstrates that AM833 has a unique pharmacological profile across diverse measures of receptor binding, activation, and regulation when compared with other selective and nonselective calcitonin receptor and amylin receptor agonists. The present data provide mechanistic insight into the actions of AM833.

Topics: Animals; Humans; Receptors, Calcitonin; Islet Amyloid Polypeptide; Calcitonin; Amylin Receptor Agonists; Rats; Male; Receptors, Islet Amyloid Polypeptide; Receptors, G-Protein-Coupled; Mice; Cricetulus; HEK293 Cells

PubMed: 33727283
DOI: 10.1124/jpet.121.000567

Review

Authors: David S Mathiesen, Asger Lund, Tina Vilsbøll...

The hormones amylin and calcitonin interact with receptors within the same family to exert their effects on the human organism. Calcitonin, derived from thyroid C cells, is known for its inhibitory effect on osteoclasts. Calcitonin of mammalian origin promotes insulin sensitivity, while the more potent calcitonin extracted from salmon additionally inhibits gastric emptying, promotes gallbladder relaxation, increases energy expenditure and induces satiety as well as weight loss. Amylin, derived from pancreatic beta cells, regulates plasma glucose by delaying gastric emptying after meal ingestion, and modulates glucagon secretion and central satiety signals in the brain. Thus, both hormones seem to have metabolic effects of relevance in the context of non-alcoholic fatty liver disease (NAFLD) and other metabolic diseases. In rats, studies with dual amylin and calcitonin receptor agonists have demonstrated robust body weight loss, improved glucose tolerance and a decreased deposition of fat in liver tissue beyond what is observed after a body weight loss. The translational aspects of these preclinical data currently remain unknown. Here, we describe the physiology, pathophysiology, and pharmacological effects of amylin and calcitonin and review preclinical and clinical findings alluding to the future potential of amylin and calcitonin-based drugs for the treatment of obesity and NAFLD.

Topics: Amylin Receptor Agonists; Animals; Body Weight; Calcitonin; Diet, High-Fat; Fatty Liver; Humans; Islet Amyloid Polypeptide; Obesity

PubMed: 33488526
DOI: 10.3389/fendo.2020.617400

Meta-Analysis Review

Authors: G Wells, J Chernoff, J P Gilligan...

Recently an association between the use of calcitonin and cancer has been postulated. We reviewed the biological rationale and performed an additional analysis of historical data with respect to the possibility. An association cannot be excluded, but the relationship is weak and causality is unlikely. The purpose of the present study is to review the strength of association and likelihood of a causal relationship between use of calcitonin and cancer. We reviewed the evidence for this association, including the molecular signaling mechanisms of calcitonin, preclinical data, an "experiment of nature," and the results of a previous meta-analysis which showed a weak association. We performed an additional meta-analysis to incorporate the data from a novel investigational oral formulation of salmon calcitonin. Review of the literature did not identify a cellular signaling mechanism of action which might account for a causal relationship or toxicologic or postmarketing data to support the thesis. Additional clinical results incorporated into previous meta-analyses weakened but did not completely negate the possibility of association. A causal association between calcitonin use and malignancy is unlikely, as there is little biological plausibility. The preponderance of nonclinical and clinical evidence also does not favor a causal relationship.

Topics: Animals; Bone Density Conservation Agents; Calcitonin; Drug Evaluation, Preclinical; Humans; Neoplasms; Product Surveillance, Postmarketing

PubMed: 26438308
DOI: 10.1007/s00198-015-3339-z

Authors: Johannes Neumüller, Kordula Lang-Illievich, Connor T A Brenna...

INTRODUCTION

Phantom limb pain (PLP) refers to pain perceived in a part of the body removed by amputation or trauma. Despite the high prevalence of PLP following amputation and the significant morbidity associated with it, robust therapeutic approaches are currently lacking. Calcitonin, a polypeptide hormone, has recently emerged as a novel analgesic with documented benefits in the treatment of several pain-related conditions.

METHODS

We present a systematic review that comprehensively evaluates the analgesic effects of calcitonin for patients with PLP. We searched MEDLINE, OLDMEDLINE, and PubMed Central databases with the key words "calcitonin" "phantom limb pain" and "phantom pain" to identify clinical studies evaluating the efficacy or effectiveness of calcitonin administration, in any form and dose, for the treatment of PLP. Additionally, Google Scholar was searched manually with the search term "calcitonin phantom limb pain". All four databases were searched from inception until 1 December 2022. The methodological quality of each included study was assessed using the Downs and Black checklist and the GRADE criteria were used to assess effect certainty and risk of bias.

RESULTS

Our search identified 4108 citations, of which six ultimately met the criteria for inclusion in the synthesis. The included articles described a mix of open-label (n = 2), prospective observational cohort (n = 1), and randomized clinical trials (n = 3). The most common treatment regimen in the current literature is a single intravenous infusion of 200 IU salmon-derived calcitonin.

CONCLUSION

The available evidence supported the use of calcitonin as either monotherapy or adjuvant therapy in the treatment of PLP during the acute phase, while the evidence surrounding calcitonin treatment in chronic PLP is heterogeneous. Given the limited treatment options for the management of PLP and calcitonin's relatively wide therapeutic index, further research is warranted to determine the role that calcitonin may play in the treatment of PLP and other pain disorders.

Topics: Humans; Amputation, Surgical; Observational Studies as Topic; Phantom Limb; Prevalence; Calcitonin

PubMed: 37261670
DOI: 10.1007/s40263-023-01010-x

Authors: Federica Rigoldi, Pierangelo Metrangolo, Alberto Redaelli...

Calcitonin is a 32-amino acid thyroid hormone that can form amyloid fibrils. The structural basis of the fibril formation and stabilization is still debated and poorly understood. The reason is that NMR data strongly suggest antiparallel β-sheet calcitonin assembly, whereas modeling studies on the short DFNKF peptide (corresponding to the sequence from Asp to Phe of human calcitonin and reported as the minimal amyloidogenic module) show that it assembles with parallel β-sheets. In this work, we first predict the structure of human calcitonin through two complementary molecular dynamics (MD) methods, finding that human calcitonin forms an α-helix. We use extensive MD simulations to compare previously proposed calcitonin fibril structures. We find that two conformations, the parallel arrangement and one of the possible antiparallel structures (with Asp and Phe aligned), are highly stable and ordered. Nonetheless, fibrils with parallel molecules show bulky loops formed by residues 1 to 7 located on the same side, which could limit or prevent the formation of larger amyloids. We investigate fibrils formed by the DFNKF peptide by simulating different arrangements of this amyloidogenic core sequence. We show that DFNKF fibrils are highly stable when assembled in parallel β-sheets, whereas they quickly unfold in antiparallel conformation. Our results indicate that the DFNKF peptide represents only partially the full-length calcitonin behavior. Contrary to the full-length polypeptide, in fact, the DFNKF sequence is not stable in antiparallel conformation, suggesting that the residue flanking the amyloidogenic peptide contributes to the stabilization of the experimentally observed antiparallel β-sheet packing.

Topics: Amyloid; Calcitonin; Humans; Molecular Dynamics Simulation; Peptides; Protein Stability; Protein Structure, Quaternary; Protein Structure, Secondary

PubMed: 28283568
DOI: 10.1074/jbc.M116.770271

Meta-Analysis Review

Authors: Ning Li, Yi Chen Gong, Jianer Chen...

OBJECTIVE

To evaluate the efficacy and safety of intranasal salmon calcitonin in the treatment of osteoporosis.

METHODS

Eight Chinese and English databases were searched by electronic search (from the establishment of the database to October 2019). The literature was screened according to the inclusion criteria and exclusion criteria, the quality was evaluated according to Cochrane software, and the Review Manager 5.2 software was used for statistical analysis.

RESULTS

A total of 374 documents were retrieved and 12 (12 original studies) were included after the screening, with a total sample capacity of 1068 cases. Meta-analysis showed that the intranasal salmon calcitonin had obvious advantages in reducing blood calcium, improving the ratio of serum creatinine and alkaline phosphatase. In addition, the intranasal salmon calcitonin had no obvious advantages in other indicators. It cannot be illustrated that the combination of intranasal salmon calcitonin and other conventional drugs is more effective than the simple use of conventional drugs.

CONCLUSION

The intranasal salmon calcitonin is superior to conventional drugs in reducing blood calcium, increasing creatinine ratio, and alkaline phosphatase, but its advantages in other indicators such as improving the bone mineral density (BMD) of lumbar vertebrae and hip have not been confirmed, and it is not clear that the combination of intranasal salmon calcitonin and other conventional drugs is better than the simple conventional drugs.

Topics: Administration, Intranasal; Bone Density Conservation Agents; Calcitonin; Humans; Lumbar Vertebrae; Osteoporosis, Postmenopausal

PubMed: 34879875
DOI: 10.1186/s40001-021-00610-x