calcitonin and Neoplasms

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

To evaluate the strength of evidence supporting a possible association between salmon calcitonin (SCT) use and cancer incidence.. Searches of MEDLINE/PubMed, MEDLINE/OVID, and EMBASE (January 1973 to September 2013) were performed using the key search terms salmon calcitonin, humans, nasal calcitonin, and (for EMBASE only) randomized controlled trial. We also performed a manual review of data reviewed by the US Food and Drug Administration (FDA) committee in 2013.. All articles identified from the data sources were evaluated and all information deemed relevant was included for this review.. Intranasal and injectable SCT are FDA-approved for the treatment of postmenopausal osteoporosis. After a safety signal suggested a possible link between SCT use and prostate cancer, the European Medicines Agency and FDA regulatory agencies conducted analyses of SCT randomized controlled trial data to assess cancer-related adverse events and to readdress the approval status of SCT. Eighteen studies were found that compared nasal or oral SCT and placebo. In 15 of the 18 studies, the percentage of malignancy was greater in the SCT arm. The studies varied in quality, outcomes, and length. Most of the studies had poor-quality methods to assess new cancer cases.. Current evidence may suggest an association between SCT use and cancer incidence based on studies with poor-quality cancer assessment methods. However, considering the lack of demonstrated efficacy of SCT to reduce fractures, clinicians should consider discontinuing its use for osteoporosis treatment regardless of the FDA's final approval decision.

Topics: Calcitonin; Humans; Neoplasms; Osteoporosis; Risk

Calcitonin (CT) inhibits osteoclast-mediated bone resorption and is being used to treat Paget's disease of bone, hypercalcemia of malignancy and postmenopausal osteoporosis. The formation of antibodies against heterologuous calcitonins like salmon calcitonin (sCT) is common and occurs in 40-70% of the patients treated for more than 4 months. Not all of these patients, however, develop a secondary resistance to sCT, therefore the clinical significance of sCT antibodies is discussed controversially. In vivo and in vitro approaches demonstrate a neutralizing effect in 35 to 60% of the patient sera with antibodies against sCT. These neutralizing antibodies appear to explain most cases of clinically relevant secondary resistance to sCT treatment, which occurs in 25-45% of the patients after treatment periods of 6 months and longer. A positive treatment response to human CT after development of secondary resistance to sCT proves the diagnosis of antibody related resistance. Few cases develop secondary resistance in the absence of sCT binding antibodies, the mechanism of this phenomenon is unclear. Antibody related resistance is a significant problem in long term treatment with sCT. Especially in conditions like postmenopausal osteoporosis, where no readily accessable marker of treatment response is available, the development of sCT antibodies and their possible neutralizing effect has to be considered.

Topics: Animals; Antibodies; Calcitonin; Drug Resistance; Female; Humans; Hypercalcemia; Neoplasms; Osteitis Deformans; Osteoporosis, Postmenopausal

Recent information on the pathophysiology and treatment of hypercalcemia of malignancy is reviewed, and the roles of two new agents, gallium nitrate and pamidronate, are discussed. Current evidence suggests that parathyroid hormone-related protein is the most important mediator of humoral hypercalcemia of malignancy. In patients with local osteolytic hypercalcemia, cytokines have been implicated as mediators. Effective treatment of hypercalcemia of malignancy may improve patients' quality of life, although an episode of hypercalcemia is a poor prognostic indicator for survival. Gallium nitrate is more effective than salmon calcitonin and possibly more effective than etidronate in the treatment of hypercalcemia of malignancy. The primary adverse effect of gallium nitrate is nephrotoxicity, and its use must be avoided in patients who have renal dysfunction or who are receiving nephrotoxic drugs. Pamidronate is more effective than etidronate in the treatment of hypercalcemia of malignancy and can be administered as a single i.v. dose. The adverse effects of pamidronate include mild fever, hypocalcemia, and hypophosphatemia. Compared with gallium nitrate, pamidronate offers a more convenient dosing regimen, is less frequently associated with nephrotoxicity, and is less expensive. Single i.v. doses of either pamidronate or plicamycin effectively lower serum calcium levels and are reasonable choices for maintenance therapy. Gallium nitrate and pamidronate may be slightly more effective than previously available agents for initial treatment of hypercalcemia. Pamidronate currently offers the best combination of effectiveness, ease of administration, and a low rate of adverse effects.

Topics: Animals; Antineoplastic Agents; Calcitonin; Diphosphonates; Etidronic Acid; Gallium; Humans; Hypercalcemia; Neoplasm Proteins; Neoplasms; Neoplasms, Experimental; Pamidronate; Parathyroid Hormone-Related Protein; Proteins; Treatment Outcome

Topics: Bone Density Conservation Agents; Calcitonin; Contraindications; Drug Approval; Female; Humans; Male; Neoplasms; Osteoporosis, Postmenopausal

Topics: Administration, Inhalation; Animals; Calcitonin; Female; Humans; Neoplasms; Osteoporosis, Postmenopausal

The mitogen-activated protein kinases (MAPKs) signaling pathway is a potential target in cancer therapy. Constitutive phosphorylated extracellular signal-regulated kinase (ERK1/2), which is one of the MAPKs has been detected in a variety of tumors. Calcitonin (CT) is a polypeptide hormone secreted by the thyroid gland and has been used to treat the osteoporosis and humoral hypercalcemia of malignancy. We report that CT decreases ERK1/2 phosphorylation in cancer cells showing constitutive phosphorylated ERK1/2. In MDA-MB-231 cells, a breast cancer cell line showing constitutive phosphorylated ERK1/2, CT phosphorylated c-Raf at Ser(259) via the protein kinase A pathway, resulting in suppression of ERK1/2 phosphorylation. CT significantly reduced the tumor volume of MDA-MB-231 cells showing constitutive phosphorylated ERK1/2 compared with saline buffer. However, CT did not exert any significant effects on the proliferation of MCF-7 cells, a breast cancer cell line, showing non-constitutive phosphorylated ERK1/2. These novel findings indicate that CT may be used to target ERK in the treatment of cancer.

Topics: Adenylyl Cyclases; Animals; Calcitonin; Cell Line, Tumor; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Enzyme Activators; Female; Humans; MAP Kinase Kinase 1; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasm Transplantation; Neoplasms; Phosphorylation; Phosphoserine; Protein Kinase C; Proto-Oncogene Proteins c-raf

Topics: Ambulatory Care; Analgesics; Calcitonin; Humans; Neoplasms; Patient Discharge; Patient Education as Topic; Quality Assurance, Health Care; Self Administration; Telephone

Topics: Administration, Intranasal; Calcitonin; Calcium; Circadian Rhythm; Dose-Response Relationship, Drug; Drug Evaluation; Humans; Hypercalcemia; Neoplasms; Time Factors

Seventeen patients with malignant hypercalcemia were treated with a combination of a single dose of 3-amino 1-hydroxypropylidene-1-bisphosphonate (APD [also known as AHPrBP or palmidronate disodium]) and salmon calcitonin given as suppositories for 3 days. To assess whether such a combined short treatment has a significant benefit leading to earlier normalization of the plasma calcium level than does APD alone, 17 additional patients matched for the type of tumor, initial plasma calcium level, urinary hydroxyproline level, and the dose of APD served as controls. All patients receiving the combination of calcitonin and APD achieved normalization of the plasma calcium level within 9 days, with a decrease from 3.22 +/- 0.90 mmol/L (mean +/- SEM) to 2.29 +/- 0.03 mmol/L. In the group receiving APD alone, the plasma calcium level normalized in only 14 of 17 patients by day 9. In the group receiving calcitonin and APD, the drop in the plasma calcium level occurred more rapidly, and the plasma calcium values were lower from days 2 to 4. This advantage was explained by the calciuric effect of calcitonin, as reflected by a significant decrease in the notional setting of renal reabsorption of calcium, reaching 2.16 +/- 0.06 mmol/L compared with 2.34 +/- 0.06 mmol/L in the group receiving APD alone. There were no side effects of both treatments, in particular neither flushing nor nausea induced by the suppositories of calcitonin. Clinical Improvement occurred after 2 days in the group receiving the combined treatment. In conclusion, the combined treatment is rapidly effective and safe in the treatment of patients with hypercalcemia, particularly when the notional setting of renal tubular reabsorption of calcium is increased and a rapid correction of the plasma calcium level is needed.

Topics: Aged; Calcitonin; Diphosphonates; Drug Therapy, Combination; Female; Fluid Therapy; Humans; Hypercalcemia; Male; Middle Aged; Neoplasms; Pamidronate; Suppositories; Time Factors

Some patients treated for the hypercalcaemia of malignancy develop renal tubular resistance to the effects of calcitonin which is independent of concurrent changes in sodium excretion. This type of resistance can be overcome by the addition of corticosteroids. In other patients apparent renal resistance to calcitonin is a consequence of reduced sodium excretion and is unaffected by corticosteroids.

Topics: Aged; Calcitonin; Calcium; Dexamethasone; Drug Synergism; Drug Therapy, Combination; Female; Humans; Hypercalcemia; Kidney Tubules; Male; Middle Aged; Neoplasms; Prednisolone; Time Factors

We evaluated the analgesic effect of salmon calcitonin (sCT) on 14 patients with intractable cancer pain. The drug was administered by epidural infusion (4-8 bolus administrations in 48 h); the dosage was 100 IU/48 h in 5 patients and 400 IU/48 h in 9 patients. Significant, although limited, pain relief and nocturnal pain relief were obtained; the requirement for conventional analgesic drugs was substantially reduced. The treatment was well tolerated and no side effect was recorded. However, only in 3/14 patients did pain relief result in improvement of mobility, with two patients becoming able to ambulate; no patient experienced absence of pain. In general, the treatment produced only limited benefit and subsequent morphine treatment was required in all instances. Widespread use of epidural sCT in intractable cancer pain is not justified as a routine procedure and more substantial evidence is required to support the clinical utility of such an approach.

Topics: Aged; Analgesia, Epidural; Calcitonin; Female; Humans; Male; Middle Aged; Neoplasms; Pain, Intractable

Although calcitonin is a natural, nontoxic, and rapid inhibitor of bone resorption, its use in the treatment of hypercalcemia is limited because of its transient efficacy and the need for repeated parenteral administration. In normal subjects, suppositories of calcitonin have been shown to be biologically active. Peak plasma concentrations of salmon calcitonin after rectal administration in six normal subjects were similar to those measured after parenteral administration. To evaluate the efficacy of calcitonin suppositories in disease states, 10 patients with moderate hypercalcemia due to malignancy were treated with salmon calcitonin, administered as suppositories containing 300 MRC units, three times a day for seven days. The mean plasma calcium level decreased significantly from 2.96 +/- 0.09 mmol/liter to 2.57 +/- 0.09 after one week (p less than 0.005) and rose again after discontinuation of treatment to 2.86 +/- 0.09 mmol/liter one week later. Urinary calcium and hydroxyproline values decreased during treatment and rose after discontinuation of treatment. The plasma calcium level decreased rapidly in six patients, becoming normal in five; three patients showed only a partial response, and one patient had no response at all. No side effects were observed, and clinical improvement was noted in nine of the 10 patients. Little or no response was observed in patients with extremely high urinary calcium or, to a lesser extent, high hydroxyproline excretion. There was a significant negative correlation between the maximal decrease in plasma calcium concentration and initial urinary calcium excretion (r -0.78, p less than 0.01). Thus, salmon calcitonin administered by the rectal route appears to be an easy, safe, and effective treatment of moderate hypercalcemia without apparent side effects.

Topics: Administration, Rectal; Aged; Calcitonin; Female; Humans; Hypercalcemia; Male; Middle Aged; Neoplasms; Suppositories

The hypocalcaemic response to salmon calcitonin was separated into its renal and skeletal components during the treatment of 21 patients with severe hypercalcaemia complicating malignant disease. Inhibition of renal tubular calcium reabsorption by calcitonin may induce a rapid fall in serum calcium. The magnitude of this response depends in part upon the correction of volume depletion which is a common feature of hypercalcaemia from any cause. The adequacy of rehydration can be assessed from the relationship between serum calcium and the calcium excretion rate expressed in mumol/l glomerular filtrate (CaE). Not all patients show a good renal response to calcitonin and this may reflect secretions by the primary tumour of substances which inhibit the renal tubular actions of calcitonin. The response to rehydration may identify such patients and this has obvious practical implications for the choice of treatment.

Topics: Adult; Aged; Calcitonin; Calcium; Female; Glomerular Filtration Rate; Humans; Hypercalcemia; Kidney; Male; Middle Aged; Neoplasms

Topics: Calcitonin; Humans; Hypercalcemia; Neoplasms