Calcitonin as an analgesic agent: review of mechanisms of action and clinical applications / Calcitonina como agente analgésico: revisão dos mecanismos de ação e das aplicações clínicas

Abstract Background and objectives: Calcitonin is a polypeptide hormone regulating the metabolism of calcium in the body. For many years calcitonin has been used to maintain and improve bone mineral density and to reduce the fracture rate. Many studies showed that calcitonin had analgesic role in several painful circumstances. This pain-ameliorating effect is irrelevant to its osteoclastic inhibitory effect and mechanisms like altering Na+ channel and serotonin receptor expression or hypothesis including the endorphin-mediated mechanism were used to explain this effect. In this study we performed a thorough review on the role of calcitonin as an analgesic agent in different scenarios and investigated the fact that calcitonin can be a feasible medication to relieve pain. Method: Many studies focused on the analgesic effect of calcitonin in several painful circumstances, including acute pains related to vertebral fractures, metastasis, migraine and reflex sympathetic dystrophy as well as neuropathic pains related to spinal injuries or diabetes, and phantom pain. Also, calcitonin was showed to be a useful additive to local anesthesia in the case of controlling postoperative pain or trigeminal neuralgia more effectively. However we faced some contradictory data for conditions like lumbar canal stenosis, complex regional pain syndrome, phantom pain and malignancies. Conclusion: This study showed that calcitonin could be helpful analgesic agent in different painful situations. Calcitonin can be considered an eligible treatment for acute pains related to vertebral fractures and a feasible alternative for the treatment of the acute and chronic neuropathic pains where other medications might fail.

Resumo Justificativa e objetivos: A calcitonina é um hormônio polipeptídico que regula o metabolismo do cálcio no organismo. Por muitos anos a calcitonina tem sido usada para manter e melhorar a densidade mineral óssea e reduzir a incidência de fraturas. Muitos estudos mostraram que a calcitonina teve efeito analgésico em várias condições físicas de dor. Esse efeito de melhoria da dor é irrelevante diante de seu efeito inibidor osteoclástico e de mecanismos, tais como a alteração do canal de Na+ e da expressão do receptor de serotonina, inclusive a hipótese do mecanismo mediado pela endorfina, que foram usados para explicar esse efeito. Neste estudo, fizemos uma revisão completa sobre o papel da calcitonina como agente analgésico em diferentes cenários e investigamos o fato de que a calcitonina pode ser uma medicação viável para aliviar a dor. Método: Muitos estudos centraram no efeito analgésico da calcitonina em várias condições de dor, inclusive dores agudas relacionadas a fraturas vertebrais, metástases, enxaqueca e distrofia simpática reflexa, bem como dores neuropáticas relacionadas a lesões medulares ou ao diabetes e dor fantasma. Além disso, a calcitonina mostrou ser um aditivo útil à anestesia local para o controle mais efecaz da dor pós-operatória ou neuralgia do trigêmeo. Porém, nos deparamos com alguns dados contraditórios em condições como estenose do canal lombar, síndrome complexa da dor regional, dor fantasma e malignidades. Conclusão: Este estudo mostrou que a calcitonina pode ser um analgésico útil em diferentes condições de dor. A calcitonina pode ser considerada um tratamento elegível para as dores agudas relacionadas a fraturas vertebrais e uma opção viável para o tratamento das dores neuropáticas agudas e crônicas em que outros medicamentos podem falhar.

Calcitonin induces connective tissue growth factor through ERK1/2 signaling in renal tubular cells

Calcitonin (CT), a polypeptide hormone, plays important roles in a variety of physiological processes. CT has been used clinically to treat osteoporosis and humoral hypercalcemia of malignancy. In order to clarify the pharmacological effects of CT in the kidney, we identified potential downstream genes induced by CT in the renal cells. Using a cDNA subtraction hybridization method, we identified connective tissue growth factor (CTGF) as a CT-induced gene in the porcine renal cell line, LLC-PK1. Furthermore, we found that CT-mediated induction of the gene was not inhibited by cycloheximide, which suggests that CTGF gene was not induced by an increased synthesis of regulating proteins. Therefore, CTGF is an immediate early gene. We further demonstrated that the regulation of CTGF gene expression by CT involved the ERK1/2 pathway, because PD98059, a MEK1 inhibitor, partially inhibited the mRNA expression of CTGF induced by CT. CT-induced CTGF protein expression was also observed in vivo. Our present findings suggest that CT induces the transcription of CTGF through ERK1/2 phosphorylation. We also identified twelve other genes induced by CT that, like CTGF, were related to wound healing. These results suggest that CT may have an effect on renal differentiation and wound healing in the kidney.

Calcitonin induces connective tissue growth factor through ERK1/2 signaling in renal tubular cells

Calcitonin (CT), a polypeptide hormone, plays important roles in a variety of physiological processes. CT has been used clinically to treat osteoporosis and humoral hypercalcemia of malignancy. In order to clarify the pharmacological effects of CT in the kidney, we identified potential downstream genes induced by CT in the renal cells. Using a cDNA subtraction hybridization method, we identified connective tissue growth factor (CTGF) as a CT-induced gene in the porcine renal cell line, LLC-PK1. Furthermore, we found that CT-mediated induction of the gene was not inhibited by cycloheximide, which suggests that CTGF gene was not induced by an increased synthesis of regulating proteins. Therefore, CTGF is an immediate early gene. We further demonstrated that the regulation of CTGF gene expression by CT involved the ERK1/2 pathway, because PD98059, a MEK1 inhibitor, partially inhibited the mRNA expression of CTGF induced by CT. CT-induced CTGF protein expression was also observed in vivo. Our present findings suggest that CT induces the transcription of CTGF through ERK1/2 phosphorylation. We also identified twelve other genes induced by CT that, like CTGF, were related to wound healing. These results suggest that CT may have an effect on renal differentiation and wound healing in the kidney.

Effect of combined treatment with calcitonin on bone densitometry of patients with treated hypothyroidism

INTRODUCTION: Thyroid hormones (TH) may affect bone metabolism and turnover, inducing a loss of bone mass among hyperthyroid and in hypothyroid patients under hormone replacement treatment. Thyroid dysfunction leads to changes in the dynamics of parathyroid hormone (PTH) and calcitonin (CT) secretion. OBJECTIVE: The objective of the study was to determine the usefulness of CT as adjuvant therapy in the prevention of bone loss during the treatment of hypothyroidism. MATERIAL AND METHODS: We studied 16 female patients with recently diagnosed primary hypothyroidism, divided into two groups: group G1 (n=8) submitted to treatment with thyroxine (L-T4), and Group 2 (n=8) that, in addition to being treated with L-T4, received a nasal CT spray. All patients were submitted to determination of TSH, free T4, bone mineral densitometry (BMD) and total bone calcium (TBC) at the time of diagnosis, after 6 to 9 months of treatment, and after 12 months of treatment. RESULTS: No statistical significant differences were detected in either group between the total BMD values obtained for the femur and lumbar spine before and after treatment. However, group G1 presented a statistical significant TBC loss after 12 months of treatment compared to initial values. In contrast, no TBC loss was observed in the group treated with LT-4 in combination with CT, a fact that may suggest that CT was responsible for the lower bone reabsorption during treatment of hypothyroidism.

Avaliaçäo da resistência óssea com e sem a administraçäo prévia de calcitonina de salmäo em ratos com desnutriçäo protéica / Evaluation of osseous resistance with and without previous adminsitration of salmon calcitonin in rats with proteic malnutrition

Foi realizado trabalho experimental com ratos da raça Wistar para avaliar a influência da calcitonina de salmao e da desnutriçao protéica, isoladas e associadas, na resistência mecânica e na rigidez do tecido ósseo. Os ratos foram divididos em quatro grupos: dieta normal, dieta normal mais calcitonina, desnutridos, desnutridos mais calcitonina. Após duas semanas, foram submetidos a fratura manual da tíbia direita e, ao término de seis semanas, sacrificados. Foram avaliados os parâmetros mecânicos de resistência e rigidez óssea das tíbias fraturadas e nao fraturadas (controle) dos quatro grupos. Concluiu-se que: a administraçao de calcitonina reduziu a resistência máxima das tíbias-controle do grupo com dieta normal; a resistência e rigidez das tíbias fraturadas (processo de consolidaçao) e controle (processo de remodelaçao) foram prejudicadas pela desnutriçao protéica; no grupo desnutrido, a administraçao de calcitonina nao compensou a diminuiçao da resistência e da regidez das tíbias, mas reduziu a ocorrência de pseudartrose.

Açäo da calcitonina na resoluçäo de perfuraçöes ósseas em coelhos: controle fotodensitométrio e histológico / Effects of calcitomin in resolution of bone perforations in rabbits: photodensitometric and histogic control

Os autores estudam os efeitos da calcitonina humana sintética (CHS) em perfuraçöes ósseas de ulnas de 13 coelhos, agrupados em uma amostra controle e um grupo tratado com CHS, na dose de 0,34UI (0,34mg) em duas administraçöes diárias por via IM durante 15 dias. Como parâmetros evolutivos utilizaram-se a microfotodensitometria, método destinado a avaliar a densidade óssea das áreas perfuradas, e também a verificaçäo das condiçöes histopatológicas locais após 15 dias de reparaçäo óssea. Os resultados obtidos ressentem-se do pequeno número da amostra; contudo, permitem supor que, através de mecanismos näo inteiramente confirmados, a calcitonina parece ter interferido positivamente na reparaçäo das perfuraçöes ósseas

Endocrine regulation of calcium and phosphate in rat eye lens and its significance in cataract formation.

Parathyroid hormone (PTH), calcitonin (CT)and calciferol (Vit. D3) operate synchronously to maintain a balance between calcium and phosphate levels in serum. An aberration of specific steps in the homeostatic process results in hypo/hyper phosphatemia. These aberrations may eventually lead to several diseased states. PTH and Vit. D3 induced hypercalcemia can, however, be significantly inhibited by calcitonin (CT). These findings have been correlated with the levels of calcium and phosphate obtained from human senile cataractous lenses of cortical and nuclear types. The comparison of the results indicate that amongst these three hormones PTH is most vulnerable in leading towards conditions for possible cataract formation in rat lens.

Effect of calcitonin on hepatic drug metabolism

A single dose of calcitonin (150 mIU/100g body weight, sc) produced a significant decrease in liver antipyrine hydroxylase and aminopyrine demethylase activities. By contrast, pentobarbital sleeping time was not altered by calcitonin treatment. The present results indicate that acute calcitonin administration depresses the metabolism of substrates of the mixed function oxidase system of rat liver