Revisión de las implicaciones clínicas del ácido zoledrónico en el tratamiento del dolor

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Abstract

Introducción: El hueso representa aproximadamente el 40% de las primeras recurrencias del cáncer, presentando una mayor incidencia en pacientes a los que se ha diagnosticado mieloma múltiple, cánceres de mama, pulmón y próstata. El dolor óseo es el tipo de dolor oncológico más frecuente y constituye un síntoma que afecta de forma considerable la calidad de vida del paciente. Se trata de un proceso que no podemos curar, pero si se ha conseguido un buen control de sus síntomas. Los bifosfonatos son potentes inhibidores de la resorción ósea normal y patológica, con un importante impacto en el tratamiento de las metástasis óseas. El ácido zoledrónico es el bifosfonato más utilizado para el tratamiento de las metástasis óseas. Está aprobado para la prevención de complicaciones óseas en pacientes con neoplasias avanzadas que afectan al hueso: mieloma múltiple, cáncer de próstata, cáncer de mama, cáncer pulmonar y otros tipos de tumores sólidos. También está indicado para el tratamiento de la hipercalcemia de origen tumoral. La Comisión Europea ha autorizado la comercialización del ácido zoledrónico para el tratamiento de la enfermedad de Paget. Eficacia: Son diversos los estudios que demuestran la eficacia del ácido zoledrónico en el tratamiento de diversas patologías. Se han llevado a cabo múltiples estudios in vitro que ponen de manifiesto la actividad antitumoral del ácido zoledrónico. También se ha demostrado que la administración de estos fármacos puede producir un efecto aditivo o sinérgico con otros agentes antitumorales. Se han realizado múltiples estudios in vivo que demuestran que el ácido zoledrónico puede inhibir la formación o progresión de las metástasis óseas y/o reducir el crecimiento del tumor óseo. Efectos adversos: Los bifosfonatos pueden producir efectos adversos a nivel renal, que en caso de administración intravenosa parecen estar relacionados con la dosis administrada y el tiempo de perfusión, aumentando al aumentar la velocidad de perfusión. Estudios in vitro e in vivo han demostrado que la tolerabilidad renal del ácido zoledrónico es mayor que la del pamidronato. En los ensayos clínicos en pacientes con metástasis óseas e hipercalcemia de origen tumoral, el ácido zoledrónico presentó un perfil de seguridad aceptable. Los acontecimientos adversos comunicados con más frecuencia fueron: síndrome seudogripal, reacciones gastrointestinales, anemia, debilidad, tos, disnea y edema. Coste efectividad: El costo económico de las complicaciones esqueléticas relacionadas con la neoplasia es muy elevado, contribuyendo al incremento del coste la radioterapia ósea y el ingreso hospitalario. No obstante existe una gran variabilidad de los costos en pacientes con cáncer en estadio avanzado, lo que dificulta la obtención de resultados. Discusión: Teniendo en cuenta la evidencia existente de la actividad antitumoral que posee el ácido zoledrónico, debemos centrarnos en el conocimiento de los mecanismos implicados y poder determinar la dosis más efectiva para poder maximizar este potencial efecto antitumoral. Los objetivos que debemos plantearnos ahora ante un paciente diagnosticado de metástasis ósea, se basan en establecer el momento adecuado de inicio de tratamiento con ácido zoledrónico así como la duración del mismo en función de la respuesta terapéutica.

Translated abstract

Introduction: Bone approximately represents 40% of cancer recurrences , with a higher incidence in patients with múltiple myeloma, breast, lung and prostate cancer. Bone pain is the most frequent and considerably affects patients´ life quality. Although resolution is not possible, symptom control is. Biphosphonates are powerful inhibitors of normal and pathological bone resorption and have an important effect on bone metastasis. Zoledronic acid is the most frequently used biphosphonate for this purpose. It has been approved for the prevention of complications related to bone metastasis in multiple myeloma , prostate, breast, lung cancer and other types of solid tumours. It is also approved for the treatment of tumour-induced hypercalcemia. The European Commission has authorized the use of zoledronic acid for the treatment of Paget disease. Effectiveness: Several studies demonstrate the effectiveness of zoledronic acid for the treatment of diverse conditions. In vitro studies showing the antitumour activity of zoledronic acid have been carried out. It has also been shown that it can have an additive or synergistic affect with other antitumour agents. Multiple in vivo studies demostrate that zoledronic acid can inhibit the formation or progression of bone metastasis and reduce the growth of bone tumour. Adverse effects: Biphosphonates can cause renal adverse effects, related to dose and rate of infusion when administered intravenously. In vitro studies demonstrate a better tolerance of zoledronic acid when compared to pamidronate. Clinical trials have shown an acceptable security profile in patients with bone metastasis and hypercalcemia of tumour origin. Reported adverse events were flu-like symptoms, gastrointestinal reactions, anemia, weakness, cough, dyspnea and edema. Cost-effectiveness: The economic cost of cancer-related skeletal complications is very high, also due to the cost of radiotherapy and hospital stay. The great variability of cost in patients with advanced cancer makes the analysis difficult. Discussion: Considering the existing evidence of the antitumour activity of zoledronic acid, it is necessary to elucidate the mechanisms involved and to determine the most effective dose, in order to maximize this potential effect. The objectives that must be considered when bone metastasis are diagnosed should be focused in the most suitable moment to start the treatment with zoledronic acid, as well as its duration depending on the therapeutic answer.

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Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients.

L Bubendorf, A Schöpfer, U. Wagner … (2000)

The prognosis of prostate cancer is mainly determined by the presence or absence of metastases. Nevertheless, the metastatic pathways in prostate cancer are not entirely understood. Among 19,316 routine autopsies performed from 1967 to 1995 on men older than 40 years of age, the reports from those 1,589 (8.2%) with prostate cancer were analyzed. Hematogeneous metastases were present in 35% of 1,589 patients with prostate cancer, with most frequent involvement being bone (90%), lung (46%), liver (25%), pleura (21%), and adrenals (13%). Several lines of evidence suggested the existence of a backward metastatic pathway through veins from the prostate to the spine in addition to classical hematogeneous tumor spread via the vena cava. First, there was an inverse relationship between spine and lung metastases, suggesting that metastasis to the spine is independent of lung metastasis. Second, the maximum frequency of spine involvement occurred in smaller tumors (4 to 6 cm) as compared with the maximum spread to lung (6 to 8 cm) and liver (>8 cm), suggesting that spine metastases precede lung and liver metastases in many prostate cancers. Third, there was a gradual decrease in spine involvement from the lumbar to the cervical level (97% v 38%), which is consistent with a subsequent upward metastatic spread along spinal veins after initial lumbar metastasis. The results of this study show that bone, lung, and liver are the most frequent sites of distant prostate cancer metastases. Besides the cava-type of metastasis through lung passage, there are strong arguments for the existence and clinical significance of a backward venous spread to the spine, which is likely to occur early in the metastatic process.

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Cellular and molecular mechanisms of action of bisphosphonates.

Alex D. Rogers, Chris Frith, Marnita Benford … (2000)

Bisphosphonates currently are the most important class of antiresorptive agents used in the treatment of metabolic bone diseases, including tumor-associated osteolysis and hypercalcemia, Paget's disease, and osteoporosis. These compounds have high affinity for calcium and therefore target to bone mineral, where they appear to be internalized selectively by bone-resorbing osteoclasts and inhibit osteoclast function. This article reviews the pharmacology of bisphosphonates and the relation between the chemical structure of bisphosphonates and antiresorptive potency, and describes recent new discoveries of their molecular mechanisms of action in osteoclasts. Bisphosphonates can be grouped into two pharmacologic classes with distinct molecular mechanisms of action. Nitrogen-containing bisphosphonates (the most potent class) act by inhibiting the mevalonate pathway in osteoclasts, thereby preventing prenylation of small GTPase signaling proteins required for osteoclast function. Bisphosphonates that lack a nitrogen in the chemical structure do not inhibit protein prenylation and have a different mode of action that may involve the formation of cytotoxic metabolites in osteoclasts or inhibition of protein tyrosine phosphatases. Bisphosphonates are highly effective inhibitors of bone resorption that selectively affect osteoclasts. After more than 30 years of clinical use, their molecular mechanisms of action are only just becoming clear.

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Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates.

J E Dunford, K Thompson, F P Coxon … (2001)

It has long been known that small changes to the structure of the R(2) side chain of nitrogen-containing bisphosphonates can dramatically affect their potency for inhibiting bone resorption in vitro and in vivo, although the reason for these differences in antiresorptive potency have not been explained at the level of a pharmacological target. Recently, several nitrogen-containing bisphosphonates were found to inhibit osteoclast-mediated bone resorption in vitro by inhibiting farnesyl diphosphate synthase, thereby preventing protein prenylation in osteoclasts. In this study, we examined the potency of a wider range of nitrogen-containing bisphosphonates, including the highly potent, heterocycle-containing zoledronic acid and minodronate (YM-529). We found a clear correlation between the ability to inhibit farnesyl diphosphate synthase in vitro, to inhibit protein prenylation in cell-free extracts and in purified osteoclasts in vitro, and to inhibit bone resorption in vivo. The activity of recombinant human farnesyl diphosphate synthase was inhibited at concentrations > or = 1 nM zoledronic acid or minodronate, the order of potency (zoledronic acid approximately equal to minodronate > risedronate > ibandronate > incadronate > alendronate > pamidronate) closely matching the order of antiresorptive potency. Furthermore, minor changes to the structure of the R(2) side chain of heterocycle-containing bisphosphonates, giving rise to less potent inhibitors of bone resorption in vivo, also caused a reduction in potency up to approximately 300-fold for inhibition of farnesyl diphosphate synthase in vitro. These data indicate that farnesyl diphosphate synthase is the major pharmacological target of these drugs in vivo, and that small changes to the structure of the R(2) side chain alter antiresorptive potency by affecting the ability to inhibit farnesyl diphosphate synthase.