

Relación del estroncio con el metabolismo mineral óseo y la osteoporosis. Una revisión de la literatura(Relationship between strontium, bone mineral metabolism and osteoporosis. A literature review)David Picón-Borregales 1, Pablo Eligio Carrero1, Luis Vicente Gutiérrez-Peña 1,2, José Ramón Vielma 2,31 Laboratorio de Espectroscopia Molecular, Facultad de Ciencias, Universidad de Los Andes (ULA), Mérida, estado Mérida, Venezuela.2 Laboratorio de Análisis Químico (LAQUNESUR), Universidad Nacional Experimental Sur del Lago “Jesús María Semprum” (UNESUR), Santa Bárbara de Zulia, estado Zulia, Venezuela.3 Laboratorio de Fisiología de Parásitos, Centro de Biofísica y Bioquímica (CBB), Instituto Venezolano de Investigaciones Científicas (IVIC), Altos de Pipe, estado Miranda, Venezuela.Recibido: 14 de Marzo de 2017. Aceptado: 17 de Julio de 2017. Publicado online: 11 de Septiembre de 2017. [REVISIÓN]PII: S2477-9369(16)06018-RResumen (español)El propósito de ésta revisión es describir la posible relación entre el estroncio, el metabolismo mineral óseo y la osteoporosis. El estroncio es un metal alcalinotérreo poco abundante en la naturaleza, actualmente utilizado en el tratamiento de los pacientes con osteoporosis que poco o nada responden al tratamiento con bifosfonatos orales o intravenosos, en este caso el fármaco de elección puede ser el ranelato de estroncio. Actualmente, el vínculo entre el estroncio y la osteoporosis es objeto de investigación y se ha sugerido a este elemento como nuevo biomarcador del metabolismo óseo. El estroncio puede intercambiarse equimolarmente con el calcio en una relación 1:10 e integrarse en los cristales de hidroxiapatita sin afectar las propiedades óseas; de igual forma se establece que favorece la formación ósea, el aumento de la densidad mineral ósea, a la vez que frena la resorción del hueso.Palabras clave (español)Osteoporosis, estroncio, fisiopatología, terapéutica.Abstract (english)The aim of this review is to describe the possible link between strontium with bone mineral metabolism and osteoporosis. Strontium is an alkaline earth metal that is not very abundant in nature, currently used, as strontium ranelate, in the treatment of patients with osteoporosis who hardly respond or do not respond to treatment with oral or intravenous bisphosphonates. The link between strontium and osteoporosis is being investigated and the possibility of including this element as new biomarker of bone metabolism has been recently suggested. Strontium can be equimolarly exchanged with calcium in a 1:10 ratio and it is integrated into the hydroxyapatite crystals without affecting bone properties; it is well-known that strontium favors both bone formation, and an increase in bone mineral density, while slows down the bone resorption.Keywords (english)Osteoporosis, strontium, pathology, therapeuticsIntroducciónLa osteoporosis es uno de los mayores problemas de salud pública a nivel mundial, la cual afecta principalmente a las mujeres posmenopáusicas, siendo considerada como la enfermedad del siglo (1-5). La enfermedad, de etiología multifactorial, es silente hasta que aparecen las fracturas, su complicación más importante, que pueden incapacitar al paciente afectando su calidad de vida. El diagnóstico se realiza a través de la densitometría ósea, aplicada principalmente en la columna vertebral y la cadera, la cual refleja la densidad mineral ósea (DMO). Una disminución en la DMO está asociada a la aparición de fracturas (6-10). Los criterios diagnóstico de esta enfermedad, según la organización mundial de la salud (OMS), consideran la evolución de los valores de la masa ósea con la edad, evaluados como DMO, la prevalencia e incidencia de las fracturas osteoporóticas en mujeres postmenopáusicas de raza blanca (11). Así se definen cuatro categorías: - Normal: cuando la DMO es superior a -1 desviación estándar (DE) en la escala T.- Osteopenia: cuando la DMO se ubica entre -1 y -2,5 DE en la escala T.- Osteoporosis: valores de DMO inferiores a -2,5 DE en la escala T.- Osteoporosis grave o establecida: cuando al criterio de osteoporosis, se le añade la presencia de fracturas (11).Los bifosfonatos, por vía oral o intravenosa, constituyen el tratamiento de elección de acuerdo con la mayor parte de las guías clínicas, siendo posibles alternativas la teriparatida, el denosumab, los moduladores selectivos de los receptores estrogénicos (SERMs) y el ranelato de estroncio (Sr) (12-15). La prolongación del tratamiento a largo plazo ha desarrollado el temor a algunas complicaciones como la osteonecrosis de maxilares o las fracturas diafisarias (16).El Sr es un metal alcalinotérreo poco abundante en la naturaleza. El Sr está presente en el ranelato de Sr, la sal dibásica del ácido ranélico, uno de los medicamentos utilizados en el tratamiento de la osteoporosis. El posible vínculo entre ciertos elementos traza, como el Sr, el boro, además de otros elementos y una enfermedad tan compleja y multifactorial como la osteoporosis, constituye una excelente línea de investigación por abordar (17-19). Además, los estudios recientes sobre pequeñas moléculas de ARN designadas como micro ARNs (miRNAs) y la creciente información sobre la epigenética de la osteoporosis, constituyen aspectos novedosos que serán comprendidos con mayor profundidad en los años venideros (20). El objetivo del presente trabajo es describir la relación del Sr con el metabolismo mineral óseo y la osteoporosis, partiendo de las hipótesis derivadas del mecanismo de acción del ranelato de Sr, la utilidad de este elemento en el tratamiento preventivo de las fracturas y como posible biomarcador del metabolismo mineral óseo.Relación del estroncio con la osteoporosisPapel biológico del estroncio. El Sr, junto al calcio y el magnesio, son metales alcalinotérreos que pertenecen al grupo 2 de la tabla periódica. La corteza terrestre contiene 0,03 % de Sr, del cual una parte es distribuido en al agua (21). Este metal ingresa al organismo por medio de la alimentación (ver figura 1). Una dieta estándar aporta de 2 a 4 mg Sr/día, que provienen, mayoritariamente, de cereales y vegetales. Un hombre sano, de 70 Kg, contiene en promedio 320 mg de Sr, por lo tanto, se considera al Sr, un metal traza en el cuerpo humano. Este elemento, tiene un comportamiento químico similar al calcio y en los fluidos biológicos, como el suero o el plasma, pueden tener grados diferentes de unión a las proteínas. Por esta razón, el Sr tiende a imitar las acciones del calcio, aunque la respuesta a la estimulación, usualmente, es más débil. El catión Sr2+ se intercambia equimolarmente con el calcio y se incorpora en los cristales de hidroxiapatita (Ca10(PO4)6(OH)2), mineral del cual está constituido el hueso (22).134El Sr aparentemente produce una acción anabólica, la cual ha generado interés, en el estudio de los mecanismos que promueven la formación de los huesos. Los primeros estudios sobre la influencia del Sr en el metabolismo óseo, fueron realizados en ratas ooforectomizadas que es “el modelo animal” para investigar la osteoporosis posmenopáusica. A este modelo experimental, se le administraron dosis variables de sales inorgánicas (23-24) y orgánicas de Sr (25-26). En ambos casos fue observado que, el tratamiento a corto y largo plazo con este metal, impedía la pérdida del hueso trabecular, que había sido inducido por la deficiencia de estrógenos (27). Figura 1. Papel biológico del estroncio en el cuerpo humano. El Sr2+ es el metal alcalinotérreo menos abundante en la naturaleza, sus principales fuentes son la celestina y la estroncianita. El ingreso ocurre principalmente por el consumo de agua y alimentos de forma natural; otra vía es la inhalación de polvos de estroncio sin riesgo para la salud humana hasta miles de partes por millón (ppm). Medicamentos a base de sales de Sr y particularmente del ranelato de Sr, permiten un intercambio dosis dependiente del metal por el calcio, en una proporción de 10 :1, sin alterar las propiedades óseas. En general los compuestos hidrosolubles de Sr pueden llegar a ser más tóxicos en comparación a los liposolubles. Altas dosis del cromato de estroncio y el isótopo radioactivo 90Sr (útil en reactores nucleares) pueden llegar a generar cáncer y comprometer la vida humanaPosteriormente algunos experimentos, llevados a cabo in vitro e in vivo, demostraron que bajas dosis de sales de Sr, estimulaban la formación y el volumen óseo en roedores y humanos (28-31). El Sr tiene una mayor tendencia a incorporarse en el hueso trabecular que en el cortical (27) y no depende únicamente de la estructura y del tipo óseo (28, 30, 32). La mayor concentración de Sr se ha encontrado en la cresta iliaca, que está formada principalmente por el hueso trabecular en comparación con la diáfisis del fémur (33).En los estudios de intervención terapéutica de osteoporosis espinal (SOTI, acrónimo en inglés), realizados a mujeres posmenopáusicas con osteoporosis, el tratamiento con ranelato de Sr redujo el riesgo relativo de padecer fracturas vertebrales, en comparación con el grupo control que fue tratado con placebo (34). De igual manera, en los estudios de tratamientos de osteoporosis periférica (TROPOS, acrónimo en inglés), el riesgo de sufrir fracturas de cadera y de otros huesos no vertebrales, se redujo en pacientes de edad avanzada (35, 36).135133Durante los estudios SOTI y TROPOS, el ranelato de Sr fue administrado a 3352 pacientes, de las cuales, 2315 recibieron el tratamiento durante, al menos, 36 meses. La incidencia conjunta de efectos adversos no presentó diferencias estadísticamente significativas con respecto al grupo control (placebo) y fueron, en general, leves y pasajeras. Los efectos secundarios más comunes fueron nauseas, diarrea, pérdida de memoria, dermatitis y eczema (34, 36). Estos últimos, también fueron señalados en pacientes tratadas con otros medicamentos contra la osteoporosis.La tabla 1 resume algunos trabajos seleccionados relacionados al efecto clínico del ranelato de estroncio en las pacientes con osteoporosis. Recientemente, la Agencia Europea de Medicamentos (AEM) señaló que el ranelato de Sr puede aumentar el riesgo de sufrir infarto al miocardio y tromboembolismo venoso (40). Por lo tanto, este medicamento está contraindicado en pacientes con antecedentes de enfermedades cardiovasculares como la enfermedad cardiaca isquémica, arteriopatía periférica, así como también, accidente o enfermedad cerebrovascular (41, 42). Por lo anteriormente expuesto, el ranelato de Sr no debe ser considerado como primera opción terapéutica, en pacientes de avanzada edad con osteoporosis. Tabla 1. Estudios clínicos controlados con el uso del ranelato de estroncio en pacientes con osteoporosis.Características generalesNúmero de pacientes del grupo de estudioNúmero de pacientes del grupo controlParámetros evaluadosObservacionesReferenciaMujeres posmenopáusicas con osteoporosis incluidas en estudios TROPOS a y SOTI b1594 mujeres tratadas con ranelato de estroncio.1624 mujeres a las que se les administró un placebo.Índice de kifosis (KI), riesgo relativo a fracturas, calidad de vida.La progresión de kifosis torácica en un período de tres años de seguimiento es menor en el grupo de estudio en comparación al control.Roux y col., 2010 (37)Mujeres posmenopáusicas con osteoporosis (TROPOS).a) Subgrupo ITT c = 2479 mujeres tratadas con ranelato de estronciob) Subgrupo de alto riesgo a fracturas = 982 mujeres tratadas con ranelato de estroncio.a) Subgrupo ITT = 2453 mujeres tratadas con placebo.b) Subgrupo de alto riesgo a fracturas = 995 mujeres a las que se les administró un placebo.Eficacia y seguridad en la prevención de fracturas no-vertebrales.El ranelato de estroncio ofrece un medio seguro y efectivo de reducción del riesgo de fracturas asociadas a la osteoporosis.Reginster y col., 2005 (36)Mujeres posmenopáusicas con osteoporosis incluidas en estudios TROPOS y SOTI.285 mujeres con fracturas no vertebrales tratadas con ranelato de estroncio.1425 mujeres a las que se les administró un placebo Relación de la posesión de la medicación (MPR)Se hace énfasis en la importancia de una buena adherencia al tratamiento para reducir el riesgo de fracturas no vertebrales y de cadera osteoporóticas en el grupo de estudio.Rabenda y Reginster, 2010 (38)5091 mujeres posmenopáusicas con osteoporosis c.2479 mujeres posmenopáusicas con osteoporosis tratadas con ranelato de estroncio.2456 mujeres (grupo placebo)Riesgo relativo a fracturas, incidencia de fracturas no vertebrales.El tratamiento de la osteoporosis posmenopáusica con el ranelato de estroncio resultó en una reducción sostenida en las fracturas no vertebrales osteoporóticas incluyendo fracturas de cadera y fracturas vertebrales durante un período de 5 años de seguimiento.Reginster y col., 2008 (39)1649 mujeres posmenopáusicas con osteoporosis d.719 mujeres integraron el grupo ITT para recibir 2 gr de ranelato de estroncio por día por 3 años.723 mujeres integraron el grupo ITT para recibir el placebo.Cuantificación de la DMO cada 6 mesesEl tratamiento con ranelato de estroncio redujo de forma temprana y sostenida el riesgo de fracturas vertebrales.Meunier y col., 2004 (34).Actualmente, existen dos hipótesis que explican el papel del Sr en la disminución del riesgo de sufrir fracturas en pacientes con osteoporosis. Uno de los posibles mecanismos de acción es el efecto del Sr en el incremento en DMO y el otro sugiere un efecto del Sr en la formación y resorción ósea. A continuación, se discutirán los resultados obtenidos por diversos investigadores que apoyan una u otra hipótesis.Efecto del estroncio en el incremento de la densidad mineral ósea136Desde mediados del siglo pasado era conocido el efecto del Sr en el metabolismo óseo. Un trabajo pionero realizado en 1952, demostró que al adicionar al hueso una cantidad moderada de lactato de Sr, mejoraba el depósito de calcio en el mismo (43). Este resultado sugirió, que este metal, podría ser útil en el tratamiento de las enfermedades óseas. Posteriormente, en un estudio realizado en pacientes con osteoporosis, se encontró que el tratamiento con lactato de Sr, reducía el dolor óseo, a la vez que mejoraba las imágenes radiológicas (44). No obstante, posiblemente debido al conocido efecto desmineralizante que se sabía que producían las dosis elevadas de Sr, éstos relevantes resultados no tuvieron gran influencia en las investigaciones de la época. A principios de los años 90, un grupo de investigación francés comprobó que el compuesto ranelato de Sr, una sal que contiene dos átomos de Sr por molécula de ácido ranélico, incrementaba el volumen óseo sin inducir efectos de desmineralización, además de disminuir la resorción ósea (24, 26). En modelos animales, se ha demostrado que el Sr puede incrementar la resistencia del hueso, por medio de cambios en las propiedades de la matriz ósea. Un estudio realizado a muestras de hueso iliaco de monos tratados con ranelato de Sr, en el cual la distribución de Sr fue determinada y cuantificada mediante de la técnica de difracción de rayos X y espectroscopia Raman, permitió observar cambios en los cristales de hidroxiapatita que forman el hueso (45). En el grupo control, constituido por 4 monos machos sin recibir tratamiento con ranelato, las trazas de Sr se distribuyeron homogéneamente por todo el tejido óseo. En contraposición, en el grupo estudio, constituido por 16 monos machos tratados con dosis diarias entre 100 y 1000 mg/Kg de ranelato, el Sr pudo detectarse solamente en la matriz calcificada, en mayor proporción en la sustancia mineral del hueso trabecular que en la cortical. Así mismo, se indicó que la incorporación del Sr al hueso es dependiente de la dosis (45). Es precisamente en el hueso trabecular donde se sugiere que ocurre la actividad metabólica, por ejemplo, el intercambio por los iones de calcio. Estudios realizados en biopsias de la cresta iliaca, de mujeres con osteoporosis, luego de 36 meses de tratamiento con ranelato de Sr, apoyados en técnicas de difracción de rayos X, demostraron que el Sr se incorpora o se deposita en los cristales de hidroxiapatita de la matriz mineral del hueso (46). El Sr se incorpora preferentemente en el hueso nuevo que en el existente (46-47). Además, se observó que dicha modificación en la composición de la hidroxiapatita, no interfiere con las otras propiedades físicas del hueso como la dureza y la consistencia (47). 137Este resultado contradice una hipótesis previa que indicaba que el Sr se adsorbía, únicamente, sobre la superficie del cristal de hidroxiapatita y que este metal producía un efecto de desmineralización en el cristal óseo. Se conoce que el intercambio de iones calcio (Ca2+) por Sr2+ en la matriz mineral ósea, se realiza a través de sustituciones iónicas, en una relación de un ion Sr2+ por cada diez iones Ca2+ por cristal mineral, dando lugar a hidroxiapatitas del tipo Ca9Sr(PO4)6(OH)2 (48). La incorporación del Sr en el cristal de hidroxiapatita, tiene un efecto en el contenido mineral óseo (CMO), a la vez que retarda la disolución del mineral.Por otro lado, estudios realizados en mujeres posmenopáusicas con osteoporosis, que presentaban fractura vertebral, indicaron que el tratamiento con ranelato de Sr, efectivamente produce un incremento en CMO de la región lumbar, así como también una disminución en la deformación vertebral (49-50). Además, los investigadores observaron un incremento significativo en la fosfatasa alcalina ósea (ALP) y de la osteocalcina, que son considerados biomarcadores de formación del hueso (18, 50-51). Una dosis de 1 a 2 g/día, de ranelato de Sr, resultó efectiva para prevenir la pérdida de masa ósea. Un estudio similar indicó que el tratamiento con Sr, por periodos mayores a un año, fue efectivo en la reducción de fracturas y se asoció a un incremento en la DMO, sugiriendo que la densitometría ósea, podría usarse como herramienta de monitoreo para la enfermedad (52). En este sentido, se ha demostrado una asociación entre el incremento en la DMO del cuello femoral y la disminución en el riesgo de fractura vertebral luego de 5 años de tratamiento con ranelato de Sr (51, 53). Una consideración importante, al momento de interpretar los datos de DMO de pacientes tratados con ranelato, es la influencia que tiene el Sr en dicho parámetro. Un estudio realizado in vitro demostró, que la presencia de Sr en el hueso, induce una sobreestimación sistemática en la medida de DMO y de CMO, cuando se utiliza la técnica de absortimetría dual de rayos X (DXA) (54). Ésta observación, se justifica con el hecho que el Sr, al tener un mayor número atómico (Z=38) que el calcio (Z=20), absorbe más fuertemente los rayos X debido al efecto Compton. La sobrestimación resultó proporcional al contenido de Sr en el hueso e independiente del tipo de equipo utilizado en las medidas. Las investigaciones realizadas al respecto han confirmado, que un contenido de 1 mol/mol% de Sr en hueso, induce una sobreestimación del 10% tanto en la DMO como en CMO (48, 55).Por lo tanto, es importante conocer el contenido de Sr en hueso (CSH) para realizar una corrección en DMO, de manera tal que indique únicamente la absorción de rayos X debida al contenido de calcio en el hueso. Se conoce, que el contenido de Sr es mayor en el hueso trabecular que en el cortical. También se conoce, que existe buena correlación entre los niveles de Sr en plasma y en hueso, por lo tanto es posible estimar el contenido de Sr en hueso a partir de la concentración de este metal en el plasma (55). Otro factor a considerar, es la permanencia del Sr en el hueso tras el tratamiento prolongado con el mismo. Por ejemplo, se estima que luego de un tratamiento prolongado, al menos durante 3 años, un 11% del elemento permanece estrechamente unido al hueso hasta una década después, pudiendo alterar futuros resultados en la DMO (56).Estos estudios apoyan la hipótesis de que el Sr incrementa la DMO, lo cual implica su papel fundamental en la resistencia del hueso frente a las fracturas, a la vez que incrementa el volumen óseo, durante el declive estrogénico propio de la menopausia.Participación del estroncio en la formación y la resorción óseaEl ranelato de Sr aparentemente produce un efecto que se fundamenta en: aumentar la formación y disminuir la resorción ósea de forma simultánea pero en magnitud moderada. De manera tal que permite restablecer el balance entre ambos procesos, en forma análoga al observado en la mujer previo a la menopausia (ver figura 2).138Figura 2. Mecanismos bioquímicos propuestos para los efectos del ranelato de estroncio sobre el metabolismo óseo.Diversas investigaciones realizadas en ratas hembra han demostrado un incremento de la masa ósea, al mismo tiempo que mantiene la mineralización ósea (27, 57). Además, tanto en ratones machos como en hembras, tratados con Sr durante periodos prolongados, se observó un incremento de los biomarcadores de formación y un descenso de los biomarcadores de resorción ósea (58). En ratas ooforectomizadas, el tratamiento con Sr reduce el número células osteoclásticas, que son las células encargadas del recambio de la matriz ósea, en la medida que aumenta la superficie osteoblástica y la tasa de formación ósea, con una magnitud de respuesta similar a la que se obtiene administrando suplementos de estrógenos (26).Este efecto del ranelato de Sr, logra prevenir la pérdida de masa ósea tanto en el fémur como en las vértebras. Incluso en modelos de inmovilización, donde la resorción ósea es alta y la formación ósea es baja, el ranelato de Sr ha logrado corregir ambos efectos y conservar la masa ósea (59).El Sr ejerce su efecto incluso en pequeñas concentraciones. Se ha demostrado que la administración de bajas dosis de sales de Sr (1 mmol L-1) estimula la replicación de las células pre-osteoblásticas en ratas (23, 25, 29, 60). Este efecto es específico para la sal de Sr, pues las sales de calcio y de sodio del ácido ranélico no fueron efectivas. Además, en cultivos celulares, el ranelato de Sr, también provoca un incremento en la síntesis del ADN en las células osteoblásticas (60). Por otro lado en experimentos realizados in vitro, en cultivos de osteoblastos primarios murinos y osteoclastos derivados de calota craneal, el ranelato de Sr fue capaz de estimular la formación osteoblástica e inhibir la osteoclástica, independientemente del grado de proliferación y diferenciación en que se encontraban las células (61).Un estudio llevado a cabo en cultivos de células pre-osteoblásticas MC3T3-E1, confirma que el Sr administrado en forma de ranelato, produce un efecto inductor potente de la osteogenésis, en comparación con el hidróxido y el cloruro de este metal (62). Dicho efecto, también estuvo acompañado de un ligero incremento en la actividad de la fosfatasa alcalina, que está asociada con el fenotipo de los osteoblastos.Así mismo, se ha encontrado evidencia de que el ranelato de Sr también influye en la expresión de los genes encargados de la fisiología ósea (ver figura 2). Bajas concentraciones de SrCl2 (5 x 10-5 mol L-1), pueden incrementar la expresión de los genes implicados en la síntesis la matriz ósea, a saber: SERPINH1 mRNA (type I collagen SERPINH1 mRNA) y reducir la producción de las metaloproteinasas (MMP-1 y MMP-2), sin modificar los niveles de los inhibidores del tejido de las metaloproteinasas (MMPs) designados como TIMPs (acrónimo en inglés) (63).La proteína SERPINH1 está involucrada en la maduración de las moléculas de colágeno. De manera similar, la literatura indica que la estimulación con Sr es capaz de incrementar la expresión de los genes relacionados con los procesos metabólicos del hueso (62) y de la diferenciación osteoblástica, a saber, Runx 2 y BSP. Este último es una sialoproteína ósea (64). Por el contrario, el metal, no ha demostrado efecto sobre el gen de la osteocalcina, proteína implicada en la regulación de la matriz osteoide.Actualmente, existe un creciente interés sobre el papel de los osteocitos en la salud del hueso y en su potencial como dianas terapéuticas. Los osteocitos no son células inactivas residuales, que proceden de osteoblastos activos atrapados en el hueso neoformado, sino que juegan un papel importante en el remodelamiento estructural (65). Estas células son las encargadas de iniciar la reparación del hueso cuando se presentan microroturas (66). Además, participan en la formación de hueso nuevo en respuesta al incremento de la carga (67).139Se ha especulado que una reducción en la densidad de osteocitos se relaciona con fracturas osteoporóticas (68) y que su descenso podría implicar una menor capacidad para detectar microlesiones de la matriz ósea. En consecuencia se producen mayor acumulación de microfracturas y fatiga del material con la edad (69).En estudios in vitro, el ranelato de Sr ha demostrado incrementar la replicación osteoblástica, induciendo un fenotipo similar al osteocito y aumentando la expresión de la fosfatasa alcalina, de STRO-1, del ARNm de la proteína de matriz de la dentina y de la esclerostina, que son biomarcadores que apoyan la existencia de un cambio fenotípico hasta osteocito (70). De esta manera, algunos investigadores sugieren que el tratamiento con Sr es capaz de favorecer la diferenciación de osteoblastos humanos a osteocitos (65). Hasta ahora se ha discutido el efecto favorable del ranelato de Sr al incrementar la formación ósea promoviendo la replicación de osteoblastos. Sin embargo, este fármaco ejerce también un efecto contrario sobre la resorción ósea, pues estudios histomorfométricos evidencian que disminuye el número de osteoclastos y de la superficie osteoclástica (26, 71). Además, dicho fármaco, inhibe, en osteoclastos previamente estimulados, la expresión de anhidrasa carbónica II y el receptor de vitronectina (71). Así como también, aparentemente estimula la producción de la proteína osteoprotegerina (OPG), conocido inhibidor de la osteoclastogénesis, a la vez que suprime el sistema RANKL, conocido como ligando de unión al receptor activador del factor nuclear potenciador de las cadenas ligeras kappa de las células B activadas, designado como NF-kB (72).Es importante mencionar que los osteoclastos son las células encargadas de la resorción de la matriz ósea, cuyo proceso se inicia cuando este tipo celular excreta enzimas lisosomales, principalmente la fosfatasa ácida y la anhidrasa carbónica, lo cual produce un microambiente ácido capaz de disolver las sales minerales del hueso. Recientemente se ha demostrado que el Sr inhibe la proliferación de los cementoblastos, células que participan en la cementogénesis, aunque estas células toleran menores concentraciones de Sr en comparación con los osteoblastos del hueso (73). Aparentemente, el Sr promueve la diferenciación de los cementoblastos por inhibición en la expresión de la esclerostina. De ésta manera, el tratamiento con ranelato de Sr, puede facilitar la reparación del cemento en la raíz dental, en pacientes en los cuales existe un desequilibrio en el proceso de formación/resorción. Tal como se ha discutido hasta este punto, la evidencia científica apoya ampliamente un mecanismo de acción dual para el ranelato de Sr, el cual consiste en la estimulación simultánea de la formación y la reducción de la resorción ósea. No obstante, un nuevo estudio pone en duda esta hipótesis, sugiriendo que ocurre una ligera supresión de la formación del hueso por un pequeño efecto sobre la resorción ósea (74).La investigación realizada en Francia, por el grupo de Chavassieux y col., (74) utilizó una muestra de 387 pacientes, de los cuales, 276 recibieron 2 g/día de ranelato de Sr y 111 recibieron 70 mg/semana de alendronato (este último un bifosfonato), de forma aleatoria. A los pacientes estudiados, antes de aplicar el tratamiento, se les practicó una biopsia del hueso transilíaco. Una segunda biopsia se colectó, a los 6 o 12 meses, luego de cumplido el tratamiento. La robustez, de este estudio, está en que realizó una comparación directa entre ambos medicamentos utilizando las biopsias de hueso obtenidas de cada paciente. Los pacientes tratados con ranelato de Sr presentaron una disminución significativa en los biomarcadores de formación ósea pero sin cambios en la resorción ósea, luego de 12 meses. En los pacientes tratados con alendronato, se observó una disminución mayor en los biomarcadores de formación y de resorción ósea, que aquellos tratados con Sr. Los investigadores concluyeron, que el ranelato de Sr no ejerce una acción anabólica significativa en la remodelación ósea (74).Aunque se habían realizado otros estudios histomorfométricos, a individuos tratados con el ranelato de Sr, estos no permitieron concluir sobre el efecto del ranelato, dado el bajo número de biopsias estudiadas (75-76). Estos resultados vienen a complementar algunos estudios previos que, demostraron que en el tratamiento con ranelato de Sr, los biomarcadores del remodelamiento (recambio óseo), evidenciaron un leve incremento en los marcadores para la formación del hueso y una ligera supresión en la resorción ósea (34).Al comparar con otros fármacos, como los bifosfonatos, se ha reportado una disminución tanto en la resorción como en la formación ósea (76). En opinión de algunos investigadores, las conclusiones del mencionado estudio, esclarecerán finalmente la larga controversia existente en torno al papel biológico o modo de acción del ranelato de Sr en la fisiología ósea y en la osteoporosis (77).Ahora bien, dado que el efecto beneficioso del ranelato de Sr, en el hueso, no se puede explicar meramente por un efecto anabólico en la remodelación del hueso (74), entonces: ¿Cuál es el mecanismo de acción del ranelato de Sr?Perspectivas y consideraciones finales, a partir de los resultados citadosEn nuestra opinión debe existir un efecto físico del Sr, como se discutió en la primera parte de esta revisión, asociado con el incremento observado en las propiedades mecánicas del hueso tales como la elasticidad, la dureza y disipación de la energía en las vértebras, que se ha obtenido por la técnica de nanoidentación, que mide la resistencia del hueso a la deformación, y microtomografía computarizada que confirman, que el ranelato de Sr, modifica la microarquitectura de la matriz ósea (nanocristales de hidroxiapatita) lo cual se refleja en una mejora en los propiedades macroscópicas del hueso y por ende de la resistencia a las fracturas (27, 78-81).Pero la modificación observada en las características físicas tiene su origen en los procesos químicos que ocurren en la matriz ósea y que resultan en la incorporación del Sr al mineral óseo. Actualmente se aceptan dos mecanismos posibles que explican la incorporación del Sr al hueso: en primer lugar, un mecanismo de sustitución interiónica que resulta en la incorporación del Sr en la red cristalina de hidroxiapatita sustituyendo al calcio y en segundo lugar, un mecanismo de intercambio superficial entre la sangre y el mineral óseo (47, 55, 82).A la luz de las últimas evidencias que indican que el ranelato de Sr no ejerce un efecto anabólico en el proceso de formación del hueso y aun sin haberse establecido un mecanismo de acción para explicar los efectos benéficos del fármaco en la población con osteoporosis, queda esperar nuevas investigaciones que permitan escalecer el papel del Sr en los procesos biológicos y químicos involucrados en la formación óseaConflictos de interésLos autores declaran no tener ningún conflicto de interés . 132ReferenciasCurtis EM, Moon RJ, Harvey NC, Cooper C. 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Laboratorio de Fisiología de Parásitos, Centro de Biofísica y Bioquímica (CBB), Instituto Venezolano de Investigaciones Científicas (IVIC), Altos de Pipe, estado Miranda, Venezuela. Teléfono: 058-261-3231179. E-mail: joravig@yahoo.com ; jvielma@ivic.gob.ve Avan Biomed. 2017; 6(2): 133-43.Avan Biomed. 2017; 6(2): 133-43.Avances en BiomedicinaPublicación Oficial del Instituto de Inmunología ClínicaMérida-VenezuelaVolumen 6(2), Agosto 2017, p 133-143Copyright: © ULA 2017Depósito Legal: PPI201102ME3935ISSN: 2477-9369PII: S2477-9369(16)06018-REstroncio, metabolismo mineral óseo y osteoporosis. Picón-Borregales D y colsPicón-Borregales D y cols. Estroncio, metabolismo mineral óseo y osteoporosis. iVBORw0KGgoAAAANSUhEUgAAAtAAAAPACAYAAAAc9k6zAAAAAXNSR0IArs4c6QAAAARnQU1BAACx
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