Menopause Live - IMS Updates

Date of release: 11 August, 2014

Long-term persistence in postmenopausal women receiving osteoporosis medications

Chronic pharmacologic treatments have the risk of low adherence and persistence which depend on the disease severity, preventive objectives, co-morbidity, other concurrent medications (polymedication) and adverse events. Wade and colleagues [1] reported follow-up data regarding osteoporosis medication persistence and switching at 24 months and 36 months in postmenopausal women from the cohort of the US Prospective Observational Scientific Study Investigating Bone Loss Experience (POSSIBLE). Postmenopausal women (n = 3011) were enrolled by 134 primary-care physicians who were considered to be the top 40% prescribers of osteoporosis medications in 2003. Medications initially prescribed were oral bisphosphonates (alendronate, risedronate, or ibandronate), oral or transdermal postmenopausal estrogen (PME), parathyroid hormone, calcitonin, raloxifene, or a non-prescription agent (calcium and/or vitamin D supplement). 


At baseline, bone mineral density (BMD) corresponded in 50% to osteopenia, in 44% to osteoporosis, and the remaining 6% did not have a densitometry measurement or had another diagnosis. Mean body mass index and age for the entire population were 26.5 kg/m2 (95% confidence interval 26.3–26.7) and 64.6 years, respectively. Twenty-three percent had a history of fractures since the age of 45 years and 9% were current smokers. Patients completed questionnaires at baseline and at semi-annual intervals regarding sociodemographic and lifestyle characteristics, the osteoporosis medications they used, the European osteoporosis-specific health-related quality of life (EuroQoL EQ-5D) and the short version of the Osteoporosis Assessment Questionnaire. Physician-relevant medical data were updated at routine visits during the 3 years of follow-up. Persistence of treatment at 24-month follow-up was 46.2% and at 36 months 36.8%. Women who initiated with a bisphosphonate and then switched during follow-up persisted using the same type of medication. Women who switched from a non-bisphosphonate treatment (including PME) were most likely to switch to a bisphosphonate. In addition, those who used PME at study entry were more likely to completely discontinue therapy both at the 24- and 36-month follow-up.


Predictors of non-persistence in newly initiating therapy or switching to a new treatment were side-effects, low quality of life, smoking and site of residency. Forty-two percent of participants had at least 24 months of treatment persistence and 28% persisted under treatment at the 36 months of follow-up.


The purpose of osteoporosis treatment is to reduce the incidence of low-intensity fractures. The study of Wade and colleagues [1] is devoted to assess the long-term persistence and switching patterns of postmenopausal women using osteoporosis therapies in the US POSSIBLE cohort. Tosteson and colleagues [2] have previously described the initial follow-up results at 1 year. The studied sample included a heterogeneous group of postmenopausal women with osteopenia, osteoporosis, and/or a history of fractures since the age of 45 years recruited by a large number of US primary-care physicians who were among the top prescribers of osteoporosis treatments. Indications for the use of the studied medications would reflect the North American clinical practice as compared to other countries, cultures and/or sociodemographic factors [3]. The most common initial medications prescribed were bisphosphonates (73%), followed by raloxifene (12%) and PME (11%), percentages which remained at the 36-month follow up. Percentages of women under the initial treatment group persisted in the 24- and 36-month follow-ups for all studied therapeutic options. Bisphosphonate users remained in the same treatment group, although a proportion of women using monthly dosing at the initial treatment moved to either a daily or a weekly dosing administration, suggesting that convenience of administration is not the sole value of a chronic treatment election. Other factors were also relevant, including side-effects, medication cost, perceived efficacy, socio-economic factors, physicians’ information, and unknown factors. It is interesting that women treated with hormone therapy discontinued therapy and did not switch to another type of treatment.
It seems that rates of compliance and persistence to osteoporosis treatment are very important to prevent fractures [4], and compliance may be a better predictor of fracture risk than medication persistence [5]. A significant positive association exists between poor adherence and increased risk of osteoporotic fractures, which becomes augmented with longer treatment duration. Poor adherence to treatment increases the risk of osteoporotic fractures in subject with long-term treatment [6]. The results from Wade and colleagues [1] reinforce this issue, although the authors did not include fracture results in the US POSSIBLE cohort. Furthermore, studied women and selected physicians in the US POSSIBLE cohort are not necessarily representative of all patients and medical practices. In fact, therapy persistence and switching of osteoporosis medication were influenced by place of residency within the US and hence patients included in the study are not necessarily representative of the entire population of subjects being treated for osteoporosis. In the POSSIBLE cohort of the European Union, almost 40% of patients received osteoporosis treatment due to a previous fracture while 25% of patients did not have a previous fracture or BMD measurement, suggesting that medications were indicated due to other risk factors [7]. 
The efficacy of anti-fracture drugs for osteoporosis depends on safety and tolerability, convenience of treatment compliance and persistence in the treatment, adverse effects and cost. It cannot be omitted that compliance to treatment also depends on the patient's expected benefits, existing co-morbidity and the patient’s priorities or wishes to treat some conditions or diseases and delays to prevent others. It is possible that novel anti-osteoporotic agents, such as denosumab or systemic bisphosphonates, may improve treatment compliance and persistence [8,9] as compared to the analyzed treatments reported by Wade and colleagues [1]. In addition, it seems that the new, long-acting, anti-osteoporotic compounds may still provide protection against fragile fractures even after treatment interruption [10].
Further studies regarding compliance and treatment persistence are warranted among postmenopausal women with osteoporosis and risk fractures that include the analysis of various other factors such as countries and cultures, perceptions and desires of women about pharmacologic osteoporosis management in the reduction of fragility fracture risk.


Faustino R. Pérez-López
Professor of Obstetrics & Gynecology, University of Zaragoza Faculty of Medicine and Lozano Blesa University Hospital, Zaragoza, Spain


  1. Wade SW, Satram-Hoang S, Stolshek BS. Long-term persistence and switching patterns among women using osteoporosis therapies: 24- and 36-month results from POSSIBLE US™. Osteoporos Int  2014 Jun 19. Epub ahead of print

  2. Tosteson AN, Do TP, Wade SW, Anthony MS, Downs RW. Persistence and switching patterns among women with varied osteoporosis medication histories: 12-month results from POSSIBLE US. Osteoporos Int 2010;21:1769-80

  3. Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY; Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2013;24:23-57

  4. Hadji P, Claus V, Ziller V, Intorcia M, Kostev K, Steinle T. GRAND: the German retrospective cohort analysis on compliance and persistence and the associated risk of fractures in osteoporotic women treated with oral bisphosphonates. Osteoporos Int 2012;23:223-31

  5. Cotté FE, Mercier F, De Pouvourville G. Relationship between compliance and persistence with osteoporosis medications and fracture risk in primary health care in France: a retrospective case-control analysis. Clin Ther 2008;30:2410-22

  6. Sampalis JS, Adachi JD, Rampakakis E, Vaillancourt J, Karellis A, Kindundu C. Long-term impact of adherence to oral bisphosphonates on osteoporotic fracture incidence. J Bone Miner Res 2012;27:202-10

  7. Roux C, Cooper C, Díez-Pérez A, et al. Prevalence of osteoporosis and fractures among women prescribed osteoporosis medication in five European countries: the POSSIBLE EU study. Osteoporos Int 2011;22:1227-36

  8. Mandema JW, Zheng J, Libanati C, Perez Ruixo JJ. Time course of bone mineral density changes with denosumab compared with other drugs in postmenopausal osteoporosis: a dose-response based meta-analysis. J Clin Endocrinol Metab 2014 Jun 10:jc20133795. Epub ahead of print

  9. Roux C, Hofbauer LC, Ho PR, et al. Denosumab compared with risedronate in postmenopausal women suboptimally adherent to alendronate therapy: efficacy and safety results from a randomized open-label study. Bone 2014;58:48-54

  10. Brown JP, Roux C, Törring O, et al. Discontinuation of denosumab and associated fracture incidence: analysis from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. J Bone Miner Res 2013;28:746-52

El siguiente comentario es una traduccin de una contribucin original en Ingls enviada a los miembros el Septiembre 16, 2013. La traduccin ha sido gentilmente efectuada por el

Dr Danny Salazar-Pousada

Controlando la ingesta calórica y el gasto energético puede no ser suficiente para mantener el peso estable

Siempre que se habla de la necesidad de mantener el peso óptimo para reducir el riesgo cardiovascular y otros peligros para la salud, uno siempre va a citar el mantra – comer sano y mantenerse en forma, lo que significa mantener el equilibrio deseado entre la ingesta calórica y el gasto energético. La ecuación estándar dice que 7000 kcal equivalen a 1 kg de grasa, por lo tanto, si el balance de energía en un periodo de tiempo es (-) 7000 kcal, esta cifra negativa también deben ser expresada mientras se está de pie en la balanza, que debería mostrar la reducción de un 1 kg de peso. Todas las guías y las recomendaciones están basadas en esta formulación, y el escenario de fracasar en mantener o reducir el peso a pesar de mantener las instrucciones se atribuye únicamente a la mala adherencia al programa de intervención. Ahora parece que puede haber otras explicaciones. Un estudio publicado recientemente en Science examinó ratones que fueron puestos en un sistema capaz de medir con precisión tanto su ingesta calórica y el gasto de energía [1]. Se compararon dos grupos: ratones normales y aquellos con deleción de la proteína accesoria 2 del receptor de la melanocortina (MRAP2), que se sabe desarrollan obesidad severa a una edad temprana. Incluso cuando se les alimenta con la misma cantidad de comida, los ratones con la deleción (nulos) aumentan más de peso que los ratones normales. Sólo cuando la cantidad de ingesta de alimentos en los ratones nulos fue restringida a un 10% (en hembras) y 13% (machos) menor que la de los ratones de tipo salvaje (normales) hubo un aumento equivalente de peso. Este fue el caso mientras los ratones eran jóvenes, pero, en etapas posteriores de su vida, los ratones nulos demostraron hiperfagia y aumento de peso asociado.


La familia del receptor de la melanocortina (MCR) se compone de cinco receptores acoplados a proteínas G (MC1R-MC5R) con diferentes funciones fisiológicas [2]. Ellos median la señalización en respuesta a la hormona adrenocorticotrópica (ACTH) y hormona α-estimulante de melanocitos (αMSH) y sus antagonistas competitivos, agouti y- proteína agouti relacionada. La actividad de los subtipos de MCR es el siguiente: MC1R controla la pigmentación, MC2R es un componente crítico del eje hipotalámico-pituitario-adrenal, MC3R y MC4R desempeñan un papel fundamental en la homeostasis de la energía, y MC5R está involucrado en la función exocrina. La proteína accesoria del receptor de melanocortina (MRAP) y su homologo MRAP2 son pequeñas proteínas transmembrana de un solo paso que han mostrados regular la expresión y función del MCR. En la glándula suprarrenal, MRAP es un factor accesorio esencial para la expresión funcional del receptor de MC2R/ACTH. MC2R también se expresa en el tejido adiposo junto con MC5R, donde controlan los efectos lipolíticos potentes de ACTH y α-MSH. Al mismo tiempo, hay evidencia de que la señalización mediada por MC2R y MC5R en los adipocitos inhibe la producción de leptina, indicando que posiblemente hay un mecanismo de control para la modulación de la función del tejido adiposo a través del eje-leptina melanocortina. La pérdida sea de MC2R o MRAP en humanos causa una grave resistencia a la ACTH, con la consiguiente deficiencia de glucocorticoides. Todos los mamíferos tienen un gen homologo, MRAP2, que se expresa predominantemente en el cerebro, más prominentemente en la protuberancia y el cerebelo, pero también en regiones que participan en la homeostasis energética, tales como el hipotálamo y el tronco cerebral. MRAP2 interactúa con MC3R, que está implicado en la regulación del peso corporal y el metabolismo energético. En ratones nulos, que carecen del gen MC3R, los nutrientes se dividen preferentemente en grasa a expensas de la masa magra [3]. Es importante destacar que el aumento de la eficiencia de alimentación, no la hiperfagia, provoca un aumento de peso en estos ratones. Para investigar si las alteraciones en MRAP2 se asocian con la obesidad humana, las personas obesas y su control se estudiaron para mutaciones potencialmente relevantes [1]. Sólo pocas variantes raras se encontraron en la cohortes de obesos, indicando que, si las mutaciones MRAP2 contribuyen a la obesidad grave en el hombre, rara vez lo hacen. Tal vez esto es un alivio, pero en mi mente el estudio abre una nueva perspectiva en la comprensión del sobrepeso ya que otras, aberraciones genéticas no identificadas podrían estar involucradas en el manejo anormal de la energía y el consiguiente aumento de peso. En conclusión, se encontró que la inactivación global o específica cerebral de MRAP2 causa obesidad en ratones y que variantes raras heterocigóticas en MRAP2 se asocian con inicio temprano de obesidad severa en los seres humanos. Los mecanismos por los cuales MRAP2 ejercen sus efectos sobre la regulación del peso corporal aún no se han establecido firmemente, pero muy probablemente impliquen alteración de señalización a través de los diversos MCR.

Department of Medicine T, Ichilov Hospital, Tel-Aviv, Israel

Department of Medicine T, Ichilov Hospital, Tel-Aviv, Israel


  1. Asai M, Ramachandrappa S, Joachim M, et al. Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science 2013;341:275-8.

  2. Novoselova TV, Jackson D, Campbell DC, Clark AJ, Chan LF. Melanocortin receptor accessory proteins in adrenal gland physiology and beyond. J Endocrinol 2013;217:R1-11.

  3. Chen AS, Marsh DJ, Trumbauer ME, et al. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet 2000;26:97102.

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