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Date of release: 16 February, 2015

Anabolic and antiresorptive therapy for osteoporosis: combination and sequential approaches


In the recent BoneKEy Reports review [1], it was noted that combinations of anabolic and antiresorptive agents have potential to improve bone density and bone strength more than either agent as monotherapy. Small clinical trials have been performed evaluating combinations of parathyroid hormone (PTH) – PTH 1-34 (teriparatide) or PTH 1-84 – with a variety of antiresorptives including hormone/estrogen therapy, raloxifene, alendronate, risedronate, ibandronate, zoledronic acid, and denosumab. Most of the studies evaluate dual-energy X-ray absorptiometry outcomes, and a few trials report bone mineral density (BMD) by quantitative computed tomography, followed by finite element modeling to calculate bone strength. None of the studies has been powered to assess differences in fracture incidence between combination therapy and monotherapy. BMD outcomes vary based on the timing of introduction of the anabolic agent (before, during, or after antiresorptive treatment), as well as the specific anabolic and antiresorptive used. Furthermore, effects of combination therapies are site-dependent. The most consistent effect of combining antiresorptive agents with PTH 1-84 or teriparatide is a superior hip BMD outcome compared with teriparatide/PTH 1-84 alone. This is most evident when teriparatide/PTH 1-84 is combined with a bisphosphonate or denosumab. In contrast to findings in the hip, in the majority of studies, there is no benefit to spine BMD with combination therapy vs. monotherapy. The two exceptions to this are when teriparatide is combined with denosumab and when teriparatide is given as monotherapy first for 9 months, followed by the addition of alendronate (with continuation administration of teriparatide). Based on what we now know, in patients previously treated with bisphosphonates who suffer hip fractures or who have very low or declining hip BMD, strong consideration should be given to starting teriparatide and continuing a potent antiresorptive agent (possibly switching to zoledronic acid or denosumab) to improve hip BMD and strength quickly. Furthermore, in treatment-naïve individuals with very severe osteoporosis, such as those with spine and hip fractures, combination therapy with teriparatide and denosumab or teriparatide followed by combination treatment with a potent bisphosphonate or denosumab should be considered to maximize early increases in BMD throughout the skeleton.

Comment

The concept of anabolic treatment for osteoporosis is based on directly stimulating bone formation, in order to increase not only bone density and strength but also to reduce osteoporotic fractures. This agent is parathyroid hormone (PTH) in its two presentations: the fraction 1-34 or teriparatide and the intact molecule PTH 1-84 [2, 3]. Therefore its bone-forming effect can be used as monotherapy or in combination therapy according to the characteristics of the patients, especially those who do not respond to other kinds of drugs. 
 
Clinical trials have shown how the combination of anabolics and antiresorptives can improve the density and quality of bone even more than monotherapy [4], and effects are now documented that occur in bone in patients with naïve treatment or in those who were already receiving another type of management.
 
The use of teriparatide in patients previously or currently managed with hormone replacement therapy or raloxifene provided additional effects on BMD in both hips (up by 16%) and spine (an increase of 6%), showing an additive effect [5].
 
When we refer to combination therapy with bisphosphonates, there are different results according to which agent is being used. PTH in combination therapy with alendronate or zoledronic acid shows no increase in spine BMD greater than that observed with monotherapy with teriparatide/PTH 1-84 [6] (PTH 6.3% vs. PTH + alendronate 6.1%) but shows a more consistent increase in hip BMD than monotherapy (teriparatide + zoledronic acid 2.2% vs. teriparatide monotherapy 1.1%) [7]. Studies show that ibandronate use for 18 months in combination therapy with PTH increases not only BMD but also bone formation markers.
 
During the first year of therapy, the combination of teriparatide with denosumab showed a greater increase in BMD at the spine, hip and femoral neck (9.1%, 4.9%, 4.2%, respectively) than with teriparatide monotherapy (6.2%, 0.7%, 0.8%), or denosumab monotherapy (5.5%, 2.5%, 2.1%). However, there were no group differences in the magnitude of these increments in the second year with the combination of teriparatide with denosumab vs. monotherapy.
 
There was no statistical significance in BMD increases when compared with the combined therapy of teriparatide + zoledronic acid [8].
 
Patients being treated for osteoporosis with any other therapy and in whom teriparatide treatment is initiated in addition have shown a rapid increase in bone formation markers and a decrease in bone resorption markers. This is called the anabolic window and represents the greatest opportunity for bone formation [9, 10].
 
It is important to note that approximately 50% of treatments with teriparatide or PTH 1-84 are initiated in patients who are already using antiresorptives and independently of whether they are used as monotherapy [11, 12] or combined therapy [13, 14]; it should be noted that in some patients such as the non-responders, anabolic therapy is an option to increase BMD.
 
In conclusion, this is a type of treatment for osteoporosis that is based on a powerful bone-forming effect and should be considered as an option at the time of patient management. Its use either alone or in combination with other drugs will be a possibly common strategy for management of osteoporosis [2].

Comentario

Andrea Mejia



Santiago Palacios
Palacios Institute of Womens Health, Madrid, Spain

    References

  1. Crandall CJ, Larson JC, Watts NB, et al. Comparison of fracture risk prediction by the US Preventive Services Task Force Strategy and two alternative strategies in women 5064 years old in the Womens Health Initiative. J Clin Endocrinol Metab 2014 Oct 16. Epub ahead of print
    http://www.ncbi.nlm.nih.gov/pubmed/25322268

  2. Quesada JM. Agentes anabólicos óseos para el tratamiento de osteoporosis [Bone anabolic agents for osteoporosis treatment]. Endocrinología y Nutricion 2004;51 (9)


  3. Sosa Henríquez M, Díez Pérez A. Parathyroid hormone in the treatment of osteoporosis. An Med Interna (Madrid) 2007;24:87-97


  4. Cosman F. Combination therapy for osteoporosis: a reappraisal. Bonekey Rep 2014;3:518
    http://www.ncbi.nlm.nih.gov/pubmed/24795812

  5. Ste-Marie LG, Schwartz SL, Hossain A, Desaiah D, Gaich GA. Effect of teriparatide [rhPTH(134)] on BMD when given to postmenopausal women receiving hormone replacement therapy. J Bone Miner Res 2006;21:2839
    http://www.ncbi.nlm.nih.gov/pubmed/16418784

  6. Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003;349:120715
    http://www.ncbi.nlm.nih.gov/pubmed/14500804

  7. Cosman F, Eriksen EF, Recknor C, et al. Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(134)] in postmenopausal osteoporosis. J Bone Miner Res 2011;26:503-11
    http://www.ncbi.nlm.nih.gov/pubmed/20814967

  8. Tsai JN, Uihlein AV, Lee H, et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet 2013;382:506
    http://www.ncbi.nlm.nih.gov/pubmed/23683600

  9. Cosman F, Nieves J, Woelfert L, et al. Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. J Bone Miner Res 2001;16:92531
    http://www.ncbi.nlm.nih.gov/pubmed/11341338

  10. Lindsay R, Nieves J, Formica C, et al. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet 1997;350:5505
    http://www.ncbi.nlm.nih.gov/pubmed/9284777

  11. Miller PD, Delmas PD, Lindsay R, et al. Early responsiveness of women with osteoporosis to teriparatide after therapy with alendronate or risedronate. J Clin Endocrinol Metab 2008;93:378593
    http://www.ncbi.nlm.nih.gov/pubmed/18682511

  12. Boonen S, Marin F, Obermayer-Pietsch B, et al. Effects of previous antiresorptive therapy on the bone mineral density response to two years of teriparatide treatment in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2008;93:85260
    http://www.ncbi.nlm.nih.gov/pubmed/18160462

  13. Cosman F, Nieves JW, Zion M, Barbuto N, Lindsay R. Effect of prior and ongoing raloxifene therapy on response to PTH and maintenance of BMD after PTH therapy. N Engl J Med 2008;19:52935
    http://www.ncbi.nlm.nih.gov/pubmed/17929072

  14. Cosman F, Nieves J, Zion M, Woelfert L, Luckey M, Lindsay R. Daily and cyclic parathyroid hormone in women receiving alendronate. N Engl J Med 2005;353:56675
    http://www.ncbi.nlm.nih.gov/pubmed/16093465


El siguiente comentario es una traduccin de una contribucin original en Ingls enviada a los miembros el Julio 8, 2013. La traduccin ha sido gentilmente efectuada por el

Dr Peter Chedraui

Medición síntomas vulvovaginales en mujeres postmenopáusicas

Erekson y colegas publicaron recientemente en la revista Menopause sobre el desarrollo de un cuestionario de síntomas vulvovaginales (VSQ) para determinar los síntomas, emociones, impacto sobre la vida, y el impacto sexual de los síntomas vulvovaginales en mujeres postmenopáusicas [1]. Ellos realizaron una serie de pruebas de validación que confirmaron la utilidad del cuestionario. Los síntomas vulvovaginales postmenopáusicos incluyen sequedad, ardor, prurito y dispareunia. Los síntomas vulvovaginales son comunes y han sido reportados por 9.6 a 44.4% de mujeres postmenopáusicas. Los autores encontraron que el VSQ es un instrumento confiable y consistente internamente para medir síntomas vulvovaginales en mujeres postmenopáusicas. Los autores demostraron una validez razonable de la VSQ, en particular en la ausencia de un estándar de oro para la medición de síntomas vulvovaginales.

Comentario

La deficiencia de estrógenos impacta sobre el tejido vaginal, reduciendo el flujo de sangre, adelgazando el epitelio vaginal, perdiendo el soporte de colágeno, obliterando los fondos de saco vaginales, aplanando los pliegues vaginales y estrechando y acortando la vagina. De ello se deduce el trasudado vaginal se reduce y la lubricación durante el coito se ve afectada. Los síntomas de la sequedad vaginal, ardor, prurito y dispareunia son comunes en mujeres postmenopáusicas, especialmente cuando a las mujeres se les pregunta directamente. Entre los cambios estructurales de la vulva tenemos labios mayores colgantes debido a la pérdida de tejido graso como resultado de la deficiencia de estrógenos. La deficiencia de estrógenos afecta la vejiga urinaria y la uretra con adelgazamiento del urotelio, en particular la del trígono. Esto se combina con una capacidad vesical reducida como resultado de actividad excesiva del detrusor y aumento del volumen residual postmiccional, lo que lleva a síntomas de frecuencia, urgencia y nocturia. El aumento del pH vaginal por encima de 5 fomenta el crecimiento de bacterias entéricas y por lo tanto el aumento de la incidencia de infección del tracto urinario. Este tema es de importancia clínica y de innecesarios gastos por la atención de la salud, ya que muchas habrán ya tenido reparaciones debido a prolapso o extensas investigaciones urológicas mucho antes de que se instaure una sencilla sustitución local de estrógenos. En la mayoría de los casos, los síntomas mejoran después de 8 semanas de tratamiento intensivo local con estriol y posterior terapia de mantenimiento con estrógenos a largo plazo. De hecho, se puede argumentar que ninguno de esos procedimientos se efectúen antes de asegurar que los tejidos vaginales estén bien estrogenizados. La principal barrera para la comprensión del impacto de estos síntomas sobre la calidad de vida, así como la presentación clínica es la vergüenza de la paciente y su renuencia a discutir los síntomas vaginales con su médico. No hay suficiente material educativo disponible que aborde específicamente la atrofia vaginal postmenopáusica y su amplia prevalencia. Además, muchos médicos no inician preguntas directas sobre los síntomas vaginales, ya que no aprecian la relevancia o se sienten incómodos sobre cómo formular la pregunta y qué respuesta van a proporcionar, abriendo por tanto vías para consultas extendidas. Además, no se entiende en la mayoría de los casos la relevancia de la deficiencia de estrógenos. Diseñar un cuestionario como el VSQ que las mujeres postmenopáusicas pueden completar antes de la consulta con el médico puede ahorrar tiempo y animar al paciente a hablar de sus síntomas. La publicación de Erekson y colegas ha contribuido a la literatura con un intento significativo de proporcionar un cuestionario bien validado que aborda el impacto de los síntomas vulvovaginales. Para el clínico interesado, proporciona un enfoque para un nuevo interrogatorio y una comprensión más profunda de la queja del paciente y ayuda a administrar rápidamente un tratamiento significativo y eficaz. Podría ser utilizado en las visitas de seguimiento para evaluar la respuesta al tratamiento. Se espera con interés el plan de los autores de evaluar las puntuaciones discriminatorias equiparadas con la significancia clínica.

Farook Al-Azzawi

Gynaecology Research Unit, University Hospitals of Leicester, Leicester, UK

References

  1. Erekson EA, Yip SO, Wedderburn TS, et al. The Vulvovaginal Symptoms Questionnaire: a questionnaire for measuring vulvovaginal symptoms in postmenopausal women. Menopause 2013 Mar 11. Epub ahead of print
    http://www.ncbi.nlm.nih.gov/pubmed/23481118

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