Williams Textbook of Endocrinology, 12 Ed

1. Williams Textbook of Endocrinology, 12 Ed

3. Site www.gilbertodenucci.com Dúvidas denucci@gilbertodenucci.com Arquivo Medicamentos utilizados na profilaxia e tratamento da osteoporose

4. Effect of calcium supplements with or without vitamin D on cardiovascular events: based on patient-level data. The panels show the time to first event for 24869 participants in five trials of calcium supplements,1811-15 and the WHI CaD Study participants not taking personal calcium supplements at baseline Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis - BMJ 2011;342:d2040 – Fig 3

5. Osso • É um órgão dinâmico que se remodela constantemente durante a vida. Este processo envolve remoção ou reabsorção de osso de uma superfície óssea e a subsequente deposição de osso novo em uma superfície próxima.

6. Osteoblastos • Células que formam o osso. Eles sintetizam a matrix orgânica e subsequentemente promovem a mineralização da mesma. A matrix orgânica sintetizada pelos osteoblastos é formada por colágeno tipo I e outras proteínas. A síntese é controlada por PTH (paratormônio) e 1,25-dihidroxi vitamina D.

7. Signals Determining Mesenchymal-Cell Differentiation toward Osteoblasts and Signals Acting on Mature Osteoblasts to Enhance Bone Formation. Mechanisms of Anabolic Therapies for Osteoporosis - n engl j med 357;9 www.nejm.org august 30, 2007

8. Elements of Wnt/β-catenin signaling. In the liganded state, binding of Wnt to the frizzled receptor inhibits GSK3 activity through mechanisms involving Axin, Frat-1, and Disheveled (Dsh). Regulation of bone mass by Wnt signaling - The Journal of Clinical Investigation http://www.jci.org Volume 116 Number 5 May 2006

9. Osteoclastos • São células responsáveis pela reabsorção óssea. Apresentam a mesma origem de macrófagos/monócitos. São estimuladas pelo PTH (não apresentam receptores para PTH), RANKL e são inibidas pela calcitonina.

10. Signals Determining Mesenchymal-Cell Differentiation toward Osteoblasts and Signals Acting on Mature Osteoblasts to Enhance Bone Formation. Mechanisms of Anabolic Therapies for Osteoporosis - n engl j med 357;9 www.nejm.org august 30, 2007

11. Elements of Wnt/β-catenin signaling. In the liganded state, binding of Wnt to the frizzled receptor inhibits GSK3 activity through mechanisms involving Axin, Frat-1, and Disheveled (Dsh). Regulation of bone mass by Wnt signaling - The Journal of Clinical Investigation http://www.jci.org Volume 116 Number 5 May 2006

12. Denosumab and bisphosphonates: Different mechanisms of action and effects

14. Osteoporose • Doença esquelética sistêmica caracterizada por baixa massa óssea e deterioração da microarquitetura do tecido ósseo com consequente aumento da susceptibilidade a fraturas

15. Formation Resorption Normal Resorption Formation Formation Resorption High turnover Low turnover Pharmacological Topics of Bone Metabolism: Recent Advances in Pharmacological Management of Osteoporosis - J Pharmacol Sci 106, 530 – 535 (2008)4

17. ??? Williams Textbook of Endocrinology, 12 Ed

18. Williams Textbook of Endocrinology, 12 Ed

19. Osteoporose nos EUA • 1-2 milhões de homens • 6 milhões de mulheres • Custos diretos e indiretos – US$ 20 bilhões nos EUA e US$ 30 bilhões CE

20. Williams Textbook of Endocrinology, 12 Ed

21. Densitometria • Mulheres acima de 65 anos • Mulheres menopausadas que apresentaram fratura • Candidatas a tratamento de osteoporose • Mulheres utilizando reposição hormonal • Mulheres menopausadas abaixo de 65 anos mas que apresentam fatores de risco para osteoporose

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24. Bone mass wich age Integrated Pharmacology – fig 20.2

25. Tratamento • Inibidores da reabsorção óssea • Promotores da formação óssea (anabólico)

26. Inibidores da reabsorção • Cálcio • Vitamina D • Terapia hormonal • Bifosfonados • Moduladores de receptores de estrógeno • Calcitonina

27. Activation of vitamin D3 to form 1,25-dihydroxycholecalciferol and role of vitamin D in controlling the plasma calcium concentration Textbook of Medical Physiology – Guyton & Hall – Fig. 79.6

28. Effect of increasing vitamin D3 intake on the plasma concentration of 25-hydroxycholecalciferol Textbook of Medical Physiology – Guyton & Hall – Fig. 79.7

29. Effect of plasma calcium concentration on the plasma concentration of 1,25-dihydroxycholecalciferol Textbook of Medical Physiology – Guyton & Hall – Fig. 79.8

30. Effect of calcium supplements with or without vitamin D on cardiovascular events: based on patient-level data. The panels show the time to first event for 24869 participants in five trials of calcium supplements,1811-15 and the WHI CaD Study participants not taking personal calcium supplements at baseline Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis - BMJ 2011;342:d2040 – Fig 3

31. Effect of calcium supplements with or without vitamin D on cardiovascular events: based on patient-level data. The panels show the time to first event for 24869 participants in five trials of calcium supplements,1811-15 and the WHI CaD Study participants not taking personal calcium supplements at baseline Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis - BMJ 2011;342:d2040 – Fig 3

32. Effect of calcium supplements with or without vitamin D on cardiovascular events: based on patient-level data. The panels show the time to first event for 24869 participants in five trials of calcium supplements,1811-15 and the WHI CaD Study participants not taking personal calcium supplements at baseline Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis - BMJ 2011;342:d2040 – Fig 3

33. Inibidores da reabsorção • Cálcio • Vitamina D • Terapia hormonal • Bifosfonados • Moduladores de receptores de estrógeno • Calcitonina

37. Inibidores da reabsorção • Cálcio • Vitamina D • Terapia hormonal • Bifosfonados • Moduladores de receptores de estrógeno • Calcitonina • Inibidores de RANKL

40. JClinEndocrinolMetab,July2012,97(7):2272–2282

41. Risedronate Wikipedia

42. Alendronate Wikipedia

43. Pamidronic acid Wikipedia

44. Zoledronate Wikipedia

45. Nitrogenous /N/-containing bisphosphonates:* Pamidronate (APD, Aredia) - 100    * Neridronate - 100    * Olpadronate - 500    * (Fosamax) - 500    * (Boniva) - 1000    * (Actonel) - 2000    * Zoledronate (Zometa, Aclasta) - 10000

46. A, Nitrogen-containing bisphosphonates selectively inhibit farnesyl pyrophosphate synthase (FPPS) within osteoclasts. B, Osteoclast endocytosis of bisphosphonate from the bone surface leads to FPPS inhibition and osteoclast apoptosis. BP = nitrogen-containing bisphosphonate; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A.

47. Effect of nitrogen-containing bisphosphonates on the mevalonate pathway by inhibiting farnesylpyrophosphate synthase. HMG-CoA, ydroxymethylglutaryl-coenzyme A; PP, pyrophosphate. Fleisch Breast Cancer Res 2002 4:30 doi:10.1186/bcr414

48. Denosumab and bisphosphonates: Different mechanisms of action and effects

49. Biphosphonates and Denosumab – different mechanisms of action Denosumab and bisphosphonates: Different mechanisms of action and effects