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Arquivo
Medicamentos utilizados na profilaxia e
tratamento da osteoporose
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.
• Osteoporosis affects ~2 million men in the
US and accounts for ~600,000
• fractures each year.
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 -
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.
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
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
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.
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
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
Denosumab and bisphosphonates: Different mechanisms of action and effects
Osteoporose
• Doença esquelética sistêmica caracterizada
por baixa massa óssea e deterioração da
microarquitetura do tecido ósseo com
consequente aumento da susceptibilidade a
fraturas
Williams Textbook of Endocrinology, 12 Ed
Formation
Resorption
Normal
Resorption
Formation
Resorption
High turnover
Formation
Low turnover
Pharmacological Topics of Bone Metabolism: Recent Advances in Pharmacological Management of Osteoporosis - J Pharmacol Sci 106, 530 – 535 (2008)4
???
Williams Textbook of Endocrinology, 12 Ed
Williams Textbook of Endocrinology, 12 Ed
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
•
Williams Textbook of Endocrinology, 12 Ed
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
???
Bone mass wich age
Integrated Pharmacology – fig 20.2
Tratamento
• Inibidores da reabsorção óssea
• Promotores da formação óssea
(anabólico)
Inibidores da reabsorção
•
•
•
•
•
•
Cálcio
Vitamina D
Terapia hormonal
Bifosfonados
Moduladores de receptores de estrógeno
Calcitonina
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 -
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
Effect of increasing vitamin D3 intake on the plasma
concentration of 25-hydroxycholecalciferol
Textbook of Medical Physiology – Guyton & Hall – Fig. 79.7
Effect of plasma calcium concentration on the plasma
concentration of 1,25-dihydroxycholecalciferol
Textbook of Medical Physiology – Guyton & Hall – Fig. 79.8
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 -
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 -
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 -
Inibidores da reabsorção
•
•
•
•
•
•
Cálcio
Vitamina D
Terapia hormonal
Bifosfonados
Moduladores de receptores de estrógeno
Calcitonina
Inibidores da reabsorção
•
•
•
•
•
•
•
Cálcio
Vitamina D
Terapia hormonal
Bifosfonados
Moduladores de receptores de estrógeno
Calcitonina
Inibidores de RANKL
JClinEndocrinolMetab,July2012,97(7):2272–2282
Risedronate
Wikipedia
Alendronate
Wikipedia
Pamidronic acid
Wikipedia
Zoledronate
Wikipedia
Nitrogenous
/N/-containing bisphosphonates:
* Pamidronate (APD, Aredia) - 100
* Neridronate - 100
* Olpadronate - 500
* (Fosamax) - 500
* (Boniva) - 1000
* (Actonel) - 2000
* Zoledronate (Zometa, Aclasta) - 10000
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.
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
Denosumab and bisphosphonates: Different mechanisms of action and effects
Biphosphonates and Denosumab –
different mechanisms of action
Denosumab and bisphosphonates: Different mechanisms of action and effects
???
JClinEndocrinolMetab,July2012,97(7):2272–2282
JClinEndocrinolMetab,July2012,97(7):2272–2282
INTRAVENOUS ZOLEDRONIC ACID IN POSTMENOPAUSAL
WOMEN WITH LOW BONE MINERAL DENSITY
N. Engl J Med, Vol. 346, No. 9 - February 28, 2002
Age-adjusted and standardized to 2006 Australian population rates of hip fracture in
women and men aged ≥60 years and prescriptions of bisphosphonates, strontium
ranelate, and hormone replacement therapy in the Australian Capital Territory from
1999 to 2008.
Bisphosphonate use and hip fracture epidemiology: ecologic proof from the contrary - Clinical Interventions in Aging 2010:5 355–362 – Fig 1
RANK and RANKL
http://cancergrace.org/cancer-101/2009/04/16/intro-to-denosumab/
Mechanism of Denosumab on Osteoclasts
http://biochemproj.blogspot.com/p/combating-osteoperosis-with-denosumab.html
Denosumab and bisphosphonates: Different mechanisms of action and effects
Calcitonina
• Reduz formação de osteoclastos
• Calcitonina de salmão administrada por via
injetável ou nasal (spray)
• Eventos adversos por via iv: náusea, rubor,
rash cutâneo – limita aderência
• Por via nasal eventos adversos bem menores
Promotores da formação óssea
• PTH
• Ranelato de estrôncio
Approximate changes in calcium and phophate concentration
during the first 5 hours of parathyroid hormone infusion at a
moderate rate
Textbook of Medical Physiology – Guyton & Hall – Fig. 79.10
PTH
• 84 aa
• Teripatida (1-34)
• Administração intermitente (20-40
microg/dia)
• Até dois anos de uso
Homeostatic responses to variation in
dietary calcium
Williams Textbook of Endocrinology, 12 Ed
???
Williams Textbook of Endocrinology, 12 Ed
Parathyroid hormone analogues in the
treatment of osteoporosis – Nature Reviews
???
Parathyroid hormone analogues in the
treatment of osteoporosis – Nature Reviews
PTH analogues in the treatment of osteoporosis
Parathyroid hormone analogues in the
treatment of osteoporosis – Nature Reviews
PTH analogues in the treatment of
osteoporosis
Parathyroid hormone analogues in the
treatment of osteoporosis – Nature Reviews
N Engl J Med 2004;350:4 59:68
N Engl J Med 2004;350:4 59:68
Proportion of Patients in the Intention-to-Treat
Population Who Had One or More New Vertebral Fractures, Assessed
According to the Semiquantitative
Method.
N Engl J Med 2004;350:459-68
Mean (+/-) Percent Change in Bone Mineral Density
Effects of Strontium Ranelate on Bone
Mineral Density in All
Patients Receiving 2 g a Day of Oral
Strontium Ranelate.
P<0.001 for all comparisons, with the use
of a step-down hierarchical procedure.
N Engl J Med 2004;350:459-68
Strontium Ranelate–Induced Changes in Serum
Biochemical Markers of Bone Metabolism.
Panel A shows absolute changes from baseline
values
in
bone-specific
alkaline
phosphatase, Panel B shows absolute changes
from base-line values in C-telopeptide crosslinks, and Panel C shows differences over time
in biochemical markers between the two
groups. Data shown are mean (±SE) values in
the strontium ranelate group minus mean
values in the placebo group. Comparisons
were performed with analyses of covariance in
which base line values were used as
covariates.
N Engl J Med 2004;350:459-68
The Anabolic Window.
Mechanisms of Anabolic Therapies for Osteoporosis - n engl j med 357;9 www.nejm.org august 30, 2007
Study Flow Diagram
Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis - Ann Intern Med. 2008;148:197-213.
Study Flow Diagram
Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis - Ann Intern Med. 2008;148:197-213.
Effect of Agents on Fracture Risk Reduction Compared with
Placebo, by Agent
Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis - Ann Intern Med. 2008;148:197-213.
Effect of Agents on Fracture Risk Reduction Compared with
Placebo, by Agent
Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis - Ann Intern Med. 2008;148:197-213.
Effect of Agents on Fracture Risk Reduction Compared with
Placebo, by Agent
Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis - Ann Intern Med. 2008;148:197-213.
Risk for vertebral fractures relative to placebo for participants who
are at high risk for fracture, by agent.
Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis - Ann Intern Med. 2008;148:197-213.
Risk for nonvertebral fractures relative to placebo for participants
who are at high risk for fracture, by agent.
Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis - Ann Intern Med. 2008;148:197-213.
Risk for hip fractures relative to placebo for participants who are at
high risk for fracture, by agent.
Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis - Ann Intern Med. 2008;148:197-213.
Overview of calcium exchange between defferent tissue compartments in a person
ingesting 1000 mg of calcium per day. Note that most of the ingested calcium is
normally eliminated in the faces, although the kidneys have the capacity to excrete
large amounts by reducing tubular reabsorption of calcium
Textbook of Medical Physiology – Guyton & Hall – Fig. 79.3
Inibidores da reabsorção
•
•
•
•
•
•
Cálcio
Vitamina D
Terapia hormonal
Bifosfonados
Moduladores de receptores de estrógeno
Calcitonina
Tratamento
• Inibidores da reabsorção óssea
• Promotores da formação óssea
(anabólico)
The Canonical Wnt–β-Catenin Signaling Pathway Used in Osteoblasts.
Mechanisms of Anabolic Therapies for Osteoporosis - n engl j med 357;9 www.nejm.org august 30, 2007
Approximate effect of plasma calcium concentration on the
plasma concentrations of parathyroid hormone and calcitonin
Textbook of Medical Physiology – Guyton & Hall – Fig. 79.11
The major enzyme target for bisphosphonates is farnesyl
pyrophosphate synthase (FPPS), and the crystal structure
elucidated for this enzyme reveals how BPs bind to and inhibit
at the active site via their critical N atoms. Inhibition of FPPS
prevents the biosynthesis of isoprenoid compounds (notably
farnesol and geranylgeraniol) that are required for the posttranslational prenylation of small GTP-binding proteins (which
are also GTPases) such as rab, rho and rac, which are essential
for intracellular signalling events within osteoclasts. The
accumulation of the upstream metabolite, isopentenyl
pyrophosphate (IPP), as a result of inhibition of FPPS may be
responsible for immunomodulatory effects on gamma delta ( )
T cells, and can also lead to production of another ATP
metabolite called ApppI, which has intracellular actions.
Williams Textbook of Endocrinology, 12 Ed
???
Williams Textbook of Endocrinology, 12 Ed
Relative potency of analogues of calcitriol in
competitive binding to vitamin D receptors
Williams Textbook of Endocrinology, 12 Ed
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 19, Number 7, 2004
Arch Orthop Trauma Surg, 29March2011 – pg 02