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Site www.gilbertodenucci.com Dúvidas denucci@ gilbertodenucci.com Arquivo Medicamentos utilizados na profilaxia e tratamento da osteoporose. Osso. - PowerPoint PPT Presentation

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Page 1: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Site

www.gilbertodenucci.com

Dúvidas

[email protected]

Arquivo

Medicamentos utilizados na profilaxia e tratamento da osteoporose

Site

www.gilbertodenucci.com

Dúvidas

[email protected]

Arquivo

Medicamentos utilizados na profilaxia e tratamento da osteoporose

Page 2: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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.

Page 3: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo
Page 4: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

• Osteoporosis affects ~2 million men in the US and accounts for ~600,000

• fractures each year.

Page 5: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 6: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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.

Page 7: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Mechanisms of Anabolic Therapies for Osteoporosis - n engl j med 357;9 www.nejm.org august 30, 2007

Signals Determining Mesenchymal-CellDifferentiation toward Osteoblasts and

Signals Acting on Mature Osteoblasts to Enhance Bone Formation.

Page 8: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 9: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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.

Page 10: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Mechanisms of Anabolic Therapies for Osteoporosis - n engl j med 357;9 www.nejm.org august 30, 2007

Signals Determining Mesenchymal-CellDifferentiation toward Osteoblasts and

Signals Acting on Mature Osteoblasts to Enhance Bone Formation.

Page 11: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 12: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Denosumab and bisphosphonates: Different mechanisms of action and effects

Page 13: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo
Page 14: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Osteoporose

• Doença esquelética sistêmica caracterizada por baixa massa óssea e deterioração da

microarquitetura do tecido ósseo com consequente aumento da susceptibilidade a

fraturas

Page 15: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Williams Textbook of Endocrinology, 12 Ed

Page 16: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo
Page 17: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

FormationResorption

Resorption

Resorption

Formation

Formation

Normal

High turnover Low turnover

Pharmacological Topics of Bone Metabolism: Recent Advances in Pharmacological Management of Osteoporosis - J Pharmacol Sci 106, 530 – 535 (2008)4

Page 18: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo
Page 19: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

???

Williams Textbook of Endocrinology, 12 Ed

Page 20: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Williams Textbook of Endocrinology, 12 Ed

Page 21: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 22: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Williams Textbook of Endocrinology, 12 Ed

Page 23: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 24: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo
Page 25: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

???

Page 26: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Bone mass wich age

Integrated Pharmacology – fig 20.2

Page 27: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Tratamento

• Inibidores da reabsorção óssea

• Promotores da formação óssea (anabólico)

Page 28: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Inibidores da reabsorção

• Cálcio• Vitamina D• Terapia hormonal• Bifosfonados• Moduladores de receptores de estrógeno• Calcitonina

Page 29: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 30: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 31: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Effect of increasing vitamin D3 intake on the plasma concentration of 25-hydroxycholecalciferol

Textbook of Medical Physiology – Guyton & Hall – Fig. 79.7

Page 32: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Effect of plasma calcium concentration on the plasma concentration of 1,25-dihydroxycholecalciferol

Textbook of Medical Physiology – Guyton & Hall – Fig. 79.8

Page 33: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 34: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 35: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 36: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Inibidores da reabsorção

• Cálcio• Vitamina D• Terapia hormonal• Bifosfonados• Moduladores de receptores de estrógeno• Calcitonina

Page 37: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo
Page 38: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo
Page 39: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo
Page 40: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Inibidores da reabsorção

• Cálcio• Vitamina D• Terapia hormonal• Bifosfonados• Moduladores de receptores de estrógeno• Calcitonina• Inibidores de RANKL

Page 41: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo
Page 42: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo
Page 43: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 48: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Nitrogenous

/N/-containing bisphosphonates:

    * Pamidronate (APD, Aredia) - 100

    * Neridronate - 100

    * Olpadronate - 500

    * (Fosamax) - 500

    * (Boniva) - 1000

    * (Actonel) - 2000

    * Zoledronate (Zometa, Aclasta) - 10000

Page 49: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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.

Page 50: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 51: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Denosumab and bisphosphonates: Different mechanisms of action and effects

Page 52: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Denosumab and bisphosphonates: Different mechanisms of action and effects

Biphosphonates and Denosumab – different mechanisms of action

Page 53: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo
Page 54: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo
Page 55: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

???

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

Page 56: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 57: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo
Page 58: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

INTRAVENOUS ZOLEDRONIC ACID IN POSTMENOPAUSAL WOMEN WITH LOW BONE MINERAL DENSITY

N. Engl J Med, Vol. 346, No. 9 - February 28, 2002

Page 59: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 60: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

http://cancergrace.org/cancer-101/2009/04/16/intro-to-denosumab/

RANK and RANKL

Page 61: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Mechanism of Denosumab on Osteoclasts

http://biochemproj.blogspot.com/p/combating-osteoperosis-with-denosumab.html

Page 62: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Denosumab and bisphosphonates: Different mechanisms of action and effects

Page 63: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 64: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Promotores da formação óssea

• PTH

• Ranelato de estrôncio

Page 65: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 66: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo
Page 67: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

PTH

• 84 aa

• Teripatida (1-34)

• Administração intermitente (20-40 microg/dia)

• Até dois anos de uso

Page 68: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Homeostatic responses to variation in dietary calcium

Williams Textbook of Endocrinology, 12 Ed

Page 69: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

???

Williams Textbook of Endocrinology, 12 Ed

Page 70: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Parathyroid hormone analogues in the treatment of osteoporosis – Nature Reviews

Page 71: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Parathyroid hormone analogues in the treatment of osteoporosis – Nature Reviews

???

Page 72: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Parathyroid hormone analogues in the treatment of osteoporosis – Nature Reviews

PTH analogues in the treatment of osteoporosis

Page 73: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Parathyroid hormone analogues in the treatment of osteoporosis – Nature Reviews

PTH analogues in the treatment of osteoporosis

Page 74: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

N Engl J Med 2004;350:4 59:68

Page 75: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

N Engl J Med 2004;350:4 59:68

Page 76: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Proportion of Patients in the Intention-to-Treat Population Who Had One or More New Vertebral Fractures, Assessed

According to the SemiquantitativeMethod.

N Engl J Med 2004;350:459-68

Page 77: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 78: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Strontium Ranelate–Induced Changes in Serum Biochemical Markers of Bone Metabolism.Panel A shows absolute changes from base-line values in bone-specific alkaline phosphatase, Panel B shows absolute changes from base-line values in C-telopeptide cross-links, 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

Page 79: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

The Anabolic Window.

Mechanisms of Anabolic Therapies for Osteoporosis - n engl j med 357;9 www.nejm.org august 30, 2007

Page 80: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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.

Page 81: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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.

Page 82: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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.

Page 83: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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.

Page 84: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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.

Page 85: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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.

Page 86: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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.

Page 87: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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.

Page 88: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 89: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Inibidores da reabsorção

• Cálcio• Vitamina D• Terapia hormonal• Bifosfonados• Moduladores de receptores de estrógeno• Calcitonina

Page 90: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Tratamento

• Inibidores da reabsorção óssea

• Promotores da formação óssea (anabólico)

Page 91: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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

Page 92: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Approximate effect of plasma calcium concentration on the plasma concentrations of parathyroid hormone and calcitonin

Textbook of Medical Physiology – Guyton & Hall – Fig. 79.11

Page 93: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

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 post-

translational 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.

Page 94: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Williams Textbook of Endocrinology, 12 Ed

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???

Williams Textbook of Endocrinology, 12 Ed

Page 96: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

Relative potency of analogues of calcitriol in competitive binding to vitamin D receptors

Williams Textbook of Endocrinology, 12 Ed

Page 97: Site gilbertodenucci Dúvidas  denucci@ gilbertodenucci Arquivo

JOURNAL OF BONE AND MINERAL RESEARCHVolume 19, Number 7, 2004

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Arch Orthop Trauma Surg, 29March2011 – pg 02