The Fascinating Living Skeleton

Neveen A.T. Hamdy

Department of Medicine, Division of Endocrinology

& Centre for Bone Quality

Leiden University Medical Center , The Netherlands

Neveen A.T. Hamdy has no Disclosures

relevant to this Talk

Bone: A Dynamic Multifunctional Organ

Functions

• Mechanical

• Protective for vital organs

• Metabolic:

• Reservoir for minerals

• Bone remodeling

Bone is a unique tissue

Complex tissue

• Cells

• Organic matrix

• Mineral

Continuously renewed tissue

A normal bone remodeling cycle is essential

for the maintenance of bone mass and quality

Seeman E and Delmas PD. N Engl J Med 2006; 354:2250–2261

Mineralisation

- calcium

- phosphate

- vitamin D

Bone Mineralization

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Bone Remodeling

The Basic Multicellular Unit (BMU) Bone Cells: The Osteoclast

Tolar et al, N Engl J Med 2004;351:2839-2849

Specific Factors Are Needed for the

Maturation of Haematopoietic Stem CellsHaematopoietic

Stem Cell

Myeloid

ProgenitorLymphoid

Progenitor

Monocyte

Progenitor

Osteoclasts

Erythrocytes

EPO

M-CSF1

SCF

RANK LigandLymphoid

Cells

Granulocytes

GM-CSF

SCF

M-CSF1

Macrophages

EPO, erythropoietin; GM-CSF, granulocyte macrophage colonies stimulating factor; M-CSF1, macrophage CSF; SCF, stem cell factor

RANK Ligand

Activated

Osteoclast

Bone

Pre-fusion

OsteoclastRANK

CFU-M

Multinucleated

Osteoclast

Activation

Growth factors

Hormones

Cytokines

Role of RANK Ligand in Osteoclastogenesis

Adapted from Boyle WJ et al. Nature 2003; 423: 337–342 (Courtesy AMGEN)

Differentiation

Survival

RANK

RANK Ligand

OPG

Role of Osteoprotegerin (OPG) in controlling

osteoclastogenesis

Osteoclast Formation, Function and

Survival Inhibited by OPG

Growth Factors

Hormones

Cytokines

Mature

Osteoclast

CFU-M

Pre-fusion

Osteoclast

Multinucleated

Osteoclast

Bone

Adapted from Boyle WJ et al. Nature 2003; 423: 337–342 (Courtesy AMGEN)

Normal bone remodeling cycle

Seeman E, Delmas PD. N Engl J Med 2006

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.A.T. H

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Regulation of Osteoblast development

and Survival

Sclerosteosis/van Buchem’s Disease

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Normal

Bone remodeling time

Sclerostin

-

Van Bezooijen et al 2004 J Exp Med

Osteocyte-derived sclerostin is a negative

modulator of bone formation

osteocytes

Normal bone remodeling = Healthy skeleton A normal bone remodeling cycle is essential

for the maintenance of bone mass and quality

Seeman E and Delmas PD. N Engl J Med 2006; 354:2250–2261

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Dysfunctional Cells

Oc Ob

Imbalanced remodelingHigh Bone turnover Dysfunctional Osteoclasts

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In bone marrow cultures from pagetic bone

• osteoclasts

– form more rapidly

– produce increased levels of IL-6

– express increased levels of IL-6 receptors

• Increased expression of RANK-ligand

Paget’s Disease of Bone

Genetic predisposition

Osteopetrosis

Before and after Bone marrow

Transplantation

Dysfunctional osteoblasts

Pathogenesis of Fibrous Dysplasia

Fibrous DysplasiaClinical Spectrum of Fibrous Dysplasia

McCune-Albright Syndrome

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Apoptosis of osteoblasts and osteocytes

Weinstein, J. Clin. Invest. 1998

Pathophysiology of glucocorticoid-induced bone loss

OPG Production in Human Ob Lineage Cells

Hofbauer, Endocrinology 1999Manolagas & Weinstein JBMR 1999

Aluminium Bone Disease

Adynamic Bone Disease

Also as a result of:

- Alcohol intoxication

- Haemochromatosis

Osteoblast Toxicity

Abnormal Collagen Synthesis- Osteogenesis Imperfecta -

Defective mineralisation

Vitamin D deficiency and defective

mineralization of the skeleton

Rickets

Osteomalacia

Severe “Renal

Rickets”(HPTP + OM)

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FGF-23

25(OH)D

Osteoporosis

PTH

Disturbed Bone & Mineral Homeostasis in CKDVitamin D deficiency and disturbed bone & mineral

homeostasis in CKDHypophosphatemic Rickets

(Mutation in the PHEX gene)

Looser zone

Sclerosteosis/van Buchem’s Disease

Bo

ne

thic

kn

ess

Normal

Bone remodeling time

Sclerostin

-

Van Bezooijen et al 2004 J Exp Med

Osteocyte-derived sclerostin is a negative

modulator of bone formation

osteocytes

First Case (1955)

van Buchem’s DiseaseUrk

(n=20)

52-kb deletion 35 kb downstream of SOST gene

(strictly affects bone formation)

Balemans et al. 2001, 2002, 2005; Brunkow 2001; Staehling-Hampton et al. 2002

van Buchem’s disease

SclerosteosisMutations of SOST gene (5 so far)(affects bone formation + digit development)

The SOST gene and sclerosing bone dysplasias Sclerosteosis / van Buchem’s Disease

1

1

2

Van Bezooijen et al 2004 J Exp Med

Sclerosteosis Van Buchem’s

No sclerostin expression

Normal Bone

Sclerostin expression by osteocytes Low sclerostin expression

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Sterno-costo-clavicular Hyperostosis

Increased Bone Turnover

Hyperparathyroid Bone Disease

Pre-PTx 6m post-PTx

Imbalance in Bone

Remodeling

Normal bone

Skeletal disorder characterized by compromised bone strength

predisposing to an increased risk of fracture. Bone

strength reflects the integration of two main features:

bone mass and bone quality

Osteoporosis

NIH Consensus Development Conference: 2000

Osteoporosis

Osteolytic bone lesions in malignancy

Breast Carcinoma Multiple Myeloma

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Osteoblastic

Metastases in Prostate Cancer

Osteolytic

Androgen deprivation

A normal bone remodeling cycle is essential

for the maintenance of bone mass and quality

Seeman E and Delmas PD. N Engl J Med 2006; 354:2250–2261

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“ In many instances, nature has arranged an

experiment in a sick individual and partly

completed it; all that is needed are the eyes of

the clinician to make certain observations, and

the background of the investigator to plan other

observations and interpret them.”

Fuller Albright, 1944

Therapeutic potential of

modulating bone remodeling

Disorders of Bone

Remodeling

?

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