(038) BONE DISEASE Flashcards by Moustafa Sharawy

Three general components of Bone matrix ?

1) colagen (structural protein)

2) non-structural proteins

3) Hydroxyapatite

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Precentage composition of bone matrix ?

90% type I collagen
10% non-structural proteins
traces of Hydroxyapatite

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non-structural proteins present in bone matrix ?

• Phosphoproteins

• Sialoprotein

• Osteonectin

• Osteocalcin

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A non-structural protein of bone matrix : that it’s blood level indicates bone turnover

Osteocalcin

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What’s Hydroxyapatite ?

Mineral crystals which enclose the collagen microfibrils to form a composite material with the required properties of stiffness, flexibility and strength.

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Role of Hydroxyapatite in the bone matrix ?

Mineral crystals which enclose the collagen microfibrils to form a composite material with the required properties of stiffness, flexibility and strength.

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This figure illustrated the three cell types in bone , name them and mention their roles

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Define the hidden and explain the role of these cells of bone

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secretions of Osteoblasts ? (Bone forming cells)

-Osteoid

-Alkaline phosphatase (ALP)

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What’s osteoid

new, unmineralized bone matrix secreted by osteoblasts

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Role of Alkaline phosphatase (ALP) ; secreted by osteoblasts

an enzyme involved in the mineralization process by liberating inorganic phosphate.

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…..is a useful circulating marker for bone cell activity.

Alkaline phosphatase (ALP)

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Osteoblasts express receptors for many hormones, eg:

• PTH

• 1,25(OH)2-vitamin D

• sex steroids

• adrenal steroids

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OB are also responsive to (and may produce):

• growth factors

• cytokines

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Role of Osteocytes ?

Osteocytes mediate adaptive bone remodeling by responding to mechanical deformation

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How are Osteocytes formed ?

• Some Osteoblasts become incorporated in the matrix & differentiate into osteocytes

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…. Is a chemical produced by Osteocytes

sclerostin – FGF 23

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What are Osteoclasts ?

Osteoclasts (OC) are multinucleate cells which resorb all the components of skeletal and dental hard tissues, unaided.

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What’s Howship’s lacunae ?

resorption pits occupied by Osteoclasts in the mineralized bone surfaces.

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sealing zone of Bone resorption ?

OC form a tight annular sealing zone with the bone, which encloses a clear zone (resorption lacuna).

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Osteoclasts express large amounts of the enzyme….

tartrate-resistant acid phosphatase (TRAP).

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Explain Bone remodeling

Throughout life, the skeleton undergoes a continual process of repair and renewal. Bone remodeling is a surface phenomenon.

Mineralized bone matrix is resorbed by OC and replaced in lamellae, by OB.

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Bone remodeling takes place in response to :

altered mechanical loading

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Figure illustrated the process of bone remodeling , define the hidden

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The age of remodeling activity ?

In young adults (20-45 years)

Characteristics of bone remodeling In young adults (20-45 years) ?

keeps bone mass relatively constant: bone may be removed from one site & deposited at another in order to achieve shape changes, whilst keeping overall bone mass constant.

If the balance of the turnover process is altered, and resorption begins to outstrip formation, this leads to…. (Disease)

Osteoporosis

General mechanism of osteoporosis ?

enhanced OC resorption or declining OB function

…. (Site) are particularly susceptible to remodeling imbalances, as a result of the relatively high turnover rate (~25% / year).

Trabecular bone sites (e.g. in vertebral bodies)

How is Bone growth and remodeling regulated ?

Bone growth and remodeling is influenced by many factors. These include: 1. Calcium regulating hormones 2. Cell signals: 3. Inorganic agents 4. Intracellular factors 5. Other molecules 6. Mechanical effects

Major general Functions of Calcium ?

• Ca 2+ is used as a vital second messenger within cells • Ca 2+ is necessary for normal blood coagulation, muscle contraction and nerve function

(>99%) of the Ca 2+ in the body exists as :

mineral deposits in the skeleton and teeth.

…….is the key PO4 3- lowering factor.

Fibroblast growth factor (FGF 23)

PO4 3- retention is toxic and implicated in…

accelerated ageing.

Mention the major Calcium Regulating Hormones

• Parathyroid hormone (PTH) • 1,25(OH)2-vitamin D (calcitriol) • Calcitonin

Effect of Parathyroid hormone (PTH) on bone regulation ?

↑ OC formation, activity ↑ OB proliferation, activity → ↑ bone turnover

Effect of continuous high-dose PTH on bone regulation (in vivo) ?

↑ bone resorption → bone loss.

Mechanism of calcitriol’s effect on bone regulation ?

↑ plasma Ca2+ ; ↑ gut Ca 2+ uptake, ↑ OB differentiation ; required for normal matrix mineralization;

Effect of Calcitonin on bone regulation ?

↓ plasma Ca 2+ by depositing Ca 2+ in bone ↓ OC formation, activity

Effect of excess Glucocorticoids on bone ?

bone loss / osteoporosis

…..&…. exert critical long term (i.e. slow acting) beneficial effects to bone

• Sex steroids (estrogens & androgens)

Effect of deficient Sex steroids on bone ?

↑ bone turnover, osteoporosis

Bone Growth factors are sectreted by…

Osteoblasts and deposited in bone matrix

Growth factors include:

Mitogens e.g.: -transforming growth factor ß (TGF ß ) -bone morphogenetic proteins (BMP) -insulin-like growth factors I &II (IGF) -platelet-derived growth factor (PDGF) -fibroblast growth factors (FGF)

……are signaling molecules that ↑ OB differentiation ,, and blocked by sclerostin.

Wnt proteins

….. is a Bone-specific protein which acts as a natural brake on bone formation, and is secreted by Osteocytes

Sclerostin

Cytokines that ↑ OC formation and activity ? (Resorbtion)

• Interleukins (IL) – 1, 6 • tumor necrosis factor (TNF) -α • RANK ligand • macrophage colony-stimulating factor (M-CSF)

Explain the role of RANK ligand in bone resorption

the major factor required for OC formation :

Cytokines that ↓ OC formation and activity ? (↑ Bone formation)

• Interleukins (IL) 4 • Interferon (IFN)-γ • granulocyte macrophage colony-stimulating factor (G-CSF)

Intracellular factors affecting bone regulation ?

-Wnt mediator: Wingless-related integration site -Nuclear factor of activated T-cells 1 (NFATc1)

WHO definition of Osteoporosis ?

bone mass < 2.5 SDs

WHO definition of Osteopenia ?

bone mass < 1 SD

Figure illustrates a condition associated with osteoporosis , what’s the condition ?

vertebral crush fractures, leading to loss of height, with the typical "Dowager's hump" (hunchback) appearance.

Why is osteoporosis 10 times more common in women than men ?

abrupt decline in circulating estrogens at menopause (Androgens decline more gradually with age)

Figure illustrates a condition associated with osteoporosis : - name the condition - it’s common age group - gender prevealance

Femoral neck ("hip") fractures: -associated with 20% mortality rates -occur in patients over age of 70 -2:1 prevalence in favor of females

Osteoporosis is much less common in….(race)

Afro-Caribbeans

main risk factors for osteoporosis :

Preventive medicine of osteoporosis ?

Hormone replacement therapy with low level estrogens in postmenopausal women effectively prevents osteoporosis

Risk of preventive osteoporosis treatment for woman Through : Hormone replacement therapy ?

associated slight increased risks of breast and endometrial cancer

Role of Intermittent PTH injections in osteoporosis treatment ?

can help restore lost bone by stimulating OB

Drugs that block OC action ?

1) bisphosphonates (mostly cheap, orally-active) 2) A synthetic antibody that binds RANK ligand

The key difference between osteomalacia and osteoporosis ?

-Osteomalacia: the proportion of mineralized bone matrix is reduced -Osteoporosis: there is loss of bone but no impairment of mineralization

Give diagnosis and explain

-Paget's disease ; It affects one or several bones throughout the skeleton It is characterized by focal areas of increased bone turnover: -greatly accelerated bone resorption at certain focal sites -bone formation by OB is increased >> The new bone formed is disorganized

Potential triggers of Paget's disease ?

• paramyxovirus infection • deficiency of dietary calcium • repetitive mechanical loading of the skeleton

Symptoms of Paget's disease ?

• bone pain (hot to the touch) • bone deformity • osteoarthritis • pathological fracture • deafness • nerve compression syndromes

Medical management of Paget's disease ?

Inhibitors of osteoclastic bone resorption are given : Bisphosphonate is primarily indicated for patients who have bone pain

Name the condition and explain it

Sclerostosis ; an autosomal recessive disorder characterized by bone overgrowth Excessive bone formation especially in the skull, mandible and tubular bones.

A severe complication of Sclerostosis ?

Increased intracranial pressure can cause sudden death in patients.

Osteopetrosis ?

• “Stone bone", or marble bone disease, is a rare inherited disorder • Bones harden, becoming too thick and heavy • The cause is understood to be malfunctioning osteoclasts leading to impaired modelling & remodeling of bone

Osteosarcoma ?

An osteoblast tumor - frequently aggressive – most common in younger individuals

Osteoclastoma ?

An osteoclast tumor which does not metastasize – not life threatening – can result in rapid local destruction of bone

….(bone tumor) is most common in younger individuals

Osteosarcoma

Cancers that metastasize to bone ?

• Breast • Lung • Kidney • Prostate • Multiple myeloma

Metabolic Acidosis ?

• Results from net addition of H + to blood  HCO 3 - ↓ and pH↓ • Chronic MA is usually the result of kidney disease

Effect of Diseased kidneys on bone resorption ?

1. Diseased kidneys lose the ability to form 1,25 (OH) 𝟐 vit D >> ↓ Ca 2+ uptake from gut >> ↓ plasma Ca 2+ >> ↑ PTH secretion >>↑ osteoclast formation and activity

Effect of Metabolic Acidosis on bone resorption ?

Osteoclasts are directly responsive to extracellular H+ low pH >> ↑ resorption pit formation >> release of alkaline bone mineral (hydroxyl apatite)

name the condition and the nerve injury causing it

Scapular winging (long thoracic nerve palsy)

This is knee MRI ; point to lesion and diagnose

Torn anterior cruciate ligament

Figure illustrates an imaging of rotator cuff ; name the imaging method and diagnose

Rotator cuff tear