Patho - 4th Asessment - Metabolic Bone Disease - 2007

Metabolic Bone Disease Dr. Issam Francis

Normal • •

206 bones (tubular, flat, cuboid) Bones play a vital role: 1. 2. 3. 4.

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mineral homeostasis house the hematopoietic elements provide mechanical support determine body size and shape

Inorganic elements (65%). Organic matrix (35%)

Inorganic component Calcium hydroxyapatite (Ca10(PO4)6(OH)2 • Gives bone strength and hardness • Storehouse for – 99% of the body’s calcium – phosphorus – sodium & magnesium

• Rate of mineralization varies • 12 -to 15-day between formation of matrix and its mineralization. • Unmineralized bone is known as osteoid.

Organic component 1- Cells & 2- Proteins The bone-forming cells: • Constitute only 2% of bone weight • Formation and maintenance of bone 1- Osteoprogenitor cells: • Pluripotential mesenchymal stem cells when stimulated • Differentiate into osteoblast

Organic component 2- osteoblasts: • On the surface of bone • Synthesize , transport, and arrange matrix proteins • Initiate mineralization • Have receptors for parathyroid hormone, vitamin D, estrogen, cytokines, growth factors 3- osteocytes: • Control of the daily fluctuations in serum calcium and phosphorus • Communicate with surface cells and other osteocytes via network canaliculi.

Organic component: 4.The osteoclast: • Responsible for bone resorption • Multinucleated (6 to 12 nuclei) • Breaks bone down to its elemental units

Proteins of bone : • Type I collagen forms backbone of matrix and 90% of the organic component • Osteoblasts deposit collagen either in • Random weave (woven bone) or • Orderly , layered manner “lamellar bone”

1-woven bone : • • • • •

in the fetal skeleton formed at growth plates produced quickly resists forces equally from all directions presence of woven bone in the adult is always pathological

2-Lamellar bone : • Gradually replaces woven bone during growth • Deposited slowly • Stronger than woven bone

Non-collagenous proteins • Grouped according to function: – – – – – –

adhesion proteins calcium-binding proteins mineralization proteins enzymes cytokines growth factors

• Osteocalcin is unique to bone in serum used as a sensitive, specific marker for osteoblast activity • • Cytokines and growth factors control bone cell proliferation, maturation, and metabolism.

Bone Modeling and Remodeling • Osteoblasts & osteoclasts act in coordination • Bone formation and resorption are tightly coupled and determine skeletal mass • With growth: (modeling) / bone formation • With maturity: (remodeling) / breakdown and renewal • Peak bone mass achieved in early adulthood • 5 to 10% of skeleton turned over or remodeled yearly

Metabolic Bone Disease: • Diseases Associated with Abnormal Matrix • Diseases Caused by Osteoclast Dysfunction • Diseases Associated with Abnormal Mineral Homeostasis •

Diseases Associated with Abnormal Matrix 1- Osteogenesis Imperfecta ( brittle bone ) • Disorders caused by deficiencies in the synthesis of type I collagen • Affect structures rich in type I collagen ( joints, eyes, ears, skin, and teeth) • Qualitatively normal collagen in decreased amounts • Abnormal collagen molecules

Clinical expression – spectrum of disorders – all marked by extreme skeletal fragility – four major subtypes

Diseases Associated with Abnormal Matrix 2- Mucopolysaccharidoses: • A group of lysosomal storage diseases • Caused by deficiencies in the enzymes that degrade • Implicated enzymes are mainly acid hydrolases • Skeletal manifestations result from abnormalities in hyaline cartilage

Patients: – short stature – chest wall abnormalities – malformed bones.

Diseases Associated with Abnormal Bone Matrix

3- Osteoporosis: • a general term denoting increased porosity of the skeleton resulting from a reduction in bone mass. • may be localized, as in disuse osteoporosis of a limb, • may involve the entire skeleton, • Generalized osteoporosis may be primary or secondary

Osteoporosis Pathogenesis • imbalance between bone resorption and formation. • Age-related changes • Reduced physical activity • calcium nutritional state • Postmenopausal osteoporosis : hormonedependent acceleration of bone loss

Diseases Caused by Osteoclast Dysfunction

1- Osteopetrosis • Rare hereditary diseases characterized by osteoclast dysfunction • Diffuse symmetric skeletal sclerosis • Bones are brittle and fracture “like a piece of chalk.” • Osteopetrosis, is also known as marble bone disease • The autosomal recessive and autosomal dominant type are the most common variants.

Diseases Caused by Osteoclast Dysfunction

1.Paget’s Disease (Osteitis Deformans) • Sir James Paget first described this condition in 1876 • Periods of furious bone resorption followed by bone formation • Result in a gain in bone mass but the newly formed bone is disordered • Common in whites in England, France, Austria,

Paget’s Disease (Osteitis Deformans) Pathogenesis • Slow virus infection caused by a paramyxovirus • In situ hybridization studies have localized a type of paramyxovirus in osteoclasts

• Target of the virus is the osteoblast with transmission to the osteoclast

Paget’s Disease (Osteitis Deformans)

Complications: • • • • • •

Microfractures Bowing of the femora and tibiae Development of secondary osteoarthritis. Compression fractures of the spine High output heart failure Osteosarcoma

Diseases Associated with Abnormal Mineral Homeostasis

1- Hyperparathyroidism • Classified into primary and secondary types • Primary Hyperparathyroidism • Results from hyperplasia or adenoma, of the parathyroid gland, • Secondary hyperparathyroidism is caused by prolonged hypocalcemia

Diseases Associated with Abnormal Mineral Homeostasis 1- Hyperparathyroidism • Increased parathyroid hormone detected by osteoblasts, which then initiate the release of mediators that stimulate osteoclast activity. • Decrease in bone mass predisposes to fractures • Control of hyperparathyroidism allows the bony changes to regress significantly or disappear completely.

Conditions are included in the differential diagnosis of hypercalcemia 1. Osteolytic tumors (metastatic cancer, multiple myeloma, leukemia) 2. Hyperparathyroidism 3. Tumors that produce ectopic PTH (pseudohyperparathyroidism) 4. Vitamin D excess 5. Hyperthyroidism 6. Excess calcium (milk) intake 7. Immobilization 8. Sarcoidosis 9. Addisonian crisis

Hyperparathyroidism Morphology • Subperiosteal resorption • Osteoblast activity is increased • Marrow spaces replaced by fibrous tissue • Hemorrhages and reactive fibrous tissue to create a mass known as “brown tumor” • Lesions undergo cystic degeneration

Diseases Associated with Abnormal Mineral Homeostasis

2- Renal Osteodystrophy All of the skeletal changes of chronic renal disease including: 1. 2. 3. 4. 5.

Increased osteoclastic bone resorption Delayed matrix mineralization (osteomalacia), Osteosclerosis Growth retardation Osteoporosis

Diseases Associated with Abnormal Mineral Homeostasis 3-Osteomalacia and Rickets: • Delayed and/or inadequate bone mineralization leading to an excess of un-mineralized matrix • Persistence of irregular masses of cartilage, • Deposition of osteoid matrix • Deformation of the skeleton

Osteomalacia and Rickets: Manifestations: 2. During infancy and childhood : • softened flattened occipital bones • frontal bossing. • Deformation of the chest • Anterior protrusion of the sternum–pigeonbreast • Lumbar lordosis and • Bowing of the legs

Osteomalacia and Rickets: Osteomalacia in the adult is characterized by loss of skeletal mass or “too little” bone, referred to as osteopenia. •

must be differentiated from other osteopenias such as – –

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osteoporosis osteitis fibrosa

Looser’s zones or Milkman’s fractures Skeletal deformities do not appear in osteomalacia Bone subject to fractures, most often of the vertebrae, hips, wrists, and ribs