Congenital and Metabolic Bone Diseases

1. Congenital and Metabolic Bone Diseases YEDİTEPE ÜNİVERSİTESİ TIP FAKÜLTESİ Ferda Özkan M.D

2. The Goals • Explain bone formation ,modeling and remodeling • Describe the metabolic disorders of bone

3. Introduction • Bone is a dynamic tissue • Osteoblasts - osteoid (type 1 collagen) • Calcium and phosphate (calcium hydroxyapatite) • Osteoclasts are multi-nucleated cells which resorb bone (PTH).

4. Bone Anatomy • Diaphysis • Metaphysis • Epiphysis – Prox/Dist • Epiphyseal line • Periosteum • Compact cortical bone • Spongy bone • Articular Cartilage • Medullary cavity • Marrow • Nutrient artery

7. Bone has two components 1) Matrix Lamellae Calcium Hydroxyapatite Type I collagen Other proteins

8. Bone has two components 2) Cells Osteoblasts Osteoclasts Resting surface cells Osteocytes Osteoblast lineage

9. Bone has two components 2) Cells a) Osteoblast lineage • Function of osteoblasts • Manufacture osteoid • Mineralise osteoid • Regulate other cells • Become • - Osteocytes • - Resting surface cells

10. Bone has two components 2) Cells a) Osteoblast lineage • Function of osteoblasts • Manufacture osteoid • Mineralise osteoid • Regulate other cells • Become • -Osteocytes • - Resting surface cells • Function of osteocytes • Respond to load • Maintain bone matrix

11. Bone has two components 2) Cells a) Osteoblast lineage • Function of osteoblasts • Manufacture osteoid • Mineralise osteoid • Regulate other cells • Become • - Osteocytes • - Resting surface cells • Function of RSC • Regulate osteoclast • access to mineral • Respond to osteocyte • and systemic signals

12. Bone has two components 2) Cells b) Osteoclast lineage • Function of osteoclasts • Break down bone • Regulate mineral stores • Involved in shaping bones (modelling)

13. The total bone mass increases with skeletal growth as bone formation exceeds resorption, • Remains constant for several years during skeletal maturity when bone formation and resorption are nearly equal

15. Vitamin D Nutrition Physical activity Age, hormones PTH IL1, TNF,TGF-β 5-10% bone / year. Bone Remodeling

16. The metabolic bone diseases may reflect disturbances in • the organic matrix, • the mineral phase, • the cellular processes of remodeling, • the endocrine, nutritional, and other factors which regulate skeletal and mineral homeostasis. • Hereditary or acquired • Usually affect the entire bony skeleton. • The acquired metabolic bone diseases are the more common and include: • osteoporosis, • osteomalacia, • the skeletal changes of hyperparathyroidism and chronic renal failure (renal osteodystrophy), • osteitis deformans (Paget's disease of bone).

17. Metabolic Bone Diseases • Developmental abnormalities of the skeleton are complex, variable, frequently genetically based, and first become manifest during the earliest stages of bone formation. • In contrast, many of the acquired diseases are usually detected in adulthood.

18. Dysostoses Developmental anomalies resulting from localized problems in the migration of mesenchymal cells and their formation of condensations are known as dysostoses. They are usually limited to defined embryologic structures and may result from mutations in certain transcription factors (Homeobox genes).

19. Dysostoses • Some of these result from defects in the formation of the mesenchymal condensations and their differentiation into the cartilage anlage. They are caused by genetic alterations that affect transcription factors, especially those coded for by the Homeobox genes, and certain cytokines. • MALFORMATIONS AND DISEASES CAUSED BY DEFECTS IN NUCLEAR PROTEINS AND TRANSCRIPTION FACTORS

20. Congenital malformations or dysostoses of bone are relatively uncommon. The more simple anomalies include • failure of development of a bone (congenital absence of a phalanx, rib, or clavicle), • the formation of extra bones supernumerary ribs or digits), • the fusion of two adjacent digits (syndactyly), • the development of long, spider-like digits.

21. Dysostoses Anomalies that affect the skull and vertebral column, such as craniorachischisis(failure of closure of the spinal column and skull), are frequently of great clinical importance. This defect produces a persistent opening through which the meninges and central nervous system herniate to produce a meningomyelocele or meningoencephalocele

22. Dysplasias Mutations in the regulators of skeletal organogenesis, such as cellular signaling mechanisms (e.g., growth factors and their receptors), and matrix components (e.g., types 1 and 2 collagen), affect cartilage and bone tissues globally, and these disorders are known as dysplasias

23. The molecular-pathogenetic classification of genetic disorders is based on the functional properties of the involved gene or protein and includes: • defects in nuclear proteins and transcription factors, • defects in hormones and signal transduction mechanisms, • defects in extracellular structural proteins, • defects in folding and degradation of molecules, • defects in oncogenes and tumor suppressor genes, • defects in metabolic pathways (enzymesion channels transporters), and • defects in RNA and DNA processing and metabolism.

24. DISEASES CAUSED BY DEFECTS IN HORMONES AND SIGNAL TRANSDUCTION MECHANISMS • Achondroplasia • Thanatophoric dwarfism

25. Achondroplasia • It is the most common disease of the growth plate and is a major cause of dwarfism. • Achondroplasia is an example of a disease that is caused by a defect in paracrine cell signaling, and it manifests as a reduction in the proliferation of the chondrocytes in the growth plate.

26. Achondroplasia • Achondroplasia is an autosomal dominant disorder; however, approximately 80% of cases represent new spontaneous mutations. • Affected individuals have shortened proximal extremities, a trunk of relatively normal length, and an enlarged head with bulging forehead and conspicuous depression of the root of the nose. • The skeletal abnormalities are usually not associated with changes in longevity, intelligence, or reproductive status.

27. Thanatophoric dwarfism • Thanatophoric dwarfism is the most common lethal form of dwarfism • The affected patients have micromelic shortening of the limbs, frontal bossing with relative macrocephaly, a small chest cavity, and a bell-shaped abdomen. • The underdeveloped thoracic cavity leads to respiratory insufficiency, and the patients frequently die at birth or soon after. • The histologic changes in the growth plate show diminished proliferation of chondrocytes and poor columnization in the zone of proliferation.

28. DISEASES ASSOCIATED WITH DEFECTS IN EXTRACELLULAR STRUCTURAL PROTEINS • Many of the organic components of bone matrix have been only recently identified, and their interactions are far more complex than originally imagined

29. Type 1 Collagen Diseases (Osteogenesis Imperfecta) Genetic defect in coding Type I collagen resulting in brittle bones Blue sclerae OI type II perinatal lethal

30. Osteogenesis Imperfecta Although osteogenesis imperfecta, or brittle bone disease, has prominent skeletal manifestations, other anatomic structures rich in type I collagen, such as joints, eyes, ears, skin, and teeth, are affected as well.

31. DISEASES ASSOCIATED WITH DEFECTS IN FOLDING AND DEGRADATION OF MACROMOLECULES • Mucopolysaccharidoses The mucopolysaccharidoses, , are a group of lysosomal storage diseases caused by deficiencies in the enzymes that degrade dermatan sulfate, heparan sulfate, and keratan sulfate.

32. Mucopolysaccharidoses The implicated enzymes are mainly acid hydrolases. Mesenchymal cells, especially chondrocytes, play an important role in the metabolism of extracellular matrix mucopolysaccharides and therefore are most severely affected..

33. Mucopolysaccharidoses • Many of the skeletal manifestations of the mucopolysaccharidoses result from abnormalities in hyaline cartilage, including the cartilage anlage, growth plates, costal cartilages, and articular surfaces. • Patients with mucopolysaccharidoses are frequently of short stature and have chest wall abnormalities and malformed bones

34. Osteopetrosis • Genetic disease characterised by reduced osteoclast bone resorption and diffuse symmetric skeletal sclerosis ( marble bone disease- Albers Schönberg disease)

35. Osteopetrosis • Infant Onset • Adult Onset • Carbonic Anhydrase 11 Deficiency

36. DISEASES ASSOCIATED WITH DEFECTS IN METABOLIC PATHWAYS (ENZYMES, ION CHANNELS, AND TRANSPORTERS) • Osteopetrosis Osteopetrosis refers to a group of rare genetic diseases that are characterized by reduced osteoclast bone resorption, resulting in diffuse symmetric skeletal sclerosis .

37. Osteopetrosis • The term osteopetrosis was coined because of the stonelike quality of the bones; however, the bones are abnormally brittle and fracture like a piece of chalk. • Osteopetrosis, which is also known as marble bone disease and Albers-Schönberg disease, is classified into variants based on both the mode of inheritance and the clinical findings.

38. DISEASES ASSOCIATED WITH DECREASED BONE MASS • Osteoporosis (Low bone mineral content )

39. Osteoporosis • Decreased volume of mineralized bone tissue per unit of bone • Cortical thinning and increased porosity • Decreased number and thickness of trabeculae • Decreased bone strength • Increased risk of fracture

40. Normal Bone Female, age 30 years

41. Moderate Osteoporosis Female, age 88 years

42. Osteoporosis

43. Osteoporosis • Osteoporosis is the most common bone disease • Increasing in prevalence with the aging of the population. • Mainly postmenopausal women. • A 'silent' risk factor for bone fracture.

44. Osteoporosis • Decrease in bone density • Thinning and increased porosity of the bone cortices and trabeculae. • As a clinical term: • a generalized loss of bone density • skeletal fragility, • bone pain, • pathological fractures (of the spine, wrist, hip, and ribs), • particularly in postmenopausal women and both

45. Osteoporosis • Primary osteoporosis, unrelated to other disease, is classified by age groups into • postmenopausal, • senile, • idiopathic (premenopausal women and younger men), • juvenile. • Postmenopausal osteoporosis is the most frequent form of osteoporosis and is the commonest metabolic bone disease.

46. Osteoporosis Pathology • The excessive bone loss • Thinning and increased porosity of the trabecular bone of the axial skeleton (vertebrae, ribs, and pelvis). • The cortices of cylindrical bones are also thinned • from the inside by endosteal resorption, resulting in enlargement of the medullary cavity without a change in the outside diameter of the bone. • The vertebral bodies, • may be weakened by microfractures • collapse anteriorly, • resulting in compression fractures and wedging of the vertebrae, • a loss of stature, • kyphotic deformity of the spine ("dowager's hump").

47. Osteoporosis Histology • The amount of cortical and cancellous bone in osteoporosis is decreased. • Bone remains has a lamellar structure and osteoid seams of normal width. • The bone cortices are thinned, and the haversian canals are widened. • The trabeculae of cancellous bone are decreased in size and number. • The trabeculae are thin, discontinuous, and widely separated.

48. Osteoporosis • Generalized cortical trabecular • Localized rheumatoid arthritis • Bone marrow disease myeloma secondary cancer lymphoma and leukemia mastocytosis histiocytosis

49. Osteoporosis • Agerelated • Hypogonadism: estrogen and testosterone • Calcium deficiency and insufficiency • Vitamin D deficiency and insufficiency • Corticosteroid Treatment and Cushing’s Disease • Immobilization • Antiepileptic Drugs • Myeloma • Thyrotoxicosis • Idiopathic