Congenital and Metabolic Bone Diseases

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

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

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).

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

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

2) Cells Osteoblasts Osteoclasts Resting surface cells Osteocytes Osteoblast lineage

2) Cells a) Osteoblast lineage Function of osteoblasts Manufacture osteoid Mineralise osteoid Regulate other cells Become - Osteocytes - Resting surface cells

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

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

2) Cells b) Osteoclast lineage Function of osteoclasts Break down bone Regulate mineral stores Involved in shaping bones (modelling)

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

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

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).

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.

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).

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

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.

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

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

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.

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

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.

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.

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.

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

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

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.

Mucopolysaccharidoses
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.

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..

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

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

Osteopetrosis Infant Onset Adult Onset
Carbonic Anhydrase 11 Deficiency

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 .

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.

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

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

Normal Bone Female, age 30 years
This image illustrates the mircroachitecture of normal trabecular bone from a 30-year-old female. Note the perpendicular orientation between the horizontal and vertical trabeculae. This interconnectivity of the three-dimensional lattice of the trabeculae makes the vertebral bodies particularly well suited to support compressive loads. Trabecular bone comprises about 20% of the skeleton and is found principally at the ends of the long bones and the vertebral bodies. Trabecular bone has a much higher metabolic rate than that of cortical bone. Bone turnover occurs on the surface of the bone and trabecular bone has a greater surface area than that of cortical bone. By inference, then, a higher metabolic rate implies that trabecular bone will be more responsive, or respond earlier to endocrine changes. It is not surprising, therefore, that the most common sites of osteoporotic fracture (spine, hip, and distal radius and ulna) have a high proportion of trabecular bone. Einhorn TA, The Bone Organ System: Form and Function, In: Osteoporosis edited by R Marcus, D Feldman, J Kelsey, Academic Press San Diego, 1996. Female, age 30 years

Moderate Osteoporosis
This image is of moderate osteoporosis in an 88-year-old woman. The loss of horizontal or lateral struts occurs before loss of vertical struts, resulting in reduced load-bearing capacity. This helps us to understand why the definition of osteoporosis includes a reference to both a loss in mass or bone density as well as microarchitectural deterioration. Female, age 88 years

Osteoporosis

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.

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

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.

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").

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.

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

Osteoporosis Age related 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

Mineralization; osteomalacia/rickets Bone turnover; pagets; primary hyperparthyroidism; secondary hyperparathyroidism Low Bone content; osteoporoses/ generalized and localized; oi; High bone content; osteopetrosis

Mineralization; osteomalacia/rickets Low bone mineral content; osteoporoses; OI High bone mineral content; osteopetrosis; bisphosphonate; benign high bone mass High bone turnover; pagets; hyperparathyroidism Low bone turnover; adynamic disease

High Bone Mineral Content
Osteopetrosis Bisphosphonate Treatment Fluorosis Benign High Bone Mass

Diseases of Mineralization: Osteomalacia and Rickets
Osteomalacia is a term that is used to encompass a group of diseases in adults, the essential feature of which is a delay in mineralization as osteoid is laid down. Rickets is the equivalent term used in children where the disease manifests particularly at the growth areas of bone

Osteomalacia and Rickets
Rickets and osteomalacia may be caused by: a deficiency or abnormal metabolism of vitamin D; a deficiency or abnormal utilization/excretion of inorganic phosphate (Pi). A deficiency of vitamin D may be due to: a dietary lack of the vitamin; insufficient ultraviolet exposure to form endogenous vitamin D; most commonly, malabsorption interfering with the intestinal absorption of fats and fat-soluble vitamin D. An abnormal metabolism of vitamin D commonly occurs in chronic renal failure.

Disease is diagnosed by histology and in severe cases by radiology Etiology is diagnosed by biochemistry, history and examination

Vitamin D Phosphate Calcium Acid Alkaline Phosphate Drugs and Toxins

Effects of Vitamin D Deficiency on Bone
Deficiency Insufficiency 2° hyperparathyroidism Ca + P deficiency Osteomalacia/rickets Increased bone turnover

Vitamin D Vitamin D Deficiency Impaired 25 OH Vitamin D production
Defective Vitamin D receptor

Active Form Vitamin D & Calcium Homeostasis…Ugh! Sunlight is critical!
Bookmark URL: /das/book/view/ /873/I870.fig/top

Rickets and osteomalacia may be caused by:
a deficiency or abnormal metabolism of vitamin D; a deficiency or abnormal utilization/excretion of inorganic phosphate (Pi). A deficiency of vitamin D may be due to: a dietary lack of the vitamin; insufficient ultraviolet exposure to form endogenous vitamin D; most commonly, malabsorption interfering with the intestinal absorption of fats and fat-soluble vitamin D. An abnormal metabolism of vitamin D commonly occurs in chronic renal failure.

The most common cause of osteomalacia
intestinal malabsorption of fats and fat-soluble vitamin D hepatic disease (biliary tract obstruction, primary biliary cirrhosis, alcoholic liver disease), chronic pancreatitis, intestinal diseases ( regional ileitis, sprue), surgical operations (gastrectomy, resection of portions of the small intestine).

Vitamin D Deficiency Environmental housebound; frail elderly; immigrant from low to high latitude; gastrectomy; malabsorption Genetic dark skin pigmentation Biochemistry D low; 25D low; 1,25D low to normal ; Ca low; PTH high; Alk Ph high; P low

Impaired 25D production Environmental hepatic failure; drugs affecting liver enzymes Genetic mutations in 25Dhydroxylase: not described Biochemistry D normal; 25D low; 1,25 D low to normal; Ca low; PTH high; Alk ph high; P low

Phosphate Environmental dietary phosphate depletion; prematurity in neonates; mesenchymal tumors; renal tubule disease Genetic mutations in PHEX; mutations in FGF

Deficiency of serum Pi peptic ulcer patients receiving long-term treatment with antacids containing aluminum hydroxide which forms insoluble complexes with Pi in the intestine and blocks its absorption.

Phosphate: Neonatal Prematurity
Dietary P insufficiency milk P intake inadequate for the requirements of a rapidly developing skeleton Biochemistry

Phosphate: Fanconi Syndrome
Disease of the renal tubule can be genetic or acquired

Phosphate: Mesenchymal Tumor
Secretion of ‘Phosphatonins’ molecules that reduce TmP and inhibit mineralization

Renal rickets Osteomalacia is often a component of renal osteodystrophy, that occur in varying degrees of severity in almost all patients with chronic renal failure (CRF). The development of osteomalacia and rickets ("renal rickets") in CRF is due to the loss of renal parenchyma accompanied by: impaired intestinal absorption of calcium and hypocalcemia; decreased renal excretion of inorganic phosphor(Pi) hyperphosphatemia decrease in serum calcium (hypocalcemia).

Drug-induced rickets and osteomalacia
anticonvulsive drug phenytoin interference with vitamin D metabolism in the liver. Rickets and osteomalacia are also associated with hypophosphatemia Renal tubular acidosis (RTA) Fanconi syndrome (sporadic or familial) X-linked hypophosphatemia (vitamin D-resistant rickets). Vitamin D-dependent rickets.

Complications Long-standing osteomalacia may produce fractures and deformities of the softened bones kyphosis bowing of the long bones- curved limb bones narrowing of the pelvis a prominent forehead (frontal bossing) due to osteoid excess beading of the ribs at the costochondral junctions (rachitic rosary) caused by overgrowth of cartilage and osteoid lateral flattening of the rib cage with forward displacement of the sternum (pigeon breast).

Sporadic Hypophosphatemic Osteomalacia

Calcium Environmental insufficiency of dietary calcium during rapid growth Biochemistry Ca low ; PTH high; Alk ph high; P low; D normal; 25D normal; 1,25 D high

Acid Environmental acquired renal tubular acidosis from renal damage
Genetic renal tubular acidosis

Drugs and Toxins Environmental Etidronate; Fluoride; Aluminum
Biochemistry Alk ph normal ; D normal; 25D normal; 1,25 D normal; Ca normal; PTH normal; P normal

The Metaphysis Increased thickness Cupping Frayed

Long Bone Findings Bowing Osteopenia Fractures

Histological Picture of Osteomalacia

Pathophysiology of Malignancy-associated Bone Disease

Pathophysiology of Malignant Bone Disease
Humoral hypercalcaemia: usually mediated by PTHrP Osteolytic/osteoblastic metastases: boneresorption / formation by osteoclasts / osteoblasts stimulated by tumour cell products

Malignancies Commonly Associated with Skeletal Disease
Lung Breast Myeloma Renal Thyroid Prostate

Oncogenic Osteomalacia

Tumour-Induced Bone Resorption

Diseases of Bone Turnover
Bone turnover is a term used to describe the rate of bone formation and resorption Bone resorption is coupled to bone formation During growth, turnover high, formation> resorption, net bone gain During adulthood, turnover moderate, formation< resorption, net bone loss

Diseases of bone turnover
High bone turnover Pagets Hyperparathyroidism Osteomalacia and rickets Thyrotoxicosis Hypogonadism Low bone turnover Adynamic bone disease; Hypophosphatasia

Bone Changes in Hyperparathyroidism
Generalized Osteitis Fibrosa Cystica, Von Recklinghausen's Disease of Bone Diffuse or focal resorptive loss Excess of osteoclastic over osteoblastic activity Fibrous replacement of bone Caused by an over-production of parathormone (PTH) in primary or secondary hyperparathyroidism.

Primary hyperparathyroidism Metabolic disorder
Secretion excessive amounts of PTH: parathyroid cells, either neoplastic or hyperplastic and in the absence of any known stimulus. usually caused by a functioning adenoma of a single parathyroid gland (80 %), diffuse hyperplasia of all four parathyroid glands (15 %), primary parathyroid carcinoma multiple parathyroid adenomas.

Secondary hyperparathyroidism Chronic renal failure
most often hyperphosphatemia and hypocalcemia. Renal osteodystrophy Complex bone changes in chronic renal failure osteomalacia, rickets ("renal rickets"), osteitis fibrosa. Non-parathyroid carcinomas lung, kidney,or elsewhere may produce a PTH-like hormone a syndrome resembling hyperparathyroidism.

The clinical presentations are divisible into three categories:
Hypercalcemia: neuromuscular weakness, fatigue, gastrointestinal symptoms, and, coma in severe hypercalcemic crisis; Renal stones (often bilateral) calcification of the kidneys (nephrocalcinosis); metastatic calcification of other tissues; Bone resorption and fibrous replacement diffuse osteopenia "cystic" or tumor-like lesions of bone ("brown tumors"); pathological fractures; generalized osteitis fibrosa cystica.

The osteoclastic and fibrous reaction (osteitis fibrosa): skull,
Pathology diffuse bone loss resulting from osteoclastic resorption and fibrous replacement of bone (osteitis fibrosa); foci of cystic lesions (osteitis fibrosa cystica) or tumor-like lesions of bone ("brown tumors"); pathological fractures. The osteoclastic and fibrous reaction (osteitis fibrosa): skull, vertebrae, shaft of long bones, and small bones. Resorptions of the medial cortex of the phalanges, the tips of the distal phalanges of the hand and lamina dura between teeth are characteristic early radiographic findings.

Microscopy Earliest changes:
resorptive loss and fibrous replacement of bone excess of osteoclastic over osteoblastic activity fibroblast proliferation in the marrow space. Characteristically, numerous osteoclasts in Howship's lacunae are seen on bone surfaces undergoing resorption, beginning in the cancellous bone and tunneling through Haversian canals in the cortex.

The focal cystic lesions (osteitis fibrosa cystica):
Often multiple Usually develop in the shaft of long bones, the jaw, and skull; Osteolytic and expansive May form a tumor-like mass of brown, yellow, or hemorrhagic tissue ("brown tumor") The foci of bone destruction are rarefied and thus "cystic" in a radiological sense. The bone lesions are not neoplastic.

Microscopy of the Brown tumor:
proliferated osteoclasts and fibroblasts a fibrous stroma, a region of hemorrhage, characteristically associated with hemosiderin deposition (which imparts a brown color). The bone changes of primary hyperparathyroidism regress or disappear within a few weeks after surgical removal of the parathyroid lesion which is usually found to be an adenoma or, less commonly, diffuse hyperplasia of the parathyroid gland.

Renal osteodystrophy Uremic bone disease
In patients with chronic renal failure (CRF). The bone disorders in renal osteodystrophy include: osteomalacia of adults rickets of children (so-called "renal rickets"); osteitis fibrosa bone changes of secondary hyperparathyroidism; osteopenia; osteosclerosis.

Pagets Disease High bone turnover High blood flow
Disordered bone architecture Weakness of bone

Paget’s Disease Current evidence suggests slow virus infection by paramyxovirus infection

Pathology The bone changes are divisible into three phases defined radiologically: osteolytic phase (active bone resorption), mixed osteolytic and osteoblastic phase (both osteoclastic and osteoblastic activity), osteosclerotic phase (sclerotic bone is formed with a characteristic "mosaic" pattern of histologic structure). mosaic pattern of cement lines outlining irregular patches of sclerotic lamellar bone.

Complications (in advanced cases): femurs and tibias may be bowed
hips deformed; the vertebral bodies may be compressed, resulting in kyphosis or scoliosis; skull may be enlarged hearing loss pathological fractures bone tumors: osteogenic sarcoma (most common); fibrosarcoma giant cell tumor.

The skeletal involvement may be limited to a single bone (monostotic) or affect many bones (polyostotic); pelvis, femur, tibia, spine, skull. The affected bones may be weakened by resorption or enlarged by reparative, although defective, new-bone formation. In the final stage of the disease, dense bone is formed, but it is poorly organized and predisposed to fracture and deformity.

Hyperparathyroidism Primary Adenoma Hyperplasia Cancer Secondary
Calcium and Vitamin D insufficiency Calcium and Vitamin D deficiency Renal Failure

Secondary Hyperparathyroidism Renal osteodystrophy
Secondary/Tertiary Uremic mixed osteodystrophy Adynamic Fractures Ectopic calcification

Mixed uremic osteodystrophy
Increased activation frequency bone formation rate marrow fibrosis osteoblasts osteoclasts

Bone is a Living tissue

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Congenital and Metabolic Bone Diseases

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