Congenital and Metabolic Bone Diseases

Congenital and Congenital and Metabolic Bone Metabolic Bone

DiseasesDiseases

Ferda Özkan M.DFerda Özkan M.D

YEDİTEPE ÜNİVERSİTESİ TIP FAKÜLTESİ

The GoalsThe Goals

Explain Explain bone formation ,modeling and bone formation ,modeling and

remodelingremodeling

Describe the Describe the metabolic disorders of bonemetabolic disorders of bone

IntroductionIntroduction

Bone is a dynamic tissue Bone is a dynamic tissue Osteoblasts - osteoid (type 1 collagen) Osteoblasts - osteoid (type 1 collagen) Calcium and phosphate (calcium Calcium and phosphate (calcium

hydroxyapatite) hydroxyapatite) Osteoclasts are multi-nucleated cells Osteoclasts are multi-nucleated cells

which resorb bone (PTH).which resorb bone (PTH).

Bone AnatomyBone Anatomy DiaphysisDiaphysis MetaphysisMetaphysis Epiphysis – Prox/DistEpiphysis – Prox/Dist Epiphyseal lineEpiphyseal line PeriosteumPeriosteum Compact cortical Compact cortical

bonebone Spongy boneSpongy bone Articular CartilageArticular Cartilage Medullary cavityMedullary cavity MarrowMarrow Nutrient arteryNutrient artery

Bone has two componentsBone has two components1) Matrix1) Matrix

Type I collagenType I collagenOther proteinsOther proteins

CalciumHydroxyapatite

Lamellae

Bone has two componentsBone has two components2) Cells2) Cells

OsteoblastsOsteoblasts

RestingRestingsurfacesurface

cellscellsOsteocytesOsteocytes

OsteoclastsOsteoclasts

Osteoblast lineageOsteoblast lineage


a) Osteoblast lineagea) Osteoblast lineage

Function of osteoblastsFunction of osteoblasts1)1) Manufacture osteoidManufacture osteoid2)2) Mineralise osteoidMineralise osteoid3)3) Regulate other cellsRegulate other cells4)4) BecomeBecome

- Osteocytes- Osteocytes- Resting surface cells- Resting surface cells

Function of osteocytesFunction of osteocytes1)1) Respond to loadRespond to load2)2) Maintain bone matrixMaintain bone matrix


-- OsteocytesOsteocytes- Resting surface cells- Resting surface cells





Function of RSCFunction of RSC1)1) Regulate osteoclast Regulate osteoclast

access to mineral access to mineral 2)2) Respond to osteocyteRespond to osteocyte and systemic signalsand systemic signals


- Osteocytes- Osteocytes- Resting surface cells- Resting surface cells


b) Osteoclast lineageb) Osteoclast lineage

Function of osteoclastsFunction of osteoclasts1)1) Break down boneBreak down bone2)2) Regulate mineral Regulate mineral

storesstores3)3) Involved in shaping Involved in shaping

bones (modelling) bones (modelling)

The total bone mass increases with The total bone mass increases with skeletal growth as bone formation exceeds skeletal growth as bone formation exceeds resorption, resorption,

Remains constant for several years during Remains constant for several years during skeletal maturity when bone formation and skeletal maturity when bone formation and resorption are nearly equalresorption are nearly equal

Bone RemodelingBone Remodeling Vitamin DVitamin D NutritionNutrition Physical activityPhysical activity Age, hormonesAge, hormones PTHPTH IL1, TNF,TGF-IL1, TNF,TGF-ββ

5-10% bone / year.5-10% bone / year.

The metabolic bone diseases may reflect The metabolic bone diseases may reflect disturbances indisturbances in the organic matrix, the organic matrix, the mineral phase, the mineral phase, the cellular processes of remodeling, the cellular processes of remodeling, the endocrine, nutritional, and other factors which the endocrine, nutritional, and other factors which

regulate skeletal and mineral homeostasis. regulate skeletal and mineral homeostasis. Hereditary or acquired Hereditary or acquired Usually affect the entire bony skeleton. Usually affect the entire bony skeleton. The acquired metabolic bone diseases are the The acquired metabolic bone diseases are the

more common and include:more common and include: osteoporosis, osteoporosis, osteomalacia, osteomalacia, the skeletal changes of hyperparathyroidism and the skeletal changes of hyperparathyroidism and

chronic renal failure (renal osteodystrophy), chronic renal failure (renal osteodystrophy), osteitis deformans (Paget's disease of bone).osteitis deformans (Paget's disease of bone).

Metabolic Bone DiseasesMetabolic Bone Diseases

Developmental abnormalities of the Developmental abnormalities of the skeleton are complex, variable, frequently skeleton are complex, variable, frequently genetically based, and first become genetically based, and first become manifest during the earliest stages of bone manifest during the earliest stages of bone formation. formation.

In contrast, many of the acquired In contrast, many of the acquired diseases are usually detected in diseases are usually detected in adulthood.adulthood.

DysostosesDysostoses

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


Some of these result from defects in the Some of these result from defects in the formation of the mesenchymal formation of the mesenchymal condensations and their differentiation into condensations and their differentiation into the cartilage anlage. They are caused by the cartilage anlage. They are caused by genetic alterations that affect transcription genetic alterations that affect transcription factors, especially those coded for by the factors, especially those coded for by the Homeobox genes, and certain cytokines.Homeobox genes, and certain cytokines.

MALFORMATIONS AND DISEASES CAUSED BY DEFECTS IN MALFORMATIONS AND DISEASES CAUSED BY DEFECTS IN NUCLEAR PROTEINS AND TRANSCRIPTION FACTORSNUCLEAR PROTEINS AND TRANSCRIPTION FACTORS

Congenital malformations or Congenital malformations or dysostoses dysostoses of bone of bone are relatively uncommon.are relatively uncommon.

The more simple anomalies include The more simple anomalies include failure of development of a bone (congenital failure of development of a bone (congenital

absence of a phalanx, rib, or clavicle), absence of a phalanx, rib, or clavicle), the formation of extra bones supernumerary the formation of extra bones supernumerary

ribs or digits), ribs or digits), the fusion of two adjacent digits (syndactyly),the fusion of two adjacent digits (syndactyly), the development of long, spider-like digits. the development of long, spider-like digits.


Anomalies that affect the skull and vertebral Anomalies that affect the skull and vertebral column, such as column, such as craniorachischisiscraniorachischisis (failure of (failure of closure of the spinal column and skull), are closure of the spinal column and skull), are frequently of great clinical importance. frequently of great clinical importance.

This defect produces a persistent opening This defect produces a persistent opening through which the meninges and central through which the meninges and central nervous system herniate to produce a nervous system herniate to produce a meningomyelocele or meningoencephalocelemeningomyelocele or meningoencephalocele

DysplasiasDysplasias

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

The molecular-pathogenetic classification of genetic The molecular-pathogenetic classification of genetic disorders is based on the functional properties of the disorders is based on the functional properties of the involved gene or protein and includes: involved gene or protein and includes:

(1)(1) defects in nuclear proteins and transcription factors, defects in nuclear proteins and transcription factors, (2)(2) defects in hormones and signal transduction defects in hormones and signal transduction

mechanisms, mechanisms, (3)(3) defects in extracellular structural proteins, defects in extracellular structural proteins, (4)(4) defects in folding and degradation of molecules, defects in folding and degradation of molecules, (5)(5) defects in oncogenes and tumor suppressor genes,defects in oncogenes and tumor suppressor genes,(6)(6) defects in metabolic pathways (enzymesion channels defects in metabolic pathways (enzymesion channels

transporters), and transporters), and (7)(7) defects in RNA and DNA processing and metabolism.defects in RNA and DNA processing and metabolism.

DISEASES CAUSED BY DEFECTS IN DISEASES CAUSED BY DEFECTS IN HORMONES AND SIGNAL TRANSDUCTION HORMONES AND SIGNAL TRANSDUCTION

MECHANISMSMECHANISMS

Achondroplasia Achondroplasia Thanatophoric dwarfism Thanatophoric dwarfism

AchondroplasiaAchondroplasia

It is the most common disease of the It is the most common disease of the growth plate and is a major cause of growth plate and is a major cause of dwarfism. dwarfism.

Achondroplasia is an example of a Achondroplasia is an example of a disease that is caused by a defect in disease that is caused by a defect in paracrine cell signaling, and it manifests paracrine cell signaling, and it manifests as a reduction in the proliferation of the as a reduction in the proliferation of the chondrocytes in the growth plate. chondrocytes in the growth plate.

AchondroplasiaAchondroplasia

Achondroplasia is an autosomal dominant Achondroplasia is an autosomal dominant disorder; however, approximately 80% of cases disorder; however, approximately 80% of cases represent new spontaneous mutations. represent new spontaneous mutations.

Affected individuals have shortened proximal Affected individuals have shortened proximal extremities, a trunk of relatively normal length, extremities, a trunk of relatively normal length, and an enlarged head with bulging forehead and and an enlarged head with bulging forehead and conspicuous depression of the root of the nose.conspicuous depression of the root of the nose.

The skeletal abnormalities are usually not The skeletal abnormalities are usually not associated with changes in longevity, associated with changes in longevity, intelligence, or reproductive status. intelligence, or reproductive status.

Thanatophoric dwarfismThanatophoric dwarfism Thanatophoric dwarfism is the most common Thanatophoric dwarfism is the most common

lethal form of dwarfism lethal form of dwarfism The affected patients have micromelic The affected patients have micromelic

shortening of the limbs, frontal bossing with shortening of the limbs, frontal bossing with relative macrocephaly, a small chest cavity, and relative macrocephaly, a small chest cavity, and a bell-shaped abdomen. a bell-shaped abdomen.

The underdeveloped thoracic cavity leads to The underdeveloped thoracic cavity leads to respiratory insufficiency, and the patients respiratory insufficiency, and the patients frequently die at birth or soon after. frequently die at birth or soon after.

The histologic changes in the growth plate show The histologic changes in the growth plate show diminished proliferation of chondrocytes and diminished proliferation of chondrocytes and poor columnization in the zone of proliferation. poor columnization in the zone of proliferation.

DISEASES ASSOCIATED WITH DEFECTS IN DISEASES ASSOCIATED WITH DEFECTS IN

EXTRACELLULAR STRUCTURAL PROTEINSEXTRACELLULAR STRUCTURAL PROTEINS

Many of the organic components of bone Many of the organic components of bone matrix have been only recently identified, matrix have been only recently identified, and their interactions are far more and their interactions are far more complex than originally imagined complex than originally imagined

Type 1 Collagen Diseases Type 1 Collagen Diseases (Osteogenesis Imperfecta)(Osteogenesis Imperfecta)

Genetic defect in coding Type I collagen Genetic defect in coding Type I collagen resulting in brittle bonesresulting in brittle bones

Blue scleraeBlue sclerae

OI type II perinatal lethalOI type II perinatal lethal

Osteogenesis ImperfectaOsteogenesis Imperfecta

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

DISEASES ASSOCIATED WITH DEFECTS IN DISEASES ASSOCIATED WITH DEFECTS IN FOLDING AND DEGRADATION OF FOLDING AND DEGRADATION OF

MACROMOLECULESMACROMOLECULES

Mucopolysaccharidoses Mucopolysaccharidoses The mucopolysaccharidoses, , are a group of The mucopolysaccharidoses, , are a group of

lysosomal storage diseases caused by lysosomal storage diseases caused by deficiencies in the enzymes that degrade deficiencies in the enzymes that degrade dermatan sulfate, heparan sulfate, and keratan dermatan sulfate, heparan sulfate, and keratan sulfate. sulfate.

MucopolysaccharidosesMucopolysaccharidoses The implicated enzymes are mainly acid The implicated enzymes are mainly acid

hydrolases. Mesenchymal cells, especially hydrolases. Mesenchymal cells, especially chondrocytes, play an important role in the chondrocytes, play an important role in the metabolism of extracellular matrix metabolism of extracellular matrix mucopolysaccharides and therefore are mucopolysaccharides and therefore are most severely affected.. most severely affected..

MucopolysaccharidosesMucopolysaccharidoses

Many of the skeletal manifestations of the Many of the skeletal manifestations of the mucopolysaccharidoses result from mucopolysaccharidoses result from abnormalities in hyaline cartilage, abnormalities in hyaline cartilage, including the cartilage anlage, growth including the cartilage anlage, growth plates, costal cartilages, and articular plates, costal cartilages, and articular surfaces. surfaces.

Patients with mucopolysaccharidoses are Patients with mucopolysaccharidoses are frequently of short stature and have chest frequently of short stature and have chest wall abnormalities and malformed boneswall abnormalities and malformed bones

OsteopetrosisOsteopetrosis

Genetic disease characterised by reduced Genetic disease characterised by reduced osteoclast bone resorption and diffuse osteoclast bone resorption and diffuse symmetric skeletal sclerosissymmetric skeletal sclerosis

( marble bone disease- Albers Schönberg ( marble bone disease- Albers Schönberg disease)disease)


Infant OnsetInfant Onset Adult OnsetAdult Onset Carbonic Anhydrase 11 DeficiencyCarbonic Anhydrase 11 Deficiency

DISEASES ASSOCIATED WITH DEFECTS IN DISEASES ASSOCIATED WITH DEFECTS IN METABOLIC PATHWAYSMETABOLIC PATHWAYS

(ENZYMES, ION CHANNELS, AND TRANSPORTERS) (ENZYMES, ION CHANNELS, AND TRANSPORTERS) OsteopetrosisOsteopetrosis OsteopetrosisOsteopetrosis refers to a group of rare refers to a group of rare

genetic diseases that are characterized by genetic diseases that are characterized by reduced osteoclast bone resorption, reduced osteoclast bone resorption, resulting in diffuse symmetric skeletal resulting in diffuse symmetric skeletal sclerosis . sclerosis .


The term The term osteopetrosisosteopetrosis was coined was coined because of the stonelike quality of the because of the stonelike quality of the bones; however, the bones are abnormally bones; however, the bones are abnormally brittle and fracture like a piece of chalk. brittle and fracture like a piece of chalk.

Osteopetrosis, which is also known as Osteopetrosis, which is also known as marble bone diseasemarble bone disease and and Albers-Albers-Schönberg disease,Schönberg disease, is classified into is classified into variants based on both the mode of variants based on both the mode of inheritance and the clinical findings. inheritance and the clinical findings.

DISEASES ASSOCIATED WITH DISEASES ASSOCIATED WITH DECREASED BONE MASSDECREASED BONE MASS

OsteoporosisOsteoporosis

((Low bone mineral content Low bone mineral content ))


Decreased volume of mineralized bone Decreased volume of mineralized bone tissue pertissue per unit of boneunit of bone

Cortical thinning and increased porosityCortical thinning and increased porosity Decreased number and thickness of Decreased number and thickness of

trabeculae trabeculae Decreased bone strengthDecreased bone strength IIncreased risk of fracturencreased risk of fracture

Normal BoneNormal Bone

Female, age 30 years

Moderate OsteoporosisModerate Osteoporosis

Female, age 88 years


Osteoporosis is the most common bone Osteoporosis is the most common bone disease disease

Increasing in prevalence with the aging of Increasing in prevalence with the aging of the population. the population.

Mainly postmenopausal women.Mainly postmenopausal women. A 'silent' risk factor for bone fracture.A 'silent' risk factor for bone fracture.

OsteoporosisOsteoporosis Decrease in bone density Decrease in bone density Thinning and increased porosity of the bone Thinning and increased porosity of the bone

cortices and trabeculae. cortices and trabeculae. As a clinical term: As a clinical term:

a generalized loss of bone density a generalized loss of bone density skeletal fragility, skeletal fragility, bone pain, bone pain, pathological fractures (of the spine, wrist, hip, and pathological fractures (of the spine, wrist, hip, and

ribs), ribs), • particularly in postmenopausal women and bothparticularly in postmenopausal women and both

OsteoporosisOsteoporosis Primary osteoporosis, unrelated to other Primary osteoporosis, unrelated to other

disease, is classified by age groups into disease, is classified by age groups into postmenopausal, postmenopausal, senile, senile, idiopathic (premenopausal women and younger men), idiopathic (premenopausal women and younger men), juvenile. juvenile.

Postmenopausal osteoporosis is the most Postmenopausal osteoporosis is the most frequent form of osteoporosis and is the frequent form of osteoporosis and is the commonest metabolic bone disease. commonest metabolic bone disease.

OsteoporosisOsteoporosisPathologyPathology The excessive bone loss The excessive bone loss Thinning and increased porosity of the trabecular bone Thinning and increased porosity of the trabecular bone

of the axial skeleton (vertebrae, ribs, and pelvis). of the axial skeleton (vertebrae, ribs, and pelvis). The cortices of cylindrical bones are also thinned The cortices of cylindrical bones are also thinned

from the inside by endosteal resorption, resulting in enlargement from the inside by endosteal resorption, resulting in enlargement of the medullary cavity without a change in the outside diameter of the medullary cavity without a change in the outside diameter of the bone. of the bone.

The vertebral bodies, The vertebral bodies, may be weakened by microfractures may be weakened by microfractures collapse anteriorly, collapse anteriorly, resulting in compression fractures and wedging of the vertebrae, resulting in compression fractures and wedging of the vertebrae, a loss of stature,a loss of stature,

• kyphotic deformity of the spine ("dowager's hump"). kyphotic deformity of the spine ("dowager's hump").

OsteoporosisOsteoporosisHistologyHistology The amount of cortical and cancellous bone in The amount of cortical and cancellous bone in

osteoporosis is decreased. osteoporosis is decreased. Bone remains has a lamellar structure and Bone remains has a lamellar structure and

osteoid seams of normal width.osteoid seams of normal width. The bone cortices are thinned, and the The bone cortices are thinned, and the

haversian canals are widened. haversian canals are widened. The trabeculae of cancellous bone are The trabeculae of cancellous bone are

decreased in size and number. decreased in size and number. The trabeculae are thin, discontinuous, and The trabeculae are thin, discontinuous, and

widely separated. widely separated.

OsteoporosisOsteoporosis GeneralizedGeneralized

corticalcorticaltrabeculartrabecular

LocalizedLocalizedrheumatoid arthritisrheumatoid arthritis

Bone marrow disease Bone marrow disease myelomamyelomasecondary cancersecondary cancerlymphoma and leukemialymphoma and leukemiamastocytosismastocytosishistiocytosishistiocytosis

OsteoporosisOsteoporosis AgeAge related related Hypogonadism: estrogen and testosteroneHypogonadism: estrogen and testosterone Calcium deficiency and insufficiencyCalcium deficiency and insufficiency Vitamin D deficiency and insufficiencyVitamin D deficiency and insufficiency Corticosteroid Treatment and Cushing’s DiseaseCorticosteroid Treatment and Cushing’s Disease ImmobilizationImmobilization Antiepileptic DrugsAntiepileptic Drugs MyelomaMyeloma ThyrotoxicosisThyrotoxicosis IdiopathicIdiopathic


Mineralization; osteomalacia/ricketsMineralization; osteomalacia/rickets Bone turnover; pagets; primary Bone turnover; pagets; primary

hyperparthyroidism; secondary hyperparthyroidism; secondary hyperparathyroidismhyperparathyroidism

Low Bone content; osteoporoses/ Low Bone content; osteoporoses/ generalized and localized; oi; generalized and localized; oi;

High bone content; osteopetrosisHigh bone content; osteopetrosis


Mineralization; osteomalacia/ricketsMineralization; osteomalacia/rickets Low bone mineral content; osteoporoses; OILow bone mineral content; osteoporoses; OI High bone mineral content; osteopetrosis; High bone mineral content; osteopetrosis;

bisphosphonate; benign high bone massbisphosphonate; benign high bone mass High bone turnover; pagets; High bone turnover; pagets;

hyperparathyroidismhyperparathyroidism Low bone turnover; adynamic diseaseLow bone turnover; adynamic disease

High Bone Mineral ContentHigh Bone Mineral Content

OsteopetrosisOsteopetrosis Bisphosphonate TreatmentBisphosphonate Treatment Fluorosis Fluorosis Benign High Bone MassBenign High Bone Mass

Diseases of Mineralization: Diseases of Mineralization: Osteomalacia and Rickets Osteomalacia and Rickets

Osteomalacia is a term that is used to Osteomalacia is a term that is used to encompass a group of diseases in adults, encompass a group of diseases in adults, the essential feature of which is a delay in the essential feature of which is a delay in mineralization as osteoid is laid down.mineralization as osteoid is laid down.

Rickets is the equivalent term used in Rickets is the equivalent term used in children where the disease manifests children where the disease manifests particularly at the growth areas of bone particularly at the growth areas of bone

Osteomalacia and RicketsOsteomalacia and Rickets Rickets and osteomalacia may be caused by: Rickets and osteomalacia may be caused by:

a deficiency or abnormal metabolism of vitamin D; a deficiency or abnormal metabolism of vitamin D; a deficiency or abnormal utilization/excretion of a deficiency or abnormal utilization/excretion of

inorganic phosphate (Pi). inorganic phosphate (Pi). A deficiency of vitamin D may be due toA deficiency of vitamin D may be due to::

a dietary lack of the vitamin; a dietary lack of the vitamin; insufficient ultraviolet exposure to form endogenous insufficient ultraviolet exposure to form endogenous

vitamin D; vitamin D; most commonly, malabsorption interfering with the most commonly, malabsorption interfering with the

intestinal absorption of fats and fat-soluble vitamin D. intestinal absorption of fats and fat-soluble vitamin D. An abnormal metabolism of vitamin D commonly An abnormal metabolism of vitamin D commonly

occurs in chronic renal failure. occurs in chronic renal failure.

Osteomalacia and RicketsOsteomalacia and Rickets

Disease is diagnosed by histology and in Disease is diagnosed by histology and in severseveree cases by radiology cases by radiology

Etiology is diagnosed by biochemistry, Etiology is diagnosed by biochemistry, history and examinationhistory and examination

Osteomalacia and RicketsOsteomalacia and Rickets

Vitamin DVitamin D PhosphatePhosphate CalciumCalcium AcidAcid Alkaline PhosphateAlkaline Phosphate Drugs and ToxinsDrugs and Toxins

Effects of Vitamin D Deficiency on BoneEffects of Vitamin D Deficiency on Bone

Deficiency Insufficiency

2° hyperparathyroidism Ca + P deficiency

Osteomalacia/rickets Increased bone turnover

Vitamin DVitamin D

Vitamin D DeficiencyVitamin D Deficiency Impaired 25 OH Vitamin D productionImpaired 25 OH Vitamin D production Impaired 1,25 OH2 Vitamin D productionImpaired 1,25 OH2 Vitamin D production Defective Vitamin D receptor Defective Vitamin D receptor

Active Form

Vitamin D & CalciumHomeostasis…Ugh!

Sunlight is

critical!

Rickets and osteomalacia may be caused by:Rickets and osteomalacia may be caused by: a deficiency or abnormal metabolism of vitamin D; a deficiency or abnormal metabolism of vitamin D; a deficiency or abnormal utilization/excretion of a deficiency or abnormal utilization/excretion of

inorganic phosphate (Pi). inorganic phosphate (Pi).

A deficiency of vitamin D may be due to:A deficiency of vitamin D may be due to: a dietary lack of the vitamin; a dietary lack of the vitamin; insufficient ultraviolet exposure to form endogenous insufficient ultraviolet exposure to form endogenous

vitamin D; vitamin D; most commonly, malabsorption interfering with the most commonly, malabsorption interfering with the

intestinal absorption of fats and fat-soluble vitamin D. intestinal absorption of fats and fat-soluble vitamin D. An abnormal metabolism of vitamin D commonly An abnormal metabolism of vitamin D commonly

occurs in chronic renal failure. occurs in chronic renal failure.

The most common cause of osteomalacia The most common cause of osteomalacia intestinal malabsorption of fats and fat-intestinal malabsorption of fats and fat-

soluble vitamin Dsoluble vitamin D • hepatic disease (biliary tract obstruction, primary hepatic disease (biliary tract obstruction, primary

biliary cirrhosis, alcoholic liver disease), biliary cirrhosis, alcoholic liver disease), • chronic pancreatitis, chronic pancreatitis, • intestinal diseases ( regional ileitis, sprue), intestinal diseases ( regional ileitis, sprue), • surgical operations (gastrectomy, resection of surgical operations (gastrectomy, resection of

portions of the small intestine). portions of the small intestine).

Vitamin D DeficiencyVitamin D Deficiency

EnvironmentalEnvironmentalhousebound; frail elderly; immigrant from housebound; frail elderly; immigrant from

low low to high latitude; gastrectomy; to high latitude; gastrectomy; malabsorptionmalabsorption

GeneticGeneticdark skin pigmentationdark skin pigmentation

BiochemistryBiochemistryD low; 25D low; 1,25D low to normal ; Ca D low; 25D low; 1,25D low to normal ; Ca low; PTH high; Alk Ph high; P low low; PTH high; Alk Ph high; P low

Impaired 25D productionImpaired 25D production

EnvironmentalEnvironmentalhepatic failure; drugs affecting liver hepatic failure; drugs affecting liver

enzymesenzymes Genetic Genetic

mutations in 25Dhydroxylase: not mutations in 25Dhydroxylase: not describeddescribed BiochemistryBiochemistry

D normal; 25D low; 1,25 D low to normal; D normal; 25D low; 1,25 D low to normal; Ca low; PTH high; Alk ph high; P lowCa low; PTH high; Alk ph high; P low

PhosphatePhosphate

EnvironmentalEnvironmentaldietary phosphate depletion; dietary phosphate depletion; prematurity in neonates; prematurity in neonates; mesenchymal mesenchymal tumors; renal tubule tumors; renal tubule diseasedisease

GeneticGeneticmutations in mutations in PHEXPHEX; mutations in ; mutations in FGFFGF

Deficiency of serum PiDeficiency of serum Pi peptic ulcer patients receiving long-term peptic ulcer patients receiving long-term

treatment with antacids containing aluminum treatment with antacids containing aluminum hydroxidehydroxide• which forms insoluble complexes with Pi in the which forms insoluble complexes with Pi in the

intestine and blocks its absorption. intestine and blocks its absorption.

Phosphate: Neonatal PrematurityPhosphate: Neonatal Prematurity

Dietary P insufficiencyDietary P insufficiencymilk P intake inadequate for the milk P intake inadequate for the

requirements of a rapidly developing requirements of a rapidly developing skeletonskeleton

BiochemistryBiochemistry

Phosphate: Fanconi SyndromePhosphate: Fanconi Syndrome

Disease of the renal tubuleDisease of the renal tubulecan be genetic or acquired can be genetic or acquired

Phosphate: Mesenchymal TumorPhosphate: Mesenchymal Tumor

Secretion of ‘Phosphatonins’Secretion of ‘Phosphatonins’mmolecules that reduce TmP and inhibit olecules that reduce TmP and inhibit mineralizationmineralization

Renal ricketsRenal rickets Osteomalacia is often a component of renal Osteomalacia is often a component of renal

osteodystrophy, that occur in varying degrees of osteodystrophy, that occur in varying degrees of severity in almost all patients with severity in almost all patients with chronic renal chronic renal failurefailure (CRF). (CRF).

The development of osteomalacia and rickets The development of osteomalacia and rickets ("renal rickets") in CRF is due to the loss of renal ("renal rickets") in CRF is due to the loss of renal parenchyma accompanied by: parenchyma accompanied by: impaired intestinal absorption of calcium and impaired intestinal absorption of calcium and

hypocalcemia; hypocalcemia; decreased renal excretion of inorganic decreased renal excretion of inorganic

phosphor(Pi)phosphor(Pi) hyperphosphatemia hyperphosphatemia decrease in serum calcium (hypocalcemia). decrease in serum calcium (hypocalcemia).

Drug-induced rickets and osteomalaciaDrug-induced rickets and osteomalacia anticonvulsive drug phenytoin anticonvulsive drug phenytoin

• interference with vitamin D metabolism in the liver. interference with vitamin D metabolism in the liver.

Rickets and osteomalacia are also Rickets and osteomalacia are also associated with hypophosphatemiaassociated with hypophosphatemia Renal tubular acidosis (RTA) Renal tubular acidosis (RTA)

• Fanconi syndrome (sporadic or familial)Fanconi syndrome (sporadic or familial)• X-linked hypophosphatemia (vitamin D-resistant X-linked hypophosphatemia (vitamin D-resistant

rickets).rickets). Vitamin D-dependent rickets.Vitamin D-dependent rickets.

ComplicationsComplications Long-standing osteomalacia may produce fractures Long-standing osteomalacia may produce fractures

and deformities of the softened bones and deformities of the softened bones kyphosiskyphosis bowing of the long bones- curved limb bones bowing of the long bones- curved limb bones narrowing of the pelvis narrowing of the pelvis a prominent forehead (frontal bossing) due to a prominent forehead (frontal bossing) due to

osteoid excessosteoid excess beading of the ribs at the costochondral junctions beading of the ribs at the costochondral junctions

(rachitic rosary) caused by overgrowth of cartilage (rachitic rosary) caused by overgrowth of cartilage and osteoid and osteoid

lateral flattening of the rib cage with forward lateral flattening of the rib cage with forward displacement of the sternum (pigeon breast).displacement of the sternum (pigeon breast).

Sporadic Hypophosphatemic Sporadic Hypophosphatemic Osteomalacia Osteomalacia

CalciumCalcium

EnvironmentalEnvironmental insufficiency of dietary calcium insufficiency of dietary calcium during during rapid growthrapid growth

BiochemistryBiochemistry Ca low ; PTH high; Alk ph high; P Ca low ; PTH high; Alk ph high; P

low;low; D normal; 25D normal; 1,25 D high D normal; 25D normal; 1,25 D high

AcidAcid

EnvironmentalEnvironmentalacquired renal tubular acidosis from renal acquired renal tubular acidosis from renal

damagedamage GeneticGenetic

renal tubular acidosis renal tubular acidosis

Drugs and ToxinsDrugs and Toxins

EnvironmentalEnvironmentalEtidronate; Fluoride; AluminumEtidronate; Fluoride; Aluminum

BiochemistryBiochemistry Alk ph normal ; D normal; 25D Alk ph normal ; D normal; 25D

normal; normal; 1,25 D normal; Ca normal; PTH 1,25 D normal; Ca normal; PTH normal; P normalnormal; P normal

The MetaphysisThe Metaphysis

Increased Increased thicknessthickness

CuppingCupping FrayedFrayed

Long Bone FindingsLong Bone Findings

BowingBowing OsteopeniaOsteopenia FracturesFractures

Histological Picture of OsteomalaciaHistological Picture of Osteomalacia

Pathophysiology Pathophysiology of Malignancy-associatedof Malignancy-associated

Bone DiseaseBone Disease

Pathophysiology of Malignant Bone Pathophysiology of Malignant Bone DiseaseDisease

Humoral hypercalcaemia: usually mediated Humoral hypercalcaemia: usually mediated by PTHrPby PTHrP

Osteolytic/osteoblastic metastases: Osteolytic/osteoblastic metastases: boneresorption / formation by osteoclasts / boneresorption / formation by osteoclasts / osteoblasts stimulated by tumour cell osteoblasts stimulated by tumour cell productsproducts

Malignancies Commonly Associated withMalignancies Commonly Associated withSkeletal DiseaseSkeletal Disease

LungLung BreastBreast MyelomaMyeloma RenalRenal ThyroidThyroid ProstateProstate

Oncogenic OsteomalaciaOncogenic Osteomalacia

Tumour-Induced Bone ResorptionTumour-Induced Bone Resorption

Diseases of Bone TurnoverDiseases of Bone Turnover

Bone turnover is a term used to describe the Bone turnover is a term used to describe the rate of bone formation and resorption rate of bone formation and resorption

Bone resorption is coupled to bone formationBone resorption is coupled to bone formation During growth, turnover high, formation> During growth, turnover high, formation>

resorption, net bone gainresorption, net bone gain During adulthood, turnover moderate, During adulthood, turnover moderate,

formation< resorption, net bone lossformation< resorption, net bone loss

Diseases of bone turnoverDiseases of bone turnover

High bone turnoverHigh bone turnoverPagets Pagets HyperparathyroidismHyperparathyroidism

Osteomalacia and ricketsOsteomalacia and ricketsThyrotoxicosisThyrotoxicosisHypogonadismHypogonadism

Low bone turnoverLow bone turnoverAdynamic bone disease; Adynamic bone disease; HypophosphatasiaHypophosphatasia

Bone Changes in Bone Changes in HyperparathyroidismHyperparathyroidism

Generalized Osteitis Fibrosa Cystica, Generalized Osteitis Fibrosa Cystica, Von Recklinghausen's Disease of BoneVon Recklinghausen's Disease of Bone

Diffuse or focal resorptive loss Diffuse or focal resorptive loss Excess of osteoclastic over osteoblastic Excess of osteoclastic over osteoblastic

activityactivity Fibrous replacement of bone Fibrous replacement of bone Caused by an over-production of Caused by an over-production of

parathormone (PTH) parathormone (PTH) in primary or secondary hyperparathyroidism.in primary or secondary hyperparathyroidism.

Primary hyperparathyroidismPrimary hyperparathyroidism Metabolic disorder Metabolic disorder Secretion excessive amounts of PTH:Secretion excessive amounts of PTH:

parathyroid cells, either neoplastic or parathyroid cells, either neoplastic or hyperplastic and in the absence of any known hyperplastic and in the absence of any known stimulus. stimulus.

usually caused by a functioning adenoma of a usually caused by a functioning adenoma of a single parathyroid gland (80 %), single parathyroid gland (80 %),

diffuse hyperplasia of all four parathyroid diffuse hyperplasia of all four parathyroid glands (15 %), glands (15 %),

primary parathyroid carcinomaprimary parathyroid carcinoma multiple parathyroid adenomas. multiple parathyroid adenomas.

Secondary hyperparathyroidismSecondary hyperparathyroidism Chronic renal failureChronic renal failure

most often hyperphosphatemia and hypocalcemia. most often hyperphosphatemia and hypocalcemia.

Renal osteodystrophyRenal osteodystrophy Complex bone changes in chronic renal failure Complex bone changes in chronic renal failure

• osteomalacia, osteomalacia, • rickets ("renal rickets"),rickets ("renal rickets"),• osteitis fibrosa. osteitis fibrosa.

Non-parathyroid carcinomasNon-parathyroid carcinomas lung, kidney,or elsewhere lung, kidney,or elsewhere may produce a PTH-like hormone may produce a PTH-like hormone a syndrome resembling hyperparathyroidism. a syndrome resembling hyperparathyroidism.

The clinical presentations are divisible into three The clinical presentations are divisible into three categories: categories: Hypercalcemia: Hypercalcemia:

• neuromuscular weakness, fatigue, gastrointestinal neuromuscular weakness, fatigue, gastrointestinal symptoms, and, coma in severe hypercalcemic crisis; symptoms, and, coma in severe hypercalcemic crisis;

Renal stones (often bilateral)Renal stones (often bilateral)• calcification of the kidneys (nephrocalcinosis); calcification of the kidneys (nephrocalcinosis); • metastatic calcification of other tissues; metastatic calcification of other tissues;

Bone resorption and fibrous replacementBone resorption and fibrous replacement• diffuse osteopeniadiffuse osteopenia• "cystic" or tumor-like lesions of bone ("brown tumors");"cystic" or tumor-like lesions of bone ("brown tumors");• pathological fractures; pathological fractures; • generalized osteitis fibrosa cystica.generalized osteitis fibrosa cystica.

PathologyPathology diffuse bone loss diffuse bone loss

resulting from osteoclastic resorption and fibrous replacement of resulting from osteoclastic resorption and fibrous replacement of bone (osteitis fibrosa); bone (osteitis fibrosa);

foci of cystic lesions (osteitis fibrosa cystica) or tumor-like foci of cystic lesions (osteitis fibrosa cystica) or tumor-like lesions of bone ("brown tumors"); lesions of bone ("brown tumors");

pathological fractures. pathological fractures. The osteoclastic and fibrous reaction (osteitis fibrosa):The osteoclastic and fibrous reaction (osteitis fibrosa): skull, skull,

vertebrae, vertebrae, shaft of long bones, and small bones. shaft of long bones, and small bones.

Resorptions of the Resorptions of the medial cortex of the phalangesmedial cortex of the phalanges, the , the tips of the distal phalangestips of the distal phalanges of the hand and of the hand and lamina dura lamina dura between teethbetween teeth are characteristic early radiographic are characteristic early radiographic findings. findings.

MicroscopyMicroscopy Earliest changes:Earliest changes:

resorptive loss and fibrous replacement of resorptive loss and fibrous replacement of bone bone

excess of osteoclastic over osteoblastic excess of osteoclastic over osteoblastic activity activity

fibroblast proliferation in the marrow space. fibroblast proliferation in the marrow space. Characteristically, Characteristically, numerous osteoclastsnumerous osteoclasts in in

Howship's lacunae are seen on bone Howship's lacunae are seen on bone surfaces undergoing resorption, beginning surfaces undergoing resorption, beginning in the cancellous bone and tunneling in the cancellous bone and tunneling through Haversian canals in the cortex. through Haversian canals in the cortex.

The focal cystic lesions The focal cystic lesions (osteitis fibrosa (osteitis fibrosa cystica): cystica): Often multipleOften multiple Usually develop in the shaft of long bones, the Usually develop in the shaft of long bones, the

jaw, and skull; jaw, and skull; Osteolytic and expansiveOsteolytic and expansive May form a tumor-like mass of brown, yellow, May form a tumor-like mass of brown, yellow,

or hemorrhagic tissue ("brown tumor")or hemorrhagic tissue ("brown tumor") The foci of bone destruction are rarefied and The foci of bone destruction are rarefied and

thus "cystic" in a radiological sense. thus "cystic" in a radiological sense. The bone lesions are not neoplastic. The bone lesions are not neoplastic.

Microscopy of the Brown tumor:Microscopy of the Brown tumor: proliferated osteoclasts and fibroblastsproliferated osteoclasts and fibroblasts a fibrous stroma, a fibrous stroma, a region of hemorrhage, a region of hemorrhage, characteristically associated with hemosiderin characteristically associated with hemosiderin

deposition (which imparts a brown color).deposition (which imparts a brown color).

The bone changes of primary The bone changes of primary hyperparathyroidism regress or disappear hyperparathyroidism regress or disappear within a few weeks after surgical removal of within a few weeks after surgical removal of the parathyroid lesion which is usually found the parathyroid lesion which is usually found to be an adenoma or, less commonly, diffuse to be an adenoma or, less commonly, diffuse hyperplasia of the parathyroid gland. hyperplasia of the parathyroid gland.

Renal osteodystrophyRenal osteodystrophy

Uremic bone diseaseUremic bone disease In patients with chronic renal failure (CRF). In patients with chronic renal failure (CRF). The bone disorders in renal osteodystrophy The bone disorders in renal osteodystrophy

include: include: osteomalacia of adults osteomalacia of adults rickets of children (so-called "renal rickets"); rickets of children (so-called "renal rickets"); osteitis fibrosa osteitis fibrosa bone changes of secondary hyperparathyroidism; bone changes of secondary hyperparathyroidism; osteopenia; osteopenia; osteosclerosis. osteosclerosis.

Pagets DiseasePagets Disease

High bone turnoverHigh bone turnover High blood flowHigh blood flow Disordered bone architectureDisordered bone architecture Weakness of boneWeakness of bone

Paget’s DiseasePaget’s Disease

Current evidence suggests slow virus Current evidence suggests slow virus infection by paramyxovirus infectioninfection by paramyxovirus infection

PathologyPathology The bone changes are divisible into three The bone changes are divisible into three

phases defined radiologically: phases defined radiologically: osteolytic phase (active bone resorption),osteolytic phase (active bone resorption), mixed osteolytic and osteoblastic phase (both mixed osteolytic and osteoblastic phase (both

osteoclastic and osteoblastic activity), osteoclastic and osteoblastic activity), osteosclerotic phase (sclerotic bone is formed osteosclerotic phase (sclerotic bone is formed

with a characteristic "mosaic" pattern of with a characteristic "mosaic" pattern of histologic structure).histologic structure).• mosaic pattern of cement lines outlining irregular mosaic pattern of cement lines outlining irregular

patches of sclerotic lamellar bone. patches of sclerotic lamellar bone.

Complications Complications (in advanced cases):(in advanced cases): femurs and tibias may be bowed femurs and tibias may be bowed hips deformed; hips deformed; the vertebral bodies may be compressed,the vertebral bodies may be compressed,

resulting in kyphosis or scoliosis; resulting in kyphosis or scoliosis; skull may be enlargedskull may be enlarged hearing losshearing loss pathological fracturespathological fractures bone tumors: bone tumors:

osteogenic sarcoma (most common); osteogenic sarcoma (most common); fibrosarcoma fibrosarcoma giant cell tumor. giant cell tumor.

The skeletal involvement may be limited to a The skeletal involvement may be limited to a single bone (monostotic) or affect many bones single bone (monostotic) or affect many bones (polyostotic);(polyostotic); pelvis, pelvis, femur, tibia, femur, tibia, spine, spine, skull. skull.

The affected bones may be weakened by The affected bones may be weakened by resorption or enlarged by reparative, although resorption or enlarged by reparative, although defective, new-bone formation. defective, new-bone formation.

In the final stage of the disease, dense bone is In the final stage of the disease, dense bone is formed, but it is poorly organized and formed, but it is poorly organized and predisposed to predisposed to fracturefracture and and deformitydeformity..

HyperparathyroidHyperparathyroidismism

Primary Primary AdenomaAdenomaHyperplasiaHyperplasiaCancerCancer

SecondarySecondary

Calcium and Vitamin D insufficiencyCalcium and Vitamin D insufficiencyCalcium and Vitamin D deficiencyCalcium and Vitamin D deficiencyRenal FailureRenal Failure

Secondary Hyperparathyroidism Secondary Hyperparathyroidism Renal osteodystrophyRenal osteodystrophy

Secondary/TertiarySecondary/TertiaryUremic mixed osteodystrophy Uremic mixed osteodystrophy Adynamic Adynamic FracturesFracturesEctopic calcificationEctopic calcification

Mixed uremic osteodystrophyMixed uremic osteodystrophy

Increased Increased activation frequencyactivation frequencybone formation ratebone formation ratemarrow fibrosismarrow fibrosisosteoblastsosteoblastsosteoclastsosteoclasts

Bone is aBone is aLiving tissueLiving tissue

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Congenital and Metabolic Bone Diseases

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