PowerPoint Presentation

Metabolic Bone Diseases Constitution of boneIt is a specialized dense connective tissueWhere the matrix is impregnated by calcium salts making it hard and rigid Matrix is made up of organic and inorganic intercellular substances and surround osteocytes

Bone has organized canalicular mechanism and is highly vascularIt consists of cells and intercellular substances It is covered by periosteumBone grows by surface deposition

Cells of bone Osteogenic cells they are precursors of other cells They are found in the inner layer of periosteumOsteoblasts they are found where active bone is being formed They lay down fibers and matrix

Osteocytes they are resting cells in the bony matrix They lie in spaces called lacunaeLacunae are surrounded by canaliculiCanaliculi anastomose with neighboring lacunae canaliculiProcesses of osteocytes occupy these canaliculi Osteoclasts they are large giant cells They have 5-15 nucleiThey remove the bone or resorption of bone All bone cells work in harmony

Intercellular substanceTwo typesInorganic matter is made up of calcium It provides rigidity Strong acids dissolve salts Organic matter is made of collagen fibers All the elements are secreted by osteoblasts Organic matter is destroyed by burning

Histological classification Two typesCompact or dense Bone is hardPresent in the shaft of long bones Cancellous or spongy Bone has larger marrow spacesBone is less hard Present in the ends of long bones

Microscopic structure of compact bone Bone is covered by periosteumIt consists of two layers Outer fibrous layerInner osteogenic and vascular layerPeriosteum is firmly bound to bone by Sharpeys fibers Compact bone is characteristic by the presence of Haversian system

Histology of boneCentrally situated Haversian canalContaining vessels and nerves Canal is surrounded by 6-12 concentric lamellae Lamellae are composed of collagen fibers with calcium deposits Collagen fibers run spirally

Histology of boneBetween the lamellae or on the lamellae are lacunae present They imprison osteocytes Canaliculi are occupied by processes of osteocyte The processes are responsible for nourishment of osteocytes

Histology of boneHaversian canals are connected with one another and communicate with marrow cavity through Volkmanns canals Interstitial lamellae lie in the angles between the adjoining the haversian lamellae They belong to older bone Near periosteum outer circumferential lamellae are present Near endosteum inner circumferential lamellae are present

Centrally situated Haversian canalContaining vessels and nerves Canal is surrounded by 6-12 concentric lamellae Lamellae are composed of collagen fibers with calcium deposits Collagen fibers run spirally

Between the lamellae or on the lamellae are lacunae present They imprison osteocytes Canaliculi are occupied by processes of osteocyte The processes are responsible for nourishment of osteocytes

Haversian canals are connected with one another and communicate with marrow cavity through Volkmanns canals Interstitial lamellae lie in the angles between the adjoining the haversian lamellae They belong to older bone Near periosteum outer circumferential lamellae are present Near endosteum inner circumferential lamellae are present

Definition & TypesMost of the diseases are associated with depletion of bone tissue.Osteoporosis- Bone mass is abnoarmally lowOsteomalacia- Osseous connective tissue(osteoid) is present but insufficiently mineralizedOsteitis Fibrosa- PTH over-production leads to bone resorption and replacement by fibrous tissue OSTEOPOROSIS18OSTEOPOROSISporous boneskeletal disorder characterised by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength Bone density (g/cm2 or g/cm3) - peak bone mass and amount of bone loss. Bone quality - architecture, turnover, damage accumulation, and mineralisation of the bone18What is Osteoporosis?Osteoporosis, or porous bone, is a disease characterized by low bone mass and structural deterioration of bone tissue. This disease can weaken your bones so much that even simple everyday activities can cause bones to break. Osteoporosis strikes both men and women, although women are afflicted in much greater numbers. While the effects of Osteoporosis are devastating, there are things you can do now to prevent and treat it. Osteoporosis is defined as a skeletal disorder characterised by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength reflects the integration of bone density and bone quality. Bone density (g/cm2 or g/cm3) is determined by peak bone mass and amount of bone loss. Bone quality refers to the architecture, turnover, damage accumulation, and mineralisation of the bone19OSTEOPOROSISNormal BoneOsteoporotic Bone

19On the left is an illustration of normal, healthy bone, and on the right, osteoporotic bone. You can see the difference in bone density clearly.Osteoporosis occurs when the holes between bone become bigger, making it fragile and liable to break easily

OSTEOPOROSIS - DEFINITION

A progressive systematic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fractureCLASSIFICATION OF OSTEOPOROSISPrimary osteoporosis in the elderly can be classified as type I or II:Type I (menopausal) osteoporosis occurs mainly in persons aged 51 to 75, is six times more common in women, and is associated with vertebral and Colles' (distal radius) fractures. Type II (senescent) osteoporosis occurs in persons > 60, is two times more common in women, and is associated with vertebral and hip fractures. Overlap between types I and II is substantial, so this classification is of limited clinical use. Primary osteoporosis is thought to result from the hormonal changes that occur with age, particularly decreasing levels of sex hormones (estrogen in women, testosterone in men). Several other risk factors are usually contributory.

Secondary osteoporosis may be due to many causes. 22

23RISK FACTORSFemaleThin or small frameLow body weightSmoker

23In addition to warning signs, there are a significant number of risk factors to consider for Osteoporosis. However, it is important to be aware that you can have no risk factors and still have Osteoporosis.The following risk factors have been identified:Being female,Having a thin or small frame andHaving a low body weight of 127 pounds or less.In addition, being a smoker is a major risk factor as are

24RISK FACTORSAdvanced ageHistory of fragility fractureFamily history- primary relative with Osteoporosis or fragility fracture

24Reaching Advanced age, andHaving a history of fragility fracture or a primary relative with a history of fragility fracture or Osteoporosis.25RISK FACTORSPost MenopausalHormonal imbalances can result in rapid bone lossWomen can lose up to 20% of their bone mass in 5-7 years25In addition, post menopausal women are at great risk because the hormonal imbalances of menopause can result in rapid bone loss.Women can lose up to 20% of their bone mass in the 5-7 years after the onset of menopause.26Risk FactorsAmenorrhea, Anorexia & BulimiaDiet low in calciumCertain medicationsLow testosterone in men26Eating disorders such as Anorexia and Bulimia,A diet low in calcium,Use of certain medications andLow testosterone in men are all risk factors as well. 27ETHNICITY & OSTEOPOROSISCaucasian & Asian-American Women High Risk

27Caucasian and Asian-American women are also at high risk. This is due largely to differences in bone mass and density.The average calcium intake among Asian-American women is about half that of their Caucasian counterparts.While Asian-American women generally have lower incidence of hip fractures than Caucasian women, the prevalence of vertebral fractures is about equal between the two populations.28MEN & OSTEOPOROSIS

Underdiagnosed Unrecognized Underreported Inadequately researched 28While Osteoporosis does strike women at higher rates, men are also at risk. Osteoporosis in men is underdiagnosed, unrecognized, and inadequately reported and researched. As with women, Caucasian men are at greater risk for Osteoporosis. Many of the same risk factors apply to men:Lifestyle, age, heredity, prolonged exposure to certain medications. chronic disease and undiagnosed levels of testosterone all put men at increased risk for Osteoporosis.29SYMPTOMS AND WARNING SIGNS29There are several symptoms and warning signs indicative of Osteoporosis to be on the lookout for:Persistent, unexplained back pain,Noticing that you are shorter than you used to be,that you dont stand up as straight as you used to, or that your posture is becoming hunched over or stooped.PATHOPHYSIOLOGY Hallmark of osteoporosis is a reduction in skeletal mass caused by an imbalance between bone resorption and bone formation.Under physiologic condition, bone formation and resorption are in fair balance.A change in either , that is, increased bone resorption or decreased bone formation may result in osteoporosisOsteoporosis can be caused both by a failure to build bone and reach peak bone mass as a young adult and by bone loss later in lifePATHOLOGYInadequate peak massExcessive bone resorption: Deficiency of estrogenCalcium metabolism, Vitamin D metabolism HyperparathyroidismInadequate bone formation during remodelling

INVESTIGATIONSRadiological evidence of decreased bone mass is more reliable.Following features may be noticed on X-rays: Loss of vertical height of a vertebra due to collapseCod fish appearance. The disc bulges into the adjacent vertebral bodies so that the disc becomes biconvexGround glass appearance of the bones, conspicuous in bones like the pelvisSinghs index: Singh et al. graded osteoporosis into 6 grades based on the trabecular pattern of the femoral neck trabeculae.Metacarpal index and vertebral index are other methods of quantification

BIOCHEMISTRY: Serum calcium, phosphates and alkaline phosphatase are within normal limitsTotal plasma proteins and plasma albumin may be lowMarkers of bone resorption: deoxy-pyridinoline, N-telopeptide

DENSITOMETRY:Method to quantify osteoporosisIn this method absorption of photons (emitted from gamma emitting isotopes) by the bone calcium is measured2 types of bone densitometry: ultrasound based and X-ray basedDual energy X-ray absorptiometry (DEXA) scan is an X-ray based bone densitometry, and is the gold standard in the quantification of bone mass NEUTRON ACTIVATION ANALYSISCalcium in the bone is activated by neutron bombing, and its activity measured

BONE BIOPSYTREATMENTPrinciple objectives of treatment are alleviation of pain and prevention of fracturesDivided into medical and orthopeadicMEDICAL TREATMENTHigh protein diet: Increasing protein intake may increase the formation of organic matrix of the boneCalcium supplementation: Helpful in cases with deficiency of calcium in their dietAndrogens: These hormones have an anabolic effect on the protein matrix of bone, and in some instances ameliorate symptomsEstrogens (HRT): Halt the progressive loss of bone mass in postmenopausal osteoporosisVitamin D: This is given, in addition to the above, to increase calcium absorption from the gutAlandronate: Used in once a day dose, empty stomach. Oesophagitis is a troubling complicationCalcitonin: Helps in building up the bone mass and also acts as an analgesic

Biphosphanates:Sodium alendronate ( 10mg/day or 70mg/week)Risedronate (5mg/day or 35mg/week)Ibandronate: once a monthSelective estrogen receptive modulator-SERM- Raloxifene

Teriparatide(recombinant PTH hormone): daily injectionUsed in established osteoporosis, very low BMD, cannot tolerate BiphosphonatesCI:Young, Pagets disease, radiation therapy

ORTHOPAEDIC TREATMENTExercises: Weight bearing is a major stimulus to bone formation. Increased guarded activity would therefore be of benefit to the patientBracing: Prophylactic bracing of the spine by using an ASH brace or Taylor brace maybe useful in prevention of pathological fractures in a severely osteoporotic spinePREVENTIONAdequate intake of dietary calciumDecreased alcohol consumption and caffeine useRegular exerciseSmoking cessationOSTEOPETROSISDefinitionOsteopetrosis is a bone disease that makes bones abnormally dense and prone to breakage (fracture).Osteopetrosis, literally "stone bone", also known asmarble bone diseaseandAlbers-Schnberg disease, is an extremely rare inheriteddisorderwhereby thebonesharden, becomingdenser.A clinical syndrome characterized by the failure of osteoclasts to resorb bone. As a consequence, bone modeling and remodeling are impaired.In contrast to more prevalent conditions likeosteoporosis, in which the bones become less dense and more brittle, orosteomalacia, in which the bones soften.Aetiology1. Failure of Bone cells and bone modeling and remodeling

Osteoblasts synthesize bone matrix, which are composed predominantly of type I collagen and are found at the bone-forming surface.Extracellular matrix surrounds some osteoblasts, which become osteocytes.Osteoclasts can tightly attach to the bone matrix by integrin receptorsto form a sealing zone, within which is a sequestered, acidified compartment.Acidification promotes solubilization of the bone mineral in the sealing zone, and various proteases, notably cathepsin K, catalyze degradation of the matrix proteins.Bone modeling and remodeling differ in that modeling implies a change in the shape of the overall bone and is prominent during childhood and adolescence.Modeling is the process by which the marrow cavity expands as the bone grows in diameter.Failure of modeling is the basis of hematopoietic failure in osteopetrosisRemodeling, in contrast, involves the degradation of bone tissue from a preexisting bony structure and replacement of the degraded bone by newly synthesized bone. Failure of remodeling is the basis of the persistence of woven bone.2. Failure of Osteoclast development and maturation

For precursor cells to mature, functional osteoclasts require the action of 2 distinct signals. The first is monocyte-macrophagecolony-stimulating factor (M-CSF), which is mediated by a specific membrane receptor and its signaling cascade. The second is the receptor activating NF-kappa B ligand (RANKL), acting through its cognate receptor, RANK. A soluble decoy receptor, osteoprotegerin, can bind RANKL, limiting its ability to stimulate osteoclastogenesis.3. Genetic and molecular defects in osteopetrosis

The primary underlying defect in all types of osteopetrosis is failure of the osteoclasts to reabsorb bone.A number of heterogeneous molecular or genetic defects can result in impaired osteoclastic function:The specific genetic defect in humans is known only in osteopetrosis caused by carbonic anhydrase II deficiencyBased on its inheritance pattern, infantile osteopetrosis seems to be transmitted in an autosomal recessive mannerViruslike inclusions have been reported in osteoclasts of some patients with benign osteopetrosis

Carbonic anhydrase isoenzyme II deficiency

This enzyme catalyzes the formation of carbonic acid from water and carbon dioxide. Carbonic acid dissociates spontaneously to release protons, which are essential for creating an acidic environment required for dissolution of bone mineral in the resorption lacunae. Lack of this enzyme results in impaired bone resorption.Clinical FeaturesInfantile osteopetrosis

Infantile osteopetrosis (also called malignant osteopetrosis) is diagnosed early in life. Failure to thrive and growth retardation are symptoms.Nasal stuffiness due to mastoid and paranasal sinus malformation is often the presenting feature of infantile osteopetrosisNeuropathies related to cranial nerve entrapment occur due to failure of the foramina in the skull to widen completelyManifestations include deafness, proptosis, and hydrocephalus.Dentition may be delayedOsteomyelitis of the mandible is common due to an abnormal blood supplyBones are fragile and can fracture easilyDefective osseous tissue tends to replace bone marrow, which can cause bone marrow failure with resultant pancytopeniaPatients suffer from anemia, easy bruising and bleeding (due to thrombocytopenia), and recurrent infections (due to inherent defects in the immune system)Extramedullary hematopoiesis may occur, with resultant hepatosplenomegaly, hypersplenism, and hemolysisOther manifestations include sleep apnea and blindness due to retinal degeneration

They are often transverse fractures with multiple areas of callus formation and normal healing.Additionally, there is crowding of the marrow, so bone marrow function is affected resulting in myelophthisic anaemia andextramedullary haematopoiesiswith splenomegaly. This may terminate inacute leukaemia.

Adult osteopetrosis

Adult osteopetrosis (also called benign osteopetrosis) is diagnosed in late adolescence or adulthood. Two distinct types have been described, type I and type II, on the basis of radiographic, biochemical, and clinical features.Approximately one half of patients are asymptomatic, and the diagnosis is made incidentally.Many patients have bone pains. Bony defects are common and include neuropathies due to cranial nerve entrapment (eg, with deafness, with facial palsy), carpal tunnel syndrome, and osteoarthritis. Bones are fragile and may fracture easily. Approximately 40% of patients have recurrent fractures. Osteomyelitis of the mandible occurs in 10% of patients.Other manifestations include visual impairment due to retinal degeneration and psychomotor retardation.CharacteristicType IType IISkull sclerosisMarked sclerosis mainly of the vaultSclerosis mainly of the baseSpineDoes not show much sclerosisShows the rugger-jersey appearancePelvisNo endobonesShows endobones in the pelvisTransverse banding of metaphysisAbsentMay or may not be presentRisk of fractureLowHighSerum acid phosphataseNormalVery highInvestigationLaboratory findings in infantile osteopetrosisSerum calcium - Generally reflects oral intake; hypocalcemia can occur and cause rickets if it is severe enoughParathyroid hormone (PTH) - Often is elevated (secondary hyperparathyroidism)Acid phosphatase - Increased due to increased release from defective osteoclastsCreatinine kinase isoform BB (CK-BB) - levels are increased due to increased release from defective osteoclasts

Laboratory findings in adult osteopetrosisAcid phosphatase and CK-BB - Concentrations are often increased in type II diseaseSerum bone-specific alkaline phosphatase - Values may also be increased in various types of the disease

Genetic screening

Mutation screening of appropriate candidate genes should be undertaken in patients whose presentation corresponds to any of the known genetic lesions.Histologic findings

Failure of osteoclasts to resorb skeletal tissue is the pathognomonic feature of true osteopetrosis. Remnants of mineralized primary spongiosa are seen as islands of calcified cartilage within mature bone. Woven bone is commonly seen. Osteoclasts can be increased, normal, or decreased in number.Radiography

Patients usually have generalized osteosclerosis.Bones may be uniformly sclerotic, but alternating sclerotic and lucent bands may be noted in iliac wings and near the ends of long bones. The bones may be clublike or may have the appearance of a bone within bone (endobone). Radiographs may also show evidence of fractures or osteomyelitis.The entire skull is thickened and dense, especially at the base. Sinuses are small and underpneumatized. Vertebrae are extremely radiodense. They may show alternating bands, known as the rugger-jersey sign

Differentiating type 1 from type 2 adult osteopetrosis

Type I disease - Sclerosis of the skull mainly affects the vault with marked thickening; the spine does not show much sclerosis.Type II disease - Sclerosis is found mainly in the base of the skull; the spine always has the rugger-jersey appearance, and the pelvis always shows subcristal sclerosis; transverse banding of metaphysis is common in patients with type II disease but not in patients with type I disease (this finding confirms type II disease, but its absence does not necessarily indicate type I disease)

Treatment1. Vitamin D analogsThese supplements increase serum calcium levels by increasing calcium absorption from the gastrointestinal tract.Calcitriol(Rocaltrol, Calcijex,Vectical) in large doses, with restricted calcium intake, sometimes improves osteopetrosis dramatically. It can be used to treat infantile osteopetrosis and appears to help by stimulating dormant osteoclasts and, thus, bone resorption. Markers of bone turnover (eg, serum osteocalcin, bone-specific alkaline phosphatase, urine hydroxyproline levels) increase during therapy. However, calcitriol usually produces only modest clinical improvement, which is not sustained after discontinuation.2. CorticosteroidsThese agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.Prednisone is an immunosuppressant used for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity. The drug stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.3. Hematopoietic Growth Factors

Epoetin alfa is a purified glycoprotein produced from mammalian cells modified with gene coding for human erythropoietin (EPO). Biological activity mimics human urinary EPO, which stimulates division and differentiation of committed erythroid progenitor cells and induces the release of reticulocytes from bone marrow into the blood stream.Darbepoetin is an erythropoiesis-stimulating protein closely related to erythropoietin, a primary growth factor produced in kidney that stimulates development of erythroid progenitor cells. Its mechanism of action is similar to that of endogenous erythropoietin, which interacts with stem cells to increase red cell production.Darbepoetin has longer a half-life than epoetin alfa and may be administered weekly or biweekly.

4. ImmunomodulatorGamma-1b interferon is synthesized by eukaryotic cells in response to viruses and a variety of natural and synthetic stimuli. It possesses antiviral, immunomodulatory, and antiproliferative activity. Gamma interferon has potent phagocyte-activating effects not seen with other interferon preparations. It works by stimulating osteoclast activity.Infantile osteopetrosis

Vitamin D (calcitriol) appears to help by stimulating dormant osteoclasts, thus stimulating bone resorption. Large doses of calcitriol, along with restricted calcium intake, sometimes improve osteopetrosis dramatically.However, calcitriol usually produces only modest clinical improvement, which is not sustained after therapy is discontinuedTreatment with gamma interferon improves white blood cell function, greatly decreasing the incidence of new infections. With treatment, trabecular bone volume substantially decreases and bone-marrow volume increases. This results in increases in hemoglobin, platelet counts, and survival rates. Combination therapy with calcitriol is clearly superior to calcitriol alone. Erythropoietin can be used to correct anemia. Corticosteroids have also been used to treat anemia, as well as to stimulate bone resorption.Adult osteopetrosis

Adult osteopetrosis requires no treatment by itself, although complications of the disease may require intervention. No specific medical treatment exists for the adult type.Surgical treatment

In pediatric osteopetrosis, surgical treatment is sometimes necessary because of fractures.In adult osteopetrosis, surgical treatment may be needed for aesthetic reasons (eg, in patients with notable facial deformity) or for functional reasons (eg, in patients with multiple fractures, deformity, and loss of function). Severe, related degenerative joint disease may warrant surgical intervention as well.Disease of mineralization : Osteomalacia / RicketsDefinitiondiseases where organic matrix of the bone fails to calcify properly, leaving large osteoid seams / inadequate mineralization of bone* osteoid throughout the skeleton is incompletely calcifiedin growing bones of children-> Ricketsin bones of adult-> Osteomalacia

RicketsDefine : inadequate mineralization of growing bones in children, affecting physeal growth and ossification, resulting in deformities of endochondral skeleton

Etiology :Type 11. due to deficiency of vitamin D- diminished intake eg malnutrition- diminished absorption eg gastric abnormalities, biliary diseases- lack of exposure to sunlight

2. due to disturbance of vit D metabolism- hepatic factor eg lack of 25 hydroxylation of vit D- renal factor eg lack of 1hydroxylation - unresponsive of target cells to 1-25 dihydroxy vit D Type 21. defective absorption of phosphates through renal tubules- hypophosphataemia rickets (X- linked dominant)- Fanconi syndrome- renal tubular acidosis- oncogenic rickets

2. diminished intake or absorption of phosphatesClinical features :- may present with tetany or convulsions- failure to thrive, listlessness and muscular faccidity- craniotabes (pressure over the soft membranous bones of the skull gives the feeling of a ping pong ball being compressed and released)- bossing of the skull (evident after age of 6 month)- broadening of ends of long bones, commonly wrists and knees - delayed teeth eruption- Harrison's sulcus (horizontal depression along lower part of chest)- Rachitic rosary (costochomdral junctions on anterior chest wall become prominent giving rise to appearance of a rosary)- muscular hypotonia (child's abdomen becomes protuberant / pot belly because of marked muscular hypotonia)- deformities- knock knees, bow legs

Investigation :- X-ray -> delayed appearance of epiphysis -> widening of epiphyseal plates (normal : 2-4mm) due to excessive accumulation of uncalcified osteoid at growth plate -> cupping of metaphysis -> splaying of the metaphysis -> bone deformities eg knock knees, bow legs, coxa vara

Widening and cupping of the metaphyseal regions (see the image below) Anteroposterior and lateral radiographs of the wrist

- serum calcium and phosphates decreases, alkaline phosphatase increases- urine calcium decreases- calcium phosphate product (calcium x phosphorus level mmol/L) normal : 3 diagnostic : < 2.4

Treatment :Medical treatment- Vit D 600 000 units single oral dose induces rapid healing If line of sclerosis(healing) on metaphyseal side of growth plate is not seen on X-ray within 3-4 weeks of therapy, same dose is repeated Unresponsive to Vit D therapy, then maintenance dose of 400 IU of Vit D is given per day

Surgical treatment (established long bone deformities)- conservative methods eg. splints (mermaid splints), orthopaedic shoes -> mild deformities correct spontanously- operative methods eg. corrective osteomies -> moderate or severe deformities often require surgery, after 6 months of starting medical treatmentPrevention :- balanced diet that contains of calcium (sources : daily products, soya beans, nuts) and Vit D (sources : oily fish, eggs)- pregnant and breastfeeding women should take daily supplement of 10ug of Vit D- Vit drops for all babies and young children aged 6 months -5 yrs old

OsteomalaciaDefine : inadequate mineralization of bones in adult, results of failure to replace turnover of calcium and phosphorus in the organic matrix of boneHence, bone content is demineralised and bone substance is replaced by soft osteoid tissue

Etiology : - malabsorption- lack of exposure to sunlight- under-nutrition during pregnancy- after partial gastrectomy

Clinical features :- bone pains (backache to diffuse bone pains may occur)- muscular tenderness (difficulty in climbing stairs)- spontaneous fractures occur usually in spine and may result in kyphosis

Investigation :- X-ray-> diffuse rarefaction of bones -> Looser's zone (pseudo-fractures) radiolucent zones occur at sites of stress, commonly at pubic rami, axillary border of scapula, ribs, medial cortex of the neck of femur -> triradiate pelvis (female) -> acetabulum protruding into pelvis- low serum calcium and phosphates, high alkaline phosphatase- bone biopsy-> excessive uncalcified osteoid

Treatment : - maintenance dose of 400 IU of Vit D daily- calcium supplementation should be given- treat underlying causesMetabolic Disease DisorderHigh bone turnoverPagets Disease and HyperparathyroidismPagets disease(Osteitis deformans)Paget disease is a localized disorder of bone remodeling that typically begins with excessive bone resorption followed by an increase in bone formation. This osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically -weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone. It is the second most common bone disorder (after osteoporosis) in elderly persons. Paget disease may involve a single bone but is more frequently multifocal. It has a predilection for the axial skeleton (ie, spine, pelvis, femur, sacrum, and skull, in descending order of frequency), but any bone may be affected. After onset, Paget disease does not spread from bone to bone, but it may become progressively worse at preexisting sites.

EtiologyThe cause of Paget disease is unknown. Both genetic and environmental factors have been implicated.Studies of potential genetic markers for Paget disease have found an association between human leukocyte antigenA (HLA-A), HLA-B, and HLA-C (class I) and clinical evidence of disease. Alterations in cytokine expression have been found in persons with Paget disease: elevated interleukin-6 (IL-6) levels are found in bone marrow plasma and peripheral blood in patients with Paget disease but not in healthy controls.Macrophage-colony stimulating factor (M-CSF) may play a role in Paget disease. M-CSF is a growth factor produced by many cells, including osteoblasts and marrow fibroblasts. Significantly high levels of M-CSF have been found in patients with untreated Paget disease.Environmental factors - Viral infection(i.e paramyxoviruses)

Symptoms

Most persons with Paget disease are asymptomatic. However, when symptoms do occur, bone pain is the most common complaint. The bone pain is dull, constant, boring, and deep below the soft tissues. It may persist or exacerbate during the night.Hip pain is most common when the acetabulum and proximal femur are involved, especially in the sclerotic stage. Bowing of the femur and long bones or protrusion of the acetabulum causes pain that becomes worse with weightbearing and is relieved with rest. Knee and shoulder pain may occur because of altered mechanical forces across the articular joints from deformed bones.Nonspecific headaches, impaired hearing, and tinnitus commonly result from skull involvement.The most common cranial symptom is hearing loss, occurring in patients with skull involvement. The most common neurologic complication is deafness as a result of involvement of the petrous temporal bone.Back and neck pain are common complaints, as Paget disease frequently affects the spine, especially the lumbar and sacral regions. Softened bone at the base of the skull may lead to platybasia, the descent of the cranium onto the cervical spine. Progressive pain, paresthesias, limb paresis, gait difficulties, or bowel and bladder incontinence may be caused by compression of the spinal cord or spinal nerve secondary to platybasia or vertebral fractures.InvestigationsMeasurement of serum alkaline phosphatasein some cases, bone-specific alkaline phosphatase (BSAP)can be useful in the diagnosis of Paget disease. Elevated levels of urinary markers, including hydroxyproline, deoxypyridinoline, C-telopeptide,andN-telopeptide, may help identify patients with Paget disease.Check for serum uric acid level- Elevated serum uric acid levels have been found in men with severe Paget disease and have been associated with gouty arthritis. Serum total acid phosphatase is an osteoclastic enzyme that may be elevated in active Paget disease. In males, however, the clinical value of this finding is compromised, as acid phosphatase levels also may be elevated in the presence of metastatic prostate carcinoma

Plain radiographs and bone scanning should be performed upon initial diagnosis. Repeated radiography may be helpful in monitoring an osteoarthritis program or in evaluating for malignant degeneration.Computed tomography (CT) scanning and magnetic resonance imaging (MRI) are not needed for the diagnosis of Paget disease of bone. However, both are useful in the evaluation of complications of Paget disease, such as neoplastic degeneration, articular abnormalities, and spinal involvement with neurologic compromise. Bone biopsies may be indicated to evaluate for malignant transformation.

TreatmentThe short-term objective of Paget disease treatment is to control disease activity. The long-term objectives of treatment are to minimize or prevent disease progression and to decrease complications from the disease, if possible.Indications for drug treatment of Paget disease are as follows: Metabolic active disease - Bone pain, fatigue fracture, skull/spine fracture, radiculopathy, osteolytic lesions, bony deformities, weight-bearing bone involvement, compression of spinal cord and nerve roots, bone compression of the eighth cranial or optic nervePreparation for orthopedic surgery (joint replacement anticipated at involved sites within 6 months)Hypercalcemia or hypercalciuria - Recurrent renal calculi due tohypercalciuria, or fractures; serum alkaline phosphatase or urine hydroxyproline levels greater than twice the upper limit of the reference range; immobilization

When Paget disease occurs around a joint, treatment is often administered in an attempt to prevent development of osteoarthritis. Drug therapy for Paget disease should include bisphosphonate treatment with serial monitoring of bone markers. Response to therapy is indicated by reduction of symptoms and decreases in levels of BSAP (a bone formation marker) and deoxypyridinoline,C-telopeptide,orN-telopeptide (bone resorption markers).Secondary osteoarthritic pain may be reduced by nonsteroidal anti-inflammatory drugs or other nonnarcotic analgesics.Orthotic devices, including canes and walkers, may be useful for patients with gait abnormalities resulting from Paget disease that involves the lower limbs.Because of the increased risk of malignancy, patients with Paget disease should be monitored indefinitely. Chemotherapy, radiation, or both may be used to treat neoplasms that arise from pagetic bone. Amputation may also be necessary in the presence of a malignant transformation.

Hyperparathyroidism

Parathyroid gland anatomy and physiology

Normally 4 in numberLocated behind the thyroid gland one behind each pole of the thyroidEach 6mm x 3mm x 2mm Dark brown colorSecreted by the chief cells of the parathyroid glandControls extracellular Calcium and phosphateRegulates intestinal reabsorptionRegulates Renal excretionRegulates exchange of Ca and PO4 ions in ECFExcess activity of Parathyroid - Rapid absorption of calcium from bones HypercalcemiaRemoval of half - no major problem, removal of - Hypoparathyroidism - Hypofunction of Parathyroid Hypocalcemia - Tetany

HyperparathyroidismClassificationPrimary : excessive release of PTH and manifests as hypercalcemia (no renal disease and no malignancy) Looses sensitivity to circulating calcium : Parathyroid adenoma Secondary: parathyroid glands become hyperplastic after long-term hyperstimulation and release of PTH Elevated PTH levels do not result in hypercalcemia Resistance to the action of PTH : Chronic renal failure, intrinsic parathyroid gland abnormalities Hyperparathyroidism + Renal pathology = Renal osteodystrophyTertiary : excessive secretion of parathyroid hormone (PTH) after a long period of secondary hyperparathyroidism and resulting in hypercalcemia Long lasting disorders of the calcium feedback control system Cannot be treated by medicationSymptomsAsymptomatic hyperparathyroidism have no signs or symptoms diagnosis being made on further investigation after a coincidental finding of hypercalcemia Symptomatic hyperparathyroidism associated with the effects of an increased level of calcium - symptoms "neurological" in origin most common symptom is fatigue and tiredness lack of energy, memory problems, depression, problems with concentration, sleeping disorders Other symptoms kidney - stones, bone pain - osteoporosisheadaches, gastroesophageal reflux, decreased sex drive, thinning hair, hypertension, and palpitations

Orthopaedic manifestations Bone pains due to Osteoporosis Radiological Subperiosteal bone resorbtion and acroosteolysis Radial side & tuft of phalanges Osteitis fibrosa cystica Brown tumor of hyperparathyroidism Pepper Pot appearance - skull

Chondrocalcinosis & pseudogoutProximal muscle weakness affecting lower more than upper limbs

Lateral radiograph skull: diffuse lytic lesions giving classical pepper pot skull appearance.DiagnosisGold Standard : PTH immunoassay

PTH Raised

RaisedCalcium levelsPrimary hyperparathyroidism PTH Raised

Normal Secondary hyperparathyroidismInvestigationsLaboratory investigationsPTH level normal range for the PTH-intact assay - 10-65 pg/ml elevated PTH levels with hypercalcemia establishes diagnosis of hyperparathyroidism in older individuals, hypercalcemia of malignancy - associated with suppressed PTH levels immunoradiometric assay for PTH detects fully intact molecule - more accurate rapid PTH assay provides an accurate PTH level used intraoperatively - determine quantitatively the excision of hyperfunctioning parathyroid tissue decrease PTH concentration - > 50% from the baseline level 5-10 mts after excision - absence of residual hyperfunctioning tissue

Calcium levels: Hypercalcemia or normal calcium depending on the type of hyperparathyroidism

Urinary calcium excretion : may be elevated

Phosphate levels: decreased serum phosphate level of < 2.5 mg/dL (0.81 mmol/L) may be seen

Increased bone turnover : elevated alkaline phosphatase and urinary pyridinoline (bone resorption)

Imaging StudiesNoninvasive imaging modalities Technetium-99m sestamibi imaging, Ultrasonography CT scanning & MRI

Ultrasonography and 99mTc sestamibi scanning widely available and relatively inexpensive

Radiologytypical radiography findingsbone-density measurements based on (DEXA) at the hip and spinebrown tumors are seen only in patients who are severely affected soft tissue calcification in joints, kidneys & lungs

CT scanning of spine provides estimates of spinal bone density serial measurements provides an early indication progressive osteopenia

Percutaneous needle biopsy - aspiration cytology & tissue PTH malignancy suspected

TreatmentEmergency Department Care

Focused on the treatment of hypercalcemia Goal of treatment is to reduce calcium level to below 11.5 mg/dL

Intravenous administration of isotonic saline First and vital step in management of severe hypercalcemia Severe hypercalcemia - nearly always accompanied by severe dehydration

Patients with hypercalcemia with alterations of mental status loop diureticsfacilitate the urinary excretion of calcium prevents volume overload - following administration of large volumes of saline Initiation of loop diuretics should only after rehydration has taken place

Postmenopausal with mild hyperparathyroidism - estrogen therapy it may inhibit demineralization of the skeleton - reduce blood calcium levels

directed at hypercalcemia symptomatic patients adviced surgery removal of the parathyroid tumor (parathyroid adenoma) Present belief : almost all patients with hyperparathyroidism should be evaluated for surgery will almost always progress as the tumor grows if surgery is not available - monitor Calcium level: via urine tests - results inform kidney function Bone density: used to assess the risk of osteoporosis Check for kidney stones: abdominal X-rays

THANK YOU