Normal bone facts



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BONE PATHOLOGY LECTURES—Elisa Furay

BONE, JOINT, & SOFT TISSUE PATHOLOGY

  • NORMAL BONE FACTS

    • Bones are made up of organic matrix (osteoid)– type 1 collagen

      • Many other proteins, including osteocalcin, which is measurable in serum as a sensitive marker for osteoblast activity

      • Osteoid is important for diagnosing osteosarcoma—you need to see new bone formation

    • Inorganic – calcium hydroxyapatite

    • New bone formation – osteocytes

    • Bone resorption – osteoclasts

      • RANK activity (receptor activator for nuclear factor) = increased osteoclast activity and these dissolve bone

      • Osteoprotegerin inhibits osteoclasts (so inhibits dissolution of bone)—think osteoPROTECTerginprotects bone s01871-026-f005

    • There is usually a balance between these. In youth the osteoblasts more active and in old age the osteoclasts win out

    • Woven bone in adults is always pathologic

      • Normally cortical bone is nice lamellar bone and should be seen without pathology

        • Can see the nice lines

      • Woven bone is always pathological


You can see the osteoclasts (multinucleated) eating the bone
OSTEOCYTES OSTEOCLASTS

      • s01871-026-f001 s01871-026-f003

    • s01871-026-f004 s01871-026-f002

      • (Pic on the Right) Notice RANK/RANK ligand

and osteoprotegerin regulate osteoclasts

      • (Pic on the Left) Notice there is a normal

balance between bone formation and

resorption



CONGENITAL AND HEREDITARY DISEASES OF BONE

  • Pathogenesis of developmental abnormalities

    • DYSOSTOSES - defects in mesenchymal migration and condensation--affects 1 or 2 bones not the whole skeleton

      • Usually focal abnormality, e.g. Supernumerary digits or ribs--6 digits or an extra rib in the neck

    • DYSPLASIAS - abnormal proliferation or maturation of chondrocytes and osteoblasts or abnormal collagen and noncollagenous proteins—effects the entire skeletal structure

      • All cartilage or bone affected, e.g. Achondroplasia or osteogenesis imperfecta

  • ACHONDROPLASIA

    • Definition

      • Impaired maturation of cartilage in the developing growth plate, due to mutation in FGFR3

      • The most common growth plate disease

      • Major cause of dwarfism

      • Fibroblast growth factor receptor 3 (normally inhibits cartilage) is constantly active due to mutation

        • So bones keep shortening and don't grow

      • 80% cases new spontaneous mutation, but if inherited it is autosomal dominant

        • Trunk is normal but the extremities don't grow - short arms and legs. Bulging head.

    • Pathogenesis

      • Dominant Mutations In gene coding for Fibroblast growth Factor receptor 3 results in defect in cell signaling Leading to sustained activation of FGFR3 leading to Inhibition of normal proliferation of cartilage At the growth plate (so bones don't lengthen)

    • Morphology-- Cartilagenous growth plates contain hypoplastic or disorganized chondrocytes

    • Appearance

      • Shortened proximal extremities

      • Trunk of relatively normal length

      • Enlarged head with bulging forehead

      • Depression at root of nose

      • Normal longevity, mental status and reproduction

  • OSTEOGENESIS IMPERFECTA

    • Definition

      • “brittle bone disease”

      • The most common inherited disorder of connective tissue

      • A spectrum (mild to lethal) of hereditary conditions characterized by abnormal development of type 1 collagen, a major component of osteoid.

        • Bones aren't as strong as they want to be

        • Kids come in to the ED with multiple bone fractures. (MUST R/O CHILD ABUSE-- parents usually accused)

    • Pathogenesis

      • Mutations interfere with Synthesis/ Secretion of Procollagen 1 or Procollagen 2  leading to abnormal Type I Collage (major component of osteoid) fragile bone

      • Procollagen alpha 1 and 2 are peptide precursors of Collagen Type I

      • Four major forms of this disease

        • Range from production of normal collagen producing mild skeletal abnormalities to severe or lethal phenotypes resulting in abnormal polypeptide chains that cannot form the triple helix.

        • Most common inherited as autosomal dominant

    • Clinical

      • Multiple bone fractures (always rule out child abuse)child abuse is way more common

        • Varying degree of this disease:

          • Possible death in utero

          • May appear later in childhood

            • They might just have a few broken bones

      • Other organs affected:

        • eyes (blue sclerae, due to decreased collagen)

        • teeth (misshapen blue-yellow)

        • ears (hearing loss, due to abnormal middle ear bones)

  • Congenital and Hereditary Bone Diseases

    • macintosh hd:users:elisafuray:desktop:screen shot 2013-04-22 at 9.05.47 pm.png

METABOLIC BONE DISEASE

  • OSTEOPETROSIS

    • Very Rare, autosomal recessive or dominant types

    • Reduced osteoclast activity—so bones become hard and bridle

      • Carbonic anhydrase deficiency leads to inability of osteoclasts to acidify and dissolve bone

      • Other mechanisms

    • AKA “marble bone disease” (clinical fractures)

    • Dense bone sclerosis, but brittle, easily fractured and misshapen

    • Medullary cavity filled with spongiosa, no hematopoiesis (anemia, repeated infections)s01871-026-f009

      • Their bone marrow is not normal (its spongiosa) so they don't have normal hematopoiesis They have neutropenia and anemia

    • On x-ray their bones have an Erlenmeyer flask appearance

      • dense bones, Erlenmeyer flask deformity at ends of radius and ulna

      • s01871-026-f010

        • Osteopetrosis in a fetus – abnormal spongiosa in medullary cavity—no hematopoiesis going on in there

  • OSTEOPOROSIS

    • Categories (***= common)

      • Primary

        • Postmenopausal *** in females after E production 

        • Senile *** in men

        • Idiopathic

      • Secondary

        • Endocrine, e.g. Hyperparathyroidism

        • Neoplasia, e.g. Multiple myeloma

        • Gastrointestinal

        • Systemic rheumatological diseases

        • Drugs-exogenous glucocorticoids ***

        • Miscellaneous

    • Pathogenesis of osteoporosis

      • Normal

        • Bone mass increases in infancy and childhood and peaks at 30 y/o

    • Peaks in 3rd decade

      • Peak bone mass determined by

        • Genetics

          • Vitamin d receptor VDR (Vit D receptors)

            • Type of Vitamin D receptor (VDR) accounts for approximately 75% maximal peak bone mass achieved

        • Physical activitys01871-026-f011

          • Stimulus to bone remodeling

        • Diet

          • Vitamin d and calcium (drinking milk is important)

            • Ca++ most important during adolescence; girls more than boys

        • Age

          • Bone loss averages 0.7%/year

            • Microfractures in the vertebral columns so you get shorter and shorter and hip fractures common

        • Hormonal status

          • Post-menopausal bone loss 2%/year cortical bone, 9%/year cancellous bone

          • This is caused by  in E production in post menopausal women so if you go into menopause early its worse on their bones

    • Definition

      • Skeletal disorder characterized by low bone mass and microarchitectural deterioration leading to bone fragility leading to  susceptibility to fractures

        • May be localized to certain bones or regions – disuse osteoporosis of a limb

        • May involve entire skeleton – Metabolic Bone Disease

    • Pathogenesis of senile osteoporosis

      •  age   osteoblastic activity and  osteoclastic activity

      • Age

        • Ostioblasts – reduced reproductive and biosynthetic potential with increasing age

        • Decreased biologic activity of matrix-bound growth factors

        • Reduced physical activity – increases rate of bone loss. Exercise acts as stimulus for bone remodeling. Weight training better than running because load magnitude impacts on bone density more than the number of lead cycles.

    • Pathogenesis of postmenopausal osteoporosis

      • Post menopausal women have  estrogen   bone mass (due to  osteoblastic acitivity and  osteoclastic activity)

        • Estrogen treatment can lead to  bone loss




      • Mechanism of postmenopausal osteoporosis

        • macintosh hd:users:elisafuray:desktop:screen shot 2013-04-24 at 10.07.22 am.png

    • Incidence

      • 50% of women will have postmenopausal osteoporosis fractures, due to loss of 35-50% of their bone mass !!!

        • Vertebral and hip fractures are common

        • 2% bone loss per year with postmeopausal osteoporosis due to loss of estrogen

      • 2% of men have senile osteoporosis—not common in men

    • Morphology

      • Mainly affects cancellous bone (senile osteoporosis leans to cortical bone loss)

      • Trabeculae thinner and farther apart

      • Increased susceptibility to fracture

      • Locations

        • Vertebral bodies

        • Weight bearing e.g. Femoral neck



        • the old woman has a Dowager’s hump (caused by microfractures in vertebral columns and collapse so they also get shorter and shorter)

      • s01871-026-f012

        • Normal vertebral body (left) compared to compression fractures of osteoporosis (right)

    • Clinical--diagnosed radiologically

      • Diagnosis by x-ray absorptiometry or CT density

    • Prevention and treatment

      • Exercise

      • Calcium & vitamin d intake

      • Estrogen replacement-

        • SERMS – selective estrogen receptor modulators; similar to estrogen without some of the dangerous side effects.

      • Bisphosphonates

        • Biphosphonates – selectively decrease osteoclast-mediated bone resorption

      • Recombinant PTH

        • Calcitonin – may reduce the frequency of vertebral fractures and may be of particular benefit to those patients who are intolerant to estrogen

      • **Fractures especially hip fractures have lots of morbidity and mortality involved with this disease especially in older females

  • PAGET DISEASE

    • Definition

      • A disorder characterized by “matrix madness”—this is all going no at the same time

        • Bone dissolves and goes from osteolytic stage and then gets to be osteoblastic at certain times and then at the end you have a burnt out vey sclerotic stage

          • Osteolytic stage

          • Mixed osteoclastic-osteoblastic stage

          • Predominant osteoblastic stage

          • Burnt-out sclerotic stage

      • End result is increased bone mass, but disorganized and architecturally abnormal—the bones don't work properly

      • Affects 5-10% of white Europeans

        • Most patients have very limited symptoms

        • This disease predisposes to osteosarcoma in some patients

    • Epidemiology

      • Uncommon <40 y/o

      • M slightly more than F

      • Familial Paget disease

        • Some linked to the long arm of chromosome 18 and others that are not.

      • Predisposes to osteosarcoma in older patients s01871-026-f013

  • Morphology

    • Osteosclerosis characterized by formation of dense, mineralized bone with few cells.

    • Mosaic pattern (jigsaw puzzle) of lamellar bone is pathognomonic

      • this is woven bone

    • Monostotic (15%)

      • Tibia, ilium, femur, skull, vertebra, humerus

    • Polyostotic (85%)-- most of the times there are multiple bones involved

      • Pelvis, spine, skull

    • Phases-- bones get involved and the vessels in there hyperdilate (you can feel the warmth above the area with this disease due to this hypervascularity and metabolism)

      • Osteoclastic activity, hypervascularity, bone loss

        • OSTEOLYTIC PHASE bone dissolved and cortex thinner

      • Mixed osteoclastic and osteoblastic activity

      • Osteosclerosis

        • Bone getting thicker: osteosclerotic phase

        • Osteosclerosis characterized by formation of dense, mineralized bone with few cells.

        • The abnormal bone is being formed

    • Dx by radiology;

      • On the x-ray to the right: 1 – lytic; 2 – mixed; 3 - sclerotic

    • Tx: most patients have mild symptoms easily treated with calcitonin and bisphosphonates

    • Clinical

      • PAIN most common complaint (caused by microfractures)

        • dissolving bones and you don't need a cast but they're painful

      • LEONTIASIS OSSEA – massive heavy/ skull (lion's skull), hearing loss (abnormal bones of the ear)

      • Platybasia of skull

      • Bowing of legs, distortion of femoral head and severe osteoarthritis

      • Chalkstick fractures of legs—b/c bone being dissolved in osteolytic areas

      • Spinal compression fractures

      • Hypervascularity leads to warm skin overlying paget bones, and high-output cardiac failure

      • Malignancy risk, esp. Osteosarcoma, MFH, chondrosarcoma (1% with monostotic disease, 10% with polyostotic disease)

        • > the more bones that are involved

      • Increased Alk. Phosphatase; Ca and PO4 normal

  • VIT. D DEFICIENCY

    • Low vit. D → hypocalcemia → excess unmineralized bone matrix

      • Inadequate sunlight or diet deficiency

        • Most milk is now supplemented with vitamin D

      • Decreased absorption

      • Inadequate or abnormal synthetic pathway—not common

      • End-organ resistance--not common

      • Phosphate depletion

    • RICKETS (KIDS)

      • Growth plates distorted and poorly mineralized leads to weak bone and skeletal deformity

      • Lumbar lordosis—curvature of the spine

      • Bowing of the legs--not mineralized and can't support the weight of the child

        • s01871-009-f025as01871-009-f025b Normal cartilage to bone maturation ( can see elongated pieces of new

        • ^ Rickets bone formation

--distorted maturation

    • OSTEOMALACIA (ADULTS)

      • Loss of bone mass (osteopenia)

  • HYPERPARATHYROIDISM

    • OSTEITIS FIBROSA CYSTICA

      • Cortical bone preferentially affected

      • X-ray loss of cortex particularly in fingers

      • Histology – dissecting mass of osteoclasts (osteoclasts dissecting into the bone spicules)

        • s01871-026-f016 Dissecting mass of osteoclasts

      • Loss of bone with microfractures leads to hemorrhage into the bone, with giant cells and fibrosis: “brown tumor”

        • Microfractures-- a common thing seen in a lot of these

        • Brown tumor—hemorrage into areas of the dissecting mass— altered Hb in there causes the brown tumors

          • s01871-026-f017 “brown tumor”

            • Looks like a tumor lots of blood in the microfractures

        • Not a ton of biopsies for this b/c the Dr. usually knows what's going on

      • Usually associated with primary hyperparathyroidism (secondary hyperparathyroidism is not as severe)

        • Osteitis fibrosa cystica is not seen frequently because of early diagnosis of Hyperparathyroidism and treatment

        • Skeletal abnormalities of secondary hyperparathyroidism are milder than the primary form because secondary is generally not as severe and prolonged

      • Entire skeleton is affected

      • macintosh hd:users:elisafuray:desktop:screen shot 2013-04-22 at 9.34.19 pm.png

  • RENAL OSTEODYSTROPHY

    • Seen in secondary hyperparathyroidism

      • kidney failure so  Phosphate excretion-> hyperphosphatemia so Ca goes down and so parathyroid glands  PTH production so you start dissolving bones to get Ca up)

    • Definition

      • Describes all skeletal changes associated with chronic renal failure

        • Increased osteoclastic bone resorption

        • Delayed matrix mineralization (osteomalacia)

        • Osteosclerosis

        • Growth retardation

        • Osteoporosis

    • Types of bone disorders with chronic renal disease

      • High-turnover osteodystrophy – increased bone resorption and formation

      • Low-turnover or aplastic disease – marked reduction in rate of mineralization, formation and resorption

      • Mixed pattern

    • Renal osteodystrophy pathogenesis

      • macintosh hd:users:elisafuray:desktop:screen shot 2013-04-22 at 9.37.01 pm.png

        • Phosphate regulates parathormone secretion

        • D1,25-[OH]2D3 drops because of decreased conversion of 25-(OH) D3

        • When you have renal failure a lot of times you are acidotic (acidosis dissolves bone also--osteoclasts make carbonic acid to chew up bones)- secondary PTH as well as acidotic bone loss

    • Renal osteodystrophy pathogenesis – summary

      • macintosh hd:users:elisafuray:desktop:screen shot 2013-04-22 at 9.39.48 pm.png

ISCHEMIC BONE LESIONS

  • OSTEONECROSIS – AVASCULAR NECROSIS

    • Ischemia of bone

    • 10% of joint replacement done for this—fairly common; usually femoral head

    • Pain most frequent presentation for subchondral infarct

    • Medullary infarct usually clinically silent

    • Commonly see Wedge-shaped infarct with fat necrosis (immediate beneath bony cortex (subchondral))

      • Increase in osteoarthritis

    • Most cases idiopathic or secondary to steroids

    • Causes

      • Mechanical vascular interruption

      • Corticosteroids

      • Thrombosis, sickle cell disease (by clotting off those little capillaries)

        • Thrombosis and embolism e.g. sickle cell, nitrogen bubbles,

      • Vessel injury

        • Vasculitis and radiation therapy

      • Increased intraosseous pressure with vascular compression

      • Venous hypertension

      • Fracture

      • Tumors Gaucher disease

      • Chronic pancreatitis probably due to release of mediators giving rise to inflammation and thromboses

    • Morphology

      • Medullary infarcts involve cancellous bone and marrow

      • Subchondral infarcts are wedge-shaped

    • Clinical

      • Subchondral

        • Chronic pain, common femoral head lesion is the most common site

        • When you dissolve bone (necrosis of bone)  bone Collapse and joint deformity leading to osteoarthritis

          • Patients get hip replacements with this

      • Medullary – remain stable; rarely, site of malignancy

    • s01871-026-f019 Subchondral wedge-shaped area of avascular necrosis of femoral head

      • wedge shaped infarcts pulling away from the bone and you'll get osteoarthritis and you'll need a joint replacement

      • 10% of joint problems caused by this

INFLAMMATORY BONE LESIONS
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