Pyogenic Osteomyelitis Acute Osteomyelitis Clinical o Infections can reach the bone by: Hematogenous route Most common

mon An antecedent focus of infection may be present elsewhere Most cases of hematogenous osteomyelitis are confined to the long tubular bones and to children Most frequently seen in a metaphyseal location Direct extension: Has no predisposition in children or in adults o Commonly encountered organisms: Staphylococcus aureus (most common) Escherichia coli, Klebsiella and Pseudomonas speciesSalmonella (in patients with sickle cell anemia): Results in a cortically based osteomyelitis Treponema, gram rods, streptococci, Haemophilus influenzae and listeria species (occur in neonates) Pseudomonas infections (addicts abusing intravenous street drugs Macroscopic o Region is often intensely hyperemic o The pressure exerted by the pus may compress smaller vessels, which may result in additional ischemic damage to the bone o The exudate follows the path of least resistance and exits through the Volkmann canals into the subperiosteal space o In the neonatal age group, the Sharpeys fibers are less well-developed; thus, considerable subperiosteal spread may occur o Medullary spread may cause additional damage o In severe cases, the combination of subperiosteal and intramedullary spread can cause the entire diaphysis to become necrotic, forming a ring sequestrum Microscopic o B one destruction, polymorphonuclear leukocytes, and cell debris Chronic Osteomyelitis Clinical o Although de novo cases also occur, the majority are a result of unresolved acute osteomyelitis o A protracted course, interspersed with acute exacerbations o Because of the low levels of causative organisms, cultures are often negative o Common organisms include: Staphylococcus aureus Streptococci (group A is more frequent) Klebsiella (may cause extensive bone damage) Aerobacter, Proteus, Brucella, Staphylococcus epidermidis, and Bacteroides Microscopic o Necrotic bone in an inflammatory background o When the necrotic fragment separates from the adjacent tissue, it is known as a sequestrum: The sequestrum is surrounded by infective granulation tissue Separation of the sequestrum generally takes months to complete The bone is often of cortical origin

o The bone surrounding a focus of chronic osteomyelitis is often dense, and is referred to as the involucrum: The involucrum is often of periosteal origin The involucrum frequently has several openings of cloacae through which exudate, bone debris, and sequestra exit and pass through sinus tracts to the surfaceConstant destruction of the neighboring soft tissues leads to scarring and squamous metaplasia of the sinus tract o The microscopic diagnosis of chronic osteomyelitis can be difficult o The inflammatory infiltrate is often sparse and may mimic the normal elements of the marrow space o Microscopic recognition of the sequestrum is helpful for the diagnosis of infection: The sequestrum is recognized by virtue of its anucleate nature; often the edges are jagged (be-cause of the action of proteolytic enzymes and osteoclastic action) Over decalcification of bone during processing can cause the bone to become artificially anucleate, making the recognition of dead bone particularly difficult Differential Diagnosis o Normal marrow: Preservation of normal fat pattern of marrow Lack of fibrous background

Tubercular Osteomyelitis Clinical o Occurs frequently in children o Occurs in vertebrae, or in long tubular bones in a metaphyseal location o In adults, vertebrae or epiphyses of the long bones may be involved Pathology o May affect the bone, the joints, or (frequently) both o Often occurs by hematogenous spread o Usually represents a reactivation of a preexisting primary focus in the lung o The emergence of multi-drug-resistant tuberculosis and the AIDS epidemic have reemphasized the importance of mycobacterial infection Microscopic o Granulomatous inflammation, often with Langerhans-type giant cells o Special stains reveal acid-fast organisms o The disease has traditionally been divided into the granular and the exudative types Osteoarthritis (OA) Intro o Also termed degenerative joint disease o Represents failure of the diarthrodial (movable, synovial lined) joint o 2 forms: Idiopathic (primary) OA: Most common No predisposing factor Secondary OA: Attributed to an underlying cause (developmental disorders, metabolic or endocrine conditions, crystal deposition, trauma, infection, avascular necrosis, neuropathic disease, etc.) Pathologically indistinguishable from idiopathic form Microscopic

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The most striking changes are seen in load-bearing areas of the articular cartilage In the early stage, the cartilage is thicker than normal The joint surface thins and the cartilage softens with progression The integrity of the surface is breached and vertical clefts develop with fibrillation Areas of fibrocartilaginous repair may develop The articular cartilage is metabolically active and the chondrocytes replicate, forming clusters (termed cloning) Later, the cartilage becomes hypocellular Remodeling and hypertrophy of bone are also major features: Appositional bone growth occurs in the subchondral region The abraded bone under a cartilage ulcer may resemble ivory wood (termed eburnation) Growth of cartilage and bone at the joint margin leads to osteophytes (spurs) Osteophytes alter the contour of the joint, restricting movement Thickening of the joint capsule along with chronic synovitis further restricts joint movement Periarticular muscle wasting follows

Neuropathic Arthropathy (Charcots Joints) Clinical o Extremely destructive joint disorder in patients with neurosyphilis o A consequence of damage to sensory innervation to the joint o With the decline of tertiary syphilis, other causes of neuropathic joints have now become more important, such as: DiabetesSyringomyeliaAmyloidAlcoholic neuropathyLeprosy Microscopic o Fragmentation of the joint surface with extensive detritic synovitis resulting from particles of bone and cartilage embedded in the synovium Crystal Arthropathies Pathogenesis Crystal arthropathy can be caused by endogenous (monosodium urate [MSU], calcium pyrophosphate [hydroxyapatite]) and exogenous (corticosteroid ester crystals, talc, polyethylene, methyl methacrylate) crystal deposition producing disease by triggering a cascade that results in cytokine-mediated cartilage destruction Gout and Gouty Arthritis Clinical o Gout is the common end point of a group of disorders that produce hyperuricemia o Marked by transient attacks of acute arthritis initiated by the crystallization of urates within and around joints o Deposition of masses of urates in joints and other sites, creating tophi o Factors that may result in the conversion of hyperuricemia into primary gout: Age (gout rarely appears before age 2030) Duration of the hyperuricemia Genetic predisposition: X-linked abnormalities of hypoxanthine-guanine phosphoribosyl transferase (HGPRT) Multifactorial inheritance Heavy alcohol consumption

Obesity Thiazide diuretics o Gout can result in: Acute arthritis Chronic tophaceous arthritis Gouty nephropathyTophi in various sites Microscopic o Characteristic needle-like crystals that are negatively birefringent under polarized light

Calcium Pyrophosphate Crystal Deposition Disease (Pseudogout, Chondrocalcinosis) Clinical o Three types: Sporadic Hereditary Secondary types linked to: Hyperparathyroidism Hemochromatosis Hypomagnesaemia, Hypothyroidism Ocronosis Diabetes o More common at age 50 or older o Joint involvement may mimic OA or rheumatoid arthritis (RA) o Pathogenesis is uncertain: Altered activity of the cartilage matrix enzyme produces and degrades pyrophosphate, resulting in its accumulation and eventual crystallization The crystals first develop in the articular matrix, menisci, and intervertebral discs Rheumatoid Arthritis (RA) Clinical o A systemic disease that manifests in the joints as a synovial lesion o The inflammatory process can be initiated by: Hypersensitivity initiates Antigen-antibody reaction: The antibody coats cell membrane of lymphocytes and plasma cells, which travel to synovium and react with antigen, causing acute inflammatory reaction Microscopic o Non-supportive chronic inflammation in the capsule of the joint: Hypertrophy and hyperplasia of the synovial cells resulting grossly in a papillary pattern on the surface of the synovium Later, a pannus forms: Combination of proliferating mesenchymal cells and granulation tissue starting at the periphery of a joint and subsequently destroying articular cartilage

Osteoporosis Definition: A condition characterized by a reduced amount of normally mineralized bone Classification o Postmenopausal (type I) o Age related (type II) o Secondary (accounts for ~5% of cases): Can be seen in a variety of conditions: Osteogenesis Imperfecta, Turner syndrome RA, Systemic mastocytosis, Hyperthyroidism, Adrenal disease, Steroid or heparin therapy, Chronic alcoholism, Space travel Clinical o Higher incidence associated with: Race (Caucasians > African Americans) Sex (F > M) Physical inactivity Slender body build Smoking Nulliparity Early menopause o The major clinical symptoms are those of fractures o Common sites include: Spinal vertebral crush fractures Hip fractures Colles or other fractures of the distal radius o The pattern of fractures varies slightly in the different osteoporotic groups: Type I: Vertebra, Distal radius, Intertrochanteric femoral fractures Type II: Vertebra, Femoral neck fractures o Laboratory investigations include the exclusion of other metabolic diseases by assessing: Serum calcium Serum phosphate Alkaline phosphatase 25-hydroxy and 1,25-dihydroxy-vitamin D Urinary calcium o Biologic markers that are useful for assessing bone turnover: Bone-specific alkaline phosphatase Serum osteocalcin Serum Type I collagen extension peptides Plasma tartrate resistant acid phosphatase Urinary levels of hydroxyproline Urinary pyridinoline crosslinks of type I collagen o Pathogenesis: Postmenopausal osteoporosis: Associated with increased osteoclastic activity May be initiated or maintained by a variety of bone cytokines, perhaps initiated by RANK and RANK-ligand interaction May be genetically predetermined by the polymorphisms of the Vitamin D receptor gene Age-related osteoporosis: Inefficiency of bone formation in a normal remodeling cycle Less bone is formed than is resorbed with each remodeling cycle throughout life Microscopic

o Cortex: Enlarged Haversian and Volkmanns canals tunneled by osteoclasts The cortex is thinned: Caused by resorption of the subperiosteal and endosteal surfaces Endosteal resorption results in a blurring of the cortical-cancellous border, referred to as trabeculization of the cortex o Trabecular bone: Thinning and perforation of the trabeculae: Perforation is an irreversible process, which occurs when an osteoclast resorbs bone all the way through a trabeculum or when two osteo-clasts fortuitously located at opposite ends of the trabeculum meet midway These thin trabeculae seem to float in the marrow space Increased osteoclastic activity may be seen in high turnover (postmenopausal) osteoporosis Rickets and Osteomalacia Definition o Syndromes (rather than specific disease entities) characterized by a failure of normal mineralization of bone and epiphyseal cartilage o Clinically characterized by bone deformities o In Rickets (which occurs in children), bone and epiphyseal cartilage is involved Causes of Rickets and Osteomalacia o Deficiency states: Diet Lack of sunlight o Gastrointestinal causes: Gastric resections Biliary and enteric causes o Renal tubular causes: Hypophosphatemic states Fanconi syndromes End organ defect Renal tubular acidosis o Unusual causes: Phosphaturic tumors Anticonvulsant therapy o Renal osteodystrophy: Renal failure Pathology o Rickets: A disease of the growing skeletonAffects the epiphyseal plate and bones of children o Osteomalacia: Occurs in adults, after the growth cartilage has fused and the epiphysis is obliterated o In both instances, there is insufficient ionized calcium or inorganic phosphate (or both) to mineralize the skeleton, leading to less mineralized bone per unit volume of bone o There may be less bone overall, but more strikingly, the bone that is present fails to mineralize properly o Trabeculae are surrounded by unmineralized osteoid, called osteoid seams: Osteoid seams >12.5 m are virtually diagnostic Bone histomorphometry has shown that the mineralization lag time is >100 days in rickets/osteomalacia (normal = 8090 days)

o All rachitic syndromes have similar histology and the individual diagnosis cannot be made on the basis of a bone biopsy o Stains for aluminum may be considered in renal osteodystrophy o In rickets, pressure effects cause deformity at the epiphysis-metaphysis junction, resulting in metaphyseal flaring and a disordered physis Primary Hyperparathyroidism Intro o This entity was defined in part by Von Recklinghausen under the term osteitis fibrosa cystica generalisata o Most often results from a hyperplasia or adenoma (and rarely a carcinoma) of the parathyroid glands: The diseased gland does not recognize the signal of high serum calcium concentration There is increased production of 1,25-dihydroxy-vitamin D and parathyroid hormone, increasing absorption of calcium from the gut and bone and preventing its excretion in the kidney Simultaneously, there is hyperphosphaturiaSerum levels of alkaline phosphatase are frequently high Microscopic o The bones are characterized by: Fibrosis of the marrow Osteoclastic resorption Osteoblastic rimming on new and often incompletely mineralized lamellar bone trabeculae (narrow osteoid seams) Brown tumors: These represent granulation tissue, inflammatory cells, and macrophages containing hemosiderin and giant cell formation There is virtually no bone present in these areas o Occasionally, cystic change may supervene o Increased osteoclastic activity is seen in subperiosteal, intracortical, endosteal, subchondral, and trabecular surfaces: Intracortical resorption is characterized by groups of osteoclasts (known as cutting cones) that tunnel through the cortex, enlarging the Haversian and Volkmanns canals: These channels are often expanded to 1 mm or more in some cases, and may be seen radio-graphically as lucent lines within the cortex Endosteal resorption is also visible radiographically as scalloping of the cortex at its marrow interface Subchondral resorption is best seen histologically (and radiographically) at the sacroiliac joint Pagets Disease (Osteitis Deformans) Clinical o Patients above the 4th decade o Slight male predominance o Common among the white population of England, France, Austria, Germany, Australia, New Zealand, and the United States o Rare in Scandinavia, China, Japan, and Africa o May be uni- or multi-focal o Most frequent involvement in the axial and the proximal appendicular skeleton o Less frequent involvement in the ribs, fibulae, and bones of the hands and feet

o Presenting symptoms: Pain Increased width of bone Weight-bearing bones may be bowed or deformed May be asymptomatic and discovered incidentally Hyperdynamic circulation may lead to high output cardiac failure The most common secondary malignancy is osteo-sarcoma o Radiographically, three phases can be discerned: lytic, mixed, and blastic: Eventually, the disease burns itself out in that particular site o Laboratory investigations reflect this increased bone turnover through increased levels of serum alkaline phosphatase and urinary hydroxyproline Etiology o Possibly related to an infection by a paramyxovirus, similar to measles or respiratory syncytial virus: In situ hybridization studies have localized canine distemper virus (a paramyxovirus) in Pagetic osteoblasts, osteoclasts, and osteocytes The target of the virus is probably the osteoblast; however, the cell-associated virus particles have only been found in the osteoclasts Retroviruses can induce the secretion of IL-6 from fibroblasts and macrophages IL-6 is thought to be important in the pathogenesis of Pagets disease and is implicated in the recruitment and activation of osteoclasts Microscopic o Pagets disease is a focal process o The histologic hallmark is mosaic lamellar bone: Produced by haphazard cement lines (jigsaw-like pattern) o Lytic phase: Waves of osteoclastic activity Numerous resorptive pits o Mixed phase: The osteoclasts are admixed with osteoblasts, which line the bone surfaces The marrow adjacent to the bone becomes replaced by loose, vascularized, connective tissue The newly formed bone is initially woven bone, and is later remodeled into lamellar bone As the mosaic pattern becomes prominent, cell activity ceases The fibrovascular tissue is replaced by normal marrow (burnt out phase) Eventually, the bone becomes larger, with thick, irregular trabeculae and porous corticies o Blastic phase: Characterized by reactive and lamellar bone

Osteopetrosis (Albers-Schonberg Marble Bone Disease) Definition o A group of hereditary diseases characterized by osteoclast dysfunction resulting in diffuse, symmetric, stone-like, skeletal sclerosis and abnormally brittle bone Clinical o Traditionally, four clinical variants are distinguished; the two most common are autosomal recessive (malignant) type and autosomal dominant (benign) type o Several variants are known:

Some are associated with a deficiency of osteoclast carbonic anhydrase II. Others are associated with a variety of genetic mutations, including mutations of c-src, macrophage colony stimulating factor, etc. o Patients have a high postnatal mortality o Survivors have anemia, fractures, and hydrocephalus o Later in life, patients are prone to cranial nerve problems and recurrent infections o Extramedullary hematopoiesis results in hepatosplenomegaly Microscopic o Bones lack a medullary cavity o The ends of the bones are bulbous (Erlenmeyer flask deformity) o Neural foramina are small, compressing the exiting nerves o Primary spongiosa consisting of ossifying cartilage persists o Medullary cavity contains little or no hematopoietic elements due to overgrowth and accumulation of the primary spongiosa o Bone is mainly woven and lacks remodeling o The numbers of osteoclasts may be normal, increased, or decreased

Fibrous Dysplasia (FD, Jaffe-Lichtenstein Syndrome) Clinical o Monoostotic FD (80%):May be seen at any age (usually <30 years old) o Polyostotic FD (20%):Generally presents before the age of puberty o Presentation:Pain, pathologic fracture, deformity (especially gnathic or upper femoral FD) May be asymptomaticSecondary sarcomas rarely develop o Associated syndromes: McCune-Albright syndrome Polyostotic FD with macular skin lesions, precocious puberty, with or without fibromyxomatous soft tissue tumors Mazabraud syndrome Associated with a soft tissue or intramuscular myxoma o Location: Monoostotic 33% involve the crani-facial bones 33% involve the tibia and femur 20% involve the ribs Polyostotic Femur, tibia, and pelvis are commonly involved Small bones of the hands and feet, the ribs, and the skull may also be involved o Pathogenesis: Somatic point mutation in the subunit of the GTP binding protein results in activation of GTPase in the absence of receptor activation X-rays and Imaging Findings o Intramedullary, geographic lesions with Lodwick 1A or1B margins and a ground-glass matrix o The lesions are intensely hot on bone scans Microscopic o Trabeculae of woven bone in a background of moderately cellular fibrous tissue o The trabeculae often obtain a variety of shapes (Cs, circles, etc.) (Chinese-letters) o Osteoid tends to merge into the background (metaplastic) o Osteoblasts are interspersed in the woven bone, but are not conspicuous around the trabeculae

o Small foci of lamellar bone may be seen o Fibro-osseous proliferation may show an infiltrative pattern at the junction with non-lesional bone o The fibrous stroma may be highly or sparsely cellular, myxomatous, or show considerable collagenization o The fibroblasts usually have plump, ovoid nuclei o Multinucleated osteoclast type giant cells may be present o Cartilage with peripheral enchondral ossification maybe present o Collections of foam cells are common Differential Diagnosis o Osteofibrous dysplasia: A cortically based lesion Most often affects the tibia or fibula in children (often <5 years) Reactive woven bone Osteoblastic rimming is more prominent o Well-differentiated intraosseous osteosarcoma: The stromal cells have larger nuclei with cytologicatypia and atypical mitotic figures o Desmoplastic fibroma: Usually heavily collagenized with prominent