Chapter 1 – Basic Sciences

Home , Chondritis, Chondrolysis, Melorheostosis, Osteochondromatosis, Panner disease

CHAPTER 1 BASIC SCIENCES Jeremy K. Rush, Dustin Lybeck, Jessica Rivera, and Matthew R. Schmitz

CONTENTS SECTION 1 ORTHOPAEDIC TISSUES, 1 SECTION 3 PERIOPERATIVE AND ORTHOPAEDIC Bone, 1 MEDICINE, 78 Cartilage and Joint, 34 Thromboprophylaxis, 78 Muscle, 52 Perioperative Disease and Comorbidities, 84 Tendon, 57 SECTION 4 OTHER BASIC PRINCIPLES, 89 Ligament, 58 Imaging and Special Studies, 89 Neural Tissue and Intervertebral Disc, 59 Biomaterials and Biomechanics, 93 SECTION 2 ORTHOPAEDIC BIOLOGY, 61 TESTABLE CONCEPTS, 107 Cellular and Molecular Biology and Immunology, 61 Infection and Microbiology, 70

SECTION 1 ORTHOPAEDIC TISSUES

BONE • These stem cells line haversian canals, endosteum, and periosteum. n Histologic features of bone • Become osteoblasts under conditions of low strain n Types (Fig. 1.1; Table 1.1) and increased oxygen tension • Normal bone: lamellar or mature • Transcription factor RUNX2 and bone • Immature and pathologic bone: woven, more random, morphogenetic protein (BMP) direct more osteocytes, increased turnover, weaker mesenchymal cells to the osteoblast lineage. • Lamellar bone is stress oriented; woven bone is not. • Core-binding factor -1 and -catenin also • α β Cortical (compact) bone stimulate differentiation into osteoblast • Constitutes 80% of the skeleton • Become cartilage under conditions of intermediate • Consists of tightly packed osteons or haversian strain and low oxygen tension systems • Become fibrous tissue under conditions of high • Connected by haversian (or Volkmann) canals strain • Contains arterioles, venules, capillaries, nerves, • Have more endoplasmic reticulum, Golgi apparatus, possibly lymphatic channels and mitochondria than do other cells (for synthesis • Interstitial lamellae: between osteons and secretion of matrix) • Fibrils connect lamellae but do not cross cement • Bone surfaces lined by more differentiated, lines. metabolically active cells • Cement lines define the outer border of an • Entrapped cells: less active cells in resting regions; osteon. maintain the ionic milieu of bone • Nutrition provided by intraosseous circulation • Disruption of the active lining cell layer activates through canals and canaliculi (cell processes of entrapped cells. osteocytes) • Receptor-effector interactions in osteoblasts are • Characterized by slow turnover rate, higher Young’s summarized in Table 1.2. modulus of elasticity, more stiffness • Osteoblasts produce the following: • Cancellous bone (spongy or trabecular bone) • Alkaline phosphatase • Less dense, more remodeling according to lines of • Osteocalcin (stimulated by 1,25dihydroxyvitamin stress (Wolff’s law) D [1,25(OH) D ]) • 2 3 Characterized by high turnover rate, smaller Young’s • Type I collagen modulus, more elasticity • Bone sialoprotein n Cellular biology (Fig. 1.2) • Receptor activator of nuclear factor (NF)- ligand • κβ Osteoblasts (RANKL) • Appear as cuboid cells aligned in layers along • Osteoprotegerin—binds RANKL to limit its activity immature osteoid • Osteoblast activity stimulated by intermittent • Are derived from undifferentiated mesenchymal stem (pulsatile) exposure to parathyroid hormone (PTH) cells

1 2 Basic Sciences

Cortical Immature

Cancellous Pathologic (giant cell tumor)

Haversian canal

Cement line Interstitial lamellae

Canaliculi Osteocyte

CORTICAL BONE DETAIL FIG. 1.1 Types of bone. Cortical bone consists of tightly packed osteons. Cancellous bone consists of a meshwork of trabeculae. In immature bone, unmineralized osteoid lines the immature trabeculae. Pathologic bone is characterized by atypical osteoblasts and architectural disor- ganization. (Colorized from Brinker MR, Miller MD: Fundamentals of orthopaedics, Philadelphia, 1999, Saunders, p 2.)

Table 1.1 Types of Bone MICROSCOPIC APPEARANCE SUBTYPES CHARACTERISTICS EXAMPLES Lamellar Cortical Structure is oriented along lines of stress Femoral shaft Strong Cancellous More elastic than cortical bone Distal femoral metaphysis Woven Immature Not stress oriented Embryonic skeleton Fracture callus Pathologic Random organization Osteogenic sarcoma Increased turnover Fibrous dysplasia Weak Flexible

Modified from Brinker MR, Miller MD:Fundamentals of orthopaedics, Philadelphia, 1999, Saunders, p 1.

• Osteoblast activity inhibited by TNF-α • Osteocytes (see Fig. 1.1) • Wnts are proteins that promote osteoblast survival • Maintain bone and proliferation. • Constitute 90% of the cells in the mature skeleton • Deficient Wnt causes osteopenia; excessive Wnt • Former osteoblasts surrounded by newly formed matrix expression causes high bone mass. • High nucleus/cytoplasm ratio • Wnts can be sequestered by other secreted • Long interconnecting cytoplasmic processes molecules such as sclerostin (Scl) and projecting through the canaliculi Dickkopf-related protein 1 (Dkk-1). • Less active in matrix production than osteoblasts • Inhibiting sclerostin or Dkk-1 will lead to • Important for control of extracellular calcium and increased bone mass phosphorus concentration Basic Sciences 3

Stem cell Myeloid progenitor

Hematopoietic progenitor

Pre-osteocytes Monocyte Myocyte

Cell-cell fusion Adipocyte

Macrophage Fibroblast

Chondroblast/ chondrocyte Multi-nuclear osteoclast Osteoblast/osteocyte

Osteocytes Chondroblasts Perichondrium Osteoblasts Lacuna Chondrocyte Isogenic group

Extracellular matrix

Myoblast Adipocyte

Stem cell

Haversian canal

Multipotential Tri- or bipotential Osteoblast daughter cell progenitor cells Chondroblast Fibroblast FIG. 1.2 Cellular origins of bone and cartilage cells.

Table 1.2 Bone Cell Types, Receptor Types, and Effects CELL TYPE RECEPTOR EFFECT Osteoblast PTH Releases a secondary messenger (exact mechanism unknown) to stimulate osteoclastic activity Activates adenylyl cyclase 1,25(OH)2 vitamin D3 Stimulates matrix and alkaline phosphatase synthesis and production of bone-specific proteins (e.g., osteocalcin) Glucocorticoids Inhibits DNA synthesis, collagen production, and osteoblast protein synthesis Prostaglandins Activates adenylyl cyclase and stimulates bone resorption Estrogen Has anabolic (bone production) and anticatabolic (prevents bone resorption) properties Increases mRNA levels for alkaline phosphatase Inhibits activation of adenylyl cyclase Osteoclast Calcitonin Inhibits osteoclast function (inhibits bone resorption) 4 Basic Sciences

Liberated Proliferation matrix-bound Osteoprogenitor cells growth factors

Inhibition of osteoblast activity Mechanical factors BMP hormones Proliferation Sclerostin Osteoclast cytokines and maturation precursor

Surface Wnt Active osteoblasts LRP5/6 osteoblasts β-catenin Mediators of osteoclastogenesis Osteoclast

Osteocyte

Microdamage

FIG. 1.3 Paracrine crosstalk between osteoblasts and osteoclasts. (From Kumar V et al, editors: Bones, joints, and soft tissue tumors. In Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2014, Saunders, Fig. 26-5.)

• Directly stimulated by calcitonin, inhibited by PTH • Border consists of plasma membrane enfoldings • Sclerostin secreted by osteocytes helps negative that increase surface area feedback on osteoblasts’ bone deposition (Fig. 1.3). • Bind to bone surfaces through cell • Differentially regulated according to mechanical attachment (anchoring) proteins loading, with decreased sclerostin in areas of • Integrin (αvβ3 or vitronectin receptor) concentrated strain • Bone resorption occurs in depressions: Howship • Downregulation is associated with increased bone lacunae. formation (via sclerostin antibody). • Effectively seal the space below the osteoclast • Potential for use in fracture healing, bone loss, • Synthesize tartrate-resistant acid phosphate osseous integration of implants, and genetic bone • Produce hydrogen ions through carbonic diseases via upregulation of sclerostin anhydrase • Osteoclasts • Lower pH • Multinucleated irregular giant cells • Increase solubility of hydroxyapatite crystals • Derived from hematopoietic cells in macrophage • Organic matrix then removed by proteolytic lineage digestion through activity of the lysosomal • Monocyte progenitors form giant cells by fusion enzyme cathepsin K • Function • Signaling • Bone resorption • Have calcitonin receptors, which inhibit • Bone formation and resorption are linked osteoclastic resorption • Stimulated primarily by RANKL binding to • Interleukin-1 (IL-1): potent stimulator of RANK receptor on cell surface osteoclast differentiation and bone resorption • Osteoblasts (and tumor cells) express • Found in membranes surrounding loose total RANKL (Fig. 1.4): joint implants • Binds to receptors on osteoclasts • In contrast, IL-10 suppresses osteoclasts. • Stimulates differentiation into mature n Matrix (Table 1.3) osteoclasts • Organic components: 40% of dry weight of bone • Inhibited by osteoprotegerin (OPG) • Collagen (90% of organic components) binding to RANKL • Primarily type I (mnemonic: bone contains the • Occurs both normally and in certain conditions, word one) including multiple myeloma and metastatic • Type I collagen provides tensile strength of bone disease bone • Denosumab is a monoclonal antibody that • Hole zones (gaps) exist within the collagen fibril targets and inhibits RANKL binding to the between the ends of molecules. RANK receptor • Pores exist between the sides of parallel • Resorption mechanism molecules. • Osteoclasts possess a ruffled (brush) border and • Mineral deposition (calcification) occurs within the surrounding clear zone hole zones and pores. Basic Sciences 5

• Cross-linking decreases collagen solubility and Vit D increases its tensile strength. • Proteoglycans PTH • Matrix proteins (noncollagenous) • Osteocalcin: most abundant noncollagenous protein in bone • Inhibited by PTH and stimulated by 1,25(OH)2D3 Osteoblast Osteoclast precursor • Can be measured in serum or urine as a marker of bone turnover − • Inorganic (mineral) components: 60% of dry weight of bone • Calcium hydroxyapatite [Ca10(PO4)6(OH)2]: + provides compressive strength • Calcium phosphate (brushite) n Tissues surrounding bone Vit • Periosteum PTH • Connective tissue membrane that covers bone • More highly developed in children • Inner periosteum, or cambium, is loose and vascular and contains cells capable of becoming osteoblasts. • These cells enlarge the diameter of bone during growth and form periosteal callus during fracture Carbonic healing. anhydrase • Outer (fibrous) periosteum is less cellular and is CA Lysosome contiguous with joint capsules. Hydrogen ions • Bone marrow—source of progenitor cells; controls inner diameter of bone • Red marrow • Hematopoietic (40% water, 40% fat, 20% protein) Integrins • Slowly changes to yellow marrow with age, Lysosome enzyme first in appendicular skeleton and later in axial skeleton • Yellow marrow FIG. 1.4 Control and function of the osteoclast. Vit, vitamin. • Inactive (15% water, 80% fat, 5% protein)

Table 1.3 Components of Bone Matrix TYPE OF MATRIX FUNCTION COMPOSITION TYPES NOTES ORGANIC MATRIX Collagen Provides tensile strength Primarily type I Constitutes 90% of organic matrix collagen Structure: triple helix of one α2 and two α1 chains, quarter-staggered to produce a fibril Proteoglycans Partly responsible for Glycosaminoglycan- Inhibits mineralization compressive strength protein complexes Matrix proteins Promote mineralization and Osteocalcin (bone Attracts osteoclasts; direct (noncollagenous) bone formation γ-carboxyglutamic regulation of bone density; most acid–containing abundant noncollagenous ma- protein) trix protein (10%–20% of total) Osteonectin (SPARC) Secreted by platelets and osteoblasts; postulated to have a role in regulating calcium or organiz- ing mineral in matrix Osteopontin Cell-binding protein, similar to an integrin Growth factors and Aid in bone cell TGF-β Present in small amounts in bone cytokines differentiation, IGF matrix activation, growth, IL-1, IL-6 and turnover BMPs INORGANIC MATRIX Calcium hydroxyapa- Provides compressive Most of the inorganic matrix; tite [Ca10(PO4)6(OH)2] strength primary mineralization in collagen gaps (holes and pores), secondary mineralization on periphery Osteocalcium Makes up the remaining inorganic phosphate (brushite) matrix 6 Basic Sciences

n Bone vascular supply • Bone receives 5%–10% of the cardiac output. • Bones with a tenuous blood supply include the scaphoid, talus, femoral head, and odontoid. A D • Hypoxia, hypercapnia, and sympathectomy increase flow. • Long bones receive blood from three sources (systems) • Nutrient artery system • Branch from systemic arteries, enter the diaphyseal cortex through the nutrient foramen, enter the medullary canal, and branch into ascending and C descending arteries (Figs. 1.5 and 1.6) • Further branch into arterioles in the endosteal cortex, which enables blood supply to at least the inner two-thirds of the mature diaphyseal cortex via the haversian system (see Fig. 1.6) FIG. 1.5 Intraoperative arteriogram (canine tibia) demonstrating ascending (A) and descending (D) branches of the nutrient artery. C, • BP in the nutrient artery system is high. Cannula. (From Brinker MR et al: Pharmacological regulation of the circulation of • 60% of cortical bone vascularized by nutrient arteries bone, J Bone Joint Surg Am 72:964–975, 1990.)

Endosteal vessels

Epiphysis

Metaphysis

Diaphysis

Periosteal vessels

Tendon

Muscular vessels

FIG. 1.6 Blood supply to bone. (From Standring S et al, editors: Functional anatomy of the musculoskeletal system. In Gray’s anatomy, ed 40, London, 2008, Elsevier, Fig. 5-20.) Basic Sciences 7

• Metaphyseal-epiphyseal system • Enchondral • Arises from the periarticular vascular plexus (e.g., • Examples: geniculate arteries) • Embryonic formation of long bones • Periosteal system • Longitudinal growth (physis) • Consists mostly of capillaries that supply the outer • Fracture callus third (at most) of the mature diaphyseal cortex • Bone formed with demineralized bone matrix • BP in the periosteal system is low. • Undifferentiated cells secrete cartilaginous matrix • Physiologic features and differentiate into chondrocytes. • Direction of flow • Matrix mineralizes and is invaded by vascular buds • Arterial flow in mature bone is centrifugal (inside that bring osteoprogenitor cells. to outside), which is the net effect of the high- • Osteoclasts resorb calcified cartilage; osteoblasts pressure nutrient artery system and the low- form bone. pressure periosteal system. • Bone replaces the cartilage model; cartilage is not • When fracture disrupts the nutrient artery system, converted to bone. the periosteal system pressure predominates and • Embryonic formation of long bones (Figs. 1.7 and 1.8) blood flow is centripetal (outside to inside). • These bones are formed from the mesenchymal • Flow in immature developing bone is centripetal anlage at 6 weeks’ gestation. because the highly vascularized periosteal system • Vascular buds invade the mesenchymal model, is the predominant component. bringing osteoprogenitor cells that differentiate • Venous flow in mature bone is centripetal. into osteoblasts and form the primary ossification • Cortical capillaries drain to venous sinusoids, centers at 8 weeks. which drain to the emissary venous system. • Differentiation stimulated in part by binding of • Regulation of bone blood flow Wnt protein to the lipoprotein receptor–related • Influenced by metabolic, humoral, and autonomic protein 5 (LRP5) or LRP6 receptor inputs • Marrow forms through resorption of the central • Arterial system: great potential for vasoconstriction cartilage anlage by invasion of myeloid precursor (from the resting state), less potential for vasodilation cells that are brought in by capillary buds. • Vessels within bone: have several vasoactive • Secondary ossification centers develop at bone receptors (β-adrenergic, muscarinic, thromboxane/ ends, forming the epiphyseal centers (growth prostaglandin) plates) responsible for longitudinal growth. • Bone blood flow is the major determinant of how • Arterial supply is rich during development, with well a fracture heals. an epiphyseal artery (terminates in the proliferative • Initial response is a decrease in bone blood flow after zone), metaphyseal arteries, nutrient arteries, and vascular disruption at the fracture site. perichondrial arteries (Fig. 1.9). • Bone blood flow increases within hours to days (as • Physis part of the regional acceleratory phenomenon), peaks • Two types of growth plates exist in immature long at approximately 2 weeks, and returns to normal in bones: (1) horizontal (the physis) and (2) spherical 3–5 months. (growth of the epiphysis). • Unreamed intramedullary nails preserve endosteal • The spherical plate is less organized than the blood supply. horizontal plate. • Reaming devascularizes the inner 50%–80% of the • Perichondrial artery—major source of nutrition of cortex and delays revascularization of the endosteal growth plate blood supply. • Delineation of physeal cartilage zones is based on n Types of bone formation (Table 1.4) growth (see Fig. 1.9) and function (Figs. 1.10 and 1.11).

Table 1.4 Types of Bone Formation TYPE OF EXAMPLES OF NORMAL EXAMPLES OF DISEASES WITH OSSIFICATION MECHANISM MECHANISMS ABNORMAL OSSIFICATION Enchondral Bone replaces a cartilage model Embryonic formation of long bones Achondroplasia Longitudinal growth (physis) Fracture callus Bone formed with the use of demineralized bone matrix Intramembranous Aggregates of undifferentiated Embryonic flat bone formation Cleidocranial dysostosis mesenchymal cells Bone formation during distraction differentiate into osteoblasts, osteogenesis which form bone Blastema bone Appositional Osteoblasts lay down new bone Periosteal bone enlargement (width) Paget disease of bone on existing bone The bone formation phase of bone Infantile hyperostosis (Caffey remodeling disease) Melorheostosis 8 Basic Sciences

Epiphyseal ossification center (secondary) Cartilage Bone Diaphyseal ossification center (primary)

Calcified Arteries Diaphyseo-epiphyseal junction cartilage

A 1 B1 C 1 D1

A BC D EF

Epiphyseal cartilage plate

Epiphysis

Diaphysis

Epiphysis GHIJ

FIG. 1.7 Enchondral ossification of long bones. Note that phases F through J often occur after birth.( From Moore KL: The developing human, Philadel- phia, 1982, Saunders, p 346.)

• Reserve zone: cells store lipids, glycogen, and • Normal matrix mineralization occurs in the proteoglycan aggregates; decreased oxygen tension lower hypertrophic zone: chondrocytes increase occurs in this zone. five times in size, accumulate calcium in their • Lysosomal storage diseases (e.g., Gaucher mitochondria, die, and release calcium from disease) can affect this zone. matrix vesicles. • Proliferative zone: growth is longitudinal, with • Chondrocyte maturation is regulated by systemic stacking of chondrocytes (the top cell is the hormones and local growth factors (PTH-related dividing “mother” cell), cellular proliferation, and peptide inhibits chondrocyte maturation; Indian matrix production; increases in oxygen tension hedgehog protein is produced by chondrocytes and proteoglycans inhibit calcification. and regulates the expression of PTH-related • Achondroplasia causes defects in this zone peptide). (see Fig. 1.11). • Osteoblasts migrate from sinusoidal vessels and • Growth hormone exerts its effect in the use cartilage as a scaffolding for bone formation. proliferative zone. • Low oxygen tension and decreased proteoglycan • Hypertrophic zone: aggregates aid in this process. • Divided into three zones: maturation, • This zone widens in rickets (see Fig. 1.11), with degeneration, and provisional calcification little or no provisional calcification. Basic Sciences 9

Proliferating Perichondrium hyaline cartilage

Hypertrophic calcifying Canals, containing Periosteum cartilage capillaries, periosteal mesenchymal cells, Thin collar of cancellous and osteoblasts bone from periosteum around diaphysis

At 8 weeks At 9 weeks

Epiphyseal capillaries Calcified cartilage Epiphyseal (secondary) ossification center Cancellous endochondral bone laid down on spicules Outer part of periosteal bone of calcified cartilage transforming into compact bone

Primordial marrow cavities Central marrow cavity

At 10 weeks At birth Articular cartilage of head Proliferating Bone of growth cartilage proximal epiphysis Hypertrophic Proximal Proximal calcifying cartilage metaphysis Epiphyseal epiphyseal ossification growth centers for plate Diaphysis; growth head and in width occurs by greater tubercle periosteal bone Sites of formation growth in length Endochondral bone of bone Epiphyseal laid down ossification on spicules of degenerating Distal metaphysis centers of Distal calcified cartilage lateral epicondyle and epiphyseal Bone of Hypertrophic medial epicondyle growth plate distal epiphysis calcifying cartilage Articular cartilage Proliferating Calcified cartilage growth cartilage At 5 years At 10 years

FIG. 1.8 Development of a typical long bone: formation of the growth plate and secondary centers of ossification.( From Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 136.) 10 Basic Sciences

CLOSE-UP VIEW OF DEVELOPING EPIPHYSIS AND EPIPHYSEAL GROWTH PLATE

Articular cartilage

Epiphyseal growth plate (poorly organized)

Secondary (epiphyseal) ossification center

Epiphyseal artery Reserve zone

Ossification groove Proliferative zone of Ranvier Maturation zone

Perichondrial fibrous Degeneration zone Hypertrophic zone ring of La Croix Zone of provisional calcification Perichondrial artery Primary spongiosa Metaphysis Last intact transverse Secondary spongiosa cartilage septum

Metaphyseal artery

Periosteum Diaphysis

Cartilage

Nutrient artery Calcified cartilage

Bone

FIG. 1.9 Structure and blood supply of a typical growth plate. (From Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 166.) Basic Sciences 11

FIG. 1.10 Zone structure, function, and physiologic features of the growth plate. (From Netter FH: CIBA collection of medical illustrations, vol 8: Musculo- skeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 164.) 12 Basic Sciences

Zones Histology Functions Exemplary diseases Defect (if known) Structures

Secondary bony epiphysis Epiphyseal artery

Diastrophic dwarfism...... Defective type II collagen (also, defects in other zones) synthesis Matrix production Pseudoachondroplasia...... Defective processing and Reserve zone (also, defects in other zones) transport of proteoglycans Storage Kneist syndrome...... Defective processing of (also, defects in other zones) proteoglycans

Gigantism...... Increased cell proliferation Matrix production (growth hormone increased) Achondroplasia...... Deficiency of cell proliferation Proliferative Hypochondroplasia...... Less severe deficiency of cell Cellular proliferation zone proliferation (longitudinal growth) Malnutrition, irradiation...... Decreased cell proliferation injury, glucocorticoid excess and/or matrix synthesis

Maturation zone

Preparation of matrix for Mucopolysaccharidosis...... Deficiencies of specific calcification (Morquio syndrome, lysosomal acid hydrolases, Hurler syndrome) with lysosomal storage of mucopolysaccharides Degenerative zone Hypertrophic zone

Zone of Rickets, osteomalacia...... Insufficiency of Ca2+ and/or provisional Calcification of matrix (also, defects in metaphysis) for normal calcification calcification of matrix

Last intact Metaphyseal chondro-...... Extension of hypertrophic transverse Vascular invasion and dysplasia (Jansen cells into metaphysis septum resorption of transverse and Schmid types) septa Primary Acute hematogenous...... Flourishing of bacteria due to spongiosa Bone formation osteomyelitis sluggish circulation, low PO2, reticuloendothelial deficiency

Osteopetrosis...... Abnormality of osteoclasts

Metaphysis Remodeling (internal remodeling) Secondary Internal: removal of spongiosa Abnormality of osteoblasts cartilage bars, replace- Osteogenesis imperfecta...... and collagen synthesis ment of fiber bone

Branches of with lamellar bone Scurvy...... Inadequate collagen formation metaphyseal External: funnelization and nutrient Metaphyseal dysplasia...... Abnormality of funnelization arteries (Pyle disease) (external remodeling)

FIG. 1.11 Zone structure and pathologic defects of cellular metabolism. (From Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 165.) Basic Sciences 13

• Mucopolysaccharide diseases (see Fig. 1.11) EPIPHYSIS affect this zone, leading to chondrocyte degeneration. • Physeal fractures probably traverse several PHYSIS zones, depending on the type of loading (Fig. 1.12). Germinal • Slipped capital femoral epiphysis (SCFE) occurs here. Columnation • Except renal osteodystrophy (through Tension metaphyseal spongiosa) • Metaphysis • Adjacent to the physis and expands with skeletal Shear growth • Osteoblasts from osteoprogenitor cells align Hypertrophic on cartilage bars produced by physeal expansion. Compression • Primary spongiosa (calcified cartilage bars) Ossification mineralizes to form woven bone and remodels to form secondary spongiosa and a “cutback zone” at the metaphysis. • Groove of Ranvier: supplies chondrocytes to the periphery for lateral growth (width) METAPHYSIS • Perichondrial ring of La Croix: dense fibrous tissue, primary membrane anchoring the periphery FIG. 1.12 Histologic zone of failure varies with the type of loading applied to a specimen. (From Moen CT, Pelker RR: Biomechanical and histo- of the physis logical correlations in growth plate failure, J Pediatr Orthop 4:180–184, 1984.) • Intramembranous ossification • Occurs without a cartilage model • Compressive forces inhibit growth; tension • Undifferentiated mesenchymal cells aggregate stimulates it. into layers (or membranes), differentiate into • Suggests that mechanical factors influence osteoblasts, and deposit an organic matrix that longitudinal growth, bone remodeling, and mineralizes. fracture repair • Examples: • May play a role in scoliosis and Blount disease • Embryonic flat bone formation • Cortical bone remodeling • Bone formation during distraction osteogenesis • Osteoclastic tunneling (cutting cones; Fig. 1.14) • Blastema bone (in young children with • The head of the cutting cone is made up amputations) of osteoclasts followed by capillaries and • Appositional ossification osteoblasts. • Osteoblasts align on the existing bone surface and • Followed by layering of osteoblasts and successive lay down new bone. deposition of layers of lamellae • Examples: • Cancellous bone remodeling • Periosteal bone enlargement (width) • Osteoclastic resorption followed by deposition of • Bone formation phase of bone remodeling new bone by osteoblasts n Bone remodeling n Bone injury and repair • General n Fracture repair (Table 1.5) • Cortical bone and cancellous bone are continuously • Stages of fracture repair remodeled throughout life by osteoclastic and • Inflammation osteoblastic activity (Fig. 1.13). • Fracture hematoma provides hematopoietic cells • Wolff’s law: remodeling occurs in response to capable of secreting growth factors. mechanical stress. • Subsequently, fibroblasts, mesenchymal cells, • Increasing mechanical stress increases bone gain. and osteoprogenitor cells form granulation tissue • Removing external mechanical stress increases around the fracture ends. bone loss, which is reversible (to varying degrees) • Osteoblasts (from surrounding osteogenic on remobilization. precursor cells) and fibroblasts proliferate. • Piezoelectric remodeling occurs in response to • Repair electric charge. • Primary callus response within 2 weeks • The compression side of bone is electronegative, • For bone ends not in continuity, bridging (soft) stimulating osteoblasts (formation). callus occurs. • The tension side of bone is electropositive, • Soft callus is later replaced through enchondral stimulating osteoclasts (resorption). ossification by woven bone (hard callus). • Hueter-Volkmann law: remodeling occurs in small • Medullary callus supplements the bridging packets of cells known as basic multicellular units (BMUs). callus, forming more slowly and later. • Such remodeling is modulated by hormones and • Fracture healing varies with treatment method cytokines. (Table 1.6). 14 Basic Sciences

• In an unstable fracture, type II collagen is • Increases time to fracture healing expressed early, followed by type I collagen. • Increases risk of nonunion (particularly in the tibia) • Amount of callus is inversely proportional to • Decreases strength of fracture callus extent of immobilization. • Increases risk of pseudarthrosis after lumbar • Progenitor cell differentiation fusion by up to 500% • High strain promotes development of fibrous • Nonsteroidal antiinflammatory drugs tissue. • Have adverse effects on fracture healing and • Low strain and high oxygen tension promote healing of lumbar spinal fusions development of woven bone. • Cyclooxygenase-2 (COX-2) activity is • Intermediate strain and low oxygen tension required for normal enchondral ossification promote development of cartilage. during fracture healing. • Remodeling • Quinolone antibiotics • Remodeling begins in middle of repair phase and • Toxic to chondrocytes and inhibit fracture continues long after clinical healing (up to 7 years). healing • Allows bone to assume its normal configuration and • Ultrasound and fracture healing shape according to stress exposure (Wolff’s law) • Low-intensity pulsed ultrasound (30 mW/cm2) • Throughout, woven bone is replaced with lamellar accelerates fracture healing and increases the bone. mechanical strength of callus • Fracture healing is complete when the marrow • A cellular response to the mechanical energy of space is repopulated. ultrasound has been postulated. • Biochemistry of fracture healing (Table 1.7) • Effect of radiation on bone • Growth factors of bone (Table 1.8) • High-dose irradiation causes long-term changes • BMP-2: acute open tibial fractures within the haversian system and decreases • BMP-3: no osteogenic activity cellularity. • BMP-4: associated with fibrodysplasia • Diet and fracture healing ossificans progressiva • Protein malnutrition results in negative effects on • BMP-7: tibial nonunions fracture healing: • BMPs activate intracellular signal molecules called • Decreased periosteal and external callus SMADs to cause osteoblastic differentiation • Decreased callus strength and stiffness • Endocrine effects on fracture healing (Table 1.9) • Increased fibrous tissue within callus • Head injury • In experimental models, oral supplementation • Can increase the osteogenic response to fracture with essential amino acids improves bone • Nicotine (smoking) mineral density in fracture callus.

Resting phase Activation

Osteoclasts

Lining cells

Osteocytes Osteocytes

Resorption Reversal Formation

Apoptotic osteoclasts Osteoclasts Osteoblasts

Preosteoblasts Osteoid

Osteocytes Osteocytes

FIG. 1.13 Bone remodeling. Osteoclasts dissolve the mineral from the bone matrix. Osteoblasts produce new bone (osteoid) that fills in the resorption pit. Some osteoblasts are left within the bone matrix as osteocytes. (From Firestein GS et al, editors: Kelley’s textbook of rheumatology, ed 8, Philadelphia, 2008, Saunders.) Basic Sciences 15

• Electricity and fracture healing • Streaming potentials: occur when • Definitions electrically charged fluid is forced over a cell • Stress-generated potentials membrane that has a fixed charge • Piezoelectric effect: tissue charges are • Transmembrane potentials: generated by displaced secondary to mechanical forces. cellular metabolism

Developing resorption Time cavity Cutting cone Osteoclast

Resorption cavity Reversal zone

Fibroblast

Osteoblast Closing Forming cone osteon

Quiescent osteoblast

Completed osteon Blood vessel

B C

FIG. 1.14 Cortical bone remodeling. (A) Longitudinal and cross sections of a time line illustrating formation of an osteon. Osteoclasts cut a cylindrical channel through bone. Osteoblasts follow, laying down bone on the surface of the channel until matrix surrounds the central blood vessel of the newly formed osteon (closing cone of a new osteon). (B) Photomicrograph of a cutting cone. (C) Higher-magnification photomicrograph; osteoclastic resorption can be more clearly appreciated. (A from Standring S et al, editors: Functional anatomy of the musculoskeletal system. In Gray’s anatomy, ed 40, London, 2008, Elsevier, Fig. 5-19.) 16 Basic Sciences

Table 1.5 Biologic and Mechanical Factors Influencing • Types of electrical stimulation Fracture Healing • Direct current: stimulates an inflammatory- like response, resulting in decreased oxygen Biologic factors Patient age Comorbid medical conditions concentrations and increase in tissue pH Functional level (similar to effects of an implantable bone Nutritional status stimulator). Nerve function • Alternating current: “capacity-coupled Vascular injury generators”; affects cyclic AMP (cAMP) Hormones Growth factors synthesis, collagen synthesis, and calcification Health of the soft tissue envelope during repair stage Sterility (in open fractures) • Pulsed electromagnetic fields (PEMFs): initiate Cigarette smoke calcification of fibrocartilage (but not fibrous Local pathologic conditions Level of energy imparted tissue) Type of bone affected n Bone grafting (Table 1.10) Extent of bone loss n Graft properties Mechanical factors Soft tissue attachments to bone • Osteoconductive matrix: acts as a scaffold or Stability (extent of immobilization) framework for bone growth Anatomic location Level of energy imparted • Osteoinductive factors: growth factors (BMP) that Extent of bone loss stimulate bone formation • Osteogenic cells: primitive mesenchymal cells, osteoblasts, and osteocytes • Structural integrity n Specific bone graft types Table 1.6 Type of Fracture Healing Based on Type of • Cortical bone graft Stabilization • Slower incorporation: remodels existing haversian TYPE OF STABILIZATION PREDOMINANT TYPE OF HEALING systems through resorption (weakens the graft) Cast (closed treatment) Periosteal bridging callus and and then deposits new bone (restores interfragmentary enchondral strength) ossification • Resorption confined to osteon borders; interstitial Compression plate Primary cortical healing (cutting- cone type or haversian lamellae are preserved. remodeling) • Used for structural defects Intramedullary nail Early: periosteal bridging callus; • Insufficiency fracture eventually occurs in 25% of enchondral ossification massive grafts. Late: medullary callus and • Cancellous graft intramembranous ossification External fixator Dependent on extent of rigidity: • Useful for grafting nonunion and cavitary defects Less rigid: periosteal bridging • Revascularizes and incorporates quickly callus; enchondral ossification • Osteoblasts lay down new bone on old More rigid: primary cortical trabeculae, which are later remodeled (“creeping healing; intramembranous substitution”). ossification Inadequate immobilization Hypertrophic nonunion (failed with adequate blood enchondral ossification); type II supply collagen predominates Table 1.7 Biochemical Steps of Fracture Healing Inadequate immobilization Atrophic nonunion STEP COLLAGEN TYPE without adequate blood supply Mesenchymal I, II, III, V Inadequate reduction with Oligotrophic nonunion Chondroid II, IX displacement at the Chondroid-osteoid I, II, X fracture site Osteogenic I

Table 1.8 Growth Factors of Bone GROWTH FACTOR ACTION NOTES Bone morphogenetic Osteoinductive; stimulates bone formation Target cells of BMP are the undifferentiated perivascular protein Induces metaplasia of mesenchymal cells into mesenchymal cells; signals through serine-threonine kinase osteoblasts receptors Intracellular molecules called SMADs serve as signaling mediators for BMPs Transforming growth Induces mesenchymal cells to produce type II Found in fracture hematomas; believed to regulate cartilage factor–β collagen and proteoglycans and bone formation in fracture callus; signals through serine/ Induces osteoblasts to synthesize collagen threonine kinase receptors Coating porous implants with TGF-β enhances bone ingrowth IGF-2 Stimulates type I collagen, cellular proliferation, Signals through tyrosine kinase receptors cartilage matrix synthesis, and bone formation Platelet-derived Attracts inflammatory cells to the fracture site Released from platelets; signals through tyrosine kinase growth factor (chemotactic) receptors Basic Sciences 17

• Vascularized bone graft • Primary mechanism of rejection is cellular rather • Although technically difficult to implant, allows than humoral. more rapid union and cell preservation; best for • Incorporation related to cellularity and MHC irradiated tissues or large tissue defects (morbidity incompatibility. may occur at donor site [e.g., fibula]) • Cellular components that contribute to antigenicity • Nonvascular bone grafts are more common are marrow origin, endothelium, and retinacular • Allograft bone activating cells. • Types • Marrow cells incite the greatest immunogenic • Fresh: increased immunogenicity response. • Fresh frozen: less immunogenic than fresh; BMP • Extracellular matrix components that contribute to preserved antigenicity are as follows: • Freeze dried (lyophilized “croutons”): loses • Type I collagen (organic matrix): stimulates cell- structural integrity and depletes BMP, is least mediated and humoral responses immunogenic, is purely osteoconductive, has • Noncollagenous matrix (proteoglycans, lowest risk of viral transmission osteopontin, osteocalcin, other glycoproteins) • Bone matrix gelatin (a digested source of BMP): • Hydroxyapatite does not elicit immune response. demineralized bone matrix is osteoconductive and • Demineralized bone matrix osteoinductive. • Acidic extraction of bone matrix from allograft • Osteoarticular (osteochondral) allograft • Osteoconductive without structural support • Immunogenic (cartilage is vulnerable to • Minimally osteoinductive despite preservation of inflammatory mediators of immune response) osteoinductive molecules • Articular cartilage preserved with glycerol or • Synthetic bone grafts: calcium, silicon, or aluminum DMSO • Calcium phosphate–based grafts: capable of • Cryogenically preserved grafts (leave few viable osseoconduction and osseointegration chondrocytes) • Biodegrade very slowly • Tissue-matched (syngeneic) osteochondral grafts • Highest compressive strength of any graft material (produce minimal immunogenic effects and • Many prepared as ceramics (heated apatite crystals incorporate well) fused into crystals [sintered]) • Antigenicity • Tricalcium phosphate • Allograft bone possesses a spectrum of potential • Hydroxyapatite; purified bovine dermal fibrillar antigens, primarily from cell surface glycoproteins. collagen plus ceramic hydroxyapatite granules and • Classes I and II cellular antigens in allograft are tricalcium phosphate granules recognized by T lymphocytes in the host. • Calcium sulfate: osteoconductive • Rapidly resorbed • Calcium carbonate (chemically unaltered Table 1.9 Endocrine Effects on Fracture Healing marine coral): resorbed and replaced by bone (osteoconductive) HORMONE EFFECT MECHANISM • Coralline hydroxyapatite: calcium carbonate skeleton Cortisone − Decreased callus proliferation is converted to calcium phosphate through a Calcitonin +? Unknown Thyroid hormone, PTH + Bone remodeling thermoexchange process. Growth hormone + Increased callus volume • Silicate-based: incorporate silicon as silicate (silicon dioxide); bioactive glasses and glass-ionomer cement

Table 1.10 Types of Bone Grafts and Bone Graft Properties PROPERTIES

OSTEOGENIC GRAFT OSTEOCONDUCTION OSTEOINDUCTION CELLS STRUCTURAL INTEGRITY OTHER PROPERTIES Autograft Cancellous Excellent Good Excellent Poor Rapid incorporation Cortical Fair Fair Fair Excellent Slow incorporation Allograft Fair Fair None Good Fresh has the highest immunogenicity Freeze dried is the least immunogenic but has the least structural integrity (weakest) Fresh frozen preserves BMP Ceramics Fair None None Fair Demineralized Good Fair None Poor bone matrix Bone marrow Poor Poor Good Poor

Modified from Brinker MR, Miller MD:Fundamentals of orthopaedics, Philadelphia, 1999, Saunders, p 7. 18 Basic Sciences

• Aluminum oxide: alumina ceramic bonds to bone • Optimal therapy: single preoperative or postoperative in response to stress and strain between implant and dose of 600–800 rad/cGy (6-8 Gy) bone • Prevents proliferation and differentiation of primordial n Five stages of graft healing (Urist) are listed in Table 1.11. mesenchymal cells into osteoprogenitor cells n Distraction osteogenesis • Preoperative radiation (600–800 rad/cGy) may be • Definition: distraction-stimulated formation of bone given in a single fraction up to 24 hours prior to • Clinical applications: surgery. • Limb lengthening • Helps prevent heterotopic ossification after THA in • Deformity correction (via differential lengthening) patients at high risk for this development • Segmental bone loss (via bone transport) • Incidence of heterotopic ossification after THA • Biologic features: among patients with Paget disease is approximately • Under optimal stability, intramembranous 50%. ossification occurs. n Normal bone metabolism • Under instability, bone forms through enchondral n Calcium ossification. • Important in muscle and nerve function, clotting, and • Under extreme instability, pseudarthrosis may many other areas occur. • More than 99% of the body’s calcium is stored in bones. • Three histologic phases: • Plasma calcium is about equally free and bound • Latency phase (5–7 days) (usually to albumin). • Distraction phase (1 mm/day [≈1 inch/mo]) • Approximately 400 mg of calcium is released from • Consolidation phase (typically twice as long as bone daily. distraction phase) • Absorbed in the duodenum by active transport • Optimal conditions during distraction osteogenesis: • Requires ATP and calcium-binding protein • Low-energy corticotomy/osteotomy • Regulated by 1,25(OH)2D3 • Minimal soft tissue stripping at corticotomy site • Absorbed in the jejunum by passive diffusion (preserves blood supply) • Kidney reabsorbs 98% of calcium (60% in proximal • Stable external fixation and elimination of torsion, tubule) shear, and bending moments • Calcium may be excreted in stool. • Latency period (no lengthening) 5–7 days • Primary homeostatic regulators of serum calcium • Distraction: 0.25 mm three or four times per day are PTH and 1,25(OH)2D3 (0.75–1.0 mm/day) • Dietary requirement for elemental calcium: • Neutral fixation interval (no distraction) during • Approximately 600 mg/day for children consolidation • Approximately 1300 mg/day for adolescents and • Normal physiologic use of the extremity, including young adults (ages 10–25 years) weight bearing • 750 mg/day for adults ages 25–50 years n Heterotopic ossification • 1200–1500 for adults over age 50 years • Ectopic bone forms in soft tissues. • 1500 mg/day for pregnant women • Most commonly in response to injury or surgical • 2000 mg/day for lactating women dissection • 1500 mg/day for postmenopausal women and for the • Myositis ossificans: heterotopic ossification in muscle patient with a healing fracture in a long bone • Increased risk with traumatic brain injury • Calcium balance is usually positive in the first three • Recurrence after resection is likely if neurologic decades of life and negative after the fourth decade. compromise is severe. n Phosphate • Timing of surgery for heterotopic ossification after • A key component of bone mineral traumatic brain injury is important: • Approximately 85% of the body’s phosphate stores • Time since injury (3–6 months) are in bone. • Evidence of bone maturation on radiographs • Plasma phosphate is mostly unbound. (sharp demarcation, trabecular pattern) • Also important in enzyme systems and molecular • Heterotopic ossification may be resected after total hip interactions as a metabolite and buffer arthroplasty (THA). • Dietary intake of phosphate is usually adequate. • Resection should be delayed for 6 months or longer • Daily requirement is 1000–1500 mg. after THA. n Reabsorbed by the kidney (proximal tubule) • Adjuvant radiation therapy may prevent recurrence n Phosphate may be excreted in urine. of heterotopic ossification. n Parathyroid hormone • An 84–amino acid peptide • Synthesized in and secreted from chief cells of the Table 1.11 Stages of Graft Healing (four) parathyroid glands STAGE ACTIVITY • N-terminal fragment 1-34 is the active portion. Inflammation Chemotaxis stimulated by necrotic • Teriparatide, the synthetic form of recombinant debris human PTH, contains this active sequence. Osteoblast differentiation From precursors • Used to treat some forms of osteoporosis Osteoinduction Osteoblast and osteoclast function • Osteoconduction New bone forming over scaffold Increased risk of osteosarcoma Remodeling Process continues for years • Effect of PTH mediated by the cAMP second- messenger mechanism downstream in osteocytes Basic Sciences 19

Table 1.12 Regulation of Calcium and Phosphate Metabolism

PARAMETER PTH (PEPTIDE) 1,25(OH)2D (STEROID) CALCITONIN (PEPTIDE) Origin Chief cells of parathyroid glands Proximal tubule of kidney Parafollicular cells of thyroid gland Factors stimulating Decreased serum Ca2+ Elevated PTH level Elevated serum Ca2+ level production Decreased serum Ca2+ level Decreased serum Pi Factors inhibiting Elevated serum Ca2+ Decreased PTH Elevated serum Ca2+ Decreased serum Ca2+ production Elevated 1,25(OH)2D Elevated serum Pi Effect on end-organs for hormone action: Intestine No direct effect Strongly stimulates intestinal ? 2+ Acts indirectly on bowel by stimulating absorption of Ca and Pi production of 1,25(OH)2D in kidney Kidney Stimulates 25(OH)D 1α-hydroxylase in ? ? mitochondria of proximal tubular cells to convert 25(OH)D to 1,25(OH)2D Increases fractional resorption of filtered Ca2+ Promotes urinary excretion of Pi Bone Stimulates osteoclastic resorption of bone Strongly stimulates osteoclastic Inhibits osteoclastic Stimulates recruitment of preosteoclasts resorption of bone resorption of bone ? Role in normal human physiology Net effect on Ca2+ and Increased serum Ca2+ level Increased serum Ca2+ level Decreased serum Ca2+ Pi concentrations in Decreased serum Pi level Increased serum Pi level level (transient) extracellular fluid and serum

Adapted from Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 179.

• PTH helps regulate plasma calcium. n Other hormones affecting bone metabolism • Decreased calcium levels in extracellular fluid • Estrogen stimulate β2 adrenoreceptors to release PTH, • Prevents bone loss by inhibiting bone resorption which acts at the intestines, kidneys, and bones • Decrease in urinary pyridinoline cross-links (Table 1.12). • Because bone formation and resorption are coupled, • PTH directly activates osteoblasts. estrogen therapy also decreases bone formation. • PTH modulates renal phosphate filtration. • Supplementation is helpful in postmenopausal • PTH may accentuate bone loss in elderly persons. women only if started within 5–10 years after onset • PTH-related protein and its receptor have been of menopause. implicated in metaphyseal dysplasia. • Risk of endometrial cancer is reduced when n Vitamin D estrogen therapy is combined with cyclic progestin • Naturally occurring steroid therapy. • Activated by ultraviolet radiation from sunlight or • Certain regimens of hormone replacement therapy utilized from dietary intake (Fig. 1.15) may increase risks of heart disease and breast cancer. • Hydroxylated to 25(OH)D3 in the liver and • Other postmenopausal pharmacologic interventions hydroxylated a second time in the kidney to one of the (alendronate, raloxifene) should be strongly considered. following: • Corticosteroids • 1,25(OH)2D3, the active hormone • Increase bone loss • 24,25(OH)2D3, the inactive form (Fig. 1.16) • Decrease gut absorption of calcium by decreasing • 1,25(OH)2D3 works at the intestines, kidneys, and binding proteins bones (see Table 1.12). • Decrease bone formation (cancellous more than • Phenytoin (Dilantin) impairs metabolism of vitamin D. cortical) by inhibiting collagen synthesis and n Calcitonin osteoblast productivity • A 32–amino acid peptide hormone produced by clear • Do not affect mineralization cells in the parafollicles of the thyroid gland • Alternate-day therapy may reduce the effects. • Limited role in calcium regulation (see Table 1.12) • Thyroid hormones • Increased extracellular calcium levels cause secretion of • Affect bone resorption more than bone formation calcitonin. • Large (thyroid-suppressive) doses of thyroxine can • Controlled by a β2 receptor lead to osteoporosis. • Inhibits osteoclastic bone resorption • Regulates skeletal growth at the physis • Osteoclasts have calcitonin receptors. • Stimulates chondrocyte growth, type X collagen • Calcitonin decreases osteoclast number and activity. synthesis, and alkaline phosphatase activity • Decreases serum calcium level • Growth hormone • May also have a role in fracture healing and in • Causes positive calcium balance by increasing gut reducing vertebral compression fractures in high- absorption of calcium more than it increases urinary turnover osteoporosis excretion 20 Basic Sciences

Solar 7-dehydrocholesterol Dietary sources of UVB vitamins D2 and D3 radiation Pre-D3 Heat Vitamin D Skin 3 Via chylomicrons and lymphatic system

Circulation Vit D Vit D DBP DBP

Vitamin D

25-OHase Liver

2+ Pi, Ca , FGF23 25(OH)-vitamin D and other factors

+ –

24-OHase 1,25(OH)2-vitamin D 1-OHase 1,25(OH)2-vitamin D Calcitroic acid Kidney Osteoblast Urine PTH – RANKL RANK Preosteoclast PTH Intestine

Parathyroid glands

Mature osteoclast Calcium and Bone 2+ 2– phosphorus 2+ 2– Ca and HPO4 Ca and HPO4 release absorption

Bone Metabolic Neuromuscular mineralization functions functions

FIG. 1.15 Vitamin D metabolism. DBP, vitamin D–binding protein; OHase, 1α-hydroxylase; Pi, inorganic phosphate. (From Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, Philadelphia, 2010, Saunders.)

• Insulin and somatomedins participate in this effect. ↓ Ca2+ • Growth factors ↓ Pi • Transforming growth factor β (TGF-β), platelet- ↑ PTH derived growth factor (PDGF), monokines, and 1,25(OH)2-vitamin D (active metabolite) lymphokines have roles in bone and cartilage repair. 25(OH)-vitamin D, n Peak bone mass 1α-hydroxylase • Believed to occur between 16 and 25 years of age 25(OH)-vitamin D • Higher in men and in African Americans 25(OH)-vitamin D, • After peak, bone loss occurs at a rate of 0.3%–0.5% per 24 hydroxylase year 24,25(OH)2-vitamin D (inactive metabolite) • Rate of bone loss is 2%–3% per year in untreated ↑ Ca2+ women during the sixth through tenth years after ↑ Pi menopause. ↓ PTH • Affects trabecular more than cortical bone FIG. 1.16 Vitamin D metabolism in the renal tubular cell. (From Simon • Increase in trabecular rods results in increased SR, editor: Orthopaedic basic science, Rosemont, IL, 1994, American Academy of anisotropy. Orthopaedic Surgeons, p 165.) Basic Sciences 21

• Cortical bone becomes thinner and intracortical • Increased osteoclastic resorption and failure of porosities increase. repair attempts (poor mineralization as a result of • Cortical bone becomes more brittle, less strong, low phosphate level) and less stiff. • Diagnosis: • Long bones have greater inner and outer • Laboratory findings diameters. • Increased serum calcium, PTH, and urinary n Bone loss phosphate • Occurs at the onset of menopause when both bone • Decreased serum phosphate formation and resorption are accelerated • Bony changes • A net negative change in calcium balance: • Osteopenia menopause decreases intestinal absorption and • Osteitis fibrosa cystica (fibrous replacement of increases urinary excretion of calcium. marrow) • Both urinary hydroxyproline and pyridinoline cross- • Brown tumors: increased giant cells, links are elevated when bone resorption occurs. extravasation of RBCs, hemosiderin staining, • Serum alkaline phosphatase level is elevated when fibrous tissue hemosiderin bone formation is increased. • Chondrocalcinosis n Conditions of bone mineralization (Tables 1.13 through 1.17) • Radiographic findings n Hypercalcemia • Deformed, osteopenic bones • Can manifest in a number of ways • Fractures • Polyuria, polydipsia, and nephrolithiasis • Shaggy trabeculae • Excessive bony resorption with or without fibrotic • Radiolucent areas (phalanges, distal clavicle, tissue replacement (osteitis fibrosa cystica) skull) • CNS effects (confusion, stupor, weakness) • Destructive metaphyseal lesions • GI effects (constipation) • Calcification of soft tissues • Can also cause anorexia, nausea, vomiting, dehydration, • Histologic changes and muscle weakness • Osteoblasts and osteoclasts active on both sides • Primary hyperparathyroidism of the trabeculae (as in Paget disease) • Overproduction of PTH usually a result of a parathyroid • Areas of destruction adenoma (surgical parathyroidectomy is curative) • Wide osteoid seams • Generally affects only one parathyroid gland • Other causes of hypercalcemia • Reflected in a net increase in plasma calcium and • Familial syndromes a decrease in plasma phosphate (as a result of • Pituitary adenomas associated with multiple enhanced urinary excretion) endocrine neoplasia (MEN) types I and II

Table 1.13 Overview of Clinical and Radiographic Aspects of Metabolic Bone Diseases DISEASE CAUSE CLINICAL FINDINGS RADIOGRAPHIC FINDINGS Hypercalcemia Hyperparathyroidism PTH overproduction: adenoma Kidney stone, hyperreflexia Osteopenia, osteitis fibrosa cystica Familial syndromes PTH overproduction: MEN/renal Endocrine and renal Osteopenia abnormalities Hypocalcemia Hypoparathyroidism PTH underproduction: idiopathic Neuromuscular irritability, Calcified basal ganglia cataracts PHP/Albright syndrome PTH receptor abnormality Short MC/MT, obesity Brachydactyly, exostosis Renal osteodystrophy Chronic renal failure: ↓ phosphate Renal abnormalities Rugger jersey spine excretion Rickets (osteomalacia) Vitamin D–deficiency rickets ↓ Vitamin D diet; malabsorption Bone deformities, hypotonia Rachitic rosary, wide growth plates, fractures Vitamin D–dependent (types I See Table 1.16 Total baldness Poor mineralization and II) rickets Vitamin D–resistant (hypo- ↓ Renal tubular phosphate Bone deformities, hypotonia Poor mineralization phosphatemic) rickets resorption Hypophosphatasia ↓ Alkaline phosphatase Bone deformities, hypotonia Poor mineralization Osteopenia Osteoporosis ↓ Estrogen: ↓ bone mass Kyphosis, fractures Compression vertebral fractures, hip fractures Scurvy Vitamin C deficiency: defective Fatigue, bleeding, effusions Thin cortices, corner sign collagen Osteodensity Paget disease of bone Osteoclastic abnormality: ↑ bone Deformities, pain, CHF, fractures Coarse trabeculae, picture- turnover frame vertebrae Osteopetrosis Osteoclastic abnormality: unclear Hepatosplenomegaly, anemia Bone within bone

↓, Decreased; ↑, increased. Table 1.14 Laboratory Findings and Clinical Data Regarding Patients With Metabolic Bone Diseases Causing Hypercalcemia CHANGES IN LEVEL OR CONCENTRATION

SERUM SERUM ALKALINE URINARY OTHER FINDINGS DISORDER CALCIUM PHOSPHATASE PHOSPHATASE PTH 25(OH)D 1,25(OH)2D CALCIUM OR POSSIBLE FINDINGS TREATMENT COMMENTS Primary ↑ None or ↓ None or ↑ ↑ None None or ↑ ↑ Active turnover Surgical excision of Most commonly caused by hyperparathyroidism observed on bone parathyroid edema parathyroid adenoma biopsy with Treatment of hyper- Because PTH stimulates peritrabecular calcemia (see text) conversion of the inactive fibrosis form to the active form Brown tumors [1,25(OH)2D] in the kidney, ↑ production of PTH leads to ↑ levels of 1,25(OH)2D Malignancy with bony ↑ None or ↑ None or ↑ None None None or ↓ ↑ Destructive lesions in Treatment of cancer ↑ Calcium levels may lead to metastases or bone and hypercalcemia ↓ PTH production through ↓ (see text) feedback mechanism ↓ 1,25(OH)2D levels result from ↓ PTH (responsible for conversion of inactive to active form of vitamin D in the kidney) Patients with multiple myeloma display abnormal urinary and serum protein electrophoresis Hyperthyroidism ↑ None None None None None ↑ ↑ Free thyroxin index Treatment of ↑ Calcium levels caused by ↑ or ↓ Thyroid-stimulating hyperthyroidism bone turnover (hypermeta- ↓ hormone bolic state) Tachycardia, tremors Vitamin D intoxication ↑ None or ↑ None or ↑ None ↑↑↑ None ↑ Normalization of History of excessive vitamin or vitamin D intake D intake ↓ and levels Dietary vitamin D is converted to 25(OH)D in the liver; very high concentrations of 25(OH)D cross-react with intestinal vitamin D receptors to ↑ resorption of calcium and cause hypercalcemia

↓, Decreased; ↑, increased. Table 1.15 Laboratory Findings and Clinical Data Regarding Patients With Metabolic Bone Diseases Causing Hypocalcemia CHANGES IN LEVEL OR CONCENTRATION

SERUM SERUM ALKALINE URINARY OTHER FINDINGS OR DISORDER CALCIUM PHOSPHASTASE PHOSPHATASE PTH 25(OH)D 1,25(OH)2D CALCIUM POSSIBLE FINDINGS TREATMENT COMMENTS Hypopara- ↓ ↑ None ↓ None ↓ ↓ Basal ganglia Calcium and vitamin D ↓ PTH production most thyroidism calcification supplementation commonly follows surgical Hypocalcemic ablation of the thyroid (with findings the parathyroid) gland ↓ PTH leads to ↓ serum calcium and ↑ serum phosphate (as result of ↓ urinary excretion of phosphate) Because PTH stimulates conversion from the inactive to the active form of vitamin D (in the kidney), 1,25(OH)2D is also ↓ Pseudohypopara- ↓ ↑ None None or ↑ None ↓ ↓ Hypocalcemic Calcium and vitamin D PTH has no effect on the thyroidism findings supplementation target cells (in the kidney, bone, and intestine) because of a PTH receptor abnormality Leads to a ↓ in the active form of vitamin D Therefore, serum calcium levels are ↓ as result of (1) lack of effect of PTH on bone and (2) ↓ levels of 1,25(OH)2D Renal osteo- ↓ or none ↑↑↑ ↑ ↑↑↑ None ↓ — Findings of Correction of ↓ Renal phosphorus dystrophy secondary underlying renal excretion leads to (high-turnover hyperparathyroid- abnormality hyperphosphatemia bone disease ism: rugger Maintenance of Phosphorus retention resulting from jersey spine normal serum phos- leads to ↓ serum calcium renal disease Osteitis fibrosa phorous and calcium and ↑↑↑ PTH (which [secondary Amyloidosis Dietary phosphate can lead to secondary hyperparathy- restriction hyperparathyroidism) roidism]) Phosphate-binding ↑ BUN and creatinine levels antacid (calcium Associated with long-term carbonate) hemodialysis Administration of the active form of vitamin D: 1,25(OH)2D (calcitriol) Renal osteodys- ↑ or none None or ↑ ↑ None or None ↓ — Rugger jersey spine Treatment of the PTH levels may be sup- trophy (low- mildly ↑ Osteitis fibrosa urinary obstruction or pressed because of (1) turnover bone Amyloidosis kidney disease frequent episodes of disease due to Osteomalacia may hypercalcemia and (2) renal disease be observed direct inhibitory effect of [aluminum aluminum on PTH toxicity]) No secondary hyperparathyroidism is present ↑ BUN and creatinine levels Associated with long-term hemodialysis

↓, Decreased; ↑, increased. 24 Basic Sciences

↓ - - D ↓ ) D ↓ 2 2 ↓

↑ D is 2 renal renal PTH ↑ Table 1.12 Table ↑ level of 1,25(OH) D levels observed ↑ 2 ↑ ↑ D 2 D] of vitamin D in the kidney D are normal, they are normal, they are D are D is normally stimulated by 2 2 2 vitamin D intake, intestinal calcium ↓ -hydroxylase. This enzymatic defect -hydroxylase. α and phosphate absorption is reduced, and phosphate absorption is reduced, leading to hypocalcemia (secondary hyperparathyroidism), and leading to bone resorption or to normal serum calcium (toward levels) fish-liver foods, and fortified milk hyperparathyroidism conversion of 25(OH)D to 1,25(OH) nor vitamin D deficiency is present of 1,25(OH)2D production 1 the inactive inhibits conversion from form [25(OH)D] to the active [1,25(OH) for 1,25(OH) highest 1,25(OH) in humans; this vitamin D– distinguishes hereditary type I, dependent rickets type II from in which the level of 1,25(OH) located in the transport (probably this leads to failure nephron); proximal of phosphate in the of reabsorption kidney and “spilling” of phosphate (phosphate diabetes) in the urine 1,25(OH) to the low with regard inappropriately of of phosphaturia; production degree 1,25(OH) (see serum phosphorous form of rickets bone, liver) isoen nonspecific (kidney, zyme of alkaline phosphatase nostic Serum calcium stimulates PTH leads to enhanced renal Serum phosphate leads to Urinary phosphoethanolamine is diag COMMENTS With ↓ of vitamin D include sunlight, Sources Hypocalcemia leads to secondary ↑ Neither secondary hyperparathyroidism ↓ 25(OH)D is a defect in renal There defect is an intracellular receptor There have the Patients with this disorder in phosphate is an inborn error There Although the absolute levels of This is the most commonly encountered in the tissue- is an inborn error There ↑ - - mg/ g/day) of IU/day) μ D or (OH)D D 2 2 administration -hydroxylase] plus -hydroxylase] g/day of elemental α (1000–6000 day) of phosphate doses (1–2 1,25(OH) daily of high-dose vitamin D analogue [1,25(OH) 1 3 calcium (anti- burosumab FGF23 monoclonal antibody), second line elemental phosphate (1–2g/day plus vita min D 0.5–1 µg/day) tion is needed to counterbalance the hypocalcemic of phosphate effect administration, which otherwise could lead secondary to severe hyperparathyroidism medical therapy TREATMENT Oral vitamin D Oral calcium (1000 Oral supplementation Oral physiologic Long-term (3–6 mo) withFirst line treatment Vitamin D administra is no established There - - - - phatemia deformities rate hypotonia tetany of the long bones similar to those for vitamin D deficiency secondary hyper are parathyroidism observed similar to (but more than) those severe of nutritional rick ets due to vitamin D deficiency similar to (but than) severe more nutritional rickets caused by vitamin D deficiency secondary hyper parathyroidism 1. Hypophos 2. Lower limb 3. Stunted growth OTHER FINDINGS OR OTHER POSSIBLE FINDINGS Osteomalacia, Muscle weakness, Bowing deformities Rachitic rosary Clinical findings No changes of Osteomalacia Clinical findings Osteomalacia Alopecia Clinical findings Osteomalacia No changes of Classic triad: Osteomalacia Early loss of teeth ↑ URINARY URINARY CALCIUM ↓ ↓ None ↓ ↓ None or D 2 ↑ ↓ ↑ or none ↑ ↓ ↑ 1,25(OH) ↓ ↑ ↑ ↓ ↑ None None ↑ ↑ 25(OH)D ↓ None None None or None or None None PTH ↑ ↑ None ↑ ↑ None None ↓ ↓ ALKALINE PHOS ↑ ↑ ↑ ↑ ↑ ↑ ↓ CHANGES IN LEVEL OR CONCENTRATION

↓ ↓ SERUM PHOS ↓ ↓ ↓ ↓ ↓ ↓ ↑ , phosphatase.

phos or none or none SERUM CALCIUM ↓ ↓ None ↓ ↓ None ↑ - - Laboratory Findings and Clinical Data Regarding Patients With Rickets and Related Diseases With Rickets Laboratory Patients Findings and Clinical Data Regarding ------, increased; , increased;

↑ D] -

2 ets: vitamin D deficiency ets: calcium deficiency ets: phosphate deficiency min D–depen dent rickets type I (pseu do–vitamin D deficiency) vitamin D– dependent rickets type II [hereditary to resistance 1,25(OH) temic rickets (also known as vitamin D–resistant rickets and phosphate dia betes; Albright is syndrome an example of a hypo phosphatemic syndrome) tasia Table 1.16 Table DISORDER Nutritional rick Nutritional rick Nutritional rick vita Hereditary Hereditary Hypophospha Hypophospha , Decreased; , Decreased;

↓ Basic Sciences 25 - - tastasis low-turnover bone disease) lization deficiency NORMAL Osteoporosis Primary hyperparathyroidism Malignancy with bony me Multiple myeloma Lymphoma Hyperthyroidism Vitamin D intoxication (only Renal osteodystrophy Sarcoidosis Milk-alkali syndrome generalized immobi Severe Nutritional rickets: calcium Hypophosphatemic rickets Hypophosphatasia - - PHOSPHORUS LEVEL metastasis deficiency deficiency deficiency dent rickets (types I and II) tastasis DECREASED Primary hyperparathyroidism Malignancy without bony Nutritional rickets: vitamin D Nutritional rickets: calcium Nutritional rickets: phosphate vitamin D–depen Hereditary Hypophosphatemic rickets Malignancy with bony me Multiple myeloma Lymphoma Hypoparathyroidism Pseudohypoparathyroidism Renal osteodystrophy - - - tastasis lization deficiency deficiency dent rickets type II INCREASED Malignancy with bony me Multiple myeloma Lymphoma Vitamin D intoxication Hypoparathyroidism Pseudohypoparathyroidism Renal osteodystrophy Hypophosphatasia Sarcoidosis Milk-alkali syndrome generalized immobi Severe Primary hyperparathyroidism Nutritional rickets: calcium Nutritional rickets: phosphate vitamin D–depen Hereditary Sarcoidosis - - - deficiency deficiency phate deficiency tastasis low-turnover bone disease) lization NORMAL Osteoporosis Pseudohypoparathyroidism Nutritional rickets: vitamin D Nutritional rickets: calcium Nutritional rickets: phos Hypophosphatemic rickets Osteoporosis Malignancy with bony me Multiple myeloma Lymphoma Vitamin D intoxication (only Renal osteodystrophy Hypophosphatemic rickets Hypophosphatasia Sarcoidosis Hyperthyroidism Milk-alkali syndrome generalized immobi Severe - - - CALCIUM LEVEL turnover bone disease) deficiency deficiency dent rickets (types I and II) tastasis metastasis lization DECREASED Hypoparathyroidism Pseudohypoparathyroidism (high- Renal osteodystrophy Nutritional rickets: vitamin D Nutritional rickets: calcium vitamin D–depen Hereditary Malignancy with bony me Malignancy without bony Multiple myeloma Lymphoma Hyperthyroidism Vitamin D intoxication Sarcoidosis Milk-alkali syndrome generalized immobi Severe - - - Differential Diagnosis of Metabolic Bone Diseases Based on Blood ChemistryDifferential Findings

metastasis tastasis lization deficiency deficiency dent rickets (types I and II) Table 1.17 Table INCREASED Primary hyperparathyroidism Hyperthyroidism Vitamin D intoxication Malignancy without bony Malignancy with bony me Multiple myeloma Lymphoma Sarcoidosis Milk-alkali syndrome generalized immobi Severe Multiple endocrine neoplasias Addison disease administration Steroid Peptic ulcer disease Hypophosphatasia Pseudohypoparathyroidism Renal osteodystrophy Nutritional rickets: vitamin D Nutritional rickets: calcium vitamin D–depen Hereditary

26 Basic Sciences

• Familial hypocalciuric hypercalcemia Low serum Ca2+ • Poor renal clearance of calcium • Malignancy (most common) • Can be life threatening; commonly associated with muscle weakness • Initial treatment should include hydration with normal saline (reverses dehydration). • Can occur in the absence of extensive bone metastasis • Most commonly results from release of systemic growth factors and cytokines that stimulate ↑ PTH osteoclastic bone resorption at bony sites not involved in the tumor process (RANKL pathway) • PTH-related protein secretion (lung carcinoma) ↑ 1,25(OH) -vitamin D • Lytic bone metastases and lesions (e.g., multiple 2 3 myeloma) • Hyperthyroidism • Vitamin D intoxication • Prolonged immobilization

• Addison disease 2+ 2+ 2+ • Steroid administration ↑ Ca ↑ Ca ↑ Ca ↑ Pi ↑ Pi ↓ Pi • Peptic ulcer disease (milk-alkali syndrome) • Kidney disease • Sarcoidosis ↑ Serum Ca2+ • Hypophosphatasia – Serum Pi • Treatment of hypercalcemia • Hydration (saline diuresis) FIG. 1.17 Body’s reaction to hypocalcemia, with consequent resorp- • Loop diuretics tion of bone. When calcium level falls, PTH is secreted, which releases calcium and Pi from bone. PTH increases renal reabsorption • Dialysis (for severe cases) of calcium while inhibiting phosphate reabsorption. These actions in • Mobilization (prevents further bone resorption) combination restore calcium concentration. If hypocalcemia persists, • Specific drugs (bisphosphonates, mithramycin, PTH stimulates renal production of 1,25(OH)2D3, which increases calcitonin, and gallium nitrate) intestinal calcium absorption. (From Goldman L, Ausiello D, editors: Cecil n Hypocalcemia (Fig. 1.17) medicine, ed 23, Philadelphia, 2008, Saunders Elsevier.) • Findings • Low plasma calcium • Results from low levels of PTH or vitamin D3 • Exostoses • Neuromuscular irritability (tetany, seizures, Chvostek • Obesity sign), cataracts, fungal nail infections, ECG changes • Diminished intelligence (prolonged QT interval), and other signs and n Pseudo-pseudohypoparathyroidism (pseudo-PHP) symptoms • Normocalcemic disorder that is phenotypically similar n Hypoparathyroidism to PHP • Reduced PTH level causes decrease in plasma calcium • However, response to PTH is normal. level and increase in plasma phosphate level • Renal osteodystrophy (Fig. 1.18) • Urinary excretion not enhanced because of the lack • A spectrum of bone mineral metabolism disorders in of PTH chronic renal disease. • Common findings: • Due to impaired excretion, which compromises • Fungal nail infections mineral homeostasis • Hair loss • Leads to abnormalities in bone mineral metabolism • Blotchy skin (pigment loss, vitiligo) • High-turnover renal bone disease • Skull radiographs may show basal ganglia calcification. • Chronically elevated serum PTH level leads to • Iatrogenic hypoparathyroidism most commonly follows secondary hyperparathyroidism (hyperplasia of thyroidectomy. parathyroid gland chief cells). n Pseudohypoparathyroidism (PHP) • Factors contributing to sustained PTH increase • A rare genetic disorder caused by lack of effect of PTH and secondary hyperparathyroidism include: on the target cells • Diminished renal phosphorus excretion; • PTH is normal or high. phosphorus retention promotes PTH • PTH action is blocked by an abnormality at the secretion by three mechanisms: receptor, by the cAMP system, or by a lack of required • Hyperphosphatemia lowers serum calcium, cofactors (e.g., Mg2+) stimulating PTH. • Defect in GNAS gene from mother • Phosphorus impairs renal 1α-hydroxylase • Albright hereditary osteodystrophy, a form of PHP activity, impairing production of • Short first, fourth, and fifth metacarpals (MCs) and 1,25(OH)2D3. metatarsals (MTs) • Phosphorus retention may directly increase • Brachydactyly the synthesis of PTH. Basic Sciences 27

• Hypocalcemia • In amyloidosis, Congo red stain causes tissue • Impaired renal calcitriol [1,25(OH)2D3] material to turn pink. • Alterations in the control of PTH gene • Laboratory findings: transcription secretion • Abnormal glomerular filtration rate (GFR) • Skeletal resistance to the actions of PTH • Increased alkaline phosphatase, blood urea • Low-turnover renal bone disease (adynamic lesion of nitrogen (BUN), and creatinine levels bone and osteomalacia) • Decreased venous bicarbonate level • Secondary hyperparathyroidism is not • Treatment directed at relieving the urologic characteristic with this condition. obstruction or kidney disease • Serum PTH level is normal or mildly elevated. • Rickets (osteomalacia in adults; Box 1.1) • Bone formation and turnover are reduced. • Failure of mineralization leading to changes in • Excess deposition of aluminum into bone the physis in the zone of provisional calcification (aluminum toxicity) negatively affects bone (increased width and disorientation) and bone mineral metabolism. (cortical thinning, bowing) • Impairs differentiation of precursor cells to osteoblasts • Impairs proliferation of osteoblasts Box 1.1 Causes of Rickets and Osteomalacia • Impairs PTH release from the parathyroid gland NUTRITIONAL DEFICIENCY • Disrupts the mineralization process Vitamin D deficiency • Adynamic lesion: accounts for the majority of Dietary chelators (rare) of calcium cases of low-turnover bone disease in patients Phytates Oxalates (spinach) with chronic renal failure PHOSPHORUS DEFICIENCY (UNUSUAL) • Osteomalacia: defects in mineralization of newly Abuse of antacids (which contain aluminum), which leads to formed bone severe dietary phosphate binding • Radiographs may demonstrate a rugger jersey GASTROINTESTINAL ABSORPTION DEFECTS spine (vertebral bodies appear to have increased Postgastrectomy (rare today) Biliary disease (interference with absorption of fat-soluble density in the upper and lower zones in a striated vitamin D) appearance, like that in childhood osteopetrosis) Enteric absorption defects and soft tissue calcification. Short bowel syndrome Rapid transit (gluten-sensitive enteropathy) syndromes • 2-Microglobulin may accumulate with long-term β Inflammatory bowel disease dialysis, leading to amyloidosis. Crohn disease • Amyloidosis may be associated with carpal tunnel Celiac disease syndrome, arthropathy, and pathologic fractures. RENAL TUBULAR DEFECTS (RENAL PHOSPHATE LEAK) • X-linked dominant hypophosphatemic vitamin D–resistant rickets or osteomalacia • Classic Albright syndrome or Fanconi syndrome type I • Fanconi syndrome type II • Phosphaturia and glycosuria ↓↓ [Ca2+] Osteitis fibrosa • Fanconi syndrome type III • Phosphaturia, glycosuria, aminoaciduria • Vitamin D–dependent rickets (or osteomalacia) type I—a Decreased PTR ↑↑ PTH genetic or acquired deficiency of renal tubular 25(OH)D α1 - tubular hyperplasia Osteomalacia hydroxylase enzyme that prevents conversion of 25(OH)D to function the active polar metabolite 1,25(OH)2D • Vitamin D–dependent rickets (or osteomalacia) type II—which Decreased represents enteric end-organ insensitivity to 1,25(OH)D and is probably caused by an abnormality in the 1,25(OH) D nuclear 1,25(OH)2-vitamin D3 2 receptor) • Renal tubular acidosis Decreased • Acquired: associated with many systemic diseases GFR • Genetic Renal • Debré–De Toni–Fanconi syndrome osteodystrophy • Lignac-Fanconi syndrome (cystinosis) Phosphate • Lowe syndrome Renal retention RENAL OSTEODYSTROPHY: MISCELLANEOUS CAUSES failure Soft tissue tumors secreting putative factors Fibrous dysplasia K = [Ca2+][HPO 2–] ion 4 Neurofibromatosis Other soft tissue and vascular mesenchymal tumors Hypocalcemia Decreased Anticonvulsant medication (induction of the hepatic P450 absorption of microsomal enzyme system by some anticonvulsants—e.g., calcium and phosphate phenytoin, phenobarbital, and primidone [Mysoline]—causes increased degradation of vitamin D metabolites) Heavy metal intoxication Fecal loss of calcium Hypophosphatasia and phosphate High-dose diphosphonates Sodium fluoride FIG. 1.18 Pathogenesis of bony changes in renal osteodystrophy. PTR, proximal tubule reabsorption. (From McPherson RA, Pincus MR, Adapted from Simon SR, editor: Orthopaedic basic science, ed 2, editors: Henry’s clinical diagnosis and management by laboratory methods, ed 21, Rosemont, IL, 1994, American Academy of Orthopaedic Surgeons, Philadelphia, 2007, Saunders Elsevier.) p 169. 28 Basic Sciences

• Nutritional rickets (see Table 1.16) • Waddling gait • Vitamin D–deficiency rickets • Radiographic findings • Rare after addition of vitamin D to milk, except • Physeal widening and cupping in the following populations: • Coxa vara • Asian immigrants • Codfish vertebrae • Patients with dietary peculiarities • Retarded bone growth (defect in the • Premature infants hypertrophic zone, widened osteoid seams) • Patients with malabsorption (celiac sprue) • In affected children, height is commonly below • Patients receiving long-term parenteral nutrition the fifth percentile for age. • Decreased intestinal absorption of calcium and • Treatment with vitamin D (1000–6000 IU daily phosphate leads to secondary hyperparathyroidism. based on weight) resolves most deformities. • Laboratory findings • Calcium-deficiency rickets Fig.( 1.19) • Low-normal calcium level (maintained by • Phosphate-deficiency rickets high PTH level) • Hereditary vitamin D–dependent rickets • Low phosphate level (excreted because of the • Rare disorders with features similar to those of effect of PTH) vitamin D–deficiency (nutritional) rickets, except • Increased alkaline phosphatase level that symptoms may be worse and patients may • Low vitamin D level have total baldness • Increased PTH level leads to higher bone • Type I: defect in renal 25(OH)D 1α- absorption hydroxylase, inhibiting conversion of inactive • Physical examination vitamin D to its active form • Enlargement of the costochondral junction • Autosomal recessive inheritance (rachitic rosary) • Gene on chromosome 12q14 • Bowing of the knees • Type II: defect in an intracellular receptor for • Muscle hypotonia 1,25(OH)2D3 • Dental disease • Familial hypophosphatemic rickets (vitamin D–resistant • Pathologic fractures (Looser zones: pseudo rickets or phosphate diabetes) fractures on the compression sides of bones) • Most commonly encountered form of rickets • Milkman’s fracture • X-linked dominant inheritance

Nutritional Calcium Deficiency

FIG. 1.19 Nutritional calcium deficiency. (From Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 184.) Basic Sciences 29

• Impaired renal tubular reabsorption of phosphate • Related to poor calcium absorption • Normal GFR with an impaired vitamin D3 response • Hip and pelvic fractures are common. • Normal serum calcium, low serum phosphorus and 1, • Laboratory studies (OH)2D3, and high serum alkaline phosphatase levels • Obtained to rule out secondary causes of low bone • Treatment: mass: • First line treatment with burosumab (anti-FGF23 • Vitamin D deficiency, hyperthyroidism, monoclonal antibody) hyperparathyroidism, Cushing syndrome, • Second line elemental phosphate (1–2 g/day plus hematologic disorders, malignancy vitamin D 0.5–1 µg/day) • Complete blood cell count; measurements of • Hypophosphatasia serum calcium, phosphorus, 25(OH)D, alkaline • Autosomal recessive phosphatase, liver enzymes, creatinine, and total • Error in the tissue-nonspecific isoenzyme of alkaline protein and albumin levels; and measurement of phosphatase 24-hour urinary calcium excretion • Leads to low levels of alkaline phosphatase, which • Results of these studies are usually unremarkable in is required for synthesis of inorganic phosphate osteoporosis. (Pi) and important in bone matrix formation • Plain radiographs not helpful unless bone loss exceeds 30% • Features are similar to those of rickets. • Special studies • Increased urinary phosphoethanolamine is diagnostic. • Single-photon (appendicular) absorptiometry • Treatment may include phosphate therapy. • Double-photon (axial) absorptiometry n Conditions of bone mineral density • Quantitative computed tomography (CT) n Bone mass is regulated by rates of deposition and • Dual-energy x-ray absorptiometry (DEXA) withdrawal (Fig. 1.20). • Most accurate with less radiation n Osteoporosis • Biopsy • Age-related decrease in bone mass • After tetracycline labeling • Usually associated with estrogen loss in • To evaluate the severity of osteoporosis and identify postmenopausal women (Fig. 1.21) osteomalacia • A quantitative, not qualitative, defect • Histologic changes • Mineralization remains normal • Thinning trabeculae • World Health Organization’s definition • Decreased osteon size • Lumbar (L2–L4) density is 2.5 or more standard • Enlarged haversian and marrow spaces deviations less than mean peak bone mass of a • Treatment (Fig. 1.22) healthy 25-year-old (T-score). • Physical activity • Osteopenia: bone density is 1.0–2.5 standard • Supplements: 1000–1500 mg calcium plus 400– deviations less than the mean peak bone mass of 800 IU of vitamin D per day a healthy 25-year-old. • More effective in type II (age-related) osteoporosis • Responsible for more than 1 million fractures per year • Bisphosphonates • Fractures of the vertebral body are most common. • Inhibit osteoclastic bone resorption—direct • History of osteoporotic vertebral compression anabolic effect on bone fractures are strongly predictive of subsequent • Categorized into two classes on the basis of vertebral fracture. presence or absence of a nitrogen side group: • After initial vertebral fracture, the risk for a second • Nitrogen-containing bisphosphonates—up to vertebral fracture is 20%. 1000-fold more potent in their antiresorptive • Vertebral compression fracture is associated with activity increased mortality rate. • Zoledronic acid (Zometa) and alendronate • Incidence of vertebral compression fractures is (Fosamax) higher among men than women. • Inhibit protein prenylation within the • Lifetime risk of fracture in white women after mevalonate pathway, blocking farnesyl 50 years of age: 75% pyrophosphate synthase • The risk for hip fracture is 15%–20%. • Results in a loss of GTPase formation, • Risk factors (Box 1.2) which is needed for ruffled border • Cancellous bone is most affected. formation and cell survival • Clinical features • Non–nitrogen-containing bisphosphonates • Kyphosis and vertebral fractures • Metabolized into a nonfunctional ATP • Compression fractures of T11–L1 that create analogue, inducing apoptosis anterior wedge-shaped defects or centrally • Decreases skeletal events in multiple myeloma depressed codfish vertebrae • Associated with osteonecrosis of the jaw • Hip fractures • Orthopaedic implications of bisphosphonate use • Distal radius fractures • Spine—reduced rate of spinal fusion in • Type I osteoporosis (postmenopausal) animal model; withholding bisphosphonate is • Primarily affects trabecular bone recommended after surgery. • Vertebral and distal radius fractures common • Hip and knee—safe for use in cementless hip • Type II osteoporosis (age-related) arthroplasty and cemented knee arthroplasty; • Patients older than 75 years may decrease rate of acetabular component • Affects both trabecular and cortical bone subsidence 30 Basic Sciences

Four Mechanisms of Bone Mass Regulation

1. Stimulation of deposition 2. Inhibition of deposition Weight-bearing activity Lack of weight-bearing activity Growth Chronic malnutrition Fluoride Alcoholism Electricity Chronic disease Normal aging Hypercortisolism More (or more active) osteoblasts (B)

B B B B B B B Fewer (or less active) osteoblasts

Osteoblasts Level of Osteoblasts bone mass More (or more active) osteoclasts

C C C C C Fewer C C (or less active) osteoclasts (C)

Level of bone mass remains constant Osteoclasts when rate of Osteoclasts deposition equals 3. Inhibition of withdrawal rate of withdrawal 4. Stimulation of withdrawal Weight-bearing activity (osteoblastic activity More (or more active) Estrogen equals osteoclastic osteoclasts Testosterone activity), whether Lack of weight-bearing both rates are high, activity (disuse) Calcitonin low, or normal Space travel (weightlessness) Adequate vitamin D intake Hyperparathyroidism Adequate calcium intake (mg/day) Hypercortisolism Hyperthyroidism Child: 400–700 Estrogen deficiency Adolescent: 1000–1500 (menopause) Adult: 750–1000 Testosterone deficiency Pregnancy: 1500 Acidosis Lactation: 2000 Myeloma Postmenopause: 1500 Lymphoma Inadequate calcium intake Normal aging

Net increase in bone mass Net decrease in bone mass

FIG. 1.20 Four mechanisms of bone mass regulation. (From Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 181.)

• Fracture healing—no good data to recommend • Expensive and may cause hypersensitivity for or against use; will decrease future fracture reactions risk • Efficacy of bone augmentation with PTH, growth • Denosumab is a monoclonal antibody that targets factors, prostaglandin inhibitors, and other therapies and inhibits RANKL binding to the RANK receptor, remains to be determined. which is found on osteoclasts. • Prophylaxis for patients at risk for osteoporosis • Other drugs (e.g., intramuscular calcitonin) may be • Diet with adequate calcium intake helpful. • Weight-bearing exercise program Basic Sciences 31

1 mm

21-year-old woman 63-year-old woman 89-year-old woman FIG. 1.21 Age-related changes in density and architecture of human trabecular bone from the lumbar spine. With progressive age, there is a quantitative decrease in bone, but the mineralization (qualitative) remains the same.

Box 1.2 Risk Factors for the Development of Osteoporosis B O • White race, female gender, • Diet low in calcium and B northern European descent vitamin D N E O (fair skin and hair) • History of breastfeeding N • Sedentary lifestyle • Positive family history of L E • Thinness osteoporosis O • Smoking • Premature menopause G S HALT LOSS • Heavy drinking S A • Phenytoin (impairs vitamin D I N metabolism) • Phosphate • Calcium • Fluoride From Keaveney TM, Hayes WC: Mechanical properties of cortical and plus trabecular bone, Bone 7:285–344, 1993. • Bisphosphonates • Vitamin D • Alendronate -Calcium (Fosamax) -Vitamin D -Calcitonin • Estrogen therapy evaluation at menopause • Calcitonin (+Ca) • Extensive exercise n Other causes of decreased mineral density • Mild exercise (biomechanical- • Idiopathic transient osteoporosis of the hip (biomechanical- electrical coupling) • Uncommon; diagnosis of exclusion electrical coupling) • Most common during third trimester of pregnancy in • Pamidronate (Aredia) women but can occur in men • Raloxifene (Evista) • Groin pain, limited ROM, and localized osteopenia • Etidronate (Didronel) without a history of trauma • Tamoxifen • Treatment: analgesics and limited weight bearing FIG. 1.22 Treatment options for osteoporosis. (Adapted from Simon • Generally self-limiting and tends to resolve SR, editor: Orthopaedic basic science, Rosemont, IL, 1994, American Academy of spontaneously after 6–8 months Orthopaedic Surgeons, p 174.) • Stress fractures may occur. • Joint space remains preserved on radiographs. • Alcoholism • Osteomalacia • Radiographic findings • Femoral neck fractures are common. • Looser zones (microscopic stress fractures) • Qualitative defect • Other fractures • Defect of mineralization results in a large amount • Biconcave vertebral bodies of unmineralized osteoid. • Trefoil pelvis • Causes: • Biopsy (transiliac) required for diagnosis • Vitamin D–deficient diet • Widened osteoid seams are histologic findings. • GI disorders • Treatment: usually includes large doses of vitamin D • Renal osteodystrophy • Osteoporosis and osteomalacia are compared in • Certain drugs Fig. 1.23. • Aluminum-containing phosphate-binding • Scurvy antacids; aluminum deposition in bone prevents • Vitamin C (ascorbic acid) deficiency mineralization • Produces a decrease in chondroitin sulfate synthesis • Phenytoin (Dilantin) • Leads to defective collagen growth and repair 32 Basic Sciences

Comparison of Osteoporosis and Osteomalacia

Osteoporosis Osteomalacia Unmineralized Unmineralized Unmineralized matrix matrix matrix Definition

Mineralized Mineralized Mineralized matrix matrix matrix

Normal Bone mass decreased, Bone mass variable, mineralization normal mineralization decreased

Age at onset

Generally in old age, Any age after menopause

Vitamin D deficiency, abnor- Endocrine abnormality, mality of vitamin D pathway, age, idiopathic cause, inactivity, Etiology hypophosphatemic syndromes, disuse, alcoholism, renal tubular acidosis, calcium deficiency hypophosphatasia

Symptoms

Pain referable to fracture site Generalized bone pain Tenderness at fracture site Signs Tenderness at fracture site and generalized tenderness

Often symmetric; pseudofractures or completed fractures

Radiographic features

Axial predominance Appendicular predominance

Laboratory findings Serum Ca2+ Normal Low or normal (high in hypophosphatasia)

Serum Pi Normal Low or normal 2+ 2+ Ca x Pi >30 Ca x Pi >30 if albumin normal (high in renal osteodystrophy) Alkaline phosphatase Normal Elevated, except in hypophosphatasia Urinary Ca2+ High or normal Normal or low (high in hypophosphatasia) Bone biopsy Tetracycline labels normal Tetracycline labels abnormal

FIG. 1.23 Comparison of osteoporosis and osteomalacia. (From Netter FH: CIBA collection of medical illustrations, vol 8: Musculoskeletal system, part I: Anatomy, physiology and developmental disorders, Basel, Switzerland, 1987, CIBA, p 228.) Basic Sciences 33

• Also leads to impaired intracellular hydroxylation • Increased levels of lipoprotein(a) of collagen peptides • Commonly affects the hip joint • Clinical features: • Leads to collapse and flattening of the femoral head, • Fatigue most frequently the anterolateral region • Gum bleeding • Associated with the following conditions: • Ecchymosis • Steroids • Joint effusions • Heavy alcohol use • Iron deficiency • Blood dyscrasias (e.g., sickle cell disease) • Radiographic findings: • Dysbarism (caisson disease) • May include thin cortices and trabeculae and • Excessive radiation therapy metaphyseal clefts (corner sign) • Gaucher disease • Laboratory studies: normal results • Cause • Histologic features • Osteonecrosis may be related to enlargement of • Primary trabeculae replaced with granulation space-occupying marrow fat cells, which lead to tissue ischemia of adjacent tissues. • Areas of hemorrhage • Vascular insults and other factors may also be • Widening of the zone of provisional significant. calcification in the physis • Idiopathic (or spontaneous) osteonecrosis is • Greatest effect on bone formation in the diagnosed when no other cause can be identified. metaphysis • Chandler disease: osteonecrosis of the femoral head • Marrow packing disorders in adults • Myeloma, leukemia, and other such disorders can • Medial femoral condyle osteonecrosis: most common cause osteopenia. in women older than 60 years • Lead poisoning • Idiopathic, alcohol, and dysbaric forms of • Results in short stature and reduced bone density osteonecrosis are associated with multiple insults. • Lead alters the chondrocyte response to PTH-related • These may be secondary to a hemoglobinopathy protein and TGF-β. (e.g., sickle cell disease) or marrow disorder (e.g., n Increased osteodensity hemochromatosis). • Osteopetrosis (marble bone disease) • Cyclosporine has reduced the incidence of • Result of decreased osteoclast (and chondroclast) osteonecrosis of the femoral head among renal function: failure of bone resorption transplant recipients. • Osteopoikilosis (spotted bone disease) • Pathologic changes • Islands of deep cortical bone appear within the • Grossly necrotic bone, fibrous tissue, and medullary cavity and the cancellous bone of the long subchondral collapse (Figs. 1.24 and 1.25) bones • Histologic findings • Especially in the hands and feet • Early changes (14–21 days) involve autolysis of • These areas are usually asymptomatic osteocytes and necrotic marrow. • This disease is accompanied by no known incidence • Followed by inflammation with invasion of buds of malignant degeneration. of primitive mesenchymal tissue and capillaries • Paget disease of bone (osteitis deformans) • Newly woven bone is laid down on top of dead • Elevated serum alkaline phosphatase and urinary trabecular bone. hydroxyproline levels • Virus-like inclusion bodies in osteoclasts— abnormal function of osteoclasts • Both decreased and increased osteodensities may be present. • Depends on phase of disease • Active phase • Lytic phase: intense osteoclastic bone resorption • Mixed phase • Sclerotic phase: osteoblastic bone formation • Inactive phase n Conditions of bone viability n Osteonecrosis • Death of bony tissue from causes other than infection • Usually adjacent to a joint surface • Caused by loss of blood supply as a result of trauma or another event (e.g., SCFE) • Idiopathic osteonecrosis of the femoral head and Legg-Calvé-Perthes disease may occur in patients with FIG. 1.24 Fine-grain micrograph demonstrating space between ar- coagulation abnormalities. ticular surface and subchondral bone: crescent sign of osteonecro- • Deficiency of antithrombin factors protein C and sis. (From Steinberg ME: The hip and its disorders, Philadelphia, 1991, Saunders, protein S p 630.) 34 Basic Sciences

• Followed by resorption of dead trabeculae and n Decreases friction and distributes loads remodeling through creeping substitution • Coefficient of friction in healthy human joint is less • The bone is weakest during resorption and than that of ice on ice (0.002–0.04). remodeling. n Shock-absorbing cushion resists shear/compression. • Collapse (crescent sign on radiographs) and • Withstands impact loads up to 25 N/mm2 fragmentation can occur. n Avascular, aneural, and alymphatic • Evaluation • Receives nutrients and oxygen from synovial fluid via • A careful history (to discern risk factors) and diffusion physical examination (e.g., to discern decreased • Heals poorly ROM, limp) should precede additional studies. n Anisotropic: Properties vary with direction of force • Other joints (especially the contralateral hip) should n Viscoelastic: Properties vary according to rate of force be evaluated to identify the disease process early. application. • The process is bilateral in the hip in 50% of cases n Biphasic—property of liquid and solid of idiopathic osteonecrosis and up to 80% of cases n Cartilage homeostasis disrupted by: of steroid-induced osteonecrosis. • Direct trauma/excess or inadequate forces • MRI and bone scanning are helpful for early • Loss of underlying bone structure diagnosis. • Genetic defects in normal structure/function • MRI: earliest study to yield positive results; • Chemical/enzymatic threats highest sensitivity and specificity n Hyaline cartilage composition • Treatment n Water • Resurfacing arthroplasty of the hip is associated • Approximately 75% of cartilage with increased risk of implant loosening and failure. • Highest at surface or superficial layers • Total hip arthroplasty is indicated in Ficat stage III • Recurrent low-level forces shifts water in and out of or IV. extracellular matrix (ECM) • Nontraumatic osteonecrosis of the distal femoral • Responsible for nutrition and lubrication condyle and proximal humerus may improve • H2O decreases with aging spontaneously without surgery. • H2O increases in osteoarthritis (Fig. 1.26) • Precise role of core decompression remains n Collagen unresolved. • Makes up approximately 15% of wet weight (60% of • Results are best when core decompression is dry weight) (Fig. 1.27; Table 1.19) performed in early hip disease (Ficat stage I). • Type II collagen: 90%–95% of collagen • Osteochondrosis (Table 1.18) • Triple helix of α chains (derived from COL2A1 gene) • Can occur at traction apophyses in children • Genetic defects of type II cause achondrogenesis • May or may not be associated with trauma, joint capsule (lethal at birth), spondyloepiphyseal dysplasia inflammation, vascular insult, or secondary thrombosis congenita, precocious arthritis • Types IX and XI are “linking collagens” CARTILAGE AND JOINT • Type X found only near calcified cartilage, including: n Hyaline cartilage characteristics • Calcified zone of articular cartilage’s tidemark n Articular bearing surface • Hypertrophic zone of the physis (genetic defect of type X leads to Schmid metaphyseal A B chondrodysplasia) C • Fracture callus and calcifying cartilaginous tumors D • Provides shear and tensile strength

E Table 1.18 Common Types of Osteochondrosis DISORDER SITE AGE (YR) Van Neck disease Ischiopubic synchon- 4–11 drosis Legg-Calvé-Perthes Femoral head 4–8 disease Osgood-Schlatter disease Tibial tuberosity 11–15 Sinding-Larsen- Inferior patella 10–14 Johansson syndrome Blount disease in infants Proximal tibial epiphysis 1–3 Blount disease in Proximal tibial epiphysis 8–15 adolescents Sever disease Calcaneus 9–11 Köhler disease Tarsal navicular 3–7 Freiberg infarction Metatarsal head 13–18 Scheuermann disease Discovertebral junction 13–17 FIG. 1.25 Pathologic features of avascular necrosis. Illustration of Panner disease Capitellum of humerus 5–10 articular cartilage (A), necrotic bone (B), reactive fibrous tissue(C) , Thiemann disease Phalanges of hand 11–19 hypertrophic bone (D), and normal trabeculae (E). (From Steinberg ME: Kienböck disease Carpal lunate 20–40 The hip and its disorders, Philadelphia, 1991, Saunders, p 630.) Basic Sciences 35

Osteoarthritis Aging

Water content

Disorderly content in severe osteoarthritis Collagen Content remains Relative concentration relatively unchanged Collagen type VI

Also, length of protein Proteoglycan core and glycosaminoglycan content chains decrease

Proteoglycan synthesis

Proteoglycan Proteoglycan degradation

Chondroitin sulfate concentration Proteoglycan aggregate Chondroitin 4-sulfate concentration

Link protein Keratan sulfate H2 O concentration

Core protein H O Chondrocyte 2 size Hyaluronate Keratan sulfate Chondroitin sulfate

Chondrocyte Proteoglycan is an extracellular macromolecule number constructed of a protein core that binds with hyaluronan, collagen, and water to form a hydrated matrix of articular cartilage, yielding both lubricant and support functions.

Modulus of elasticity

FIG. 1.26 Articular cartilage changes in osteoarthritis and aging. Arrows indicate an increase (when pointing up) or a decrease (when pointing down). (From Brinker MR, Miller MD: Fundamentals of orthopaedics, Philadelphia, 1999, Saunders, p 9.) 36 Basic Sciences

Cartilage

Bone

Type II

Type Type Tendon Type I Ligament I I

EM banding

¼ Stagger array

Collagen molecule

Triple helix

Alpha chain

HO CH2 H2C Vit C CH2 C CH2 H N CH2 Hydroxylated amino acids H C N H C proline and lysine H COOH H COOH Proline Hydroxyproline

FIG. 1.27 Macrostructure to microstructure of collagen. Although the majority of the collagen in bone, tendon, and ligament is type I, most of the collagen in cartilage is type II. Collagen is composed of microfibrils that are quarter-staggered arrangements of tropocollagen. Note the hole and pore regions for mineral deposition (for calcification). Vitamin C (ascorbic acid) is an enzymatic cofactor needed to form the hydroxylated version of the amino acids proline and lysine, which allow the twists to form the triple helix from the polypeptide α chains. EM, Electron microscopy. (Modified from Brinker MR, Miller MD: Fundamentals of orthopaedics, Philadelphia, 1999, Saunders.)

Table 1.19 Collagen Types, Locations, and Related Genetic Disordersa TYPE LOCATION GENETIC DISEASE I Bone, tendon, meniscus Osteogenesis imperfecta Disc annulus, eye (sclera), skin Ehlers-Danlos syndrome II Articular cartilage Achondrogenesis (lethal) Disc nucleus pulposus, eye (vitreous humor) Hypochondrogenesis Spondyloepiphyseal dysplasia congenita Kniest dysplasia Stickler syndrome Precocious arthritis III Skin, blood vessels Ehlers-Danlos syndrome IV Basement membrane: kidney, ear, eye (basal lamina) Alport syndrome V Articular cartilage (in small amounts) Ehlers-Danlos syndrome VI Articular cartilage (in small amounts); tethers chondrocyte to pericellular matrix Bethlem myopathy Ullrich congenital muscular dystrophy VII Basement membrane (epithelial) Epidermolysis bullosa VIII Basement membrane (epithelial) Corneal endothelial dystrophy IX Articular cartilage (in small amounts) Multiple epiphyseal dysplasia (one type) X Hypertrophic zone or tidemark of cartilage (associated with calcified cartilage) Metaphyseal chondroplasia, Schmid type XI Articular cartilage (in small amounts); acts as an adhesive Otospondylomegaepiphyseal dysplasia XII Tendon XIII Endothelial cells aMore common orthopaedic diseases are in bold. Basic Sciences 37

• Contributes to viscoelastic behavior in that it • BMP-2 and the transcriptional factor SOX-9 restrains “swelling” of aggrecan important in regulating chondrocyte n Proteoglycans differentiation and formation • Make up approximately 10% of wet weight (30% of dry • Mechanotransduction—metabolism modulated via weight) (Fig. 1.28). mechanical stimulation • Half-life of 3 months • Cyclical loads of walking stimulate chondrocytes to • Provide compression strength form matrix • Responsible for cartilage’s porous structure • Low loads (1–5 MPa) at moderate frequency (≈1 Hz) • Trap and hold water • Primary cilia are the mechanosensory organ • Produced by chondrocytes “antennae” for cells. • Most common is aggrecan. • Produce the extracellular matrix of collagen and • Large macromolecules shaped like bristle brushes proteoglycans (see Fig. 1.28) • Intracellular synthesis of procollagen, link peptide, • Composed of repeating disaccharide subunits or hyaluronic acid, proteoglycans glycosaminoglycans attached to protein core • Extracellular assembly of component parts • Repeating carboxyl and sulfate groups which are • Produce proteins and enzymes and maintain matrix − − ionized in solution to COO and SO3 • IL-1β (also from synovium and WBCs): main • Repel each other but attract positive cations cartilage destroyer • Increase osmotic pressure, which traps and • Metalloproteinases—break down cartilage matrix holds water and is responsible for ECM’s • Collagenase—dissolves collagen (matrix hydrophilic behavior metalloproteinase 13 [MMP-13]) • Provides turgor of matrix • Aggrecanase—degrades proteoglycans • Chondroitin sulfate (most prevalent (extracellular protease enzyme ADAMT) glycosaminoglycan in cartilage) • Enzyme inhibitors—protect cartilage • Chondroitin 4-sulfate decreases with age • Tissue inhibitors of metalloproteinases (TIMPs) • Chondroitin 6-sulfate remains constant • Plasminogen activator inhibitor-1 (PAI-1) • Keratin sulfate • Chondrocytes are most dense and most active in the • Increases with age. superficial zone. • Multiple core proteins in turn attached to hyaluronic • Deeper cartilage zone chondrocytes less metabolically acid (through link proteins) producing proteoglycan active aggregate • Decreased rough endoplasmic reticulum n Chondrocytes • Increased intraplasmic filaments (degenerative • 1%–5% of wet weight products) • Only cells in cartilage n Other matrix components • Derived from undifferentiated mesenchymal precursors • Nonaggregating proteoglycans

O O OSO O O O Sugar bond O S O O O N O O N O O O O O O O O O O O O O O O O O S O O O O O O O S O O O N O O N O OOS O O O O O O O O O O O Chondroitin O Keratan Chondroitin sulfate

Proteoglycan aggrecan molecule Link Keratin protein sulfate

Hyaluronic Protein acid core

Proteoglycan aggregate FIG. 1.28 Proteoglycan aggregate and bristle brush–shaped aggrecan molecule. Sulfate ions are transmitted by DTDST protein; a defect in the DTSDT gene causes diastrophic dysplasia (short stature with hitchhiker’s thumbs and cauliflower ears).( Modified from Brinker MR, Miller MD: Fundamentals of orthopaedics, Philadelphia, 1999, Saunders, p 9.) 38 Basic Sciences

• Also known as small leucine-rich proteoglycans (SLRP) • Type X collagen found here • Important in matrix assembly and cell signaling n Articular cartilage damage and healing • Decorin and fibromodulin bind to type I and type II n Cartilage is avascular tissue with very limited healing collagens and organize and stabilize framework response • Other matrix proteins n Chondrocyte viability disrupted by: • Fibronectin—binds to integrins (transmembrane • High-impact loads—trauma or lacerations receptors) • Prolonged excessive stress—obesity, dysplasia, varus/ • Increased in osteoarthritis valgus • Chondronectin—mediates attachment of • Prolonged lack of stress—inactivity/disuse chondrocytes to type II collagen • Chemical issues: • Anchorin CII—binds chondrocytes to type II • Changes in pH: (normally at 7.4) collagen • Enzymes—metalloproteases n Articular cartilage layers (Fig. 1.29) • Laceration depth is key factor n Zone 1: superficial or tangential zone (10%–20% of • Lacerations above tidemark demonstrate thickness) chondrocyte cloning • Thin lamina splendens • Limited increases in numbers of chondrocytes • Flat chondrocytes • Limited repair • Collagen fibers • Lacerations extending below the tidemark into • Highest concentration subchondral bone • Parallel to joint surface strength against shear • Cause an inflammatory response • Greatest tensile stiffness • Marrow mesenchymal stem cells respond and • Lowest concentration of proteoglycans produce less durable fibrocartilage (type I • Highest concentration of water collagen) n Zone 2: middle or transition zone (40%–60% of • Forms the basis of the ICRS (International Cartilage thickness) Repair Society) grading system • Collagen fibers more random and less dense • Grade 0: normal cartilage • High levels of water and proteoglycan • Grade 1: nearly normal (superficial lesions) n Zone 3: deep zone (30% of thickness) • Grade 2: abnormal (lesions extend <50% of • Lower water content cartilage depth) • Highest concentration of proteoglycan • Grade 3: severely abnormal (>50% of cartilage depth) • Chondrocytes and collagen fibers arranged • Grade 4: severely abnormal (through the perpendicular to articular surface subchondral bone) n Zone 4: calcified cartilage zone n Blunt trauma and strenuous loading cause cell apoptosis • Begins at tidemark • Effects look similar to those of osteoarthritis • Transitions stiffness from flexible cartilage to rigid • Cartilage thinning and proteoglycan loss subchondral bone n Joint immobilization leads to atrophy or cartilage • Low concentration of proteoglycans degeneration

Articular Superficial cell Cartilage layers surface protein (also known as lubricin) Superficial zone Decorin and biglycan Layer Collagen Width (µm) Characteristic orientation Function Pericellular region (cell EM in layer) (decorin, type VI collagen) Middle zone Tangential Superficial ↓ Metabolic activity Highest [H O] (Gliding zone) 2 Opposes shear Highest [Lubricin] N 40 Flat chondrocytes Territorial region (more intact aggrecan) Oblique to vertical Deep zone Interterritorial region ↑ Metabolic activity Aggrecan most (degraded aggrecan) Cell size Middle zones ↑ C IF concentrated and Collagen size (Transitional and radial) ↑ Opposes collagen content at ↑ [Proteoglycan] compression its lowest here Lowest [H O] 500 – 1000 2 N

Tidemark Type X collagen Calcified zone Calcified zone Ca++ crystals N As an anchor Hypertrophic chondrocyte (Begins at tidemark) (Hydroxyapatite) opposes shear Type X collagen 300 Subchondral bone Subchondral bone marrow

FIG. 1.29 The layers of articular cartilage and their characteristics and functions. C, Cytoplasm; EM, electron micrograph; IF, intermediate filaments; N, nucleus. (Composite from Mark R. Brinker MR, Daniel P, O’Connor DP: Basic science. In Miller MD et al, editors: Miller orthopaedic review, Philadelphia, 2012, Saunders, Fig. 1.40; Buckwalter JA, Mankin HJ: Articular cartilage. Part I: tissue design and chondrocyte-matrix interactions, J Bone Joint Surg Am 79:600–611, 1997.) Basic Sciences 39

• Continuous passive motion is believed to benefit n Other periarticular tissue cartilage healing n Synovium • Four weeks of immobilization decreases proteoglycans/ • Loose connective tissue rich in capillaries collagen ratio • Lacks a basement membrane; no tight junctions • Ratio returns to normal after 8 weeks of joint • Type A synovial cells—macrophage-like mobilization • Involved in phagocytosis n Joint instability allows abnormal shearing loads • Type B synovial cells derived from mesenchymal cells— • Early (≈4 weeks): proteoglycan/collagen ratio is fibroblast-like decreased. • Produce synovial fluid and lubricin • Late (≈12 weeks): proteoglycan/collagen is elevated and • Lubricin hydration is increased. • Mucinous glycoprotein that binds to hyaluronic • Instability markedly reduces hyaluronan (disuse does acid not). • Also present in lamina splendens n Beneficial effects of exercise • Contributes to boundary lubrication • Increased glycosaminoglycans • Lubricant is present between two surfaces but • Runners may have increased cartilage thickness its thickness is inadequate to prevent contact • Likely due to chondrocyte modulation through throughout the surfaces mechanotransduction • Defect associated with camptodactyly- n Growth factors and cartilage injury arthropathy–coxa vara–pericarditis (CACP) • IL-1 stimulates MMP, COX-2, and nitric oxide syndrome synthetase, which degrades cartilage. • Elastohydrodynamic lubrication • TGF-β stimulates synthesis of ECM and decreases • Major mode of lubrication in joints activity of IL-1 and MMP’s • Lubricant pressure causes elastic deformation of • Also stimulates chondrogenesis in vitro the opposing surfaces. • BMP-2, BMP-7, and IGF-1 also stimulate ECM • This elastic deformation increases conformity. production n Synovial fluid n Changes with aging (see Fig. 1.26) • Ultrafiltrate of plasma n Decreased number of chondrocytes (but larger in size) • Hyaluronic acid, lubricin, proteinase, collagenases, and n Increased lysosomal enzymes prostaglandins n Senescence markers of chondrocytes include telomere • Nourishes and lubricates cartilage erosion, higher β-galactosidase expression, and reduced • Nonnewtonian fluid: shear thinning (thixotropic) Wnt2 expression • Viscosity decreases with increased shear rate. n Lower response to growth factors (TGF-β) • Normally contains no RBCs, WBCs, or clotting factors • Decreased matrix production and matrix maintenance • Joint fluid analysis − • Decreased chondroitin SO4 (but increased keratan • Noninflammatory arthritis − SO4 ) • Clear, straw color, high viscosity n Proteoglycan molecules smaller, so less able to hold • WBCs: fewer than 200 cells/μL, with 25% water (lower water content) polymorphonuclear leukocytes (PMNs) n Increase in advanced glycosylation end products • Inflammatory arthritis • Yellows and stiffens cartilage • Yellow-green tinged with low viscosity n Greater stiffness or modulus of elasticity but less tensile • WBC count: 2000–75,000 cells/μL, up to 50% strength PMNs • Increased decorin—decorates collagen for cross-links • Complement is decreased in rheumatoid arthritis • Increased collagen cross-links and diameter (RA) (normal in ankylosing spondylitis [AS]) n “Dried up old cartilage is yellow, weak, brittle, & stiff” • Crystals seen in gout and calcium pyrophosphate n Changes with osteoarthritis (dihydrate crystal) deposition disease (CPDD) n Increase in cells early (cloning) • Septic arthritis n Loss of smooth lamina leads to fibrillation/fissures. • Cloudy to opaque • Higher coefficient of friction • WBC count above 50,000–80,000 cells/μL n Chondrocytes react to IL-1β and TNF and produce nitric • Low glucose and high lactate may also be seen oxide • Traumatic n IL-1 stimulates MMPs, which degrade matrix. • Increased RBC and protein values • Collagenases (MMP-13)—first irreversible step • Concern for intraarticular fracture if fat globules • Aggrecanase—degrade proteoglycans (ADAMTs) present • Stromelysin • MRI neapolitan effusion—fat above plasma above • Decreased size and content of proteoglycan molecules RBCs − • Decreased keratan SO4 and increased chondroitin/ n Meniscus (labrum in hip/shoulder) keratan ratio • Increases contact area and distributes load • Increase in percentage of nonaggregated • Deepens the articular surfaces of various synovial glycosaminoglycans joints • Higher water content and greater permeability initially • 90% type I collagen followed by lower water content in later stages • Fibroelastic cartilage n Decreased modulus of elasticity (less stiff) and tensile • Fibrochondrocyte is responsible for meniscal healing strength • More elastic and less permeable than articular cartilage 40 Basic Sciences

• Blood supplies only the peripheral 25% of the knee menisci. • Leprosy (Hansen disease) • Nerve fibers found in peripheral two-thirds. • Second most common cause in upper extremity n Arthritides (Table 1.20) • Other neurologic problems n Osteoarthritis • Myelomeningocele: ankle and foot • Progressive loss of cartilage structure and function • Spina bifida and spinal trauma (seeFig. 1.33G) • Most common form of arthritis • Congenital insensitivity to pain • May be idiopathic n Rheumatoid arthritis (see Table 1.20) • May be secondary to: • Most common inflammatory arthritis • Genetics (Col2 defect); women affected more than men • Affects 0.5%–1% of population; three times more • Overload: obesity, labor, dysplasia/femoral acetabular common in women impingement, varus/valgus • 15% concordance rate in monozygotic twins • Trauma: fractures, ligament injuries, impact • Clinical presentation (see Fig. 1.32) • Tissue changes: • Insidious subacute onset over 6 weeks • Cartilage: enzymatic degradation and loss as • Fatigue, malaise, anemia discussed previously (Fig. 1.30) • Morning stiffness and polyarthritis with swelling • Synovium: inflammation, vascular hypertrophy • Hand and foot deformities are most common and • Ligaments: tightened on concave side of deformity are discussed in respective subsequent chapters • Bone: sclerosis, osteophytes, and subchondral cysts • Also common in the knees, elbows, shoulders, • Osteophyte formation due to pathologic ankles, and cervical spine activation of endochondral ossification by • Subcutaneous rheumatoid nodules (Fig. 1.34) periarticular chondrocytes through Indian • Juxtaarticular erosions and periarticular osteopenia on hedgehog (Ihh) mechanism radiographs • Muscles: atrophied from inactivity • 2010 American College of Rheumatology Classification • Radiographic findings Figs.( 1.31 and 1.32) Criteria for RA are summarized in Table 1.21. • Joint space narrowing, often asymmetric, with • Diagnosis requires score 6 or more osteophyte formation • Criteria include • Eburnation of bone • Number of joints involved and duration of • Subchondral cysts “geodes” involvement • Treatment discussed within individual chapters (see • Positive laboratory test results often found Chapter 5, Adult Reconstruction) • Erythrocyte sedimentation rate (ESR), C-reactive n Neuropathic arthropathy (Charcot joint disease) protein (CRP) • Extreme form of arthritis caused by disturbed sensory • Rheumatoid factor (RF) titer innervation • Antibody (immunoglobulin [Ig] M) against • Unstable, painless, swollen, red joint the Fc (crystallizable fragment) portion of IgG • Effusion may show hemarthrosis • Positive result in about 80% • Histologic findings: osteochondral fragments • Test for anticyclic citrullinated protein (anti- imbedded in synovium CCP) antibodies • Less pain than would be expected radiographically • Also known as anti-CCP antibodies (ACPAs) • Etiology: two theories • Most sensitive and specific test ≈( 90% • Neuropathic loss of proprioception specific) • Repetitive trauma causes microfractures • Presence linked to more aggressive disease • Hyperemia due to loss of sympathetic control • Pathogenesis • Stimulates osteoclasts, weakens bones • T cell–mediated immune response from an infectious • Radiographic findings Fig.( 1.33) or environmental antigen (smoking is one known • Severe destructive changes on both sides of the joint trigger) in a genetically susceptible individual (HLA- • Scattered “chunks” of bone embedded in fibrous tissue DR4 and HLA-DW4) • Joint distension by fluid • Mononuclear cells are primary mediator of RA tissue • Heterotopic ossification damage • Charcot arthropathy versus osteomyelitis • Initial response in soft tissues—neovascularization • May be difficult with physical examination and and synovitis radiograph • CD4+ T lymphocytes (helper cells) activate synovial • Both display swelling, warmth, and erythema and are cells through direct cell-cell contact common in diabetic patients • Synoviocytes produce cytokines • Indium (In) 111–labeled WBC scan results • Macrophages (type A): main source for TNF-α, IL-1 • “Hot” (positive) for osteomyelitis • Fibroblast (type B): main source for MMPs, • “Cold” (negative) for Charcot arthropathy proteases, and RANKL • Treatment includes bracing or casting (see Chapter 6) • B lymphocytes (plasma cells): make RF, anti-CCP • Neuropathic arthropathy also seen in antibodies • Syringomyelia (see Fig. 1.33C and D) • TNF-α, IL-1, IL-6, IL-7 upregulated • Most common cause of upper extremity • IL-1: Regulator of inflammation and matrix neuroarthropathy destruction • 80% of cases in shoulder and elbow (see Fig. 1.33D) • TNF-α: • Joint disease develops in 25% of patients with • Upregulates endothelial adhesion molecules and syringomyelia. stimulates angiogenesis Basic Sciences 41 - - - Continued osteotomy, TJA osteotomy, cated synovitis, reconstructive surgery matoid arthritis osteotomy sulfa? matoid arthritis disease, symptomatic therapy TREATMENT NSAIDs, arthrodesis, Brace; TJA contraindi Symptomatic Supportive for Pyramid treatment Drug therapy as for rheu ASA; 75% remission Supportive, dapsone? NSAID, Physical therapy, NSAID, Physical therapy, Drug therapy as for rheu for bowel Treatment - - - - ginatum nod ules, carditis pulmonary disease pancytopenia conjunctivitis, ulcer tivitis nodosum, pyoderma SYSTEMIC MANI SYSTEMIC FESTATIONS None None Erythema mar Spondylosis and Pericardial renal, Cardiac, Iridocyclitis, rash Otic, cardiac Uveitis Urethritis, Rash, conjunc Erythema - - - - ing, eburnation, cysts, osteo phytes topic bone calcification periarticular row, resorption osteopenia bamboo spine periostitis cup deformity RADIOGRAPHIC FINDINGS Asymmetric narrow Destruction/hetero Usually normal Destruction, disc Symmetric nar Less destruction Juxtaarticular late, Normal arthritis, Sacroiliac MT head erosion, DIP joint: pencil-in- Normal - disease tisic acid phosphatase, CPK, HLA-B27 HLA-B27 LABORATORY LABORATORY TESTS Nonspecific For underlying ASO titer Urine homogen RF ESR, CRP, ANA RF/ANA ESR ESR, alkaline ESR, WBC count, ESR, HLA-B27 ESR, HLA-B27 - - - - stable joint; rash claw toes joint; rash normal color volved chin on chest discharge, conjunctivitis digit, pitting trointestinal manifesta tions ROM, crepitus ROM, locking PHYSICAL PHYSICAL EXAMINATION ↓ un Effusion, Red, tender ↓ Ulnar deviation, Red, swollen Swollen joint, Eye, ear in Rigid spine, Urethral Rash, sausage Synovitis, gas - lower extrem ity joints spine joint, knee hip joints JOINTS Hip, knee, CMC Foot, ankle, Migratory; large joints/ Large Hands, feet PIP joint, MCP Knee, multiple All joints spine, Sacroiliac, Weight-bearing DIP joint, small Weight-bearing SYMMETRY Asymmetric Asymmetric Asymmetric Asymmetric Symmetric Symmetric Symmetric Symmetric Symmetric Asymmetric Asymmetric Asymmetric INCIDENCE BY SEX M > F M > F M = F M = F F > M F > M F > M M = F M > F M > F M = F M > F AGE GROUP AFFECTED Elderly Elderly Children Adults adults Young adults Young Children Elderly adults Young adults Young adults Young adults Young - Comparison of Common Arthritides Comparison of Common - -

fever erythemato sus rheumatoid arthritis chondritis spondylitis (Reiter syn drome) Table 1.20 Table ARTHRITIS NONINFLAMMATORY Osteoarthritis Neuropathic Acute rheumatic Ochronosis INFLAMMATORY Rheumatoid Systemic lupus Juvenile Relapsing poly SPONDYLOARTHROPATHIES Ankylosing Reactive arthritis Psoriatic Enteropathic

42 Basic Sciences - avoid surgery antibiotics amphotericin TJA atic therapy TREATMENT Colchicine, indomethacin Symptomatic therapy; I&D, intravenous Antibiotics ± I&D Penicillin, tetracycline 5-flucytosine, Support, synovectomy, Supportive and symptom excision Surgical - - - - - stones hyperparathy hypo roidism, thyroidism infection chronicum migrans rash, neurologic, cardiac mised bleeding necrosis SYSTEMIC MANI SYSTEMIC FESTATIONS renal Tophi, Ochronosis, chills, Fever, Lung, multiorgan Erythema Immunocompro Soft tissue osteo Infarcts, None erosions fibrocartilage calcified RADIOGRAPHIC FINDINGS Soft tissue swelling, Articular (late) Joint narrowing Both sides, cysts Usually normal Minimal changes patella Squared-off Osteonecrosis Juxtacortical erosion crystals rhombus- shaped crystals ESR, bacterial cultures cultures cultures preparation LABORATORY LABORATORY TESTS Uric acid: Birefringent Birefringent WBC count, PPD, AFB, ELISA Culture, Special studies/ factor VIII PTT, Sickle Aspirate, biopsy ROM ↓ partial thromboplastin time. partial thromboplastin swollen swollen swelling PTT, ROM, swelling PHYSICAL PHYSICAL EXAMINATION red, Tophi, Acute swelling Red, hot, Indolent, Acute effusion Indolent ↓ Pain, Pain, synovitis extremity extremity extremity extremity (elbow, shoulder) extremity JOINTS toe, lower Great Knee, lower Any joint Spine, lower Any joint Any joint Knee, upper Hip, any bone Knee, lower creatine phosphokinase; creatine CPK, SYMMETRY Asymmetric Asymmetric Asymmetric Asymmetric Asymmetric Asymmetric Asymmetric Asymmetric Asymmetric antistreptolysin O; antistreptolysin INCIDENCE BY SEX M > F M = F M = F M > F M = F M > F M M = F M = F ASO, AGE GROUP AFFECTED Young Elderly All Elderly Young All Young Young Young acid-fast bacilli; Comparison of Common Arthritides—cont’d Comparison of Common - -

AFB,

nosis ease villonodular synovitis ARTHRITIS DEPOSITION DISEASE CRYSTAL Gout Chondrocalci INFECTIOUS Pyogenic Tuberculous disease Lyme Fungal HEMORRHAGIC Hemophilia Sickle cell dis Pigmented Table 1.20 Table , Decreased; , Decreased; ↓

Basic Sciences 43

(from synoviocytes, chondrocytes, IL-1 neutrophils, monocytes, etc.)

CHONDROCYTE

Stromelysin (L) TPA

TIMP PAI-1 Plasminogen (from serum and Collagenase (L) synovial fluid)

Stromelysin (A) Plasmin (A) Matrix Proteoglycan proteins Collagen Collagenase (A)

MATRIX

Inhibitor Activator (L) Latent enzyme (A) Active enzyme Activation Inhibition Proteolytic action

FIG. 1.30 Enzyme cascade of IL-1–stimulated degradation of articular cartilage. TPA, Tissue plasminogen activator. (From Simon SR, editor: Ortho- paedic basic science, Rosemont, IL, 1994, American Academy of Orthopaedic Surgeons, p 40.)

A B

3 C D

FIG. 1.31 (A) Radiograph showing joint space narrowing, osteophytes, and bony sclerosis. (B) Macrosection of an osteoarthritic human femoral head demonstrating subarticular cysts, sclerotic bone formation, and a superior femoral head osteophyte. (C) Low-power micrograph of osteoarthritis showing fibrillation, fissures, and cartilage loss. D, Gross pathology of femoral head demonstrating cartilage thinning(1) , subarticular cyst (2 [“geode”]), and normal hyaline cartilage remaining (3). (A Courtesy Marc DeHart, MD, and Texas Orthopedics; B from Simon SR, editor: Orthopaedic basic science, Rosemont, IL, 1994, American Academy of Orthopaedic Surgeons; C and D from Horvai A: Bones, joints, and soft tissue tumors. In Kumar V et al, editors: Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Elsevier, Fig. 26-93.) 44 Basic Sciences

Rheumatoid arthritis Osteoarthritis

FIG. 1.32 Differences between rheumatoid arthritis and osteoarthritis. Left side of illustration demonstrates the main historical characteristics of RA, including symmetric involvement (both right and left joints as well as both medial and lateral compartments of the knees). Bilateral hand involvement is characteristic and usually involves wrist joints and proximal metacarpal joints. Right side of figure demonstrates osteoarthritis, which often is much more severe in one joint or one compartment of the knee. Hand involvement more commonly involves the distal interphalangeal joints (Heberden nodes) and proximal interphalangeal joints (Bouchard nodes) joints as well as the base of the thumb.

• Promotes influx of leukocytes and activates • Periarticular bone erosions synovial fibroblasts • Cytokines stimulate osteoblasts and synovial B • Promotes pain receptor pathways cells to make RANKL, which joins with RANK • Drives osteoclastogenesis to activate osteoclasts. Responsible for bone • Later response destruction. • Synovial cells invade cartilage “pannus” and release • Osteoclasts secrete cathepsin K and carbonic MMPs, causing chondrolysis anhydrase. Basic Sciences 45

C D

FIG. 1.33 Neuropathic arthritis. Arthritic degeneration due to lack of sensation can be caused by many diseases. All share radiographic findings that are more severe than the symptoms (often painless) and the fragments from bony destruction. Often findings take many years to develop. (A and B) Diabetic Charcot arthropathy of the foot is easily recognized by most of the industrialized world. (C and D) The most common cause of upper extremity neuropathic joint is syringomyelia (syrinx = fluid-filled sac in central cord that causes insidious loss of pain and temperature early). (E–G) Tabetic arthropathy (tertiary syphilis) is the most common neuropathic arthritis of the knee and can often involve the hip. (From Yablon CM et al: A review of Charcot neuroarthropathy of the midfoot and hindfoot: what every radiologist needs to know, Curr Probl Diagn Radiol 39:187–199, 2010; Atalar AC et al: Neuropathic arthropathy of the shoulder associated with syringomyelia: a report of six cases, Acta Orthop Traumatol Turc 44:328–336, 2010; and Allali F et al: Tabetic arthropathy. A report of 43 cases, Clin Rheumatol 25:858–860, 2006.) 46 Basic Sciences

ARTHRITIS TYPES DEMONSTRATED IN HANDS

Rheumatoid arthritis Osteoarthritis

Heberden Bouchard nodes nodes

B Heberden node

FIG. 1.34 Upper extremity changes in common arthritis types. Left side of figure shows rheumatoid changes. (A) Swan neck deformity of index, middle, and ring fingers, with PIP joints extended and DIP joints flexed. (B) Boutonnière deformity: PIP joints E flexed, DIP joints extended. (C) Bilateral wrist swelling with both ulnar metacarpal phalangeal joint deformities and swan neck deformities of fingers and left thumb. (D) Rheumatoid nodes noted on posterior olecranon region. Right side of figure shows osteoarthritic C changes. (E) DIP changes (Heberden nodes) and PIP changes (Bouchard nodes). (F) Radiograph showing osteoarthritic changes at the base of the thumb. (From O’Dell JD: Rheumatoid arthritis. In Goldman L, Schafer AI, editors: Goldman-Cecil medicine, Philadelphia, 2016, Elsevier, Fig. 264-3; Sweeney SE et al: Clinical features of rheumatoid arthritis. In Firestein GS et al: Kelley’s textbook of rheumatology, Philadelphia, 2013, Elsevier, Fig. 70-4; and http://medsci.indiana.edu/c60 D F 2web/602/c602web/jtcs/docs/heber1.html.)

• Systemic manifestations • DMARDs • Rheumatoid vasculitis • Intended to address underlying autoimmune • Distal splinter hemorrhage response • Cutaneous ulcers (pyoderma gangrenosum) • Conventional DMARDs take 2–6 months to • Visceral arteritis work • Pericarditis and pericardial effusion • Methotrexate: folate analogue • Pulmonary disease including nodules and fibrosis • Inhibits purine metabolism and T-cell activation • Felty syndrome: severe erosive RA with splenomegaly • Inhibits neovascularization and leukopenia • Adverse reactions (ADRs): toxic to bone marrow, • Treatments and their perioperative considerations liver, and lung • Regimen variable and often employs multiple agents • Usually can continue through surgery • NSAIDs: help symptoms early—antiinflammatory • Azathioprine: immunosuppressive agent effects • ADR: neutropenia • Should be held for 7–10 days preoperatively. • Cyclosporine: immunosuppressive agent • Low-dose steroids • Inhibits activation of CD4+ T cells • Decrease prostaglandins and leukotrienes • ADRs: nephrotoxicity, neurotoxicity, gingival • Used initially as “bridge therapy” to disease- hyperplasia modifying antirheumatic drugs (DMARDs) • Hydroxychloroquine (Plaquenil) • “Stress dose” steroid should be used perioperatively • Inhibits toll-like receptor 9 (TLR9) for patients on long-term steroid therapy • ADR: retinal toxicity (requires ophthalmology follow-up) Basic Sciences 47

Table 1.21 The 2010 ACR-EULAR Classification Criteria for • Heart/kidney—pericarditis/nephritis Rheumatoid Arthritis • Blood vessels—vasculitis • Clinical findings CRITERIA SCORE • Bone and joint involvement—most common A. JOINT INVOLVEMENT feature 1 Large Joint 0 • Nonerosive polyarthritis affects over 75% (hand 2–10 Large Joints 1 and wrist most common). 1–3 Small Joints 2 • Osteonecrosis (especially with steroids) 4–10 Small Joints 3 >10 Joints (at least 1 small joint) 5 • Butterfly malar rash—classic feature B. SEROLOGY (at least 1 test result is needed) • Fever, pancytopenia Negative RF and negative ACPA 0 • Pharmacologic treatment similar to that for RA. Low-positive RF or low-positive ACPA 2 n Seronegative spondyloarthropathies High-positive RF or high-positive ACPA 3 • Characterized by negative RF titer result and, often, C. ACUTE-PHASE REACTANTS (at least 1 test result is needed) positive HLA-B27 test result Normal CRP and normal ESR 0 Abnormal CRP or abnormal ESR 1 • Symptoms D. DURATION OF SYMPTOMS • Inflammatory back pain <6 weeks 0 • Peripheral arthritis >6 weeks 1 • Enthesitis—heel pain • Dactylitis—sausage digit From Aletaha D et al: 2010 rheumatoid arthritis classification criteria: an • American College of Rheumatology/European League Against Rheu- Eye—uveitis (iritis), conjunctivitis matism collaborative initiative, Arthritis Rheum 62:2569–2581, 2010. • Skin, mucosal, GI, urethral • Similar treatment routines, including NSAIDs, steroids, and DMARDs • Usually can continue through surgery n Ankylosing spondylitis (AS) (Fig. 1.36; see Table 1.20) • Sulfasalazine • Male/female ratio 3:1; ages 20–40 years • Decreases synthesis of inflammatory mediators • Most common in Northern European whites • ADRs: granulocytopenia, hemolytic anemia • 90% HLA-B27 positive (Table 1.22) (glucose-6-phosphate dehydrogenase [G6PD]) • Symptoms and findings • Usually can continue through surgery • Bilateral sacroiliitis (earliest symptom) • Minocycline • Improves with exercise, not better with rest, pain at • Inhibits MMP collagenase night • ADR: cutaneous hyperpigmentation • Associated morning stiffness • Biologic DMARDs • Progressive spinal flexion deformities over life • Target TNF-α: etanercept, infliximab, • Chin-on-chest deformity adalimumab • Modified Schober test (loss of lumbar flexion) (see • Targets IL-1: anakinra Fig. 1.36C) • Targets CD20: rituximab • Two marks are made10 cm apart over lumbar • Surgery should be scheduled at end of dosing spine in erect patient. cycle (e.g., in a patient taking etanercept • With patient in maximum spinal flexion, schedule, surgery should occur the second week increase of less than 4 cm between marks after the first withheld dose). indicates loss of flexion. • Risks of opportunistic infection and • Hip involvement at young age—poor prognosis lymphoma • Enthesitis: inflammation of tendon insertion • Surgical treatment is discussed within respective • Loss of chest expansion chapters. • Uveitis: red, painful eye in 40% n Juvenile idiopathic arthritis (JIA) is discussed in Chapter 3, • Aortic insufficiency and heart block Pediatric Orthopaedics. • Radiographic changes n Systemic lupus erythematosus (Fig. 1.35; see Table 1.20) • Squaring of the vertebrae • Chronic inflammatory disease of unknown origin • Vertical syndesmophytes • 90% of cases in women (blacks > whites) • Bamboo spine • Initially mediated by tissue-binding autoantibodies and • Autofusion of sacroiliac joints (see Fig. 1.36B) immune complexes (type III hypersensitivity) • Whiskering of the entheses • Pathophysiology • Surgical treatment for AS is discussed within Chapter 8, • Susceptible genetics stimulated by environment Spine. • Immune system autoregulatory failure n Reactive arthritis (Reiter syndrome) (Fig. 1.37; see Table • Sustained production of antibody to self-antigens 1.20) • Antinuclear antibodies (ANAs)—best screen; positive • Classical triad presentation: “Can’t see, can’t pee, can’t in 95% climb a tree.” • Anti-dsDNA, anti-Sm, anti-La (SS-B), antihistone • Young white males (18–40 years) antibodies—drug-induced lupus • Follows an infection at another site (hence “reactive”) • Immune complexes accumulate in various tissues • Chlamydia, Shigella, Yersinia, Salmonella and cause chronic inflammation • Findings • Skin/joints—rash and arthritis • Conjunctivitis, urethritis, and oligoarticular arthritis 48 Basic Sciences

Heavy chain Light chain Disulfide bond

V Domain

(binds to antigen) C Domain (activates

A complement and phagocytes) Antibody

D E

FIG. 1.35 Systemic lupus erythematosus. (A) Autoantibodies to DNA and DNA-binding proteins form immune complexes that stimulate immune system–directed inflammation throughout the body (type III hypersensitivity reaction). (B) Direct immunofluorescence with anti–immunoglobulin G antibodies shows immune complex deposits at two different places: a bandlike deposit along the epidermal basement membrane—positive result of lupus band test—and within the nuclei of the epidermal cells (ANAs). (C) Most patients have skin and joint involvement. The classic butterfly rash of SLE occurs in 10%–50% of patients with acute SLE. (D) The same immune complexes are seen in the basement membrane of the renal glomerulus. (E) Flea-bitten appearance of kidney specimen, with lupus nephritis causing various degrees of proteinuria, hematuria, and cellular casts. (From Habif TP: Clinical dermatology, ed 5, St Louis, Mosby/Elsevier, 2009; Wikimedia Commons: Diffuse proliferative lupus nephritis. http://en.wikipedia. org/wiki/Lupus_nephritis#mediaviewer/File:Diffuse_proliferative_lupu C s_nephritis.jpg ; and Wikimedia Commons: Lupus band test. http://en.wikipe dia.org/wiki/Systemic_lupus_erythematosus#mediaviewer/File:Lupu s_band_test.jpg.)

• Sudden asymmetric swelling and pain in knee, ankle, • Painless mucocutaneous ulcers (penile) and oral hip stomatitis (see Fig. 1.37B) • May persist 3–5 months • Urethritis (dysuria), prostatitis, or cervicitis • Feet affected more often than hands (heel pain) • Pustular lesions on the extremities, palms, and soles • Calcaneal periostitis and metatarsal head erosion (keratoderma blennorrhagicum) • Dactylitis: sausage digit of one finger/toe (seeFig. 1.37E) • Treatment: NSAIDs and PT • 60% of patients with chronic disease have sacroiliitis. Basic Sciences 49

n Psoriatic arthropathy (PsA) (see Table 1.20) • Affects 5%–30% of patients with psoriasis • Usually skin disease precedes arthritis • Men and women (aged 30–40 years) equally affected • Characteristic changes • Distal interphalangeal (DIP) involvement (rare in other inflammatory arthritides) • Nail changes in 90% • Pitting, fragmentation, and discoloration • 30% have sausage digits • Prominent enthesitis and tenosynovitis • Arthritis mutilans—most destructive form • Telescoping (shortening) of digits • Pathophysiology • Upregulated RANKL in synovium (B-type cells) A • Marked increase in osteoclast precursors • Radiographic findings • Pencil-in-cup deformity, DIP • Small joint ankylosis • Osteolysis of metacarpal (MC) and phalangeal bone • Periostitis and bony enthesitis n Enteropathic arthritis (see Tables 1.20 and 1.22) • Arthritis in presence of inflammatory bowel disease • Varied clinical picture, but joint erosions uncommon • 10%–50% of patients experience peripheral joint arthritis. • Acute monoarticular synovitis precedes bowel symptoms. • Nondeforming arthritis • More common in large weight-bearing joints • 10%–15% of cases associated with ankylosing spondylitis n Crystal deposition arthropathy n Pathology from accumulation of crystal formation or B deposition in or around joints • Gout: monosodium urate • CPDD, also called pseudogout: calcium pyrophosphate • Tumoral calcinosis: calcium apatite • Calcium oxalate n Gout (see Table 1.20) 10 cm 15 cm • Disorder of purine nucleic acid metabolism, causing hyperuricemia • Deposition of monosodium urate crystals in joints • Crystals activate inflammatory mediators • Inflammatory mediators are inhibited by colchicine. • Attacks precipitated by dehydration, excess alcohol or dietary purines, chemotherapy C • Diagnosis • Recurrent acute joint pain • Men aged 40–60 years, postmenopausal women FIG. 1.36 Ankylosing spondylitis is an axial seronegative spondy- • Usually lower extremity, great toe (podagra) loarthropathy that causes progressive cervical and thoracic kyphosis • Crystal deposition as tophi when chronic and bamboo spine but has earliest involvement in the sacroiliac joints. (A) Early sacroiliitis demonstrated by loss of clarity and scle- • Ear helix, eyelid, olecranon, Achilles tendon rosis in the lower third of the sacroiliac joints, particularly affecting • Renal disease or stones—second most common site the iliac side of the right sacroiliac joint (hip joints are normal). (B) • Radiographic findings Advanced disease with ankylosis or fusion of both the sacroiliac and • Soft tissue swelling early: edema, tophi hip joints. (C) Schober test; two marks made 10 cm apart on lumbar • Punched-out or rat bite periarticular erosions spine in erect stance should be less than 14 to 15 cm during forward flexion.( From Raychaudhuri S: The classification and diagnostic criteria of anky- • Sclerotic overhanging borders losing spondylitis, J Autoimmun 48–49:128–133, 2014.) • Synovial fluid findings • Concomitant septic arthritis must be ruled out • WBC count: wide range (5,000–80,000 cells/μL; average, 15,000–20,000 cells/μL), mostly PMNs 50 Basic Sciences

Table 1.22 Associations Between HLA Alleles and Susceptibility to Some Rheumatic Diseases FREQUENCY (%) IN FREQUENCY (%) IN DISEASE HLA MARKER PATIENTS (WHITES) CONTROLS (WHITES) RELATIVE RISK Ankylosing spondylitis B27 90 9 87 Reactive arthritis (Reiter syndrome) B27 79 9 37 Psoriatic arthritis B27 48 9 10 Inflammatory bowel disease with spondylitis B27 52 9 10 Adult rheumatoid arthritis DR4 70 30 6 Polyarticular juvenile rheumatoid arthritis DR4 75 30 7 Pauciarticular juvenile rheumatoid arthritis DR8 30 5 5 DR5 50 20 4.5 DR2.1 55 20 4 Systemic lupus erythematosus DR2 46 22 3.5 DR3 50 25 3 Sjögren syndrome DR3 70 25 6

Adapted from Nepom BS, Nepom GT: Immunogenetics and the rheumatic diseases. In McCarty DJ, Koopman WJ, editors: Arthritis and allied conditions: a textbook of rheumatology, ed 12, Philadelphia, 1993, Lea & Febiger.

FIG. 1.37 Reactive arthritis (formerly Reiter syndrome). (A) Conjunctivitis. (B) Circinate balanitis (urethritis not shown). (C) Oligoarthritis (single knee effusion). (D) Fluffy calcaneal periostitis. (E) Dactylitis (sausage digit). (From Miller MD et al: Review of orthopaedics, ed 6, Philadelphia, 2012, Saunders; and Wu IB, Schwartz RA: Reiter’s syndrome: the classic triad and more, J Am Acad Dermatol 59:113–121, 2008.) Basic Sciences 51

• Yellow, needle-shaped crystals when parallel to • Severe degenerative joint disease compensator (Fig. 1.38A) • Calcific tendinitis of rotator cuff and hip abductors • Strong negative birefringence • Destructive arthropathy can occur in the knee and • Treatment: shoulder. • NSAIDs and colchicine (microtubule inhibitor that • Milwaukee shoulder: calcium phosphate deposition inhibits mitosis) for acute attack with cuff tear arthropathy • Chronic/maintenance therapy n Calcium oxalate deposition • Weight loss, low-purine diet, limit of alcohol intake • Primary oxalosis—rare genetic defect of liver enzymes • Probenecid: uricosuric agent • Alanine glyoxylate aminotransferase (AGT) • Allopurinol: xanthine oxidase inhibitor • Glyoxylate reductase (GR) • Febuxostat in renally impaired patients • Nephrocalcinosis, renal failure, and death by age 20 n Pseudogout (see Table 1.20) years • Deposition of calcium pyrophosphate dehydrate • Treatment: liver/kidney transplantation (CPPD) crystals in joints • Secondary oxalosis—more common • Associated with lupus, renal dialysis, hemochromatosis, • Metabolic abnormalities of chronic renal hyperparathyroidism, RA, Wilson disease insufficiency • Chondrocalcinosis • Associated with calcium oxalate arthritis/periarthritis • Calcification within hyaline or fibrocartilage or menisci and nephrolithiasis • Seen in pseudogout but also in other conditions • Diagnosis: synovial fluid usually contains fewer than • Genetic version: ANKH gene mutation 2000 WBCs/μL. • Increases extracellular pyrophosphate • Birefringent bipyramidal crystals (see Fig. 1.38C) • Synovial fluid findings n Hemophilic arthropathy (Fig. 1.39) • WBC counts 5000–100,000 cells/μL (average, n X-linked recessive defect of factor VIII (A) or IX (B); 24,000 cells/μL) discussed further in Chapter 3, Pediatric Orthopaedics • Rhomboid-shaped crystals in WBCs n Decreased ROM and eventually ankylosis • Weakly positively (blue) birefringent when parallel n Pathophysiology (see Fig. 1.38B) • Recurrent bleeds and chronic synovitis • Radiographic findings: fine linear calcification in • Synovial hypertrophy/hyperplasia hyaline cartilage and more diffuse calcification • Iron-laden phagocytic type A synovial cells of menisci and other fibrocartilage (triangular • Synovium destroys cartilage fibrocartilage complex, acetabular labrum) n Radiographic findings • Treatment with NSAIDs and, potentially, steroid • Flat condylar surface and widened notch in knee injection • Inferior patellar squaring n Calcium hydroxyapatite crystal deposition disease • Talar flattening in ankle • Apatite is primary crystal of normal bone. n Treatment • Accumulates abnormally in areas of tissue damage or • Early: prevention of bleeds/factor replacement in hypercalcemic or hyperparathyroid states (chronic • Radiation ablation of synovium with yttrium (Y) 90 kidney disease [CKD]) microspheres and phosphorus (P) 32 colloid • Associated with • Late: arthroplasty • Acute attacks of bursitis/synovitis

ABCD E

FIG. 1.38 Synovial fluid crystals. (A) Gout: yellow uric acid parallel to compensator, most common in first metatarsophalangeal joint. (B) Cal- cium pyrophosphate (dihydrate crystal) deposition disease (CPDD) or pseudogout crystals: blue rhomboid crystals (arrow) most common in knees and wrists. (C) Calcium oxalate crystals (arrow) are pyramidal and almost exclusively seen in patients with renal damage and oxalosis. (D) Platelike cholesterol crystals are rare and can be found in inflammatory synovial fluid and in fluids drained from bursas of patients with rheumatoid arthritis, systemic lupus erythematosus, and seronegative spondyloarthropathy. (E) Calcium apatite crystals from tumoral calcinosis on histology slide from tissue. (From McPherson RA, Pincus MR, editors: Henry’s clinical diagnosis and management by laboratory methods, ed 21, Philadelphia, 2007, Saunders Elsevier; Firestein GS et al, editors: Kelley’s textbook of rheumatology, ed 8, Philadelphia, 2008, Saunders; Courtney P, Doherty M: Joint aspiration and injection and synovial fluid analysis,Best Pract Res Clin Rheumatol 23:161–192, 2013; Martínez-Castillo A et al: Synovial fluid analysis, Rheumatol Clin 6:316–321, 2010; and Topaz O et al: A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis, Am J Hum Genet 79:759–764, 2006.) 52 Basic Sciences

MUSCLE • Extends into cell surrounding myofibrils • Forms the transverse tubules (Fig. 1.41). n Skeletal muscle anatomy (Fig. 1.40) • Multiple nuclei: typically located adjacent to n Cellular anatomy sarcolemma • Sarcolemma: plasma membrane surrounding cell • Sarcoplasmic reticulum (SR) • Smooth endoplasmic reticulum that surrounds the individual myofibrils • Stores calcium in intracellular membrane–bound channels. • Ryanodine receptors (e.g., RYR-1) regulate the release of calcium from the SR and serve as a connection between the SR and sarcolemma-derived transverse tubule. • Abnormality of ryanodine receptors is implicated in persons susceptible to malignant hyperthermia. • Dantrolene decreases loss of calcium from the SR. n Contractile elements • Sarcomere: basic functional unit of muscle contraction • Myofibrils A • Set of sarcomeres parallel to axis of cell • (1–3 μm in diameter and 1μ2 cm long) • Sarcomere organization causes the banding pattern (striations) seen in skeletal muscle (Table 1.23; see Fig. 1.40). • Costamere connects the sarcomere to the sarcolemma at the Z disc. • Z disc (or line) represents terminus of sarcomere • Contains desmin, α-actinin, and filamin • A-band (or dark band) represents thick filaments. • Thick filaments composed of myosin • Also contains myosin [H-band], M protein, C protein, titin, and creatine kinase • I-band represents thin filaments. • Primarily composed of actin • Also contains B C • Troponin: has binding site for Ca • Tropomyosin: prevents myosin-actin interaction • Attach to Z disc • Involved in delayed-onset muscle soreness (DOMS) n Gross anatomy • Fascia (tough connective tissue) covers muscle and allows sliding. • Epimysium (more delicate) surrounds bundles of fascicles. • Perimysium surrounds individual muscle fascicles (hundred of muscle fibers). • Endomysium surrounds individual myofibers. • Stretch receptors • Muscle spindles: located within muscle, transmit D E muscle length to CNS, control muscle stiffness • Golgi tendon organ: located at musculotendinous FIG. 1.39 Hemophilic arthropathy. (A) Recurrent knee effusions and synovitis. (B) Radiograph of end-stage arthropathy. (C) Synovial junction, helps prevent excess tendon lengthening proliferation of hemophilic arthropathy demonstrates phagocytic • Myotendinous junction (type A) synovial cells laden with iron pigment but no giant cells, • Often the site of tears with eccentric contraction polymorphonuclear leukocytes, and rare lymphocytes. (D) Bloody (forced lengthening of the myotendinous junction ankle effusion presentation of teen whose grandfather had a history during contraction), which places maximum stress of bleeding disorder. (E) End-stage hemophilic arthropathy of ankle demonstrates flattening of the talus(arrow) . (From Rodriguez-Merchan EC: across this area Musculoskeletal complications of hemophilia, HSS J 6:37–42, 2010; Mainardi CL • Myofilament bundles are linked directly onto et al: Proliferative synovitis in hemophilia: biochemical and morphologic observa- collagen fibrils, with sarcolemma filaments tions, Arthritis Rheum 21:137–144, 1978; photo courtesy Texas Orthopedics Sports interdigitating with the basement membrane (type IV Medicine and Rehabilitation; and Rodriguez-Merchan EC: Prevention of the muscu- collagen) and tendon tissue (type I collagen). loskeletal complications of hemophilia, Adv Prev Med 2012:201271, 2012.) Basic Sciences 53

Epimysium

Perimysium

Endomysium

Fascicle

Fiber

Myofibril

Thin filament Z M Z line line line Thick filament

H band

I band A band I band

FIG. 1.40 Skeletal muscle architecture. (From Brinker MR, Miller MD: Fundamentals of orthopaedics, Philadelphia, 1999, Saunders, p 10.)

Myofibrils

Table 1.23 Sarcomere Transverse tubule BAND DESCRIPTION Lateral sacs A band Contains actin and myosin I band Contains actin only Cisternae H band Contains myosin only M line Interconnecting site of the thick filaments Z line Anchors the thin filaments

Triad From Brinker MR, Miller MD: Fundamentals of orthopaedics, Philadel- phia, 1999, Saunders, p 11.

FIG. 1.41 Sarcoplasmic reticulum. Action potentials travel down the transverse tubules, causing release of calcium from the outer vesicles. (From DeLee JC et al, editors: DeLee and Drez’s orthopaedic sports medicine: principles and practice, ed 3, Philadelphia, 2009, Saunders.) 54 Basic Sciences

Neuromuscular junction

Muscle fibers

Motor neuron from ventral horn of the spinal cord A B Axon

End plate region

Myelin Mitochondrion Nerve

Schwann Nerve Microtubules terminal cell Active zone or Basement release site membrane Synaptic Acetylcholinesterase space

Primary Acetylcholine cleft receptors Muscle Secondary cleft Actin-myosin complex Na+ channels

D FIG. 1.42 Structure of the adult motor end plate (neuromuscular junction). (A) Motor nerve. (B) Nerve branches that innervate many individual muscle fibers. (C) Presynaptic boutons, which terminate on the muscle fiber. (D) Nerve terminal.( From Miller RD et al: Miller’s anesthesia, ed 7, Philadel- phia, 2010, Churchill Livingstone.)

n Muscle physiology • ACh diffuses across the synaptic cleft (50 nm) and n Motor unit binds to postsynaptic receptors on sarcolemma, which • The α-motoneuron and the myofibers it innervates begin depolarization. • Each myofiber is innervated by a single axon but an • Myasthenia gravis is due to IgG antibodies to the axon can innervate multiple myofibers Ach receptor. Manifests initially as ptosis and • Smaller and more delicate muscles have fewer diplopia. Weakness worse with muscle use. myofibers per motor unit (<5 fibers per unit in • Botulinum A injections reduce spasticity by blocking extraocular muscles but as many as 1800 fibers per presynaptic acetylcholine release. Commonly used unit in gastrocnemius muscle) for spastic muscles in cerebral palsy. n Contraction • Agents affecting impulse transmission are listed in • Response to mechanical or electrochemical stimuli Table 1.24. generated at the motor end plate (neuromuscular • Sarcoplasmic reticulum releases calcium. junction) where the axon contacts an individual • Ca binds to troponin and causes conformational myofiber Fig.( 1.42). change, which stops tropomyosin inhibition of myosin- • Depolarization reaches motor neuron axon terminal, actin cross-bridges. and acetylcholine (ACh) is released from presynaptic • Myosin binds to actin, hydrolyzes ATP, and “pushes” vesicles. actin on thin filament, leading to muscle contraction. Basic Sciences 55

Table 1.24 Agents That Affect Neuromuscular Impulse Transmission AGENTS SITE OF ACTION MECHANISM EFFECT Nondepolarizing drugs (curare, Neuromuscular junction Competitively bind to acetylcholine Paralytic agents (long term) pancuronium, vecuronium) receptor to block impulse transmission Depolarizing drugs Neuromuscular junction Bind to acetylcholine receptor to cause Paralytic agents (short term) (succinylcholine) temporary depolarization of muscle membrane Anticholinesterases Autonomic ganglia Prevent breakdown of acetylcholine to Reverse effects of nondepolarizing (neostigmine, edrophonium) enhance its effect drugs; muscarinic effects (bronchospasm, bronchorrhea, bradycardia)

Table 1.25 Types of Muscle Contractions TYPE OF MUSCLE CONTRACTION DEFINITION EXAMPLE PHASES Isotonic Muscle tension is constant Biceps curls with Concentric contraction: Muscle shortens during contraction. throughout ROM. Muscle free weights Tension within muscle is proportional to externally applied length changes throughout load. Example of an isotonic concentric contraction is the ROM. This is a measure of curl (elbow moving toward increasing flexion) portion of a dynamic strength. biceps curl. Eccentric contraction: Muscle lengthens during contraction (internal force < external force). Eccentric contractions are the most efficient way to strengthen muscle but have the greatest potential for high muscle tension and muscle injury. Example of an isotonic eccentric contraction is the negative (elbow moving toward increasing extension) portion of a biceps curl. Isometric Muscle tension is gener- Pushing against an ated, but muscle length immovable object remains unchanged. This (e.g., wall) is a measure of static strength. Isokinetic Muscle tension is gener- Isokinetic exercises Concentric contraction ated as muscle maximally require special Eccentric contraction contracts at a constant equipment (e.g., velocity over a full ROM. Cybex machine). Isokinetic exercises are best for maximizing strength and are a measure of dynamic strength.

n Types of muscle contractions are summarized in Table 1.25. n Types of muscle fibers Table( 1.26) • Muscle cross-sectional area is a reliable predictor of the n Subtypes are based on variability in myosin heavy chains potential for contractile force. • Type I • Muscle tension is determined by the contractile force • Slow-twitch, oxidative, “red” fibers (mnemonic: generated. “slow red ox”) • Muscle contraction velocity is determined by fiber • Aerobic length. • Have more mitochondria, enzymes, and triglycerides • A well-conditioned muscle may be able to fire more (energy source) than type II fibers than 90% of its fibers simultaneously. • Low concentrations of glycogen and glycolytic • At any velocity, fast-twitch (type II) fibers produce enzymes (ATPase) more force. • Enable performing endurance activities, posture, • Isokinetic exercises produce more strength gains than balance do isometric exercises (see Table 1.25). • Are the first lost without rehabilitation • Plyometric (“jumping”) exercises, the most efficient • Type II method of improving power, consist of a muscle stretch • Fast-twitch, glycolytic, “white” fibers followed immediately by a rapid contraction. • Anaerobic • Closed-chain exercise involves loading an extremity • Contract more quickly and have larger, stronger with the most distal segment stabilized or not moving, motor units (increased ATPase) than type I fibers allowing for muscular cocontraction around a joint and • Less efficient than type I but with large amount minimizing joint shear (e.g., less stress on the ACL). of force per cross-sectional area, high contraction • Open-chain exercise involves loading an extremity speeds, and quick relaxation times with the distal segment of the limb moving freely (e.g., • Well suited for high-intensity, short-duration biceps curls). activities (e.g., sprinting) 56 Basic Sciences

Table 1.26 Characteristics of Types of Human Skeletal Muscle Fibers TYPES

CHARACTERISTIC TYPE I TYPE IIA TYPE IIB Red, slow-twitch White, fast-twitch Fast glycolytic Slow oxidative Fast oxidative glycolytic Speed of contraction Slow Fast Fast Strength of contraction Low High High Fatigability Fatigue-resistant Fatigable Most fatigable Aerobic capacity High Medium Low Anaerobic capacity Low Medium High Motor unit size Small Larger Largest Capillary density High High Low

From Simon SR, editor: Orthopaedic basic science, Rosemont, IL, 1994, American Academy of Orthopaedic Surgeons, p 100.

ATP-CP system 100 • Rapid fatigue Glycolytic system—anaerobic glycolysis • Low intramuscular triglyceride stores O2 system • Two subtypes: 50 • Type IIA is intermediate. • Type IIB is most fatigable and has highest 0 anaerobic capacity. Replenishment of ATP 0 30 60 90 120 150 180 n Energetics (Fig. 1.43) during maximal exercise n ATP–creatine phosphate (phosphagen) system Duration (sec) • Converts stored carbohydrates to energy without the FIG. 1.43 Energy sources for muscle activity. CP, creatine phos- use of oxygen and without producing lactate. phate. (From Simon SR, editor: Orthopaedic basic science, Rosemont, IL, 1994, • Intense muscle activities lasting up to 20 seconds American Academy of Orthopaedic Surgeons, p 102.) (sprinting) • Creatine supplementation can increase work produced • Improves neural activation in the first few maximum-effort anaerobic trials but • Both endurance training and strength training delay the does not increase peak force production. lactate response to exercise. • Creatine shifts fluid intracellularly; the shift may • A significant decline in aerobic fitness (“detraining”) present a risk for dehydration, although cramps are the occurs after only 2 weeks of no training. more common side effect. n Denervation n Lactic anaerobic system (lactic acid metabolism) • Causes muscle atrophy and increased sensitivity to • Muscle glycogen and blood glucose anaerobically acetylcholine converted to ATP • Leads to spontaneous fibrillations at 2–4 weeks after • Incomplete oxidation leads to excess pyruvate, which is injury converted to lactic acid (via lactate dehydrogenase) n Immobilization • Intense muscle activities lasting 20 to 120 seconds • Accelerates granulation tissue response n Aerobic system • Immobilization in lengthened positions decreases • Aerobic oxidation of glycogen and fatty acids contractures and maintains strength. through Krebs cycle • Atrophy results from disuse or altered recruitment. • Sustained exercise such as distance running • Muscles that cross a single joint atrophy faster n Athletic training, injury, and adaptation (nonlinear fashion). n Training • Sarcomeres at the myotendinous junction are especially • Specific training can selectively alter fiber composition. affected • Endurance athletes—higher percentage of slow- • Electrical stimulation can help offset these effects. twitch fibers n Muscle strains • Sprinters and athletes in “strength” sports—higher • Most common sports injury percentage of fast-twitch fibers • Most occur at the myotendinous junction. • Endurance training—decreased tension and increased • Occur primarily in muscles crossing two joints repetitions (hamstring, gastrocnemius) that have increased type II • Induces hypertrophy of slow-twitch fibers fibers • Increases capillary density, mitochondria, and • Initially there is inflammation, and later, fibrosis oxidative capacity mediated by TGF-β occurs. • Increases resistance to fatigue and cardiac output • Immobilization or rest for 3–5 days followed by • Improves blood lipid profiles progressive stretching and strengthening • Strength training—increased tension and decreased n Muscle tears repetitions • Most occur at the myotendinous junction (e.g., rectus • Induces hypertrophy (increased cross-sectional area) femoris tear at anterior inferior iliac spine). of fast-twitch (type II) fibers • Often occur during a rapid (high-velocity) eccentric • Induces myofibrillar muscle protein synthesis (MPS) contraction Basic Sciences 57

• Satellite cells act as stem cells and are most responsible • Also responsible for “toe region” of stress-strain curve for muscle healing. • Proteoglycans • Alternatively, the defect can heal with bridging • Decorin—most predominant proteoglycan in scar tissue. TGF-β stimulates proliferation of tendons. Regulates tendon diameter and provides myofibroblasts and increases fibrosis. cross-links between collagen fibers. Also shown • Surgical repair of clean lacerations in the muscle to have antifibrotic properties via inhibition of midbelly usually results in minimal regeneration of TGF-β1. muscle fibers distally, scar formation at the laceration, • Aggrecan—present at points of tendon compression and recovery of about half the muscle strength. • Biglycan • Prevention of tears—muscle activation (through stretching) • Tenocytes (fibroblasts): allows twice the energy absorption before failure. • Derived from mesoderm n DOMS • Function to synthesize ECM, collagen, and • This phenomenon occurs 24–72 hours after intense proteoglycans exercise. • Assemble early collagen fibrils and produce matrix- • Associated with eccentric muscle contractions degrading enzymes (MMPs) • Most common in type IIB fibers • Detect strain during tendon loading though • Caused by edema and inflammation in the connective deflection of cell cilia tissue, with a neutrophilic response present after acute • Tenocyte production of collagen increases tendon muscle injury healing and reduces repair ruptures. • May be associated with changes in the I band of the • Role in tendinopathy (due to inflammatory mediator sarcomere production) • NSAIDs relieve DOMS in a dose-dependent manner. • Tenocytes produce type III collagen in response to • Other modalities (ice, stretching, ultrasonography, rupture. electrical stimulation) have not been shown to affect • Greater proportion of type III collagen, naturally DOMS. seen in Achilles tendon, predisposes tendons to rupture. n TENDON (Fig. 1.44) Structure • Strands of collagen (triple helix of two α1 chains and n Structure and composition one α2 chain) organized into microfibrils, which in turn n Composition make up fibrils, fascicles, and tendon • Water: 50%–60% of total tendon weight • Fascicles surrounded by endotendon (contiguous with • Collagen: 75% of dry weight epitendon covering entire tendon) • 95% type I collagen, also type III collagen • Carry the neurovascular and lymphatic supply of • Elastin: 1%–2% of dry weight tendons • Highly elastic protein that allows tendon to resume • Composed of type III collagen its shape after stretching • With aging, more type I collagen strands interdigitate between type III collagen strands. • Covered by paratenon (Achilles, patellar tendons) versus synovium (digital flexor tendons) • Higher vascularity of paratenon leads to increased healing. • Sheathed tendons • Vincula (extension of synovium) carry blood supply to one tendon segment (Fig. 1.45). • Some nutrition from synovial fluid (found between the two layers of the synovial sheath) via diffusion • Myotendinous junction Ligament • Actin microfilaments extend from the last Z line Tendon • These are linked to the sarcolemma, which in turn connects to the collagen fibril–rich matrix of the tendon. Tendon or • Bone-tendon junction (direct vs. indirect) ligament Fascicle • Direct (fibrocartilaginous) insertion • Usually in areas subject to high tensile load Fibril • Four layers: tendon, fibrocartilage, mineralized Subfibril fibrocartilage, and bone Microfibril • Indirect Insertion • Fibers insert directly into periosteum through Sharpey fibers Tropocollagen n Mechanical properties n Anisotropic: properties vary depending on direction of applied force FIG. 1.44 Tendon and ligament architecture. (From Brinker MR, Miller n Viscoelastic: properties vary depending on rate of force MD: Fundamentals of orthopaedics, Philadelphia, 1999, Saunders, p 15.) application 58 Basic Sciences

• Extrinsic: cells from surrounding tissue invade damaged area. • Faster but primary source of adhesions n Achilles, patellar, and supraspinatus tendons are prone to rupture at hypovascular areas. • Achilles tendon is hypovascular 4–6 cm proximal to calcaneal insertion. n Responsive to different cytokines and growth factors • PDGF genes transfected into tenocytes show collagen formation. • VEGF genes transfected into tenocytes show TGF-β upregulation and adhesion formation. • When exposed to PMNs (as with inflammation), tenocytes upregulate genes for inflammatory cytokines, A TGF-β, and MMPs while suppressing type I collagen expression. n Surgical tendon repairs: weakest at 7–10 days • Maximum strength achieved at 6 months, reaching two- thirds of original strength. • No evidence in favor of a trough (exposing tendon to cancellous bone) over direct repair to cortical bone. n Motion and mechanical loading have beneficial effects on tenocyte function. n Immobilization decreases strength at tendon-bone interface.

LIGAMENT (see Fig. 1.44) n Characteristics n Originates and inserts on bone B n Stabilizes joints and prevents displacement of bones n Contains mechanoreceptors and nerve endings that FIG. 1.45 (A) India ink specimen demonstrating the vascular supply facilitate joint proprioception of the flexor tendons via vincula. (B) Close-up of the specimen.( From n Like tendon, displays viscoelastic behavior Simon SR, editor: Orthopaedic basic science, ed 2, Rosemont, IL, 1994, American n Structure and composition Academy of Orthopaedic Surgeons, p 51.) n Composition • Similar to that of tendon • Creep: increasing deformation under constant load • Water: 60%–70% of total weight • Stress relaxation: decreasing stress with constant • Collagen: 80% of dry weight deformation (elongation) • 90% type I collagen; also types III, V, VI, XI, and • Hysteresis: during loading and unloading, the XIV collagen unloading curve is different from the loading curve. The • More collagen type I is seen at the origin and difference between the two represents the amount of insertion, with collagen III seen midsubstance. energy that is lost during loading. • Elastin (1% dry weight) n Stress-strain curve • Proteoglycans (1% dry weight)—function in water • Rest: collagen fibers are “crimped.” retention and contribute to viscoelastic behavior • Toe region: flattening of crimp; nonlinear; tendon • Fibroblast stretched easily • Primary cell, oriented longitudinally • Linear region: intermediate loads • Functions to synthesize ECM, collagen, and • Failure proteoglycans n Injury and healing • Epiligament n Three stages of tendon healing • Similar to that in epitenon; carries the neurovascular • Inflammation and lymphatic supply of tendons • Hematoma formation following by resorption • Compared with tendon • Type III collagen is produced at the injury site by • Less total collagen but more type III collagen tenocytes. • More proteoglycans and therefore more water • Weakest stage of repair • Less organized collagen fibers that are more highly • Proliferation: maximal type III collagen production cross-linked and intertwined • Remodeling: • “Uniform microvascularity”—receives supply at • Begins at 6 weeks insertion site by the epiligamentous plexus • Decreases cellularity • Insertion • Type I collagen predominates • Similar to that of tendon n Two mechanisms: • Direct (fibrocartilaginous) insertion • Intrinsic: recruitment of local stem/progenitor cells from • Four layers: tendon, fibrocartilage, mineralized endotenon and epitenon fibrocartilage, and bone Basic Sciences 59

• More common • Axons: one or more processes that connect the neuron • Deep fibers attach at 90-degree angles to the spinal cord or end-organ • Indirect • Dendrites: processes extending from the cell body that • Superficial fibers insert into the periosteum and receive signals from surrounding nerve cells deep fibers insert into bone via Sharpey fibers • Myelin sheath (perforating calcified collagen fibers). • Composed primarily of galactocerebroside n Injury • Speeds wave propagation or conduction (thicker n Knee and ankle ligaments are most commonly injured sheath increases conduction speed) n Ligaments do not plastically deform. • Produced by Schwann cells in PNS • They “break, not bend.” • Schwann cells originate in neural crest and are n Midsubstance ligament tears are common in adults. important in posttraumatic nerve regeneration. n Avulsion injuries are more common in children. • Produce nerve growth factor-β, brain-derived growth n Typically occurs between unmineralized and mineralized factor, insulin-like growth factor 1 (IGF-1), and fibrocartilage layers erythropoietin n Healing • One Schwann cell surrounds a single axon in • Increased number of collagen fibers but myelinated fibers • Fewer mature cross-links (45% of normal at • Footprint of approximately 100 μm 1 year) • Space between cells is called node of Ranvier • Decrease in mass and diameter (concentrated Na+ channels) n Three phases, as in bone • Allows for salutatory conduction between nodes of • Inflammatory—early acute mediators (PMNs and then Ranvier macrophages), with production of type III collagen and • One Schwann cell surrounds multiple axons in growth factors unmyelinated fibers • Proliferative—around 1–3 weeks, with replacement n Neurophysiology of type III collagen by type I collagen (Think of • Axolemma macrophages as weakening the structure—weakest • Specialized membrane that surrounds axon and point.) maintains membrane potential • Remodeling and maturation • Maintains resting potential utilizing Na-K pumps n Factors that impair ligament healing • Approximately −70 mV (cell interior has relative • Intraarticular ligamentous injury negative charge) • Old age, smoking, NSAID use • Action potential (AP) • Diabetes mellitus • Neurotransmitters cross synapse and trigger opening • Alcohol use of Na+ channel. • Local injection of corticosteroids • This triggers voltage-gated Na+ channels n Factors that improve ligament healing experimentally (responsible for generation of AP) in axon • Extraarticular ligamentous injury hillock when membrane potential increases to • Compromised immunity −50 mV. • IL-10 (antiinflammatory) • Membrane potential spikes to 30 mV as membrane • IL-1 receptor antagonists depolarizes. • Mesenchymal stem cells • Potential propagates down axon and triggers voltage- • Scaffolds (such as collagen–platelet-rich plasma gated Ca2+ channel at axon terminus. hydrogels) • Ca2+ enters axon and triggers neurotransmitter • Neuropeptides release • Calcitonin gene–related peptide • Voltage-gated K+ channels stay open longer than Na+ n Immobilization channels. n Adversely affects ligament strength: elastic modulus • Leads to hyperpolarization (−75 mV) decreases • Propagation faster in myelinated and larger nerves n In rabbits, breaking strength reduced dramatically (66%) • Absolute refractory period after 9 weeks of immobilization. • Period when voltage-gated Na+ channels cannot be n Effects reverse slowly upon remobilization. activated n Prolonged immobilization disrupts collagen structure, • Responsible for antegrade propagation of signal which may not return to normal within insertion sites. • Relative refractory period n Exercise • Period when larger than normal stimuli propagate n Improves mechanical and structural properties a second AP n Increases strength, stiffness, and failure load • Result of the hyperpolarization phase of the previous n NEURAL TISSUE AND INTERVERTEBRAL DISC Peripheral nerves • Highly organized structures composed of nerve fibers, n The spine and spinal trauma are covered in Chapters 2, 8, and blood vessels, and connective tissues (Fig. 1.46) 11. Peripheral nerve injuries are discussed in Chapter 7. • Nerve fibers vary in size according to function Table( n Anatomy and physiology of the peripheral nervous system (PNS) 1.27). n Neuron (see Fig. 1.49) • Erlanger and Gasser classification • Cell body (metabolic center; 10% of size of a neuron) • Afferent and efferent nerves • Tapers into axon at axon hillock • Uses Roman and Greek letters 60 Basic Sciences

Fascicle

Blood vessels

Epineurium

Perineurium

Endoneurium Axon: Unmyelinated Myelinated

Myelin sheath Node of Cell body Ranvier

Cell body Dendrites

FIG. 1.46 Nerve architecture. (From Brinker MR, Miller MD: Fundamentals of orthopaedics, Philadelphia, 1999, Saunders, p 13.)

Table 1.27 Types and Characteristics of Nerve Fibers TYPE DIAMETER (MM) MYELINATION SPEED EXAMPLES A 10–20 Heavy Fast Touch B <3 Intermediate Medium Autonomic nervous system C <1.3 None Slow Pain

• Lloyd and Hunt classification • Unipolar neuron with cell body in ventral horn of • Only afferent nerves spinal cord • Uses Roman numerals • Motor unit: an α-motoneuron and the muscle fibers • Can be composed of one fascicle (monofascicular), it innervates a few fascicles (oligofascicular), or several fascicles • Internal topography (polyfascicular) • Cross section of nerve changes along length of nerve • Axons coated with a fibrous tissue called endoneurium (divisions, anastomosis, and migration) • Groups of axons (fascicles) covered by perineurium • Fibers within fascicle organized by locations they • Nerve covered by epineurium innervate. • External epineurium is continuous with dural sleeve • Around joints, nerves typically have more and of spinal cord. smaller fascicles to accommodate joint motion and • Afferent nerves convey information from sensory organ decrease risk of injury. to CNS. • Radial nerve at spiral groove has fewer and larger • Pseudounipolar neuron with cell body in dorsal root fascicles (higher risk of neurapraxia with humeral ganglia (DRG) fracture) • Central branch extends away from neuron and n Sensory receptors (Table 1.28) travels through spinal cord via dorsal horn. • The four attributes of a stimulus are quality, intensity, • Efferent nerves convey information from CNS to periphery. duration, and location. Basic Sciences 61

Table 1.28 Receptor Types • A reflex pathway involves a sensory organ (receptor), an interneuron, and a motoneuron. FIBER • Monosynaptic reflex: only one synapse is involved RECEPTOR TYPE TYPE QUALITY between receptor and effector. NOCICEPTORS • Polysynaptic reflex: one or more interneurons are Mechanical Aδ Sharp, pricking pain involved. Most reflexes are polysynaptic. Thermal and mechanothermal Aγ Sharp, pricking pain n Intervertebral discs (IVDs) Thermal and mechanothermal C Slow, burning pain n Polymodal C Slow, burning pain Allow spinal motion and stability CUTANEOUS AND SUBCUTANEOUS MECHANORECEPTORS n Also function as cushioning for axial loads on the spine Meissner corpuscle Aβ Touch n Two components Pacini corpuscle Aβ Flutter • Central nucleus pulposus Ruffini corpuscle Aβ Vibration • Derived from notochord Merkel receptor Aβ Steady skin indentation Hair-guard, tylotrich hair A Steady skin indentation • Hydrated gel with compressibility β • Low collagen (type II)/high proteoglycan (and Hair down Aβ Flutter MUSCLE AND SKELETAL MECHANORECEPTORS glycosaminoglycan) content Muscle spindle, primary Aα Limb proprioception • Proteoglycans make up higher percentage of dry Muscle spindle, secondary Aβ Limb proprioception weight. Golgi tendon organ Aα Limb proprioception • With time, the nucleus pulposus undergoes loss Joint capsule mechanoreceptor A Limb proprioception β of proteoglycans and water (desiccation). Adapted from Kandel ER et al, editors: Principles of neural science, ed • Surrounding annulus fibrosis 3, Norwalk, CT, 1991, Appleton & Lange, p 342. • Derived from mesoderm • Extensibility and increased tensile strength • High collagen (type I)/low proteoglycan content Table 1.29 Summary of Spinal Reflexes • Proteoglycans make up lower percentage of dry SEGMENTAL weight. REFLEX RECEPTOR ORGAN AFFERENT FIBER • Superficial layer contains nerve fibers. Phasic stretch Muscle spindle Type Ia (large n Composition: reflex (primary endings) myelinated) • Water (85%) Tonic stretch reflex Muscle spindle Type II (intermediate • Proteoglycans (secondary endings) myelinated) • Type II collagen (20% of dry weight) in the nucleus Clasp-knife Muscle spindle Type II (intermediate response (secondary endings) myelinated) pulposus Flexion withdrawal Nociceptors (free Flexor-reflex • Type I collagen (60% of dry weight) in the annulus reflex nerve endings), afferents: small fibrosis touch and pressure unmyelinated n Neurovascularity receptors cutaneous affer- • Dorsal root ganglion gives rise to the sinuvertebral nerve, ents (Aδ, C, and muscle afferent which then innervates the superficial fibers of the annulus. fibers, group III) • Avascular—nutrients and fluid diffuse from the Autogenic Golgi tendon organ Type Ib (large vertebral end plates. This diffusion is impaired by inhibition myelinated) calcification with aging. n Aging disc From Simon SR, editor: Orthopaedic basic science, Rosemont, IL, 1994, American Academy of Orthopaedic Surgeons, p 350. • Early degenerative disc disease is an irreversible process, with IL-1β stimulating the release of MMPs, nitric oxide, IL-6, and prostaglandin E2 (PGE2). • Modalities • Decreased water content and conversion to fibrocartilage • Nociceptors (pain and temperature) • A result of decreased hydrostatic pressure due to • Cutaneous and subcutaneous mechanoreceptors fewer large proteoglycans (aggrecan) (touch and vibration) • Fibronectin cleavage or fragmentation is also • Muscle and skeletal mechanoreceptors associated with degeneration. (proprioception) • Increase in keratan sulfate concentration and decrease n Spinal cord reflexes Table( 1.29) in chondroitin sulfate • These reflexes are “stereotyped responses” to a specific • Increase in relative collagen concentration, with no sensory stimulus. change in absolute quantity

SECTION 2 ORTHOPAEDIC BIOLOGY

CELLULAR AND MOLECULAR BIOLOGY AND IMMUNOLOGY • DNA has a double-helix structure with linked nucleotides (adenine linked to thymine; guanine linked n Chromosomes to cytosine) on a sugar-phosphate backbone n 46 chromosomes in 23 pairs: 22 pairs of autosomes, 1 • Three nucleotides = 1 codon, which corresponds to pair of sex chromosomes one amino acid n Composed of DNA coiled around histone proteins 62 Basic Sciences

n Translation (see Fig. 1.47) • Building of a protein out of amino acids from mRNA template 5′ • Transfer RNA carries a specific amino acid to the Gene ribosome, based on the mRNA codon. RNA polymerase • Antibodies to tRNA synthetase (anti–Jo-1 antibodies) are seen in dermatomyositis. Gene transcription: n Cell cycle and ploidy DNA becomes Intron RNA • Ploidy is the number of sets of chromosomes in a cell Intron annotated by XN. Intron Intron Exon • The cell cycle entails the events within a cell that result in 5′ Exon DNA duplication, with production of two daughter cells. Exon Modification of the RNA • Growth 0 (G0)—stable phase of cells with diploid and export from the nucleus (2N) DNA content • Growth 1 (G1)—upon stimulus, cells begin growth 5′ mRNA but remain diploid (2N). • Synthesis (S)—period of DNA replication resulting in AAAAAAAAAAA tetraploidy (4N) • Growth 2 (G2)—phase of cell growth and protein Translation: mRNA is “read” and blueprint is synthesis that is tetraploid (4N) throughout used to assemble a chain • Mitosis (M)—sequence of events that result in two of amino acids to form a protein identical daughter cells that are each 2N Protein • Separation of chromosomal material for daughter cells occurs by spindle fibers’ attachment to centromeres that link sister chromatids FIG. 1.47 DNA information is transcribed into RNA in the nucleus. • Anticentromere antibodies are seen in CREST Messenger RNA is then transported to the cytoplasm, where ribo- syndrome. somes complete translation into proteins. (From Jorde LB et al, editors: • Certain proteins regulate progression through the Medical genetics, ed 2, St Louis, 1999, Mosby.) cell cycle. Genetic defects and alterations of these tumor suppressor proteins can predispose a cell to dysregulated growth. • String of codons code for a string of amino acids = • pRb-1 (retinoblastoma protein) undergoes protein progressive cell cycle–regulated phosphorylation. • Gene : a section of DNA that codes for one protein • Targets E2F, a transcription factor that regulates n Transcription—DNA to mRNA (Fig. 1.47) genes important for cell cycle control. • Unwinding of DNA for transcription occurs by DNA • Implicated in retinoblastoma and osteosarcoma topoisomerase. • p53—prevents entry to S phase • Topoisomerase-1 (scl-70) antibodies are seen • Implicated in osteosarcoma, rhabdomyosarcoma, in scleroderma and CREST (calcinosis, Raynaud and chondrosarcoma phenomenon, sclerodactyly, telangiectasia) n Genetics syndrome. n Mendelian inheritance • RNA polymerase “reads” unwound DNA and builds • Due to transmission of alleles to offspring corresponding mRNA • Phenotype refers to the features (traits) exhibited • RNA : single-stranded ribose sugar composed of because of genetic makeup (genotype). nucleotides adenine, guanine, cytosine, and uracil n Mendelian traits may be inherited by one of four modes • Uracil in RNA links to adenine of DNA because there (Tables 1.30 and 1.31). is no thymine in RNA • Autosomal dominant (AD) • Posttranscription modification • Involves a gene on an autosomal chromosome; one • Exons are regions of DNA that code for mRNA of the two alleles for the chromosome pair must be (mnemonic: EXons are EXpressed). abnormal for the disease phenotype to occur. • Introns are regions of DNA that are between exons; • Examples: syndactyly/polydactyly, Marfan 97% of the human genome consists of noncoding syndrome, hereditary multiple exostoses DNA. (HME), malignant hyperthermia, Ehlers- • Splicing is the processing and removal of introns Danlos syndrome, achondroplasia, osteogenesis along with the combining of exons to make final imperfecta (types I and IV) mRNA used in translation. • Autosomal recessive (AR) (most enzyme/biochemical • Small nuclear ribonucleoproteins (snRNPs) deficiencies) are RNA-protein complexes that mediate this • Involves a gene on an autosomal chromosome; both posttranscriptional modification. alleles for the chromosome pair must be abnormal • Examples of these proteins are the U1 and Smith for the disease phenotype to occur. proteins. • Example: diastrophic dysplasia, due to a mutation • Anti-Smith antibodies are specific to SLE. in the DTDST (SLC26A2) gene on chromosome 5 • Anti–U1-RNP antibodies are seen in mixed that encodes for a sulfate transport protein connective tissue disease. • X-linked dominant Table 1.30 Mendelian Inheritance INHERITANCE PATTERN DESCRIPTION PUNNETT SQUARE(S) Autosomal dominant Autosomal dominant disorders typically represent structural defects. A a • A is the mutant domi- Disorder is manifested in the heterozygous state (Aa). nant allele. Affects 50% of offspring (assuming only one parent is affected) a Aa aa Normal offspring do not transmit the condition. a Aa aa There is no gender preference. Autosomal recessive Autosomal recessive disorders typically represent biochemical or enzymatic A a • a is the mutant reces- defects. sive allele. Disorder is manifested in the homozygous state (aa). A AA Aa Parents are unaffected (they are most commonly heterozygotes). a Aa aa Affects 25% of offspring (assuming each parent is a heterozygote). There is no gender preference. X-linked dominant X-linked dominant disorders are manifested in the heterozygous state (X′X or X′Y). X Y • X′ is the mutant domi- Affected female (mating with unaffected male) transmits the X-linked gene to 50% of nant X allele. daughters and 50% of sons. X′ X′X X′Y Affected male (mating with unaffected female) transmits the X-linked gene to all X XX XY daughters and no sons.

X′ Y X X′X XY

X X′XXY

X-linked recessive Heterozygote (X′Y) male manifests the condition. X′ Y • X is the mutant reces- Heterozygote (X′X) female is unaffected. sive X allele. Affected male (mating with unaffected female) transmits the X-linked gene to all X X′X XY daughters (who are carriers) and no sons. X X XXY Carrier female (mating with unaffected male) transmits the X-linked gene to 50% of ′ daughters (who are carriers) and 50% of sons (who are affected). X Y X′ X′X X′Y X XX XY

Table 1.31 Comprehensive Compilation of Inheritance Pattern, Defect, and Associated Gene in Musculoskeletal Disorders DISORDER INHERITANCE PATTERN DEFECT ASSOCIATED GENE DYSPLASIAS Achondroplasia Autosomal dominant Defect in the fibroblast growth FGF3R factor receptor 3 Diastrophic dysplasia Autosomal recessive Mutation of a gene coding for a DTDST sulfate transport protein Kniest dysplasia Autosomal dominant Defect in type II collagen COL 2A1 Laron dysplasia (pituitary dwarfism) Autosomal recessive Defect in the growth hormone receptor McCune-Albright syndrome (polyos- Sporadic mutation Germline defect in the Gsα Mutation of Gsα subunit of the totic fibrous dysplasia, café-au-lait protein receptor/adenylyl cyclase– spots, precocious puberty) coupling G proteins Metaphyseal chondrodysplasia: Jansen form Autosomal dominant PTH; PTH-related protein McKusick form Autosomal recessive RMRP Schmid-tarda form Autosomal dominant Defect in type X collagen COL 10A1 Multiple epiphyseal dysplasia Autosomal dominant (most Cartilage oligomeric matrix COMP commonly) protein Spondyloepiphyseal dysplasia Autosomal dominant (con- Defect in type II collagen Linked to Xp22.12-p22.31, genita form) SEDL (tarda), and COL 2A1 X-linked recessive (tarda (congenita) form) Achondrogenesis Autosomal recessive Fetal cartilage fails to mature Apert syndrome Sporadic mutation/autosomal FGF2R dominant Chondrodysplasia punctata Conradi-Hünerman Autosomal dominant Rhizomelic form Autosomal recessive Defect in subcellular organelles (peroxisomes) Cleidocranial dysplasia (dysostosis) Autosomal dominant Mutation of a gene coding for a CBFA1 protein related to osteoblast function Dysplasia epiphysealis hemimelica Unknown (Trevor disease) Ellis–van Creveld syndrome (chondro- Autosomal recessive EVC ectodermal dysplasia) Table 1.31 Comprehensive Compilation of Inheritance Pattern, Defect, and Associated Gene in Musculoskeletal Disorders—cont’d DISORDER INHERITANCE PATTERN DEFECT ASSOCIATED GENE Fibrodysplasia ossificans progressiva Sporadic mutation/autosomal dominant Geroderma osteodysplastica (Walt Autosomal recessive Disney dwarfism) Grebe chondrodysplasia Autosomal recessive Hypochondroplasia Sporadic mutation/autosomal FGF3R dominant Kabuki makeup syndrome Sporadic mutation Mesomelic dysplasia (Langer type) Autosomal recessive Mesomelic dysplasia Nievergelt type Autosomal dominant Reinhardt-Pfeiffer type Autosomal dominant Werner type Autosomal dominant Metatrophic dysplasia Autosomal recessive Progressive diaphyseal dysplasia Autosomal dominant (Camurati-Engelmann disease) Pseudoachondroplastic dysplasia Autosomal dominant COMP Pyknodysostosis Autosomal recessive Spondylometaphyseal chondrodys- Autosomal dominant plasia Spondylothoracic dysplasia (Jarcho- Autosomal recessive Levin syndrome) Thanatophoric dwarfism Autosomal dominant FGF3R Tooth-and-nail syndrome Autosomal dominant Treacher Collins syndrome (mandibu- Autosomal dominant lofacial dysostosis) METABOLIC BONE DISEASES Hereditary vitamin D–dependent Autosomal recessive See Table 1.16 rickets Hypophosphatasia Autosomal recessive See Table 1.16 PHEX Hypophosphatemic rickets (vitamin X-linked dominant See Table 1.16 PHEX D–resistant rickets) Osteogenesis imperfecta Autosomal dominant (types I Defect in type I collagen COL IA1, COL IA2 and IV) (abnormal cross-linking) Autosomal recessive (types II and III) Albright hereditary osteodystrophy Uncertain PTH has no effect at the target (pseudohypoparathyroidism) cells (in the kidney, bone, and intestine) Infantile cortical hyperostosis (Caffey Unknown disease) Ochronosis (alkaptonuria) Autosomal recessive Defect in the homogentisic acid oxidase system Osteopetrosis Autosomal dominant (mild, CLCN7, TC1RG1 tarda form) Autosomal recessive (infantile, malignant form) CONNECTIVE TISSUE DISORDERS Marfan syndrome Autosomal dominant Fibrillin abnormalities (some FBN1 or TGF-βR2 patients also have type I collagen abnormalities) Ehlers-Danlos syndrome (there are at Autosomal dominant (most Defects in types I and III colla- COL 3A1 (for type III; most least 13 varieties) common) gen have been described for common) some varieties; lysyl oxidase COL 1A2 (for type VII) abnormalities Homocystinuria Autosomal recessive Deficiency of the enzyme cys- tathionine β-synthase MUCOPOLYSACCHARIDOSIS Hunter syndrome (gargoylism) X-linked recessive Hurler syndrome Autosomal recessive Deficiency of the enzymeα -L- iduronidase Maroteaux-Lamy syndrome Autosomal recessive Morquio syndrome Autosomal recessive Sanfilippo syndrome Autosomal recessive Scheie syndrome Autosomal recessive Deficiency of the enzymeα -L- iduronidase MUSCULAR DYSTROPHIES Duchenne muscular dystrophy X-linked recessive Defect on the short arm of the Dystrophin gene X chromosome Becker dystrophy X-linked recessive Fascioscapulohumeral dystrophy Autosomal dominant Limb-girdle dystrophy Autosomal recessive Steinert disease (myotonic dystrophy) Autosomal dominant

Continued Table 1.31 Comprehensive Compilation of Inheritance Pattern, Defect, and Associated Gene in Musculoskeletal Disorders—cont’d DISORDER INHERITANCE PATTERN DEFECT ASSOCIATED GENE HEMATOLOGIC DISORDERS Hemophilia (A and B) X-linked recessive Hemophilia A: factor VIII deficiency Hemophilia B: factor IX deficiency Sickle cell anemia Autosomal recessive Hemoglobin abnormality (presence of hemoglobin S) Gaucher disease Autosomal recessive Deficient activity of the enzyme β-glucosidase (glucocerebrosidase) Hemochromatosis Autosomal recessive Niemann-Pick disease Autosomal recessive Accumulation of sphingomyelin in cellular lysosomes Smith-Lemli-Opitz syndrome Uncertain Thalassemia Autosomal recessive Abnormal production of hemoglobin A von Willebrand disease Autosomal dominant CHROMOSOMAL DISORDERS WITH MUSCULOSKELETAL ABNORMALITIES Down syndrome Trisomy of chromosome 21 Angelman syndrome Chromosome 15 abnormality Clinodactyly Associated with many genetic anomalies, including trisomy of chromosomes 8 and 21 Edward syndrome Trisomy of chromosome 18 Fragile X syndrome X-linked trait (does not follow Xq27-28 the typical pattern of an X-linked trait) Klinefelter syndrome (XXY) An extra X chromosome in affected boys and men Langer-Giedion syndrome Sporadic mutation Chromosome 8 abnormality Nail-patella syndrome Autosomal dominant LMX1B Patau syndrome Trisomy of chromosome 13 Turner syndrome (XO) One of the two X chromosomes SHOX missing in affected girls and women NEUROLOGIC DISORDERS Charcot-Marie-Tooth disease Autosomal dominant (most Chromosome 17 defect for PMP22 common) encoding peripheral myelin protein-22 Congenital insensitivity to pain Autosomal recessive Dejerine-Sottas disease Autosomal recessive Friedreich ataxia Autosomal recessive Huntington disease Autosomal dominant Menkes syndrome X-linked recessive Inability to absorb and use copper Pelizaeus-Merzbacher disease X-linked recessive Defect in the gene for proteo- lipid (a component of myelin) Riley-Day syndrome Autosomal recessive Spinal muscular atrophy (Werdnig- Autosomal recessive Hoffman disease and Kugelberg- Welander disease) Sturge-Weber syndrome Sporadic mutation Tay-Sachs disease Autosomal recessive Deficiency in the enzyme hex- osaminidase A DISEASES ASSOCIATED WITH NEOPLASIAS Ewing sarcoma 11;22 chromosomal translocation (EWS/FL11 fusion gene) Multiple endocrine neoplasia (MEN): Type I Autosomal dominant RET Type II Autosomal dominant Type III Autosomal dominant Chromosome 10 abnormality Neurofibromatosis (von Recklinghau- Autosomal dominant NF1: chromosome 17 defect; NF1, NF2 sen disease) type 1 (NF1) and type codes for neurofibromin 2 (NF2) NF2: chromosome 22 defect Synovial sarcoma (X;18) (p11;q11) chromosomal translocations (STT/SSX fusion gene) MISCELLANEOUS DISORDERS Malignant hyperthermia Autosomal dominant Osteochondromatosis Autosomal dominant Postaxial polydactyly Autosomal dominant GLI3 (types A, A/B) GJA1 (type IV) Camptodactyly Autosomal dominant

Continued 66 Basic Sciences

Table 1.31 Comprehensive Compilation of Inheritance Pattern, Defect, and Associated Gene in Musculoskeletal Disorders—cont’d DISORDER INHERITANCE PATTERN DEFECT ASSOCIATED GENE Cerebrooculofacioskeletal syndrome Autosomal recessive Congenital contractural arachnodactyly Fibrillin gene (chromosome 5) Distal arthrogryposis syndrome Autosomal dominant Dupuytren contracture Autosomal dominant (with partial sex limitation) Fabry disease X-linked recessive Deficiency ofα -galactosidase A Fanconi pancytopenia Autosomal recessive Freeman-Sheldon syndrome (cranio- Autosomal dominant carpotarsal dysplasia; whistling Autosomal recessive face syndrome) GM1 gangliosidosis Autosomal recessive Hereditary anonychia Autosomal dominant Holt-Oram syndrome Autosomal dominant Humeroradial synostosis Autosomal dominant Autosomal recessive Klippel-Feil syndrome Faulty development of spinal segments along the embryonic neural tube Klippel-Trénaunay-Weber syndrome Sporadic mutation Krabbe disease Autosomal recessive Deficiency of galactocerebroside β-galactosidase Larsen syndrome Autosomal dominant Autosomal recessive Lesch-Nyhan disease X-linked trait Absence of the enzyme hypo- xanthine guanine phosphori- bosyl transferase Madelung deformity Autosomal dominant Mannosidosis Autosomal recessive Deficiency of the enzymeα - mannosidase Maple syrup urine disease Autosomal recessive Defective metabolism of the amino acids leucine, isoleu- cine, and valine Meckel syndrome (Gruber syndrome) Autosomal recessive Möbius syndrome Autosomal dominant Mucolipidosis (oligosaccharidosis) Autosomal recessive A family of enzyme deficiency diseases Multiple exostoses Autosomal dominant EXT1: greater burden of disease and risk of malignancy EXT2/EXT3 Multiple pterygium syndrome Autosomal recessive Noonan syndrome Sporadic mutation Oral-facial-digital (OFD) syndrome OFD I: X-linked dominant OFD II (Mohr syndrome): autosomal recessive Osler-Weber-Rendu syndrome (he- Autosomal dominant reditary hemorrhagic telangiectasia) Pfeiffer syndrome (acrocephalosyn- Sporadic mutation/autosomal FGF2R dactyly) dominant Phenylketonuria Autosomal recessive Enzyme deficiency characterized by the inability to convert phenylalanine to tyrosine because of a chromosome 12 abnormality Phytanic acid storage disease Autosomal recessive Progeria (Hutchinson-Gilford progeria Autosomal dominant syndrome) Proteus syndrome Autosomal dominant Prune-belly syndrome Uncertain Localized mesodermal defect Radioulnar synostosis Autosomal dominant Rett syndrome Sporadic mutation/X-linked dominant Roberts syndrome (pseudothalido- Sporadic mutation/autosomal mide syndrome) recessive Russell-Silver syndrome Sporadic mutation (possibly X-linked) Saethre-Chotzen syndrome Autosomal dominant Sandhoff disease Autosomal recessive Enzyme deficiency of hexosa- minidases A and B Schwartz-Jampel syndrome Autosomal recessive Seckel syndrome (so-called bird- Autosomal recessive headed dwarfism) Basic Sciences 67

Table 1.31 Comprehensive Compilation of Inheritance Pattern, Defect, and Associated Gene in Musculoskeletal Disorders—cont’d DISORDER INHERITANCE PATTERN DEFECT ASSOCIATED GENE Stickler syndrome (hereditary pro- Autosomal dominant Collagen abnormality gressive arthroophthalmopathy) Thrombocytopenia-aplasia of Autosomal recessive radius (TAR) syndrome Tarsal coalition Autosomal dominant Trichorhinophalangeal syndrome Autosomal dominant Argininemia Autosomal recessive Argininosuccinic aciduria Autosomal recessive Carbamyl phosphate synthetase Autosomal recessive deficiency Citrullinemia Autosomal recessive Ornithine transcarbamylase defi- X-linked ciency VATER association Sporadic mutation Werner syndrome Autosomal recessive Zygodactyly Autosomal dominant

TGF-βR2, TGF-β receptor 2; VATER, vertebral defects, imperforate anus, tracheoesophageal fistula, and radial and renal dysplasia.

• Example: hypophosphatemic rickets, due to PHEX n Chromosomal abnormalities gene mutation (Xp.22) • Disruptions in the normal arrangement or number of • X-linked recessive chromosomes • Examples: Duchenne and Becker muscular • Trisomy: one chromosome pair has an extra dystrophies, Hunter syndrome, hemophilia, chromosome (total: 47 chromosomes) spondyloepiphyseal dysplasia (SED) tarda • Trisomy 21 (Down syndrome)—ligamentous n Nonmendelian traits may be inherited through “polygenic” laxity, atlantoaxial instability, patellar and hip transmission caused by the action of several genes dislocations, severe flatfoot, and bunions • Charcot-Marie-Tooth disease (AD, AR, and X-linked forms) • Deletion: absence of a section of one chromosome (in a • Osteopetrosis (AD and AR) chromosome pair). • Osteogenesis imperfecta (AD and AR) • Duplication: presence of an extra section of one • Neurofibromatosis (AD and AR) chromosome (in a chromosome pair). • SED (AD and X-linked) • Translocation: exchange of a portion of one n Mutations chromosome with a portion of another chromosome • Genetic disorders arise from alterations (mutations) in • Inversion: a broken portion of a chromosome reattaches the genetic material. to the same chromosome in the same location but in a • Most skeletal dysplasias are single-gene mutations. reverse direction. • Collagen type I (bone) defects n Genetics of musculoskeletal conditions and abnormalities • Osteogenesis imperfecta (types I–IV)—COL1A1 are summarized in Table 1.31. and COL1A2 genes n Techniques used to study genetic (inherited) disorders • Ehlers-Danlos—COL5A1 and COL5A2 genes • Restriction enzymes • Collagen type II (cartilage) defects • Used to cut DNA at precise, reproducible cleavage • SED—COL2A1 gene, usually random mutations locations • Others • Identify polymorphisms (alternative gene • Multiple epiphyseal dysplasia—COMP (cartilage expressions) oligomeric matrix protein) gene; also associated • Agarose gel electrophoresis with pseudoachondroplasia) • Molecules are suspended in agarose gel that is • Marfan syndrome—FBN1 (fibrillin-1) gene exposed to an electric field. • Achondroplasia—FGFR3 (fibroblast growth • Molecules move through the gel according to size factor receptor) gene and polarity • Spinal muscular atrophy—SMN1 (survival • Southern blot: detects DNA motor neuron-1) gene • Northern blot: detects RNA n Epigenetics • Western blot: detects protein • Genetic alterations that are not caused by mutations in • Plasmid vectors DNA sequence • A plasmid is a small, extrachromosomal, circular • DNA methylation piece of DNA that replicates independently of the • Histone posttranslational modifications host DNA. Plasmids can confer antibiotic resistance • Genomic imprinting (parent-of-origin phenotypes) between bacteria. • An example of genomic imprinting is the loss • The recombinant plasmid is inserted into a of a region in chromosome 15 with Prader-Willi bacterium (the vector) by a process called syndrome (paternal; obesity, hypogonadism, transformation. The bacterium then produces a hypotonia) and Angelman syndrome (maternal; recombinant protein encoded by the inserted gene. epilepsy, tremors, smiling). • Cytogenetic analysis 68 Basic Sciences

Microbe

Innate immunity Adaptive immunity

B lymphocytes Epithelial Antibodies barriers

Phagocytes Effector T cells T lymphocytes

Complement NK cells

Hours Days 0612 14 7 Time after infection

FIG. 1.48 Innate immunity and adaptive immunity. The mechanisms of innate immunity provide the initial defense against infections. Adaptive immune responses develop later and consist of activation of lymphocytes. (From Abbas AK et al: Cellular and molecular immunology, ed 6, Philadelphia, 2009, Saunders.)

• Gross examination of chromosomes under • Urinary tract microscope with the use of techniques of banding • Recognition of pathogens by innate system and fluorescent in situ hybridization • Pathogen-associated molecular patterns • Used to detect chromosomal translocations (PAMPs) on microbes are recognized by • t(X;18)—in synovial sarcoma TLRs on innate immune system cells (e.g., • t(11;22)—in Ewing sarcoma macrophages and dendritic cells). • t(2;13)—in rhabdomyosarcoma • Example of a PAMP is bacterial lipopolysaccharide • t(12;16)—in myxoid liposarcoma (LPS), which is recognized by TLR-4. • t(12;22)—in clear cell sarcoma • There is an upregulation of NF-κB transcription • Transgenic animals factor, resulting in release of immune mediators • Bred to investigate the function of cloned genes. (e.g., IL-1, IL-6, TNF-α). • PCR amplification • IL-6 causes the liver to release inflammatory • Repetitive synthesis (amplification) of a specific DNA mediators such as CRP. sequence in vitro • Arachidonic acid released from cell membranes • Screening DNA for gene mutations (e.g., prenatal is acted on by COX and 5-lipoxygenase to make diagnosis of sickle cell) prostaglandins and leukotrienes that mediate • Reverse transcription PCR (RT-PCR) exudation, chemotaxis, and bronchospasm. • Reverse transcriptase is used to “reverse transcribe” • Ibuprofen inhibits COX and reduces RNA to complementary DNA. prostaglandin production, preventing renal • Typically used to study RNA viruses efferent arteriolar relaxation and increasing • Silencing RNA (siRNA) GFR. • Blocks transcription of mRNA in order to study • Factor (XII)—inflammatory protein made in the liver result of gene’s loss of function • When exposed to collagen under damaged n Immunology endothelium, activates coagulation n The immune system is broadly categorized into two • Acute production of coagulation factors elevates branches: the innate and the adaptive, with interaction ESR. and overlap between the two (Fig. 1.48). • Complement • The innate system is primitive, nonspecific, the first • Activated by IgM or IgG antigen (Ag) line of defense using complement and leukocytes. complexes, microbial products, or mannose on • Is antigen independent and involves NK cells, microorganisms mast cells, basophils, eosinophils, macrophages, • Mediates chemotaxis of PMNs, opsonization neutrophils, and dendritic cells (tagging of evasive bacteria for elimination in the • Barriers—physical and chemical components (e.g., spleen), and membrane attack complex lysis of enzymes, pH) microbes, among other functions • Skin—sebum, sweat (lysozyme, RNases and • The adaptive system is more complex, is antigen DNases, defensins, cathelicidins) dependent, and works through antigen presentation • Mucous membranes (IgA is most common with B and T lymphocytes and antibodies. immunoglobulin) • Response to a pathogen generates an immunologic • Respiratory epithelium memory in the adaptive system. Basic Sciences 69

• Antigens are ligands recognized by the immune • Once secreted, antibodies can defend by a variety system. The smallest part of an antigen “seen” by a of mechanisms. T- or B-cell receptor is an epitope. • Neutralization of viruses and toxins • Cell mediated—T lymphocytes (helper, CD4+; • Opsonization cytotoxic, CD8+), macrophages • Complement activation (IgG and IgM) • Targets intracellular bacteria, virus, fungi, • Antibody cellular cytotoxicity parasites, tumors, and transplanted organs/ • Prevention of adherence and colonization (IgA) orthopaedic hardware • Cellular response in inflammation • Antigen-presenting cells (APCs—macrophages, • Neutrophil response—first cells recruited to sites dendritic cells, certain B cells, and Langerhans of tissue injury cells) process antigens. • Margination, rolling, adhesion, chemotaxis, and • Humoral—B lymphocytes and their matured phagocytosis counterparts, plasma cells. Both produce antibodies. • Macrophage response—follows neutrophil • Targets exotoxin-mediated disease, encapsulated response bacterial infection, other viral infections • Initiate inflammatory response in osteolysis • Each B cell makes antibodies specific to one single or aseptic loosening (occurs in response to epitope (antigen). B cells use immunoglobulins particles <1 μm in diameter) (IgM and IgD) as cell membrane receptors. • Mast cells—activated by trauma, complement, or • Terminally differentiated B cells are called IgE cross-linking, releasing histamine granules plasma cells. The difference is that they secrete • Histamine mediates the peripheral nerve axon immunoglobulins into fluid. reflex that results in vascular smooth muscle • Immunoglobulins (Fig. 1.49) (mnemonic: relaxation. MADGE) • Excessive endothelial vasodilation with • IgM: heaviest, first in the adaptive response respiratory smooth muscle constriction • IgA: in mucosal surfaces (e.g., MALT [mucosa- is an emergency mediated by IgE–type I associated lymphoid tissue]) and secretions hypersensitivity reaction and can lead to • IgD: only on B-cell surfaces shock and death. • IgG: also on B-cell surface but also secreted. n Autoimmunity • Mediates opsonization; later in the adaptive • Recognition of epitopes from the “self” response • ANAs, which are seen in many disease processes • IgE: on the surface of mast cells (allergic • Anti-Sm—SLE reactions), basophils, and eosinophils (response • Anti-RNP—mixed connective tissue disease to parasite). • Anti–scl-70—scleroderma • Anti-dsDNA—SLE; also implicated in SLE Secreted IgC nephritis • Antihistone—drug-induced lupus Heavy chain Antigen- • Anti-Ro and Anti-La—Sjögren syndrome Light • HLA gene on chromosome 6 can be rearranged to chain binding site make an antigen-specific receptor on APCs for up to N N V 15 N H N 10 different epitopes. • HLA-B27 is associated with a variety of rheumatologic diseases (mnemonic: PAIR) C VL H1 • Psoriatic arthritis • AS CL • C C Fab Inflammatory bowel disease region • Reactive arthritis (Reiter syndrome) Hinge • Also juvenile RA Fc receptor/ • HLA-DR3: myasthenia gravis and SLE complement CH2 • HLA-DR4: RA binding sites Fc n region Hypersensitivity reactions • Type I: mediated by IgE CH3 • Anaphylaxis or allergic response, immediate response, mast cell degranulation • Food allergy (milk, egg, peanut, seafood, etc.) and Tail piece drug allergies CC • Type II: mediated by IgM or IgG, cytotoxic, antibody- Disulfide bond mediated response • Heparin-induced thrombocytopenia Ig domain • Rheumatic fever • Myasthenia gravis • Type III: immune complex mediated (antigen-antibody FIG. 1.49 Basic subunit structure of the immunoglobulin molecule. [e.g., IgG-Ag]) CH and CL, Constant regions; Fab, antigen-binding fragment; Fc, crystallizable fragment; VH and VL, variable regions. (From Katz VL et al: • SLE Comprehensive gynecology, ed 5, Philadelphia, 2007, Mosby.) • RA 70 Basic Sciences

• Type IV: cell-mediated (no antibodies); helper T cells • M protein: group A Streptococcus pyogenes—inhibits activate cytotoxic cells and macrophages to attack phagocytosis tissue; delayed response. • Inhibits activation of alternative complement • TB screening with PPD (purified protein derivative)/ pathway on cell surface Mantoux test • Toxins • Type 1 diabetes mellitus • Endotoxin: gram-negative lipopolysaccharide • Multiple sclerosis capsules • Type IV response to metallic orthopaedic • Exotoxin implants • Clostridium perfringens: lecithinase—tissue- • Pseudotumor hypersensitivity response can occur destroying alpha toxin years after THA. • Myonecrosis and hemolysis of gangrene n Cytokines • Clostridium tetani: tetanospasmin—blocks • Low-molecular-weight proteins that bind to receptors inhibitory nerves and elicit cellular responses. • “Lockjaw” or muscle spasms • Each cytokine can serve a variety of functions: • Clostridium botulinum: botulism—blocks • IL-1—initiates acute phase response acetylcholine release • Induces bone loss through activation of • “Floppy” baby (also wrinkle relaxers and osteoclasts via RANK/RANKL pathway. antispasmodic for cerebral palsy) • IL-2—promotes growth and activation of • Community-associated MRSA: Panton-Valentine lymphocytes leukocidin (PVL) cytotoxin • IL-6—induces synthesis of acute-phase proteins from • Pore-forming toxin specific to neutrophils liver (e.g., CRP) • Superantigens • IL-6 is key to growth and survival of multiple • Activate approximately 20% of T cells myeloma (MM) cells. • Trigger cytokine release • Generated in autocrine (MM cells) and paracrine • Systemic inflammation; appears as septic shock (bone marrow stromal cells and osteoblasts) • S. pyogenes (group A streptococci): M protein fashion • S. aureus: TSS toxin-1 causes toxic shock syndrome • IL-10—antiinflammatory • Acute febrile illness with a generalized • TNF-α—helps mediate inflammatory response to scarlatiniform rash intracellular infections • Hypotension (shock) with organ system failure • TGF-β—limits inflammation and promotes fibrosis • Desquamation of palmar/plantar skin lesions (if the patient lives) INFECTION AND MICROBIOLOGY • Treatment: • Removal of foreign object (retained sponge or n Musculoskeletal infections overview tampon) n Treatment overview • Supportive care with fluids and anti- • Empirical treatment: based on the presumed type of Staphylococcus antibiotics infection as determined from clinical findings and n Staphylococcus: roughly 80% of orthopaedic infections symptoms. Staphylococcus and Streptococcus are the • Antibiotic resistance most common organisms infecting skin, soft tissue, and • Penicillin (β-lactam antibiotic)—inhibits bone. peptidoglycan bonds of bacterial cell walls • Definitive treatment: based on final culture and • β -Lactamases are enzymes produced by bacteria that sensitivity results when available provide resistance by breaking down the antibiotic • Surgical treatment: draining of contained infections, structure. débridement of dead tissue, restoration of vascularity • MRSA n Bacterial virulence • mecA gene • Antibiotic resistance—plasmid • Located on staphylococcal chromosome cassette • β -Lactamase (bla gene)—makes staphylococci mobile element–carrying IV (SCCmecIV) resistant to penicillin • Encodes for penicillin-binding protein 2A, • Penicillin-binding protein 2a (mecA gene)—makes which has a low affinity forβ -lactam antibiotics Staphylococcus aureus MRSA • Community versus hospital • Increased surface adhesion • Hospital-acquired MRSA (HA-MRSA) or health care– • Fnb gene—fibronectin inS. aureus acquired (HC-MRSA) • Increases adhesion to titanium • Seen in patients from nursing homes, those • Glycocalyx-biofilm-slime-polysaccharide capsule with recent bacteria have larger SCCmec genetic • Improves attachment to inert surfaces elements • Protects bacteria from desiccation • Multiple antibiotic resistance genes • Cell protection from phagocytosis • More drug resistance; known as “super bugs” • Glycocalyx-biofilm-slime-polysaccharide capsule— • Community-acquired MRSA (CA-MRSA) inhibits phagocytosis • Bacteria have smaller SCCmec genetic elements • Hides PAMPs • Less drug resistance • Protects bacteria from toxic enzymes/chemicals • Almost all have PVL cytotoxin • Protein A: S. aureus—inhibits phagocytosis • γ -Hemolysin: a pore-forming toxin that can lyse • Binds immunoglobulins (Fc region of IgG) PMNs Basic Sciences 71

• Seen in young adults with recurrent boils and • Skin microcirculation thrombosis and later necrosis severe hemorrhagic pneumonia • Early—pain out of proportion, swelling and edema • At-risk groups: athletes, IV drug abusers, • Late homeless persons, military recruits, prisoners • Blisters/bullae • Risk factors • Skin that does not blanch (skin is dying) • Previous antibiotic use within 1 year • Skin becomes numb (nerves are dying) • Frequent skin-to-skin contact with others • Difficult diagnosis—paucity of cutaneous findings so • Frequent sharing of personal items high clinical suspicion needed • Compromised skin integrity • Less than one-fifth of cases diagnosed at n Infection by tissue type admission; preadmission antibiotics mask n Soft tissue infections: superficial to deep Table( 1.32) severity • Erysipelas: infection of dermis and lymphatics—group • Repeated examinations noting margins that A streptococci migrate quickly despite antibiotic treatment • Painful raised lesion with a red, edematous, • Surgical findings indurated (peau d’orange) appearance and an • Grayish necrotic fascia advancing raised border • Lack of normal muscular fascial resistance to blunt • Treatment: penicillins or erythromycin dissection • Cellulitis: subcutaneous infection most commonly • Lack of bleeding of the fascia during dissection group A streptococci or S. aureus • Foul-smelling “dishwater” pus • Acute spreading infection with pain, erythema, and • Treatment: broad-spectrum antibiotics warmth, with or without lymphadenopathy; may • Early operative débridement of all necrotic develop into abscess (may surround abscess or ulcer) tissue—level selected should be ahead of the • Treatment: routine for cellulitis—penicillin, infection dicloxacillin; but IV cefazolin or nafcillin if • Amputation/disarticulation should be considered. systemic systems prominent or patient is at high • Second-look procedure should be performed 24 risk (asplenia, neutropenia, immunocompromise, hours later for reevaluation. cirrhosis, cardiac or renal failure, local trauma, or • Gas gangrene preexisting edema) • C. perfringens (obligate anaerobe) most common • Abscess: pus-filled inflammatory subcutaneous nodule organism that produces gas and toxins in (furuncle = “boil”) that may be multiple and may subcutaneous tissues and muscle coalesce (carbuncle): almost always S. aureus. Small • Dirty wound managed with primary closure: war lesions sometimes mistaken as spider bites. wounds, tornado, lawn mower • Painful pus under pressure • Inadequate débridement of more severe devitalizing • Treatment: incision and drainage (I&D), then left open, injuries with culture and sensitivity testing to select antibiotics. • Clostridial dermonecrotizing exotoxin lecithinase • For simple abscesses, addition of systemic antibiotics • Crepitance of soft tissue, air in soft tissues on x-rays, has not been shown to improve cure rate or decrease foul “sweet”-smelling discharge recurrence above I&D alone. • Treatment • Systemic antibiotics only for (Infectious Disease • Early, adequate, and thorough surgical Society of America Guidelines): débridement • Severe or extensive disease • Delayed closure and second-look procedure 24 • Rapid progression in the presence of associated hours later for reevaluation cellulitis • High-dose IV penicillin and hyperbaric oxygen can • Signs and symptoms of systemic illness help if available. • Associated comorbidities or immunosuppression, • Surgical site infection extremes of age • Infections are the product of bacteria that take hold • Abscess in an area difficult to drain in a favorable wound environment in a host with a • Associated septic phlebitis susceptible immune system. • Lack of response to incision and drainage • Bacterial issues • Empirical antibiotics selected should aim at MRSA. • Load • Necrotizing fasciitis • More than 105 colony-forming units (CFUs) • Rare, rapidly progressive, life-threatening infection of needed in normal host to cause infection the fascia and subcutaneous tissue • Need only about 100 CFUs if foreign object present • Causes liquefactive necrosis with thrombosis of the • Prevention cutaneous microcirculation • Prophylactic antibiotics • Most commonly polymicrobial, but group A • Given from less than 1 hour before until 24 hours β-hemolytic (“flesh-eating”) streptococci the most after procedure common monomicrobial cause (i.e., S. pyogenes). • Repeated if preceding time is more than 4 hours • Risk factors: diabetes, peripheral vascular disease, (longer than half-life of antibiotic selected) liver failure • Repeated if blood loss more than 1000 mL • Death most related to delay in treatment for more • Doubled if patient weighs more than 80 kg (>176 lb) than 24 hours • Avoidance of hematogenous seeding • Fascial infection spreads faster than the observed • No active infections in elective cases—legs, feet, skin changes. toes checked preoperatively Table 1.32 Soft Tissue Infections TYPE AFFECTED TISSUES CLINICAL FINDINGS ORGANISMS TREATMENT Cellulitis, Superficial, Erythema; tenderness; warmth; Group A streptococci (most common) Initial antibiotic treatment: penicillin G or penicillinase-resistant erysipelas subcutaneous lymphangitis; lymphadenopathy Staphylococcus aureus (less common) synthetic penicillins (nafcillin or oxacillin) Alternative therapies: erythromycin, first-generation cephalosporins, amoxicillin/clavulanate, azithromycin, clarithromycin, tigecycline, or daptomycin Necrotizing Muscle fascia Aggressive, life-threatening; may be Four types: Extensive emergency surgical débridement (involving entire fasciitis associated with an underlying Groups A, C, and G streptococci length of the overlying cellulitis) and intravenous antibiotics vascular disease (particularly Clostridia Initial antibiotic treatments: penicillin G for streptococcal or diabetes) Polymicrobial (aerobic plus anaerobic) clostridial infection; imipenem, doripenem, or meropenem for Commonly occurs after surgery, trau- MRSA polymicrobial infections ma, or streptococcal skin infection Add vancomycin or daptomycin if MRSA suspected Gas gangrene Muscle; commonly in Progressive, severe pain; edema Classically caused by Clostridium Primary treatment: surgical (radical) débridement with fascioto- grossly contami- (distant from the wound); perfringens, Clostridium septicum, or mies nated, traumatic foul-smelling, serosanguineous other histotoxic Clostridium spp. Hyperbaric oxygen may be a useful adjuvant therapy, although wounds, particu- discharge; high fever; chills; These gram-positive, anaerobic, its larly those that are tachycardia; confusion spore-forming rods produce exotoxins effectiveness remains inconclusive closed primarily Clinical findings consistent with that cause necrosis of fat and muscle Initial antibiotic treatment: clindamycin plus penicillin G toxemia and thrombosis of local vessels Alternative therapies include ceftriaxone or erythromycin Radiographs typically show widespread gas in the soft tissues (facilitates rapid spread of the infection) Tox shock syndrome: Staphylococcal Toxemia, not septi- Fever, hypotension, an erythematous Caused by toxins produced by S. aureus Irrigation and débridement and intravenous antibiotics with cemia macular rash with a serous exudate intravenous immune globulin In orthopaedics, TSS (gram-positive cocci are present) Initial antibiotic treatment: penicillinase-resistant penicillins (naf- is secondary to The infected wound may look benign, cillin or oxacillin), vancomycin if MRSA colonization of sur- which may belie the seriousness of Alternative therapies include first-generation cephalosporins gical or traumatic the underlying condition Patients may also require emergency fluid resuscitation wounds (even after minor trauma) TSS can be associated with tampon use through colonization of the vagina with toxin-producing S. aureus Streptococcal Toxemia, not septi- Similar to staphylococcal TSS Toxins from group A, B, C, or G Initial antibiotic treatment: clindamycin plus penicillin G cemia Streptococcus pyogenes Alternative therapy includes ceftriaxone or clindamycin Commonly associated Intravenous immune globulin may be used; associated with with erysipelas or decrease in organ failure, but no effect on all-cause mortality necrotizing fasciitis in children Surgical wound Varies S. aureus; groups A, B, C, and G Initial antibiotic treatment: trimethoprim-sulfamethoxazole or infection streptococci clindamycin Other organism may be involved MRSA species are best treated with vancomycin (alternatives for MRSA include daptomycin and ceftobiprole). Marine injuries Varies History of fishing (or other marine Marine injuries involve organisms that can V. vulnificus is best treated with ceftazidime plus doxycycline; activity) injury, with signs of infec- cause indolent infections cefotaxime and ciprofloxacin are alternatives tion Vibrio vulnificus is the most likely organism M. marinum is best treated with clarithromycin, minocycline, Culture specimens at 30°C (60°F); in infected wounds that were exposed to doxycycline, trimethoprim/sulfamethoxazole, or rifampin plus organisms may take several weeks brackish water or shellfish; can cause a ethambutol to grow on culture media devastating infection Atypical mycobacteria (e.g., Mycobacterium marinum) should also be considered for injuries with indolent, low-grade infection Basic Sciences 73

• If urologic symptoms: urinalysis and culture • Antibiotic prophylaxis controversial • Postpone surgery if: • Should be considered for bites to hands, feet, face • Over 103 CFUs and dysuria/frequency • Wounds hard to clean—deep punctures, edema/ • Symptoms of urinary obstruction crush injury • Reduced force, hesitancy, straining • Bites involving tendon, cartilage, or bone • Foley catheterization should be discontinued as • Bites in immunocompromised or asplenic host soon as possible after surgery. • Bite prophylaxis antibiotics: amoxicillin- • MRSA: carrier screening and eradication, “active clavulanate detection and isolation (ADI)” • For penicillin-allergic patient, trimethoprim- • Nasal carriage—important risk factor, with some sulfamethoxazole plus clindamycin controversy; if patient part of high-risk population • Antibiotic treatment: oral unless infection rapidly • Screening spreads or patient is febrile or high risk; then IV • Swab culture versus PCR • Bite organisms • If positive screen result: postoperative • Most oral flora is polymicrobial in nature. Some infection rates are two to nine times higher bacteria are more specific to source of “bite.” • Use vancomycin 1 g every 12 hours • Human bites: Streptococcus viridans common, • 2% intranasal mupirocin ointment twice Eikenella corrodens daily × 5 days • “Fight bite” x-rays for cartilage divots, broken • 2% chlorhexidine showers daily × 5 days teeth, and formal identification • Nutrition (malnutrition associated with wound • Cat bites: Pasteurella multocida dehiscence and infection) • 50% require surgery—puncture wounds to • Clinical evaluation tendons/joints • History of weight loss (10% over 6 months or • Dog bites: P. multocida, Pasteurella canis 5% over 1 month) • Marine injuries • Albumin value less than 3.5 g/dL, total • Mycobacterium marinum lymphocyte count less than 1500 cells/μL, • Slow culture at low temperature (30°C) transferrin level less than 200 mg/dL • Noncaseating granulomas • Obesity—body mass index (BMI) more than 30 • Treatment: 3 months of minocycline or kg/m2; higher numbers = more wound problems clarithromycin • Bariatric consultation should be considered early • Erysipelothrix rhusiopathiae in course for patient likely to progress to need • Erysipeloid—fish handler’s (also swine handler’s) large elective procedure. disease • Smoking: two to four times more infections/ • Gram-positive bacillus osteomyelitis • Painful, itchy, spreading, purple ring-shaped • Hypoxia—CO binds to Hb = carboxyhemoglobin lesion (Hbco) • Treatment: oral penicillin • Nicotine—microvascular vasoconstriction • Vibrio vulnificus • Reduced bone, skin, soft tissue healing • Oyster bite • Cessation of smoking 4 to 6 weeks preoperatively • Bullae and necrotizing fasciitis from gram- leads to decreased complications. negative motile rod • Alcohol: heavy alcohol use (blood alcohol >200 mg/ • Gastroenteritis from eating bad oyster dL) increases rate of infections 2.6 times • Treatment: I&D and broad-spectrum antibiotics • Reduced fibroblast production of collagen type I (ceftazidime) • Inhibits osteoblasts: reduced osteocalcin, inhibits • Tick bite (Ixodes): Lyme disease Wnt/β-catenin pathway • Borrelia burgdorferi (a spirochete) • Impairs fracture healing • Erythema migrans: bull’s-eye lesion • Associated with “bad behaviors,” cirrhosis, and • Vector: white-footed deer mouse in northeast and liver failure Pacific north • Diabetes • Knee effusions • Chronic issues well known: cardiac, renal, • Neurologic disease: Bell palsy common peripheral vascular, neuropathy • Treatment: amoxicillin versus doxycycline • Best measured with HbA1c—goal is less than • Rabies (neurotropic virus) 6.9% of total hemoglobin • Raccoon/skunk/bat bites • Acute hyperglycemia is also a threat • CNS irritation, “hydrophobia,” paralysis, and death • Collagen synthesis suppressed at blood glucose • Death if not treated before symptoms occur value of 200 mg/dL—impaired wound healing • Treatment: human rabies immune globulin • WBC phagocytosis impaired at blood glucose • Septic bursitis value of 250 mg/dL—decreased ability to fight • Similar pathology whether in olecranon, prepatellar, infection or pretibial bursa n Special soft tissue infections • Redness, swelling, pain, and subcutaneous • Bite infections (Table 1.33) fluctuance • Initial treatment: exploration of wound, removal of • About 80% caused by S. aureus, others streptococci foreign objects, débridement, and irrigation • Chronic recurrent cases can be fungal or • Consider delayed primary closure at 48–72 hours mycobacterial 74 Basic Sciences

• Aspiration with Gram stain and culture if redness is • Hematogenous: most common osteomyelitis in children presence • Pediatric patients • Treatment • Immature immune system • Serial aspirations and oral antibiotics • Metaphysis or epiphysis of long bones • IV antibiotics for systemic symptoms and in • Lower extremity more often than upper immunocompromised patients • Adult patients • Bursectomy for persistent or recurrent cases • Immunocompromised (elderly, undergoing • Tetanus chemotherapy transplant recipient) • Potentially lethal neuroparalytic disease leading to • Vertebrae most common adult hematogenous site trismus (lockjaw) • Patient undergoing dialysis—rib and spine • Exotoxin from anaerobe C. tetani osteomyelitis • Tetanospasmin blocks inhibitory nerves. • IV drug abuser—medial or lateral clavicle • Deep wounds and devitalized tissues are at high risk. osteomyelitis • Wounds more than 6 hours old, more than 1 cm • Acute osteomyelitis deep, ischemic, crush, grade III • Short duration, usually less than 2 weeks • Contaminated with soil or feces, animal bite • Symptoms include tenderness, limb, refusal to use limb • Vaccination • Fever and systemic symptoms variable • Tetanus toxoid (Td) 0.5-mL diphtheria-tetanus • Laboratory findings: toxoid booster every 10 years • CRP—most sensitive test (increased in ≈97%) • Adults with at-risk wounds, give Td booster • Most rapid rise and fall—good measure of • Status unknown or history of fewer than three treatment success doses: give both Td and tetanus immune globulin • ESR—increased in approximately 90% (TIG) • CBC—WBCs increased in only a third n Osteomyelitis • Aspiration and biopsy cultures—most specific test • Exogenous: most common osteomyelitis in adults • Histopathology: bony spicules with live osteocytes • Acute osteomyelitis from open fracture or bone surrounded by inflammatory cells exposed at surgery • Treatment • Chronic osteomyelitis from neglected wounds: • 6 weeks of antibiotics directed at specific diabetic feet, decubitus ulcers organisms identified by culture

Table 1.33 Bite Injuries SOURCE OF BITE ORGANISM PRIMARY ANTIMICROBIAL (OR DRUG) REGIMEN Human Streptococcus viridans (100%) Early treatment (not yet infected): amoxicillin/clavulanate (Augmen- Bacteroides spp. (82%) tin) Staphylococcus epidermidis (53%) With signs of infection: ampicillin/sulbactam (Unasyn), cefoxitin, Corynebacterium spp. (41%) ticarcillin/clavulanate (Timentin), or piperacillin-tazobactam Staphylococcus aureus (29%) Patients with penicillin allergy: clindamycin plus either ciprofloxacin Peptostreptococcus spp. or trimethoprim/sulfamethoxazole Eikenella spp. Eikenella organisms are resistant to clindamycin, nafcillin/oxacillin, metronidazole, and possibly to first-generation cephalosporins and erythromycin; susceptible to fluoroquinolones and trimethoprim/sulfamethoxazole; treated with cefoxitin or ampicillin Dog Pasteurella canis Amoxicillin/clavulanate (Augmentin) or clindamycin (adults); S. aureus clindamycin plus trimethoprim/sulfamethoxazole (children) Bacteroides spp. P. canis is resistant to doxycycline, cephalexin, clindamycin, and Fusobacterium spp. erythromycin Capnocytophaga spp. Antirabies treatment should be considered Only 5% of dog bite wounds become infected Cat Pasteurella multocida Amoxicillin/clavulanate, cefuroxime axetil, or doxycycline S. aureus Cephalexin should not be used Possibly tularemia P. multocida is resistant to doxycycline, cephalexin, and clindamycin; many strains are resistant to erythromycin Of cat bite wounds, 80% become infected; culture Rat Streptobacillus moniliformis Amoxicillin/clavulanate or doxycycline Spirillum minus Antirabies treatment is not indicated Pig Polymicrobial (aerobes and anaer- Amoxicillin/clavulanate, third-generation cephalosporin, ticarcillin/ obes) clavulanate (Timentin), ampicillin/sulbactam, or imipenem-cilas- tatin Skunk, raccoon, bat Varies Amoxicillin/clavulanate or doxycycline Antirabies treatment is indicated Pit viper (snake) Pseudomonas spp. Antivenin therapy Enterobacteriaceae Ceftriaxone S. epidermidis Tetanus prophylaxis Clostridium spp. Brown recluse spider Toxin Dapsone Catfish sting Toxins (may become secondarily Amoxicillin/clavulanate prophylaxis infected)

Adapted from Gilbert DN et al: The Sanford guide to antimicrobial therapy, Hyde Park, VT, 2010, Antimicrobial Therapy, p 48. Basic Sciences 75

• Surgery is reserved for draining abscesses or failure • Arterial disease, venous stasis, irradiation, to improve on antibiotics. scarring, smoking • Subacute osteomyelitis: Brodie abscess • BS (systemic): compromised immune system • Residual of acute osteomyelitis versus hematogenous • Diabetes mellitus, malnutrition, end-stage renal seeding of growth plate trauma disease, malignancy, alcoholism, rheumatologic • Painful limp with no systemic signs diseases, immunocompromised status • Adolescent to early adult (<25 years)—stronger • HIV, immunosuppressive therapy, DMARDs immune system • BL/S (combined local and systemic) • Localized radiolucency with sclerotic rim at • C: compromised patient (palliative care or metaphysis of long bones amputation) • Almost exclusively S. aureus (may be lower virulence) • No quality-of-life improvement if cured • Treatment: surgical débridement and 6 weeks of IV • Morbidity of procedure exceeds that of the disease. antibiotics • Poor prognosis, poor cooperation with care • Rule out tumors (chondroblastoma): “Biopsy all • Anatomic lesion classification Fig.( 1.50) infections, culture all tumors.” • I: medullary—nidus endosteal • Chronic osteomyelitis • Residual hematogenous or intramuscular infected • History nonunion • Prior trauma/surgery or soft tissue wound • Treatment: unroofing • Previous acute osteomyelitis or septic arthritis • II: superficial—infection on surface defect of • Should be considered in all nonunions coverage • Often chronic wound or draining sinus • Full-thickness soft tissue wounds: venous stasis/ • Laboratory findings pressure ulcer • Less helpful, can be normal • Treatment: decortication and soft tissue coverage • Open bone biopsy/culture best test (sinus tract • III: localized—cortical infection without loss of cultures not helpful) stability • Histopathology • Infected fracture union with butterfly fragment or • Dead bone (avascular) (osteocytes have no nuclei) prior plate • Fibrosis of marrow space • Treatment: sequestrectomy, soft tissue coverage, • Chronic inflammatory cells with or without bone graft • Treatment • IV: diffuse—permeative throughout bone, unstable • Surgery required for chronic osteomyelitis before or after débridement • Basic principles • Periprosthetic infection, septic arthritis or infected • Multiple procedures frequently required nonunions • Removal of infected hardware • Treatment: stabilization, soft tissue coverage, and • Removal of dead bone, which serves as a bone graft “foreign object” • Imaging of osteomyelitis • Débridement of bone until punctate bleeding is • Radiographs restored (“paprika sign”) • Acute osteomyelitis • Débridement of compromised or necrotic soft • Soft tissue swelling (early) tissue • Consideration of preoperative sinus tract injection with methylene blue • Consideration of antibiotic spacers: PMMA cement versus biologics • Restoration of vascularity or soft tissue muscle coverage • Six weeks of antibiotics directed at specific cultures • Adequate minimal inhibitory concentration (MIC) of antibiotics at site of infection • Host classification (Cierny-Mader;Table 1.34) Medullary Superficial • A: healthy • B: wound healing comorbidities • BL (local): compromised vascularity

Table 1.34 Chronic Osteomyelitis: Infected Host Types TYPE DESCRIPTION RISK A Normal immune response; nonsmoker Minimal B Local or mild systemic deficiency; Moderate Localized Diffuse smoker C Major nutritional or systemic disorder High FIG. 1.50 Cierny’s anatomic classification of adult chronic osteomyelitis. 76 Basic Sciences

• Bone demineralization or regional osteopenia • Puncture wounds through rubber/synthetic shoes (≈2 weeks after infection) • TB osteomyelitis • Chronic osteomyelitis • One-third of the world is infected with TB. • Periosteal reaction, cortical erosions, bony • One-third of TB in pediatric and HIV-positive lucency, and sclerotic changes patients is extrapulmonary. • Bony lysis around hardware and prosthetic joints • Spine most common: Pott disease (spinal gibbus) • Sequestra—dead bone nidus with • One-fourth of extrapulmonary TB is in hips and knees. surrounding granulation tissue • Often involves bones on both side of joint • Involucrum—periosteal new bone forming later • Fungal osteomyelitis • MRI best method to show early osteomyelitis and • Long-term IV medications or parental nutrition anatomic location • Immunosuppression by disease or drugs (RA, • Penumbra sign transplantation) • Bright signal in surrounding bone • Candida —most common; is part of normal flora • Darker abscess and sclerotic bone • Aspergillus —rare in bone • Negative finding rules out osteomyelitis • Regional varieties—via inhalation or direct inoculation • Positive finding may overestimate extent of disease • Coccidioides —southwest United States to South • Fluorodeoxyglucose positron emission tomography America (FDG-PET) • Histoplasma —soil and bird/bat guano, Ohio and • Shows malignancies and infections: increased Mississippi river valleys glycolysis • Blastomyces —rotting wood, central southeastern • Most sensitive test for chronic osteomyelitis United States • More specific than MRI or bone scan • Cryptococcus —pigeon droppings, northwest • Empiric treatment for osteomyelitis prior to definitive United States/Canada culture findings • Treatment • Newborn (up to 4 months of age) • Débridement of osteonecrosis, resection of sinuses • S. aureus, gram-negative bacilli, and group B and/or synovitis streptococci • Antifungals: amphotericin • Nafcillin or oxacillin plus a third-generation • Chronic regional multifocal osteomyelitis (CRMO) cephalosporin (also chronic nonbacterial osteomyelitis [CNO]) • If MRSA: vancomycin plus a third-generation • Children/adolescents with multifocal bone pain cephalosporin but no systemic symptoms • Children 4 months of age or older • Exacerbations and remissions, more than 6 months • S. aureus and group A streptococci of pain • Nafcillin or oxacillin versus vancomycin (MRSA) • Autoinflammatory disease; a diagnosis of exclusion • Immunization has almost eliminated Haemophilus • No abscess, fistula, or sequestrum influenzae bone infections. • Laboratory findings: WBC count normal; ESR, • Adults (21 years of age or older) CRP may be elevated • S. aureus • X-rays demonstrate multiple metaphyseal lytic or • Nafcillin or oxacillin versus vancomycin (MRSA) sclerotic lesions. • Antibiotic spacers/beads • Whole-body spin tau inversion recovery (STIR) • Provide very high antibiotic levels at local area MRI more sensitive • 2–4 g per bag (40 g) of cement (>2 g reduces • Culture results negative—antibiotics do not help compressive strength) • Histologic findings • Pouch can be formed and covered with adherent film. • Early: PMNs and osteoclasts • Antibiotics must be heat stable. • Later: lymphocytes, fibrosis, and reactive bone • Cephalosporins, aminoglycosides, vancomycin, • Especially in the medial clavicle, distal tibia, clindamycin and distal femur • Antibiotics inactivated by heat must be avoided • Treatment: symptomatic; resolves spontaneously; • Tetracycline, fluoroquinolones, polymyxin B, NSAIDs help chloramphenicol • SAPHO (synovitis, acne, pustulosis, hyperostosis, • Antibiotics elute out over 2–6 weeks. osteitis) syndrome • Elution increased with • Also called acquired hyperostosis syndrome • Surface area—beads • Young to middle-aged adults with bone pain and • Higher porosity—vacuum mixing should not skin involvement be used. • Suspicion that Propionibacterium acnes serves as • Larger antibiotic crystals—cement should be antigenic trigger mixed until doughy, then antibiotics added. • Humoral induction of sclerosis and erosions • Atypical or unusual organisms • Sternoclavicular region most commonly involved • Salmonella osteomyelitis—sickle cell • Axial skeleton involvement and unilateral • Microinfarcts of bone and bowel sacroiliitis common • Spleen dysfunction • Palmopustular psoriasis, acne, or hidradenitis • Bone crisis versus diaphyseal osteomyelitis suppurativa • Pseudomonas osteomyelitis • Laboratory findings: ESR, CRP moderately elevated • IV drug abuse and osteomyelitis of medial/lateral • Bone scan (gold standard): bull’s head sign, clavicle sacroiliac joint uptake Basic Sciences 77

• MRI: erosion of vertebral body corner • Diagnosis: potassium hydroxide (KOH) versus • Pathology: sterile neutrophilic pseudoabscesses 6-week culture • Cultures: occasional P. acnes • Treatment • Treatment: NSAIDs, rheumatology consult, • I&D methotrexate, and biologics • IV antibiotics best based on culture results n Septic arthritis • Empiric antibiotics based on Gram stain results: • Sources • Gram-positive cocci: vancomycin • Hematogenous spread • Gram-negative cocci: ceftriaxone • Extension of metaphyseal osteomyelitis at • Gram-negative rods: ceftazidime, carbapenem, or intraarticular physis fluoroquinolone • Proximal femur—most common • Negative Gram stain: vancomycin and ceftazidime • Proximal humerus, radial neck, distal fibula or fluoroquinolone • Direct inoculation—penetrating trauma, iatrogenic • Progress can be monitored with CBC, ESR, CRP (best complication measure of success) • Diagnosis n Periprosthetic septic arthritis: see Chapter 5, Adult • Progressive development of joint pain, swelling Reconstruction, for details. (effusion), warmth, redness n Infectious risks of practice • Progressive loss of function n HIV infection • Loading or moving a joint hurts • Obligate intracellular retrovirus • Differential diagnosis of acute monoarthritis • Primarily affects lymphocyte and macrophage cell lines • Gout/pseudogout—may be history of prior episodes • Decreases helper cells (CD4+ cells) • Reactive arthritis—uveitis, urethritis, heel/back pain, • Approximately 50,000 new cases/year reported by the colitis, psoriasis CDC • Viral arthritis • Increased in: homosexual men, patients with • Fever and systemic symptoms more common in hemophilia, and IV drug abusers younger patients • One-fifth of those infected know they are HIV positive. • Laboratory findings • AIDS • Elevations of CRP, ESR, WBC • Diagnosis requires an positive HIV test result plus • Aspiration—best test one of the following: • Cell count: greater than 50,000 WBCs/μL; left • One of the opportunistic infections (e.g., shift pneumocystis) • Gram stain—helpful if positive • CD4+ cell count of less than 200 cell/μL (normal, • Cultures: aerobic and anaerobic 700–1200 cells/μL) • Crystals • Transmission rate • S. aureus most common bacteria, but following • Increases with amount of blood exposed and viral load organisms should also be considered: • Decreases with postexposure antiviral prophylaxis • Group B streptococci (GBS): neonate • From a contaminated needlestick: 0.3% • H. influenza: Unvaccinated children younger than 2 • From mucous membrane exposure: 0.09% years • From a blood transfusion: approximately 1 per • Kingella kingae: slower progressing or less virulent 500,000 per unit transfused septic arthritis in young children • From frozen bone allograft: less than 1 per 1 million • Toddler (aged 1–4 yr) with painful joint • Donor screening—most important factor in • After upper respiratory infection in fall/winter preventing viral transmission • Gram-negative coccobacilli—hard to culture; • No cases from fresh frozen bone allograft have blood bottles should be used been reported since 2001. • PCR should be considered • Most sensitive screen—nucleic acid amplification • Group A strep: post-varicella testing (NAAT) • Neisseria gonorrhoeae: sexually active young adults • HIV positivity is not a contraindication to performing • P. acnes required surgical procedures. • Most common cause after mini–open repair of • HIV-positive patients more likely to have THA rotator cuff • Higher association with liver disease, drug abuse, • Shoulder replacement (second only to S. aureus) coagulopathy • Indolent low-grade common contaminant • Development of acute renal failure and postoperative • More than one culture needed; grows very slowly infection more likely (7–10 days) • Asymptomatic HIV-positive individuals have no • Gram-positive anaerobic rod that fluoresces under significant difference in short-term infection risks. ultraviolet light • Orthopaedic manifestations more common in later stages • Less sensitive to cefazolin (penicillin, vancomycin, • Increased infections: clindamycin) • Polymyositis: viral muscle infection • Fungal infections • Pyomyositis: S. aureus • Chronic effusions, synovitis • TB • Immunocompromise: especially cellular immunity • Bacillary angiomatosis (Bartonella henselae) from cats • IV drug abuse • Reactive arthritis (Reiter syndrome) • Aspiration: 10,000–40,000 WBCs/μL, 70% • Non-Hodgkin lymphoma and Kaposi sarcoma PMNs • Osteonecrosis 78 Basic Sciences

Table 1.35 Mechanism of Action of Antibiotics CLASS OF ANTIBIOTIC EXAMPLES MECHANISM OF ACTION β-Lactam antibiotics Penicillin, cephalosporins Inhibit cross-linking of polysaccharides in the cell wall by blocking transpeptidase enzyme Aminoglycosides Gentamicin, tobramycin Inhibit protein synthesis (the mechanism is through binding to cytoplasmic 30S-ribosomal subunit) Clindamycin and Clindamycin, erythromycin, Inhibit the dissociation of peptidyl-transfer RNA from ribosomes during macrolides clarithromycin, azithromycin translocation (the mechanism is through binding to 50S-ribosomal subunit) Tetracyclines Inhibit protein synthesis (binds to 50S-ribosomal subunit) Glycopeptides Vancomycin, teicoplanin Interfere with the insertion of glycan subunits into the cell wall Rifampin Inhibits RNA polymerase F Quinolones Ciprofloxacin, levofloxacin Inhibit DNA gyrase ofloxacin Oxazolidinones Linezolid Inhibit protein synthesis (binds to 50S-ribosomal subunits)

Table 1.36 Antibiotic Indications and Side Effects ANTIBIOTICS SENSITIVE ORGANISMS COMPLICATIONS/OTHER INFORMATION Aminoglycosides G−, PM Auditory (most common) and vestibular damage is caused by destruction of the cochlear and vestibular sensory cells from drug accumulation in the perilymph and endolymph Renal toxicity Neuromuscular blockade Amphotericin Fungi Nephrotoxic Aztreonam G− Ineffective against anaerobes Carbenicillin/ticarcillin/piperacillin Better against G− than G+ Platelet dysfunction, increased bleeding times Cephalosporins: Nausea, vomiting, diarrhea First generation Prophylaxis (surgical) Cefazolin is the drug of choice Second generation Some G+, some G− Third generation G−, fewer G+ Hemolytic anemia (bleeding diathesis [moxalactam]) Chloramphenicol Haemophilus influenzae, anaerobes Bone marrow aplasia Ciprofloxacin G−, MRSA Tendon ruptures; cartilage erosion in children; antacids reduce absorption of ciprofloxacin; theophylline increases serum concentrations of ciprofloxacin Clindamycin G+, anaerobes Pseudomembranous enterocolitis Daptomycin G+, MRSA Muscle toxicity Erythromycin G+ In cases of PCN allergy Ototoxic Imipenem G+, some G− Resistance, seizure Methicillin/oxacillin/nafcillin Penicillinase resistant Same as penicillin; nephritis (methicillin); subcutaneous skin slough (nafcillin) Penicillin Streptococcal, G+ Hypersensitivity/resistance; hemolytic Polymyxin/nystatin GU Nephrotoxic Sulfonamides GU Hemolytic anemia Tetracycline G+ In cases of PCN allergy Stains teeth/bone (contraindicated up to age 8 yr) Vancomycin MRSA, Clostridium difficile Ototoxic; erythema with rapid IV delivery

G−, Gram-negative; G+, gram-positive; GU, genitourinary; PCN, penicillin; PM, polymicrobial.

n Hepatitis • Single-stick transmission rate ≈3% • Hepatitis B (HB) • Advances in screening have decreased the risk of • Blood transmission: bite/sexual/occupational transfusion-associated infection. • Singlestick transmission rate in the unvaccinated: • Most sensitive method to screen and test early: approximately 30% • PCR = NAAT • Causes cirrhosis, liver failure, and hepatocellular n Antibiotics carcinoma n Prophylactic treatment of open fractures • Screening and vaccination have reduced the risk of • Gustilo I and II fractures: first-generation transmission for health care workers. cephalosporins the treatment of choice • Immune globulin is administered after exposure in • Gustilo IIIA: first-generation cephalosporin plus an unvaccinated persons. aminoglycoside • Allografts are screened for HB surface antigen and • Gustilo IIIB (grossly contaminated): first-generation HB core antibody. cephalosporin plus an aminoglycoside plus penicillin • Hepatitis C (non-A, non-B) (HCV) n Mechanisms of action of antibiotics are summarized in • Blood transmission: two-thirds of U.S. HCV-positive Table 1.35. individuals have IV drug abuse history; 2% of cases n Antibiotic indications and side effects are listed in Table are occupational 1.36. Basic Sciences 79

SECTION 3 PERIOPERATIVE AND ORTHOPAEDIC MEDICINE

THROMBOPROPHYLAXIS • Hypercoagulability • Clotting cascade’s final product is thrombin n Thromboembolic disease • Converts soluble fibrinogen to insoluble fibrin n Common orthopaedic complication n Risk factors and epidemiology • Thrombosis: clotting at improper site • Reported risks of thromboembolic disease vary by: • Embolism: clot that migrates • Definitions: asymptomatic versus symptomatic n Most clinically silent but can be fatal • Location n Complications of thromboembolic disease: • Distal: those below popliteal space have very low • Postthrombotic syndrome: chronic venous insufficiency PE risk • Venous hypertension (HTN) • Proximal: those above popliteal space have higher • Chronic skin issue with swelling, pain PE risk • Pigmentation, induration, ulceration • Patient-specific risks factors Fig.( 1.52) • Recurrent deep venous thrombosis (DVT): risk four to • Prior thromboembolic disease a strong risk factor eight times higher after first DVT • Risk increases exponentially with age (>40 years) • Pulmonary embolism (PE) (Fig. 1.53) n Pathophysiology (Virchow triad) (Fig. 1.51) • Genetic factors—thrombophilias • Endothelial damage: trauma or surgery • Decreased anticlotting factors • Exposes collagen—triggers platelets • Antithrombin III, protein C, protein S • Platelets—three roles: deficiencies • Adhesion and activation • Increased clotting factors or factor activity • Secretion of prothrombotic mediators • Factor V Leiden • Aggregation of many platelets • Mutated factor V not inactivated as effectively • Stasis: allows bonds of clotting proteins and cells by activated protein C, so clotting process • Immobility: pain, stroke, paralysis remains active for longer than normal • Blood viscosity: polycythemia, cancer, estrogen • Elevated factor VIII • Decreased inflow: tourniquet, vascular disease • Hyperhomocysteinemia • Decreased outflow: venous scarring, CHF • Prothrombin G20210A (factor II mutation)

1µ 1 2 A Stasis B Fibrin formation Activated factors accumulate Thrombin absorbed by fibrin and Thrombin formation neutralized A Platelet aggregation Platelet “release reaction” 3

D 4

C Clot retraction B D Propagation Thrombin release → Platelet Successive layers of fibrin and aggregation platelets

E F

C E G H FIG. 1.51 Left, Electromicrograph panel (A through E). (A) Scanning electron micrograph (SEM) of free platelets. (B) SEM of platelet adhesion. (C) SEM of platelet activation. (D) Transmission electron micrograph of aggregating platelets. 1, Platelet before secretion; 2 and 3, platelets secreting contents of granules; 4, collagen of endothelium. (E) SEM of fibrin mesh encasing colorized red blood cells.Right, Illustration panel (A through H) showing venous thromboembolus formation. (A) Stasis. (B) Fibrin formation. (C) Clot retraction. (D) Propagation. (E–H) Continu- ation of this process until the vessel is effectively occluded. (From Miller MD, Thompson SR, editors: DeLee and Drez’s orthopaedic sports medicine: principles and practice, ed 4, Philadelphia, 2014, Saunders; platelet electron micrographs courtesy James G. White, MD, Department of Laboratory Medicine and Pathology, University of Minnesota School of Medicine; Miller MD et al: Review of orthopaedics, ed 6, Philadelphia, 2012, Saunders; and Simon SR, editor: Orthopaedic basic science, Rosemont, IL, 1994, American Academy of Orthopaedic Surgeons, p 492.) 80 Basic Sciences

The secondary hypercoagulable states Most common hypercoagulable Relative Prevalence Venous genetic (primary) disorders risk (%) thromboembolism Abnormalities Abnormalities of Abnormalities of patients (%) of blood flow blood composition vessel wall Hyperviscosity

Decreased antithrombotic factors Venous stasis

Obesity Antithrombin III deficiency20 0.02 2 Postoperative state

Protein C deficiency 6.5 0.3 4 Trauma Protein S deficiency 5 0.003 2 Pregnancy Myeloproliferative disorders Increased prothrombotic factors Cancer

Factor V Leiden–homozygous 80 0.02 Oral contraceptives (C resistance) Nephrotic syndrome Paroxysmal nocturnal hemoglobinuria Factor V Leiden–heterozygous 7 4.8 20 (C resistance) Hyperlipidemia Heparin-associated thrombosis Elevated factor VIII 5 11 25 Diabetes mellitus Thrombotic Hyperhomocysteinemia 3 610 thrombocytopenic purpura

Antiphospholipid syndrome Prothrombin G20210A (increased 3 2.7 7 factor II) Vasculitis

FIG. 1.52 Genetic (primary) disorders (table on left) and secondary hypercoagulable states (figure onright ). (Data from Ginsberg MA: Venous thromboembolism. In Hoffman R et al, editors: Hematology: basic principles and practice, ed 4, Philadelphia, 2005, Churchill Livingstone, pp 2225–2236; Perry SL, Ortel TL: Clinical and laboratory evaluation of thrombophilia, Clin Chest Med 24:153–170, 2003; and Schafer AI: Thrombotic disorders: hypercoagulable states. In Goldman L, Ausiello D, editors: Cecil textbook of medicine, ed 22, Philadelphia, 2004, Saunders, pp 1082–1087.)

Thromboembolic disease by age 6

5 Hypercoagulability

4 Virchow Endothelial Condition Relative risk damage triad 3 Age >70 yr 10–15× Cancer 6× Stasis Pregnancy 5× 2 Lupus antiphospholipid antibodies 4×

Annual incidence per 1000 Oral contraceptive pills 3–4× Obesity (body mass index >29 kg/m2) 3× 1 Smoking 3× Diabetes 2× Hypertension 2× 0 010203040 50 60 70 80 Age

FIG. 1.53 Top, The three primary influences of thromboembolic disease (Virchow triad).Bottom, The relative risks of various patient conditions; note that age has an exponentially increasing risk. (Composite from Miller MD, Thompson SR, editors: DeLee and Drez’s orthopaedic sports medicine: principles and practice, ed 3, Philadelphia, 2014, Saunders; and data from Anderson FA Jr et al: A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study, Arch Intern Med 151:933–938, 1991.)

• Procedure-specific factors (Fig. 1.54) n Diagnosis • PE risk lower with distal procedures versus hip • Clinical diagnosis favors assessment of risk factors. procedures • Physical exam is unreliable: most cases are • Risk higher with longer procedures asymptomatic. • Total knee arthroplasty (TKA) has higher total DVT • DVTs can cause calf pain, palpable cords, swelling. risk but lower PE risk • 50% with classic signs have no DVT according to • Risk with hip fracture is higher than that with THA. studies Basic Sciences 81

Procedure sDVT (%) PE (%)

All hospital admission 0.048–0.07 0.023–0.03

Major orthopaedic procedures: THA, TKA, HFS

In 2 weeks no prophylaxis 1.8 1

In 35 days no prophylaxis 2.8 1.5

In hospital with prophylaxis 0.26–0.8 0.14–0.35

In 35 days with prophylaxis 0.45 0.20

Knee arthroscopy 0.25–9.9 0.028–0.17

ACL reconstruction 0.3 0.8

Hip arthroscopy 0–3.7 0

Shoulder arthroscopy 0.01–0.26 0.01–0.21

Shoulder fracture 0 0.2

Shoulder arthroplasty 0.19–0.2 0.1–0.4

Elbow arthroplasty — 0.25

Foot and ankle surgery 0–0.22 0.02–0.15

Ankle fracture 0.05–2.5 0.17–0.47

Ankle arthroscopy 0 0

ACL, Anterior cruciate ligament; HFS, hip fracture surgery; PE, pulmonary embolism; sDVT, symptomatic deep vein thrombosis; THA, total hip arthroplasty; TKA, total knee arthroplasty.

FIG. 1.54 Rates of symptomatic thromboembolism in orthopaedic sports medicine. (From DeHart M: Deep venous thrombosis and pulmonary embolism. In Miller MD, Thompson SR, editors: DeLee and Drez’s orthopaedic sports medicine: principles and practice, ed 4, Philadelphia, 2014, Saunders, p 207.)

• 50% with venogram positive for clot have normal n Thromboembolic prophylaxis physical findings • Preventing DVTs has been shown to be possible, although • PEs: most asymptomatic whether such prevention avoids death is unproven. • Signs/symptoms include pleuritic chest pain, • Guidelines vary in their recommendations (Fig. 1.57). dyspnea, tachypnea • Prophylaxis recommended for all patients undergoing • Saddle emboli can manifest as death. arthroplasty. • Laboratory studies • Those undergoing THA may benefit from extended • d-dimer studies not helpful after injury/surgery but treatment (≈30 days). negative result rules out significant clot. • For patients without risk-related conditions, • ECG: rule out MI prophylaxis is not recommended for • Nonspecific findings; most common finding is sinus • Upper extremity procedures, arthroscopic procedures, tachycardia. surgery for isolated fractures at knee and below • Radiologic studies (Fig. 1.55) • Mechanical measures • Venogram—best for distal (below popliteal) lesions • Early mobilization (clinical relevance?) • Graduated elastic hose—not sufficient alone • Duplex compression ultrasound—most practical • Intermittent pneumatic compression devices (IPCDs) • Noninvasive, easily repeatable bedside test • Stimulate fibrinolytic system • Finding of “noncompressible vein” about 95% • Low bleeding risks sensitive/specific • Grade IC by 2012 American College of Chest • Guidelines strongly against routine duplex screening Physicians (ACCP) guidelines • Chest x-ray • Continuous passive motion (CPM) of no benefit • Early findings: usually normal, “oligemia,” or • Pharmacologic prophylaxis: prominent hilum (Fig. 1.56B) • Surgical Care Improvement Project (SCIP) quality • Late findings: wedge or platelike atelectasis (see measures require DVT prophylaxis. Fig. 1.56C) • Aspirin • Spiral CT angiography—best.. for suspected PE • Irreversibly binds and inactivates COX in • Ventilation-perfusion (V/Q) scan—most helpful for platelets, thereby reducing thromboxane A2 dye-sensitive patients • Weakest: Use of IPCD encouraged 82 Basic Sciences

FIG. 1.55 Top left to right, Venogram showing deep vein thrombosis). Intraluminal filling defects(arrows) seen on two or more views of a venogram. The left and middle images are at the knee, and the right image is at the hip. Middle, Doppler ultrasound for proximal DVT in femoral vein thrombosis. (A) Longitudinal view shows presence of flow light( blue) in the more superficial vein over an occlusive throm- bus (dark gray). (B) A transverse view without compression shows an open superficial vein, appearing as a black oval (white arrow) and a thrombosed deeper vein as a dark gray circle with an echogenic center (red arrow). (C) A transverse view with compression shows the flattened compressible RT FV PX superficial vein white( arrow) and the unchanged noncompressible thrombosed deeper vein (red arrow). Bottom left, Spiral CT pulmonary angiography. (A) Large pulmonary embolism (arrows). (B) Normal CT. Right images, high probability V/Q scan showing full lung fields on ventilation scan (upper) and multiple areas lacking tracer on the perfusion A Color = flow BCNo compression With compression scan (lower). ant, Anterior; LAO, left anterior oblique; post, posterior; RPO, right posterior oblique. (DVT panel from Jackson Ventilation JE, Hemingway AP: Principles, techniques and complications of angiography. In Grainger RG, editor: Grainger & Allison’s diagnostic radiology: a textbook of medical imaging, ed 4, Philadelphia, 2011, Churchill Livingstone. Original images courtesy Austin Radiological Association and Seton Family of Hospitals.)

L post R RPO

A R ant L LAO

Perfusion

L post RL RPO R

B R ant LR LAO L Basic Sciences 83

A BC

FIG. 1.56 Chest radiographs. (A) Diffuse bilateral fluffy patchy infiltrates, worse at bases, are consistent with ARDS (acute respiratory distress syndrome). (B) A focal area of oligemia in the right middle zone (Westermark sign [white arrow]) and cutoff of the pulmonary artery in the upper lobe of the right lung are both seen with acute pulmonary embolism. (C) The peripheral wedge-shaped density without air bronchograms at lateral right lung base (Hampton hump [black arrow]) develops over time after a pulmonary embolism. (B from Krishnan AS, Barrett T: Images in clinical medicine: Westermark sign in pulmonary embolism, N Engl J Med 366:e16, 2012; C from Patel UB et al: Radiographic features of pulmonary embolism: Hampton hump, Postgrad Med J 90:420–421, 2014.)

Recommendations on prevention of VTE in hip and knee arthroplasty Grade of recommendation: ! Strong + Moderate ~ Weak * Consensus ? Inconclusive Notes from other guidelines: 1 ACCP, 2 NICE, 3 AHRQ ! No “screening” duplex US + History of normal risks of VTE and bleeding, use drugs and/or IPC + D/C platelet inhibitors preop (aspirin, clopidogrel, prasugrel) Discuss with medical team, stop 1 week prior2 + Neuraxial anesthesia to decrease bleeding (no effect on VTE) Caution with drugs and neuraxial1; wait 12 hours after drugs2 ~ Ask history of previous VTE * Hx of VTE, get IPC and drugs DRUGS: LMWH, fondaparinux, dabigatran, rivaroxaban, VKA, aspirin1 * Ask Hx of bleeding disorder (hemophilia) and active liver disease * Hx of bleeding disorder (hemophilia or active liver disease) only IPC If bleeding risk, IPC or nothing1; if bleeding risk > clotting risk, IPC2 * Discuss duration with patient ≥10 days, consider 35 days1 * Early mobilization ? Assess other clotting risk factors ? Assess other bleeding risk factors ? No one technique optimal Drugs and IPC1,2 ; D/C drugs when TKA mobile2 ? IVC filter If VTE risks high and contraindication to prophylaxis2 Guideline title Source: 2011 AAOS Preventing Venous Thromboembolic Disease http://www.aaos.org/research/guidelines 2012 ACCP Prevention of VTE in Orthopedic Surgery Patient http://journal.publications.chestnet.org/ 2012 AHRQVTE Prophylaxis in Orthopedic Surgery, CER 49 http://effectivehealthcare.ahrq.gov/ 2010 NICE Reducing the Risk of VTE in patients admitted to hospital http://guidance.nice.org.uk/CG92/

FIG. 1.57 Recommendations on prevention of VTE in hip and knee arthroplasty. Hx, history; US, ultrasonography.

• Low bleeding risk: Should be considered for • Activates antithrombin III (ATIII), which then patients at higher risk for bleeding. inactivates factor Xa and thrombin • Warfarin (Coumadin) • Protamine sulfate can reverse • Prevents vitamin K γ-carboxylation in liver • Short half-life: 2 hours • Inhibits factors II, VII, IX, X, and proteins C and S • High bleeding rate in arthroplasty • Vitamin K and fresh frozen plasma can reverse • Binds platelets—heparin-induced • Multiple reactions with drugs and diet thrombocytopenia • Must be monitored with international normalized • Low-molecular-weight heparin (LMWH) ratio (INR; goal, 2–3) • Reversibly inhibits factor Xa through ATIII and • Heparin factor II 84 Basic Sciences

• Protamine sulfate can reverse Association (ACC/AHA) elements for assessing risk • No monitoring needed • Clinical risk factors in perioperative cardiac risk • Less heparin-induced thrombocytopenia • Major predictors • Higher risk for bleeding than with warfarin • Unstable/severe angina, recent MI (<6 weeks) • Fondaparinux • Worsening or new-onset CHF • Irreversibly but indirectly inhibits factor X • Arrhythmias through ATIII • Atrioventricular (AV) block • Synthetic pentasaccharide • Symptomatic ventricular dysrhythmia: bradycardia • No monitoring (<30 beats/min), tachycardia (>100 beats/min) • No antidote • Severe aortic stenosis or symptomatic mitral stenosis • Higher risk for bleeding than with LMWH • Other • Rivaroxaban • Prior ischemic heart disease • Direct Xa inhibitor • Prior CHF • Oral drug • Prior stroke/ TIA • Higher risk for bleeding than with LMWH • Diabetes • Hirudin • Renal insufficiency (creatine >2 mg/dL) • Direct thrombin (IIa) inhibitor • Functional exercise capacity—measured in metabolic • Intramuscular and oral (dabigatran) versions equivalents (METs) • No antidote • MET: 3.5 mL O2 uptake/kg/min • Inferior vena cava (IVC) filter use: controversial • Perioperative risk elevated if unable to meet 4-MET • Should be considered in following conditions: demand • Contraindication to prophylaxis • Walk up flight of steps or hill (= 4 METs) • Cerebral bleed/trauma • Heavy work around house (>4 METs) • Spine surgery • Can patient walk four blocks or climb two flights • Prior complication of prophylaxis of stairs? n Treatment of thromboembolic disease • Surgery-specific risk: • Pharmacologic treatment • High risk (>5% risk of death/MI) • Prolonged therapy often recommended • Aortic, major or peripheral vascular procedures • Approximately 3 months after DVT, approximately • Intermediate risk (1%–5% risk of death/MI) 12 months after PE • Orthopaedic, ENT, abdominal/thoracic or • Early mobilization—no bed rest procedures • Risk of dislodgment less than risk of more clots in • Low risk (<1% risk of death/MI)—usually do not these high-risk patients need further clearance • Graduated elastic compression hose for 2 years • Ambulatory surgery, endoscopic or superficial • May prevent postthrombotic syndrome procedures • Thrombolytics, thrombectomy, embolectomy controversial n Twelve-lead ECG if: n Special venous thromboembolism (VTE) situations • CAD and intermediate-risk procedure • Isolated calf thrombosis smaller than 5 cm rarely needs • One clinical risk factor and intermediate-risk procedure treatment. n Noninvasive evaluation of left ventricular function if: • Follow with serial ultrasound scans. • Three or more clinical risk factors and intermediate-risk • Upper extremity blood clot in athlete procedure • “Effort thrombosis” (Paget-Schroetter syndrome) • Dyspnea of unknown origin • Axillary–subclavian vein thrombosis • CHF with worsening dyspnea without testing in 12 • Complaints months • Pain, swelling n β -Blockers and statins should be continued around the • Dilated veins time of surgery. • Feeling of heaviness n Acetylsalicylic acid (ASA) should be stopped 7 days prior • Diagnosis: duplex ultrasound to surgery. • Treatment: thoracic outlet decompression should be n Cardiology consultation should be considered for patients considered taking other agents (clopidogrel, prasugrel). • Risk of stent thrombosis balanced with that of surgical PERIOPERATIVE DISEASE AND COMORBIDITIES bleed n Shock n Orthopaedic surgeons who evaluate their patients with care n Cardiovascular collapse with hypotension, followed by preoperatively can be rewarded with fewer perioperative impaired tissue perfusion and cellular hypoxia. May be a problems. result of orthopaedic pathology or a complication of surgery. n Goals include finding correctable issues and identifying risks to n Metabolic consequence provide accurate risk/benefit assessment for proper consent. • O2 is unavailable—no oxidative phosphorylation n Cardiac issues • Cells shift to anaerobic metabolism and glycolysis n Coronary artery disease (CAD): leading cause in those • Pyruvate is converted to lactate—metabolic acidosis older than 35 years • Lactate—indirect marker of tissue hypoperfusion n Leading cause of cardiac death in young sports • Best measures of adequate resuscitation population: hypertrophic cardiomyopathy • Clinical measure of organ function: urine output n American College of Cardiology/American Heart more than 30 mL/h Basic Sciences 85

• Laboratory measure: serum lactate less than 2.5 • Blood products make better resuscitation fluids mg/dL than saline. n Types of shock n Perioperative pulmonary issues • Neurogenic shock n Higher in cases that involve thorax such as scoliosis • High spinal cord injury (also anesthetic accidents) n Highest in patients with prior disease • Loss of sympathetic tone and of vasomotor tone of • Spinal/epidural anesthesia favored over general peripheral arterial bed • Medical treatment should be maximized around surgery. • Bradycardia, hypotension, warm extremities n COPD • Treatment: vasoconstrictors and volume • Symptomatic COPD: anticholinergic inhalers • Septic shock (vasogenic) (ipratropium) • Number one cause of ICU death • May require corticosteroids • Mortality 50% n Asthma • Bacterial toxins stimulate cytokine storm. • Presence of wheezes or shortness of breath: β-agonist • Examples: gram-negative lipopolysaccharides inhalers (albuterol) • Toxic shock superantigen • Perioperative oral steroids safe • Inflammatory mediators cause endothelial • Systemic glucocorticoid should be considered if dysfunction and peripheral vasodilation forced expiratory volume in 1 minute (FEV1) or peak • Treatment expiratory flow rate (PEFR) is below 80% predicted • Identification and treatment of infections values/personal best. • Prompt resection of dead tissue n Postoperative atelectasis • Appropriate antibiotics • Like the associated cough, the workup is usually • Cardiogenic shock nonproductive. • Bad pump • Deep breathing/incentive spirometry—equally effective • Extensive MI, arrhythmias n Postoperative pneumonia takes up to 5 days to manifest. • Blocked pump (obstructive shock) • Productive cough, fever/chills, increased WBC count • Massive “saddle” pulmonary embolism • Radiograph: pulmonary infiltrates • Tension pneumothorax n Smoking cessation improves outcomes • Decreased lung sounds, hypertympany, tracheal • Patients should stop 6–8 weeks preoperatively. deviation • Nicotine supplements do no harm to wound. • Treated with needle decompression followed by • Fewer pulmonary complications tube thoracostomy • Smokers have six times more pulmonary • Cardiac tamponade complications. • Beck triad: hypotension, muffled heart sounds, • Fewer wound healing issues and wound infections neck vein distension • Lower nonunion rate • Pulsus paradoxus • Shoulder, neck, and thoracic pain in smokers • Decreased systolic BP with inspiration • Prompts careful evaluation of lung fields • Treatment: pericardiocentesis • Superior sulcus tumor (Pancoast tumor) • Hypovolemic shock • Intrinsic atrophy of hand—C8–T1 • Most common shock of trauma n Acute respiratory distress syndrome (ARDS) • Volume loss from bleeds or burns n Pulmonary failure due to edema (see Fig. 1.56A) • “Third spacing” also a cause n Pathophysiology • Neuroendocrine response: save heart and brain • Complement pathway activated • Peripheral vasoconstriction • Increased pulmonary capillary permeability • BP may be normal • Intravascular fluid floods alveoli • Pale, cold, clammy extremities • Results • Percentage of blood loss key to symptoms/signs • Hypoxia, pulmonary HTN • Class I: up to 15% blood volume loss • Right heart failure • Vital signs can be maintained. • 50% mortality • Pulse below 100 beats/min n Etiology • Class II: 15%–30% blood volume loss • Blunt chest trauma, aspiration, pneumonia, sepsis • Tachycardia (>100 beats/min), orthostatic • Shock, burns, smoke inhalation, near drowning • Anxious • Orthopaedic: Long-bone trauma • Increased diastolic BP n Clinical symptoms • Class III: 30%–40% blood volume loss • Tachypnea, dyspnea, hypoxia, decreased lung compliance • Decreased systolic BP • Pao2/Fio2 ratio below 200 • Oliguria n Imaging • Confusion, mental status changes • Radiographs: diffuse bilateral infiltrates, “snowstorm” • Class IV: more than 40% blood volume loss • CT: ground glass appearance • Life threatening; patient is obtunded n Treatment • Narrowed pulse pressure • Prompt diagnosis and treatment of musculoskeletal • Immeasurable diastolic BP infections • Treatment • Prompt treatment of long-bone fractures • First, ABCs of resuscitation: then, bleeding must • Ventilation with positive end-expiratory pressure (PEEP) be stopped. • 100% O2 86 Basic Sciences

n Fat emboli syndrome—classic clinical triad • Bipolar sealant, topical sealants, autologous donation • Hepatitis B—approximately 1 in 250,000 n Petechial rash: fat to skin • Reinfusion systems, routine transfusions over 8 g/dL Hb n Renal and urologic issues n Neurologic symptoms: fat to brain n Preoperative techniques to address anemia n ARF (acute kidney injury [AKI]) • Mental status changes: confusion, stupor • Oral iron 30–45 days preoperatively • Edema, HTN, urinary output less than 30 mL/hour • Rigidity, convulsions, coma • Vitamin C increases iron absorbtion (<0.5 mL/kg/h) n Pulmonary collapse: fat showers lung • Folate and vitamin B12 deficiency also a source of anemia • Laboratory findings: creatinine increased over 1.5 times • ARDS: hypoxia, tachypnea, dyspnea • Erythropoietin if preoperative Hb below 13 baseline n Associated with long-bone fractures n Transfusions • Hyperkalemia can be fatal. n Bleeding and blood products • Ratio of 1:1:1 blood product resuscitation is superior to • For blood potassium level more than 5.5 mmp/L, n Bleeding complications can be avoided through saline fluid dialysis should be considered. preoperative identification of risk. • Preoperative Hb most significant predictor of need • Prerenal renal failure (most common ARF): decreased n Common inherited bleeding disorders • Various guidelines for when to transfuse kidney perfusion • Von Willebrand disease: autosomal dominant • Hb less than 6 g/dL: transfusion • Hypovolemia/hypotension from blood loss • Most common genetic coagulation disorder • Hb 7–8 g/dL: transfusion of postoperative patients • Intrinsic renal failure • Von Willebrand factor dysfunction • Hb 8–10 g/dL: transfusion of symptomatic patients • ATN: most frequent intrinsic ARF • Binds platelets to endothelium • Restrictive transfusion strategies • Ischemia, sepsis, nephrotoxic drugs • Carrier for factor VIII • Lower 30-day mortality trend • Myoglobin from rhabdomyolysis • Treatment: desmopressin • Lower infection risk trend • Acute interstitial nephritis (AIN): fever, eosinophils • Hemophilia A (VIII): X-linked recessive • Greatest benefits to orthopaedic patients in blood/urine • Hemophilia B (IX) Christmas disease: X-linked recessive • No difference in functional recovery • Glomerular disease: hematuria, proteinuria, HTN, edema n Medicines/supplements that should be stopped prior to n Transfusions risks • SLE, poststreptococcal, IgA nephropathy, hepatorenal surgery • Leading risk: transfusion of wrong blood to patient • Postrenal ARF: obstruction • Platelet-inhibitor drugs (aspirin, clopidogrel, prasugrel, • Occurs in 1 in 10,000 to 1 in 20,000 RBC units n Chronic kidney disease (CKD) NSAIDs) transfused • Definition: GFR below 60 mL/min per 1.73 2m or urine • Drugs that cause thrombocytopenia • Transfusion reactions albumin loss greater than 30 mg/day • Penicillin, quinine, heparin, LMWH • Febrile nonhemolytic transfusion reaction • Retained phosphate and secondary to • Anticoagulants (see earlier discussion on DVT) • Most common hyperparathyroidism • Supplements • 1–6 hours post-transfusion • Causes increased extraskeletal calcification • Fish oil, omega-3 fatty acids, vitamin E • From leukocyte cytokines released from stored cells • High perioperative complications • Garlic, ginger, Ginkgo biloba • Leukoreduction decreases incidence • Increased cardiovascular risk • Dong quai, feverfew • Acute hemolytic transfusion reaction • Hyperkalemia and fluid adjustments n Diseases associated with increased bleeding • Medical emergency • Increased bleeding complications • Chronic renal disease—uremia causes platelet • ABO incompatibility • Poor BP control dysfunction • IgM anti-A and anti-B, which fix complement • Higher infection rates • Chronic liver failure—decreased liver proteins of • Rapid intravascular hemolysis • Higher complications/revisions clotting cascade • Classic triad: fever, flank pain, red/brown urine • Higher morbidity n Techniques to avoid blood loss at surgery (rare) n Perioperative urinary retention • Tourniquets: tissue effect relates to time and pressure • Can cause disseminated intravascular • Outflow obstructions: benign prostatic hypertrophy • Used no longer than 2 hours coagulation (DIC), shock, and acute renal failure (BPH) in men (common) • Time to restoration of equilibrium (ARF) due to acute tubular necrosis (ATN) • Bladder muscle (detrusor) compromise • 5 minutes after 90 minutes of use • Positive direct antiglobulin (Coombs) test result • Overdistention • 15 minutes after 3 hours • Delayed hemolytic transfusion reactions • Excess fluid/long procedures • Prolonged use can cause tissue damage. • Reexposure to previous antigen (i.e., Rh or Kidd) • Neurogenic • Nerve damage compressive (not ischemic) • History of pregnancy, prior transfusion, • Spinal trauma, tumor, stroke, diabetes • Electromyography: subclinical abnormalities in transplantation • “Neurogenic” atonic bladder 70% with routine use • 3–30 days post-transfusion • Medications • Slight increase in pain • Anemia, mild elevation of unconjugated bilirubin, • Anticholinergic and sympathomimetic drugs • Wider tourniquets distribute forces spherocytosis • Opioids, antidepressants, pseudoephedrine, • Pad underneath prevents skin blisters in TKA • Anaphylactic reactions: about 1 in 20,000 diphenhydramine • Lowest pressure needed for effect should be used • Rapid hypotension, angioedema • Can cause postrenal ARF (AKI) • 100–150 mm Hg above systolic BP • Shock, respiratory distress • Associated with higher rates of urinary tract infections • 200 mm Hg upper extremity • Frequently involve anti-IgA and IgE antibodies • Increased 2-year mortality after hip fracture • 250 mm Hg lower extremity • Treatment: cessation of transfusions, ABCs of • Treatment • Tranexamic acid resuscitation, epinephrine • α -Blockers—tamsulosin 0.4 mg/day • Synthetic lysine analogue; acts on fibrinolytic system • Urticarial reactions: about 1%–3% • Bladder ultrasound if no voiding by 3–4 hours • Competitive inhibitor of plasminogen activation • Mast cell/basophils release of histamine—hives • If ultrasound shows more than 400–600 mL, in-and- • Reduces blood loss with no increase in DVT. • Infectious risks out (IO) urinary catheter should be used. • Temperature • Bacterial: 0.2 per million packed red blood cell • Trauma patient—no catheter if bloody meatus or • Mild hypothermia increases bleeding time and blood (PRBC) units transfused scrotal hematoma present loss. • Gram-positive organisms n Perioperative UTI • Intraoperative “cell saver” may be cost-effective if: • Cryophilic organisms: Yersinia, Pseudomonas • “Irritative symptoms”: dysuria, urgency, frequency • About 1000 mL of blood loss is expected • HTLV—approximately 1 in 2 million • Account for 30%–40% of hospital-acquired infections • Recovery of 1 or more unit of blood is anticipated. • HIV—approximately 1 in 2 million • Most common organisms: Escherichia coli and • Techniques not yet found to be effective or cost-effective • Hepatitis C—approximately 1 in 2 million Enterococcus Basic Sciences 87

• Hepatitis B—approximately 1 in 250,000 • Diagnosis n Renal and urologic issues • If symptoms, urinalysis and culture/sensitivity testing n ARF (acute kidney injury [AKI]) • WBCs (leukocyte esterase positive) • Edema, HTN, urinary output less than 30 mL/hour • Bacterial count over 103 CFU/mL, treated preoperatively (<0.5 mL/kg/h) • Treatment • Laboratory findings: creatinine increased over 1.5 times • Antibiotics for gram-negative organisms baseline • Trimethoprim-sulfamethoxazole or • Hyperkalemia can be fatal. fluoroquinolone • For blood potassium level more than 5.5 mmp/L, n GI motility disorders (Fig. 1.58) dialysis should be considered. n 1.5% of hip/knee arthroplasties • Prerenal renal failure (most common ARF): decreased n Common presentation kidney perfusion • Abdominal pain • Hypovolemia/hypotension from blood loss • Distension • Intrinsic renal failure • Nausea with or without vomiting • ATN: most frequent intrinsic ARF n Prevention • Ischemia, sepsis, nephrotoxic drugs • Chewing gum: vagal (parasympathetic stimulation) • Myoglobin from rhabdomyolysis • Early mobility • Acute interstitial nephritis (AIN): fever, eosinophils • Spinal (sympathetic block) in blood/urine • Limiting dose and length of IV opioids • Glomerular disease: hematuria, proteinuria, HTN, edema n Postoperative adynamic ileus • SLE, poststreptococcal, IgA nephropathy, hepatorenal • Gut autonomic nerve imbalance: • Postrenal ARF: obstruction • More common in spine (≈7%) and joint arthroplasty (≈1%) n Chronic kidney disease (CKD) • X-rays: dilated small and large bowel (see Fig. 1.58A) • Definition: GFR below 60 mL/min per 1.73 2m or urine • Treatment: nothing by mouth status, nasogastric tube albumin loss greater than 30 mg/day • Electrolyte control • Retained phosphate and secondary to • Cessation of narcotics hyperparathyroidism n Superior mesenteric artery (SMA) syndrome (cast • Causes increased extraskeletal calcification syndrome) • High perioperative complications • Occlusion of duodenum by SMA • Increased cardiovascular risk • Orthopaedic causes • Hyperkalemia and fluid adjustments • Hip spica cast • Increased bleeding complications • Following scoliosis surgery • Poor BP control • Following THA with severe hip flexion contracture • Higher infection rates • Following traumatic quadriplegia • Higher complications/revisions • Also found in patients with rapid, large weight loss • Higher morbidity • X-rays: distended stomach and upper duodenum (see n Perioperative urinary retention Fig. 1.58B) • Outflow obstructions: benign prostatic hypertrophy • CT (BPH) in men (common) • Aortomesenteric artery angle less than 25 degrees • Bladder muscle (detrusor) compromise • Aortomesenteric distance less than 8 mm • Overdistention • Treatment: nothing by mouth status, nasogastric tube • Excess fluid/long procedures n Acute colonic pseudoobstruction (Ogilvie syndrome) • Neurogenic • Large bowel dilation • Spinal trauma, tumor, stroke, diabetes • Abdominal distension the prominent symptom • “Neurogenic” atonic bladder • Colonic perforation should be avoided. • Medications • Risk factors • Anticholinergic and sympathomimetic drugs • Elderly or male patient • Opioids, antidepressants, pseudoephedrine, • Previous bowel surgery diphenhydramine • Diabetes, hypothyroidism • Can cause postrenal ARF (AKI) • Electrolyte disorders • Associated with higher rates of urinary tract infections • Radiographic findings • Increased 2-year mortality after hip fracture • Distended transverse and descending colon and • Treatment cecum (see Fig. 1.58C) • α -Blockers—tamsulosin 0.4 mg/day • Colonic diameter more than 10 cm risks perforation. • Bladder ultrasound if no voiding by 3–4 hours • Treatment • If ultrasound shows more than 400–600 mL, in-and- • Nothing by mouth status out (IO) urinary catheter should be used. • Neostigmine • Trauma patient—no catheter if bloody meatus or • Colonic decompression scrotal hematoma present n Pseudomembranous colitis: potentially fatal diarrhea n Perioperative UTI • Most common antibiotic-associated colitis • “Irritative symptoms”: dysuria, urgency, frequency • Change in colon flora favorsClostridium difficile • Account for 30%–40% of hospital-acquired infections • Makes enterotoxin-A and cytotoxin-B • Most common organisms: Escherichia coli and • Many antibiotics Enterococcus • Clindamycin, fluoroquinolones 88 Basic Sciences

• Penicillins and cephalosporins • Model for End-Stage Liver Disease (MELD) score • Can become severe fulminant colitis (http://www.mayoclinic.org/medical-professionals/ • Toxic megacolon and perforations model-end-stage-liver-disease/meld-model) • Risk factors • Formula based on bilirubin, INR, creatinine • Elderly hospitalized patient • Studies highlight mortality at 90 days relative to • Severe illness MELD score • Antibiotic use • <9: about 2% mortality • Proton pump inhibitor use • 10–19: about 6% mortality • Diagnosis • 20–29: about 20% mortality • Watery diarrhea with fever • 30–39: about 53% mortality • Leukocytosis, lower abdominal pain • >40: about 71% mortality • Laboratory findings • Complication rates from surgery are extremely high. • WBC count more than 15,000 cells/μL • In patients undergoing arthroplasty, MELD score • Stool specimen should be tested for C. difficile above 10 predicted toxin • Three times the complication rate • PCR or ELISA • Four times the rate death • KUB (kidney, ureter, bladder) (plain abdominal) n Perioperative CNS issues radiograph n Stroke • Toxic megacolon: greater than 7 cm • Rare (0.2% of joint arthroplasties) • Thumbprinting (see Fig. 1.58D) • Mortality roughly 25% at 1 year • Treatment • Ischemic more common than hemorrhagic • Oral metronidazole • Risk factors • Oral vancomycin (IV will not work) • Advanced age, CVA, TIA • Fidaxomicin • MI, coronary artery bypass graft, atrial fibrillation, or • Colectomy if unresponsive and severe ECG rhythm abnormality • Megacolon, WBC count more than 20,000 cells/μL • Left ventricular dysfunction n Perioperative hepatic issues • Cardiac valvular disease n Liver failure: critical for producing proteins and • General anesthesia higher risk than regional metabolizing toxins • Diagnosis: head CT or MRI • Laboratory findings • Treatment: ABCs of resuscitation, hospitalist/neurology • Increased aspartate aminotransferase (AST), alanine consultation aminotransferase (ALT), and bilirubin n Delirium: approximately 40% in patients with hip fractures • INR above 1.5, low platelets (<150,000 cells/μL) • Fluctuating levels of consciousness • Acute—most commonly viral and drug induced • Impairment of memory and attention • Acetaminophen—number one cause in United States • Disorientation, hallucinations, agitation • Other toxins: alcohol, occupational, mushrooms • Associated with increased length of stay • Viral hepatitis • Decubitus ulcers, failure to regain function • Chronic—cirrhosis is end-stage fibrosis of liver • Feeding issues, urinary incontinence • Common: hepatitis (B, C), alcoholism, • Mortality and nursing home placement hemochromatosis • Risk factors • Classifications can be helpful to estimate risks • Older patients • Child classification—most widely used • History of prior postoperative confusion • Based on laboratory results and physical • History of alcohol abuse examination • Acute surgery more than elective

AB C D

FIG. 1.58 Perioperative gastrointestinal mobility radiographs. (A) Dilated loops of both small bowel and large bowel consistent with ileus. (B) Characteristic dilation with air-fluid levels in the stomach and right-sided upper duodenum, seen in mesenteric artery syndrome (cast syndrome). (C) Isolated dilation of the large bowel seen in acute colonic pseudoobstruction (Ogilvie syndrome). (D) Dilated loops of both small and large bowel in a patient with watery diarrhea after antibiotic use. Wide, thickened, transverse bands of nodular colon wall replace normal haustral folds (thumbprinting), as seen in pseudomembranous colitis. (A and C from Nelson JD et al: Acute colonic pseudo-obstruction [Ogilvie syndrome] after arthroplasty in the lower extremity, J Bone Joint Surg Am 88:604–610, 2006; B from Tidjane A et al: [Superior mesenteric artery syndrome: rare but think about it], [article in French] Pan Afr Med J 17:47, 2014; and D from Thomas A et al: “Thumbprinting,” Intern Med J 40:666, 2010.) Basic Sciences 89

• Night-time surgery STOP-BANG scoring method • Long duration of anesthesia Every Yes answer = 1 point • Intraoperative pressures below 80 mm Hg • Use of meperidine (Demerol) Snoring: Do you snore loudly (loud enough to be Ye sNo heard through closed doors)? • Diagnosis: anemia ruled out, infection, electrolyte issues Tired: Do you often feel tired, fatigued, or sleepy Ye s No • Treatment during daytime? • O2 saturation above 95%, systolic BP above 90 mm Observed: Has anyone observed you stop breathing Ye s No Hg during your sleep? Blood Pressure: Do you have or are you being Ye s No • Correction of medical issues treated for high blood pressure? • Family/friends BMI more than 35? Ye s No • Medications for sedation: used with caution Age older than 50 years? Ye s No • Restraints as last resort Neck circumference greater than 40 cm? Ye s No n Special anesthesia issues Gender male? Ye s No n Obstructive sleep apnea (OSA) • Intermittent hypercapnia and hypoxia 5 or more = high risk for Obstructive Sleep Apnea • Decreased CO -induced respiratory drive Initiate or continue CPAP machine 2 Avoid/minimize narcotics – maximize local blocks • Extreme sensitivity to opioids • Leads to FIG. 1.59 STOP-BANG screening questionnaire for identification of • Pulmonary HTN obstructive sleep apnea. (From Shilling AM et al: Anesthesia and perioperative • Cardiac arrhythmias medicine. In Miller MD, Thompson SR, editors: DeLee and Drez’s orthopaedic sports • GERD (reflux) directly related to BMI medicine: principles and practice, ed 4, Philadelphia, 2014, Saunders, p 365.) • Delayed gastric emptying • Increased risks for aspiration/intubation • HTN, arrhythmias, CHF, cardiovascular • Higher risk for complications (2–4 times greater) disease, and metabolic syndrome • Respiratory failure, ICU transfers, increased length • Metabolic syndrome = obesity, of stay hypertension, hypercholesterolemia, • Increased postoperative O2 desaturation dyslipidemia, and insulin resistance • Increased intubation, aspiration pneumonia, ARDS • Avoidance of flat supine position; sitting • Increased MI, arrhythmias (atrial fibrillation) position opens airway. • Screening tools: STOP-BANG (Fig. 1.59) n Malignant hyperthermia • S noring, tired, observed apnea, pressure (HTN) • Autosomal dominant genetic defect of T-tubule of BMI over 35, age older than 50 years, neck sarcoplasmic reticulum circumference larger than 40 cm, gender male • Ryanodine receptor defect (RYR1) • Five or more factors present—high risk of severe • Dihydropyridine receptors (DHP) OSA • Triggered by volatile anesthetics and • Best practices succinylcholine • Initiation or continuation of CPAP use • Creates an uncontrolled release of Ca2+ • More than 2 weeks of preoperative CPAP • Sustained muscular contraction (masseter rigidity) improved HTN, O2 saturation, apneic events • Increased end-tidal CO2 • Pulmonary HTN: in 20%–40% of patients with • Earliest and most sensitive sign OSA • Mixed respiratory and metabolic alkalosis • Preoperative serum bicarbonate predicts hypoxia • Hyperthermia is classic but occurs later. in OSA • Muscle damage • Chronic respiratory acidosis • Myoglobin from rhabdomyolysis can cause ARF. • Site of service (American Society of Anesthesiology • Elevated creatine kinase consensus statement) • Hyperkalemia can lead to ventricular arrhythmias. • Ambulatory surgery under local/regional—lower • Treatment with dantrolene risk • Decreases intracellular Ca2+ • Avoid procedures requiring opioids—greater • Stabilizes sarcoplasmic reticulum risk • Treatment of high serum potassium • Comorbid conditions must be optimized for • Hydration outpatient surgery. • Cooling

SECTION 4 OTHER BASIC PRINCIPLES

IMAGING AND SPECIAL STUDIES • Use of large C-arm rather than mini C-arm n Factors to decrease the amount of radiation exposure n Radiation safety • Minimizing exposure time n Should be considered for every fluoroscopic case • Using collimation to manipulate the x-ray beam n Increased radiation exposure associated with • Use of protective shielding • Imaging of larger body parts • Maximizing the distance between the surgeon and the • Positioning the extremity closer to the x-source radiation beam 90 Basic Sciences

• Utilizing mini C-arm whenever feasible (associated with • Radiolabeled monoclonal antibodies minimal radiation exposure) • May identify primary malignancies and metastatic • Surgeon control of the C-arm disease n Nuclear medicine n DVT/PE scan n Bone scan (Table 1.37) • Radioactive iodine • Technetium Tc 99m phosphate complexes • Labels fibrinogen in clot on scanning • Reflect increased blood flow and metabolism • Inaccurate near surgical wounds (infection, trauma, neoplasia) n Single-photon emission computed tomography (SPECT) • Absorbed onto hydroxyapatite crystals in bone • Scintigraphy with CT to evaluate overlapping structures • Whole-body views and more detailed (pinhole) views • Femoral head osteonecrosis possible • Patellofemoral syndrome • Uses • Spondylolysis • Subtle or stress fractures n Arthrography • Avascular necrosis n Commonly used in association with advanced imaging • Hypoperfused early (CT or MRI) • Increased uptake in reparative phase n Improves sensitivity of intraarticular soft tissue pathology • Osteomyelitis (labral tear in shoulder, triangular fibrocartilage complex • Also in conjunction with gallium citrate Ga 67 or [TFCC], and intercarpal ligament tears in wrist) indium In 111 scan n Also frequently used in pediatric population • THA and TKA loosening n Hip • Especially femoral components • Aspiration for infection • In conjunction with gallium scan to rule out • Following reduction of developmental dysplasia of the infection hip (DDH) • Phase studies • Assessing deformity in Legg-Calvé-Perthes disease • Three-phase (or even four-phase) studies n MRI • Helpful for reflex sympathetic dystrophy and n Excellent for evaluating soft tissues and bone marrow osteomyelitis • Study of choice for evaluating knee ligamentous/ • First phase (blood flow, immediate) meniscal injuries and shoulder cuff injuries • Blood flow through the arterial system n Ineffective in evaluating trabecular bone and cortical bone • Second phase (blood pool, 30 minutes) • These tissues have virtually no hydrogen nuclei. • Equilibrium of tracer throughout the n Used to evaluate osteonecrosis, neoplasms, infection, and intravascular volume trauma • Third phase (delayed, 4 hours) n Contraindications • Displays sites of tracer accumulation • Pacemakers n Gallium scan • Cerebral aneurysm clips • Localizes in sites of inflammation and neoplasia • Shrapnel or hardware, in certain locations • Exudation of labeled serum proteins n Basic principles of MRI (Tables 1.38 through 1.41) • Delayed imaging required (24–48 hours or more) • Radiofrequency pulses on tissues in a magnetic field • Less dependent on vascular flow than technetium • Images in any desired plan • May identify foci otherwise missed • Nuclei with odd numbers of protons/neutrons (with a • Difficulty differentiating cellulitis from osteomyelitis normally random spin) aligned parallel to a magnetic field n Indium scan • Labeled WBCs (leukocytes) Table 1.38 Magnetic Resonance Imaging Terminology • Collect in areas of inflammation • Do not collect in areas of neoplasia TERM EXPLANATION • Uses T1 Time constant of exponential growth of magne- • Acute infections (e.g., osteomyelitis) tism; T1 signal measures how rapidly a tissue gains magnetism • Possibly total joint arthroplasty (TJA) infections T2 Time constant of exponential decay of signal after an excitation pulse; a tissue with a long T2 signal (such as that with a high water content) Table 1.37 Nuclear Medicine Studies maintains its signal (is bright on T2-weighted image) STUDY USES COMMENTS T2* Similar to T2 but includes the effects of magnetic Bone scan Subtle fractures Three-phase scan field homogeneity Avascular necrosis useful for osteomy- TR Time to repetition; the time between successive Osteomyelitis elitis, reflex sym- excitation pulses; short TR <80 ms, long TR Total joint loosening pathetic dystrophy, >80 ms Osteochondritis acute scaphoid TE Time to echo; the time that an echo is formed by fractures the refocusing pulse; short TE <1000 ms, long Gallium Inflammation Localizes in sites of TE >1000 Neoplasms inflammation NEX Number of excitations; higher NEX results in Requires prolonged decreased noise with better images uptake FOV Field of view Indium Acute infections Labeled WBC uptake Spin-echo A commonly used pulse sequence (In 111) Possible arthroplasty in areas of infection FSE Fast spin-echo; a type of pulse sequence infections GRE Gradient-recalled echo; a type of pulse sequence Basic Sciences 91

• Field strength: 0.5–15 T (1 T = 10,000 G) • T1-weighted images best for demonstrating anatomic • 3.0 T has nine times greater proton energy than structure 1.5T • T2-weighted images best for contrasting normal and • Nuclear magnetic moments of these particles are abnormal tissues deflected by radiofrequency pulses; deflection results in • Magic angle phenomenon: an image. • Tendon or ligament tissue oriented near 55 degrees • The use of surface coils decreases the signal-to-noise to the field produces bright T1-weighted images. ratio. • False appearance of pathologic process • Body coils are used for large joints • Most common in shoulder, ankle, knee • Smaller coils are available • Techniques for identifying contrast between fluid and • Sequences developed to demonstrate the differences in nonfluid elements (e.g., bone, fat) T1 and T2 relaxation between tissues • STIR imaging • Dark on T1- and bright on T2-weighted images • Fat-suppressed T2-weighted imaging • Water • Specific applications • Cerebrospinal fluid • Osteonecrosis • Acute hemorrhage • Highest sensitivity and specificity for early • Soft tissue tumors detection • Tissues showing similar intensity on both T1- and T2- • Detects early marrow necrosis weighted images: • Detects ingrowth of vascularized mesenchymal • Dark: cortical bone, rapidly flowing blood, fibrous tissue tissue • Specificity of 98% and high reliability for • Gray: muscle and hyaline cartilage estimating age and extent of disease • Bright: fatty tissue, nerves, slowly flowing (venous) • Diseased marrow dark on T1-weighted images blood, bone marrow • Allows direct assessment of overlying cartilage • Infection and trauma • Excellent sensitivity to increased free water • Shows areas of infection and fresh hemorrhage Table 1.39 Signal Intensities on Magnetic Resonance Imaging • Dark on T1-weighted images, bright on T2- APPEARANCE ON APPEARANCE ON weighted images T1-WEIGHTED T2-WEIGHTED • Excellent (accurate and sensitive) for occult TISSUE IMAGE IMAGE fractures Cortical bone Dark Dark • Particularly in hip in elderly patients Osteomyelitis Dark Bright • Neoplasms Ligaments Dark Dark • MRI has many applications in the study of primary Fibrocartilage Dark Dark Hyaline cartilage Gray Gray and metastatic bone tumors. Meniscus Dark Dark • Primary tumors are well demonstrated. Meniscal tear Bright Gray • Particularly tumors in soft tissue (extraosseous Yellow bone marrow Bright Gray and marrow) (fatty-appendicular) • Used in evaluating skip lesions and spinal Red bone marrow Gray Gray (hematopoietic-axial) metastases Marrow edema Dark Bright • Nuclear medicine study remains the procedure Fat Bright Gray of choice for seeking metastatic foci in bone. Normal fluid Dark Bright • Demonstrates benign bony tumors Abnormal fluid (pus) Gray Bright • Typically bright on T1-weighted images and Acute blood collection Gray Dark Chronic blood collection Bright Bright dark on T2-weighted images Muscle Gray Gray • Demonstrates malignant bony lesions Tendon Dark Dark • Often bright on T2-weighted images Intervertebral disc Gray Bright • Differential diagnosis is best made on the basis of (central) plain radiographs. Intervertebral disc Dark Gray (peripheral) • Spine • Disc disease is well demonstrated on T2-weighted Modified from Brinker MR, Miller MD:Fundamentals of orthopaedics, images. Philadelphia, 1999, Saunders, p 24. • Degenerated discs lose water.

Table 1.40 Magnetic Resonance Imaging of Bone Marrow Disorders DISORDER PATHOLOGIC FEATURES EXAMPLES MRI CHANGES Reconversion Yellow → red Anemia, metastasis ↓ T1-weighted intensity Marrow infiltration Tumor, infection ↓ T1-weighted intensity Myeloid depletion Anemia, chemotherapy ↓ T1-weighted intensity Marrow edema Trauma, complex regional pain ↓ T1-weighted intensity, ↑ T2- syndrome weighted intensity Marrow ischemia Osteonecrosis ↓ T1-weighted intensity

↑, Increased; ↓, decreased. 92 Basic Sciences

Table 1.41 Magnetic Resonance Imaging Changes of • Hematoma Meniscal Disease • Tendon rupture • Abscesses DISEASE GROUP CHARACTERISTICS • Foreign body location I Globular areas of hyperintense signal • Intraspinal disorders in infants II Linear hyperintense signal • Intraarticular injections III Linear hyperintense signal that communicates n with the meniscal surface (tears) Myelography IV Vertical longitudinal tear/truncation • More invasive than MRI but shows excellent detail • Useful in patients with contraindications to MRI • Useful in failed back (surgery) syndrome • Appear dark on T2-weighted images • Can be used with other studies such as CT • Extent of herniation of discs is also well shown. n Discography • Recurrent disc herniation is best diagnosed with • Use controversial gadolinium MRI scan. • Helpful for evaluating symptomatic disc degeneration • Differentiation from scar • Pathologic discs: reproduction of pain with injection • T1-weighted image and characteristic changes on discograms • Scar: decreased signal • Commonly used with CT • Free fragment: increased signal n Measurement of bone density (noninvasive) • Extruded disc: decreased signal • Single-photon absorptiometry • T2-weighted image • Cortical bone density is inversely proportional to • Scar: increased signal quantity of photons passing through it. • Free fragment: increased signal • Radioisotope iodide 125 (125I) emits a single energy • Extruded disc: decreased signal beam of photons. • MRI is most sensitive for diagnosing early • 125I passes through bone. discitis. • A sodium iodide scintillation counter detects the • Decreased signal on T1-weighted images, transmitted photons. increased signal on T2-weighted images • Denser bone attenuates the photon beam. • Bone marrow disorders • Fewer photons reach the scintillation counter. • Best demonstrated by MRI (poor specificity) (see • Best used in the appendicular skeleton Table 1.40) • Radius: diaphysis or distal metaphysis n Other imaging studies • Findings are unreliable in the axial skeleton n Computed tomography • Soft tissue depth alters the beam. • Demonstrates details of bony anatomy better than any • Dual-photon absorptiometry other study • Also an isotope-based method • Hounsfield units used to identify tissue types • Allows for measurement of the axial skeleton and the • −100 HU = air femoral neck • −100–0 HU = fat • Accounts for soft tissue attenuation • 0 HU = water • Quantitative CT • 100 HU = soft tissue • Preferred for measurement of trabecular bone density • 1000 HU = bone • Trabecular bone is at greatest risk for early • In spine, shows herniated nucleus pulposus better than metabolic changes myelography alone • Simultaneous scanning of phantoms of known • CT may be helpful differentiating disc herniation density from scar • Creating a standard calibration curve • IV contrast material is taken up in scar tissue but not • Accuracy within 5%–10% in disc tissue. • Radiation dose higher than that for DEXA • Frequently used with contrast material • DEXA • Arthrographic CT, myelographic CT • Most accurate and reliable for predicting fracture risk • CT digital radiography (CT scanography) • Radiation dose lower than that for quantitative CT • Accurate demonstration of leg length discrepancy • Measures bone mineral content and soft tissue with minimal radiation exposure components • Particularly when joint contractures exist (lateral n Electrodiagnostic studies scanography) n Nerve conduction studies • Images distorted by metal implants • Evaluation of peripheral nerves n Ultrasonography: uses continue to expand • Nerve impulses stimulated and recorded by surface • Shoulder: evaluation of rotator cuff tears electrodes • Hip • Allows calculation of conduction velocity • Diagnosis and follow-up of DDH • Measures latency (time from stimulus onset to • Dynamic examination of femoroacetabular response) and response amplitude impingement • Late responses (F wave, H reflex) allow evaluation of • Knee proximal lesions. • Determination of articular cartilage thickness • Impulse travels to the spinal cord and returns • Identification of intraarticular fluid n Electromyography • Soft tissue masses Basic Sciences 93

Table 1.42 Nerve Conduction Study Results CONDITION LATENCY CONDUCTION VELOCITY EVOKED RESPONSE Normal study Normal Upper extremities: >45 m/sec; lower Biphasic extremities: >40 m/sec Axonal neuropathy Increased Normal or slightly decreased Prolonged, decreased amplitude Demyelinating neuropathy Normal Decreased (10%–50%) Normal or prolonged, with decreased amplitude Anterior horn cell disease Normal Normal (rarely decreased) Normal or polyphasic, with prolonged duration and decreased amplitude Myopathy Normal Normal Decreased amplitude; may be normal Neurapraxia: Proximal to lesion Absent Absent Absent Distal to lesion Normal Normal Normal Axonotmesis: Proximal to lesion Absent Absent Absent Distal to lesion Absent Absent Normal Neurotmesis: Proximal to lesion Absent Absent Absent Distal to lesion Absent Absent Absent

Modified from Jahss MH:Disorders of the foot, Philadelphia, 1982, Saunders.

• Use of intramuscular needle electrodes to evaluate n Newton’s laws muscle units • First law: inertia • Used to evaluate denervation • If the net external force (F) acting on a body is zero, • Fibrillations; earliest sign usually at 4 weeks the body remains at rest or moves with a constant • Sharp waves velocity. • Abnormal recruitment pattern • This law allows static analysis: ΣF = 0 (sum of • Interpretation external forces = zero) • Peripheral nerve entrapment syndromes • Second law: acceleration • Distal motor and sensory latencies more than 35 m/sec • Acceleration (a) of an object of mass (m) is directly • Nerve conduction velocities less than 50 m/sec proportional to the force (F) applied to the object: • Changes over a distinct interval (Table 1.42) F = ma BIOMATERIALS AND BIOMECHANICS • This law is used in dynamic analysis. • Third law: reactions n Basic concepts • For every action (force), there is an equal and n Definitions opposite reaction (force). • Biomechanics—science of forces, internal or external, • This law leads to free-body analysis. on the living body • This law also assists in the study of interacting • Statics—action of forces on rigid bodies in a system in bodies. equilibrium n Scalar and vector quantities • Dynamics—bodies that are accelerating and the related • Scalar quantities forces • Have magnitude but no direction • Kinematics—study of motion (displacement, velocity, • Examples: volume, time, mass, and speed (not and acceleration) without reference to forces velocity) • Kinetics—relates the effects of forces to motion • Vector quantities n Principal quantities • Have magnitude and direction • Basic quantities—described by International System of • Examples: force and velocity Units (SI); metric system • Vectors have four characteristics • Length (m), mass (kg), time (sec) • Magnitude (length of the vector) • Derived quantities: derived from basic quantities • Direction (head of the vector) • Velocity • Point of application (tail of the vector) • Time rate of change of displacement (meters/ • Line of action (orientation of the vector) second) • Vectors can be added, subtracted, and split into • Rate of translational displacement: linear velocity components (resolved) • Rate of rotational displacement: angular velocity • Resultant of two vectors: principle of • Acceleration “parallelogram of forces” • Time rate of change of velocity (m/sec2) n Free-body analysis • Can also be linear or angular • Forces, moments, and free-body diagrams to analyze • Force the action of forces on bodies • Action causing acceleration of a mass (body) in a • Force certain direction • A mechanical push or pull (load) that causes external • Unit of measure: newton (N) = kg • m/sec2 (acceleration) and internal (strain) effects 94 Basic Sciences

• Unit of measure: the newton (N) • Friction (f) • Force vectors (F): can be split into independent • Resistance to motion when one body slides over components for analysis another • Usually in the x and y directions (Fx, Fy). • Produced at points of contact • With angle (θ) between Fx and Fy. • Oriented opposite to the applied force • A normal force is perpendicular to the surface on • When applied force exceeds f, motion begins. which it acts. • Proportional to coefficient of friction and applied • A tangential force is parallel to the surface. normal (perpendicular) load • A compressive force shrinks a body in the direction • Independent of contact area and surface shape of the force. • Piezoelectricity • A tensile force elongates a body. • Electrical charge when a force deforms a crystalline • Moment (M) structure (e.g., bone) • Rotational effect of a force • Concave (compression) side: charge is • Moment = force (F) multiplied by the perpendicular electronegative distance (the moment arm or lever arm = d) from • Convex (tension) side: charge is electropositive point of rotation: n Biomaterials n Strength of materials M F d = × • Study of relations between externally applied loads and • Torque is a moment from a force perpendicular to the resulting internal effects long axis of a body, causing rotation. • Loads • A bending moment is from a force parallel to the long axis. • Forces acting on a body • The mass moment of inertia is the resistance to • Compression, tension, shear, and torsion rotation. • Deformations • Product of mass times the square of the moment • Temporary (elastic) or permanent (plastic) change in arm: shape 2 • Load changes produce deformational changes. I = m × d • Elasticity—ability to return to resting length after • Affects angular acceleration undergoing lengthening or shortening • Free-body diagram • Extensibility—ability to be lengthened • A free-body diagram is a sketch of a body (or • Stress segments) isolated from other bodies that shows all • Intensity of internal force forces acting on it. • Stress = force/area • The weight of each object acts through its center of • Internal resistance of a body to a load gravity. • Unit of measure: pascal (Pa) = N/m2 • Center of gravity in the human body is just anterior • Normal stresses to S2. • Compressive or tensile n Finite element analysis • Perpendicular to the surfaces on which they act • Complex geometric forms and material properties are • Shear stresses modeled. • Parallel to the surfaces on which they act • A structure is modeled as a finite number of simple • Cause a part of a body to be displaced in relation geometric forms. to another part • Typically triangular or trapezoidal elements • Stress differs from pressure: • A computer matches forces and moments between • Pressure is the distribution of an external force to a neighboring elements. solid body. • Finite element analysis is often used to estimate internal • However, they share the same definition (force/ stresses and strains. area) and unit of measure (Pa). • Example: stress/strain at bone-implant interface • Strain n Other important basic concepts • Relative measure of deformation (six components) • Work resulting from loading • The product of a force and the displacement it causes • Strain = change in length/original length • Work (W) = force (F; vector components parallel to • Can also be normal or shear displacement) × distance (displacement produced • Strain is a proportion; it has no units. by F) • Strain rate • Unit of measure: joule (J) = N • m • Strain divided by time load is applied (units = sec−1). • Energy • Hooke’s law: stress is proportional to strain up to a limit. • Ability to perform work (unit of measure is also joule) • The proportional limit • Laws of conservation of energy: • Within the elastic zone • Energy is neither created nor destroyed. • Young’s modulus of elasticity (E) • It is transferred from one state to another. • Measure of material stiffness • Potential energy • Also a measure of the material’s ability to resist • Stored energy deformation in tension • Potential of a body to do work as a result of its • E = stress/strain position or configuration (e.g., strain energy) • E is the slope in the elastic range of the stress- • Kinetic energy—energy caused by motion (½mv2) strain curve. Basic Sciences 95

Yield point Ultimate n Material definitions (proportional strength • Brittle materials (e.g., PMMA) limit) • Stress-strain curve is linear up to failure. • These materials undergo only recoverable (elastic) deformation before failure. • They have little or no capacity for plastic Stress Breaking deformation. E point • Ductile materials (e.g., metal) • These materials undergo large plastic deformation before failure. Elastic zone • Ductility is a measure of post-yield deformation. • Viscoelastic materials (e.g., bone and ligaments) • Stress-strain behavior is time-rate dependent. • Depends on load magnitude and rate at which the Strain load is applied Plastic strain • A function of internal friction deformation • Exhibit both fluid (viscosity) and solid (elasticity) properties FIG. 1.60 Stress-strain curve. E, Young’s modulus of elasticity. • Modulus increases as strain rate increases. • Exhibit hysteresis • The critical factor in load-sharing capacity • Loading and unloading curves differ. • Linearly perfect elastic material • Energy is dissipated during loading. • A straight stress-strain curve to the point of failure • Most biologic tissues exhibit viscoelasticity. • Modulus = stress at failure (ultimate stress) • Isotropic materials divided by strain at failure (ultimate strain) • Mechanical properties are the same for all directions • E is unique for every type of material of applied load (e.g., as with a golf ball). • A material with a higher E can withstand greater • Anisotropic materials forces than can material with a lower E. • Mechanical properties vary with the direction of the • Shear modulus applied load. • Ratio of shear stress to shear strain • Example: bone is stronger with axial load than with • A measure of stiffness radial load. • Unit of measure: pascal (Pa) • Homogeneous materials • Stress-strain curve (Fig. 1.60) • Have a uniform structure or composition throughout • Derived by loading a body and plotting stress versus • Rigidity strain • Bending rigidity of a rectangular structure: • The curve’s shape varies by material. • Proportional to the base multiplied by the height • Proportional limit—transition point at which stress cubed: 3 and strain are no longer proportional bh/12 • The material returns to its original length when • Bending rigidity of a cylinder stress is removed: elastic behavior. • Related to the fourth power of the radius • Elastic limit (yield point) • Examples: intramedullary nails, half-pins • This is the transition point from elastic to plastic n Metals behavior. • Fatigue failure • Beyond this point, the material’s structure is • Occurs with cyclic loading at stress below ultimate irreversibly changed. tensile strength • The elastic limit equals 0.2% strain in most metals. • Depends on magnitude of stress (S) and number of • Plastic deformation—irreversible change after load is cycles (n) removed • Endurance limit • Occurs in the plastic range of the curve • Maximum stress under which the material will not • After the elastic limit, before the breaking point fail regardless of number of loading cycles • Ultimate strength—maximum strength obtained by • If the stress is below this limit, the material may be the material loaded cyclically an infinite number of times (>106 • Breaking point—point at which the material fractures cycles) without breaking. • Ductile—if deformation between elastic limit and • Above this limit, fatigue life is expressed by the S-n breaking point is large curve: • Brittle—if deformation between elastic limit and • Creep (cold flow) breaking point is small • Progressive deformation response to constant force • Strain energy (toughness) over an extended period • Capacity of material (e.g., bone) to absorb energy • Sudden stress followed by constant loading causes • Area under the stress-strain curve continued deformation. • Total strain energy = recoverable strain energy • Can produce permanent deformity (resilience) + dissipated strain energy • May affect mechanical function (e.g., in TJA) • A measure of the toughness of material • Corrosion (Table 1.43) • Ability to absorb energy before failure • Chemical dissolving of metals 96 Basic Sciences

1. Al2O3 (ceramic) Table 1.43 Types of Corrosion 1 2 2. Co-Cr-Mo (Alloy) CORROSION DESCRIPTION 3 3. Stainless steel 4 4. Titanium Galvanic Dissimilar metalsa; electrochemical 5 5. Cortical bone destruction 6 6. Matrix polymers Crevice Occurs in fatigue cracks with low O2 7. PMMA 7 tension 8. Polyethylene Stress Occurs in areas with high stress 8 9. Cancellous bone gradients Stress 10. Tendon/ligament Fretting From small movements abrading 11. Cartilage outside layer 9 Other For example, inclusion, intergranular 10 aMetals such as 316 L stainless steel and cobalt-chromium-molybdenum (Co-Cr-Mo) alloy produce galvanic corrosion. 11

• May occur in the body’s high-saline environment • Stainless steel (type 316L) Strain • The metal most susceptible to both crevice FIG. 1.61 Comparison of Young’s modulus (relative values, not to corrosion and galvanic corrosion scale) for various orthopaedic materials. Al2O3, Alumina; Co-Cr-Mo, • Risk of galvanic corrosion highest between 316L cobalt-chromium-molybdenum; PMMA, polymethylmethacrylate. stainless steel and cobalt-chromium (Co-Cr) alloy • Polishing, passivation, and ion implantation • Modular components of THA improve its fatigue properties. • Direct contact between similar or dissimilar metals • Titanium is extremely biocompatible at the modular junctions • Rapidly forms an adherent oxide coating (self- • Results in corrosion products passivation); decreases corrosion • Examples: metal oxides, metal chlorides • Most closely emulates axial and torsional • Corrosion can be decreased in the following ways: stiffnesses of bone • Using similar metals • High yield strength • Proper implant design • Tantalum—passive material designed to elicit a • Passivation by an adherent oxide layer response (bone ingrowth) • Effectively separates metal from solution • Surface oxide layer as barrier to corrosion • Example: stainless steel coated with chromium • Used as augmentation of cancellous defects oxide • Stiffness (E) differences (Fig. 1.61) • Types of metals n Nonmetal materials • Orthopaedic implants • Polyethylene (discussed in Chapter 5, Adult R • Three types of alloys: steel (iron-based), cobalt- reconstruction) based, titanium-based • PMMA (bone cement) • 316L stainless steel • Used for fixation and load distribution for implants • Iron-carbon, chromium, nickel, molybdenum, • Acts as a grout, not an adhesive manganese • Mechanically interlocks with bone • Nickel: increases corrosion resistance and • Reaches ultimate strength within 24 hours stabilizes molecular structure • Can be used as an internal splint for the patient with • Chromium: forms a passive surface oxide, poor bone stock improving corrosion resistance • PMMA can be used as a temporary internal splint • Molybdenum: prevents pitting and crevice until the bone heals. corrosion • If bone fails to heal, PMMA will ultimately fail. • Manganese: improves crystalline stability • Poor tensile and shear strength • “L”—low in carbon: greater corrosion resistance • Is strongest in compression and has a low E • Cobalt alloys • Not as strong as bone in compression • Cobalt-chromium-molybdenum (Co-Cr-Mo) • Reducing voids (porosity) increases cement strength • 65% cobalt, 35% chromium, 5% and decreases cracking. molybdenum • Vacuum mixing, centrifugation, good technique • Special forging process • Cement failure often caused by microfracture and • Nickel may be added to improve ease of fragmentation. forging. • Insertion can lead to a precipitous drop in BP. • Greater ultimate strength than titanium • Wear particles can incite a macrophage response • Ion release • Leads to prosthesis loosening • Co-Cr: macrophage proliferation and • Silicones synovial degeneration • Polymers for replacement in non–weight-bearing • Ions excreted through the kidneys joints • Titanium alloy (Ti-6Al-4V) • Poor strength and wear capabilities • Poor resistance to wear (notch sensitivity) • Frequent synovitis with extended use • Particulate may incite a histiocytic response. • Ceramics • The relationship between titanium and • Metallic and nonmetallic elements bonded ionically neoplasms is uncertain. in a highly oxidized state Basic Sciences 97

• Good insulators (poor conductors) • Cortical defects can reduce strength 70% or more. • Biostable (inert) crystalline materials such as Al2O3 • Oval defects less than rectangular defects (alumina) and ZrO2 (zirconium dioxide) • Smaller stress riser (concentration) • Bioactive (degradable) noncrystalline substances • Fracture such as bioglass • Type is based on mechanism of injury. • Typically brittle (no elastic deformation) • Tension: typically transverse and perpendicular • High modulus (E) to load and bone axis • High compressive strength • Compression: crush fracture • Low tensile strength • Shear • Low yield strain • Commonly around joints • Poor crack resistance characteristics • Load parallel to the bone surface • Low resistance to fracture • Fracture parallel to the load • Best wear characteristics, with polyethylene and a • Bending low oxidation rate • Eccentric loading or direct blows • High surface wettability and high surface tension • Begins on the tension side of the bone • Highly conducive to tissue bonding • Continues transversely/obliquely • Less friction and diminished wear (“smooth • May bifurcate to produce a butterfly fragment surface”) • High-velocity bending: produces comminuted • Small grain size allows an ultrasmooth finish. butterfly fracture • Less friction • Four-point bending: produces segmental • Calcium phosphates (e.g., hydroxyapatite) may fracture be useful as coatings (plasma sprayed) to increase • Torsion attachment strength and promote bone healing. • Shear and tensile stresses around the n Mechanical properties of tissue longitudinal axis • Bone • Most likely to result in a spiral fracture • Composite of collagen and hydroxyapatite • Torsional stresses proportional to the distance • Collagen: low E, good tensile strength, poor from the neutral axis to the periphery of a compressive strength cylinder • Calcium apatite: stiff, brittle, good compressive • Greatest stresses in a long bone under torsion strength are on the outer (periosteal) surface • Anisotropic • Comminution • Strongest in compression • A function of the amount of energy • Weakest in shear transmitted to bone • Intermediate in tension • Ligaments and tendons • Resists rapidly applied loads better than slowly • Can sustain 5%–10% tensile strain before failure. applied loads • In contrast, bone can sustain only 1%–4% tensile • Cancellous bone is 25% as dense, 10% as stiff, and strain. 500% as ductile as cortical bone. • Failure commonly results from tension rupture of • Cortical bone excellent at resisting torque. fibers and shear failure among fibers. • Cancellous bone good at resisting compression • Most ligaments can undergo plastic strain to the and shear. point that function is lost but structure remains in • Bone is dynamic. continuity. • Able to self-repair • Articular cartilage • Changes with aging: stiffer and less ductile • Ultimate tensile strength is only 5% that of bone. • Changes with immobilization: weaker • E is only 0.1% that of bone. • Bone aging • However, because of its viscoelastic properties, is • To offset loss in material properties, bone remodels well suited for compressive loading. to increase inner and outer cortical diameters. • Is biphasic • Area moment of inertia increases. • Solid phase depends on structural matrix. • Bending stresses decrease. • Fluid phase depends on deformation and shift of • Stress concentration effects water within solid matrix. • Occur at defect points within bone or at implant- • Relatively soft and impermeable solid matrix requires bone interface (stress risers) high hydrodynamic pressure to maintain fluid flow. • Reduce overall loading strength • Significant support provided by the fluid • Stress shielding by load-sharing implants component • Induces osteoporosis in adjacent bone • Stress-shielding effect on the matrix • Decreases normal physiologic bone stresses n Metal implants • Common under plates and at the femoral calcar in • Screws high-riding THA • Pitch: distance between threads • A hole measuring 20%–30% of bone diameter • Lead: distance advanced in one revolution reduces strength up to 50%. • Root diameter: minimal/inner diameter is • Regardless of whether it is filled with a screw proportional to tensile strength • Area returns to normal 9–12 months after screw • Outer diameter: determines holding power (pullout removal. strength) 98 Basic Sciences

• To maximize pullout strength • Larger contact area • Large outer diameter • A larger nail; increased rigidity and strength • Small root diameter • Unslotted nails • Fine pitch • Smaller diameter • Plates • Stronger fixation • Strength varies with material and moment of inertia. • At the expense of flexibility • Bending stiffness is proportional to the third • Increased torsional stiffness: greatest advantage power of the thickness (t3). of closed-section nails over slotted nails • Doubling thickness increases bending stiffness • Intramedullary nail insertion for femoral shaft eightfold. fracture • Plates are load-bearing devices. • Hoop stresses are lowest for a slotted titanium • Most effective on a fracture’s tension side alloy nail with a thin wall • Types include: • Posterior starting points decrease hoop stresses • Static compression and iatrogenic comminution of fractures • Best in upper extremity • Implant failure is more common with smaller- • Can be stressed for compression diameter unreamed nails • Dynamic compression n External fixators • Example: tension band plate • Conventional external fixators • Neutralization • Fracture reduction is the most important factor for • Resists torsion stability of fixation with external fixation. • Buttress • Other factors to enhance stability (rigidity) include • Protects bone graft • Larger-diameter pins (second most important • Stress concentration at open screw holes can factor) lead to implant failure. • Additional pins • Blade • Decreased bone-rod distance • Increased resistance to torsional deformation • Pins in different planes • Locking • Pins separated by more than 45 degrees • Absorb axial forces transmitted from screws • Increased mass of the rods or stacked rods • Do not require compression to bone; preserve • A second rod in the same plane increases periosteal blood supply resistance to bending. • Biomechanical advantages for osteoporotic • Rods in different planes fractures without cortical contact • Increased spacing between pins • Hybrid locking • Placement of central pins closer to the fracture site • Both nonlocked and locked screws are used. • Placement of peripheral pins farther from the • Nonlocked screws assist in reduction. fracture site (near-near, far-far). • Locked screws create a fixed-angle device or can • Circular (Ilizarov) external fixators be used in patients with osteoporosis. • Thin wires (usually 1.8 mm in diameter) • Bicortical locked screws provide increased • Fixed under tension (usually between 90 and strength in torsion compared with unicortical 130 kg) locked screws. • Circular rings • Intramedullary nails • Half-pins may also be used. • Load-sharing devices • Offer better purchase in diaphyseal (not • Require high polar moment of inertia to maximize metaphyseal) bone torsional rigidity and strength • Optimum orientation of implants on the ring • Mechanical characteristics • At a 90-degree angle to each other • Torsional rigidity • Maximizes stability • Amount of torque needed to produce a unit • A 90-degree angle not always possible angle of torsional deformation • Anatomic constraints such as neurovascular • Depends on both material properties (shear structures modulus) and structural properties (polar • Bending stiffness of frame moment of inertia) • Independent of the loading direction • Bending rigidity • Because the frame is circular • Amount of force required to produce a unit • Each ring should have at least two implants. amount of deflection • Wires or half-pins may be used. • Depends on both material properties (elastic • The construct is most stable when an olive wire modulus) and structural properties (area and a half-pin are at a 90-degree angle to each moment of inertia, length) other on a ring. • Related to the fourth power of the nail’s radius • Two wires are used on a ring. • Increasing nail diameter by 10% increases • One wire should be superior to the ring and one bending rigidity by 50%. inferior. • Better at resisting bending forces than • Tensioned wires on the same side can cause the rotational forces ring to deform. • Reaming • Factors that enhance stability of circular external • Allows greater torsional resistance fixators Basic Sciences 99

• Larger-diameter wires (and half-pins) ROLLING CONTACT ROLLING CONTACT • Decreased ring diameter • Use of olive wires • Additional wires or half-pins (or both) • Wires (or half-pins or both) crossing at a 90-degree O O Equal angle distance • Increased wire tension (up to 130 kg) • Placement of the two central rings close to the A P B P = ICR fracture site • Decreased spacing between adjacent rings Zero relative velocity (no sliding) • Increased number of rings n Joint arthroplasty implants: discussed in Chapter 5, Adult Reconstruction chapter ROLLING AND SLIDING PURE SLIDING CONTACT n Biomechanics CONTACT n General definitions • Degrees of freedom O = ICR • Rotations and translations each occur in the x, y, and O z planes. • Thus six parameters, or degrees of freedom, ICR describe motion. • Translations may be relatively insignificant for many C P D P joints. Nonzero relative • Are often ignored in biomechanical analyses velocity • Joint reaction force (R) • R is the force within a joint in response to forces FIG. 1.62 (A) Rolling contact occurs when the circumferential distance of the rolling object equals the distance traced along the acting on the joint. plane. This can occur only when there is no sliding—that is, when • Both intrinsic and extrinsic the relative velocity at the point of contact (P) is zero. (B) For rolling • Muscle contraction about a joint: the major contact, the point P of the wheel has zero velocity because it is in contributing factor contact with the ground. Therefore P is the instant center of rotation (ICR) of the wheel. This diagram shows the actual velocity of points • R is correlated with predisposition to degenerative along the wheel as it rolls along the ground. (C) Rolling and sliding changes. contact occurs when the relative velocity at the contact point is not • Joint contact pressure (stress) can be minimized by zero. (D) Pure sliding occurs when the wheel rotates about a station- • Decreasing R ary axis (O). In this case, the wheel would have no forward motion. • Increasing contact area (From Buckwalter JA et al: Orthopaedic basic science: biology and biomechanics of the musculoskeletal system, ed 2, Rosemont, IL, 2000, American Academy of • Coupled forces—rotation about one axis causes obligatory Orthopaedic Surgeons, p 145.) rotation about another axis (occurs in some joints). • Such movements (and associated forces) are coupled. • Example: lateral bending of the spine accompanied by axial rotation • Pure sliding • Joint congruence • Occurs with pure translation or rotation about a • Related to the fit of two articular surfaces stationary axis • A necessary condition for joint motion • No angular change in position • Can be evaluated radiographically • No instant center of rotation • High congruence increases joint contact area • “Slipping” of one surface on the other • Low congruence decreases joint contact area • Friction and lubrication • Movement out of a position of congruence increases • Friction : resistance between two objects as one slides stress in cartilage. over the other • Allows less contact area for distribution of joint • Not a function of contact area reaction force • Coefficient of friction: 0 = no friction • Predisposes the joint to degeneration • Lubrication: decreases resistance between surfaces • Instant center of rotation • Articular surfaces, lubricated with synovial fluid, • Point about which a joint rotates have a coefficient of friction 10 times better than • In some joints (knee), the instant center changes that of the best synthetic systems. during the arc of motion, following a curved path. • Coefficient of friction for human joints: 0.002–0.04 • Effect of joint translation and morphologic features • Coefficient of friction for metal-on-UHMWPE • It normally lies on a line perpendicular to the (ultra-high-molecular-weight polyethylene) joint tangent of the joint surface at all points of contact. arthroplasty: 0.05–0.15 • Rolling and sliding (Fig. 1.62) • Not as good as that of human joints • During motion, almost all joints roll and slide to • Elastohydrodynamic lubrication remain in congruence. • Primary lubrication mechanism for articular • Pure rolling: cartilage during dynamic function • Instant center of rotation is at the rolling surfaces. n Hip biomechanics • Contacting points have zero relative velocity. • Kinematics • No “slipping” of one surface on the other • ROM (Table 1.44) 100 Basic Sciences

• Instant center Table 1.44 Hip Biomechanics: Range of Motion • Simultaneous triplanar motion for this ball-and- socket joint makes analysis impossible. AVERAGE RANGE FUNCTIONAL RANGE MOTION (DEGREES) (DEGREES) • Kinetics • Joint reaction force (R) in the hip can reach three to Flexion 115 90 (120 to squat) Extension 30 six times body weight (W). Abduction 50 20 • Primarily as a result of contraction of the muscles Adduction 30 crossing the hip Internal rotation 45 0 • Decreases with cane in contralateral hand External rotation 45 20 • Other considerations • Stability • Deep-seated ball-and-socket joint is intrinsically stable. • A few degrees of passive motion are possible at • Sourcil 30 degrees of flexion. • Condensation of subchondral bone under • Knee motion is complex about a changing instant superomedial acetabulum center of rotation. • R is maximal at this point • Polycentric rotation • Gothic arch • Excursions of 0.5 cm for the medial meniscus and • Remodeled bone supporting the acetabular roof 1.1 cm for the lateral meniscus are possible during • Sourcil at its base a 120-degree arc of motion. • Neck-shaft angle • Joint motion • Varus angulation • Instant center traces a J-shaped curve about the • Decreases R femoral condyle. • Increases shear across the neck • Moves posteriorly with flexion • Leads to shortening of the lower extremity • Flexion and extension involve both rolling and sliding. • Alters muscle tension resting length of the • Femur rotates internally (tibia rotates externally) abductors during the last 15 degrees of extension • May cause a persistent limp • “Screw home” mechanism • Valgus angulation • Related to differences in radii of curvature for • Increases R the medial and lateral femoral condyles and the • Decreases shear musculature • Neutral or valgus angulation better for THA • Posterior rollback increases maximum knee • PMMA resists shear poorly flexion. • Arthrodesis (Fig. 1.63) • Tibiofemoral contact point moves posteriorly. • Position: 25–30 degrees of flexion, 0 degrees of • Normal rollback is compromised by PCL abduction and rotation sacrifice of posterior cruciate ligament (PCL), as • External rotation is better than internal rotation. in some TKAs. • If the implant is fused in abduction, the patient • Axis of rotation of the intact knee is in the medial will lurch over the affected lower extremity with an femoral condyle. excessive trunk shift. • Patellofemoral joint has sliding articulation • This will later result in low back pain. • Patella slides 7 cm caudally with full flexion. • Effects • Instant center is near the posterior cortex above • Increases oxygen consumption the condyles. • Decreases gait efficiency to approximately 50% • Kinetics of normal • Knee stabilizers • Increases transpelvic rotation of the contralateral • Ligaments and muscles play the major stabilizing hip role (Table 1.45). n Knee biomechanics • ACL • Kinematics • Typically subjected to peak loads of 170 N • ROM during walking • 10 degrees of extension (recurvatum) to 130 • Up to 500 N with running degrees of flexion • Ultimate strength in young patients: about 1750 • Functional ROM is nearly full extension to about N 90 degrees of flexion. • Failures by serial tearing at 10%–15% elongation • 117 degrees: required for squatting and lifting • PCL: sectioning increases contact pressures in the • 110 degrees: required for rising from a chair medial compartment and the patellofemoral joint. after TKA • Joint forces • Rotation varies with flexion • Tibiofemoral joint • At full extension, rotation is minimal. • Knee joint surface loads • At 90 degrees of flexion, ROM is 45 degrees • Three times body weight during level walking of external rotation and 30 degrees of internal • Up to four times body weight with stair walking rotation. • Menisci • Amount of abduction or adduction is essentially 0 • Help with load transmission degrees. • Bear one-third to one-half body weight • Removal increases contact stresses Basic Sciences 101

ARTHRODESIS MAN

Position in which to fuse joints

• A few degrees of passive motion are possible at Shoulder 30 degrees of flexion. • 20 to 25° forward flexion • Knee motion is complex about a changing instant • 15 to 20° abduction center of rotation. • 40 to 50° internal rotation • Polycentric rotation • Excursions of 0.5 cm for the medial meniscus and 1.1 cm for the lateral meniscus are possible during a 120-degree arc of motion. Elbow • Joint motion If unilateral • Instant center traces a J-shaped curve about the • 90° flexion femoral condyle. • Moves posteriorly with flexion If bilateral Hip • • 110° flexion • 25 to 30° flexion Flexion and extension involve both rolling and sliding. (one elbow to • Femur rotates internally (tibia rotates externally) • 0° abduction reach mouth) • 0° rotation during the last 15 degrees of extension • 65° flexion (one elbow for • “Screw home” mechanism Wrist • Related to differences in radii of curvature for perineal hygiene) • 10 to 20° dorsiflexion the medial and lateral femoral condyles and the (extension) musculature • Posterior rollback increases maximum knee CMC flexion. MCP • Tibiofemoral contact point moves posteriorly. PIP • Normal rollback is compromised by PCL DIP PIP Knee sacrifice of posterior cruciate ligament (PCL), as • 10 to 15° flexion Hand in some TKAs. • 0 to 7° valgus • Axis of rotation of the intact knee is in the medial MCP joint flexion femoral condyle. • Index 25° • Patellofemoral joint has sliding articulation • Long 30° • Patella slides 7 cm caudally with full flexion. • Ring 35° • Small • Instant center is near the posterior cortex above 40° the condyles. PIP joint • Kinetics • Index 40° • Knee stabilizers • Long 45° • Ligaments and muscles play the major stabilizing • Ring 50° role (Table 1.45). • Small 55° • ACL DIP joint Ankle • 5° hindfoot valgus • Typically subjected to peak loads of 170 N • Index 10° • 5 to 10° external rotation during walking • Long 10° • Neutral dorsiflexion • Up to 500 N with running • Ring 10° • Ultimate strength in young patients: about 1750 • Small 10° N First Great Toe • Failures by serial tearing at 10%–15% elongation MTP fusion • PCL: sectioning increases contact pressures in the • 10 to 15° dorsiflexion medial compartment and the patellofemoral joint. • Slight valgus • Joint forces • Neutral rotation • Tibiofemoral joint FIG. 1.63 Recommended positions for arthrodesis of common joints. CMC, Carpometacarpal; DIP, distal interphalangeal; MCP, metacar- • Knee joint surface loads pophalangeal; MTP, metatarsophalangeal; PIP, proximal interphalangeal. • Three times body weight during level walking • Up to four times body weight with stair walking • Up to four times the load transfer to bone • Increases the lever arm • Menisci • Quadriceps produces maximum anterior force • Stress distribution • Help with load transmission on the tibia at 0–60 degrees of knee flexion • Has the thickest cartilage in the entire body • Bear one-third to one-half body weight • Patellofemoral joint • Bears the greatest load • Removal increases contact stresses • Patella aids in knee extension. • Bears half the body weight with normal walking 102 Basic Sciences

Table 1.45 Knee Stabilizers DIRECTION STRUCTURES Medial Superficial MCL (primary), joint capsule, me- Vertical axis dial meniscus, ACL/PCL 3° Lateral Joint capsule, IT band, LCL (middle), lateral 6° Mechanical axis of the meniscus, ACL/PCL (90 degrees) entire lower extremity Anterior ACL (primary), joint capsule Anatomic axis Posterior PCL (primary), joint capsule; PCL tightens of the femur with internal rotation Rotatory Combinations: MCL checks external rotation; ACL checks internal rotation

IT, Iliotibial.

• Bears seven times the body weight with 81° 99° squatting and jogging • Loads proportional to ratio of quadriceps force to knee flexion • In descending stairs, compressive force reaches two to three times body weight. • Patellectomy Knee joint axis • Length of the moment arm is decreased by 3° width of patella: 30% reduction. • Power of extension is decreased by 30%. • During TKA, the following factors enhance Mechanical axis patella tracking of the tibia • External rotation of the femoral component (this is also the • Lateral placement of the femoral and tibial anatomic axis components of the tibia • Medial placement of the patellar component in a normal individual) • Avoidance of malrotation of the tibial component • These actions avoid internal rotation. • Axes of the lower extremity (Fig. 1.64) • Mechanical axis of the lower extremity • Center of femoral head to center of ankle • Normally passes just medial to the medial tibial spine FIG. 1.64 Axes of the lower extremity. (Modified from Helfet DL: Fractures of the distal femur. In Browner BD et al, editors: Skeletal trauma, Philadelphia, • Vertical axis 1992, Saunders, p 1645.) • From the center of gravity to the ground • Anatomic axes • Along the shafts of the femur and tibia • Instant center of rotation within the talus • Where these axes intersect at the knee, valgus • Lateral and posterior points at the tips of the angle is normal. malleoli • Mechanical axis of the femur • Change slightly with movement • From center of the femoral head to center of the • Talus described as a cone knee • Body and trochlea wider anteriorly and laterally • Mechanical axis of the tibia • Therefore talus and fibula externally rotate • From center of the tibial plateau to center of the slightly with dorsiflexion ankle • Dorsiflexion and abduction are coupled. • Relationships • ROM • Mechanical axis of the lower extremity is in 3 • Dorsiflexion: 25 degrees degrees of valgus angulation from the vertical • Plantar flexion: 35 degrees axis. • Rotation: 5 degrees • Anatomic axis of the femur is in 6 degrees of • Kinetics valgus angulation from the mechanical axis. • Tibiotalar articulation • Nine degrees versus the vertical axis • Major weight-bearing surface of the ankle • Anatomic axis of the tibia is in 2–3 degrees of • Supports compressive forces up to five times varus angulation from the mechanical axis. body weight (W) • Arthrodesis (see Fig. 1.63) • Shear (backward to forward) forces are • Position: 0 to 7 degrees of valgus angulation, 10 to decreased by muscle activation/contraction 15 degrees of flexion • Large weight-bearing surface area decreases joint n Ankle and foot biomechanics stress • Ankle • Fibular/talar joint transmits about one sixth of the • Kinematics force Basic Sciences 103

Table 1.46 Arches of the Foot ARCH SKELETAL COMPONENTS KEYSTONE LIGAMENT SUPPORT MUSCLE SUPPORT Medial longitudinal Calcaneus, talus, navicular, Talus head Spring Tibialis posterior, flexor digitorum three cuneiform bones, first (calcaneonavicular) longus, flexor hallucis longus, to third metatarsals adductor hallucis Lateral longitudinal Calcaneus, cuboid, fourth and Plantar aponeurosis Abductor digiti minimi, flexor fifth metatarsals digitorum brevis Transverse Three cuneiform bones, Peroneus longus, tibialis posterior, cuboid, metatarsal bases adductor hallucis (oblique)

Table 1.47 Range of Motion of Spinal Segments FLEXION/EXTENSION LATERAL BENDING ROTATION LEVEL (DEGREES) (DEGREES) (DEGREES) INSTANT CENTER Occiput–C1 13 8 0 Skull, 2–3 cm above dens C1–C2 10 0 45 Waist of odontoid C2–C7 10–15 8–10 10 Vertebral body below Thoracic spine 5 6 8 Vertebra below/disc centrum Lumbar spine 15–20 2–5 3–6 Disc annulus

• Highest net muscle moment occurs during • Motion is limited. terminal-stance phase of gait. • Foot • Other considerations • Transmits 1.2 times body weight with walking • Stability based on articulation shape (mortise • Three times body weight with running maintained by talar shape) and ligament support • Has three arches (Table 1.46) • Stability is greatest in dorsiflexion. • Second metatarsal (Lisfranc) joint is “keylike.” • During weight bearing, tibial and talar articular • Stabilizes second metatarsal surfaces contribute most to stability. • Allows it to carry the most load with gait • Windlass action • First metatarsal bears the most load during standing • Full dorsiflexion is limited by the plantar • Expected life of Plastazote shoe insert in active adults aponeurosis. is less than 1 month. • Further tension on the aponeurosis (toe • Fatigues rapidly in compression and shear dorsiflexion) raises the arch. • Should be replaced frequently or supported with • A syndesmosis screw limits external rotation. other materials such as Spenco or PPT foam • Arthrodesis (see Fig. 1.63): neutral dorsiflexion, n Spine biomechanics 5–10 degrees of external rotation, 5 degrees of • Kinematics hindfoot valgus angulation • ROM by anatomic segment (Table 1.47) • Surgeon should anticipate 70% loss of sagittal • Analysis based on the functional unit plane motion of the foot. • Motion segment: two vertebrae and the intervening • Subtalar joint (talus-calcaneus-navicular) soft tissues • Axis of rotation • Six degrees of freedom exist about all three axes. • In the sagittal plane: 42 degrees • Coupled motion • In the transverse plane: 16 degrees • Simultaneous rotation, lateral bending, and flexion • Functions like an oblique hinge or extension • Pronation coupled with dorsiflexion, abduction, • Especially axial rotation with lateral bending and eversion • Instant center of rotation within the disc • Supination coupled with plantar flexion, • Normal sagittal alignment of the lumbar spine: adduction, and inversion 55–60 degrees of lordosis • ROM • The lordosis exists because of the disc spaces (not • Pronation: 5 degrees the vertebrae). • Supination: 20 degrees • Most lordosis occurs between L4 and S1. • Functional ROM: approximately 6 degrees • Loss of disc space height can cause loss of normal • Transverse tarsal joint (talus-navicular, calcaneal-cuboid) lumbar lordosis. • Motion based on foot position • Iatrogenic flat back syndrome of the lumbar spine • Two axes of rotation: talonavicular and • Result of a distraction force calcaneocuboid • Supporting structures • Eversion (early stance) • Anterior supporting structures • The joint axes are parallel. • Anterior longitudinal ligament • ROM is allowed. • Posterior longitudinal ligament • Inversion (late stance) • Vertebral disc • External rotation of the lower extremity causes the • Posterior supporting structures joint axes to intersect. • Intertransverse ligaments 104 Basic Sciences

• Capsular ligaments and facets Table 1.48 Shoulder Biomechanics: Muscle Forces • Ligamentum flavum (yellow ligament) • Halo vest—most effective device for controlling MOTION MUSCLE FORCES COMMENTS cervical motion GLENOHUMERAL • Because of pin purchase in the skull Abduction Deltoid, supraspinatus Cuff depresses head • Apophyseal joints Adduction Latissimus dorsi, pectoralis major, teres major • Resist torsion during axial loading Forward Pectoralis major, deltoid • Attached capsular ligaments resist flexion. flexion (anterior), biceps • Guide the motion segment Extension Latissimus dorsi • Direction of motion determined by orientation of the Internal Subscapularis, teres facets of the apophyseal joint rotation major External Infraspinatus, teres minor, • Varies with each level rotation deltoid (posterior) • Cervical spine facets SCAPULAR • Orientation: 45 degrees to the transverse plane Rotation Upper trapezius, levator Works through a force • Parallel to the frontal plane scapulae (anterior), couple • Thoracic spine facets serratus anterior, lower trapezius • Orientation: 60 degrees to the transverse plane Adduction Trapezius, rhomboid, • Also 20 degrees to the frontal plane latissimus dorsi • Lumbar spine facets Abduction Serratus anterior, pecto- • Orientation: 90 degrees to the transverse plane ralis minor • Also 45 degrees to the frontal plane • They progressively tilt up (transverse) and inward (frontal). • Vertebral body stiffness is decreased in osteoporosis. • Cervical facetectomy of more than 50% causes loss of • Caused by loss of horizontal trabeculae stability in flexion and torsion. • Spinal arthrodesis is helpful • Torsional load resistance in the lumbar spine • Increasing implant stiffness • Facets contribute 40% • Increases probability of successful fusion • Disc contributes 40% • Increases likelihood of decreased bone mineral • Ligamentous structures contribute 20% content of the bridged vertebrae • Kinetics n Shoulder biomechanics (Table 1.48) • Disc • Kinematics • Behaves viscoelastically • Scapular plane • Demonstrates creep • Positioned 30 degrees anterior to the coronal plane • Deforms with time • The preferred reference plane for ROM • Demonstrates hysteresis • Abduction requires external rotation of the humerus. • Absorbs energy with repeated axial loads • To prevent greater tuberosity impingement • Later decreases in function • With internal rotation contractures, abduction • Compressive stresses highest in the nucleus limited to 120 degrees pulposus • Abduction • Tensile stresses highest in the annulus fibrosus • Glenohumeral motion: 120 degrees • Stiffness increases with compressive load. • Scapulothoracic motion: 60 degrees • Higher loads increase deformation and creep rate. • In ratio of 2:1 • Repeated torsional loading (shear forces) • Varies over the first 30 degrees of motion • Such repeated loading may separate the nucleus • Scapulothoracic motion pulposus from the annulus and end plate. • Acromioclavicular joint movement during the early • Nuclear material may then be forced through an part annular tear. • Sternoclavicular movement during the later • Loads increase with bending and torsional portion stresses. • With clavicular rotation along the long axis • After subtotal discectomy, extension is the most • Surface joint motion in the glenohumeral joint is a stable loading mode. combination of rotation, rolling, and translation. • Disc pressures are lowest with lying supine, higher • Kinetics with standing, and highest with sitting. • Zero position • Carrying loads • Abduction of 165 degrees in the scapular plane • Disc pressures are lowest when the load is close • Minimal deforming forces about the shoulder to the body. • Ideal position for reducing shoulder dislocations • Vertebrae • Also for reducing “fractures with traction” • Strength is related to bone mineral content and • Stability vertebrae size. • Limited about the glenohumeral joint • Increased in lumbar spine • Humeral head surface area larger than glenoid area: • Fatigue loading may lead to pars fractures. • 48 × 45 mm versus 35 × 25 mm • Compression fractures occur at the end plate. • Bony stability is limited Basic Sciences 105

• Relies on humeral head inclination (125 degrees) Table 1.49 Columns of the Wrist and retroversion (25 degrees) • Also relies on slight glenoid retrotilt COLUMN FUNCTION COMMENTS • Inferior glenohumeral ligament (anterior band) Central Flexion-extension Distal carpal row and • The most important static stabilizer lunate (link) Medial Rotation Triquetrum • Superior and middle glenohumeral ligaments: Lateral Mobile Scaphoid secondary stabilizers to anterior humeral translation • Inferior subluxation prevented by negative intraarticular pressure • Provided partially by articular congruity • Rotator cuff muscles • Three necessary and sufficient constraints for stability • Dynamic contribution to stability • Coronoid • Arthrodesis (see Fig. 1.63): 15–20 degrees of • Lateral (ulnar) collateral ligament (LCL) abduction, 20–25 degrees of forward flexion, 40–50 • Anterior band of the MCL degrees of internal rotation • Most important: anterior oblique fibers • Excessive external rotation should be avoided • Stabilizes against both valgus angulation and • Other joints distractional force at 90 degrees • Acromioclavicular joint • Most important secondary stabilizer against valgus • Scapular rotation through the conoid and stress: radial head trapezoid ligaments • About 30% of valgus stability • Scapular motion through the joint itself • Important at 0 to 30 degrees of flexion and • Sternoclavicular joint pronation • Clavicular protraction/retraction in a transverse • In extension, capsule is the primary restraint to plane through the coracoclavicular ligament distractional forces. • Clavicular elevation and depression in the frontal • Lateral stability is provided by LCL, anconeus, and plane joint capsule. • Also through the coracoclavicular ligament • Unilateral arthrodesis (see Fig. 1.63): 90 degrees of • Clavicular rotation around the longitudinal axis flexion n Elbow biomechanics • Bilateral arthrodesis (see Fig. 1.63) • Functions • One elbow at 110 degrees of flexion for the hand • A component joint of the lever arm when the hand is to reach the mouth positioned • Other at 65 degrees of flexion for perineal hygiene • Fulcrum for the forearm lever • Arthrodesis is difficult to perform and (fortunately) • Weight-bearing joint in patients using crutches rarely required. • Activities of daily living • Forearm • Kinematics • Ulna transmits 17% of the axial load • Flexion and extension • Line of the center of rotation runs from radial head • 0–150 degrees to distal ulna • Functional ROM: 30 to 130 degrees n Wrist and hand biomechanics • Axis of rotation: the center of the trochlea • Wrist • Pronation and supination • Part of an intercalated link system • Pronation: 80 degrees • Kinematics • Supination: 85 degrees • Normal ROM • Functional pronation and supination: 50 degrees • Flexion: 65 degrees each • Functional: 10 degrees • Axis: capitellum through radial head to ulnar head • Extension: 55 degrees (forms a cone) • Functional: 35 degrees • Carrying angle • Radial deviation: 15 degrees • Valgus angle at the elbow • Functional: 10 degrees • For boys and men: 7 degrees; for girls and women: • Ulnar deviation: 35 degrees 13 degrees • Functional: 15 degrees • Decreases with flexion • Flexion and extension • Kinetics • Two-thirds radiocarpal • Flexion is accomplished primarily by the brachialis • One-third intercarpal and biceps. • Radial deviation • Extension is accomplished by the triceps. • Primarily intercarpal movement • Pronation is accomplished by pronators (teres and • Ulnar deviation quadratus). • Relies on radiocarpal and intercarpal motion • Supination is accomplished by the biceps and • Instant center is usually the head of the capitate, supinator. but it varies. • Static loads approach, and dynamic loads exceed, • Columns of the wrist are listed in Table 1.49. body weight. • Link system • Stability • A system of three links in a “chain” 106 Basic Sciences

• Radius, lunate, and capitate Table 1.50 Recommended Positions of Flexion for • Less motion is required at each link. Arthrodesis of the Joints of the Hand • However, it adds to instability of the chain. • Stability is enhanced by strong volar ligaments. JOINT DEGREES OF FLEXION OTHER FACTORS • Also by the scaphoid, which bridges both carpal MCP 20–30 rows PIP 40–50 Less radial than ulnar DIP 15–20 • Relationships Thumb CMC • Carpal collapse Thumb MCP 25 MC in opposition • Ratio of carpal height to third MC height: Thumb IP 20 normally 0.54 • Ulnar translation • Ratio of ulna-to-capitate length to third MC height • Hand pulleys prevent bowstringing and decrease • Normal is 0.30 tendon excursion. • Distal radius normally bears about 80% of distal • Bowstringing increases moment arms. radioulnar joint load. • Sagittal bands allow MCP extension. • Distal ulna bears 20% • With hyperextension of the MCP, the intrinsic • Ulnar load bearing increases with ulnar muscles must function to produce PIP extension, lengthening and decreases with ulnar because the extension tendon is lax. shortening. • Normal grasp • Wrist arthrodesis is relatively common. • For boys and men: 50 kg • Dorsiflexion of 10–20 degrees is good for • For girls and women: 25 kg unilateral fusion (see Fig. 1.63). • Only 4 kg needed for daily function • Bilateral fusion • Normal pinch • Avoided if possible • For boys and men: 8 kg • If necessary, other wrist should be fused at 0–10 • For girls and women: 4 kg degrees of palmar flexion. • Only 1 kg needed for daily activities • Hand • Kinetics • Kinematics • Joint loading with pinch mostly in MCP • ROM • Because MCP joints have large surface area, • Metacarpophalangeal (MCP) joint however, contact pressures (joint load/contact • Universal joint, 2 degrees of freedom area) are lower. • Flexion: 100 degrees • DIP joints have the most contact pressure. • Abduction-adduction: 60 degrees • Subsequently develop the most degenerative • Proximal interphalangeal (PIP) joints changes with time (Heberden nodes) • Flexion: 110 degrees • Grasping contact pressures are decreased, focused • DIP joints on MCP. • Flexion: 80 degrees • Patients with MCP arthritis often had • Arches occupations in which grasping was required. • Two transverse arches • Compressive loads occur at the thumb with • Proximal through carpus pinching. • Distal through metacarpal heads • At interphalangeal joint: 3 kg • Five longitudinal arches • At MCP joint: 5 kg • Through each of the rays • At carpometacarpal (CMC) joint: 12 kg • Stability • An unstable joint • MCP joint • Frequently leads to degeneration • Volar plate and the collateral ligaments • Recommended positisions for arthrodesis of the hand • Collateral ligaments: taut in flexion, lax in are summarized in Table 1.50. extension • PIP and DIP joints SELECTED BIBLIOGRAPHY • Rely more on joint congruity The selected bibliography for this chapter can be found on • Ratio of ligament surface to articular surface is large. https://expertconsult.inkling.com. • Other concepts Basic Sciences 107

TESTABLE CONCEPTS

SECTION 1 ORTHOPAEDIC TISSUES • NSAIDs adversely affect healing of fractures as well as of lumbar I. Bone spinal fusions. COX-2 activity is required for normal enchondral os- • Haversian canals carry nerves and blood vessels longitudinally in sification during fracture healing. bone, and Volkmann canals connect different haversian canals. • Bone grafts have three properties. Osteoconduction acts as a scaffold • Cellular biology: for bone growth; osteoinduction involves growth factors that stimulate • Osteoblasts are derived from undifferentiated mesenchymal stem bone formation; osteogenic grafts contain primitive mesenchymal cells, and RUNX2 is the multifunctional transcription factor that cells, osteoblasts, and osteocytes. directs this process. • Calcium phosphate–based grafts are capable of osteooconduction • Wnt/Beta-catenin (B-catenin) pathways are involved in osteoblast and osteointegration. They have the highest compressive strength differentiation. of any graft material. Calcium sulfate is osteoconductive but rapidly • Sclerostin and Dkk-1 inhibit binding of the Wnt molecule to resorbed. LRP5/6. • The primary homeostatic regulators of serum calcium are PTH and 2+ • Inhibition of sclerostin or Dkk-1 will lead to increased bone mass. 1,25(OH)2D3. PTH results in increased serum Ca level and de- • BMPs work through SMAD to cause osteoblastic differentiation. creased inorganic phosphate level. • Osteoblasts produce type I collagen (i.e., bone), alkaline phos- • Bone mass peaks between 16 and 25 years of age. Physiologic bone phatase, osteocalcin, bone sialoprotein, and RANKL. loss affects trabecular bone more than cortical bone. • Osteocytes are former osteoblasts surrounded by newly formed • Both urinary hydroxyproline and pyridinoline cross-links are elevated matrix. They are important for control of extracellular calcium and when there is bone resorption. phosphorous concentration, and are less active in matrix produc- • Serum alkaline phosphatase increases when bone formation in- tion than are osteoblasts. creases. • Osteoclasts are derived from hematopoietic cells in the mac- • The most common cause of hypercalcemia is malignancy. Initial treat- rophage lineage. RANKL is produced by osteoblasts, binds to ment is with hydration, which causes a saline diuresis, along with loop immature osteoclasts, and stimulates differentiation into active, diuretics. mature osteoclasts that result in an increase in bone resorption. • Renal osteodystrophy is a spectrum of disorders observed in chronic OPG inhibits bone resorption by binding and inactivating RANKL. renal disease. The majority of cases are caused by phosphorous • Denosumab is a monoclonal antibody that targets and inhibits retention and secondary hyperparathyroidism. binding of RANKL to the RANK receptor, which is found on osteo- • Rickets (in children) and osteomalacia (in adults) are caused by a clasts. failure of mineralization. In rickets, the width of the zone of provisional • Osteoclasts bind to bone surfaces by means of integrins (vitronec- calcification is increased, which causes physeal widening and cupping. tin receptor), effectively sealing the space below, and then create • Premature arrest following growth plate injury is attributed to vascular a ruffled border and remove bone matrix by proteolytic digestion invasion across the physis. through the lysosomal enzyme cathepsin K. • Osteoporosis is a quantitative defect in bone. It is defined as a lumbar • Bisphosphonates directly inhibit osteoclastic bone resorption. bone density of 2.5 or more standard deviations less than the peak Nitrogen-containing bisphosphonates are up to 1000-fold more bone mass of a healthy 25-year old (T-score). potent than non–nitrogen-containing bisphosphonates. Bisphos- • Loss of function of the OPG gene results in osteoporosis. phonates function by inhibiting farnesyl pyrophosphate synthase in • Treatment of osteoporosis includes calcium supplements of 1000– the mevalonate pathway. They are associated with osteonecrosis 1500 mg/day as well as bisphosphonates. of the jaw, and in animal models, they have reduced the rate of • Scurvy results from ascorbic acid deficiency, which causes a decrease spinal fusion. in chondroitin sulfate synthesis and ultimately defective collagen • Bone matrix is 60% inorganic (mineral) components and 40% organic growth and repair. Widening in the zone of provisional calcification is observed. components. Calcium hydroxyapatite Ca10(PO4)6(OH)2 constitutes the majority of the inorganic matrix. Type I collagen is 90% of the organic • Osteogenesis imperfecta is caused primarily by a mutation in genes component, and osteocalcin is the most abundant noncollagenous responsible for metabolism and synthesis of collagen type I. protein in bone. II. Cartilage and Joint • Wolff’s law: Remodeling occurs in response to mechanical stress. Hueter-Volkmann law: Compressive forces inhibit growth, whereas • Cartilage is viscoelastic (properties vary depending on rate of force tension stimulates it. application). • There are three major types of bone formation. In enchondral forma- • Composed of water (75%), collagen (25% wet weight, 90%–95% is tion, bone replaces a cartilage model. Intramembranous formation type II), and proteoglycans (10% wet weight) occurs without a cartilage model; aggregates of undifferentiated • Collagen contributes to viscoelastic behavior in that it restrains mesenchymal differentiate into osteoblasts, which form bone. In ap- “swelling” of aggrecan. positional formation, osteoblasts lay down new bone on existing bone; • Aggrecan is most common proteoglycan. the groove of Ranvier supplies the chondrocytes. • Increases osmotic pressure and is responsible for ECM’s hydro- • There are three stages of fracture repair: inflammation, repair, and philic behavior remodeling. Fracture healing type varies with treatment method. In • Chondrocytes are only cell in cartilage. closed treatment, healing occurs through periosteal bridging callus • BMP-2 and the transcriptional factor SOX-9 important in regulating and interfragmentary enchondral ossification. In compression plate differentiation and formation. treatment, primarily cortical healing occurs. • Have cilia that serve as mechanosensory organs or “antennae.” • BMP-2 is used for acute open tibia fractures; BMP-7 is used for tibial • Cartilage layers: nonunions. BMP-3 has no osteogenic activity. • Zone 1 (superficial) has highest concentration of collagen and lowest of PG. 108 Basic Sciences

TESTABLE CONCEPTS

• Zone 2 (middle or transition) has high levels of PG and water IV. Tendon • Zone 3 (deep) has highest concentration of PG • Composed of water (50%–60%), collagen (75% dry weight, 95% is • Zone 4 (calcified cartilage) contains type X collagen type I), PG, and elastin • Growth factors: • Elastin is a highly elastic protein than is responsible for “toe region” of • IL-1 stimulates MMP, COX-2, and nitric oxide synthetase, which stress-strain curve. degrades cartilage • Decorin is most predominant PG, regulates fibril diameter, and inhibits • TGF- stimulates synthesis of ECM and decreased activity of IL-1 β TGF- 1. and MMPs β • Sheathed tendons have vincula (extensions of synovium), which carry • Changes with aging: blood supply. • Fewer chondrocytes but larger • Following injury, the inflammatory stage is weakest stage of repair • Decreased chondroitin but increased keratin and is characterized by production of collagen type III. • Smaller PG molecules (less able to hold water) • Increased advanced glycosylation end products V. Ligament • Increased stiffness (modulus of elasticity) • Similar in composition to tendon but (1) more water, (2) less total col- • Changes with arthritis: lagen but more type III, and (3) higher PG content. • Decreased keratin but increased chondroitin/keratan ratio • Following injury, healing ligament demonstrates increased collagen • Increased water content and permeability initially followed by fibers but fewer mature cross-links at 1 year. decreased water content in later stages • Like tendons, ligaments have direct or indirect (Sharpey fibers) inser- • Decreased stiffness (modulus of elasticity) tions. • Osteophyte formation due to pathologic activation of endochondral ossification by periarticular chondrocytes through Indian hedgehog VI. Neural Tissue and Intervertebral Disc (Ihh) mechanism • Myelin sheath composed of galactocerebroside and speeds wave • Lubricin is a mucinous glycoprotein that binds to hyaluronic acid and propagation (thicker sheath increases speed). contributes to boundary lubrication. • Action potential created when neurotransmitters cross synapse and • Major mode of lubrication in joints is elastohydrodynamic (lubricant trigger voltage-gated Na+ channels. pressure causes elastic deformation of the opposing surfaces which • Intervertebral disc: increases conformity). • Nucleus pulposus derived from notochord and has a high concen- • Rheumatoid arthritis: tration of proteoglycan • Rheumatoid factor is antibody (IgM) against the Fc portion of IgG • Annulus fibrosis derived from mesoderm • Anti-CCP test more sensitive and specific, and presence of anti- • Avascular; nutrients and fluid diffuse from vertebral end plates bodies linked to aggressive disease • Early degenerative disc disease is an irreversible process, with IL-1 • DMARDs: β stimulating the release of MMPs, NO, IL-6, and PGE . • Target TNF- : etanercept, infliximab, adalimumab 2 α • Aging disc has decreased water content as a result of fewer large PGs. • Target IL-1: anakinra • Fibronectin cleavage and fragmentation associated with degeneration • Target CD20: rituximab • Risks of opportunistic infection and lymphoma • Crystalline arthropathies: SECTION 2 ORTHOPAEDIC BIOLOGY • Gout: monosodium urate (strongly negatively birefringent, needle- I. Cellular and Molecular Biology shaped crystals) • Antibodies against nuclear content (ANAs) are implicated in several • Pseudogout: calcium pyrophosphate dehydrate (CPP) (weakly conditions, including scleroderma (scl-70) and CREST syndrome. • Alterations in ploidy occur during mitosis and gametogenesis, result- positive birefringent, rhomboid-shaped crystals) ing in conditions such as trisomy-21. III. Muscle • Marfan syndrome and malignant hyperthermia are examples of disor- • A-band represents thick filaments composed of myosin. ders with autosomal dominant inheritance. • I-band represents thin filaments composed of actin. • Duchenne muscular dystrophy is an example of a disorder with X- • Z-disk represents terminus of sarcomere. linked recessive inheritance. • Fluorescent in situ hybridization is used to examine chromosomes for • Motor unit is composed of the α-motoneuron and the myofibers it innervates. translocations predictable of diseases, including: • Contraction: • t(X;18): synovial sarcoma • ACh diffuses across the synaptic cleft and binds to postsynaptic • t(11;22): in Ewing sarcoma receptors on sarcolemma, which begin depolarization. • t(12;22): in clear cell sarcoma • Myasthenia gravis is due to IgG antibodies to the AcH receptor. • Bacterial LPS is recognized by TLRs on innate immune system cells. Manifests initially as ptosis and diplopia. Weakness worse with use. • Adaptive immunity is conferred with the production of antibodies. • Botulinum A reduces spasticity by blocking presynaptic acetylcho- • Cell-mediated hypersensitivity (type IV) causes reaction to orthopaedic line release. implants. • Following muscle injury, TGF- stimulates proliferation of myofibro- β II. Infection and Microbiology blasts and increases fibrosis. • Delayed-onset muscle soreness more common after eccentric exer- • Roughly 80% of orthopaedic infections are due to Staphylococcus. • CA-MRSA at-risk groups: athletes, IV drug abusers, homeless persons, cises and may be associated with changes in I-band. military recruits, prisoners Basic Sciences 109

TESTABLE CONCEPTS

• C-reactive protein is the most sensitive monitor of the course of infec- II. Perioperative Disease and Comorbidities tion; it has a short half-life and dissipates about 1 week after effective • Ratio of 1:1:1 blood product resuscitation is superior to saline fluid. treatment. • Fat embolism syndrome classical triad = petechial rash, neurologic • Necrotizing fasciitis is most commonly polymicrobial and associated symptoms, respiratory decline. with diabetes. • Malignant hyperthermia is autosomal dominantly inherited defect in • Requires early débridement/amputation above level of infection. ryanodine receptor. • Only 100 bacteria are required to cause infection in the presence of a • Caused by an uncontrolled release of calcium foreign object; fibronectin increases adhesion, and glycocalyx-biofilm- • Triggered by volatile anesthetics (and succinylcholine) slime-polysaccharide capsule inhibits phagocytosis. • Early sign is increasing end-tidal CO • Three basic mechanisms of antibiotic resistance have been identified: 2 • Treatment is 100% O and dantrolene (stabilizes sarcoplasmic avoidance, decreased susceptibility, and inactivation. Biofilm forma- 2 reticulum). tion is an example of avoidance; the biofilm creates a physical barrier. • Superantigens like TSS toxin-1 trigger cytokine release from T cells. • Smoking leads to two to four times more infections/osteomyelitis. SECTION 4 OTHER BASIC PRINCIPLES • Hyperglycemia impairs wound healing and decreases ability to fight I. Imaging and Special Studies infection. • Increased radiation exposure associated with: • Lyme arthritis can be treated effectively with oral antibiotics. Adults • Imaging of larger body parts can be given amoxicillin, doxycycline, or cefuroxime for 4 weeks. • Positioning the extremity closer to the x-source • Clostridium tetani produces an exotoxin leading to tetanospasm. Td • Use of large C-arm rather than mini C-arm vaccine is recommended every 10 years. • 3.0 T MRI has 9 times greater proton energy than 1.5T. • Sequestrum is the dead bone nidus with surrounding granulation tis- II. Biomaterials and Biomechanics sue. Involucrum is periosteal new bone formation. • MRI is the best method to show early osteomyelitis but may overesti- • Work is the product of force and the displacement it causes (Joule). mate extent of disease. • Energy is the ability to perform work. • Kingella kingae can be difficult to culture; PCR should be considered • Potential energy is stored in the toddler with a septic knee. • Kinetic energy is energy caused by motion: 1/2 mv2. • Staphylococcus epidermidis is the most common organism in • Stress is the internal resistance of body to a load (force/area). implant-associated infections. • Strain is relative measure of deformation = change in length/original • Antibiotic therapy according to Gustilo classification of open fractures: length (no units). • Gustilo I and II: first-generation cephalosporins the treatment of choice • Young’s modulus of elasticity (E) = stress/strain. • Gustilo IIIA: first-generation cephalosporin plus an aminoglycoside • Unique for every material • Gustilo IIIB (grossly contaminated): first-generation cephalosporin • High E to low E: ceramic, cobalt chrome, stainless steel, titanium, plus aminoglycoside plus penicillin cortical bone, PMMA, polyethelene, cancellous bone, tendon/liga- • Antibiotics: ment, cartilage • Aminoglycosides inhibit translation through irreversible binding of • Viscoelastic materials have a stress-strain behavior that is time/rate the 30S ribosomal subunit, inhibiting translation of proteins. dependent. • Cephalosporins inhibit cell-wall production by preventing pepti- • Isotropic materials have mechanical properties that are the same for doglycan cross-linkage. all directions loaded (golf ball). • Glycopeptides, such as vancomycin, inhibit cell-wall production by • Anisotropic materials have mechanical properties that vary with the interfering with the addition of cell-wall subunits. direction of the applied load (bone is stronger in axial load than with • Rifamycin inhibits DNA-dependent RNA polymerase F and displays bending moment). excellent biofilm penetration. Bacteria develop rapid resistance to • Corrosion: rifampin used as monotherapy. • Galvanic corrosion occurs when dissimilar metals are in direct • Macrolides, like erythromycin, bind the 50S ribosomal subunits. contact (cobalt chrome and stainless steel). • Fluoroquinolones, such as ciprofloxacin, inhibit DNA gyrase. • Crevice corrosion occurs in fatigue cracks with low oxygen ten- • Beta-lactam antibiotics, like penicillin, work by inhibiting pep- sion. tidoglycan synthesis by binding to the bacterial cell membrane • Fretting corrosion comes from small movements abrading the outside layer. surface penicillin-binding proteins. • Stress corrosion occurs in areas with high stress gradients. SECTION 3 PERIOPERATIVE AND ORTHOPAEDIC MEDICINE • Joint arthrodesis: • Hip: 25–30 degrees of flexion; 0 degrees of abduction/rotation Thromboprophylaxis I. • Knee: 0–7 degrees of valgus; 10–15 degrees of flexion • Virchow triad: endothelial damage, stasis or decreased blood flow, • Ankle: 5 degrees of hindfoot valgus; 5–10 degrees of external and hypercoagulability. rotation; neutral dorsiflexion • Aspirin irreversibly binds and inactivates COX enzyme in platelets, • Shoulder: 15–20 degrees of abduction; 20–25 of forward flexion; reducing thromboxane A . 2 40 degrees of internal rotation • Warfarin can be reversed with fresh frozen plasma and vitamin K. • Elbow: 90 degrees of flexion if unilateral; if bilateral, one at 65 • Heparin and low-molecular-weight heparin act through ATIII and can degrees and one at 110 degrees be reversed by protamine sulfate. • Wrist: 10–20 degrees of dorsiflexion; if bilateral, then the opposite • Rivaroxaban is a direct factor Xa inhibitor. should be in 10 degrees of palmarflexion. • Lactate is an indirect marker of tissue hyperperfusion and serves as best measure of resuscitation. 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