Professional Documents
Culture Documents
ORTHO BULLETS
Volume
Nine
Basic Science
2017
Collected By : Dr AbdulRahman AbdulNasser
drxabdulrahman@gmail.com
OrthoBullets 2017
OrthoBullets 2017
Preface
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Table of Contents
I. Musculoskeletal biology ..................................................................................................... 0
A. Bone Basic Science ....................................................................................................... 1
1. Types of Bone ................................................................................................................. 1
2. Bone Cells ...................................................................................................................... 3
3. Bone Matrix .................................................................................................................... 8
4. Bone Marrow .................................................................................................................. 9
5. Bone Circulation ........................................................................................................... 10
6. Bone Signaling & RANKL .............................................................................................. 12
7. Normal Bone Metabolism .............................................................................................. 14
B. Bone Formation & Healing ........................................................................................... 19
1. Embryology .................................................................................................................. 19
2. Endochondral Bone Formation ..................................................................................... 25
3. Intramembranous Bone Formation ............................................................................... 28
4. Bone Remodeling ......................................................................................................... 29
5. Fracture Healing .......................................................................................................... 30
6. Nonunion ...................................................................................................................... 34
7. Bone Growth Factors.................................................................................................... 36
8. Bone Grafting ............................................................................................................... 39
9. PTH & Vit D Physiology ................................................................................................. 44
C. Biologic Tissues .......................................................................................................... 46
1. Muscle Biology & Physiology ........................................................................................ 46
2. Ligaments..................................................................................................................... 49
3. Tendons ....................................................................................................................... 53
4. Articular Cartilage ........................................................................................................ 56
5. Cartilage ...................................................................................................................... 61
6. Synovium & Synovial Fluid ............................................................................................ 63
7. Collagen ....................................................................................................................... 65
D. Molecular Biology ........................................................................................................ 68
1. Molecular Biology Basics.............................................................................................. 68
2. Immunology .................................................................................................................. 70
3. Inheritance Patterns of Orthopaedic Syndromes .......................................................... 72
4. Genetic Pearls .............................................................................................................. 74
OrthoBullets 2017
3. Pustulosis palmoplantaris............................................................................................166
4. Acute Rheumatic Fever ...............................................................................................168
F. Metabolic Disease ......................................................................................................169
1. Hypercalcemia ............................................................................................................169
2. Hypocalcemia..............................................................................................................170
3. Hypoparathyroidism ....................................................................................................172
4. Hyperparathyroidism...................................................................................................173
5. Hypophosphatasia .......................................................................................................175
6. Pseudohypoparathyroidism .........................................................................................177
7. Scurvy .........................................................................................................................179
III. Medications & Toxicity ...................................................................................................182
A. Medications ................................................................................................................183
1. Bisphosphonates .........................................................................................................183
2. Prophylaxis Antibiotics ................................................................................................185
3. Antibiotic Classification & Mechanism .........................................................................187
4. Anti-inflammatory Medications ....................................................................................194
5. Analgesic Medications.................................................................................................196
6. Anesthesia ..................................................................................................................200
7. Platelet-Rich Plasma ....................................................................................................208
B. Toxicology ..................................................................................................................209
1. Lead Toxicity ...............................................................................................................209
IV. Clinical Science .............................................................................................................210
A. Clinical Studies ...........................................................................................................211
1. Statistic Definitions .....................................................................................................211
2. Level of Evidence ........................................................................................................218
3. Clinical Trial Design .....................................................................................................220
4. Outcome Measure Tools ..............................................................................................223
B. Healthcare Worplace ..................................................................................................228
1. Occupational Health ....................................................................................................228
2. Legal and Ethics ..........................................................................................................229
OrthoBullets2017 | Bone Basic Science
ORTHO BULLETS
I.Musculoskeletal biology
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Basic Science
1. Types of Bone
Introduction
Bone can be classified based on both anatomy and structure
o anatomic
long bones
flat bones
o structure
macroscopic level
cortical
cancellous
microscopic level
lamellar
woven bone
Anatomic classification
Long bones
o e.g. femur, humerus, tibia, forearm bones
o three anatomic regions in long bones
diaphysis
thick cortical bone surrounding a central canal of cancellous bone
outer region covered by periosteum
metaphysis
thin cortical bone surrounding loose trabecular bone
epiphysis
end of bone that forms the articular surface
contains the physis and the subchondral region under the articular cartilage
Flat bones
o e.g. skull, pelvis, scapula
o varied structure of either purely cortical bone or cortical bone with a thin central trabecular
region
Macroscopic structural classification
Cortical
o 80% of skeleton
o metabolism
characterized by slow turnover rate and high Young's modulus
o structure
made of packed osteons or Haversian systems
osteons
I:1 In this image we see mature,
outer border defined by cement lines lamellar cortical bone. 1 - A new
vascular canals Haversian system or osteon 2 -
Haversian canal 3 - Interstitial region
contain arterioles, venules, capillaries, and nerves between osteons
if oriented along long axis of bone: Haversian canals
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OrthoBullets2017 Musculoskeletal biology | Bone Basic Science
if oriented transversely to long axis of bone: Volkmann canals
interstitial lamellae
the region between osteons
Cancellous bone (spongy or trabecular bone)
o metabolism
lower Young's modulus and more elastic
high turnover to remodel according to stress across the bone
o structure
boney struts organized into a loose network
each strut is approximately 200 micrometers in diameter
I:2 Cancellous bone is a trabecular
30-90% of bone is porous and contains bone marrow framework of bone which is highly
increased porosity in osteoporosis porous. The porous region of the bone
contains bone marrow. Metaphyseal
Microscopic structural classification regions have larger amounts of cancellous
bone and subsequently better healing
Woven bone potential than diaphyseal regions.
o immature or pathologic bone that is woven and random and is not stress oriented
o compared to lamellar bone, woven bone has:
more osteocytes per unit of volume
higher rate of turnover
o weaker and more flexible than lamellar bone
Lamellar bone
o secondary bone created by remodeling woven bone
o organized and stress oriented
o stronger and less flexible than woven bone
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Basic Science
2. Bone Cells
Osteoblasts
Origin
o derived from undifferentiated mesenchymal cells
o mesenchymal cells then differentiate into osteoprogenitor cells
Structure
o contain increased amounts of endoplasmic reticulum, Golgi apparatus, and mitochondria than
other cells
o allows for synthesis and secretion of bone matrix
Function
o form bone by producing non-mineralized matrix
alkaline phosphatase
type I collagen
osteonectin
osteocalcin
stimulated by 1,25 dihydroxyvitamin D
o regulate osteoclast function
Signaling
o osteoblastic differentiation
BMP stimulates mesenchymal cells to become osteoprogenitor cells
core binding factor alpha-1 (cbf alpha -1: RUNX2)
stable beta-catenin plays a major role in inducing cells to form osteoblasts with resulting
intramembranous bone formation
platelet derived growth factor (PDGF) induces osteoblast differentiation
insulin derived growth factor (IDGF) induces osteoblast differentiation
o osteoblast bone production
PTH receptor
stimulates alkaline phosphatase and type I collagen production
1,25 dihydroxyvitamin D receptor
stimulates matrix and alkaline phosphatase synthesis
production of bone specific proteins (osteocalcin)
estrogen inhibits bone resorption and stimulates bone production by inhibiting adenylyl
cyclase
glucocorticoids inhibit collagen and bone matrix production
prostaglandins stimulate bone resorption by activating adenylyl cyclase
o osteoclast signaling
interconnected signaling allows coupling of bone resorption and formation
osteoclast activation
PTH receptors on osteoblast bind to PTH which when leads to expression of RANKL
RANKL binds to RANK receptor on osteoclast and bone resorption
osteoclast inhibition
osteoblasts can secrete OPG (osteoprotegrin)
OPG binds to RANKL on the osteoblast, preventing RANK activation
inhibits osteoclast activity
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OrthoBullets2017 Musculoskeletal biology | Bone Basic Science
Location
o more metabolically active cells at the bone surface
o less active cells in more central bone
activated by disruption of the more peripheral osteoblasts
Osteoclasts
Function
o reabsorb bone
osteoblasts regulate osteoclast bone reabsorbtion (see above)
steps in resorption cycle
migration to resorption site
bone attachment
polarization (formation of membrane domains)
dissolution of hydroxyapatite
degradation of organic matrix
removal of degradation products from resorption lacuna
apoptosis of the osteoclasts or return to the non-resorbing stage.
Origin
o originate from hematopoietic cells from macrophage cell lineage
o monocyte progenitors fuse together to form mature multinuclear cells
Cellular biology
o cellular anatomy
multinucleated giant cells
o cellular physiology
bone reabsorbtion occurs at ruffled border
Howship's lacunae
are site of bone resorption where ruffled border meets bone surface
tartrate resistant acid phosphate
secreted by osteoclasts to lowers the Ph (utilizing carbonic anhydrase) and increases
the solubility of hydroxyapatite crystals
deficiency of carbonic anhydrase prevents bone resorption
proteolytic digestion
the organic matrix is then removed by proteolytic digestion
cathepsin K
is one major proteolytic enzyme that degests organic matrix at ruffled border
bisphosphonates mechanism
prevents osteoclasts from forming ruffled border and producing acid hydrolases
Molecular biology
o osteoclast-bone attachment
osteoclast attaches to bone matrix at sealing zone
attach to bone surfaces via integrins on osteoclast surface
integrins include αVβ3, αVβ5, α2β1, αVβ1
αVβ3 (on osteoclast) is a receptor for vitronectin (on bone surface)
Arg-Gly-Asp (RGD) sequence of extracellular bone proteins directly allows binding
to integrins
antibodies to αVβ3 and RGD inhibit bone resorption
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Basic Science
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OrthoBullets2017 Musculoskeletal biology | Bone Basic Science
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Basic Science
o osteoclast polarization
contain specialized membrane domains
ruffled border (RB)
functional secretory domain (FSD)
basolateral membrane (BL)
o mineralized bone matrix degradation
hydroxyapatite crystals dissolved by HCl secreted through ruffled border into resorption
lacuna (RL)
RL is an extracelllular space between RB and bone matrix, sealed from ECF by sealing
zone
uses ATP-consuming proton pumps in RB and in intracellular vacuoles
H+ come from carbonic anhydrase II
RB has high number of chloride channels (maintain electroneutrality)
o organic bone matrix degradation
lysosomal cysteine proteinases
matrix metaloproteinases (MMPs), esp MMP-9
cathepsin K : mutation in cathepsin K gene leads to pycnodysostosis
o removal of degradation products
by transcystosis to FSD, where they are secreted into ECF
tartrate-resistant acid phosphatase (TRAP) is localized in transcytotic vesicles, generates
reactive O2 species that destroys collagen
o osteoclast-osteoblast signaling
osteoblasts upregulate and downregulate osteoclast activity
osteoclast activation
RANKL (NF-kB ligand)
expressed by osteoblasts and tumor cells to activate osteoclasts
IL-1
found adjacent to loose total joint implants and known to activate osteoclasts
osteoclast inhibition
calcitonin
IL-10
Osteocytes
Origin
o are former osteoblasts trapped in the matrix they produced
o account for 90% of cells in the mature skeleton
Structure
o high nucleus to cytoplasm ratio
o have long cellular processes which communicate with other cells via canalculi in the bone
Function
o maintain bone and cellular matrix
o important in regulation of calcium and phosphorous concentrations in bone
o do not express alkaline phosphatase
Signaling
o stimulated by calcitonin
o inhibited by PTH
o communicate with adjacent osteocytes via gap junctions in canaliculi
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OrthoBullets2017 Musculoskeletal biology | Bone Basic Science
Osteoprogenitor Cells
Origin
o originate from mesenchymal stem cells
o environment will determine their function
Function
o become osteoblasts under low strain and high oxygen tension
o become cartilage under intermediate strain and low oxygen tension
o become fibrous tissue under high strain
3. Bone Matrix
Introduction
Bone is made up of
o organic component
40% of dry weight
o inorganic component
60% of dry weight
Organic component
Components include
o collagen
90% of organic component
primarily type I collagen
provides tensile strength
it is a triple helix composed of one alpha-2 and two alpha-1 chains
o proteoglycans
responsible for compressive strength
inhibit mineralization
composed of glycosaminoglycan-protein complexes
o matrix proteins
includes noncollagenous proteins
function to promote mineralization and bone formation
three main types of proteins involved in bone matrix
osteocalcin
most abundant non-collagenous protein in the matrix (10%-20% of total)
produced by mature osteoblasts
function
promotes mineralization and formation of bone
directly involved in regulation of bone density
attracts osteoclasts
signaling
stimulated by 1,25 dihydroxyvitamin D3
inhibited by PTH
clinical application
marker of bone turnover
can be measured in urine or serum
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Basic Science
osteonectin
secreted by platelets and osteoblasts
function
believed to have a role in regulating calcium or organizing mineral in matrix
osteopontin
function : cell-binding protein
o cytokine and growth factors
small amounts present in matrix
aid in bone cell differentiation, activation, growth, and turnover
include
IL-1, IL-6, IGF, TGF-beta, BMPs
Inorganic component
Components include
o calcium hydroxyapatite (Ca10(PO4)6(OH)2
provides compressive strength
o osteocalcium phosphate (brushite)
4. Bone Marrow
Introduction
Gelatinous tissue found in the inner spaces of bone that contains progenitor cells and stromal cells
Types of bone marrow
o red marrow
hematopoietic tissue
composition
40% water
40% fat
20% protein
o yellow marrow
fatty tissue
composition
15% water
80% fat
5% protein
Function
o primary function of hematopoiesis
o controls the inner diameter of bone
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OrthoBullets2017 Musculoskeletal biology | Bone Basic Science
Yellow Bone Marrow
Location
o most commonly found in diaphysis or shaft of long bones
femur, humerus, tibia
Function
o contains mostly fat cells
o may revert to red bone marrow if there is an increased demand for red blood cells (e.g. trauma)
5. Bone Circulation
Introduction
Bone receives 5-10% of cardiac output
Bones that receive tenuous blood supply
o scaphoid
o talus
o femoral head
o odontoid
Blood supply to long bone comes from three sources
o nutrient artery system
o metaphyseal-epiphyseal system
o periosteal system
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Basic Science
o then branch into ascending and descending branches
then branch into arterioles and supply the inner 2/3 of mature bone via the haversion system
Metaphyseal epiphyseal system
Arteries arise from periarticular vascular plexus
o e.g. geniculate arteries
Periosteal System
Low pressure system that supplies the outer 1/3 of bone
o connected by
Volkman's artery (perpendicular to long axis)
Haversion system (parallel to long axis)
Intracortical Vascularization
Intracortical vessels travel within canals
o Primary Haversian canals
o Secondary Volkmann canals
Growth Plate
Perichondrial artery is the major source of nutrition of the growth plate
Pathoanatomy
Fractures
o patterns of blood flow following fracture
immediate phase
initial decrease in blood flow after fracture
flow is centripetal (outside to inside)
because high pressure nutrient artery system is disrupted
low pressure periosteal system predominates
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OrthoBullets2017 Musculoskeletal biology | Bone Basic Science
o hours to days
increase in blood flow (regional acceleratory phenomenon)
peaks at 2 weeks and returns to normal in 3-5 months
Intramedullary nails
o unreamed intramedullary nails preserve endosteal blood supply
o reaming devascularizes inner 50-80% of the cortex and delays revascularization of endosteal
blood supply
o loose fitting nails spare cortical perfusion and allow more rapid reperfusion
o tight fitting nails compromise cortical perfusion and reperfusion is slow
Osteoclast Activation
Osteoclast activation stimulates bone resorption
Molecules that stimulate bone resorption
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Basic Science
o RANKL
RANKL (ligand) is secreted by osteoblasts and binds to the RANK receptor on osteoclast
precursor and mature osteoclast cells
o PTH (secreted by many cancer cells)
activation of its receptor stimulates adenylyl cyclase
binds to cell-surface receptors on osteoblasts to stimulate production of RANKL and M-CSF
o interleukin 1 (IL-1)
stimulates osteoclast differentiation and thus bone resorption
o 1,25 dihydroxy vitamin D
stimulates RANKL expression
o prostaglandin E2
activates adenylyl cyclase and stimulates resorption
o IL-6 (myeloma)
o MIP-1A (myeloma)
Osteoclast Inhibition
Osteoclast Inhibition decreases bone resorption
Molecules that inhibit bone resorption
o osteoprotegerin (OPG)
decoy receptor produced by osteoblasts and stromal cells that binds to and sequesters
RANKL
inhibits osteoclast differentiation, fusion, and activation
o calcitonin
interacts directly with the osteoclast via cell-surface receptors
o estrogen (via decrease in RANKL)
stimulates bone production (anabolic) and prevents resorption
inhibits activation of adenylyl cyclase
o transforming growth factor beta (via increase in OPG)
o interleukin 10 (IL-10) : suppresses osteoclasts
Clinical Implications
Osteopetrosis
o condition caused by a genetic defect resulting in absence of osteoclastic bone resorption
o a mouse RANKL knockout model creates a osteopetrosis-like condition
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OrthoBullets2017 Musculoskeletal biology | Bone Basic Science
Osteoyltic bone metastasis
o found to be mediated by the RANK and RANKL pathway
o RANKL is produced directly by the cancer cells
o blocking of RANKL by OPG results in decreased skeletal metastasis in animal models
o bisphosphonates decrease skeletal events in cancer metastasis
Calcium
Location
o bone (99%)
o blood and extracellular fluid (0.1%)
o intracellular (1%)
Function
o calcium has a wide range of function including
muscle cell contraction
nerve conduction
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Basic Science
clotting mechanisms
Forms of calcium
o bone
majority is hydroxyapatite
o serum
Ca++ bound to protein (45%)
free-ionized Ca++ (45%)
bound to various anions, eg. citrate, bicarbonate (10%)
Regulation
o absorption from the digestive tract
o resorption from bone
o resorption in the kidneys
Dietary requirements
o 2000 mg/day for lactating women
o 1500 mg/day for pregnant women, postmenopausal woman, and patients with a healing bone
fracture
o 1300 mg/day for adolescents and young adults
o 750 mg/day for adults
o 600 mg/day for children
Dysfunction
o hypercalcemia
o hypocalcemia
Phosphate
Location
o bone (86%)
o blood and extracelluar fluid (0.08%)
o intracellular (14%)
Function
o key component of bone mineral
o important in enzyme systems and molecular interactions
Forms of phosphate
o bone
majority is hydroxyapatite
o serum
mostly inorganic phosphate (H2PO4-)
Regulation
o plasma phosphate is mostly unbound and reabsorbed by the kidney
o may be excreted in urine
o elevated serum phosphate can lead to increased release of PTH and bone resorption
Dietary intake
o 1000-1500 mg/day
PTH
Structure
o 84 amino acid peptide
Origin
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OrthoBullets2017 Musculoskeletal biology | Bone Basic Science
o synthesized and secreted from chief cells in the four parathyroid glands
Net effect
o increases serum calcium
o decreases serum phosphate
Mechanism
o bone
PTH stimulates osteoblasts to secrete IL-1, IL-6 and other cytokines to activate osteoclasts
and increase resorption of bone
Increases osteoblast production of M-CSF (macrophage colony-stimulating factor) and
RANKL, which increases number of osteoclasts.
Paradoxically, osteoclasts do not express receptor for PTH
o kidney
stimulates enzymatic conversion of 25-(OH)-vitamin D3 converted to 1,25-(OH)2-vitamin
D3 (active hormone form) which:
increases resorption of Ca++ in kidney (increasing serum Ca++)
increases excretion of PO4- from kidney (decreasing serum phosphate)
o intestine
no direct action
indirectly increase Ca++ absorption by activating 1,25-(OH)2-vitamin D3
Dysfunction
o PTH-related protein and its receptor have been implicated in metaphyseal dysplasia
Parathyroid hormone-related protein (PTHrP) has related effects to PTH as it binds to the same
receptors on osteoblasts and renal cells to increase serum calcium
Calcitonin
Structure
o 32 amino-acid peptide hormone
Origin
o produced by clear cells in the parafollicles of the thyroid gland (C cells)
Net effect
o limited role in calcium homeostasis
o inhibit number and activity of osteoclasts
Function
o bone
inhibits osteoclastic bone resorption by decreasing number and activity of osteoclasts
osteoclast have receptor for calcitonin
Inc. serum Ca > secretion of calcitonin > inhibition of osteoclasts > dec. Ca (transiently)
Dysfunction
o secreted by medullary thyroid tumors and mulitple endocrine neoplasia type II tumors
o Recombinant calcitonin used to treat Paget disease, osteoporosis, and hypercalcemia in
malignancy
Vitamin D
Structure
o fat soluble secosteroid (steroid with a 'broken ring')
Origin
o produced by skin when exposed to sunlight (UV B-generated Vitamin D)
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Basic Science
o dietary intake (lipid-soluble vitamin D3)
o active metabolite 1,25-(OH)2-vitamin D3 formed by two hydroxylations in the liver and kidney,
respectively
Net effect
o maintains normal serum calcium levels by activating osteoclasts for bone resorption and
increasing intestinal absorption of calcium (increase serum Ca++)
o promotes the mineralization of osteoid matrix
Function
o liver
activated-vitamin D3 converted to 25-(OH)-vitamin D3
o kidney
25-(OH)-vitamin D3 converted to 1,25-(OH)2-vitamin D3 (active hormone form)
activated by
increased levels of PTH
decreased levels of serum Ca++, P
1,25-(OH)2-vitamin D3 (active hormone form)can be inactivated to 24,25-(OH)2-vitamin D3
inactivity occurs with:
decreased levels of PTH
increased levels of serum Ca++, P
vitamin D parallels that of PTH by increasing reabsorption of Ca in the kidneys
o bone
1,25-(OH)2-vitamin D3 stimulates terminal differentiation of osteoclasts
when osteoclasts mature they do not respond to 1,25-(OH)2-vitamin D3 and respond mostly
to cytokines released by osteoblasts
1,25-(OH)2-vitamin D3 promotes the mineralization of osteoid matrix produced by
osteoblasts
Dysfunction
o Vitamin D deficiency causes osteomalacia and rickets
o phenytoin (dilantin) causes impaired metabolism of vitamin D
Estrogen
Structure
o D ring steroid hormone
Origin
o predominantly in the ovaries
o synthetic forms available
Net effect
o prevents bone loss by decreasing the frequency of bone resorption and remodeling
Function
o alone, because bone formation and resorption are coupled, it also indirectly decreases bone
formation
o leads to an increase in bone density of the femoral neck and reduces the risk of hip fracture
o most important sex-steroid for peak bone mass attainment in both men and women
Therapeutic estrogen
o outcomes
decreases bone loss if started within 5-10 years after onset of menopause
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OrthoBullets2017 Musculoskeletal biology | Bone Basic Science
significant side effects so risk/benefit ratio must be evaluated
gains in bone mass usually limited to an annual increase of 2-4% for the first 2 years of
therapy
o secondary effects
increases risk of
heart disease
breast cancer
decreases risk of
hip fracture
endometrial cancer (if combined with cyclic progestin)
o laboratory
will see a decreases in
urinary pyridoline
serum alkaline phosphatase
Thyroid Hormone
Function
o regulates skeletal growth at the physis by stimulating
chondrocyte growth
type X collagen synthesis
alkaline phosphatase activity
o thyroid hormones increase bone resorption and can lead to osteoporosis
large doses of therapeutic thyroxine can mimic this process and cause osteoporosis
Growth Hormone
Function
o increases serum calcium by
increased absorption in intestine
decreasing urinary excretion
o function is interdependent with insulin, somatomedins, and growth factors (TGF-B, PDGF,
mono/lyphokines)
Gigantism
o oversecretion or increased response to growth hormone effecting the proliferative zone of the
growth plate
Steroids
Function
o increase bone loss by
decreasing Ca++ absorption in intestine through a decrease in binding proteins
decreasing bone formation (cancellous more so than cortical bone) by
decreasing collagen synthesis
inhibiting osteoblast activity
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Formation & Healing
1. Embryology
Limb Development
Overview
o the appendicular system forms between the 4-8 weeks of gestation
o limb bud development
appears to be under the control of fibroblast growth factors (FGF)
enlargement of the limb bud is due to the interaction between the apical ectodermal ridge
(AER) and the mesodermal cells in the progress zone.
Steps of limb development
o notochord expresses Shh
o Shh regulates limb bud formation
limb bud is combination of lateral plate mesoderm and somatic mesoderm
growing outwards into ectoderm (called apical ectodermal ridge)
limb bud formed at embryonic stage 12 (26 days after fertilization)
o mesenchyme condenses into preskeletal blastemal at core of limb bud
o chondrification occurs where mesenchyme differentiates into chondrocytes
All upper limb bones are endochondral except distal parts of distal phalanges (membranous)
From proximal (humerus, 36 days after fertilization) to distal (distal phalanges, 50 days)
Factors required for chondrification
transcription factors – Sox-5, Sox-6, Sox-9
transforming growth factor superfamily – TGF-b, BMP-2
FGF family
receptor mutation leads to acrocephalosyndactyly (Apert syndrome)
patients with severe craniofacial features have mild hand syndactyly (gain of function
in FGFR2c affinity for FGF2 expressed in craniofacial area )
patients with mild craniofacial features have severe hand syndactyly (loss of function
in FGFR2c specificity for FGF2, and is now able to bind FGF10, more expressed in
hands)
retinoids
hedgehog gene products
PTHrP
cadherins
WNT5a and WNT7a
o Formation of joints requires repression of chondrogenesis at sites of future joints
proteins involved – WNT4, WNT14, growth and differentiation factor 5 (also known as
cartilage-derived morphogenetic protein 1)
shoulder interzone appears at 36 days, hand interzones appear at 47 days
o Finger separation
digital rays are evident within hand paddle at stage 17 (41 days)
interdigital mesenchyme cells undergo programmed cell death (stage 19 to 22)( days 47-54)
transcription factor Msx2 is expressed in interdigital mesenchyme, regulates BMP4-mediated
programmed cell death pathway
transcription factor Hox-7 also expressed in interdigital zones
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OrthoBullets2017 Musculoskeletal biology | Bone Formation & Healing
Limb patterning
o Proximodistal
first signaling center to appear is AER
controls proximal to distal growth
forms under FGF10 stimulation
removal /defect in AER results in proximal limb truncation
example is central deficiency (cleft hand)
another example is radial clubhand (radial dysplasia, absence of radius)
FGFs expressed in AER include FGF4, FGF8, FGF9, and FGF 17
FGF8 expressed earliest and is obligatory for normal limb development
FGF4, 9 and 17 are redundant
disrupted FGF signalling leads to arrested limb development
o Anteroposterior (radioulnar) limb growth (nomenclature: ulnar=posterior, radius=anterior)
second signaling center to appear is ZPA (zone of polarizing activity), along posterior limb
bud
grafting ZPA on anterior limb margin leads to mirror-image digit duplication (ulnar
dimelia, or mirror hand)
signaling molecule is Shh compound (dose dependent)
normal
high concentration of Shh on posterior (ulnar) side for small finger development
low concentration of Shh on anterior (radial) side for thumb development
posterior/ulnar side abnormalities
abnormal upregulation of Shh in the ZPA results in polydactly on the ulnar (posterior)
side
extent of duplication is dose dependent (higher dose = more replication)
downregulation of Shh (on the posterior/ulnar side) leads to loss of ulnar digits
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Formation & Healing
anterior/radial side abnormalities
abnormal upregulation of Shh in the anterior aspect of the limb bud (where Shh
concentration is supposed to be low) leads to loss of thumb
timing
posterior elements (little finger/ulna) are formed EARLY prior to anterior elements
which are formed LATE (radius/thumb)
disruption of AP patterning will result in loss of later forming elements
(radius/thumb)
o Dorsoventral axis
third signaling center is non-AER limb ectoderm /Wnt signalling center (progress zone, PZ)
dorsal limb ectoderm expresses WNT7a
activates Lmx1b (LIM-homeodomain factor) to regulate dorsal patterning
WNT7a is responsible for all dorsal features (including nails)
ventral ectoderm expresses en-1 (engrailed-1 protein, antagonistic to WNT7a)
inhibits WNT7a (and restricts it to dorsal ectoderm)
allows ventral limb development
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OrthoBullets2017 Musculoskeletal biology | Bone Formation & Healing
Key Genes
o Sonic Hedgehog (Shh) genes
secreted by ZPA
involved with HOX gene expression
anterior-posterior (radioulnar) growth
anterior (radial) mesoderm expresses ALX4
posterior (ulnar) mesoderm expresses Hox8
concentration gradient dictates formation of digits
little finger develops where there is highest Shh concentration
thumb develops where there is lowest Shh concentration
activates Gremlin
Gremlin inhibits BMPs that would otherwise block FGF expression in the AER
o Hox genes
anterior-posterior (radioulnar) patterning
together with Shh
regulate somatization of the axial skeleton, essentially patterning digit formation
o Wnt genes (Wnt7a)
expressed in dorsal (non-AER) ectoderm (Wnt signalling center)
dorsal-ventral growth
Mutations
o removal of AER
truncated limb
o duplication of ZPA
mirror-image duplication of the limb
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Formation & Healing
Key Genes/Regions
Gene/Region Expresses Regulates
Apical ectodermal ridge (AER) FGF8 is dominant (also FGF 4, Proximal to distal growth and
9, 17, which are redundant) interdigital necrosis
Zone of polarizing activity (ZPA) Shh Anterior-posterior (radio-ulnar)
growth
Non-AER limb ectoderm (dorsal) Dorsal ectoderm expresses Dorso-ventral growth
WNT7a, that activates Lmx1b
(regulates dorsal patterning)
Non-AER limb ectoderm (ventral) Ventral ectoderm expresses en- Dorso-ventral growth
1, antagonistic to WNT7a
(regulates ventral patterning)
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Formation & Healing
Anatomy
Blood supply
o perichondrial artery
You have not been
heard from for a while.
major source of
nutrition to physis
Longitudinal Physeal Growth
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OrthoBullets2017 Musculoskeletal biology | Bone Formation & Healing
Physeal Growth Plate
(letters on left correspond to histology in top right)
Cells store lipids, glycogen, and proteoglycan Gaucher's
Reserve Zone aggregates for later growth and matrix diastrophic dysplasia
production Kneist*
Low oxygen tension Pseudoachondroplasia*
Proliferative Proliferation of chondrocytes with longitudinal Achondroplasia
growth and stacking of chondrocytes. Gigantism
Zone Highest rate of extracellular matrix production MHE
Increased oxygen tension in surroundings
inhibits calcification
Hypertrophic Zone of chondrocyte maturation, chondrocyte SCFE (not renal)
hypertrophy, and chondrocyte calcification. Rickets (provisional calcification zone)
Zone Three phases occur in the hypertrophic zone Enchondromas
o Maturation zone: preparation of matrix Mucopolysarcharide disease
for calcification, chondrocyte growth acromegaly
o Degenerative zone: further preparation SED
of matrix for calcification, further MED
chondrocyte growth in size (5x) Schmids
o Provisional calcification zone: Kneist*
chondrocyte death allows calcium Pseudoachondroplasia*
release, allowing calcification of matrix Fractures most commonly occur
Chondrocyte maturation regulated by local through the zone of provisional
growth factors (parathyroid related peptides, calcification, specifically Salter-Harris I
expession regulated by Indian hedgehog fractures
gene)
Type X collagen produced by hypertrophic
chondrocytes important for mineralization
Primary Spongiosa Vascular invasion and resportion of Metaphyseal "corner fracture" in child
transverse septa. abuse
(metaphysis) Osteoblasts align on cartilage bars produced Scurvy
by physeal expansion.
Primary spongiosa mineralized to form woven
bone and then remodels to become
secondary spongiosa (below)
Secondary spongiosa Internal remodeling (removal of cartilage Renal SCFE
(metaphysis) bars, replacement of fiber bone with lamellar
bone)
External remodeling (funnelization)
Physis Periphery
Groove of Ranvier During the first year of life, the zone spreads Osteochondroma
over the adjacent metaphysis to form a
fibrous circumferential ring bridging from the
epiphysis to the diaphysis.
This ring increases the mechanical strength
of the physis and is responsible for
appositional bone growths
o supplies chondrocytes to periphery
Perichondrial Dense fibrous tissue that is the primary
fibrous ring of La limiting membrane that anchors and supports
Croix the physis through peripheral stability
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Formation & Healing
I:9 Illustration of relationship of the perichondrial ring of La Croix providing peripheral stability.
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OrthoBullets2017 Musculoskeletal biology | Bone Formation & Healing
Embryonic Long Bone Formation
Overview
o allows growth in width and length
o formed from mesenchymal anlage around 6th week in utero.
Steps of formation include
o vascularization
vascular buds invade the mesenchymal model
o primary ossification centers form
(at ~ 8 weeks) osteoprogenitor cells migrate through vascular buds and differentiate into
osteoblasts forming the primary ossification centers
o cartilage model forms
grows through appositional (width) and interstitial (length) growth
o marrow forms
marrow is formed by resorption of central portion of the cartilage anlage by myeloid
precursor cells that migrate in through the vascular buds
o secondary ossification centers form
develop at bone ends and lead to epiphyseal ossification center (growth plate)
4. Bone Remodeling
Introduction
Wolff's Law
o bone remodels in response to mechanical stress
Piezoelectic charges
o bone remodels is response to electric charges
o compression side is electronegative and stimulates osteoblast formation
o tension side is electropostive and stimulates osteoclasts
Hueter-Volkmann Law
o theory that bone remodels in small packets of cells known as
Basic Multicellular Units (BMUs)
o theory suggest that mechanical forces influence longitudinal
growth
o compressive forces inhibit growth
o may play role in scoliosis
Remodeling Mechanism
Cortical bone
o remodels by osteoclastic tunneling (cutting cone)
osteoclastic resorption > layering of osteoblasts > layering of lamellae > cement line laid
down
osteoclast make up head of cutting cone, followed by capillaries and then osteoblasts which
lay down the osteoid to fill the cutting cone
sclerostin inhibits osteoblastogenenesis to decrease bone formation
o cortical bone continues to change over time
cortical area decreases as age increases
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linked to increase fracture risk
medullary canal volume increases as age increases
Cancellous bone remodels by
o osteoclastic resorption
o osteoblastic deposition of layers of lamellae
5. Fracture Healing
Introduction
Fracture healing involves a complex and sequential set of events to restore injured bone to pre-
fracture condition
o stem cells are crucial to the fracture repair process
the periosteum and endosteum are the two major sources
Fracture stability dictates the type of healing that will occur
o the mechanical stability governs the mechanical strain
o when the strain is below 2%, primary bone healing will occur
o when the strain is between 2% and 10%, secondary bone healing will occur
Modes of bone healing
o primary bone healing (strain is < 2%)
intramembranous healing
occurs via Haversian remodeling
occurs with absolute stability constructs
o secondary bone healing (strain is between 2%-10%)
involves responses in the periosteum and external soft tissues.
enchondral healing
occurs with non-rigid fixation, as fracture braces, external fixation, bridge plating,
intramedullary nailing, etc.
o bone healing may occur as a combination of the above two process depending on the stability
throughout the construct
Inflammation Hematoma forms and provides source of hemopoieitic cells capable of secreting growth factors.
Macrophages, neutrophils and platelets release several cytokines
o this includes PDGF, TNF-Alpha, TGF-Beta, IL-1,6, 10,12
o they may be detected as early as 24 hours post injury
o lack of TNF-Alpha (ie. HIV) results in delay of both enchondral/intramembranous
ossification
Fibroblasts and mesenchymal cells migrate to fracture site and granulation tissue forms around
fracture ends
o during fracture healing granulation tissue tolerates the greatest strain before failure
Osteoblasts and fibroblasts proliferate
o inhibition of COX-2 (ie NSAIDs) causes repression of runx-2/osterix, which are critical for
differentiation of osteoblastic cells
Repair Primary callus forms within two weeks. If the bone ends are not touching, then bridging soft
callus forms.
o the mechanical environment drives differentiation of either osteoblastic (stable enviroment)
or chondryocytic (unstable environment) lineages of cells
Enchondral ossification converts soft callus to hard callus (woven bone). Medullary callus also
supplements the bridging soft callus
o cytokines drive chondocytic differentiation.
o cartilage production provides provisional stabilization
Type II collagen (cartilage) is produced early in fracture healing and then followed by type I
collagen (bone) expression
Amount of callus is inversely proportional to extent of immobilization
o primary cortical healing occurs with rigid immobilization (ie. compression plating)
o enchondral healing with periosteal bridging occurs with closed treatment
Remodeling Begins in middle of repair phase and continues long after clinical union
o chondrocytes undergo terminal differentiation
complex interplay of signaling pathways including, indian hedgehog (Ihh), parathyroid
hormone related peptide (PTHrP), FGF and BMP
these molecules are also involved in terminal differentiation of the appendicular
skeleton
o type X collagen types is expressed by hypertrophic chondrocytes as the extraarticular
matrix undergoes calcification
o proteases degrade the extracellular matrix
o cartilaginous calcification takes place at the junction between the maturing chondrocytes
and newly forming bone
multiple factors are expressed as bone is formed including BMPs, TGF-Betas, IGFs,
osteocalcin, collagen I, V and XI
o subsequently, chondrocytes become apoptotic and VEGF production leads to new vessel
invasion
o newly formed bone (woven bone) is remodeling via organized osteoblastic/osteoclastic
activity
Shaped through
o Wolff's law: bone remodels in response to mechanical stress
o piezoelectic charges : bone remodels is response to electric charges: compression side is
electronegative and stimulates osteoblast formation, tension side is electropostive and
simulates osteoclasts
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Variables that Influence Fracture Healing
Internal variables
o blood supply (most important)
initially the blood flow decreases with vascular disruption
after few hours to days, the blood flow increases
this peaks at 2 weeks and normalizes at 3-5 months
un-reamed nails maintain the endosteal blood supply
reaming compromises of the inner 50-80% of the cortex
looser fitting nails allow more quick reperfusion of the endosteal blood supply versus
canal filling nails
o head injury may increase osteogenic response
o mechanical factors
bony soft tissue attachments
mechanical stability/strain
location of injury
degree of bone loss
pattern (segmental or fractures with butterfly fragments)
increased risk of nonunion likely secondary to compromise of the blood supply to the
intercalary segement
External variables
o Low Intensity Pulsed Ultrasound (LIPUS)
exact mechanism for enhancement of fracture healing is not clear
alteration of protein expression
elevation of vascularity
development of mechanical strain gradient
accelerates fracture healing and increases mechanical strength of callus (including torque and
stiffness)
the beneficial ultrasound signal is 30 mW/cm2 pulsed-wave
healing rates for delayed unions/nonunions has been reported to be close to 80%
o bone stimulators
four main delivery modes of electrical stimulation
direct current
decrease osteoclast activity and increase osteoblast activity by reducing oxygen
concentration and increasing local tissue pH
capacitively coupled electrical fields (alternating current, AC)
affect synthesis of cAMP, collagen and calcification of carilage
pulsed electromagnetic fields
cause calcification of fibrocartilage
combined magnetic fields
they lead to elevated concentrations of TGF-Beta and BMP
o COX-2
promotes fracture healing by causing mesenchymal stem cells to differentiate into osteoblasts
o radiation (high dose)
long term changes within the remodeling systems
cellularity is diminished
Patient factors
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Formation & Healing
o diet
nutritional deficiencies
vitamin D and calcium
as high as 84% of patients with nonunion were found to have metabolic issues
greater than 66% of these patients had vitamin D deficiencies
in a rat fracture model
protein malnourishment decreases fracture callus strength
amino acid supplementation increases muscle protein content and fracture callus
mineralization
gastric bypass patients
calcium absorption is affected because of duodenal bypass with Roux-en-Y procedure
leads to decreased Ca/Vit D levels, hyperparathyroidism (secondary) & increased Ca
resportion from bone
treat these patients with Ca/Vit D supplementation
gastric banding does not lead to these abnormalities because the duodenum is not
bypassed
o diabetes mellitus
affects the repair and remodeling of bone
decreased cellularity of the fracture callus
delayed enchondral ossification
diminished strength of the fracture callus
fracture healing takes 1.6 times longer in diabetic patients versus non-diabetic patients
o nicotine
decreases rate of fracture healing
inhibits growth of new blood vessels as bone is remodeled
increase risk of nonunion (increases risk of pseudoarthrosis in spine fusion by 500%)
decreased strength of fracture callus
smokers can take ~70% longer to heal open tibial shaft fractures versus non-smokers
o HIV
higher prevalence of fragility fractures with associated delayed healing
contributing factors
anti-retroviral medication
poor intraosseous circulation
TNF-Alpha deficiency
poor nutritional intake
o medications affecting healing
bisphosphonates are recognized as a cause of osteoporotic fractures with long term usage
recent studies demonstrated longer healing times for surgically treated wrist fractures in
patients on bisphosphonates
long term usage may be associated with atypical subtrochanteric/femoral shaft fractures
systemic corticosteroids
studies have shown a 6.5% higher rate of intertrochanteric fracture non unions
NSAIDs
prolonged healing time becaue of COX enzyme inhbition
quinolones
toxic to chondrocytes and diminishes fracture repair
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6. Nonunion
Introduction
A nonunion is an arrest in the fracture repair process
o progressive evidence of non healing of a fracture of a bone
o a delayed union is generally defined as a failure to reach bony union by 6 months post-injury
this also includes fractures that are taking longer than expected to heal (ie. distal radial
fractures)
o large segmental defects
should be considered functional non-unions
Pathophysiology
o multifactorial
most commonly, inadequate fracture stabilization and poor blood supply lead to nonunion
infection
eradication needs to occur along with the achieving fracture union
location
scaphoid, distal tibia, base of the 5th metatarsal are at higher risk for nonunion because
blood supply in these areas
pattern
segmental fractures and those with butterfly fragments
increased risk of nonunion like because of compromise of the blood supply to the
intercalary segment
Classification
Types of nonunion
o septic nonunion
o pseudoarthrosis
o hypertrophic nonunion
caused by inadequate immobilization with adequate blood supply
type 2 collagen is elevated
typically heal once mechanical stability is improved
o atrophic nonunion
caused by inadequate immobilization and inadequate blood supply
o oligotrophic nonunion
produced by inadequate reduction with fracture fragment displacement
Presentation
Symptoms
o important to discern injury mechanisms, non operative interventions, baseline metabolic,
nutritional or immunologic statuses and use of NSAIDs and/or nicotine containing products
o assess pain levels with axial loading of involved extremity
Physical exam
o important to complete a thorough neurovascular exam, including the status of the soft tissue
envelope
o assess mobility of the nonunion
o assess extremity for the presence of deformity
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Formation & Healing
Imaging
Radiographs
o plain radiographs are the cornerstone for evaluation of fracture healing; four views should be
included
o full length weight bearing films should obtained if a limb length discrepancy is present
CT
o if the status of union is in question, a CT scan should be obtained; hardware artifact may limit
utility of the CT scan
Treatment
Nonoperative
o fracture brace immobilization
o bone stimulators
contraindications include synovial pseudoarthroses, nonunions
that move and greater than 1 cm between fracture ends
Operative
o infected nonunion
often associated with pseudoarthrosis
chance of fracture healing is low if infection isn't eradicated
staged approach often important
modalities
need to remove all infected/devitalized soft tissue
use antibiotic beads, VAC dressings to manage the wound
with significant bone loss, bone transport may be an option
muscle flaps can be critical in wound management with soft tissue loss
o pseudoarthrosis
may be found in association with infection
joint capsule may be encountered with operative exposure
modalities
removal of atrophic, non-viable bone ends
internal fixation with mechanical stability
maintenance of viable soft tissue envelope
o hypertrophic nonunions
often have biologically viable bone ends
issue with fixation, not the biology
modalities
internal fixation with application of appropriate mechanical stability
o oligotrophic nonunions
often have biologically viable bone ends
may require biological stimulation
modalities
internal fixation
o atrophic nonunions
often have dysvascular bone ends
mobile
modalities
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need to ensure biologically viable bony ends are apposed
fixation needs to be mechanically stable
bone grafting
autologous iliac crest (osteoinductive) is gold standard
BMPs
osteoconductive agents (ie. crushed cancellous chips, DBM)
establishment of healthy soft tissue flap/envelope
Techniques
Bone stimulators
o four main delivery modes of electrical stimulation
direct current
decrease osteoclast activity and increase osteoblast activity by reducing oxygen
concentration and increasing local tissue pH
capacitively coupled electrical fields (alternating current, AC)
affect synthesis of cAMP, collagen and calcification of carilage
pulsed electromagnetic fields
cause calcification of fibrocartilage
combined magnetic fields
o bone simulators work through induction coupling, which stimulates bone growth through the
following direct effects
increasing expression of BMP7
increasing expression of BMP7
increasing expression of BMP2
increasing expression of TGF-beta1
increasing expression of osteoblasts proliferation
increasing expression of BMP2
increasing expression of TGF-beta1
increasing expression of osteoblasts proliferation
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Formation & Healing
Bone Morphogenetic Protein (BMP) & SMADs
Overview
o BMPs belong to the TGF-B superfamily
o BMP 2,4,6, and 7 all exhibit osteoinductive activity
o BMP 3 does not exhibit osteoinductive activity
o Mutations in BMP-4 are associated with Fibrodysplasia ossificans progressiva
Mechanism
o osteoinductive
leads to bone formation
activates mesenchymal cells to transform into osteoblasts and produce bone
Signaling Pathways and Cellular Targets
o BMP targets undifferentiated perivascular mesenchymal cells
o activates a transmembrane serine/threonine kinase receptor that leads to the activation of
intracellular signaling molecules called SMADs
SMADS are primary intracellular signaling mediators
currently eight known SMADs, and the activation of different SMADs within a cell leads to
different cellular responses.
Clinical applications
o FDA-approved uses
rhBMP-2
single-level ALIF from L2 to S1 levels in degenerative disc disease together with the
lumbar tapered fusion device (LT Cage; Medtronic)
open tibial shaft fractures stabilized with an IM nail and treated within 14 days of the
initial injury
rhBMP-7
as an alternative to autograft in recalcitrant long bone nonunions where use of autograft is
unfeasible and alternative treatments have failed
as an alternative to autograft in compromised patients (with osteoporosis, smoking or
diabetes) requiring revision posterolateral/intertransverse lumbar fusion for whom
autologous bone and bone marrow harvest are not feasible or are not expected to promote
fusion
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o contraindications
pregnancy
allergy to bovine type I collagen or recombinant human rhBMP-2
infection
tumor
skeletal immaturity
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Formation & Healing
Fibroblast Growth Factor (FGF)
Overview
o FGF-1 and FGF-2 are most abundant
o promote growth and differentiation of a variety of cells
epithelial cells
myocytes
osteoblasts
chondrocytes
Mechanism
o binds to membrane spanning tyrosine kinase
o associated with angiogenesis and chondrocyte and osteoblast activation
o involved in early stages of fracture healing
8. Bone Grafting
Introduction
A material with either osteoconductive, osteoinductive, and/or osteogenic properties
o autografts
o allografts
o demineralized bone matrix (DBM)
o synthetics
o bone morphogenetic protein (BMP)
o stem cells
Epidemiology
o incidence
almost 1 million bone grafting procedures performed in US each year, with a growth of
almost 13% per year
Indications
o assist in healing of fractures, delayed unions, or nonunions
o assist in arthrodeses and spinal fusions
o replace bone defects from trauma or tumor
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Resorption rates
o relative resorption rates of bone graft substitutes
fastest to slowest
calcium sulfate > tricalcium phosphate > hydroxyapatite
Outcomes
o allograft retrieval
retrieval studies are helpful in understanding the body's response to allografts
5 years after implantation, allograft articular cartilage is completely acellular - no donor or
recipient chondrocytes will be present
Properties
Bone graft has aspects of one or more of these three properties
o osteoconductive
material acts as a structural framework for bone growth
demineralized bone matrices (DBMs)
the various three-dimensional makeups of the material dictate the conductive properties
o osteoinductive
material contains factors that stimulate bone growth and induction of stem cells down a bone-
forming lineage
bone morphogenetic protein (BMP) is most common from the transforming growth factor
beta (TGF-B) superfamily
o osteogenic
material directly provides cells that will produce bone including primitive mesenchymal stem
cells, osteoblasts, and osteocytes
mesenchymal stem cells can potentially differentiate down any cell line
osteoprogenitor cells differentiate to osteoblasts and then osteocytes
cancellous bone has a greater ability than cortical bone to form new bone due to its larger
surface area
autologous bone graft (fresh autograft and bone marrow aspirate) is the only bone graft
material that contains live mensenchymal precursor cells
Antigenicity
Allograft is a composite material and therefore has many potential antigens (cell surface
glycoproteins)
o Class I and Class II antigens on graft are recognized by host T lymphocytes and elicit an immune
response
o immunogenic cells are marrow-based, endothelium, and retinacular-activating cells
bone marrow cells elicit the greatest immune response
extracellular matrix also acts as an antigen
type I collagen stimulates both humoral and cell-mediated responses
noncollagenous matrix (proteoglycans, osteocalcin)
o hydroxyapatite has not been shown to elicit an immune response
primary rejection is cell-mediated related to the major histocompatibility complex (MHC)
incompatibility
Overview
See table next page
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Formation & Healing
Types of Bone Graft
Autograft
Cancellous - Less structural support
- Greater osteoconduction
- Rapid incorporation via creeping substitution
Cortical - Slower incorporation due to need to remodel existing Haversion canals
- Interstitial lamellae preserved
- Provides more structural support
- 25% of massive grafts sustain insufficiency fractures
Vascularized bone - Technically challenging with quicker union and cell preservation
graft - Examples include: free fibula strut graft (peroneal artery), free iliac crest (deep
circumflex iliac arteries), distal radius used for scaphoid fx (1-2 intercompartmental
superretinacular artery branch of radial artery)
Allograft
Fresh
- Highest risk of disease transmission and immunogenicity
- BMP preserved and therefore osteoinductive
Fresh frozen - Less immunogenicity than fresh
- BMP preserved and therefore osteoinductive
Freeze dried - Least immunogenic
(croutons) - Least structural integrity
- BMP depleted (purely osteoconductive)
- Lowest likelihood of viral transmission
Demineralized Bone Matrix
Grafton DBM - Osteoinductive and osteoconductive
- Contains: collagen, bone morphogenetic proteins, transforming growth factor-
beta, residual calcium
- Does NOT contain mesenchymal precursor cells
Synthetics
Silicate based
grafts
Aluminum oxide Alumina ceramic bonds bind to bone in response to stress and strain
Calcium - Osteoconduction and osteointegration
phosphate grafts - Biodegrade very slowly
- Highest compressive strength
- Many prepared as ceramics (heated to fuse into crystals)
- Examples include: tricalcium phosphate, Norian (Synthes), hydroxyapatitie (tradename
Collagraft by Zimmer)
Calcium sulfate - Osteoconductive
- Quick resorption
- Examples include: OsteoSet (Wright medical)
Coralline - Calcium carbonate skeleton is converted to calcium phosphate via a thermoexchange
hydroxyapatine process (Interpore)
Calcium carbonate - Chemically unaltered marine coral
- Osteoconductive
- Examples include: Biocora (Inoteb, france)
Bone Growth Factors
BMP see Rank-L and Bone Growth Factors
TGF-B
IGF-II
PDGF
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OrthoBullets2017 Musculoskeletal biology | Bone Formation & Healing
Autograft
Bone graft transferred from one body site to another in the same patient
Indications
o gold standard
Properties
o osteogenic, osteoinductive, and osteoconductive
o least immunogenic
o cortical, cancellous, or corticocancellous
o vascular or nonvascular
Donor sites
o bone marrow aspirate
source of osteogenic mesenchymal precursor cells
iliac crest and vertebral body most common sites
variable number of cells depending on patient age
o iliac crest is the most common site for autograft
provides both cancellous and cortical graft
higher complication rate with anterior versus posterior harvesting
2% to 36% complication rate
blood loss and hematoma
injury to lateral femoral cutaneous or cluneal nerves
hernia formation
infection
fracture
cosmetic defect
chronic pain
o fibula and ribs are most common sources of vascularized autografts
o tibial metaphysis
Allograft
Bone graft obtained from a cadaver and inserted after processing
Most commonly used bone substitute
Properties
o osteoconductive only due to lack of viable cells
the degree of osteoconduction available depends on the processing method (fresh, frozen, or
freeze-dried) and type of graft (cortical or cancellous)
o cortical, cancellous, corticocancellous, and osteoarticular (tumor surgery)
Osteoarticular allograft
o immunogenic
o preserved with glycerol or dimethyl sulfoxide (DMSO)
o cryogenically preserved (few viable chondrocytes remain)
o tissue-matched (syngeneic) grafts decrease immunogenicity
Processing methods
o debridement of soft tissue, wash with ethanol (remove live cells), gamma irradiation
(sterilization)
dose-dependent higher doses of irradiation kills bacteria and viruses but may impair
biomechanical properties
o fresh allograft
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Formation & Healing
cleansing and processing removes cells and decreases the immune response improving
incorporation
indications
rarely used due to disease transmission and immune response of recipient
o frozen or freeze-dried
reduces immunogenicity while maintaining osteoconductive properties
reduces osteoinductive capabilities
shelf life
one year for fresh frozen stored at -20 degrees C
five years for fresh frozen stored at -70 degrees C
indefinite for freeze-dried
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OrthoBullets2017 Musculoskeletal biology | Bone Formation & Healing
Graft Healing
Vitamin D Physiology
Overview
o Vitamin D and PTH play an important role in calcium homeostasis
skin, liver, parathyroid gland, kidney, bone, and small intestine all play a role
Increased PTH and Vitamin D leads to increase serum calcium levels
Synthesis
o 7-Dehydrocholesterol
precursor to calcitriol is stored in the skin where UV exposure converts it to previtamin D3.
o cholecalciferol (Vitamin D3)
Previtamin D3 is then bound to vitamin-D binding protein (DBP) where it is carried to the
liver and metabolized to 25-hydroxyvitamin D3
o 25-hyrdoxyvitamin D3
when calcium is low, parathyroid hormone (PTH) levels become elevated which activates 1-
alpha-hydroxylase in the kidney
1-alpha-hydroxylase converts 25-hydroxyvitamin D to the active Vitamin D (calcitriol)
laboratory study of choice to determine Vitamin D deficiency
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Bone Formation & Healing
o 1,25-dihydroxyvitamin D3 (Vitamin D, calcitriol)
active form that controls calcium homeostasis in body by targeting intestines and bones (see
function below)
Function
2+
o ↑ serum Ca and phosphate via
↑ absorption of calcium and phosphate from the intestine
2+
↑ bone resorption of Ca and phosphate
2+
o recall PTH functions to ↑ serum Ca but ↓ serum phosphate
Regulation
o PTH stimulates 1,25-(OH)2 vitamin D production
o hypocalcemia/hypophoshatemia stimulates 1,25-(OH)2 vitamin D production
o 1,25-(OH)2 vitamin D feedback negatively on itself
PTH Physiology
Synthesis
o secreted by the chief cells of parathyroid
Function
2+
o ↑ serum Ca and ↓ serum phosphate in response to hypocalcemia/hypomagnesemia via
↑ bone resorption of calcium and phosphate (bone is destroyed)
PTH receptor is on the osteoblasts which secretes IL-1 to activated osteoclasts
↑ kidney resorption of calcium in distal convoluted tubule
↓ kidney resorption of phosphate
↑ 1,25-(OH)2 vitamin D production
Clinical Conditions
Conditions related to PTH
o hypoparathyrodism
o pseudohypoparathyroidism
o renal osteodystrophy
Conditions related to Vitamin D
o Rickets
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OrthoBullets2017 Musculoskeletal biology | Biologic Tissues
C. Biologic Tissues
Gross Anatomy
Myotendinous junction
o weak link in muscle and often site of tears (especially with eccentric contraction)
o involution of muscles cells maximized surface area for attachment
Noncontractile elements
o Epimysium surrounds muscle bundles
o Perimysium surrounds muscle fascicles
o Endomysium surrounds individual fibers
Muscle Contraction
Contractile elements
o derived from myoblasts
o the muscles fiber (an elongated cell) is the basic unit of contraction
o a myofibril is a collection of sarcomeres
Sarcomere composition
o filaments
thick myosin filaments
thin actin filaments
o bands
H band is myosin only
I band is actin only
A band is both actin and myosin
Z line flanks each sarcomere and acts as site of attachment for actin filament
during muscle contraction
A band stays the same length
I band reduces in length
H zone reduces in length
Action stimulation
o nerve cell body delivers electrical signal to motor endplate (junction between muscle and nerve)
nerve action potentials are started with passage of sodium ions through voltage gated
channels
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o Ach is released and diffuses across synaptic cleft to bind to Ach receptor
myasthenia gravis patient has shortage of Ach receptors
botox blocks release of Ach from end plate
o Ach binding triggers depolarization of sarcoplasmic reticulum and release of calcium into
muscles cytoplasm
o excitation-contraction coupling
in low calcium environment
tropomyosin blocks myosin-binding sites on actin
in high calcium environment
calcium binds to troponin (on thin filaments) leading to a configuration change of
tropomyosin (on thin filaments)
exposing myosin-binding sites on actin filament
actin forms cross-bridges to myosin, and the ATP breakdown, the two fibers contract past
one another
Types of muscle contraction
o isometric
muscle contracts with constant length (e.g. pushing against an immovable object)
o isokinetic
muscle contracts with constant speed (requires specific equipment like cybex machines)
o plyometric
rapid lengthening followed by contraction of muscle groups (e.g. jumping up and down on
boxes)
o isotonic - muscle contract with constant tension
concentric
muscle shortens during contraction (e.g. biceps curl)
eccentric
muscle lengthens during contraction (e.g. "negative" of a biceps curl)
Force generation
o force generated is most dependent on muscle cross-sectional area
o muscle fiber size increases with strength conditioning
Contraction speed
o duration and speed of contraction is most dependent on fiber type
Muscle Types
Type I muscle Type II muscle
(slow twich - ST) (fast twitch - FT)
"slow red ox muscles"
Metabolism • aerobic / oxidative • anaerobic / glycolytic
Energy • Aerobic system (oxidative • ATP-CP system
source phosphorolation via Krebs cycle)
Exercise • endurance (distance running) • high strength of contraction
duration • low strength of contraction • high speed of contraction (large force
• low speed of contraction generation per cross sectional area)
• first to atrophy with deconditoning • fatigue rapidly
• sprinting is example
Note • high yield ATP • high yield ATP (increased ATPase)
• requires O2 and thus more vascular • low intramuscular triglycerine stores
• increase mitochondria in cells
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Metabolic Systems
Three systems are used to generate energy for muscles
o ATP-CP anaerobic system
(adenosine triphosphate-creatinine phosphate system, "phosphagen system")
basis for creatine phosphate supplementation (main side effect: muscle cramping)
used for intense metabolic exercise lasting less than 20 seconds (e.g., 100 meter sprint)
converts carbohydrates stored within muscle into energy
anaerobic (does not use oxygen and does not produce lactate)
formulas
ATP –» ADP + P + energy
ADP –» AMP + P + energy
o lactic anaerobic system (lactic acid metabolims)
intense muscle activity lasting 20 to 120 seconds (e.g., 400 meter sprint)
involves hydrolysis of one glucose molecule
formula
glucose –» lactic acid + energy
o aerobic system
used in longer duration and lower intensity exercises
Krebs cycle generates ATP from glucose and fatty acids through oxidative phosphorylation
Muscle Injury
Muscles soreness
o caused by edema and inflammation in the connective tissue
neutrophils are the most abundant cells early on after acute injury
generates free radicals that possibly increase muscle damage
o worse with unaccustomed eccentric exercise
o peaks at 24-48 hours
o elevated CK levels seen in serum
Muscles strain
o occur at myotendinous junction (off during eccentric contraction which produces highest forces
in skeletal muscle)
o pathoanatomy in inflammation followed by fibrosis
Muscle atrophy
o caused by disuse or nerve injury
o leads to fatty infiltration and increased fatigability
o muscles crossing a single joint atrophy faster
o loss of cross-sectional area leads to decreased force generation
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2. Ligaments
Introduction
Ligaments function to
o restrict joint motion
o stabilize joint
o have mechanoreceptors and free nerve endings that help with joint proprioception
Composition
Extracellular components consist of
o water
o Type I collagen (70% of dry weight)
o elastin
higher elastin content than tendons
o lipids
o proteoglycans
o epiligament coat
present in some ligaments, not all
analogous to epitenon of tendons
Cellular component
o the main cell type in both tendons and ligaments is the fibroblast
o both tendons and ligaments have low vascularity and cellularity
Ligaments vs. tendons
o composition
compared to tendons, ligaments have
lower percentage of collagen
higher percentage of proteoglycans and water
less organized collagen fibers
rounder fibroblasts
Bone insertion
Two types of ligament bone insertion
o indirect (fibrous insertion)
most common form of bone insertion
superficial fibers insert into the periosteum
deep fibers insert directly into bone via perforating collagen fibers called Sharpey fibers
at insertion, endotenon becomes continuous with periosteum
examples
MCL inserting into proximal tibia
o direct (fibrocartilaginous insertion)
has both deep and superficial fiber insertion
deep fibers
have four transitional zones of increasing stiffness that allow for force dissipation and
reduce stress concentration
Zone 1 (tendon or ligament proper)
consists of well aligned type I collagen fibers with small amounts of proteoglycan
decorin
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Zone 2 (fibrocartilage)
consists of types II and III collagen, with small amoutns of type I, IX and X
collagen, and proteoglycans aggrecan and decorin
Zone 3 (mineralized fibrocartilage)
consists of type II collagen, with significant amounts of type X collagen and
aggrecan
Zone 4 (bone)
is made up of type I collagen, with high mineral content
examples : supraspinatus insertion
Blood Supply
Origin
o receives blood supply at insertion site (different from tendons)
ACL (and PCL) receives blood supply from middle geniculate artery
o have uniform microvascularity within ligament
Biomechanical Properties
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Ligament vs. tendons
o stress-strain differences between tendons and ligaments
tendons carry higher loads, recruit fibers quickly
smaller toe region
ligaments recruit fibers gradually
elongated toe region
Ligament Failure
Mechanism
o rupture of sequential series of collagen fibers
o ligaments do not plastically deform
Failure site
o usually midsubstance in adults
o usally at bony insertion in children
ligament avulsion
occurs at junction of mineralized and unmineralized fibrocartilage layers
Classification
o ligament injuries are classified into 3 grades
Grade I
corresponds to mild sprain
Grade II
corresponds to moderate sprain/partial tear
Grade III
corresponds to complete tear
Ligament Healing
Phases
o inflammatory phase
occurs at 1-7days
influx of neutrophyils and macrophages
production of type III collagen
growth factors involved
TGF-β1
IGF
PDGF
BMPs -12 and -13
bFGF
o proliferation phase
occurs at 7-21 days
gradually replaced by type I collagen
tendons and ligaments are weakest at day 5-21
o remodeling phase
occurs at >14 days
o maturation phase
up to 18 months
Factors that impair ligament healing
o intra-articular
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extra-articular ligaments (e.g. knee MCL) have a greater capacity to heal compared with
intra-articular ligaments (e.g. knee ACL)
o increasing age
o immobilization
reduces strength of both intact and repaired ligament
o smoking
o NSAIDS
including indocin, celcoxib, parecoxib
o diabetes
o alcohol intake
o decreased growth factors
bFGF, NGF, and IGF-1
o decreased expression of genes involved with tendon and ligament healing
examples include
procollagen I
cartilage oligomeric matrix protein (COMP)
tenascin-C
tenomodulin
scleraxis
Factors that improve ligament healing (experimental)
o extra-articular
extra-articular ligaments (e.g. knee MCL) have a greater capacity to heal compared with
intra-articular ligaments (e.g. knee ACL)
o compromised immune response
CD44 (receptor for lymphocyte activation) knockout mice have faster patellar tendon healing
Interleukin 10 (anti-inflammatory cytokine) improves patellar tendon healing in mice
Interleukin 1 (inflammatory mediator) receptor antagonist inhibits loss of mechanial
properties in patellar tendons in rabbits
depletion of macrophages (source of TGF-β1 that stimulates fibrosis) improves ACL graft
healing in mice (less scar, more fibrocartilage)
o mesenchymal stem cells
improved healing of tendon graft in bone tunnel in rabbits and rats
promote healing of partial tears of digital flexor tendons in horses
insufficient for rat rotator cuff repair (shear stresses too high)
o growth factors
PDGF-BB
increases cellular proliferation and limits adhesions in dog flexor tendon repairs, but
provides no improvement in tensile strength
GCSF
improves tendon incorporation into bone tunnels in ACL reconstruction in dogs
BMP-2 and -12
improves healing in animal rotator cuff models
o scaffolds to help primary ligament healing (instead of reconstruction)
collagen-platelet-rich plasma hydrogel helps primary ACL repair
but still inferior to native ACL strength
o neuropeptides
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denervation degrades tendons and ligaments
calcitonin gene-related peptide improves MCL healing in rabbits
Scarring
o tendons and ligaments heal with scar tissue that
reduces ultimate strength
causes adhesions
3. Tendons
Introduction
Function
o transfer forces from muscle to bone to produce joint motion
o tendons orient themselves along stress
Types
o paratenon covered tendons
e.g., patellar, achilles tendons
have rich vascular supply and thus heal better
often injured due to trauma and most often fail at the
musculotendinous junction
tendon-bone junction
o sheathed tendons
e.g., hand flexor tendons
less vascularized and have avascular areas that receive nutrition by diffusion
often injured due to laceration and at risk for adhesions
Anatomy
Composition
o groups of collagen bundles (fascicles) separated by endotenon and surrounded by epitenon
o composed of
water
tendons primarily composed of water
collagen
Type I collagen makes up 85% of dry weight of tendons
Type III collagen make up 0-5% of dry weight of tendons
proteoglycans
make up 0-5% of dry weight of tendons
decorin
is the most predominant proteoglycan in tendon
regulates collagen fiber diameter (length of 300nm, diameter of 1.5nm)
forms cross-links between collagen fibers and transfers loads between collagen fibers
aggrecan
is proteoglycan found in areas of tendon compression
Structure
o has a highly ordered hierarchical structure
o microfibrils<subfibrils<fibrils<fascicles<tendon unit
o insert into bone via 4 transitional tissues of increasing modulus)
tendon
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type I and III collagen, elastin, proteoglycans, tendon fibroblasts
uncalcified fibrocartilage
aggrecan, types I, II and III collagen, fibrochondrocytes
tidemark - straight, basophilic line separating uncalcified and calcified fibrocartilage, a
mechanical boundary between soft-hard tissue
calcified fibrocartilage (separated from fibrocartilage by tidemark)
type II collagen, aggrecan, types I and X collagen, fibrochondrocytes
irregular boundary, with interlocking of calcified fibrocartilage zone with bone
bone
osteocytes, osteoclasts, osteoblasts, type I collagen, apatite
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Fibrocartilaginous Enthesis (Direct
Fibrous Enthesis (Indirect Attachment)
Attachment)
Attachment Metaphysis and diaphysis of long bones Epiphysis and apophysis
4 distinct zones (tendon, fibrocartilage,
Composition Perforating mineralized collagen fibers
calcified fibrocartilage, and bone)
Insertion angle changes slightly during Insertion angle changes greatly during
Angle of Insertion
motion motion (thus prone to overuse injury)
Deltoid-humerus attachment, adductor
Example magnus-linea aspera attachment, pronator Rotator cuff, Achilles tendon
teres attachment
Material Properties
Characteristics
o tendons contain more collagen and are less viscoelastic than ligaments
o viscoelastic behavior with nonlinear elasticity
the rate at which tendon sees force can influence the mechanical property
o biomechanical effects
exercise has positive effect
immobilization has detrimental effect
age dependent
increase in strength from birth to maturity
decrease in strength after maturity
laser/heat causes tendons to shrink
vary with exposure to hydration, temperature, pH
tendons should be tested under physiologic relevant conditions I:12 Load-elongation or stress-
strain curve
Advantages
o strong in tension (can withstand 5-10% as opposed to 1-4% in bone)
Disadvantages
o buckle in compression
o demonstrate creep and stress relaxation
Load-elongation or stress-strain curve
o toe region
initial nonlinear segment of curve during low loads due to tendons being "crimped"
o linear region
intermediate loads
o failure region : high loads
Tendon Healing
Stages of tendon healing
Stages of Soft Tissue Healing (including tendons)
Hemostasis Platelets initiate coagulation cascade 5-15 minutes
Fibrin clot and fibronectin interaction leading to
chemotaxis to stabilize torn tendon edges
Inflammation Fibroblasts produce type III collagen 1-7 days
macrophages help initiate healing and remodeling
Organogenesis Tissue modeling via large amounts of disorganized 7-21 days
collagen and angiogenesis
Remodeling Tissue remodeling replacing type III collagen to type I up to 18 mos.
collagen
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Tendon Surgical Repair
Strength following repair
o tendon repairs are weakest at 7-10 days
o most of strength by 21-28 days
o maximum strength at 6 months
final strength only reaches 2/3 of normal even years after repair
Early mobilization
o allows earlier ROM but decreased tendon repair strength
o beneficial for flexor tendon healing to prevent adhesion formation
4. Articular Cartilage
Introduction
Articular cartilage is one of five forms of cartilage
o hyaline or articular cartilage
o fibroelastic cartilage (meniscus)
o fibrocartilage (at tendon and ligament insertion into bone)
o elastic cartilage (trachea)
o physeal cartilage (growth plate)
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Biologic Tissues
5. Cartilage
Introduction
Main types of cartilage include
o articular (hyaline) cartilage
o fibrocartilage (tendon/ligament junction with bone) and fibroelastic cartilage (menisci)
o elastic cartilage (trachea)
o epiphyseal cartilage (growth plates)
Cartilage contents (avascular, aneural, and alymphatic)
o cells
chondrocytes
o extracellular matrix
water
collagen
proteoglycans
noncollagenous proteins
Cell differentiation
o cartilage is formed from mesenchymal stem cells designated towards the cartilagenous lineage
multi-step process involving activation and migration of cells to necessary sites
SOX-9 is a key transcription factor involved in the differentiation of cells towards the
cartilage lineage
Metabolism
o regulated through mechanical stimulation
o pH of cartilage is 7.4
disruption in pH can lead to an abnormal cartilage structure
Nutrition
o oxygen and other nutrients supplied to cartilage from synovial fluid diffusion
Loading
o physiologic loading is chondroprotective
o underloading leads to cartilage thinning, tissue softening, and reduced proteoglycan content,
leading to cartilage fibrillation, ulceration and erosion
o overloading leads to cartilage damage (in vitro only)
has not been shown in clinical setting
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Function
o decreases friction and distributes loads
o cartilage exhibits stress-shielding of the solid matrix components due to its high water content,
the incompressibility of water, and the structural organization of the proteoglycan and collagen
molecules
Fibrocartilage
Location
o tendon/ligament junction with bone
o pubic symphysis
o annulus fibrosis of the intervertebral disc
o menisci
Composition
o fibrous cartilage
Type I collagen (predominantly)
extracellular matrix
proteoglycans I:13 Fibrocartilage
chondrocytes
water
o fibroelastic cartilage
fewer proteoglycans and glycoproteins compared to
hyaline cartilage
Function
o healing response to injury of articular cartilage including
chondroplasty microfracture
drilling
abrasion arthroplasty
o compressive strength
I:14 Elastic cartilage
Elastic Cartilage
Location
o auricle of external ear
o epiglottis
o auditory tube
Composition
o chondrocytes surrounded by a thin collagenous network
Type II collagen (predominantly)
elastin fiber network
extracellular matrix
proteoglycans and glycoproteins
chondrocytes
water
Function
o highly elastic
o designed to tolerate repetitive deformation
I:15 Epiphyseal cartilage
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Biologic Tissues
Epiphyseal cartilage
Location
o also known as the epiphyseal plate or epiphyseal ossification center
o between the epiphysis and metaphysis at each end of long bones
Composition
o stacked chondrocytes are divided into different zones of maturation
o proteoglycans and growth factor (e.g.BMP-2) are found in the extracellular matrix between
chondrocytes
o progressive chondrocyte maturation and calcification of the extracellular matirix
o infiltration of osteoprogenitor cells to produce osteoblasts and osteoid
Histology of Epiphyseal cartilage
o Reserve zone
o Proliferative zone
o Hypertrophic zone
o Primary spongiosa
o Secondary spongiosa
Function
o linear growth via endochondral ossification
o can allow extensive bone deformity remodeling potential
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Synovial Fluid
Function
o lubricates articular cartilage and provides nourishment through diffusion
Origin
o made from a ultrafiltrate of blood plasma
regulated by synovium
healthy knee contains ~2mL of synovial fluid
Consists of
o hyaluronin
uridine diphosphoglucose dehydrogenase enzyme critical for its synthesis
o lubricin
a key lubricating glycoprotein
o proteinase
o collagenases
o prostaglandins
Biomechanics
o synovial fluid exhibits non-Newtonian flow characteristics
the viscosity coefficient is not a constant
the fluid is not linearly viscous
viscosity increases as the shear rate decreases
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Biologic Tissues
7. Collagen
Overview
Collagen is a naturally occurring family of proteins
o over 25 types of collagen have been described
Makes up the most abundant type of protein found in humans
o ~25% of the whole-body protein content is composed of some type of collagen
o found in multiple tissues like cartilage, tendon, bone, ligament, skin (see table below)
o multiple different forms of collagen exist, each with different biomechanical properties suited to
the environment in which that form is expressed
Collagen is made of elongated fibrils formed by fibroblast cells
o synthesis of collagen is unique in that it occurs both inside and outside the cell
Biochemisty
Composition
o collagen is composed of a triple helix of
two alpha1 chains
one alpha2 chain
o several common amino acid sequences are found in collagen including
Glycine-X-Hydroxyproline
Glycine-Proline-X
Formation of collagen fibers
o alpha chains
three alpha chains (two alpha1 and one alpha 2) are formed
o procollagen
two alpha1 and one alpha2 combine to form procollagen
o tropocollagen
procollagen is processed by extracellular protein modification into a tropocollagen molecule
after being expressed from the golgi apparatus
o collagen fibril
aldehyde formation on tropocollagen lysine and hydroxylysine allow for covalent bonding
between tropocollagen molecules forming the collagen fibril
o collagen fiber
multiple collagen fibrils aggregate to form a collagen fiber
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Types of Collagen
Type
Location I II III IV V VI VII VIII IX X XI
Bone o
Ligament o
Tendon o
Meniscus o
Disc - Annulus o
Disc - Pulposus o
Cartilage - Articular o o o o
Cartilage - Basement Membrane o
Cartilage - Deep calcified layer o o
Cartilage - Reparative(fibrocartilage) o o
Skin o o
Blood Vessels o
Epithelial Basement Membrane o o
Collagen lattice o
Type I Collagen
o accounts for more than 90% of the total collagen content in the body
o found in
bone
ligament
tendon
meniscus
annulus of intervertebral disks
skin
healed cartilage
scar tissue
nerves
o related clinical conditions
osteogenesis imperfecta
Ehlers-Danlos syndrome
Type II Collagen
o is found
articular (hyaline) cartilage
nucleus pulposus of intervertebral disks
o type II collagen has a very long half life
Type III Collagen
o found in skin and blood vessels
o related clinical conditions
Ehlers-Danlos syndrome
Dupuytren's contracture
Type IV Collagen
o found in basement membranes
o related clinical conditions
renal diseases like Goodpasture's and Alport syndromes
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Molecular Biology
Type V, VI, IX Collagen
o occur in small amounts in articular cartilage
o type IX collagen gene deletion linked to development of OA in women and in knockout mice
o mutations in COL9A1, COL9A2, COL9A3 linked to multiple epiphyseal dysplasia (MED)
however 70% of MED is associated with COMP
fragmented ossific centers
coxa vara hips
genu valgum
shortened, stunted metacarpals
Type VII and VIII Collagen
o basement membrane (epithelial)
Type X Collagen
o is found in the deep calcified layer of cartilage
o produced only by hypertrophic chondrocytes during enchondral ossification (growth plate,
fracture callus, heterotopic ossification)
associated with calcification of cartilage in the deep zone of articular cartilage
o increased in early arthritis
o related clinical conditions
Schmid metaphyseal chondrodysplasia
Type XI Collagen
o an adhesive with the function of holding the collagen lattice together in cartilage
D. Molecular Biology
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Molecular Biology
Genetic Terms
Nucleotides
o thymine, adenine, guanine, and cytosine
Codon
o sequence of three nucleotides
o each codon correlates to one of the 20 amino acids
o linking of the amino acids create a protein
Gene promotor
o regulatory portion of DNA that controls initiation of transcription
Gene enhancers
o site on DNA that transcription factors bind to
o regulate transcription
Transcription
o DNA => mRNA
Translation
o mRNA => protein
Haploid
o Haploid is the amount of DNA in a human egg or sperm cell (half the amount of DNA in a
normal cell)
Cell Cycle
Phases
o G0
represents a "stable" phase
cells are diploid (2N) in the G0 and G1 phases
o G1
initial growth phase
cells are diploid (2N) in the G0 and G1 phases
oS
DNA replication/synthesis phase
cells become tetraploid (4N) at the end of S and
for the entire G2 phases
o G2
gap phase
cells become tetraploid (4N) at the end of S and for the entire G2 phases
oM
mitosis phase
Apoptosis
Defined as programmed cell death
Requires a series of intracellular signaling events
Different from cell lysis - where a cell releases its contents into the surrounding area
One hallmark of cancer is the cell's loss of apoptosis
Research techniques
Agarose gel electrophoresis
o separates DNA based on size
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o DNA is negatively charged
o gel exposed to electric field
o smaller pieces moves through gel faster
Southern blotting
o restriction enzymes cut up DNA
o separate on agarose gel
o identifies DNA sequence
Northern blotting
o restriction enzymes cut up RNA
o separate on agarose gel
o identifies RNA sequence
Western blotting
o SDS-PAGE gel
o identifies protein
DNA ligation
o combining different DNA fragments not found together naturally to create recombinant DNA
Plasmid vector
o an extrachromosomal element, often circular, that can replicate and be transferred independently
of the host chromosome
o one example of the function of a plasmid is antibiotic resistance
o can be introduced into bacteria in the process of transformation
Polymerase chain reaction (PCR)
o DNA => DNA
o a molecular biology tool used to generate many copies of a DNA sequence
o uses "primers" specific to a segment of DNA
o requires temperature-mediated enzyme DNA polymerase
Reverse transcription polymerase chain reaction (RT-PCR)
o RNA => DNA
o variant of polymerase chain reaction (PCR) used in molecular biology to generate many copies
of a DNA sequence from fragments of RNA
o RNA strand is first reverse transcribed into its DNA complement
o amplification of the resulting DNA proceeds using polymerase chain reaction
2. Immunology
Introduction
Types of Immune Responses
o innate response
not specific to a type of immunological challenge
represents the immune response which does not have memory
e.g., anatomic barriers (skin), inflammation, complement cascade
recognizes structures common to multiple microbes
found in nearly all forms of life
cells include
natural killer cells
mast cells
eosinophils
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Molecular Biology
basophils
phagocytic cells (macrophages, neutrophils, and dendritic cells)
o acquired response
portion of immune response which has memory
occurs in a pathogen and antigen specific mechanism
requires antigen processing and presentation
performed by antigen presentation cells (APC)
B cells and dendritic cells are two examples of APCs
the APC breaks down the protein antigen in a multitude of enzymatic reactions and
presents key peptide sequences via the major histocompatibility complex (MHC)
receptors
once presented on the surface of the APC, the T-cell receptor recognizes the
MHC/antigen complex prior to T-cell activation
cells include
CD8+ T lymphocytes
T helper cells
delta gamma T cells
B cells and plasma cells
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Immunologic Variations
Benign Ethnic Neutropenia
o Most common neutropenia in the world
o Approximately 25%-50% of people of African descent and some sub-groups in the Middle East
found to have low ANC without increased infection risk
o ANC < 1.5 x 10(9) cells/L considered "abnormally low" without clear clinical relevance.
4.5% African Americans, 0.79% white Americans, 0.38% Mexican-Americans below this
ANC
o Also more common in males vs females, athlete vs non-athlete, and children under age 5
Pedigree Analysis
A pedigree chart displays a family tree and the members of the family affected by a genetic trait
Use
o a pedigree chart can be used to determine the mode of transmission
o dominance
whether the trait is dominant or recessive
o linkage : whether the trait is X-linked or autosomal
Key
o shapes
circles represent females
squares represent males
o color
a black circle/square represents an individual affected by the genetic trait
a white circle/square represents an individual that is not affected by the trait
o lines
horizontal
a male and female connected by a horizontal line have mated and have children
vertical
vertical lines connect parents to their children
Autosomal Dominant
Description
o only need to get the abnormal gene from one parent in order for you to inherit the disease.
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Molecular Biology
Examples
o Syndactyly
o Polydactyly
o Marfan's syndrome
o Cleidocranial Dysostosis
o Hereditary Multiple Exostosis
o Achondroplasia
o MED |( Multiple Epiphyseal Dysplasia)
o Metaphyseal chondrodysplasia (Schmid and Jansen types)
o Kniest dysplasia
o Malignant hyperthermia
o Ehlers-Danlos syndrome
o Osteogenesis imperfecta (types I and IV)
o Osteochondromatosis/Multiple Hereditary Exostosis
o Osteopetrosis (tarda, mild form)
Autosomal Recessive
Description
o an autosomal recessive disorder means two copies of an abnormal gene must be present in order
for the disease or trait to develop.
Examples
o Diastrophic Dysplasia
o Friedreich's Ataxia
o Gaucher disease
o Spinal muscular atrophy
o Sickle cell anemia
o Osteogenesis imperfecta (II and III)
o Hypophosphatasia
o Osteopetrosis (infantile, malignant form)
Sex-linked Dominant
Examples
o Hypophosphatemic rickets
o Leri-Weill dyschondrosteosis (bilateral Madelung's deformity)
4. Genetic Pearls
Pediatric Dwarfisms
Genetic Pearls of Skeletal Dysplasia
Autosomal Dominant
Achondroplasia FGFR-3 Inhibition of chondrocytes proliferation
Apert Syndrome FGFR-2 Inhibition of chondrocytes proliferation
CMT (80-90%) * PMP22 Nerve demyelination
Pseudoachondroplasia COMP Abnormal cartilage formation
SED congenital ** COL2A1 / Type II collagen Defect in cartilage matrix formation
Kniest's Syndrome Type II collagen Type II collagen
MED - Type I *** COMP Type II collagen
MED - Type II *** Type IX collagen
Jansen's metaphyseal PTHrP Functional defect in parathyroid hormone
chondrodysplasia
Schmid's metaphyseal Type X Collagen Defect in cartilage matrix formation
chondrodysplasia
Cleidocranial dysplasia CBFA-1 Impaired intramembranous ossification
Osteogenesis Imperfecta COL1A1/COL1A2 Type I collagen
(Type I, IV)
Autosomal Recessive
Diastophic dysplasia DTD (Sulfate Transport Protein) Defect in sulfaction of proteoglycan
Friedreich's Ataxia Frataxin
Osteo. Imperfecta COL1A1/COL1A2 Type I collagen
(Type II, III)
McKusick metaphyseal Unknown
X Linked Recessive
SED tarda ** COL2A1 Type II collagen
CMT (10-20%) * connexin gene Nerve demyelination
* CMT = Charcot-Marie-Tooth Disease (peroneal muscular atrophy) See these topics in Pediatrics.
** SED congenita = Spondyloepiphyseal Dysplasia ***MED = Multiple Epiphyseal Dysplasia
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Epigenetics
Overview
o epigenetic changes include inheritable genetic alteration (developmental or environmental cues)
that do NOT involve DNA mutation
o DNA methylation, histone modification, nucleosome location, or noncoding RNA are
components of epigenetics
o osteoarthritis is thought to have epigenetic mechanisms that influence the disease process
Translocations
Overview
o translocations allow expression of genes (oncogenes) that are usually not active.
o cytogenetic analysis allows for the detection of gene translocations by evaluating the size and
number of chromosomes isolated from the cell nucleus.
Examples
o present in up to 95% of sarcomas.
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Oncogenes
Definition
o induce uncontrolled growth
o normal function causes leads to uncontrolled cell
Examples
o FAK
focal adhesion kinase)
o Erb-2
epidermal growth factor variant
Tumor Antigens
Definition
o tumor antigens are used in the diagnosis, monitoring of treatment response, and are being
researched for treatment options as anti-cancer vaccines
Examples
o carcinoembryonic antigen (CEA)
colorectal carcinoma
o carbohydrate antigen 19-9 (CA-19-9)
pancreatic cancer
o carbohydrate antigen 125 (CA-125)
ovarian cancer
o cancer antigen 15-3 (CA-15-3)
breast cancer
o alpha fetoprotein (AFP)
can be seen in many cancers, but is most commonly seen in hepatocellular carcinomas
Assays
Western blot
o detects protein
Southern blot
o detects DNA
Northern blot
o detects RNA
Southwestern blot
o detects DNA binding proteins
RT-PCR
o reverse transcription PCR
o highly sensitive, detects low copy number of RNA
o reversed transcribed into complimentary DNA (cDNA)
o may be used together with Northern blot
siRNA
o blocks translation of mRNA
o useful for loss-of-function experiment designs
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Material Science
E. Material Science
1. Material Properties
Introduction
Biomaterials encompasses all synthetic and natural materials used during orthopaedic procedures
Basic definitions
o load : a force that acts on a body
o stress
definition : intensity of an internal force
calculation : force / area
units : Pascal's (Pa) or N/m2
o strain
definition : relative measure of the deformation of an
object
calculation : change in length / original length
units : none
Mechanical property definitions
o elastic deformation
reversible changes in shape to a material due to a load
material returns to original shape when load is removed
o plastic deformation
irreversible changes in shape to a material due to a load
material DOES NOT return to original shape when load is removed
o toughness
definition : amount of energy per volume a material can absorb before failure (fracture)
calculation : area under the stress/strain curve
units : joules per meter cubed, J/m3
o creep : increased load deformation with time under constant load
o load relaxation : decrease in applied stress under conditions of constant strain
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o hysteresis (energy dissipation)
characteristic of viseoelastic materials where the loading curve does not follow the unloading
curve
the difference between the two curves is the energy that is dissipated
o finite element analysis
breaking up a complex shape into triangular or quadrilateral forms and balancing the forces
and moments of each form to match it with its neighbor
Material Strength: Stress vs Strain Curve
Derived from axially loading an object and plotting the stress verses strain curve
Elastic zone
o the zone where a material will return to its original shape
for a given amount of stress
o "toe region" see graph below
applies to a ligaments stress/strain curve
represents straightening of the crimped ligament
fibrils
Yield point
o the transition point between elastic and plastic
deformation
Yield strength
o the amount of stress necessary to produce a specific amount of permanent deformation
Plastic zone
o the zone where a material will not return to its orginal shape for a given amount of stress
Breaking point
o the object fails and breaks
Ultimate (Tensile) strength
o defined as the load to failure
Hooke's law
o when a material is loaded in the elastic zone, the stress is proportional to the strain
Young's modulus of elasticity
o measure of the stiffness (ability to resist deformation) of a material in the elastic zone
o calculated by measuring the slope of the stress/strain curve in the elastic zone
o a higher modulus of elasticity indicates a stiffer material
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Material Science
Young's Modulus of Metals and Biologics
Relative values of Young's modulus of elasticity (numbers correspond to numbers on illustration to
right)
o Ceramic (Al2O3)
o Alloy (Co-Cr-Mo)
o Stainless steel
o Titanium
o Cortical bone
o Matrix polymers
o PMMA
o Polyethylene
o Cancellous bone
o Tendon / ligament
o Cartilage
Material Descriptions
Brittle material
o a material that exhibits linear stress stain relationship up until the point of failure
o undergoes elastic deformation only, and little to no plastic deformation
o examples
PMMA
ceramics
Ductile Material
o undergoes large amount of plastic deformation before
failure
o example
metal
Viscoelastic material
o a material that exhibits a stress-strain relationship that is
dependent on duration of applied load and the rate by
which the load is applied (strain rate)
a function of the internal friction of a material
examples
ligaments
bone
Isotropic materials
o possess the same mechanical properties in all directions
example
golf ball
Anisotropic materials
o possess different mechanical properties depending on the direction of the applied load
o examples
ligaments
bone
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Metal Characteristics
Fatigue failure
o failure at a point below the ultimate tensile strength secondary to repetitive loading
depends on magnitude of stress and number of cycles
Endurance limit
o defined as the maximal stress under which an object is immune to fatigue failure regardless of
the number of cycles
Creep
o phenomenon of progressive deformation of metal in response to a constant force over an
extended period of time
Corrosion
o refers to the chemical dissolving of metal. Types include
galvanic corrosion
dissimilar metals leads to electrochemical destruction
mixing metals 316L stainless steel and cobalt chromium (Co-Cr) has highest risk of
galvanic corrosion
can be reduced by using similar metal
crevice corrosion
occurs in fatigue cracks due to differences in oxygen tension
316L stainless steel most prone to crevice corrosion
fretting corrosion
description
a mode of destruction at the contact site from the relative micromotion of two
materials or two components
clinical significance
common at the head-neck junction in hip arthroplasty
most common cause of mid-stem failure in modular revision type stems
arthroplasty involving modular implants are at risk for fretting corrosion and
failure between the components of the final implant
increased risk with the increased number of interfaces between the various
components
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Material Science
Specific Metals
Titanium
o uses
fracture plates
screws
intramedullary nails
some femoral stems
o advantages
very biocompatable
forms adherent oxide coating through self passivation
corrosion resistant
low modulus of elasticity makes it more similar to biologic materials as cortical bone
o disadvantages
poor resistance to wear (notch sensitivity) (do not use as a femoral head prosthesis)
generates more metal debris than cobalt chrome
Stainless Steel (316L)
o components
primarily iron-carbon alloy with lesser elements of
chromium
molybdenum
manganese
nickel
o advantages
very stiff
fracture resistant
o disadvantages
susceptible to corrosion
stress shielding of bone due to superior stiffness
Cobalt alloy
o components
cobalt
chromium
molybdenum
o advantages
very strong
better resistance to corrosion than stainless steel
Specific Non-Metals
Ultra-high-molecular-weight polyethylene
o advantages
tough
ductile
resilient
resistant to wear
o disadvantages
susceptible to abrasion
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wear usually caused by third body inclusions
thermoplastic (may be altered by extreme temperatures)
weaker than bone in tension
o other
gamma irradiation
increases polymer chain cross-linking which improves wear characteristics
decreases fatigue and fracture resistance
Polymethylmethacrylate (PMMA, bone cement)
o functions
used for fixation and load distribution in conjunction with orthopaedic implants
functions by interlocking with bone
may be used to fill tumor defects and minimize local recurrence
o properties
2 component material
powder
polymer
benzoyl peroxide (initiator)
barium sulfate (radio-opacifier)
coloring agent (green chlorophyll or blue cobalt)
liquid
monomer
DMPT (N,N-Dimethyl para-toluidine, accelerator)
hydroquinone (stabilizer)
o advantages
reaches ultimate strength at 24 hours
strongest in compression
Young's modulus between cortical and cancellous bone
o disadvantages
poor tensile and shear strength
insertion can lead to dangerous drop in blood pressure
failure often caused by microfracture and fragmentation
Silicones
o polymers that are often used for replacement in non-weight bearing joints
o disadvantages
poor strength and wear capability responsible for frequent synovitis
Ceramics
o advantages
best wear characteristics with PE
high compressive strength
o disadvantages
typically brittle, low fracture toughness
high Young's modulus
low tensile strength
poor crack resistance characteristics
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Material Science
Bone
Bone composition
o composed of collagen and hydroxyapatite
o collagen
low Young's modulus
good tensile strength
poor compressive strength
o hydroxyapatite
stiff and brittle
good compressive strength
Mechanical properties
o advantages
strongest in compression
a dynamic structure
remodels geometry to increase inner and outer cortex to alter the moment of inertia and
minimize bending stresses
o disadvantages
weakest in shear
Failure (fracture)
o tension
usually leads to transverse fracture secondary to muscle pull
o compression
due to axial loading
leading to a crush type fracture
bone is strongest in resisting compression
o bending
leads to butterfly fragment
o torsion
leads to spiral fracture
the longer the bone the greater the stresses on the outer cortex under torsion
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2. Structural Properties
Introduction
Charateristics of orthopaedic implants depend
o structural properties (this topic)
o material properties
Structural characteristic differs from strength characteristic
o not only depends on the material, but also the structural
configuation of the object (cylinder, rectangle)
o the stuctural properties can also be demonstrated in a stress
vs. strain curve
Bending Rigidity (stiffness)
Definitions
o defined as the slope of the curve in the elastic range on a structure stress-strain curve
o stress shielding of proximal bone in THA is related to implant stem stiffness
Solid Cylinder
o proportional to the radius to 4th power for a solid cylinder
o cylinder A has great rigidity than cyliner B on illustration above (and thus has greater radius)
Hollow Cylinder
o proportional to the radius to the 3rd power for a hollow cylinder
Rectangular Object
o proportional to the (base x height) to the 3rd power
Deflection
Proportional to: (applied force/elastic modulus)(area moment of inertia)
3. Orthopaedic Implants
Introduction
Characteristics of orthopaedic implants depends on
o material properties
o structural properties
Screws
Definitions
o pitch : distance between threads
o lead : distance advanced with one revolution
o screw working distance (length) Cancellous screw Cortical screw
defined as the length of bone traversed by the screw
o outer diameter
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Material Science
o root (inner) diameter
o bending strength is proportionate to inner (minor) diameter^3
o pullout strength is proportionate to outer (major) diameter^2
maximized by
large outer diameter difference
fine pitch Locking screw
pedicle screw pullout most affected by quality of bone (degree of osteoporosis)
Types of screws
o cortical screws
o cancellous screws
o locking screws
Plate Properties
Overview & definitions
o a load-bearing devic
o e that is most effective when placed on the tension side
o plate working distance
the length between the 2 screws closest to the fracture on each end of the fracture.
decreasing the working distance increases the stiffness of the fixation construct
Structural properties
o bending rigidity proportional to thickness to the 3rd power
o titanium has Young's modulus of elasticity that most closely approximates cortical bone
Biomechanics
o absolute stability
constructs heal with primary (Haversian) healing
must eliminate micromotion with lag screw fixation
must be low strain at fracture site with high fixation stiffness
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o relative stability
constructs heal with enchondral healing
strain rates must be <10%, or fibrous union will predominate
Plate Variations
Concave plates
o placing a concave bend on a plate is useful in transverse fractures to ensure compressive forces
occur on both the far and near cortices of the fracture
Compression plates
o compression plates work by placing a cortical screw eccentrically into an oval hole in the plate
Locking plates
o advantages of locking plates
locked plate/screw constructs compared to non-locked plate/screw constructs result in less
angulation in comminuted metaphyseal fractures
o indications for locking plate technology
indirect fracture reduction
diaphyseal/metaphyseal fractures in osteoporotic bone
bridging severely comminuted fractures
plating of fractures where anatomical constraints prevent plating on
the tension side of the bone (e.g. short segment fixation).
o locking plate screw biomechanics
bicortical locking screws have significantly more resistance to all
applied forces, with resistance to torsion increased the most (versus
unicortical)
unicortical locking screws have less torsion fixation strength than
non-locking bicortical constructs
o percutaneous locking plates
application has less soft-tissue stripping but higher chance malunion
o hybrid locked plates
utilize locking and nonlocking screws in order to assist with fracture
reduction (nonlocking screws) as well as provide a fixed angle
construct (locking screws). I:16 Radiograph: Example
o locking plate construct stability increases with: of compression plating of a
bicortical locking screws midshaft humerus fracture
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Material Science
Illustration: Example of a hybrid AP Radiograph: Example of distal AP and lateral views AP Radiograph: Bending
plate. Locking hole is threaded femoral locking plate. This fixed after plate fixation of rigidity of hollowed femoral
and left empty, while this screw is angle construct was utilized for both bone forearm nail proportional to 3rd
placed in the eccentrically bridging across the fracture site. fractures. Bridge plate power, while torsional
located compression slot hole. fixation of radius was rigidity proportional to 4th
utilized due to amount power.
of comminution
Intramedullary nails
Overview
o a load-sharing device
Structural Properties
o stiffness
torsional rigidity
defined as amount of torque needed to produce torsional (rotational) deformation
proportional to the radius to the 4th power
depends on
shear modulus
polar moment of inertia
increased by reaming
decreased by slotting of nail
bending rigidity
proportional to the radius to the 4th power for a solid nail
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Radius of curvature
o intramedullary nail radius of curvature is greater
(straighter) than the radius of curvature of the femur
Interlocking options
o dynamic locking-->axially and rotationally stable fractures
o static locking-->axially and rotationally unstable fractures
o secondary dynamization for nonunion I:17 Larger radius of curvature of nail in
remove proximal interlocking screw or move proximal comparison to femur bone can cause anterior
perforation at anterior distal femur.
interlocking screw from the static to dynamic slot
External fixators
Factors that increase stability of conventional external fixators
o contact of ends of fracture
o larger diameter pins (most important)
o additional pins
o decreased bone to rod distance
o pins in different planes
o increasing size or stacking rods
o rods in different planes
o increased spacing between pins
Factors that increase stability of circular (Ilizarov) external fixators
o larger diameter wires I:18 External Fixator
o decreased ring diameter
o olive wires
o extra wires
o wires cross perpendicular to each other
o increased wire tension
o placement of two central rings close to fracture
o increased number of rings
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Material Science
4. Bioabsorbable Materials
Introduction
Bioabsorbable materials were invented to address issues with synthetic implants including
o migration
o growth disturbance
o rigidity
o radioopacity
o infection
o need for implant removal operations
Indications include but are not limited to
o pediatric orthopaedics
transphyseal SR PLGA 80/20 screws only cause temporary growth arrest in rabbits (unlike
nonbioabsorbable implants)
o osteomyelitis
antibiotic eluting PLA
o carriers for growth factors
rhBMP2 and rhBMP7
o augmentation of bone healing at iliac crest bone harvest site
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less crystallic and more rapidly degraded than PLLA alone
example is P(L/D)LA 70/30 in oral-maxillofacial surgery
simple and self-reinforced forms
o PLGA copolymers
combination of PLA and PGA
low crystallinity
used in oral-maxillofacial surgery
simple and self-reinforced forms
Self reinforcing (SR)
o composite structure made from partially crystalline/amorphous material made of orientated
fibers/fibrils and binding matrix
o better biomechanical properties
improved rigidity and strength along longitudinal axis
malleable at room temperature
no need for heating-cooling
can withstand 4 times bending
minimal "memory" (tendency to return to previous shape after bending)
can be sterilized by gamma irradiation
gamma irradiation cannot be used with non-reinforced materials
will reduce its molecular weight and adversely affect the mechanical properties of the
implant
Biodegradation
Primary mechanisms of biodegradation
o poly-hydroxy-acid degradation
breakdown is by random hydrolysis of ester bonds, which leads to
reduction of molecular weight
loss of mechanical properties
final products are CO2, H2O, and products of TCA (tricarboxylic acid, Krebs) cycle
o kidney excretion
PDS and PGA products can be excreted by the kidney
o enzyme breakdown
enzymes are involved with PLA and PGA degradation
o lowered pH
polymer breakage produces products that lower pH
accelerating the breakdown
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Material Science
o material crystallinity
determines hydrophobicity and degradation speed
amorphous and hydrophillic materials degrade faster
more contact with water molecules
crystalline and hydrophobic
materials degrade slower
less contact with water molecules
Additional variable that affect degradation
o chemical composition and molecular weight
o fiber orientation (SR or simple)
o monomer concentration (in polymers)
o stereoisomerism and conformation
o pores and surface area/volume ratio
o pores and surface area/volume ratio
o sterilization method (gamma irradiation vs others)Degradation method (enzymatic vs hydrolysis)
Histopathology
Granulomatous inflammation
o cellular reactions around bioabsorbale implants are characterized by
T lymphocytes (CD4>CD8)
plasma cells
endothelial cells
birefringent polymer debris
thin macrophage layer
multinucleated giant cells
Capsule formation
o a capsule forms around implants that consists of
internal cell layer
2-3 cells thick
type III collagen predominance
external fibrous layer
few spindle shaped cells
type I collagen predominance
Stages
o begins with infiltration of neutrophils
tissue reaction to trauma
o followed by CD4 T lymphocytes infiltration
o macrophages infiltration is last
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symptoms appear late in materials with low degradation rate
e.g. PLLA at 5 years postop
o physical exam
synovitis
discharging sinus
Labs
o fluid cultures are sterile
unless there is secondary bacterial infection after bursting
Radiography
o osteolysis is seen in up to 60% of cases
Treatment
o nonoperative
observation
healing without active treatment
o operative
aspiration and/or surgical debridement
implant removal
indicated if there is sterile implant failure
or if there is secondary bacterial infection
arthrodesis
if there is severe osteoarthritis
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Wheelchair propulsion
o 9% increase in energy expenditure compared to ambulation in normal subjects
Ambulation assistive devices
o cane
o axillary crutch
2 axillary crutches are required for proper gait if lower extremity is non-weightbearing or toe-
touch weightbearing
Patient specific factors need to be considered when identifying the correct prosthesis for a patient
Low demand patients may not require a prosthesis for activities of daily living
Pearls for prosthetic gait abnormalities
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wrist disarticulation or long transradial amputation with sufficient pronation,
supination, and elbow flexion and extension
o shoulder units
due to increased energy expenditure and weight of prosthesis many choose to use a purely
cosmetic prosthesis
indications
forequarter or shoulder level amputation
Knee Prosthesis
Knee prostheses provide controlled knee motion
Indications
o transfemoral and knee disarticulation amputations
Technique
o the prosthesis needs to be in line with the weightbearing axis of the patient's knee
o errors in technique
slightly posterior knee center of rotation allows better control of stance phase with more
difficult flexion
slightly anterior knee center of rotation flexion is easier with less control
Socket
o the connection between the stump and the prosthesis
o protects the stump and transmits forces
o preparatory socket may need to be adjusted several time as edema resolves
o patellar tendon-bearing prosthesis is most common
Suspension systems
o attaches prosthesis to residual limb using belts, wedges, straps, and suction
o suction suspension
standard suction
form-fitting rigid or semi-rigid socket which fits onto residual limb
silicon suction
silicon-based sock fits over the stump and is then inserted into the socket
silicon provides an airtight seal between prosthesis and amputated stump
Knee joint
o polycentric (four-bar linkage) knee
indications
transfemoral amputation
knee disarticulations
bilateral amputations
techniques
variable knee center of rotation
controlled flexion
ability to walk at a moderately fast pace
supports increased weight compared to constant friction
I:24 Polycentric knee
knee
o stance-phase control (weight-activated) knee
indications
older patients with proximal amputations
patients walking on uneven terrain
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Material Science
techniques
acts like a constant-friction knee in swing phase
weightbearing through the prosthesis locks up through the high-friction housing
o fluid-control (hydraulic and pneumatic) knee
indications
active patients willing to sacrifice a heavier prosthesis for more utility and variability
techniques
allows for variable cadence via a piston mechanism
prevents excess flexion
extends earlier in the gait cycle
o constant friction (single axis) knee
indications
general use
patients walking on uneven terrain
most common pediatric prosthesis I:25 Constant friction knee
not recommended for older or weaker patients
technique
hinge that uses a screw or rubber pad to apply friction to the knee to decrease knee swing
only allows a single speed of walking
relies on alignment for stance phase stability
o variable-friction (cadence control)
technique
multiple friction pads increase knee flexion resistance as the knee extends
variable walking speeds are allowed
not very durable
o manual locking knee
technique
constant friction knee hinge with an extension lock
extension lock can be unlocked to allow knee to act like a constant-friction knee
Pylon
o simple tube or shell that attaches the socket to the terminal device
o newer styles allow axial rotation and absorb, store, and release energy
o exoskeleton
soft foam contoured to match other limb with hard outer shell
o endoskeleton
internal metal frame with cosmetic soft covering
Terminal device
o Most commonly a foot, but may take other forms
Foot Prosthesis
Single axis foot
o ankle hinge allows dorsiflexion and plantar flexion
o disadvantages
poor durability
I:26 SACH foot
poor cosmesis
SACH (solid ankle cushioned heel) foot
o indications
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general use in patients with low activity levels
use is being phased out
o disadvantages
overloads the nonamputated foot
Dynamic response (energy-storing) foot
o indications
general use for most normal activities
patients who regularly ambulate over uneven surfaces likely benefit from multi-axial
articulated protheses
o articulating and non-articulating dynamic-response foot prostheses are available
articulating
allows inversion, eversion, and rotation of the
foot I:27 Dynamic response foot
indications
patients walking on uneven surfaces
advantages
allows inversion, eversion, and foot
rotation
absorbs loads and decreases shear forces
flexible keels
acts as a spring to decrease
contralateral loading, allow dorsiflexion, and provide a spring-like push-off
posterior projection from keel gives a smooth transition from heel-strike
sagittal split allows for inversion and eversion
non-articulating
have short or long keels
shorter keels are not as responsive and are indicated for moderate-activitiy patients
longer keels are indicated for high-demand patients
different feet for running and lower-demand activities available
Prosthetic Complications
General issues
o choke syndrome
caused by obstructed venous outflow due to a socket that is too snug
acute phase
red, indurated skin with orange-peel appearance
chronic phase
hemosiderin deposits and venous stasis ulcers
o skin problems
contact dermatitis
most commonly caused by liner, socks, and suspension mechanism
treatment
remove the offending item with symptomatic treatment
cysts and excess sweating
signs of excess shear forces and improperly fitted components
scar
massage and lubricate the scar for a well-healed incision
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By Dr, AbdulRahman AbdulNasser Musculoskeletal biology | Material Science
o painful residual limb
possible causes include heterotopic ossification, bony prominences, poorly fitting prostheses,
neuroma formation, and insufficient soft tissue coverage
Transtibial prostheses
o swing-phase pistoning
ineffective suspension system
o stance-phase pistoning
poor socket fit
stump volume changes (stump sock may need to be changed)
o foot alignment abnormalities
inset foot
varus strain, circumduction and pain
outset foot
valgus strain, broad-based gait and pain
anterior foot placement
stable increased knee extension with patellar pain
posterior foot placement
unstable increased knee flexion
dorsiflexed foot
increased patellar pressure
plantar-flexed foot
drop-off and increased patellar pressure
o pain or redness related to pressure
o prosthetic foot abnormalities
heel is too soft
leads to excessive knee extension
heel is too hard
leads to excessive knee flexion and lateral rotation of toes
Collected By : Dr AbdulRahman
AbdulNasser
drxabdulrahman@gmail.com
In June 2017
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OrthoBullets2017 Systemic Disease | Material Science
ORTHO BULLETS
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Metabolic Bone Disease
Prognosis
o prior fragility fracture is the strongest predictor of a future fracture from low energy trauma
o vertebral fractures
associated with 15% increase in 5-year mortality
associated with increased morbidity
back pain
loss of height
poor balance
respiratory compromise
restrictive lung disease
pneumonia
history of 1 vertebral fracture results in 5 fold increased risk of 2nd vertebral fracture and 5
fold increased risk of hip fracture
history of 2 vertebral fractures is the strongest indicated for further compression fractures in
postmenopausal women
o hip fractures
associated with 20% increase in mortality
men have higher mortality rates following hip fractures than women
associated with increased morbidity
reduced quality of life
only one third of patients with hip fractures return to their previous level of function
history of 1 hip fracture results in up to 10 fold increased risk of 2nd hip fracture
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Metabolic Bone Disease
o FRAX score
WHO fracture risk assessment tool that calculates the 10-year risk of hip fracture and 10-year
risk of major osteoporosis-related fracture
factors include age, sex, personal history of fracture, low BMI, oral steroid use, secondary
osteoporosis, parental history of hip fracture, smoking status and alcohol intake.
Classification
Type I (Post menopausal) Type II (Senile)
Post menopausal (highest incidence in 50-70 years
Age group >70 years old
old)
Bone affected Almost exclusively trabecular Trabecular > cortical
Bones fractured Distal radius and vertebral Hip and pelvis
Net negative change in calcium levels because of
Effect on calcium decreased intestinal absorption and increased urinary Poor calcium absorption
excretion of calcium.
Reduced circulating levels of total (but not free) 1,25
Effect on Vit D
dihydroxyvitamin D.
Labs
25 hydroxyvitamin D level
o low 25 hydroxy cholecalciferol levels (25 hydroxy vit D) in patients sustaining low energy
fractures
Imaging
Radiographs
o indications
suspicion of fracture
loss of height
pain in thoracic or lumbar spine
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o recommended views
lateral spine radiograph
AP pelvis or hip
o findings
thinned cortices
loss of trabecular bone
kyphosis
codfish vertebra
o sensitivity and specificity
usually not helpful unless > 30% bone loss
Dexa Scan (Dual Energy Xray Absorptiometry)
o usually performed in
lumbar spine: measures BMD from L2 to L4 and compiles scores
hip: measure BMD from femoral neck, trochanter, and intertrochanter region and compiles
scores
o sensitivity and specificity
most accurate with the least radiation exposure
The blue areas on the graph show the usual bone mass for DEXA Scan: This graph plots Bone Mineral Density
women of different ages. As illustrated, the bone mass is lower (BMD), going up the left edge against age along the
among elderly women. A 70-year-old woman's bone mass is bottom. The blue band across the graph shows the
indicated by a cross in the figure. It is estimated that 95 per cent range of normal BMD across the span of a lifetime. You
of the population belong within the blue areas. Those in the dark can see that bone density is highest between ages 20 to
blue area have a bone mass above average in relation to age, 45, then decreases. The little white square stands for the
while people belonging to the light blue area are below average patient's estimated BMD (1.036) at her current age (55).
in relation to their age. The curve for men is similar but is higher The DEXA scanner puts the box at the lower end of the
placed on the chart and shows a smaller decline with age. In normal blue zone for her age.
this example I believe we are looking at the graph for the Neck
region of the hip only. The dexa scan of her neck shows a BMD
is 0.543 as demonstrated by the cross on the graph. This gives
her a T score of -3.52 for the femoral neck. Based on the fact
that she falls in the blue, I believe her BMD is normal in the
neck. However, the diagnosis of osteoporosis is based on the
Central Dexa Scan, which includes the total hip which includes
the neck, troch, and intertroch region. Her total score is 0.664.
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Metabolic Bone Disease
DEXA Scan Report: The Z Score: This DEXA scan report says that this patient's lumbar spine density compared to women
her age is 0.7 standard deviations below average. The T-Score: This number compares this patient's bone density with a
twenty-year old female and shows that she is 1.4 standard deviations below mean. Impression: The patient is 2.6 times as
likely as other women her age to suffer a compression fracture of a vertebral body.
Term Definition
BMD absolute, patient-specific score determined from certain anatomic areas
T score BMD relative to normal young matched controls (30-year-old women)
Z score BMD relative to similar aged patients
L2-4 lumbar density of 1 to 2.5 standard of deviations (T score -1 to -2.5) below
Osteopenia
the peak bone mass of a 25 year old individual
L2-4 lumbar density > 2.5 standard of deviations (T score <-2.5) below the peak
Osteoporosis
bone mass of a 25 year old individual
Studies
Biopsy
o after tetracycline labeling
o indications
may be helpful to rule out osteomalacia
Histology
o thinned trabeculae
o decreased osteon size
o enlarged haversian and marrow spaces
o osteoclast ruffled border
Increases osteoclast ruffled border seen with
PTH I I:1 Slide demonstrating loss of interconnected trabecular
bone (stained with Masson's trichrome)
1,25 dihydroxy Vit D3
Prostaglandin E
flattened ruffled border seen with
Bisphosphonates
Calcitonin
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OrthoBullets2017 Systemic Disease | Metabolic Bone Disease
Differential
Osteoporosis Osteomalacia
Reduced bone mass, normal
Definition Bone mass variable, reduced mineralization
mineralization
Post menopausal (Type I)
Age Any age
or elderly (Type II)
Vit D deficiency or abnormal vit D pathway,
Endocrine abnormality, age, idiopathic,
Etiology hypophosphatemia, hypophosphatasia, renal
inactivity, alcohol, calcium deficiency
tubular acidosis
Symptoms
Pain and tenderness at fracture site Generalized bone pain and tenderness
and signs
Appendicular fracture predominance, symmetric,
Xray Axial fracture predominance
includes pseudofractures (Looser zones)
Serum Ca Normal Low or normal
Serum PO4 Normal Low or normal
ALP Normal Elevated (except hypophosphatasia)
Urinary Ca High or normal Normal or low (high in hypophosphatasia)
Bone biopsy Tetracycline labeling normal Tetracycline labeling abnormal
Treatment
Nonoperative
o lifestyle modification & vitamins
indications
calcium and Vitamin D
o pharmacologic treatment
indications
2008 National Osteoporosis Foundation Guidelines for Pharmacologic Treatment of
Osteoporosis suggests that pharmacologic treatment be considered for
postmenopausal women and men >= 50yrs old with:
hip/vertebral fracture
T score between -1.0 and -2.5 at the femoral neck/spine and
10-year risk of hip fracture ≥ 3% or
10-year risk of major osteoporosis-related fracture ≥ 20% by FRAX calculation
T score -2.5 or less at the femoral neck/spine.
pharmacologic agents
calcium and Vitamin D
bisphosphonates
Conjugated Estrogen-progestin hormone replacement (HRT)
Estrogen-only replacement (ERT)
Salmon calcitonin (Fortical or Miacalcin)
Raloxifene (Evista)
Teriparatide (Forteo)
Operative
o osteoporotic vertebral compression fracture
o femoral neck fracture
o distal radius fracture
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Metabolic Bone Disease
Pharmacologic Agents
Bisphosphonates
o 1st line therapy
o indications for pharmacologic treatment
hip or vertebral fracture
T-score <2.5 at the femoral neck or spine (after exclusion of secondary causes)
low bone mass (T-score between -1.0 and -2.5) and
10-year probability of a hip fracture ≥ 3% or greater or
10-year probability of a major osteoporosis-related fracture ≥ 20% based on WHO
algorithm
o mechanism
accumulate at sites of bone remodeling and are incorporated into bone matrix
are released into acid environment once bone is resorbed, and are then taken up by
osteoclasts
decrease osteoclastic bone resorption, flattening of osteoclast ruffled border and increased
osteoclast apoptosis
renal excretion without undergoing metabolism
exact mechanism depends on presence of nitrogen on alkyl chain (see table below)
o technique
improved rates of treatment when coordinated by treating orthopedic surgeon and referral to
osteoporosis clinic is made
DEXA scan and referral to endocrinologist
o outcomes
alendronate reduces the rate of hip, spine and wrist fractures by 50%
risedronate reduces vertebral and nonvertebral fractures by 40% (each) over 3 years
IV zolendronic acid reduces the rate of spine fractures by 70% and hip fractures by 40% over
3 years
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Contraindications/
Drug Indications Mechanism Effects Characteristics
Adverse Effects
Calcium reduces
fracture risk by
34%.
daily calcium and
Vit D Vitamin D
supplementation requirements are as
reduces hip follows:
fracture risk by Age 1-3yrs -
10% and 500mg/d
prophylactic in all
nonvertebral Age 4-8yrs -
Calcium & Vit D patients, best for
fracture risk by 800mg/d
Type II (senile)
7%. Age 9-18yrs - 1000
to 1500mg/d
High dose vitamin
Age >50 yrs- 1200
D (median,
to 1500 mg/d calcium
800IU/d) reduces
800-1,000 IUs Vit.
hip fractures by
D
24% and
nonvertebral
fractures by 30%.
Esophagitis,
dysphagia, gastric
T score <-2.5SD,
Non-nitrogen ulcers, osteonecrosis
fragility fracture of Produce toxic ATP etidronate, clodronate,
containing of the jaw (ONJ),
the hip, in both men analog, tiludronate
Bisphosphonates atypical
and women
subtrochanteric
fractures
Alendronate
reduces vertebral
fractures by 48%
and nonvertebral
fractures by 47%.
Risedronate
pamidronate,
Inhibit farnesyl reduces vertebral Esophagitis,
T score <-2.5SD, alendronate
Nitrogen pyrophosphate fractures by 65% dysphagia, gastric
fragility fracture of (Fosamax), risedronate
containing synthase and nonvertebral ulcers, ONJ, atypical
the hip, in both men (Actonel),
bisphosphonates (mevalonate fractures by 39%. subtrochanteric
and women zolendronate (Reclast),
pathway) fractures
ibandronate (Boniva)
Ibrandronate
reduces
vetebralfracture
risk by 77%, hip
fractures by 41%
and nonvertebral
fractures by 15%.
Decreased the risk of
hip fracture, but it also
Conjugated led to small increases
Estrogen-progestin in women with in a woman's risk
hormone Type I (within 6 of breast cancer, CAD
replacement years of menopause) and heart
(HRT) attack, stroke, PE,
DVT, and Alzheimer's
disease
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Metabolic Bone Disease
Contraindications/
Drug Indications Mechanism Effects Characteristics
Adverse Effects
Taking unconjugated
indicated for women estrogen
Estrogen receptors are
Estrogen-only with prior (alone) increases the
present on osteoblasts
replacement (ERT) hysterectomy risk of endometrial
and osteoclasts
hyperplasia / uterine
cancer)
Men with low levels Not yet approved by
Testosterone
of testosterone FDA for osteoporosis
Women >5y
Intranasal - Transient
postmenopause,
Binds membrane rhinitis. Injectable -
Salmon calcitonin decreases pain in Injection or nasal
receptors on nausea, vomiting,
(Fortical or acute vertebral spray (destroyed by
osteoclasts to flushing,
Miacalcin) compression gastric acid)
inhibit resorption hypersensitivity
fractures (acts as
reactions
neurotransmitter)
Selective estrogen
Agonist on estrogen receptor modulator
receptors in bone (SERM), slows bone
(reduce osteoclast resorption and mild Hot flashes, leg
Raloxifene resorption). increase in bone cramps.
Women
(Evista) Antagonizes thickness. Reduces Contraindicated in
estrogen receptor in risk of vertebral patients with VTE
breast, reducing fractures only (not
breast cancer risk. non-vertebral
fractures).
Transient
Receptors on
1-34 amino terminal hypercalcemia,
osteoblasts
residues of parathyroid dizziness, nausea,
(activates
Severe hormone (1-84) ; given headache.
Teriparatide osteoblasts) and
osteoporosis/high by daily subcutaneous
(Forteo) renal tubule cells,
fracture risk injections (continuous Contraindicated in
also stimulates
infusion leads to bone Paget's disease due to
intestinal absorption
resorption) potential
Ca and PO4
osteosarcoma risk
Monoclonal Ig2 Arthralgia,
Reduced vertebral
against RANKL nasopharyngitis,
Postmenopausal fractures by 68%,
Denosumab (inhibits binding of SC injection to arm, back pain.
women at high risk hip fractures by
(Prolia) RANKL to RANK, thigh, abdomen
of fracture 40%, nonvertebral
like Contraindicated in
fractures by 20%.
osteoprotegerin) severe hypocalcemia
Complications
Osteonecrosis of the jaw (ONJ) is associated with IV bisphosphonates (but not oral bisphosphonates)
o incidence : rare
o treatment : stop bisphosphonates
Atypical subtrochanteric transverse stress fractures (in patients on long-term bisphosphonates)
o incidence : rare
o mechanism
extremely low bone turnover rates
shown by reduced markers of bone resorption (e.g. urinary collagen type 1 cross-linked N-
telopeptide, NTx)
o treatment : operative fixation with intramedullary nail and stop bisphosphonates
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OrthoBullets2017 Systemic Disease | Metabolic Bone Disease
2. Renal Osteodystrophy
Introduction
Definition
o a spectrum of disease seen in patients with chronic renal disease.
o characterized by bone mineralization deficiency due to electrolyte and endocrine abnormalities
o common cause of hypocalcemia
Pathophysiology
o hypocalcemia
due to the inability of the damaged kidney to convert vitamin D3 to calcitrol (the active form)
because of phosphate retention (hyperphosphatemia)
o hyperparathyroidism and secondary hyperphosphatemia
caused by hypocalcemia and lack of phosphate excretion by damaged kidney
o uremia related phosphate retention
is a key pathological step
Associated conditions
o orthopaedic manifestations
osteomalacia (adults) and growth retardation (children)
AVN
tendinitis and tendon rupture
carpal tunnel syndrome
deposition of amyloid (β2 microglobulin)
pathologic fracture
from brown tumors (hyperparathyroidism) or amyloid deposits
osteomyelitis and septic arthritis II:2 Pathologic fracture
Classification
High-turnover renal bone disease (high PTH disease)
o chronically elevated phosphate leads to secondary hyperparathyroidism
hyperphosphatemia lowers serum Ca, stimulating PTH
phosphorus impairs renal 1α-hydroxylase, reducing 1,25(OH)2 vitamin D3 production
phosphorus retention directly stimultes PTH production
hyperplasia of chief cells of parathyroid gland
o associated lab values
decreased calcium, increased serum phosphate, increased alkaline phosphate, increased
parathyroid hormone
Low turnover renal bone disease (normal PTH disease)
o characterized by lack of secondary hyperparathyroidism
o normal levels of PTH with characteristic bone lesions marked by low levels of bone formation
o excess deposition of aluminium into bone affects bone mineralization
impairs differentiation of precursors into osteoblasts, and osteoblast proliferation
impairs PTH release from parathyroid gland
disrupts mineralization
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Metabolic Bone Disease
Presentation
Symptom
o weakness
o bone pain
o pathological fracture
commonest complication
o skeletal deformity
o symptoms of hypocalcemia
abdominal pain
muscle cramps
dyspnea
convulsions/seizures
mental status changes
Physical exam
o provocative tests for tetany
Trousseau's Sign
carpalpedal spasm after blood pressure readings
Chvostek's Sign
facial muscle contractions after tapping on the facial nerve
Imaging
Radiographs
o findings
Looser's zones
brown tumor
osteosclerosis
from mineralization of osteomalacic bone
rugger jersey spine
widened growth plate and zone of provisional calcification (children)
varus deformity of the femurs (children)
fracture
soft-tissue calcification
osteopenia
CT
o osseous resorption
Looser zone in the femoral Looser zone in the distal brown tumor
neck of an adult fibula of a child
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OrthoBullets2017 Systemic Disease | Metabolic Bone Disease
Treatment
Nonoperative
o treat underlying renal condition or relieve urologic obstruction
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Metabolic Bone Disease
3. Rickets
Introduction
A defect in mineralization of osteoid matrix caused by inadequate calcium and phosphate
o prior to closure of physis known as rickets
o after physeal closure called osteomalacia
Pathophysiology
o disruption of calcium/phosphate homeostasis
o poor calcification of cartilage matrix of growing long bones
o occurs at zone of provisional calcification
o leads to increased physeal width and cortical thinning and bowing
o Vitamin D and PTH play an important role in calcium homeostasis
Associated conditions
o orthopaedic manifestations include
brittle bones with physeal cupping/widening
bowing of long bones
ligamentous laxity
flattening of skull
enlargement of costal cartilage (rachitic rosary)
kyphosis (cat back)
Classification
Types include
o familial hypophosphatemic (vitamin D-resistant) (see below)
o vitamin D-deficient (Nutritional)
o vitamin D-dependent (type I & type II)
o renal osteodystrophy
o hypophosphatasia
Imaging
Radiographs
o recommended views
AP and lateral of affected bone
o findings
physeal widening
metaphyseal cupping
Looser's zones (pseudofracture on the compression side of bone)
decreased bone density
prominence of rib heads at the osteochondral junction (rachitic rosary)
bowing (often genu varum)
Studies
Laboratory studies
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Histology
o zone of proliferation is disordered and elongated in growthplate
o widened osteoid seams
o swiss cheese trabeculae
o poorly defined zone of provisional calcification
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Metabolic Bone Disease
Physiology
o low Vitamin D levels lead to decreased intestinal absorption of calcium
o low calcium levels leads to a compensatory increase in PTH and bone resorption
o bone resorption leads to increased alkaline phosphatase levels
Clinical findings
o rachitic rosary (enlargement of costochondral junction)
o bowing of knees
o codfish vertebrae
o retarded bone growth (widened osteoid seams, physeal cupping)
o muscle hypotonia
o dental disease
o pathologic fractures
o waddling gate
Laboratory values
o low to normal serum calcium
o low serum phosphate
o elevated alkaline phosphatase
o elevated parathyroid hormone
o low vitamin D
Treatment
o Vitamin D (5000 IU daily)
indications
resolves most deformities
Hereditary Vitamin D-Dependent Rickets (Type I and II) II:4 Codfish vertebrae
Rare disorder
Clinical features similar to Vitamin D-Deficient Rickets but more severe
Clinical characteristics
o Type I
joint pain/deformity, hypotonia, muscle weakness, growth failure, and hypocalcemic seizures
or fractures in early infancy
o Type II
bone pain, muscle weakness, hypotonia, hypocalcemic convulsions, growth retardation,
severe dental caries or teeth hypoplasia
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OrthoBullets2017 Systemic Disease | Metabolic Bone Disease
Pathophysiology
o Type I
caused by defect in renal 25-(OH)-vitamin D1 alpha-hydroxylase
prevents conversion of inactive form of vitamin D to active form
responsible gene 12q14
o Type II
caused by a defect in intracellular receptor for 1,25-(OH)2-vitamin D
Genetics
o type II
autosomal recessive
Laboratory values
o type II is distinguished from type I by markedly elevated levels of 1,25-(OH)2-Vitamin D
Treatment
o physiologic doses (1-2 micrograms/day) of 1,25-(OH)2-Vit D
indications
type I
o daily high dose Vitamin D + elemental calcium
indications
type II
4. Osteomalacia
Introduction
A metabolic bone disease where defective mineralization results in a large amount or unmineralized
osteoid
o qualitative defect as opposed to a quanitative defect like osteoporosis
o rickets and osteomalacia are manifestations of the same pathologic process
Epidemiology
o incidence
rare in the US (approximately 1 in 1000)
much less common than osteoporosis
because of adequate exposure to sunlight and dairy products fortified with vitamin D
o demographics
rickets is found in children (open physis)
osteomalacia is found in adults (closed physis)
o risk factors
the following conditions predispose a patient to osteomalacia
vitamin-D deficient diets
malabsorption e.g. celiac disease
renal osteodystrophy
hypophosphatemia
chronic alcoholism
tumors (tumor-induced osteomalacia)
drugs
drugs associated with vitamin D deficiency
phenytoin
phenobarbital
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Metabolic Bone Disease
rifampin
cholestyramine
cadmium
glucocorticoids
drugs affecting phosphate homeostasis
aluminium-containing phosphate-binding antacid
ifosfamide
drugs affecting bone mineralization
aluminium
etidronate
fluoride
1,25-(OH) Urinary
Serum Ca Serum P Alk phos PTH 25-(OH)vit D
vit D Ca
Osteomalacia low low high high low low low
Osteoporosis normal normal variable normal normal normal normal
Tumor induced
low very low low low low low low
osteomalacia
Osteopetrosis normal normal high normal normal normal normal
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Histology
o requires transiliac biopsy for definitive diagnosis
o Histology
Characteristic histology includes
o technique
requires transiliac biopsy for definitive diagnosis
o findings
widely separated osteoid seams
greater amounts of unmineralized osteoid than normal
o Treatment
Nonoperative
o large doses of oral vitamin D (1000IU/day), treat underlying cause
indications
most patients
o technique
specific subgroups of patients
on long-term anticonvulsant therapy
supplement with 400-800IU/day of vitamin D
with hepatobiliary disease
supplement with 25(OH)-vit D
with renal disease
supplement with 1,25(OH)2 vit D
5. Oncogenic Osteomalacia
Introduction
Definition
o paraneoplastic syndrome of renal phosphate wasting
o caused by bone tumor or soft tissue tumor
Epidemiology
o demographics
age bracket
age of onset is late childhood to early adulthood
Pathophysiology
o the tumor secretes a humoral factor ("phosphatonin") that affects the proximal renal tubules
o reduces calcitriol production in the kidney and inhibits phosphate transport
o leads to increased renal phosphate excretion, hypophosphatemia and osteomalacia
o types of tumors that cause oncologic osteomalacia (known as phosphaturic mesenchymal tumor)
benign tumors (more common)
phosphaturic mesenchymal tumors (mixed connective tissue variant) e.g.
hemangiopericytoma (commonest cause)
osteoblastoma-like tumors
ossifying fibrous tumors
nonossifying fibrous tumors
malignant causes (rare)
osteosarcoma
fibrosarcoma
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Metabolic Bone Disease
Genetics
o mutations
phosphatonin gene is FGF23
Associated conditions
o orthopaedic manifestations
pathological fractures of long bones and vertebrae
Presentation
Symptoms
o generalized bone and muscle pain
o fractures of long bones, ribs and vertebrae
o proximal muscle weakness II:8 Bilateral superior and inferior pubic ramus
Looser's zones (also note right transcervical fracture
o fatigue and diffuse osteopenia)
Imaging
Radiographs
o findings
diffuse osteopenia
Looser's zones (pseudofractures)
Octrotide scans (radiolabeled somatostatin analog)
o gallium-68 DOTA-octreotate PET scan
o indium-111 pentetreotide SPECT/CT
o indications
to identify primary tumors when TIO is suspected
will only identify tumors expressing somatostatin receptors
Studies
25-(OH)vit 1,25- Urinary
Serum Ca Serum P Alk phos PTH
D (OH)vit D Ca
Osteomalacia low low high high low low low
Osteoporosis normal normal variable normal normal normal normal
Tumor induced
low very low low low low low low
osteomalacia
normal
Osteopetrosis normal normal high normal normal normal
Treatment
Nonoperative
o phosphate supplementation with 1,25-dihydroxyvitamin D
Operative
o tumor removal
outcomes
resolution of hypophosphatemia and low vitamin D levels within hours of resection
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OrthoBullets2017 Systemic Disease | Joint Diseases
B. Joint Diseases
1. Gout
Introduction
A monosodium urate crystal deposition disorder
o primary gout
an idiopathic disorder of nucleic acid metabolism that leads to hyperuricemia and deposition
of monosodium urate crystals in joints (a purine breakdown product)
o secondary gout
is associated with a disease with high metabolic turnover (psoriasis, hemolytic anemia,
leukemia, chemotherapy)
Epidemiology
o demographics
recurrent attacks seen in men from ages 40-60 years
o location
usually seen in lower limb
podagra (arthritis attacks of great toe)
crystal deposition as tophi
ear helix, eyelid olecranon, Achilles tendon
o risk factors
chemotherapy
Pathophysiology
o dysfunctional nucleic acid metabolism causing hyperuricemia
o deposition of monosodium urate crystals in synovium of joint
o crystals lead to an inflammatory response activating
proteases
prostaglandins
leukotriene B4
free oxygen radicals
Associated conditions
o renal stones
o septic arthritis
the presence of uric acid crystals does not exclude septic arthritis
Presentation
Symptoms
o pain in joint
o can resemble septic arthritis
o symptoms of renal stones
Physical exam
o may have decreased range of motion due to pain
o white toothpaste-like appearance of tophus aspirate
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Joint Diseases
Imaging
Radiographs
o recommended views
AP and lateral of affected joint
o findings
may see punched out periarticular erosion with sclerotic overhanging borders
may see soft tissue crystal deposition (tophi)
Studies
Labs
o serum uric acid
elevated uric acid is not diagnostic (80% of people with an elevated uric acid will never have
a gout attack)
Crystal analysis
o diagnosis made by joint aspiration and crystal analysis
o monosodium urate (MSU) crystals are
thin, tapered, needle-shaped intracellular crystals
yellow when aligned parallel to red compensator
blue when aligned across the direction of polarization
strongly negatively birefringent
Treatment
Acute gout
o indomethacin vs. colchicine
indications
first line of treatment
medications
indomethacin (indocin) 50mg tid
NSAID
inhibits phagocytosis
colchicine
indicated in acute attacks if patient has a history of peptic ulcers
inhibits inflammatory mediators
can be given intravenously
o oral, intraarticular or IV glucocorticoid
indication
patient unable to take NSAID or colchicine
Chronic gout
o allopurinol
indications
first line of treatment for chronic gout attack
medications
allopurinol is an xanthine oxidase inhibitor
o colchicine
indications
for prophylaxis after recurrent attacks
up to 85% effective
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OrthoBullets2017 Systemic Disease | Joint Diseases
2. Pseudogout (CPPD)
Introduction
A metabolic disease resulting in deposition of calcium pyrophosphate dihydrate (CPPD) crystals
within the joint space
o characterized by recurrent monoarticular arthritis
Epidemiology
o commonly affects the elderly
o rarely affects younger patients, unless occurring in conjunction with other disease
Associated conditions
o hemochromatosis
o hyperparathyroidism
o SLE
o gout
o RA
o Wilson's disease
o hemophilia
o long term hemodialysis can cause a pyrophosphate like deposition disorder
o chondrocalcinosis is present in 7% of patients
Mimics gout except
o affects older patients > 60 years old
o affects more proximal joints
o positively-birefringent crystal
Presentation
Symptoms
o acute, onset joint tenderness
o warm, erythematous joint
o commonly on knee and wrist joints
Physical exam
o erythematous, monoarticular arthritis
o joints tender to palpation
o may observe superficial mineral deposits under the skin at affected joints
Imaging
Radiographs
o may see calcification of fibrocartilage structures
(chondrocalcinosis)
TFCC in wrist
meniscus in the knee
Evaluation
Joint aspiration crystal analysis
o weakly positively birefringent rhomboid-shaped crystals
Treatment
Acute pseudogout
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Joint Diseases
o nonoperative
NSAIDS
splint
intra-articular steroids
splints for comfort
Chronic pseudogout
o nonoperative
intraarticular yttrium-90 injections
colchicine ( 0.6 mg PO bid for recurrent cases)
prophylactic colchine can help to prevent recurrence
Complications
Can result in permanent damage to the joints and renal disease
3. Hemochromatosis
Introduction
A chronic and often silent disorder that results from inappropriate levels of iron in the blood and
tissue
Epidemiology
o prevalence
1 in 200 people of northern European extraction
o demographics
usually presents in 4th-5th decade of life
women usually present later than men due to the protective effect of iron loss during menses
and pregnancy
o location
multi-system disease
hypogonadism
diabetes
liver cirrhosis
cardiomyopathy
arthritis
may be unilateral or bilateral
may affect one or multiple joints
Pathophysiology
o increased dietary iron absorption and/or increased iron release from cell
o leading to inappropriate levels of iron into organs and tissues
Genetics
o inheritance
autosomal recessive
o mutations
C282Y allele is most common
Prognosis
o produces arthritis and chondrocalcinosis in > 50% of patients
o treatment returns life expectancy to normal if patient non cirrhotic and no diabetic
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Presentation
Symptoms
o classically presents with non-specific symptoms
fatigue
lethargy
joint or muscle pain
o may present with systemic symptoms
impotence
diabetes
skin hyperpigmentation
Examination
o arthropathy
most often in PIPJ, MCPJ of index and middle finger
larger joints may also be affected
highly suspicious with bilateral ankle OA
Imaging
Radiographs
o may identify arthritis of the joints
o chonrocalcinosis presents in >50% of patients
Studies
Labs
o serum ferritin levels
o serum iron levels (>30 µmol/L)
o total iron-binding capacity
o TSH
o lipid profile
Liver Biopsy (gold standard)
o hemosiderin in parenchymal cells
Treatment
Nonoperative
o decrease iron intake
indications
standard of treatment to reduce iron overload
methods
reduced consumption of red meat
avoid raw shellfish
limit supplemental vitamin C
avoid excessive alcohol (secondary liver damage)
o phlebotomy regime
indications
weekly blood letting sessions to reduce serum ferritin levels
contraindications
severe anemia
congestive heart failure
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Joint Diseases
Operative
o total joint arthroplasty
indications
large joint involvement
Orthopaedic Manifestations
Bilateral ankle arthritis
o hemochromatosis should be suspected when symmetrical ankle arthropathy occurs in young men
Classification
Eichenholtz Classification
Stage 0 • Joint edema
• Radiographs are negative
• Bone scan may be positive in all stages
Stage 1 • Joint edema
• Radiographs show osseous fragmentation with joint dislocation
Stage 2 • Decreased local edema
• Radiographs show coalescence of fragments and absorption of fine bone debris
Stage 3 • No local edema
• Radiographs show consolidation and remodeling of fracture fragments
Stage 0 - hot foot, normal Stage 1 - fragmentation, Stage 2 - coalescence, Stage 3 - Remodelling
x-rays; MR shows bone bone resorption, sclerosis, fracture healing,
edema and fractures dislocations, fractures debris resorption
Presentation
Symptoms
o swollen shoulder or elbow
o 50% have pain, 50% are painless
o loss of function
Physical exam
o inspection
swollen, warm, erythematous joint
mimics infection
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Joint Diseases
o motion
joint may be mechanically unstable
loss of active motion, but passive motion is maintained
o neurovascular
a neurologic evaluation is essential
Imaging
Radiographs
o recommended views
standard views of affected joint
AP and scapula Y of the shoulder
AP and lateral of the elbow II:9 Neuropathic shoulder joint due to
o findings syringomyelia. Characteristic radiographic
findings include obliteration of joint space,
early changes fragmentation of both articular surfaces of a
degenerative changes may mimic osteoarthritis joint leading to subluxation or dislocation.
and surrounding soft tissue edema.
late changes
obliteration of joint space
fragmentation of both articular surfaces of a joint leading
to subluxation or dislocation
scattered "chunks" of bone in fibrous tissue
joint distention by fluid
surrounding soft tissue edema
heterotopic ossification
fracture
MRI
o indications
MRI of cervical spine to rule out syrinx when neuropathic
shoulder arthropathy is present II:10 A sagittal MRI of the
Bone scan cervical spine reveals a syrinx
or fluid-filled cavity within
o technetium bone scan the spinal cord.
findings
may be positive (hot) for neuropathic joints and osteomyelitis
o indium WBC scan
findings
will be negative (cold) for neuropathic joints and positive (hot) for osteomyelitis
useful to differentiate from osteomyelitis
Differential
Osteomyelitis/septic joint
o difficult to distinguish from osteomyelitis based on radiographs and physical exam
common findings in both conditions
swelling, warmth
elevated WBC and ESR
technetium bone scan is "hot"
unique to Charcot joint disease
indium leukocyte scan will be "cold" (negative)
will be "hot" (positive) for osteomyelitis
Treatment
Nonoperative
o rest, elevation, protected immobilization with a sling, and restriction of activity
indications : neuropathic shoulder joint
o functional bracing
indications : neuropathic elbow joint
technique : should allow flexion-extension, but neutralizes varus-valgus stresses
Operative
o arthrodesis
do not attempt during acute inflammatory stage (Eichenholtz 0-2) because of continued bone
erosion
only perform during quiescent stage (Eichenholtz 3)
requires long periods of immobilization
o total joint replacement
indications
Charcot joint is a contraindication to total joint replacement
due to poor bone stock, prosthetic loosening, instability, and soft-tissue compromise
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Joint Diseases
5. Ochronosis
Introduction
Degenerative arthritis that results from alkaptonuria
Pathophysiology
o excess homogentistic acid is deposited in the joints
o acid polymerizes in joint and leads to early joint arthritis
Genetics
o rare inborn defect in homogentisic acid oxidase enzyme system
Associated conditions
o orthopaedic manifestations
ochronotic spondylitis
commonly occurs in fourth decade
progressive degenerative changes in spine
calcification
narrowing of disc spaces
Presentation
Symptoms
o may complain of black urine
caused by polymerization of homogentistic acid
Imaging
Radiographs
o spine
findings
irregular calcification
narrowing of intervertebral discs
Treatment
Nonoperative
o no current medical treatment available
6. Reiter's
Introduction
A seronegative spondyloarthropathy characterized by:
o urethritis
o conjunctivitis or uveitis
o arthritis
Epidemiology
o incidence
rare
o demographics
occurs most commonly in young man (<40 years of age)
rarely occurs in children, but sometimes appears in adolescents
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o location
arthritis
may be unilateral or bilateral
may affect one or multiple joints
Pathophysiology
o associated infections
mycoplasma
yersinia
salmonella
shigella
chlamydia
campylobacter
Genetics
o may be genetic component making certain individuals more susceptible
Prognosis
o most cases resolve within weeks, but can last up to months
o recurrence occurs in up to half of cases over period of several years
Presentation
Symptoms
o urinary discomfort or pain
usually appears within days or weeks of infection
o inflammation or dryness of the eye
o joint pain
may develop within weeks of initial infection and urinary symptoms
o other non-specific pain symptoms including
heel pain (Achilles tendon pain)
low back pain
Physical exam
o nongonococcal urethritis
o conjunctivitis or uveitis
o arthritis
o skin lesions on palms/soles
may resemble psoriasis
genital skin lesions
o low-grade fever
Imaging
Radiographs : may identify arthritis of the joints
Studies
Diagnosis is based primarily on symptoms and presentation
Labs
o HLA-B27 positive in 75% of cases
o CRP elevated
o ESR elevated
Urinalysis : may identify signs of active infection
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Joint Diseases
Treatment
Nonoperative
o antibiotics, symptomatic treatment, observation
indications : standard of treatment in most cases
medications
direct antibiotics at underlying infection
azithromycin and doxycycline indicated for Chlamydia
NSAIDs for pain and inflammation
o systemic steroids
indications : severe or recalcitrant cases
Complications
Aortic insufficiency
Arrhythmia
7. Psoriatic Arthritis
Introduction
A seronegative spondyloarthropathy that presents with the following orthopaedic manifestations
o 5 patterns of arthritis
asymmetric oligo/monoarticular arthritis affecting DIPJ, PIPJ, MCPJ
DIP-predominant arthritis
arthritis mutilans
symmetric, RF-negative polyarthritis
psoriatic spondyloarthropathy
Epidemiology
o incidence : affect up to 5-20% of patients with psoriasis
o demographics : equally affects men and women
Genetics
o HLAB27 found in 50%
Presentation
Symptoms
o arthritic symptoms in hands
Physical exam
o rash with silvery plaques over extensor surfaces (elbows, knees)
typically precede joint involvement by several years (80-85% of time)
o hands
dactylitis (sausage digit)
onychodystrophy (nail pitting)
onycholysis (lifting of nail plate starting distally)
arthritis mutilans
opera glass hands (la main en lorgnette)
excess skin from the shortening of the phalanx bones becomes folded transversely, as
if retracted into one another like opera glasses
o chronic uveitis
o entheses such as achilles tendonitis, posterior tibial tendonitis, and plantar fasciitis
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II:11 Rash with silvery plaques II:12 Sausage digit II:13 Nail pitting
Imaging
Radiographs
o hands
distal phalanx acrolysis
DIP arthritis
classic finding is "pencil-in-cup" deformity
simultaneous destruction of the head of the middle
phalanx and expansion of the base of the distal
phalanx
different than DJD by presence of centripetal erosions
which cause joint space widening)
small joint erosions or fusions (PIP, MCP, and wrist
commonly involved)
fluffy periostitis (caused by periosteal ossification)
acroosteolysis (resorption of the distal phalanx tuft)
flail digits
o spine in axial disease
sacroiliitis
syndesmophytes
paravertebral ossification
destructive discovertebral lesions
DIP joint erosion and acrolysis in a patient with psoriatic arthritis pencil-in-cup deformity
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Joint Diseases
Studies
HLAB27 found in 50%
RA and ANA tests are usually negative
Treatment
Nonoperative
o NSAIDS, methotrexate, sulfasalazine, cyclosporine,TNF-alpha inhibitors
indications : mainstay of treatment , similar to RA
Operative
o digit fusion vs resection arthroplasty
indications : advanced joint diseas
8. Hemophilic Arthropathy
Introduction
A condition characterized by repetitive hemarthroses and ultimately joint deformation in patients
with bleeding disorders
Epidemiology
o incidence
has decreased significantly due to home factor treatment
o demographics
young males
affects patients between 3-15 years old
o location
knee is most commonly affected
elbow, ankle, shoulder and spine are also involved
Pathophysiology
o mechanism of injury
persistent minor trauma
o root bleeding disorder may be
hemophilia A
X-linked recessive
decrease factor VIII
hemophilia B - Christmas disease
X-linked recessive
decreased factor IX
von Willebrand's disease
rare cause of joint bleeds
more commonly mucosal bleeding
autosomal dominant
abnormal factor VIII with platelet dysfunction
o pathoanatomy
synovitis -> cartilage destruction (enzyme based) -> joint deformity
Associated conditions
o orthopaedic manifestations
hemarthrosis
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intramuscular hematoma (pseudotumor)
may lead to nerve compression
femoral nerve palsy may be caused by iliacus hematomas
leg length discrepancy
due to epiphyseal overgrowth
fractures
due to generalized osteopenia
normal healing chronology
o medical conditions and comorbidities
HIV
prevalence up to 90% in hemophiliacs
Prognosis
o prognostic variables
degree of factor deficiency
determines severity of disease
mild: 5-25%
moderate: 1-5%
severe: 0-1%
presence of factor VIII inhibitors (including IgG antibodies)
IgG antibody inhibits response of therapeutic factor treatment (monocolonal recombinant
factor VIII)
found in 5-25% of hemophiliac patients
is a relative contraindication for surgical interventions
should be screened for preoperatively
Classification
Arnold-Hilgartner Staging
Stage 1 • Shows swelling of the soft tissues
Stage 2 • Shows osteoporotic changes
Stage 3 • Shows development of subchondral cysts
• Joint is grossly intact
Stage 4 • Shows cartilage loss with narrowing of the joint
Stage 5 • Demonstrates severe arthritis of affected joint
Imaging
Radiographs
o knee
squaring of patella and femoral condyles (Jordan's sign)
ballooning of distal femur
widening of intercondylar notch
joint space narrowing
patella appear long and thin on
lateral
o ankle
joint arthritis
o elbow
joint arthritis
o epiphyseal overgrowth
o generalized osteopenia
o fractures
MRI
o can be used to identify early
degeneratve joint disease II:15 widening of the intercondylar notch I I:14 Coronal MRI of a patient
Ultrasound and ballooning of the distal femur with hemophilic arthropathy of the
ankle. Note the cartilaginous
o often helpful to follow intramuscular destruction of the talus.
hematomas
Studies
Labs
o screening for factor VIII inhibitors (including IgG antibodies)
indicated prior to surgery as presence will negate effects of factor treatment
Histology
o hypertrophy and hyperplastic changes to the synovium
Differential
Septic arthritis : concomitant infection should be ruled out by physical exam and joint aspiration
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Treatment
Nonoperative
o compressive dressings, analgesics, short term immobilization followed by rehabilitation
indications : joint pain
modalities
steroids for to help reduce inflammation
splints and braces
physical therapy to prevent contracture development
o factor administration
indications
vigorous physical therapy
increase factor VIII to 20%
acute hematomas (including intramuscular hematomas)
increase factor VIII to 30%
acute hemarthrosis and soft tissue surgery
increase factor VIII to 40-50%
skeletal surgery
increase factor VIII to 100% for first week following surgery then maintain at > 50%
for second week following surgery
modalities
home transfusion therapy
has reduced the severity of arthropathies
o desmopressin
indications : mild or moderate hemophillia A
Operative
o synovectomy
indications : recurrent hemarthroses recalcitrant to medical management
techniques : increase factor VIII to 40-50%
outcomes
decreases incidence of recurrent hemarthroses
limits pain and swelling
o synoviorthesis
indications : chronic hemophiliac synovitis that is recalcitrant to medical management
technique
destruction of synovial tissue with intra-articular injection of radioactive agent
colloidal phosphorus-32 chromic phosphate
o total joint arthroplasties
indications : end stage arthropathy
perioperative care
increase factor VIII to 100% for first week postoperatively then maintain at > 50% for
second week postoperatively
o arthrodesis
indications : arthropathy of the ankle
perioperative care
increase factor VIII to 100% for first week postoperatively then maintain at > 50% for
second week postoperatively
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Blood Conditions
C. Blood Conditions
Diagnosis Criteria
Major (1)
o hypoxemia (PaO2 < 60)
o CNS depression (changes in mental status)
o petechial rash
o pulmonary edema
Minor (4)
o tachycardia
o pyrexia
o retinal emboli
o fat in urine or sputum
o thrombocytopenia
o decreased HCT
Additional
o PCO2 > 55
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o pH < 7.3
o RR > 35
o dyspnea
o anxiety
Presentation
History
o symptoms usually present within 24 hours of inciting event
Symptoms
o patient complains of feeling "short of breath"
o patient appears confused
Physical exam
o tachycardia
o tachypnea
o petechiae
axillary region
conjunctivae
oral mucosa
Studies
ABG
o hypoxemia (PaO2 < 60 mmHg)
Treatment
Nonoperative
o mechanical ventilation with high levels of PEEP (positive end expiratory pressure)
indications : acute fat emboli syndrome
Prevention
o early fracture stabilization
indications
early fracture stabilization (within 24 hours) of long bone fracture is most important
factor in prevention of FES
techniques to reduce the risk of fat emboli
overreaming of the femoral canal during a TKA
use of reamers with decreased shaft width reduces the risk during femoral reaming for
intramedullary fixation
use of external fixation for definitive fixation of long bone fractures in medically unstable
patients decreases the risk
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Blood Conditions
Risk factors for thromboembolism
o Virchow's triad
venous stasis
hypercoagulable state
intimal injury
o primary hypercoagulopathies (inherited)
MTHFR/C677T/TT gene mutation carries highest risk
factor V Leiden mutation
antithrombin III deficiency
protein C deficiency
protein S deficiency
activated protein C resistance
o secondary factors (acquired)
malignancy
recently been associated with up to 20% of all new diagnoses of VTE
elevated hormone conditions
recombinant erythropoeitin
hormone replacement
oral contraceptive therapy
late pregnancy
elevated antiphospholipid antibody conditions
lupus anticoagulant
anticardiolipin antibody
history of thromboembolism
obesity
aging
CHF
varicose veins
smoking
general anesthetics (vs. epidural and spinal)
immobilization
increased blood viscosity
Pathophysiology
Mechanism of clot formation
o stasis
o fibrin formation
thromboplastin (aka Tissue Factor (TF), platelet tissue factor, factor III, or CD142) is
released during dissection which leads to activation of the extrinsic pathway and fibrin
formation
o clot retraction
o propagation
Prophylaxis
Overview
o prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) is most important
factor in decreasing morbidity and mortality
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o prophylaxis treatment should be determined by weighing risk of bleeding vs risk of pulmonary
embolus
AAOS risk factors for major bleeding
bleeding disorders
history of a recent gastrointestinal bleed
history of a recent hemorrhagic stroke
AAOS risk factors for pulmonary embolus
hypercoagulable state
previous documented pulmonary embolism
Prophylaxis in hip & knee replacement
o mechanical prophylaxis
compressive stockings recommended
pneumatic compression devices are recommended by the AAOS across all risk (low to high
risk of either bleeding or pulmonary embolism) groups undergoing total hip or total knee
arthroplasty
increase venous return and endothelial-derived fibrinolysis
decrease venous compliance and venous stasis
o medical treatment
see anticoagulation section below
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Blood Conditions
o vena cava filter placement
indications
preoperative identification of DVT in a patient with lower extremity or pelvic trauma who
is high risk for DVT development
see anticoagulation
Pulmonary Embolism
Introduction
o 700,000 asymptomatic PE/yr in USA
of these 200,000 are fatal
o procedures associated with pulmonary embolism
hip fracture
elective total hip arthroplasty
the greatest risk of activation of the clotting cascade during total hip arthroplasty occurs
during insertion of the femoral component
elective total knee arthroplasty
spine fracture with paralysis
o early diagnosis and treatment is most important factor for survival
Presentation
o PE should be suspected in postoperative patients with
acute onset pleuritic pain and dyspnea
tachypnea
tachycardia
Evaluation
o EKG
o ABG
Imaging
o CXR
o nuclear medicine ventilation-perfusion scan (V/Q)
o pulmonary angiography
is gold standard
o helical chest CT
widely considered first line imaging modality
Treatment
o continuous IV heparin infusion followed by warfarin therapy
indications
in most cases as first line treatment
technique
continuous IV heparin infusion typically given for 7-10 days
warfarin therapy typically given for 3 months
monitor heparin therapy with PTT (partial thromboplastin time)
monitor coumadin therapy with INR (international normalized ratio)
o thrombolytics
indications
in specific cases
technique
see anticoagulation
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3. Anticoagulation
Introduction
The coagulation cascade comprises a series of reactions that lead to formation of fibrin, which leads
to platelet activiation and clot formation
o an imbalance of the coagulation cascade can cause thromboembolism and DVT
Virchow's triad describes risk factors for thromboembolism and DVT and includes
o venous stasis
o endothelial damage
o hypercoagulable state
Orthopaedic surgery predisposes high risk of thromboembolism and certain procedures may require
anticoagulation
o there are many choices of anticoagulants, each has advantages and disadvantages
Compression Stocking
Mechanism
o increases fibrinolytic system
o decreases venous stasis
Evidence : literature supports efficacy in TKA
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Blood Conditions
ASA (acetylsalicylic acid)
Introduction
o thromboxane function
under normal conditions thromboxane is responsible for the aggregation of platelets that
form blood clots
o prostaglandins function
prostaglandins are local hormones produced in the body and have diverse effects including
the transmission of pain information to the brain
modulation of the hypothalamic thermostat
inflammation
Mechanism of ASA
o inhibits the production of prostaglandins and thromboxanes through irreversible inactivation of
the cyclooxygenase enzyme
acts as an acetylating agent where an acetyl group is covalently and irreversibly attached to
a serine residue in the active site of the cyclooxygenase enzyme.
this differentiates aspirin different from other NSAIDs which are reversible inhibitors
Metabolism
o renal
Fondaparinux
Overview
o trade name: Arixtra
o has advantage of not requiring lab value monitoring
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Mechanism
o indirect factor Xa inhibitor (acts through antithrombin III)
Metabolism
o renal
Evidence
o studies show decreased incidence of DVT when compared to enoxaparin in hip fx and TKA
patients
Risk
o highest bleeding complications
not to be used in conjunction with epidurals
Warfarin
Mechanism of anticoagulation
o inhibits vitamin K 2,3-epoxide reductase
prevents reduction of vitamin K epoxide back to active vitamin K
o vitamin K is needed for gamma-carboxylation of glutamic acid for factors
II (prothrombin), VII (first affected), IX, X
protein C, protein S
Monitoring
o target level of INR (international normalized ratio) is 2-3 for orthopaedic patients
o not achieved for 3 days after initiation
Reversal
o vitamin K (takes up to 3 days)
o fresh frozen plasma (acts immediately)
Risk
o difficult to dose requires the frequent need for INR lab monitoring
o can have adverse reaction with other drugs including
rifampin
phenobarbital
diuretics
cholestyramine
Rivaroxaban (Xarelto)
Overview
o others in the same class include apixaban (Eliquis) and edoxaban (Savaysa or Lixiana)
o Mechanism of action of these drugs can be deduced from the name.
Rivaro(Identifier)-xa(FactorXa)-ban(inhibitor)
Mechanism
o direct Xa inhibitor
Metabolism
o liver
Antidote
o no current antidote
o andexanet alpha being investigated
Risk
o Bleeding
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Neurologic Diseases
Dabigatran (Pradaxa)
Mechanism
o reversible direct thrombin (factor IIa) inhibitor
Metabolism : renal
Antidote : idarucizumab (FDA approved Oct 2015)
Risk
o GI upset
o bleeding
Herbal Supplements
Increased bleeding
o gingko, ginsing, and garlic have been found to increase the rate of bleeding
o related to effect on platelets
o proper history taking can avoid complications
Increased warfarin effect (increase INR)
o omega-3 fish oil
affects platelet aggregation and vitamin K dependent coagulation factors
Reduced warfarin effect (reduces INR)
o coenzyme Q10
o green tea
direct warfarin antagonist (reduces INR)
o St John's wort
increases catabolism of warfarin (reduces INR)
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D. Neurologic Diseases
1. Stroke
Introduction
Acute onset of focal neurologic deficits resulting from
o diminished blood flow (ischemic stroke)
o hemorrhage (hemorrhagic stroke)
Epidemiology
o incidence
o risk factors include
diabetes
smoking
atrial fibrillation
cocaine
Pathophysiology
o etiology include
35% - atherosclerosis of the extracranial vessels (carotid atheroma)
30% -cardiac and fat emboli, endocarditis
15% - lacunar
occur in areas supplied by small perforating vessels and result from
atherosclerosis
hypertension
diabetes
10% - parenchymal hemorrhage
10% - subarachnoid hemorrhage
Watershed occurs at areas at border of two arterial supplies
o often follow prolonged hypotension
TIA is charcaterized by transient neurologic deficits for less than 24 hours (usually less than 1 hr.)
Presentation
Edema occurs 2-4 days post-infarct.
Watch for symptoms
o decorticate (cortical lesion): flexion of arms
o decerebrate (midbrain or lower lesion): extension of arms
hemiparesis.
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Neurologic Diseases
Other stroke syndromes
o lateral medullary infarct (Wallenburg syndrome)
loss of pain and temp on ipsilateral face and contralateral body, vestibulocerebellar
impairment, Horner's syndrome
Imaging
CT without contrast
o indicated for acute presentation
o important to diagnose as ischemic or hemorrhagic
MRI
o indicated for subacute
o vascular studies of intra and extracranial vessels
Studies
Labs
o should include coagulation studies
o lumbar puncture to r/o encephalitis
Echo
o to check for mural thrombus, rule out endocarditis
EEG to rule out seizure
Differential
Brain tumor, epi / subdural bleeds, brain abscess, endocarditis, multiple sclerosis, metabolic
(hypoglycemia), neurosyphillis
Treatment
Nonoperative
o thrombolytics
indications : for occlusive disease
modalities
give IV tPA if within 3-4.5 hours
can consider intra-arterial thrombolysis in select patients (major MCA occlusion) up to 6
hours after onset of symptoms
o warfarin/aspirin therapy
indications
for embolic disease and hypercoagulable states give warfarin / aspirin once the
hemorrhagic stroke has been ruled out
o anti-hypertensive medications
Do not overtreat hypertension. Allow BP to rise to 200/100 to maintain perfusion
Operative
o thrombectomy
indications
Within 6 hours in an ischemic stroke with a proximal cerebral arterial occlusion,
compared to alteplase alone, improved reperfusion, early neurological recovery, and
functional outcome.
o endarterectomy
indications
if corotid > 70% occluded
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Prognosis, Prevention, and Complications
Less than 1/3 achieve full recovery
For embolic disease give warfarin / aspirin for prophylaxis
Carotid endarterectomy if stenosis is > 70%. Contraindicated if vessel is 100% occluded.
Manage hypertension
2. Multiple Sclerosis
Introduction
A chronic inflammatory disease that causes demyelination and widespread axonal injury in the
central nervous system, leading to motor and sensory dysfunction
Epidemiology
o incidence
5 per 100,000 people in the US
o demographics
20-40 years old
women>men
northern latitude
o risk factors
genetic
not considered a hereditary disease
environment
stress
smoking
decreased sunlight/low vitamin D exposure
Pathophysiology
o pathophysiology
believed to be caused by a combination of genetic, environmental and infectious factors
recent research suggests a T-cell mediated autoimmune mechanism
Associated conditions
o orthopaedic
increased fracture risk
relating to increased risk of falling and decreased bone mineral density
osteoporosis
relating to physical inactivity, vitamin D deficiency, immunomodulatory medication
gait abnormalities
muscle paralysis causing foot drop, etc
muscle and joint spasticity
Prognosis
o patterns of disease progression
remitting-relapsing (most common)
primary progressive
secondary progressive
progressive relapsing
o life expectancy
5 to 10 years lower than that of unaffected people
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Neurologic Diseases
Presentation
History
o clinically defined by two or more episodes of neurological dysfunction (brain, spinal cord or
optic nerves) that are separated in time and space
Symptoms
o symptoms of disease are based on the systems involved
psych
fatigue, depression, mood disorders
central nervous system
optic neuritis, diplopia, nystagmus
ENT
dysarthria, dysphagia
MSK
weakness, loss of balance and coordination, spasms, ataxia, falls
neuro
parasthesis, hypoesthesia, peculiar sensory phenomena's (e.g. sensation of wetness)
GI
incontinence, diarrhea, constipation
urology
incontinence, frequency, retention
Physical exam
o inspection
assess for gait abnormalities (e.g. wide-based gait, limb ataxia, slapping foot)
joint or muscle contractures
o neurological examination
muscle spasticity
increased deep tendon reflexes
muscle weakness
Babinski positive
o special tests
fundoscopy
MLF syndrome (Internuclear Ophthalmoplegia)
Lhermitte's sign
Evaluation
Laboratory studies
o CBC, lytes, TSH, comprehensive metabolic panel
used to exclude concomitant illnesses
usually normal
o CSF analysis
Mononucleur pleocytosis (25%)
elevated CSF IgG (80%)
oligoclonal bands on electrophoresis
Imaging studies
o MRI
indications : obtain MRI with gadolinium of brain and spinal cord
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findings
multiple focal demyelination scattered in brain and spinal cord
asymmetric periventricular plaques
Differential
Cervical myelopathy, CNS mass lesion, vitamin B12 deficiency, sarcoidosis, CNS infections
Treatment
Nonoperative
o immunomodulators
indications
treatment attempt to return function after an attack, prevent new attacks, and prevent
disability
modalities
corticosteroids
indicated for acute exacerbations
prophylactic immunosuppresants (interferon beta)
may decrease the number and severity of relapses
has been shown to decrease the progression of relapsing remitting multiple sclerosis
o antispasticity agents
indications
increased muscle tone with spasms
modalities
oral agents
baclofen, gabapentin, clonazapem
botox injections
o physiotherapy
indications
improve gait and balance
modalities
gentle stretching exercises for spasticity
progressive resistant-training
o osteoporosis management
Complications
Increased fracture risk
o relating to increased risk of falling and decreased bone mineral density
Osteoporosis
o relating to physical inactivity, vitamin D deficiency, immunomodulatory medication
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Neurologic Diseases
Presentation
Symptoms
o painless weakness in one extremity that extends to the other extremities
o fasciculations
o impaired speech or swallowing
o reduced head control
o breathing difficulty
o muscle cramping
o urinary frequency or incontinence (late findings)
o sensory remains normal
Physical exam
o neck ptosis (neck drop) due to neck extensor weakness
o manual muscle testing elicits muscle cramping
o upper motor neuron (UMN) signs
spasticity
hyperreflexia
(+) Hoffman's
(+) Babinski's
spastic dysarthria
o lower motor neuron (LMN) signs
muscular atrophy
weakness
clinical fasciculations
clumsiness
Evaluation
Diagnosis
o dependent on demonstration of both UMN and LMN involvement
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o combination of UMN and LMN in the same extremity, in the absence of pain or sensory
symptoms, and cranial nerve findings is highly indicative of ALS
o often misdiagnosed as cervical myelopathy or radiculopathy
Laboratory diagnosis
o there are currently no laboratory tests that confirm the diagnosis
EMG / NCS - shows denervation + reinnervation
o widespread decreased amplitude of CMAP and slowed motor conduction velocity
o denervation (fibrillations and positive waves) + decreased recruitment in ≥ 3 extremities
o reinnervation
o abnormal spontaneous fibrillation & fasciculation potentials
o normal sensory studies (SNAP, sensory nerve action potentials)
Differentials
Peripheral compressive neuropathy
o hyperreflexia and other UMN signs (Babinski, Hoffman) are present in ALS (which can present
in a single extremity mimicking cubital/carpal tunnel syndrome), but absent in peripheral
neuropathy
o ALS has normal sensory studies on EMG/NCS
Treatment
Nonoperative
o currently no cure or effective treatment
goals of treatment
provide supportive care
prevent progression
maintain independent patient function and comfort
o riluzole
indications
modest benefits only
prolongs life by 2-3 months
mechanism
blocks tetrodotoxin-sensitive sodium channels associated with damaged neurons
delays onset of ventilator-dependence and may prolong survival
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Neurologic Diseases
Prevention
o vitamin C 500 mg daily x 50 days in distal radius fractures treated conservatively
200mg daily x 50 days if impaired renal function
o vitamin C also has been shown to decrease the incidence of CRPS (type I) following foot and
ankle surgery
o avoid tight dressings and prolonged immobilization
Prognosis
o responds poorly to conservative and surgical treatments
Classification
Presentation
Cardinal signs
o exaggerated pain
o swelling
o stiffness
o skin discoloration
Physical exam
o vasomotor disturbance
o trophic skin changes
o hyperhidrosis
o "flamingo gait" if the knee is involved
Imaging
Radiographs
o patella osteopenia if the knee is involved
Three-phase bone scan
o indications
to rule out CRPS type I (has high negative predictive value)
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o findings
RSD shows positive phase III that does not correlate with positive phase I and phase II
phase background
phase I (2 minutes) : shows an extremity arteriogram
phase II (5-10 minutes) : shows cellulitis and synovial inflammation
phase III (2-3 hours) : shows bone images
phase IV (24 hours) : can differentiate osteomyelitis from adjacent cellulitis
Thermography
o questionable utility
EMG/NCV
o may show slowing in known nerve distribution e.g. slowing of median nerve conduction for
CRPS type II in forearm
Studies
Diagnosis
o diagnosis is clinical, but can be confirmed by pain relief with sympathetic block
o early diagnosis is critical for a successful outcome
Treatment
Nonoperative
o physical therapy and pharmacologic treatment
indications : indicated as first line of treatment
modalities
gentle physiotherapy
tactile discrimination training
graded motor imagery
medications
NSAIDs
alpha blocking agents (phenoxybenzamine)
antidepressants
anticonvulsants
calcium channel blockers
GABA agonists
o nerve stimulation
indications : symptoms present mainly in the distribution of one major peripheral nerve
programmable stimulators placed on affected nerves
o chemical sympathectomy
indications
acts as another option when physical therapy and less aggressive nonoperative
management fails
Operative
o surgical sympathectomy
indications : failed nonoperative management, including chemical block
o surgical decompression
indications : CRPS type II with known nerve involvement e.g. carpal tunnel release if median
nerve involved
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Systemic Diseases
E. Systemic Diseases
1. Rheumatoid Arthritis
Introduction
A chronic systemic autoimmune disease with a genetic predisposition
Epidemiology
o incidence : most common form of inflammatory arthritis
o demographics : affects 3% of women and 1% of men
Pathophysiology
o immunology
cell-mediated (T cell-MHC type II) immune response against soft tissues (early), cartilage
(later), and bone (later)
rheumatoid factor
an IgM antibody against native IgG antibodies
immune complex is then deposited in end tissues like the kidney as part of the
pathophysiology
mononuclear cells
are the primary cellular mediator of tissue destruction in RA
IL-1, TNF-alpha
are part of cascade that leads to joint damage
immune response thought be related to
infectious etiology or
HLA locus
o pathoanatomy
cascade of events includes
antigen-antibody and antibody-antibody reactions >
microvascular proliferation and obstruction >
synovial pannus formation (histology shows prominent intimal hyperplasia) >
joint subluxation, chondrocyte death/joint destruction, and deformity >
tendon tenosynovitis and rupture
Genetics
o associated with specific HLA loci (HLA-DR4 & HLA DW4)
o ~15% rate of concordance amongst monozygotic twins
Associated conditions
o orthopaedic manifestations
see below
o medical conditions & comorbidities
rheumatoid vasculitis
pericarditis
pulmonary disease
Felty's syndrome (RA with splenomegaly and leukopenia)
Still's disease (acute onset RA with fever, rash and splenomegaly)
Sjogren's syndrome (autoimmune condition affecting exocrine glands)
Decreased secretions from salivary and tear duct glands
Lymphoid tissue proliferation
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Prognosis
o significant advances in pharmacologic management have led to a decrease in surgical
intervention
Presentation
Symptoms
o insidious onset of morning stiffness and polyarthropathy
o usually affects hands and feet
DIP joint of hand is usually spared
may also affect knees, cervical spine, elbows, ankle and shoulder
Physical exam
o subcutaneous nodules in 20% (strong association with positive serum RF)
o ulnar deviation with metacarpophalangeal (MCP) subluxation, swan neck deformity
o hallux valgus, claw toes, metatarsophlanageal (MTP) subluxation
o joints become affected at later stage in disease process
Imaging
Radiographs
o periarticular erosions and osteopenia
o protrusio acetabuli
medial migration of femoral head past the radiographic teardrop
Also seen in Marfan's syndrome, Paget's disease, Otto's pelvis and other metabolic bone
conditions
o joint space narrowing
o central glenoid erosion
Studies
Labs
o anti-CCP (cyclic citrullinated peptide, most sensitive and specific test)
o anti-MCV (mutated citrullinated vimentin)
o elevated ESR
o elevated CRP
o positive RF titer (most commonly IgM)
targets the Fc portion of IgG
elevated in 75-80% of patients with RA
o joint fluid testing
decreased complement
may have elevated RF levels
Pharmacologic Management of RA
1st Line:
Low dose steroids
Corticosteroids
2nd Line:
Disease modifying anti-rheumatic drugs (DMARDs)
Methotrexate a folate analogue with anti-inflammatory properties linked to inhibition of
neovascularization
therapeutic effects increased when combined with tetracyclines due to anti-
collagenase properties
Leflunomide an inhibitor of pyrimidine synthesis
Sulfasalazine exact mechanism unknown, but associated with a decrease in ESR and CRP
blocks the activation of toll-like receptors (TLR), which decreases the activity of
Hydroxychloroquine
dendritic cells, thus mitigating the inflammatory process
Others D-penicillamine
3rd Line:
DMARDS / Biologic Agents / TNF antagonists
Etanercept (Enbrel) TNF-alpha receptor fusion protein (TNF type II receptor fused to IgG1: Fc portion)
that binds to TNF-alpha
Infliximab (Remicade)
human mouse chimeric anti-TNF-alpha monoclonal antibody
Adalimumab (Humira) human anti-TNF-alpha monoclonal antibody
Golimumab (Simponi) human anti-TNF-alpha monoclonal antibody
Certolizumab (Cimzia) pegylated human anti-TNF-alpha monoclonal antibody
4th Line:
DMARDS / Biologic Agents / IL-1 antagonists
Anakinra (Kineret) recombinant IL1 receptor antogonist
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Biologic Agents: Other
Rituximab (Rituxan) monoclonal antibody to CD20 antigen (inhibits B cells)
Abatacept (Orencia) selective costimulation modulator that binds to CD80 and CD86 (inhibits T cells)
IL6 receptor inhibitor (2nd line treatment for poor response to TNF-antagonist
Tocilizumab (Actemra)
therapy)
TNF antagonists (etanercept, Continue for minor procedures. Stop etanercept 1wk before for
major procedures. Plan surgery at the end of dosing interval for
infliximab, adalimumab)
adalimumab and infliximab. Restart all 10-14days after.
Continue for minor procedures. Stop 1-2 days before for major
IL-1 antagonist (anakinra)
procedures. Restart 10 days after.
Cervical Spondylitis
Cervical spondylitis includes
o atlantoaxial subluxation
o basilar invagination
o subaxial subluxation
Finger Conditions
Rheumatoid nodules
o epidemiology
most common extra-articular manifestation of RA
seen in 25% of patients with RA and associated with aggressive disease
an extraarticular process found over IP joints, over olecranon, and over ulnar border of the
forearm
o prognosis
erosion through skin may lead to formation of sinus tract
o presentation
patients complain of pain and cosmetic concerns
o treatment
non operative
steroid injection
operative
surgical excision
indications
cosmetic concerns, pain relief, diagnostic biopsy
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Systemic Diseases
Arthritis Mutilans
o seen in patients with RA or psoriatic arthritis
o digits develop gross instability with bone loss (pencil in cup deformity, wind chime fingers)
o treated with interposition bone grafting and fusion
Ulnar drift at MCP joint
o introduction
volar subluxation associated with ulnar drifting of digits
pathoanatomy
joint synovitits >
radial hood sagittal fiber stretching >
concomitant volar plate stretching
extrinsic extensor tendons subluxate ulnarly >
lax collateral ligaments allow ulnar deviation deformity >
ulnar intrinsics contract further worsening the deformity >
wrist radial deviation further worsens >
flexor tendon eventually drifts ulnar
o presentation
extensor lag at level of MCP joint
o treatment
operative
synovectomy, extensor tendon centralization,
and intrinsic release
indications
early disease
MCP arthroplasty
silicone MCP arthroplasty is most common
indications
late disease
thumb MCP involvement + thumb IP involvment
techniques
important to correct wrist deformity at same time if it is radially deviated
synovectomy, volar capsular resection, ulnar collateral ligament release, radial
collateral ligament repair/reconstruction, extensor tendon realignment, intrinsic
tendon release
outcomes
ultimate function is less predictable
overall patient satisfaction of 70%
1 year followup shows improved ulnar drift and extensor lag
complications
infection
implant failure
deformity recurrence
MCP fusion
indications
thumb MCP involvement without IP involvement
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Boutonniere deformity
o pathoanatomy
synovitis of PIP leads to central slip and dorsal capsule attenuation
increasing PIP flexion
lateral bands subluxate volar to axis of rotation of PIP
oblique retinacular ligament contracture causes extension contracture of DIP
o treatment
splinting
for flexible PIP
extensor reconstruction (central slip imbrication or
Fowler distal tenotomy)
for moderate deformity
PIP arthrodesis or arthroplasty
for rigid contractures
Swan neck deformity
o pathoanatomy
terminal tendon rupture from DIP synovitis leads to DIP flexion/PIP hyperextension
FDS, volar plate and collateral ligament attenuation from synovitis leads to decreased volar
support of PIP, and hyperextension deformity
lateral band subluxate dorsal to PIP axis of rotation
contracture of triangular ligament, attenuation of transverse retinacular ligament
o treatment
splinting
for flexible PIP (prevent hyperextension)
FDS tenodesis or proximal Fowler tenotomy
for flexible PIP and failed splinting
dorsal capsule release, lateral band mobilization, collateral ligament and intrinsic
release, extensor tenolysis
for rigid deformities
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Systemic Diseases
Thumb Conditions
Wrist Conditions
Caput-ulna syndrome
o pathoanatomy
synovitis in the DRUJ > ECU subsheath stretching > ECU subluxation > supination of the
carpal bones away from the head of the ulna > volar carpal subluxation > increased pressure
over the extensor compartments > tendon rupture
distinguish from extensor lag caused by PIN compression neuropathy (seen in RA due to
elbow synovitis)
o treatment
Darrach distal ulna resection
must also relocate ECU dorsally with a retinacular flap or perform ECU stabilization of
ulna
ulnar hemiresection
Sauvé-Kapandji (ulnar pseudoarthrosis)
has advantage of preserving the TFCC
good option for younger patients
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Systemic Diseases
Radiocarpal Destruction
o pathoanatomy
synovitis and capsular distension leads to supination, radial deviation (angulation) of carpus
ulnar and volar translocation of the carpus on the radius
with scaphoid flexion, radiolunate widening, lunate translocation (ulnarwards)
secondary radioscaphoid arthrosis
ulnar deviation of the fingers at the MP joints creating the classic zigzag deformity
o treatment
synovectomy
indications
early disease
technique
transfer of ECRL to ECU to diminish deforming forces (Clayton's procedure)
radiolunate fusion (Chamay) or radioscapholunate fusion
indications
intermediate disease with preserved midcarpal joint
wrist fusion
indications
advanced disease, poor bone stock
remains gold standard
often combined with Darrach
total wrist arthroplasty
indications
sedentary patients with good bone stock
advantages over fusion is motion and best in patients with reasonable motion preop
Elbow Conditions
Rheumatoid elbow
o nonoperative
rheumatoid elbow is mainly managed with medical management and cortisone injections
o operative
synovectomy and radial head excision
indications
focus of degeneration is in radiohumeral joint
posterior interosseous nerve compression secondary to radial head synovitis
technique
performed through lateral approach to elbow
interposition arthroplasy
indications
young active patients who are not candidates of TEA
technique
resection and contouring of humeral surface
cover humeral surface with cutis autograft, Achilles tendon, fascia, or dermal allograft
some use distraction external fixator to unload membrane and enhance its bonding to
bone and improve motion
results less predictable than TEA, but avoids prosthetic complications
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total elbow arthoplasty
indications
pain
loss of motion
instability
technique
semiconstrained device has best results
outcomes
reliable procedure for advanced RA of elbow
5 lb single arm weight lifting restriction
Shoulder Conditions
Introduction
o RA is most prevalent form of inflammatory process affecting the shoulder with >90% developing
shoulder symptoms
o commonly associated with rotator cuff tears
Evaluation
o classic radiographic findings include
central glenoid wear
periarticular osteopenia
cysts
Hip Conditions
Protrusio acetabuli
Knee Conditions
Operative II:16 Protrusio acetabuli
o synovectomy of knee
decreases pain and swelling but does not alter prevent radiographic progression and does not
prevent the need for TKA in the future
normal synovium reforms, but degenerates to rheumatoid synovium over time
range of motion is not improved
o total knee arthroplasty
rheumatoid arthritis is considered an indication for resurfacing of the patella during total knee
arthroplasty
Foot & Toe Conditions
Introduction
o usually bilateral and symmetric
o forefoot joints are the first to be affected
o human leukocyte antigen (HLA)-DR4 positive
Toe hyperextension deformity
o the earliest manifestation of rheumatoid arthritis of the forefoot is synovitis of the MTP joints
with eventual hyperextension deformity of the MTP joints including distal migration of the
forefoot pad, painful plantar callosities and skin ulcerations over bony prominences.
o treatment
arthrodesis of the 1st MTP joint and lesser MTP joint resections
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Systemic Diseases
Talonavicular arthritis
o common to have degenerative changes
o treat with fusion
Cervical Conditions
Present in 90% of patients with RA
o diagnosis often missed
Cervical rheumatoid spondylitis includes three main patterns of instability
o atlantoaxial subluxation
most common form of instability
o basilar invagination
o subaxial subluxation
Complications
Postoperative infection
o history of prior surgical site infection (SSI)
is the most significant risk factor for development of another SSI
o immunosuppressive therapy
the literature is controversial whether RA patients on immunosuppressive therapy have
significantly increased infection rates for orthopaedic procedures
pharmacologic therapy may need to be changed prior to surgical interventions
surgery should be performed when immunosuppressive agents are at their lowest levels
etanercept should be discontinued 3 days prior to surgical procedures
adalimumab should be discontinued 10 days prior to surgery
the lowest level of infliximab is found 2 weeks prior to the next scheduled infusion
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Presentation
Symptoms
o fever
o pain in multiple joints : hip pain (osteonecrosis)
Physical exam
o butterfly malar rash
o large joint swelling and synovitis
o hand and wrist manifestation are common (90%)
swelling and synovitis of PIPs, MCPs, and carpus
ligamentous laxity
Raynaud's phenomenon
dorsal subluxation of ulna at DRUJ
Imaging Studies
Radiographs
o usually no evidence of joint destruction
o osteonecrosis of hips is common
Labs
Usually positive for
o ANA (95%)
o anti-DNA antibodies
o HLA-DR3
o few are RF positive
Treatment
Nonoperative
o NSAIDS, methotrexate, sulfasalazine, cyclosporine, antimalarials, DMARDs
treatment is similar to RA
Operative
o digit fusion vs resection arthroplasty for hand
indicated in advanced joint disease
soft tissue procedures have high failure rates
arthrodesis is treatment of choice for PIP or DIP deformities
3. Pustulosis palmoplantaris
Introduction
Crops of sterile pustules that occur on one or both hands and feet, also known as pustular psoriasis
Introduction
o demographics : more common in middle-aged men than in women
rare in children
o risk factors
the majority of patients are smokers (65–90%)
increased stress
infection (i.e acute or chronic tonsillitis)
drugs (i.e.TNF-alpha inhibitors)
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By Dr, AbdulRahman AbdulNasser Systemic Disease | Systemic Diseases
Pathophysiology
o unknown
therories
activated nicotine receptors in the sweat glands cause an inflammatory process
Associated conditions
o orthopaedic conditions
chronic recurrent multifocal osteomyelitis
synovitis–acne–pustulosis–hyperostosis–osteomyelitis (SAPHO) syndrome
rare presentations of arthropathy
o medical conditions & comorbidities
autoimmune diseases
gluten sensitive enteropathy (celiac disease)
thyroid disease
type 1 diabetes
Prognosis
o not contagious
o varies in severity and can persist for many years
o little effect on general health
Presentation
Symptoms
o pruritis, bruning sensation and occasionally pain
o worsend by pressure, rubbing and friction
o may have discomfort walking
o significant psychologic effect
Physical exam
o inspection
1 to 10 mm sterile pustules on palms +/- soles of feet
surrounding erythema and fissures
usually bilateral
o motion
joint pain suggestive of SAPHO
Studies
Labs
o no serological tests are specific for disease
o laboratory tests for bacterial infection are negative
Biopsy and diagnositc injections
o skin biopsy may be helpful but is rarely necessary
Treatment
Non-operative
o general measures
smoking cessation
skin moiturization
avoidance of irritants
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o topical corticosteroids, oral retinoid, photochemotherapy
indications
first-line therapy
outcomes
low-risk for adverse effects with topical corticosteriod therapy
Presentation
Symptoms
o extremely painful joints; usually knees and ankles
Physical exam
o red and tender joints with effusions
F. Metabolic Disease
1. Hypercalcemia
Introduction
Causes of hypercalcemia include
o malignancy
o hypercalcemia in malignancy caused by parathyroid-related hormone protein (PTHrP)
o characterized by:
hypercalcemia, hypophosphatemia, low PTH
examples of malignancies:
Paget's Disease
Multiple Myeloma
Squamous cell cancer of the lung
ectopic production of PTH
Multiple endocrine neoplasia (type I and II)
Pituitary adenoma
o medical conditions
primary hyperparathyroidism
sarcoidosis
Familial hypocalciuric hypercalcemia
hyperthyroidism
Addison's disease
Zollinger-Ellison syndrome
o drugs
thiazide diuretics
o dietary
calcium ingestion (milk-alkali syndrome)
hypervitaminosis D
hypervitaminosis A
Presentation
Symptoms
o CNS
confusion
stupor
weakness
o gastrointestinal
constipation
anorexia
nausea
vomiting
o kidney
polyuria
kidney stones
polydipsia
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Treatment
Hydration
o saline diuresis
Drug therapies
o loop diuretics
o bisphosphonates
o mithramycin
o calcitonin
o galium nitrate
Dialysis (severe)
2. Hypocalcemia
Introduction
Causes of hypocalcemia include
o decreased PTH that can be caused by
hypoparathyrodism
pseudohypoparathyroidism
renal osteodystrophy
o decreased vitamin D3
Presentation
Symptom
o symptoms of hypocalcemia
paresthesia
fingertip, toes, perioral
abdominal pain, biliary colic
muscle cramps, tetany
dyspnea (laryngospasm, bronchospasm)
convulsions
mental status changes
anxiety, fatigue, mood swings
Physical exam
o findings of tetany
Trousseau's Sign
carpopedal spasm after blood pressure readings
inflate BP cuff 20mmHg above systolic BP x 3-5min
hand adopts a MCP flexed, DIP and PIP extended position
more sensitive than Chvostek's sign
Chvostek's Sign
facial muscle contractions after tapping on the facial nerve
o dermatologic
fungal nail infections
hair loss
blotchy skin
pigment loss, vitiligo
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Radiographs
Basal ganglia calcification
o comprises striatum, globus pallidus, substantia nigra, subthalamic nucleus
Evaluation
Serum calcium, phosphate, vit D, PTH
Serum albumin
o low serum albumin (low protein) leads to low total calcium
but ionized calcium levels will be normal
pH
o alkalosis increases albumin binding to ionized calcium
leads to hypocalcemia
EKG
o prolonged QT interval
Serum Serum
PTH Common Cause
Ca Phos
Hyperparathyroidism ↑ ↓ ↑ adenoma
Hypoparathyroidism ↓ ↑ ↓ parathyroidectomy
Ectopic PTH ↑ ↓ ↓ malignancy
celiac disease, other GI
Vit D malabsorption ↓ ↓ ↑
isease
Hypo vit D with no phosphate excretion renal failure, pseudo
↓ ↑ ↑
from the kidney. hypoparathyroidism
Treatment
Nonoperative
o calcium gluconate infusion
with cardiac monitoring to prevent hypercalcemia)
o activated vitamin D (calcitriol)
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3. Hypoparathyroidism
Introduction
Decreased production of parathyroid hormone (PTH) by chief cells of the parathyroid gland
resulting in
o decreased plasma calcium levels
o increased plasma phosphate levels
o decreased 1,25(OH)2 Vitamin D levels
Etiology
o Iatrogenic : thyroidectomy most common cause
Pathophysiology
o decreased PTH levels cause
decreased urinary excretion of phosphate at kidneys
serum phosphate levels increase
decreased conversion of inactive form of vitamin D to active form
1,25(OH)2-vitamin levels decrease
Prognosis
o no current hormone replacement therapy available
o treatment is aimed at supplementing vitamin D and calcium levels
Presentation
Symptoms
o hypocalcemia
more common in hypoparathyroidism
neuromuscular irritability
Chvostek's sign
seizures
tetany
cataracts
fungal infections of the nail
hair loss
skin changes
vitiligo
blotchiness of skin
Imaging
Radiographs
o skull
basal ganglia calcification
Evaluation
Labs
o decreased
PTH
calcium
1,25-Vit D
urinary calcium
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o increased
serum phosphate
o normal
alkaline phosphatase
pH
o alkalosis increases albumin binding to ionized calcium
leads to hypocalcemia
EKG
o prolonged QT interval
Serum Serum
PTH Common Cause
Ca Phos
Hyperparathyroidism ↑ ↓ ↑ adenoma
thyroidectomy (including
Hypoparathyroidism ↓ ↑ ↓
parathyroid)
Ectopic PTH ↑ ↓ ↓ malignancy
Vit D malabsorption ↓ ↓ ↑ celiac disease, other GI disease
hypo vit D with no phosphate excretion from renal failure, pseudo
↓ ↑ ↑
the kidney hypoparathyroidism
Treatment
Nonoperative
o calcium and vitamin D supplementation
indications
decreased serum calcium level
decreased levels of vitamin D
outcomes
must monitor labs on a regular basis
4. Hyperparathyroidism
Introduction
Increased parathyroid hormone (PTH) production that may be of primary, secondary or tertiary
causes
Epidemiology
o incidence
occurs in 0.1% of the population
90% result form a single adenoma
remaining 10% from parathyroid hyperplasia
o demographics
more common in women
hyperparathyroidism and maligncacy make up the majority of patients with hypercalcemia
Pathophysiology
o PTH indirectly stimulates osteoclasts by binding to its receptor on osteoblasts, inducing RANK-
L and M-CSF synthesis
o Excessive PTH leads to over-stimulation of bone resorption
cortical bone affected more than cancellous
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Associated conditions
o Brown tumor
Resembles a giant cell tumor of bone relating to focal demineralization of bone in the setting
of hyperparathyroidism.
Classification
Primary
o typically the result of hypersecretion of PTH by a parathyroid adenoma/hyperplasia
o may result in osteitis fibrosa cystica
breakdown of bone, predominently subperiosteal bone
commonly involves the jaw
Secondary
o secondary parathyroid hyperplasia as compensation from hypocalcemia or hyperphosphatemia
2+
↓ gut Ca absorption
↑ phosphorous
o associated conditions
chronic renal disease
renal disease causes hypovitaminosis D
2+
leads to ↓ Ca absorption
renal osteodystrophy
bone leisons due to secondary hyperparathyroidism
Tertiary
o parathyroid glands become dysregulated after secondary hyperparathyroidism
2+
secrete PTH regardless of Ca level
Presentation
Symptoms
o often asymptomatic
o weakness
o kidney stones ("stones")
o bone pain ("bones")
o constipations ("groans")
o uncommon cause of secondary hypertension
Evaluation
Serology
o primary
hypercalcemia
↑ PTH
o secondary
hypocalcemia/normocalcemia
↑ PTH
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o malignancy
↓ PTH
o ↑ alkaline phosphatase
o normal anion gap metabolic acidosis
↓ renal reclamation of bicarbonate
Urinalysis
o primary
hypercalciuria (renal stones)
↑ cAMP
Radiograph
o cystic bone spaces ("salt and pepper")
often in the skull
o loss of phalange bone mass
↑ concavity (see key image of this topic)
EKG
o shortened QT
Treatment
Acute hypercalcemia
o IV fluids
o Loop diuretics
Symptomatic hypercalcemia is treated surgically
o treat with parathyroidectoy
o complications include post-op hypocalcemia
o manifests as numbness, tingling, and muscle cramps
o should be treated with IV calcium gluconate
Complications
Peptic ulcer disease
2+
o ↑ gastrin production stimulated by ↑ Ca
Acute pancreatitis
2+
o ↑ lipase activity stimulated by ↑ Ca
CNS dysfunction
o anxiety, confusion, coma
o result of metastatic calcification of the brain
Osteoporsis
o Bone loss occurs as result of bone resorption due to excess PTH
5. Hypophosphatasia
Introduction
Metabolic bone disease characterized by a generalized impairment of bone mineralization
Incidence
o estimated to be 1 in 100,000
Pathophysiology
o low levels of alkaline phosphate result in decreased synthesis of inorganic phosphate necessary
for bone matrix formation
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o osteoid that forms in the hypertrophic zone of the growth plate fails to mineralize
o the zone of provisional calcification never forms and growth is inhibited
Genetics
o inheritance pattern
autosomal recessive
o caused by a mutation in the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP)
Associated conditions
o orthopaedic manifestations
similar to rickets
bow legs
short stature
o non-orthopaedic manifestations
abnormal tooth formation
loss of teeth
Presentation
Clinical findings
o presentation similar to rickets
genu varum
short stature
o abnormal dentition
Imaging
Radiographs
o recommended : AP and lateral of affected bone
o findings
abnormal bone formation
"deossification of bone" adjacent to growth plate
physeal widening
Evaluation
Labs
o serum
decreased serum alkaline phosphatase
o urine
phosphoethanolamine in the urine diagnostic for hypophosphatasia
Treatment
Nonoperative
o no approved therapies
phosphate therapy under investigation but not utilized at this time
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6. Pseudohypoparathyroidism
Introduction
Rare genetic disorder
Mechanism
o PTH resistance
decreased target cell response to PTH
Classification
Type 1a - Albright hereditary osteodystrophy
o defect in GNAS1 (Gsα protein)
defective gene from mother
upstream defect
proximal to formation of cAMP
o skeletal defects
short 4th, and 5th metacarpals and metatarsals or short 4th metacarpal only
"knuckle, knuckle, dimple, dimple" sign on closed fist
differentials
Turner syndrome
short 4th metacarpal only
"knuckle, knuckle, dimple, knuckle"
Down syndrome
short middle phalanx
brachydactyly
exostoses
o round facies
o obesity
o short stature
o diminished intelligence
Type 1b
o defect in GNAS1 (Gsα protein)
o normal appearance
Type 2
o unknown gene defect
o downstream defect
distal to formation of cAMP
o normal appearance
Presentation
Symptom
o symptoms of hypocalcemia
paresthesia : fingertip, toes, perioral
abdominal pain, biliary coli
muscle cramps, tetany
dyspnea (laryngospasm, bronchospasm)
convulsions
mental status changes : anxiety, fatigue, mood swings
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Physical exam
o findings of tetany
Trousseau's Sign
carpopedal spasm after blood pressure readings
inflate BP cuff 20mmHg above systolic BP x 3-5min
hand adopts a MCP flexed, DIP and PIP extended position
more sensitive than Chvostek's sign
Chvostek's Sign
facial muscle contractions after tapping on the facial nerve
o dermatologic
fungal nail infections
hair loss
blotchy skin : pigment loss, vitiligo
Evaluation
Laboratory
o high PTH
o low calcium
o high phosphate
o low vit D
Ellsworth-Howard test
o method to differentiate type 1 and type 2 by administering exogenous PTH
Type 1
will show no increase in urinary cAMP and phosphate
Type 2
will show increased excretion of urinary cAMP and phosphate
Differential
Causes of hypocalcemia
o renal osteodystrophy (low Ca, high PTH, high phosphate, high ALP)
o hypoparathyrodism (low Ca, low PTH, high phosphate)
o pseudopseuodohypoparathyroidism
mechanism
no PTH resistance
normal target cell response to PTH
genetics
defect in GNAS1 (Gsα protein)
defective gene from father
skeletal defects
also has short 4th metacarpal and metatarsal
metastatic calcification
laboratory
normal PTH
normal calcium
normal phosphate
normal vit D
o decreased vitamin D3
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Response to
Type Appearance PTH Calcium Phos Vit D PTH Genetics
administration
Hypoparathyroidism Normal ↓ ↓ ↑ ↓ - -
no increase in
Pseudohypoparathyroidism Type Skeletal GNAS1 (maternal
↑ ↓ ↑ ↓ urinary cAMP
1a defects defect, upstream)
or phosphate
Pseudohypoparathyroidism Type GNAS1 and
Normal ↑ ↓ ↑ ↓
1b STX16
increased
GNAS1
Pseudohypoparathyroidism Type 2 Normal ↑ ↓ ↑ ↓ urinary cAMP
(downstream)
and phosphate
Skeletal GNAS1 (paternal
Pseudopseudohypoparathyroidism N N N N
defects defect)
Treatment
Nonoperative
o oral calcium and 1alpha-hydroxylated vitamin D metabolites
indications
all patient with pseudohypoparathyroidism
o IV calcium replacement
indications : patients with severe symptoms of hypocalcemia
7. Scurvy
Introduction
Definition
o Vitamin C (ascorbic acid) deficiency
Epidemiology
o incidence
8% of men and 6% of women in the US have vitamin C deficiency
o demographics
male: female ratio is 4:3
o bimodal age bracket
infants 5-10months
uncommon in infants <7mths who are being breast fed as breast milk has vitamin C
men >60 years
o location
wrists, knees, sternal ends of ribs
areas of rapid growth in children
o risk factors
elderly, especially men who live alone
chronic malnutrition
overcooking destroys vitamin C
alcoholic
smokers
malabsorptive conditions (Whipple's disease, inflammatory bowel disease, cancer
chemotherapy)
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Pathophysiology
o humans are unable to synthesize L-ascorbic acid because the enzyme L-gluconolactone oxidase
is nonfunctional
o Vitamin C deficiency leads to decrease in chondroitin sulfate and collagen synthesis and repair
o impaired intracellular hydroxylation of collagen peptides
o net effect is altered bone formatin with the greatest effect occuring in the metaphysis
o defect in spongiosa of the metaphysis at the growth plate
o because the demand for type I collagen is greatest during new bone formation
Prognosis : excellent prognosis if treated early
Presentation
History
o infant diet consisting of evaporated or
condensed milk
o "tea and toast" diet in elderly
Symptoms
o malaise and fatigue
o pain
bone pain
myalgia, because of reduced carnitine production
o bleeding
gum bleeding and loosening of teeth
hematuria
hematemesis
hemorrhage
iron deficiency
Physical exam
o petechiae and ecchymosis
o joint effusions
o swelling over long bones because of subperiosteal hemorrhage
o scorbutic rosary (costochondral separation)
angular step-off deformity in children
differentiated from rachitic rosary, which is rounded and nodular
Imaging
Radiographs
o recommended views
wrist radiographs
knee
sternal ends of ribs
o findings
the white line of Frankel
widened zone of provisional calcification
between epiphysis and metaphysis
Trummerfeld zone
transvese radiolucent band in the metaphysis adjacent to the Frankel line
also known as the scurvy line
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Wimberger ring
ring of increased density surrounding epiphysis
Pelkin spur and fracture
metaphyseal spurs and fractures
corner sign of Park
metaphyseal clefts
thin cortices ("pencil-point" cortex)
decreased trabeculae with ground-glass osteopenia
subperiosteal elevation
epiphyseal separation
fractures and dislocations
Studies
The diagnosis is usually made based on history, clinical and radiological picture, and resolution of
symptoms following vitamin C administration. Lab tests are usually not helpful.
Labs
o fasting serum ascorbic acid level is low
Histology
o replacement of primary trabeculae with granulation tissue
o areas of hemorhage
o widening zone of provisional calcification of the physis
Treatment
Nonoperative
o vitamin C replacement
o indications
signs and symptoms of scurvy
chronic malnutrition
o techniques II:17 Pencil-point cortices characteristic of
oral vitamin C at 250mg qid x 1 week in adults scurvy, Ground glass osteopenia
characteristic of scurvy.
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ORTHO BULLETS
III.Medications &
Toxicity
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By Dr, AbdulRahman AbdulNasser Medications & Toxicity | Medications
A. Medications
1. Bisphosphonates
Introduction
Overview
o class of drugs that prevent bone mass loss by inhibiting osteoclast resorption
prevent formation of osteoclast ruffled borders microtubules, causing apoptosis
inhibition of osteoclasts also infereres with normal bone healing and remodeling
o there are two types of bisphosphonates
non-nitrogen containing
tiludronate
clodronate
etidronate
nitrogen containing
alendronate
risedronate
pamidronate
zolendronate
zoledronic acid - relatively new and appealing to patients, due to IV adminstration
every 12 months
Indications
o osteoporosis
o metastatic bone disease
o multiple myeloma
o paget's disease
o polyostotic fibrous dysplasia
o total joint arthroplasty to prevent osteolysis
o early stage avascular necrosis
o osteogenesis imperfecta
o metastatic hypercalcemia
Contraindications
o severe renal disease
primary mode of excretion is renal
o following lumbar fusion
decreased spinal fusion rates in lab animal models (increased fusion mass size, but decreases
the actual fusion rate)
Mechanism
Delivery
o bisphophonates accumulate in high concentration in bone due to binding affinity to calcium
o bisphosphonates are ingested by osteoclasts and work by two different methods depending on
presence of nitrogen atom on the alkyl chain
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Nitrogen containing bisphosphonates mechanism
o inhibits osteoclast farnesyl pyrophosphate synthase enzyme, required in mevalonate (cholesterol
pathway)
inhibits GTPase formation
Non-nitrogen containing bisphosphonates (simple) mechanism
o induce osteoclasts to undergo premature death and apoptosis
does so by forming a toxic adenosine triphosphate (ATP) analogue
Treatment
Vertebral Compression Fractures
o indications
vertebral compression fracture in osteoporotic patient
bone mineral density 2.5 or more standard deviations below that of young healthy adults
(T score < 2.5 SD)
o outcomes
1 year of treatment with a pharmacologic antiosteoporotic medication, the risk of vertebral
fracture decreases by 50-60%
Non-vertebral Fragility fractures
o indications
fragility fracture in osteoporotic patient
o outcomes
effective in reducing the risk of multiple fractures
Osteogenesis imperfecta
o cyclical IV pamidronate administration
reduces bone pain and fracture incidence III:1 Complications: Jaw osteonecrosis
increases level of ambulation and bone density
Multiple myeloma
o indications
diagnosis of multiple myeloma
o outcomes
reduced incidence of skeletal events in multiple myeloma
Avascular necrosis
o indications
early, precollapse AVN
o outcomes III:2 Complicatios : Atypical
still considered investigational subtrochanteric and femoral stress
fractures
randomized clinical trial showed that bisphosphonate
treatment was more effective at preventing head collapse than placebo at 2 years
(bisphosphonate collapse 6.9% vs placebo collapse 76%)
Side Effects & Complications
Jaw osteonecrosis
Atypical subtrochanteric and femoral stress fractures
Radiographic changes consistent with osteopetrosis
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2. Prophylaxis Antibiotics
Perioperative Abx Overview
Includes preoperative and postoperative antibiotics
o 25-50% of all antibiotics used are for prophylaxis
Indications
o routine adminstration of prophylactic antibiotics is accepted in
patients who will have a foreign body implanted
bone grafting procedures
large dissection resulting in significant dead space or hematoma
expecting significant blood loss
o orthopaedics procedures that do not require prophylactic antibiotics
carpal tunnel surgery
diagnostic arthroscopy is more controversial
Most likely pathogens to cause infection in orthopaedic procedures includes
o S aureus
o S epidermidis
o aerobic streptococci
o anaerobic cocci
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Dental Procedure Abx Prophylaxis in TJR Patients (AAOS & ADA)
Indications
o TJA patients at increased risk of hematogenous seeding should be given prophylactic antibiotics
prior to dental procedures. This includes
all patients for the first two years after TJA
immunocompromised patients
drug induced immunosuppression
radiation induced immunosuppression
inflammatory arthropathies including SLE and RA
comorbidities including
previous prosthetic joint infection
Type I (insulin-dependent) diabetes
malnourishment
hemophilia
HIV
malignancy
o evidence to support recommendations
AAOS and ADA recognizes there is limited or inconclusive evidence to support the
recommendations above and practitioners should use clinical judgment
Administration
o antibiotics is given 1 hour before dental procedure
o patients NOT allergic to penicillin should be given
amoxicillin or cephalexin 2 grams orally
if unable to take oral medications than 1 gram cefazolin or 2 gram ampicillin IV or IM
o if allergic to penicillin
clindamycin 600 mg orally
if unable to take oral medications than clindamycin 600 mg IV
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Penicillinase Second
Resistant Generation
Methicillin Cefacor
Nafcillin Cefotetan (Cefotan)
Oxacillin other
other
Aminopenicillins Third Generation
Ampicillin Ceftriaxone
(Rocephin)
other
Fourth Generation
Cefpirome
Cefepime
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Antibiotic Classification & Indications
Inhibits Cell Wall Synthesis
Penicillins
(bactericidal: blocks cross linking via competitive inhibition of the transpeptidase enzyme)
Class/Mechanism Drugs Indications (**Drug of Toxicity
Choice)
Penicillin Penicillin G Strep. pyogenes (Grp.A)** Hypersensitivity reaction
Aqueous penicillin G Step. agalactiae (Grp.B)** Hemolytic anemia
Procaine penicillin G C. perfringens(Bacilli)**
Benzathine penicillin G
Penicillin V
Aminopenicillins Ampicillin Above + Above
Amoxicillin ↑ Gram-negative:
E. faecalis**
E. Coli**
Penicillinase-resistant- Methicillin Above + Above +
penicillins Nafcillin PCNase-producingStaph. Interstitial nephritis
Oxacillin aureus
Cloxacillin
Dicloxacillin
Antipseudomonal Carbenicillin Above + Above
penicillins Ticarcillin Pseudomonas
Piperacillin aeruginosa**
Cephalosporins
(bactericidal: inhibits bacterial cell wall synthesis via competitive inhibition of the transpeptidase enzyme)
1st generation Cefazolin Staph. aureus** Allergic reaction
Cephalexin Staph. epidermidis** Coombs-positive
Some Gram-negatives: anemia (3%)
E. Coli
Klebsiella
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Aztreonam Aztreonam Gram-negative rods
Aerobes
Hospital-acquired infections
Polymyxins Polymyxin B Topical Gram-negative
Polymyxin E infections
Bacitracin Bacitracin Topical Gram-positive
infections
Protein Synthesis Inhibition
Anti-30S ribosomal subunit
Aminoglycosides Gentamicin Aerobic Gram-negatives Nephrotoxicity
(bactericidal: irreversible Neomycin Enterobacteriaceae Ototoxicity
binding to 30S) Amikacin Pseudomonas
Tobramycin
Streptomycin
Tetracyclines Tetracycline Rickettsia Hepatotoxicity
(bacteriostatic: blocks tRNA) Doxycycline Mycoplasma Tooth discoloration
Minocycline Spirochetes (Lyme's Impaired growth
disease)
Demeclocycline Avoid in children < 12
years of age
Anti-50S ribosomal subunit
Macrolides Erythromycin Streptococcus Coumadin Interaction
(bacteriostatic: reversibly Azithromycin H. influenzae (cytochrome P450)
binds 50S) Clarithromycin Mycoplamsa pneumonia
Chloramphenicol Chloramphenicol H influenzae Aplastic Anemia
(bacteriostatic) Bacterial Meningitis Gray Baby Syndrome
Brain absces
Lincosamide Clindamycin Bacteroides fragilis Pseudomembranous
(bacteriostatic: inhibits S aureus colitis
peptidyl transferase by Coagulase-negative Hypersensitivity
Staph & Strep Reaction
interfering with amino acyl-
Excellent Bone Penetration
tRNA complex)
Linezolid Linezolid Resistant Gram-positives
(variable)
Streptogramins Quinupristin VRE
Dalfopristin GAS and S. aureus skin
infections
DNA Synthesis Inhibitors
Fluoroquinolones
(bactericidal: inhibit DNA gyrase enzyme, inhibiting DNA synthesis)
1st generation Nalidixic acid Steptococcus Phototoxicity
Mycoplasma Achilles tendon rupture
Aerobic Gram + Impaired fracture
healing
2nd generation Ciprofloxacin As Above +Pseudomonas as above
Norfloxacin
Enoxacin
Ofloxacin
Levofloxacin
3rd generation Gatifloxacin As above + Gram-positives as above
4th generation Moxifloxacin As above + Gram-positives + as above
Gemifloxacin anaerobes
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Other DNA Inhibitors
Metronidazole Metronidazole (Flagyl) Anaerobics Seizures
(bacteridical: metabolic Crebelar dysfunction
biproducts disrupt DNA) ETOH disulfram
reaction
RNA Synthesis Inhibitors
Rifampin Rifampin Staphylococcus Body fluid discoloration
(bactericidal: inhibits RNA Mycobacterium (TB) Hepatoxicity (with INH)
transcription by inhibiting
RNA polymerase)
Mycolic Acids Synthesis Inhibitors
Isoniazid Isoniazidz TB
Latent TB
Folic acid Synthesis Inhibitors
Trimethoprim/Sulfonamides Trimethoprim/Sulfamethoxazole UTI organisms Thrombocytopenia
(bacteriostatic: inhibition with (SMX) Proteus Avoid in third trimester
PABA) Sulfisoxazole Enterobacter of pregnancy
Sulfadiazine
Pyrimethamine Pyrimethamine Malaria
T. gondii
Bacteria Overview
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Antibiotic Resistance Mechanisms
Bacteria develop ability to hydrolyze these drugs using β lactamase
o confers resistance to penicillin
o e.g. E. coli, Staph epidermidis, Pseudomonas aeruginosa, Klebsiella pneumoniae
o add β lactamase inhibitor e.g. clavulanic acid in amoxicillin-clavulanate (Augmentin)
Genetic mutation of mecA
o carried by Staphylococcal cassette chromosome (SCCmec) mobile genetic unit
o a bacterial gene encoding a penicillin-binding protein (PBP2a).
PBP2a has reduced affinity for antibiotics
confers resistance to methicillin, oxacillin, nafcillin
e.g. MRSA
SCCmec type IV has less genetic elements and is specific to CA-MRSA, making CA-
MRSA less multi-drug resistant
Altered cell wall permeability
o confers resistance to tetracyclines, quinolones, trimethoprim and β lactam antibiotics
Creation of biofilm barrier
o provides an environment where offending bacteria can multiply safe from the hoste immune
system
Salmonella
Staph epidermidis
Active efflux pumps
o confers resistance to erythromycin and tetracycline
o e.g. msrA gene in Staph
Altered peptidoglycan subunit (altered D-alanyl-D-alanine
of NAM/NAG-peptide)
o confers resistance to vancomycin
o e.g. vancomycin resistant enterococcus (VRE) III:3 D zone test
Ribosome alteration
o erm gene confer inducible resistance to MLS (macrolide lincosamide streptogranin) agents via
methylation of 23s rRNA
o demonstrate using D zone test
for inducible clindamycin resistance in Staph and beta hemolytic Strep
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By Dr, AbdulRahman AbdulNasser Medications & Toxicity | Medications
Penicillins
Mechanism
o interfer with bacterial cell wall synthesis
Subclassification and tested examples
o natural
penicillin G
o penicillinase-resistant
methicillin (Staphcillin)
o aminopenicillins
ampicillin (Omnipen, Polycillin)
Cephalosporins
Overview
o bactericidal
Mechanism
o disrupts the synthesis of the peptidoglycan layer of bacterial cell walls
does so through competitive inhibition on PCB (penicllin binding proteins)
peptidoglycan layer is important for cell wall structural integrity.
o same mechanicsm of action as beta-lactam antibiotics (such as penicillins)
Subclassification and tested examples
o first generation
cefazolin (Ancef, Kefzol)
o second generation
cefaclor (Ceclor)
o third generation
cefriazone (Rocephin)
o fourth generation
cefepime (Maxipime)
Fluoroquinolones
Mechanism
o blocks DNA replication via inhibition of DNA gyrase
Side effects
o inhibit early fracture healing through toxic effects on chondrocytes
o Increased rates of tendinitis, with special predilection for the Achilles tendon.
Tenocytes in the Achilles tendon have exhibited degenerative changes when viewed
microscopically after fluoroquinolone administration.
Recent clinical studies have shown an increased relative risk of Achilles tendon rupture of
3.7.
Subclassification and tested examples
o ciprofloxacin (Cipro)
o levofloxacin (Levaquin)
Aminoglycosides
Mechanism
o bactericidal
o inhibition of bacterial protein synthesis
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work by binding to the 30s ribosome subunit, leading to the misreading of mRNA. This
misreading results in the synthesis of abnormal peptides that accumulate intracellularly and
eventually lead to cell death. These antibiotics arebactericidal.
Subclassification and tested examples : gentamicin (Garamycin)
Vancomycin
Coverage : gram-positive bacteria
Mechanism
o bactericidal
o an inhibitor of cell wall synthesis
Resistance
o increasing emergence of vancomycin-resistant enterococci has resulted in the development of
guidelines for use by the (CDC)
o indications for vancomycin
serious allergies to penicillins or beta-lactam antimicrobials
serious infections caused by susceptible organisms resistant to penicillins (MRSA, MRSE)
surgical prophylaxis for major procedures involving implantation of prostheses in institutions
with a high rate of MRSA or MRSE
Rifampin
Most effective against intracellular phagocytized Staphylococcus aureus in macrophages
Linezolid
Linezolid binds to the 23S portion of the 50S subunit and acts by preventing the formation of
the initiation complex between the the 30S and 50S subunits of the ribosome.
Splenectomy
Splenectomy patients or patients with functional hyposplenism require the following vaccines and/or
antibiotics
o Pneumococcal immunization
o Haemophilus influenza type B vaccine
o Meningococcal group C conjugate vaccine
o Influenza immunization
o Lifelong prophylactic antibiotics (oral phenoxymethylpenicillin or erythromycin)
4. Anti-inflammatory Medications
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDS) have the following effects
o anti-inflammatory
o antipyretic
o analgesic
o antiplatelet
Mechanism
o inhibit the COX (cyclooxygenase) enzymes ultimately inhibiting the synthesis and release of
prostaglandins
COX enzymes catalyze the formation of prostaglandins and thromboxane from arachidonic
acid
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COX Inhibitors
NSAIDS inhibit both COX-1 and COX-2
o Aspirin (ASA)
salicylate that irreversibly binds a serine COX enzyme residue
half life >1 week
binds to COX and blocks active site
inhibits thromboxane A2 blocking platelet aggregation
o ibuprofen
reversible competitive COX inhibitor
o indomethacin
acts on the lipoxygenase side of the arachidonic metabolic pathway
inhibibits leukotriene inflammatory mediators
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Benefits
o selective inhibition of COX-2 results in anti-inflammatory action without disrupting the
beneficial effects of COX-1 (maintaining gastric mucosa, regulating renal blood flow,
influencing platelet aggregation)
o can be used in the perioperative period because they do not affect platelet function
o no more efficacious in treating osteoarthritis than non-specific COX inhibitors
Side effects : cardiac toxicity
Side Effects
Renal dysfunction
Gastrointestinal side effects
o pain and dyspepsia
o peptic ulcer perforation, bleeding, or obstruction
2% to 4% occurence in chronic users
o risk factors
concurrent anticoagulant use (most important)
age >60 years
history of previous gastrointestinal disorder
Delayed fracture healing
o animal fracture models have shown decreased endochondral ossification in the absence of a
COX-2 enzyme
Platelet dysfunction
Cardiac Toxicity
Corticosteroids (Systemic)
Steroid Dose Pack
o efficacy
o side effects
Corticosteroid Intra-articular-Injections
Efficacy
Side Effects
o Local flare
o Fat atrophy
o Skin pigmentation changes
o Facial flushing
5. Analgesic Medications
Introduction
Definitions
o acute pain
implies presence of tissue damage
o chronic pain (3-6 months)
no implication of tissue damage necessary
o pathologic pain
pain from abnormal nervous system functioning (neuropathic)
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Pathophysiology
o afferent pain pathways
nociceptors
transduce signal through various substances
Substance P
a sensory neurotransmitter that plays an important role in pain
depletion of substance P increases the threshold to painful stimuli
Capsaicin is thought to function by decreasing Substance P
peripheral nerves
nociceptors transmit pain to type A and C peripheral nerve fibers
spinal cord
peripheral nerves transmit the pain signal via the dorsal column and spinothalamic tract
brainstem
spinal cord transmits the pain signal to the thalamus
site of pain modulation with endogenous opiates
Agents (details below)
o Acetaminophen
o NSAIDS
o Opiates
o Gaba synthesis agents
o Adjunctive agents
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Acetaminophen
Mechanism
o not fully understood
o inhibits prostaglandin synthesis
o minimal antinflammatory effects
As effective for pain control as aspirin
Toxicity
o overdose leads to hepatic disfunction
o contraindicated in the setting of pre-existing hepatic dysfunction
NSAIDs
Mechanism : decrease transduction of pain
See anti-inflammatory medications
Local anesthetics
Mechanism
o decrease transduction of pain
o interfere with nerve conduction to provide a reversible loss of sensation in a specific location
affects the depolarization phase of action potentials (cells fail to depolarize enough to fire
after excitation leading to a blocked action potential)
Examples
o amide family
lidocaine (Xylocaine)
bupivacaine (Marcaine)
o esters of p-aminobenzoic acid
procaine (Novocain)
butethamine (Monocaine)
o esters of meta-aminobenzoic acid
cyclomethycaine (Surfacaine)
metabutoxycaine (Primacaine)
o esters of benzoic acid
cocaine
ethyl aminobenzoate (Benzocaine)
Adverse effects
o FDA warning on the administration of continuous intra-articular infusion of local anesthetics for
pain control
Some patients have been noted to have chondrolysis following infusion
Opiates
Overview
o useful in chronic nociceptive pain
Mechanism
o perispinal method affects modulation of pain
o systemic opiates change the perception and modulation of pain
Administration
o oral, IV, intraspinal
o oral administration preferred (more convenient and less costly)
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bony procedures require more analgesia than soft tissue procedures
o patient compliance can improve with long-acting preparations that providue more uniform serum
drug levels
o implantable systems are available for intrathecal administration
Prescription dosing guide for upper extremity surgery
o no narcotics
trigger finger release, nonop Dupuytren's release, small lumps/bumps
o 10 narcotic tablets
mucous cyst, carpal tunnel, deQuervain‟s, Dupuytren‟s releases and small joint fusion
o 20 narcotic tablets
wrist ganglion cysts, hand fracture ORIF, LRTI and tendon transfers
o 40 narcotic tablets
large trauma, wrist fusion, open carpal surgery and DRUJ reconstruction
Chronic use
o addiction occurs in a minority of patients
o chronic opiates should be prescribed by pain management specialists
o written contracts should be obtained
o prescriptions should always be refilled in person
Methadone
Synthetic diphenylheptaine-derivative opioid receptor agonist
High bioavailability (three times as much as morphine), effective, and inexpensive
Metabolism
o cytochrome P450 system
Rapid distribution phase (2-3 hours) and prolonged elimination phase (15-60 hours)
Caution
o can accumulate to high levels with repeated dosing
o rates of elimination vary considerably
o risk of respiratory depression, cardiac toxicity (torsades de pointes)
o consult with a qualified pain specialist when prescribing for the first-time
GABA agents
Agents
o Pregabalin (Lyrica)
o Gabapentin (Neurontin)
Mechanism
o decrease transduction of pain
Reduce hyper-excitability of voltage dependent Ca2+ channels in activated neurons.
Gabapentin is an anticonvulsant also used to treat neuropathic pain
o binds presynaptic calcium channels to inhibit release of neurotransmitters
Efficacy
o evidence of effectiveness primarily for postherpetic neuralgia, diabetic nueropathy, and
fibromyalgia
o little evidence for other uses, though often prescribed for other forms of chronic neuropathic pain
(such as complex regional pain syndrome, CRPS)
o gabapentin has been shown to be as effective and less expensive than pregabalin
Discontinuation requires a tapering dose
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Muscle relaxants
Overview : Useful to treat pain secondary to muscle spasms
Agents
o Cyclobenzaprine (Flexeril)
mechnism of action not fully understood
centrally acting
potentiates norepinephrine and binds serotonin receptors
Use
o may decrease pain during first two weeks after an injury
o no proven benefit after first two weeks
o may be effective for fibromyalgia
o not effective to reduce spasticity secondary to neuromuscular disorders
Toxicity
o overdose rare
o may interact with other substances
MAOIs
alcohol
Adjuvant agents
Heterogeneous class of medications the provide additive analgesic effect to traditional NSAIDs and
opioids
o anticonvulsants
o antidepressants
o antihistamines
o psychostimulants
o anti-spasmodics
6. Anesthesia
Anesthesia
Components of anesthesia
o amnesia
o anxiolysis
o analgesia
o akinesia
o attenuation of autonomic repsonses to noxious stimuli
General Anesthesia
Pharmacologically induced, reversible loss of conciousness, irrespective of airway management
o inhalational anesthesia
by volatile liquids vaporized in a carrier gas including
isoflurane
sevoflurane
desflurane
nitrous oxide
associated with increased gaseous abdominal distension
leads to increased difficulty with fluoroscopic identification during pelvic and spinal
procedures
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o intravenous anesthesia
non-opioids
propofol
etomidate
benzodiazepines
dexmedetomidine
ketamine
opioids
fentanyl, alfentanil, sufentanil, remifentanil
morphine
hydromorphone
neuromuscular blocking agents
depolarizing agents
bind to, depolarize, and transiently block ACh receptor
short-acting: succinylcholine
no intermediate or long-acting agents
non-depolarizing agetns
bind to and transiently block ACh receptor, but do not depolarize
no short-acting agents
intermediate-acting: rocuronium, vecuronium, atracurium, cisatracurium
long-acting: pancuronium
III:5 Location of an infraclavicular block, which is used for operations involving the arm and forearm,
from the lower humerus down to the hand
Axillary block
o indications
postoperative analgesia for surgery to the elbow, forearm, wrist and hand
Bier block
o indications
short (< 60 mins) operative procedures (i.e., carpal tunnel release) in the hand and forearm
o technique
Esmarch exsanguination and tourniquet inflation
inject lidocaine through a small, distal (hand) intravenous catheter on the surgical side
deflate tourniquet after a minimum of 30 minutes to avoid venous release of local anesthetic
and potential local anesthetic systemtic toxicity (LAST)
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Local Anesthesia - Spinal
Spinal
o indications
often used for knee and hip arthroplasty
o technique
a single injection with a small 24 or 27-gauge needle
combination of morphine and bupivacain is often used
o complications
spinal headache (decreased with small gauge needle), hematoma and opioid side effects
(nausea, vomiting, purities, respiratory depression)
Epidural
o indication
often used for knee and hip arthroplasty
o technique
similar to spinal anesthesia, except an indwelling catheter is placed
combination of opioid and local anesthetic
o complications
postoperative hypotension and motor impairment
spinal headache, hematoma and opioid side effects (nausea, vomiting, pruritus, respiratory
depression)
Combined spinal epidural
o indications
often used for knee and hip arthroplasty
o technique
an epidural needle is placed into the epidural space and spinal anesthesia is administered
through a spinal needle followed by placing an epidural catheter
o complications
postoperative hypotension and motor impairment
spinal headache, hematoma and opioid side effects (nausea, vomiting, purities, respiratory
depression)
Local Anesthesia - Lower Extremity
Lumbar plexus/ psoas compartment nerve block
o indications
surgeries involving the hip, anterior thigh and knee
a sciatic block can be given concomitantly to provide pain relief to the entire lower extremity
o technique
targets the lumbar plexus (L1 to L4 spinal nerves) which form the obturator nerve, lateral
femoral cutaneous nerve, and femoral nerve
the injection is usually placed 3-5 cm lateral to the spinous process of L4 and is often guided
by ultrasound and nerve stimulators
o complications
nerve damage and intravascular injection
epidural diffusion, retroperitoneal hematomas, intrathecal injections and an increased risk of
falls
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Femoral nerve block
o indications
surgeries around the knee
concomitant sciatic nerve block can be done to increase analgesia around the knee
o technique
targets the femoral nerve (L2-L4)
the injection occurs just lateral to the femoral artery and on a line connecting the anterior
superior iliac spine to the pubic symphysis
o complications
nerve damage and intravascular injection
increased risk of falls, prolonged quadriceps weakness and infections
Sciatic nerve block
o indications
surgeries involving the leg, ankle and foot
can be combined with the femoral or lumbar plexus block to provide analgesia to the entire
lower extremity
o technique
targets the sciatic nerve providing analgesia to the common peroneal and tibial nerves
multiple techniques have been described
lines are drawn between the greater trochanter and the posterior superior iliac spine
(PSIS), and the greater trochanter and the sacral hiatus
halfway between the greater trochanter and the PSIS a perpendicular line is drawn, and
the injection is placed where the perpendicular line crosses the line between the greater
trochanter and the sacral hiatus
complications
nerve damage and intravascular injection
vascular injury, heel ulcers and a delay in diagnosis of nerve injuries after surgery
Obturator nerve block
o indications
adductor muscle spasm, severe hip pain from osteoarthritis
adjuvant pain management for knee surgeries
o technique
targets the anterior and posterior branch of the obturator nerve
blocking the anterior branch leads to decreased sensation at the hip joint and inner thigh,
where blocking the posterior branch decreases sensation around the knee
injection site is usually 2 cm inferior
and 2 cm lateral to the pubic tubercle
o complications
nerve injury and intravascular
injection
damage to structures in the pelvic
cavity
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Popliteal nerve block
o indications
used for surgery around the foot and ankle
often used in conjunction with the saphenous nerve block
o technique
targets the sciatic nerve prior to its bifurcation
injection site is often 10 cm proximal to the popliteal crease
o complications
nerve injury and intravascular injection
hematoma, persistent foot drop and pressure sores
Saphenous nerve block
o indications
procedures around the medial aspect of the knee, leg and ankle
o technique
targets the saphenous nerve
multiple different techniques, but it is often blocked behind the sartorius muscle
o complications
nerve injury and intravascular injection
hematoma and infection
Blood Management
Risks of transfusion
o transfusion errors
o allergic reaction
o infection
o down-modulation of immune system
Ways to reduce postop anemia and need for allogeneic transfusion
o surgical
hemostasis
meticulous dissection
o transfusion triggers
example of strict transfusion triggers based on hemoglobin levels
average patient, 8.1g/dl
young (<60yr) patients without co-morbidity, 6.5g/dl
compromised patients, 9.7g/dl
o subcutaneous epoetin injections
used preop for patients with low Hb (10-13g/dl)
able to bring up Hb by 1.9d/dl
administer with supplementary PO iron
dosing
long interval to surgery
600IU/kg once weekly x 3wk before surgery
short interval to surgery
300IU/KG daily x 2wk
o autologous blood donation (ABD) and acute normovolemic hemodilution (ANH)
ABD
donate 1-2 units preoperatively
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ANH
collect 2-3 units at 1 hour preoperatively
receive crystalloid/colloid intraoperatively
re-infuse ABD blood postoperatively
o COX2 inhibitors analgesia (instead of COX1 NSAIDS)
Avoids antiplatelet effects of
o anti-coagulation management
stop anticoagulation a few days preoperatively
restart just before surgery
o platelet rich plasma (PRP), fibrin sealants, anti-fibrinolytics
PRP
apply PRP to wounds might reduce capsule/subcutaneous bleeding
fibrin sealants
very low risk of infection from microbial/viral contamination during processing
antifibrinolytics
aprotinin
tranexamic acid (TXA)
topical
IV
o hypotensive epidural anesthesia (HEA)
epidural dermatomal block from T2 distal
blocks cardio-accelerator fibers of sympathetic chain
causes bradycardia which is treated with low-dose epinephrine
lowers MAP to 50mmHg
keeps normal heart rate, CVP, stroke volume, cardiac output
can be used in high risk patients with
hypertension
poor cardiac function
chronic kidney disease
o cell saver
expensive
intraoperative
washed vs unwashed (filtered)
indications
revision surgery
high EBL
contraindications
infection
malignancy
EBL <500ml
postoperative
filtering of shed blood (trap clots and debris)
within 6h of end of surgery to avoid bacterial contamination, febrile reaction
after 6h, converted to vacuum drain (not retransfused)
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Complications
Malignant hyperthemia
o rare (1:15,000 to 1:50,000) life-threatening condition
o autosomal dominant transmission
abnormalities in the ryanodine receptor (RYR1) gene
o triggers
volatile inhalational anesthetic agents
succinylcholine
o symptoms
hypermetabolic state
increased skeletal muscle contraction and metabolism
rigidity
masseter spasm
rapid oxygen depletion
increased carbon dioxide concentration (EtCO2) and body temperature
o outcome
if untreated, leads to circulatory collapse and death
o treatment
provide antidote
active cooling
o antidote
dantrolene (calcium blocker)
Local anesthetic systemic toxicity (LAST)
o intravascular bupivicaine
effect
CNS
seizures, coma, respiratory arrest
CVS
asystole, ventricular fibrillation, cardiac arrest
antidote
intravenous 20% lipid emulsion
Bone cement implanation syndrome
o associated with use of bone cement during joint arthroplasty procedures
o symptoms
hypotension
hypoxemia
o treatment
intravenous fluids
vasopressors
100% inspired oxygen
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7. Platelet-Rich Plasma
Introduction
Platelet rich plasma (PRP) consists of plasma sample from one's own blood enriched with
autologous platelets
o indications
controversially used in orthopaedics for possible stimulation of bone and soft tissue healing
o preparation technique
PRP is created by centrifugation of blood to separate platelet rich plasma layer from a sample
of whole blood
calcium chloride used to initiate platelet activation in the prepared sample of PRP
o optimal concentration
3-5x that of whole blood
>5x inhibits healing
Platelet function
o plays an important role in the inflammatory cascade response after injury
o growth factors released from platelets include
PDGF
TGF-B
VEGF
IGF-1
EGF (epidermal growth factor)
CTGF (connective tissue growth factor)
FGF-2
Proposed function of PRP
o increase ECM deposition
o reduce pro-apoptotic signals
o minimize joint inflammation
Clinical Application
PRP efficacy is controversial due to small amount of high level studies in literature
o soft tissue injury healing
no consensus for acute ligamentous, tendon and muscle injuries or chronic tendonopathies
o osteoarthritis
no consensus in evidence, lack of studies with long term followup
o fracture healing / fusion
limited evidence for bone formation (some studies show detrimental effects)
o ACL reconstruction
literature does NOT support PRP for ligamentization/graft maturation, patient reported
outcomes
direct application to patellar and tibial plug donor sites (BPTB) linked to improved patient-
reported outcomes of knee function and decreased patellar tendon gap
o meniscal repair
no clear evidence to support use in meniscal repair
o rotator cuff repair
no benefit in augmenting RC repair (possible detrimental effects)
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By Dr, AbdulRahman AbdulNasser Medications & Toxicity | Toxicology
o tendon healing
lateral epicondylar tendinosis (tennis elbow)
potential benefit (improved patient reported outcomes and pain scores)
midsubstance/insertional Achilles tendinopathy
current literature does NOT support
Summary
Potential benefits for BPTB donor sites and tennis elbow
B. Toxicology
1. Lead Toxicity
Lead Toxicity
Lead toxicity inhibits parathyroid hormone-related peptide (PTHrP) and may affect bone mineral
density
Imaging
o radiographs can reveal radiodense metaphyseal bands
Collected By : Dr AbdulRahman
AbdulNasser
drxabdulrahman@gmail.com
In June 2017
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ORTHO BULLETS
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By Dr, AbdulRahman AbdulNasser Clinical Science | Clinical Studies
A. Clinical Studies
1. Statistic Definitions
Introduction
This topic covers the following statistical principles
o Measures of Central Tendency
o Sensitivity
o Specificity
o False Positive Rate
o False Negative Rate
o Positive Predictive Value
o Negative Predictive Value
o Likelihood Ratio
o Incidence
o Prevalence
o Relative Risk
o Odds Ratio
o Number Needed to Treat
o Post-test Odds of Disease
o Power
o Effect Size
o Variance
o Type II (beta) Error
o Type I (alpha) Error
o Confidence Interval
o Statistical Inference
o Funnel plot
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Mean
o defined as arithmetic average
o the most frequently used measure of central tendency
o uses all values of data
o highly sensitive to extreme values (especially skewed distributions)
Sensitivity
Definition
o probability that test results will be positive in patients with disease
Equation
o sensitivity = a / (a + c) or
o sensitivity = TP / (TP + FN)
Relevance
o sensitive tests are useful for screening since they are unlikely to miss a patient with disease
Example
o a new test is developed to quickly diagnose HIV. There are 10 patients in the study group with
the disease. Upon testing of all 10 patients, only 6 results return positive. What is the sensitivity
of the new test?
o solution
sensitivity = a / (a + c)
sensitivity = 6 / 10
sensitivity = 60%
disease pos disease neg
true positive false positive
test pos
a (6) b
false negative true negative
test neg
c (4) d
TOTAL 10 b+d
Specificity
Definition
o probability test result will be negative in patients without disease
Equation
o specificity= d / (b + d) or
o specificity = TN / (FP + TN)
Relevance
o specific tests are useful for confirmation as they don't result in treatment of an unaffected
individual
Example
o in a population of 90 patients who are disease free, a test incorrectly diagnoses 5 patients with
disease. What is the specificity of this test?
o solution
specificity = d / (b + d)
specificity = 85 / 90
specificity = 94.4%
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disease pos disease neg
true positive false positive
test pos
a b (5)
false negative true negative
test neg
c d (85)
TOTAL a+c b + d (90)
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disease pos disease neg
true positive false positive
test pos
a (9) b (4.5)
false negative true negative
test neg
c (1) d (85.5)
TOTAL a+c (10) b+d (90)
PPV = a / (a + b)
PPV = 9 / (9 + 4.5)
PPV = 67%
Likelihood Ratio
Definition
o likelihood that a given test result would be expected in a patient with the target disorder
compared to the likelihood that that same result would be expected in a patient without the target
disorder
Classification
o positive likelihood ratio
definition
describe how the likelihood of a disease is changed by a positive test result
equation : positive likelihood ratio = sensitivity / (1 - specificity)
o negative likelihood ratio
definition
describe how the likelihood of a disease is changed by a negative test result
equation : negative likelihood ratio = (1 - sensitivity) / specificity
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By Dr, AbdulRahman AbdulNasser Clinical Science | Clinical Studies
Incidence
Number of newly reported cases of a disease in specific time period per unit measurement of
population
Prevalence
The total number of cases of a disease present in a location at any time point
Relative Risk
Definition
o risk of developing disease for people with known exposure compared to risk of developing
disease without exposure
obtained from cohort studies
when RR > 1, the incidence of the outcome is greater in the exposed/treated group
Equation
o incidence risk of YES = a / (a + b)
o incidence risk of NO =c / (c + d)
o relative risk = [(a / a + b)] / [(c / c + d)]
Disease Status
Risk Present Absent
Yes a b
No c d
Example
o a study is performed concerning the relationship between blood transfusions and the risk of
developing hepatitis C. A group of patients is studied for three years.
Disease Status
Transfused Hepatitis C Healthy
Yes 75 595
No 16 712
solution
o disease incidence in transfused
"YES" = 75 / (75 + 595) = .112
o disease incidence in patients not transfued
"NO" = 16 / (16 + 712) = .022
o relative risk (RR) = 0.112 / 0.022 = 5.09
Odds Ratio
Definition
o probability of having a risk factor if one has a disease
obtained from case control studies (retrospective)
Equation
o OR = (odds of developing disease in exposed patients) / (odds of developing disease in
unexposed patients)
Number Needed to Treat
Definition
o number of patients that must be treated in order to achieve one additional favorable outcome
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Equation
o number needed to treat = (1 / absolute risk reduction)
Example
o you learn the number-needed-to-screen with FOBT is nearly 1000 to prevent colon cancer. What
is the absolute risk reduction associated with FOBT?
o solution
absolute risk reduction (ARR) = 1 / number needed to treat
ARR = 1 / 1000
ARR = .1%
Power
Definition
o an estimate of the probability a study will be able to detect a true effect of the intervention
Equation
o power = 1 - (probability of a type-II, or beta error)
Effect size
Definition
o magnitude of the difference in the means of the control and experimental groups in a study with
respect to the pooled standard deviation
Variance
Definition
o an estimate of the variability of each individual data point from the mean
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By Dr, AbdulRahman AbdulNasser Clinical Science | Clinical Studies
o bydefinition, alpha-error rate is set to .05, meaning there is a 1/20 chance a type-I error has
occurred
Related principle
o Bonferroni correction
post-hoc statistical correction made to P values when several dependent or independent
statistical tests are being performed simultaneously on a single data set
Confidence Interval
Definition
o the interval that will include a specific parameter of interest, if the experiment is repeated
Statistical Inference
Definition
o used to test specific hypotheses about associations or differences among groups of
subjects/sample data
Classification
o parametric inferential statistics
continuous data that is normally distributed
o nonparametric inferential statistics
categorical data that is not normally distributed
Study types
o when comparing two means
student t-test
used for parametric data
mann-whitney or wilcoxon sum rank test
used for non-parametric data and
o when comparing proportions or categorical data
chi-square test
used for two or more groups of categorical data
fisher exact test
used when sample sizes are small or
number of occurrences in a group is low
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2. Level of Evidence
Introduction
A method utilized in evidenced based medicine to determine the clinical value of a study
See details of Clinical Design Trials
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JBJS LOE
AAOS Recommendations
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Randomized controlled trial
Definition
o a study in which patients are randomly assigned to the treatment or control group and are
followed prospectively
o provides the most compelling evidence that the study treatment causes the expected effect on
human health
o randomization minimizes study bias
Crossover design
o administration of two or more therapies, one after the other, in a random order
o susceptible to bias if washout period is inadequate
o single blinded study vs. double blinded study
Analysis
o intent-to-treat analysis
outcomes based on the group into which they were randomized, regardless of whether the
patient actually received the planned intervention
minimizes non-responder bias
o per protocol
excludes patients who were not compliant with the protocol guidelines
Example
o you want to determine whether your new toothpaste prevents cavities better than your old
toothpaste. You randomly assign a large number of patients to either an intervention group,
which uses the new toothpaste, or to a control group, which uses the old toothpaste. You would
then measure the amount of cavities between the groups over time.
Orthopaedic Literature Examples
o Surgical vs nonoperative treatment for lumbar disk herniation: the Spine Patient Outcomes
Research Trial (SPORT): a randomized trial. JAMA. 2006.
o Should insertion of intramedullary nails for tibial fractures be with or without reaming? A
prospective, randomized study with 3.8 years' follow-up. J Orthop Trauma. 2004.
o Nonoperative treatment compared with plate fixation of displaced midshaft clavicular fractures.
A multicenter, randomized clinical trial. J Bone Joint Surg Am. 2007.
Cohort study
Definition
o a study in which patient groups are separated non-randomly by exposure or treatment, with
exposure occurring after (prospective), or before (retrospective), the initiation of the study
Evidence
o Level II or III evidence
Analysis
o results usually reported as relative-risk
Example
o you want to determine if smoking is a risk factor for the development of lung cancer. You
identify a group of smokers and a group of non-smokers, and follow them over time measuring
the desired outcome, in this case, lung cancer.
Orthopaedic Literature Examples
o A prospective cohort study of the effects of lower extremity orthopaedic surgery on outcome
measures in ambulatory children with cerebral palsy. J Pediatr Orthop. 2009.
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o Functional outcomes following displaced talar neck fractures. J Orthop Trauma. 2004.
o Risk of revision for fixed versus mobile-bearing primary total knee replacements. J Bone Joint
Surg Am. 2012.
Case-control study
Definition
o a study in which patient groups are separated by the current presence (cases) or absence
(controls) of disease and examined for the prior exposure of interest
Evidence
o Most are Level III evidence
Analysis
o usually reported as odds-ratio
Example
o you want to determine if smoking is a risk factor for the development of lung cancer. You
compare the smoking history of individuals with lung cancer (cases) and those without
(controls).
Orthopaedic Literature Examples
o Fluoride in drinking water and risk of hip fracture in the UK: a case-control study. Lancet. 2000.
o Risk factors for retained instruments and sponges after surgery. N Engl J Med. 2003.
o Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care
setting in the United Kingdom. Arch Intern Med. 2007.
Meta-analysis
Definition
o a systematic review that summarizes results of other studies
Evidence
o may be used in increase the statistical power of several under-powered studies
Example
o you want to determine if wearing sunscreen results in fewer cases of melanoma. You pool the
results of 9 randomized controlled studies and statistically analyze the data to determine the
effect of the relationship.
Orthopaedic Literature Examples
o Internal fixation compared with arthroplasty for displaced fractures of the femoral neck. A meta-
analysis. J Bone Joint Surg Am. 2003.
o Vertebroplasty and kyphoplasty: a systematic review of 69 clinical studies. Spine (Phila Pa
1976). 2006.
o Influence of osteoporosis on fracture fixation--a systematic literature review. Osteoporos Int.
2008.
Cross-sectional Study
Definition
o study group is analyzed at a given time ("snapshot") with no follow-up
Example
o you want to determine the prevalence of baseball injuries during the 2003 little-league season
Orthopaedic Literature Examples
o Variability in the definition and perceived causes of delayed unions and nonunions: a cross-
sectional, multinational survey of orthopaedic surgeons. J Bone Joint Surg Am. 2012.
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o Hypovitaminosis D in patients scheduled to undergo orthopaedic surgery: a single-center
analysis. J Bone Joint Surg Am. 2010.
o Treatment preferences for displaced three- and four-part proximal humerus fractures. J Orthop
Trauma. 2010.
Case Series
Definition
o a retrospective account of multiple patients with the same injury or treatment with no control or
comparison group
useful for generating hypotheses for additional studies
Evidence
o level IV evidence
Example
o you have found that several of your patients who have used a new lipid lowering medication
have developed hemorrhagic cysts. You want to alert other members of the community of this
possible association.
Orthopaedic Literature Examples
o Familial bilateral osteochondritis dissecans of the femoral head. J Bone Joint Surg Am. 2009.
o Familial osteofibrous dysplasia. A case series. J Bone Joint Surg Am. 2005.
o Treatment of posterior cruciate ligament tibial avulsion fractures through a modified open
posterior approach: operative technique and 12- to 48-month outcomes. J Orthop Trauma. 2008.
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Harris Hip Score
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Achilles tendinosis
plantar fasciitis
Consists of 5 subscales:
o pain
o other symptoms
o function in daily living (ADL)
o function in sport and recreation
o foot and ankle-related Quality of Life (QOL)
Scoring
o last week is taken into consideration when answering the questionnaire
o each question gets a score from 0 to 4
normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) is
calculated for each subscale.
the result can be plotted as an outcome profile
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o if all 10 sections are completed the score is calculated as follows:
Example: 16 (total scored), 50 (total possible score) x 100 = 32%
o if one section is missed or not applicable the score is calculated:
16 (total scored) 45 (total possible score) x 100 = 35.5%
o interpretation of scores
Survivorship Analysis
Overview
o often used to measure success of joint replacements
o analyzes data from patients with different lengths of follow-up
for analysis, it is assumed that all patients had their operation simultaneously
o chance of implant surviving for a particular length of time is calculated as the survival rate
calculation method is either life table or product limit method
LIfe table method
o number ofjoints being
followed and the number of failures are determined for
each year after operation (number of joints being followed and the number of failures
are determined foreach year after operation each year of follow-up, failure rate is
calculated from the number of failures and the „number at risk‟
o annual success rate, determined from the failure rate, is cumulated to give a survival rate for each
successive year, this can change only once per year
Product limit method
o same as life table method, but the survival rate is recalculated each time a failure occurs
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OrthoBullets2017 Clinical Science | Healthcare Worplace
B. Healthcare Worplace
1. Occupational Health
Risk of Transmission
Risk of HIV transmission
o needlestick
seroconversion from a contaminated needlestick is ~ 0.3%
exposure to large quantities of blood increases risk
seroconversion from exposure to HIV contaminated mucous membranes is ~0.09%
o frozen bone allograft
risk of transmission is <1 per million
donor screening is the most important factor in prevention
no reported cases of transmission from frozen bone allograft since 2001
o blood transfusion
risk of transmission from blood transfusion is 1/500,000 per unit transfused
seronegative blood may still transmit virus due to delay between HIV infection and antibody
development
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By Dr, AbdulRahman AbdulNasser Clinical Science | Healthcare Worplace
Risk of Hepatitis B transmission
o needlestick
37% to 62% eventually seroconvert following needlestick
22 to 31% develop clinical Hepatitis B infection following needlestick
Risk of Hepatitis C transmission
o needlestick
0.5 to 1.8% risk of transmission
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By Dr, AbdulRahman AbdulNasser Clinical Science | Healthcare Worplace
o "improper performance" makes up 45% of lawsuits
o the most commonly associated procedures
1. operative procedures of joint structures (not including spinal fusion)
2. open reduction of dislocation
3. closed reduction of fractures
4. operative procedures on bones
5. operative procedures on cranial and peripheral nerves
Most common clinical diagnosis associated with orthopaedic lawsuits (as of 2008)
1. osteoarthritis (21%)
2. disorder of joint, not including arthritis
3. fracture of femur
Legislation
Patient Protection and Affordable Care Act - 2010
Physician Payments Sunshine Act - 2010
o Requires collection and reporting of financial relationships between physicians / teaching
hospitals and businesses (manufacturers of drugs, devices, medical supplies)
o All payments beyond $10 must be reported to Centers for Medicare and Medicaid Services
Physician Impairment
Impairment of a healthcare professional is the inability or impending inability to practice according
to accepted standards as a result of substance use, abuse, or dependency (addiction).
A surgeon (resident, fellow or attending) who discovers chemical impairment, dependence, or
incompetence in a colleague or supervisor has the responsibility to ensure that the problem is
identified and treated.
Medical Negligence
Negligence is the failure to provide the standard of health care resulting in medical injuries
A second-opinion physician has an ethical obligation, but not legal obligation, to disclose if the
standard of care has been breached by a treating physician.
A successful patient-plaintiff lawsuit for medical negligence against a physician requires that the
following FOUR elements be alleged and proven in a court of law
o duty
the duty of the physician is to provide care equal to the same standard of care ordinarily
executed by surgeons in the same medical specialty.
o breach of duty
breach of duty occurs when action or failure to act deviates from the standard of care.
o causation
causation is present when it is demonstrated that failure to meet the standard of care was the
direct cause of the patient‟s injuries.
o damages
damages are monies awarded as compensation for injuries sustained as the result of medical
negligence
Workers Compensation
A Workers' Compensation patient is determined to reach maximum medical improvement
when further restoration of function is no longer anticipated and can then settle his/her claim.
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Ability for worker's compensation patients to choose their own physician varies by the statutes of
each state.
Legal definitions
o impairment
loss of function resulting from an anatomic or physiologic derangement.
o disability
limitation of an individual‟s capacity to meet certain personal social or occupational
demands.
Relations with Industry and Hospitals
Acceptable Standards of professionalism
o practicing orthopaedic surgeons may accept tuition, travel, and modest hospitality (including
meals and receptions) to attend an industry sponsored non-CME course given at a local
convention center
o must disclose relationships with industry to patients, colleagues, and their institution
o can only receive gifts with a market value under $100
Medical Innovation
Royalties
o if an implant is used by which the surgeon is receiving royalties, this information must be
disclosed to the patient
Patient Transfer
EMTALA
o all patients must be appropriately screened in the original emergency room/hospital
o risk of patient transfer must be less than the risk of keeping patient
o accepting hospital/center must know of, and accept patient
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Physician Advertising
Advertising by physicians becoming more commonplace
o AMA and AAOS can't prevent physicians from advertising services
o FTC, AAOS, state medical boards can sanction for false advertising
o things to avoid
using terms such as "cure" if no cure truly exists
using terms such as "painless" or "bloodless" to describe surgery
overstating credentials such as "board certified in joint replacement" if no such qualification
exists
using terms such as "world renowned"
Diversity
Important to understand cultural differences
o patient-physician relationships are enhanced
o disparities in health care are eliminated
o access to orthopaedic care is optimized
Important to understand your own implicit biases
o Implicit bias is present when your unconscious prejudices or stereotypes influence the care
delivered to the patient.
o Implicit bias is a determinant of health disparities.
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