Diseases of the musculoskeletal system

Question 1

Describe bone composition

Answer 1

Bone consists of two components (disease can result to any of these areas):
- An organic component (collagen, bone-forming and bone-related proteins) 30%
-> Cellular (osteoblasts/ osteoclasts)
-> Non-cellular (collagen, bone matrix proteins)
- An inorganic (mineral) component (calcium phosphate = hydroxyapatite crystals) 70%

Question 2

Describe the functions of bone

Answer 2

• obvious locomotor roles bones play
• protect internal organs
• key in the regulation of serum calcium and phosphate - storage for these
• house the marrow, from which hematopoietic cells (red blood cells, white blood cells, platelets) originate. - hematopoiesis
• Energy - fat from the marrow - if needed can be used for energy, but typically not used.

Question 3

Describe the morphological classification of bones

Answer 3

• Can be classified as axial - skull, vertebrae, sternum, coccyx, sacrum, and ribs. Or appendicular - the limbs; scapula, humerus, femur, tibia, etc.
• Bones can be categorized on their gross appearances into several forms:
  1. Tubular bones -1) long tubular - femur, tibia, fibular, humerus, ulna, radius; 2) short tubular (rounded, elongated) - phalanges, metacarpals, metatarsals).
  2. Flat bones - ribs, sternum, scapula
  3. Short (epiphysoid) bones (cuboidal) - carpals in hands, tarsals in feet
  4. Irregular bones - pelvis, vertebrae, skull

Question 4

Describe tubular bones

Answer 4

The tubular bones can be divided into 3 regions:
- epiphysis (above the growth plate also known as the physis)
- metaphysis (directly below the growth plate)
- diaphysis (area between metaphyses at either end of the bone) - middle portion of the bone.
Care about this for surgeons, pathologists, radiologists, etc. differential diagnoses - e.g. some tumours have preferences for specific areas.

Question 5

Describe the similar design of bone

Answer 5

Despite the different gross morphological appearances of bones within the human body, they all essentially have a similar design with a thick outer rim of dense cortical bone and a less dense, spongy, or honeycomb like interior called medullary or cancellous bone.
- Bone cells called osteocytes. Will be found in the area surrounding the haversian canals.
- Both types of bone are made of the same building blocks but look and act very differently.

Question 6

Describe the cortex region of bone

Answer 6

The cortex resists bending and provides structural integrity. Unit structure = osteons. Very dense.
-> Blood vessels travel within spaces of the cortex called haversian canals.
-> Periosteum is a connective fibrous layer connected to cortex - attached by perforating fibers - importance, has dormant cells, and then when they wake up, these cells can become what is needed - e.g during fracture.
-> Fibres throughout that allow the cells to communicate with each other and transmit forces, etc.

Question 7

Describe the medullary region of bone

Answer 7

The medullary bone, or trabecular bone (where marrow is) is where metabolic processes take place - blood cell production (hematopoiesis), calcium and phosphate homeostasis.
- Have bone trabeculae, with fatty bone marrow between.
- If full with hematopoietic cells, often something wrong - leukemia? Often will do bone marrow biopsy.
- Formed of sheets of bone - lots of surface area for processes to take place - not good for resisting forces, this is what cortical bone is for.

Question 8

Describe the histological classification of bones. what are the 5 types?

Answer 8

Under the microscope, bone can have different appearances depending on how well organised the collagen fibres are and whether or not the organic component of bone is mineralized or not.
1. Lamellar bone
2. Woven (non-lamellar) bone
3. Mineralized vs non-mineralized bone (osteoid)
4. Cortical bone
5. Cancellous bone / trabecular bone

Question 9

Describe lamellar bone

Answer 9

collagen fibres arranged in parallel layers or sheets (lamellae), 98% of bone is lamellar from infancy to adulthood. Layer on layer. Very organised.

Question 10

Describe woven (non-lamellar bone)

Answer 10

randomly oriented (not as organised) coarse collagen fibres, seen in fetuses, initial new bone formation in disease states (for instance: fracture, bone, tumours, etc). Lamellar and woven bone are readily distinguished by viewing bone under polarised light. Precursor to lamellar bone.

Question 11

Describe mineralized vs non-mineralized bone (osteoid)

Answer 11

new bone typically forms on pre-existing bone (appositional growth). When it is laid down there is a mineralization lag time of about 10 days. The presence of increased osteoid may signal disease of mineralization (rickets/ osteomalacia)
- osteoid means unmineralized bone tissue and is a key structure in the development of mature mineralized bone.

Question 12

Describe cortical bone

Answer 12

consists of concentrically arranged lamellar bone around a vascular core (haversian canal) to form an osteon, it is dense and resists bending

Question 13

Describe cancellous bone / trabecular bone

Answer 13

spongy bone which is made up of a series of interconnecting plates of bone perforated by holes providing greater surface area for metabolic activity

Question 14

What are the 5 different types of bone cells?

Answer 14

1. Osteoblasts
2. Osteocytes
3. Osteoclasts
4. Chondroblasts / chondrocytes
5. Periosteal cells

Question 15

Describe osteoblasts

Answer 15

flat to round cells produce organic component of bone, lie on surface of bone, mesenchymal derivation. These are the cells that replace the cartilage with bone. Active form.
- Make bone
- Osteoblasts and osteoclasts work together

Question 16

Describe osteocytes

Answer 16

osteoblast embedded within bone (once they are surrounded by matrix), connected to other osteocytes/cells and interstitial fluid via long processes within numerous canaliculi. Live cells communicating with eachother.
- Due to derivation from osteoblasts, these cells are highly specialized in nature and are responsible for the maintenance of the bony matrix.

Question 17

Describe osteoclasts

Answer 17

multinucleated giant cells which resorb bone, derived from hematopoietic stem cells (bloodborne monocyte). Very large.
- Opposite job of osteoblasts, its job is to remove bone - resorption.
- Come to bone surface, can sense weak bones, and will remove so that new strong bone can come in. remove bone by surrounding and making a tight seal, to release hydrogen ions, acid, to cause leaching or demineralization of the bone - left with organic part. Then the osteoclasts release enzymes, that then degrade the bone.
- Takes 2 years approximately to replace your bone.

Question 18

Describe chondroblasts / chondrocytes

Answer 18

round cells that produce cartilage matrix, analogous to osteoblasts/ osteocytes. Sit in space called lacuna.
- chondroblasts = not surrounded by matrix yet

Question 19

Describe periosteal cells

Answer 19

firmly adherent thin tough fibrous membrane which covers bone surface except at articular surface and insertion of tendons and ligaments; inner layer (layer closest to bone) forms bone, allowing for growth in width

Question 20

Describe bone development. What are the 2 mechanisms?

Answer 20

Embryologically, and initial precursor skeleton made of immature uncommitted mesenchyme is formed which then forms bone via two mechanisms:
1. Endochondral ossification
2. Intramembranous ossification
* Bone is not static and is continuously undergoing changes in its microscopic structure (remodelling) in response to various stresses. Remodelling is achieved by the actions of the osteoblast and osteoclasts which are so closely coordinated that they are often referred to as the bone structural unit or the bone remodelling unit.

Question 21

Describe endochondral ossification

Answer 21

all bones in the body except the craniofacial bones form by this mechanism.
- An initial primitive/ precursor cartilage model is made that eventually undergoes calcification killing the chondrocytes, becoming bone.
- Blood vessels grow in from the periosteum and bone is deposited on the remaining cartilage matrix.
- This process normally occurs in the mid-diaphysis and extends in both directions (primary ossification centre). Eventually a secondary centre of ossification forms in the epiphyses by the in-growth of additional blood vessels, leaving behind the growth plate (physis) which allows for continued vertical growth, until adolescence at which point it also is invaded by vessels and undergoes ossification leaving an epiphyseal scar and stopping further growth.
- Cartilage dies, and mineralized cartilage is laid down - then bone forms from this. This is what occurs in tubular bones, from the growth plates. Most bones formed this way.

Question 22

Describe intramembranous ossification

Answer 22

the craniofacial bones form by this mechanism.
- Primitive mesenchymal cells directly lay down bone. There is no pre-existing cartilage model.
- Immature mesenchyme, and then stimulates do differentiate to become osteoblasts, which make bone. Become surrounded by matrix, they become osteocytes. Then the matrix becomes mineralized and get hard bone.
- Get bone on top of bone

Question 23

What is coupling? What would cause coupling not to occur?

Answer 23

• Bone is not static and is continuously undergoing changes in its microscopic structure (remodelling) in response to various stresses. Remodelling is achieved by the actions of the osteoblast and osteoclasts which are so closely coordinated that they are often referred to as the bone structural unit or the bone remodelling unit.
• If a bone has been sufficiently remodelled that changes are visible by the unaided eye, the bone is said to have undergone modelling.
• Under normal conditions bone formation equals bone resorption and equilibrium is maintained, this phenomenon is referred to as coupling.
• Unless you are still young and growing, in which case bone formation is higher than bone resorption.
• Factors promoting net bone formation include estrogen, testosterone, growth hormone, and weight bearing activity.
• Factors promoting net bone resorption include corticosteroids, excess thyroid hormone, parathyroid hormone and lack of weight bearing activity.

Question 24

Describe the classification of the diseases of bone

Answer 24

1. Metabolic diseases
   -> Abnormal synthesis of organic matrix components
   -> Abnormal formation of inorganic matrix components (mineralization)
   -> Abnormal cell linkage / coupling
   -> Accumulation of abnormal metabolic products
2. Infectious bone diseases
3. Bone tumours

Question 25

Describe one of the diseases resulting from abnormal synthesis of organic matrix components. what? classification? results/ symptoms? microscopically? prognosis? treatment?

Answer 25

As the formation of normal collagen molecules is complex, it can be affected at various stages of its production. Interestingly, the various collagen defects manifest clinically quite differently but have in common that tissues in which collagen is prevalent are affected.
1. Osteogenesis imperfecta (OI):
- Rare, inherited disease
- Name given to a heterogeneous group of conditions which have in common the production of abnormal type I collagen - abnormalities in collagen formation
- Different presentation depending on where defect in collagen synthesis occurs
- Can be inherited in autosomal dominant, autosomal recessive or spontaneous mutations and present at birth (congenita) or later in childhood (tarda)
- OI - is classified into 4 categories based on specific phenotypes, biochemical data, and hereditary patterns:
1. Neonatal lethal (10%)
2. Severe nonlethal (20%)
3. Moderate and deforming
4. Mild nondeforming
- Defects in collagen result in weak, brittle bone and abnormalities of other tissues in which collagen is a significant component: sclerae, teeth, ligaments - brittle bones disease - multiple fractures
- Results: osteopenia, bone fractures with deformities, blue sclerae, lax joints, deafness, malformed teeth (dentinogenesis imperfecta) in 25% of patients
- Short stature (many fractures over time cause this), limb deformities, blue sclerae (white portion of the eye becomes thinner and may look blueish - can see retina), malformed teeth (bones like the skull are not properly formed, affects teeth), hearing loss (compression on nerves - may cause vision loss as well)
- Microscopically the bone is hypercellular and predominantly woven. The cortices are thinned, the trabeculae are short, thin, widely spaced and disorganized. Decreased bone.
- Depending on severity of disease patients may die shortly after birth or may live relatively normal lives.
- Treatment - no therapy currently exists to alter the course of the disease. Correction of deformation and fracture prevention is all that can be attempted. Often treatment is just supportive - perhaps rods in the bones/ limbs to support them.

Question 26

Describe one of the diseases resulting from abnormal formation of inorganic matrix components / disturbancs in mineral homeostasis. what? how? symptoms? appearance/ radiographically? treatment?

Answer 26

Calcium and phosphate play a crucial role in human biologic processes. About 99% and 85% are contained within the skeleton respectively as hydroxyapatite. Calcium homeostasis is regulated by several endocrine hormones including parathyroid hormone, vitamin D, and calcitonin. Its regulation is also dependent upon the normal functioning of target organs (kidney, gut, bone). A major bone disease resulting from disordered mineralization is rickets/ osteomalacia.
1. Rickets (children) / Osteomalacia (adults):
- Rickets / osteomalacia result from failure of normal mineralization of bone due to inadequate vitamin D (most often), or calcium or phosphate deficiency, ingredients essential for normal bone mineralization.
- Increased non-mineralized bone (osteoid)
- Deficiencies may result from numerous causes:
-> Inadequate diet or sun exposure (malnourished)
-> Liver disease
-> Kidney disease
-> Genetic enzyme defects
- Weak bone
- Children present with skeletal deformities including beading of costochondral junctions of the ribs (rachitic rosary), a chicken-breasted appearance (bend in the spine forward), enlarged wrists, knees and ankles, and curvature of the long bones (anterior bowing of the legs). You may see evidence of past fractures or micro fractures on radiographs.
- In adults bone pain is the most common symptom secondary to micro fractures.
- Radiography reveals generalized osteopenia (decreased bone production) and fractures. Macroscopically there is a marked increase in the amount of non mineralized matrix (osteoid) on the surfaces of the cortical bone, frequent micro fractures, and resorptive change typical of secondary hyperparathyroidism.
- Treatment is aimed at replenishing the missing ingredient(s) necessary for mineralization.

Question 27

What are two bones diseases resulting from abnormal cell linkage/ coupling?

Answer 27

1. Paget disease of bone
2. Osteoporosis

Question 28

What is Paget disease of bone?

Answer 28

Metabolic bone disease - abnormal cell linkage (coupling) - initial excessive osteoclastic activity (bone lysis / resorption), then balanced osteoclastic/ osteoblastic activity. Finally excessive osteoblastic activity/ deposition (bone sclerosis - increased bone density) - end result: sclerotic excess bone that is disorganized and weak, prone to fracture. thick, disorganised, sclerotic bones. - larger bones
- This disease typically affects northern europeans.
- Most often the disease is monostotic (affects one bone) and asymptomatic and is detected incidentally. Patients with polyostotic disease come to clinical attention due to bone pain, fractures, deformities, arthritis, or nerve impingement.
- The axial bones (skull, vertebrae, pelvis) are more commonly affected. Occasionally the disease can be generalised.
- The disease is felt related to a slow-virus infection of osteoclasts leading to their activation. Osteoblasts react in turn by laying down new bone which however is disorganised and too much (overcompensated).
- Microscopically, increased numbers of resorbing osteoclasts are seen initially along with fibrovascular changes of the marrow. This is followed by osteoblastic proliferation and osteoid deposition leading to the classic mosaic pattern.
- A rare complication of Paget’s disease is the development of malignancy in one of the affected bones - osteosarcoma, something goes wrong during the excess bone formation. Can also get congestive heart failure as there is an increased number of blood vessels feeding into the larger, increased bone.
- Bone biopsy used to diagnose?
- Potentially related to a paramyxovirus - slow developing virus, activates osteoclasts, then probably get rid of virus, but the series of events continues onto Paget’s disease.

Question 29

What is osteoporosis?

Answer 29

systemic skeletal disease characterised by low bone mass and microarchitectural bone fragility and susceptibility to fractures - normal bone structure, normal structure - just decreased amount of bone
- Increased bone fragility and susceptibility to fractures
- Refers to decreased density of normally mineralized bone. This disease has a high prevalence and associated morbidity.
- Females are affected more often (3:1).
- Normal bone density peaks at about age 35. Thereafter net bone loss is a normal consequence of aging. If this loss is excessive and fractures ensue the condition is pathological. Most cases (95%) are unknown etiology. The remaining cases result from increased bone resorption.
-> Men generally start with denser bones
-> At age 35, 0.2-1% bone loss per year
-> Women - loss of estrogen at menopause, increased loss of bone per year of 3-5% per year for a while, and then this drops back down - but still more at risk than men
- hip fractures related to OP

Question 30

What are the risk factors of Osteoporosis?

Answer 30

• Race / genetics / sex - poorly understood, more common in caucasians + asians, female more than males, probably due to decreased peak bone mass
• Genetic - primary determinant of peak bone mass
• Age, net bone loss progresses with age
• Estrogen, bone loss is accelerated postmenopausally as estrogen normally inhibits osteoclast activity. Other causes of decreased estrogen include anorexia nervosa, exercise-induced amenorrhea, turner syndrome, hypopituitarism, oophorectomy
• Low body weight - load bearing is good on bones. Physical activity.
• Hypercortisolism, endogenous cushing syndrome, exogenous corticosteroid therapy
• Hyperparathyroidism
• Immobilization, weight bearing exercises supplies mechanical stresses necessary for maintenance of bone integrity
• Nutritional deficiency
• Prolonged steroids usage
• Others - alcohol, smoking, malignancy

Question 31

Presentation, diagnosis, and treatment of osteoporosis

Answer 31

• The most common presentation is major and minor fractures. Micro fractures result in vertebral crush fractures, leading to loss of vertebral height, kyphosis (spinal curve - rounding of upper back) and Dowager’s hump. - vertebrae which are normally brick shaped, take on a more honeycomb shape usually. Intervertebral disks protrude into bone - causes compression fractures when bending/ leaning forward. Spine curves/ bends forward usually.
• Diagnosed through clinical findings - which alert, typically fractures (e.g. hip fractures, spine/ compression fractures, distal radius, proximal humerus). Can do a bone mineral densitometry test - measurement of the density of someone’s bone - can compare to other individuals within age range. Typically do not do bone biopsy.
• Those with established osteoporosis are 20x more likely to have another fracture. Very porous bone.
• Mineralization is normal but the cancellous bones are thin, elongated, and disconnected from one another. Numerous micro fractures are identifiable.
• Osteoporosis may be slowed or prevented by exercise, good diet, calcium supplementation, and hormone replacement therapy.
  -> Nutritional supplementation
  -> Calcium - modest decrease in fracture risk
  ->Vit D - helps calcium absorption, reduces non-vertebral fracture rate
  -> Hormone replacement therapy (HRT) - estrogen + progesterone (this was first line therapy for a long time). Study - terminated prematurely after demonstrating risks > benefits
  -> Benefits : prevent hip fractures, reduce vertebral and other osteoporotic fractures, menopausal symptom relief
  -> Risks: increased CAD (cardiovascular disease), increased strokes, increased PE (pulmonary embolism), increased breast cancer
  -> Treatment tailored to the individual - weigh the risks, is the person already at risk for these consequences - if not may be safe.
• Usually treat complications rather than the disease itself - need more prevention and screening.

Question 32

What are two common malignant bone tumours?

Answer 32

1. Osteosarcoma
2. Chondrosarcoma

Question 33

Describe osteosarcoma

Answer 33

• Aggressive bone producing tumour with predilection for young - malignant
• Bone producing tumour - increased density, lacelike - increased cellularity - produces complex bone, disorganised like woven
• Usually arises in long bones at sites of increased growth (metaphysis) - proximal tibia, distal femur, knee, etc
• Often diagnosed late in stage - already large tumour and metastasis - from diagnosis often treated as systemic disease
• Need a bone biopsy - determine whether osteosarcoma, or whether metastasis from elsewhere
• Associated with pain, rapidly enlarging mass (in medullary cavity), fractures, destruction of involved bone, early metastasis. High grade tumour.
• Histologically categorized into osteoblastic, chondroblastic, fibroblastic subtypes, but all have similar behaviour other variants exist and are separated based on behaviour, location and associated underlying conditions (i.e. familial predisposition)
• Almost uniformly fatal 20 years ago, current combined chemotherapy and surgery (chemo then surgery then chemo again) achieves, 60-80% survival ~85% 5 yr survival
• Limb salvage therapy is used increasingly resulting in improved patient functioning
• Pathologists to assess tumour response after chemotherapy:
  -> Cut bone in longitudinal axis
  -> Map cross section
  ->Responders -> 90% tumour necrosis - Keep going with current chemotherapy
  -> Non-responders -< 90% tumour necrosis - Chemotherapy + additional chemotherapy and other regimens

Question 34

Describe chondrosarcoma

Answer 34

• Occurs in older, skeletally mature patients (older than 50 usually) - 55% males, 45% females
• Involves pelvic bones, proximal long tubular bones - not bones of acral sites (hands and feet) - more axial bones - vertebrae, ribs, pelvis
• Large destructive lesions with characteristic arc and ring-like calcifications on radiographs - popcorn-like calcifications
• Consist of atypical cartilage cells in hyaline cartilage - malignant
• Tumour produces cartilage rather than bone. Often within medullary cavity - can get extension outside the cortex like osteosarcoma. More gelatinous material - pearly colour - soft and supple.
• Locally aggressive, higher grade tumours will metastasize
• Slow growing, mild pain, increasing over time - do not become aware until large mass present or fracture, etc. It is a low grade tumour, can metastasize, but not usually.
• Diagnosis requires a bone biopsy
• Treatment is surgery; chemo and radiotherapy have little effect
  Morphological variants exist including clear cell chondrosarcoma, mesenchymal chondrosarcoma, dedifferentiated chondrosarcoma (the last two behave more aggressively).
• pathologists to assess tumour margins - if not clear, may use some localized chemo

Question 35

Describe the normal joint structure and classification

Answer 35

• A joint consists of the ends of contiguous bones together with their surrounding soft tissue components, ligaments, tendons, and synovium.
• Nice smooth articular cartilage and subchondral bone underneath. There should be a space between the cartilages of the two connecting structures within the joint.
• Joints can be classified according to the type of tissue present at the articulating interface as follows:
  1. Solid
  1a. Bony joints (skull sutures) - synostosis
  1b. Fibrous joints (pubis symphysis) - syndesmosis - tibia and fibula
  1c. Cartilaginous joints - symphis - intervertebral disk
  2. Cavitated
  2a. Synovial e.g. knee
  -> Contain cartilage, and other components, as well as a space known as the synovium - these cells produce fluid to lubricate the joint in order to allow smoother movement
  -> Has muscles and tendons for structure and bursa for cushioning.

Question 36

Describe the normal joint physiology and function. What are the properties of cartilage that make it good for joints?

Answer 36

• Top lining = synovial cells (two diff types). Beneath this thin layer have fibrous connective tissue, fat and blood vessels. No inflammatory cells. Rare mast cell.
• The two diff types of synovial cells have diff functions include 1. More involved in synovial fluid, 2. More phagocytic in nature, if any debris will take care of
• Cartilage has several properties that make it ideal for joint functioning. Cartilage is firm yet pliable and changes shape under increasing loads such that the surfaces of the joint come into increasing contact thereby distributing the load more equitably. Cartilage is also elastic by virtue of its abundant extracellular matrix which retains water. When forces are transmitted from one bone to the adjacent bone, the cartilage of the joint is compressed and extracellular water is extruded. Upon removal of the force the extracellular matrix draws the water back in and the cartilage recovers its original shape.
• Cartilage is avascular and therefore receives all nourishment from synovial fluid. Because joints are not perfectly congruous, during compression, flow of synovial fluid occurs. Like bone, the articular surfaces (cartilage and subchondral bone) are dynamic and are constantly undergoing remodeling in order to optimize load distribution.
• The normal functioning of a joint is dependent on three features: 1) the maintenance of stability during use 2) freedom of opposed articular surfaces to move painlessly over one another within a normal range of motion 3) correct distribution of load across joint tissues in order to avoid damage. These aspects of joint function are governed by the shape of the articulating surfaces of the joint, the integrity of the supporting tissues of the joint, and the biologic cellular control of the mechanical properties of the tissues forming the joint. Disturbances of any one of these may lead to joint disease.

Question 37

What are the 3 categories of the diseases of the joint?

Answer 37

1. Inflammation/ degeneration e.g. arthritis (arthritides)
2. Infections e.g. septic arthritis
3. Tumours (least common)

Question 38

What are the classifications of arthritis?

Answer 38

1. Non-inflammatory arthritis
   -> osteoarthritis
2. Inflammatory arthritis
   -> infectious
   -> non-infectious (rheumatoid arthritis, seronegative anthropathies, and crystal induced arthritis)
   - Distinction of the arthritides requires good clinical information, by the time a joint has been affected many of the morphological and histological changes are the same for the various entities. In the majority of cases the etiology is at best unclear.

Question 39

Describe osteoarthrities

Answer 39

Degenerative joint disease - non-inflammatory
Osteoarthritis (OA) is the most common form of arthritis in the Western world affecting nearly 10% of individuals greater than 60 years of age. Typically the disease is limited to a single or only a few, large, weight-bearing joints, usually the knee or hip. Patients with OA usually complain of decreased mobility of the affected joint(s), stiffness, and pain that worsens with use and is relieved with rest.
- pain and non functional joint over time
- Most common arthritis in North America
- 10% of individuals >60 yo
- Increasing incidence with age
- Very common
- Narrowing of joint space (x-ray)
- Increased bone production (osteophytes)
- No inflammation
- Not systemic - no manifestation elsewhere in the body - outside the joint
- Interfere with function
- Treatment - symptomatic (treat symptoms)

Question 40

What are the clinical features of osteoarthritis?

Answer 40

• Insidious development
• Pain, stiffness, decreased mobility
• Worse with movement - gets worse throughout the day
• Large, weight bearing joints (hips, knees and ankles)
• Single, asymmetrical joints (one side at a time - other side may be affected down the road tho)
• Muscle atrophy - not moving as much
• Can affect the hands as well - often see large joints in the hands because osteocytes have formed.

Question 41

What are the radiographic features of osteoarthritis?

Answer 41

• loss of the joint space
• osteophyte formation
• increased density of the bone immediately beneath the articular cartilage (subchondral bone sclerosis)
• subchondral cyst formation.

Question 42

What are the pathologic features? gross and microscopic

Answer 42

Gross features:
the articular surface and bone are misshapen with the formation of peripherally located bone spurs (osteophytes). Rather than being smooth, pearly-blue, and shiny, the articular cartilage will show areas of thinning, roughening (fibrillation), red-brown discoloration, and often areas of complete loss of articular cartilage with exposure of the underlying bone which becomes quite smooth resembling polished marble (eburnation). After cross-sectioning the articular surface and bone, subchondral bone sclerosis and subchondral cysts may be identified. Despite the loss of cartilage, regenerative changes at the periphery exceed loss such that the joint is actually larger than the normal joint.
- Fibrillation of cartilage
- Complete loss of cartilage and eburnation of subchondral bone
- articular cartilage is being destroyed
- get more bone growth = bone spurs, osteocytes - potentially very large (feel)

Microscopic:
these include duplication and irregularity of the tidemark (the line where cartilage begins to undergo endochondral ossification), chondrocyte clones (large clusters of chondrocytes trying to replace the lost articular cartilage), synovial cell hyperplasia/hypertrophy, villous change of the synovium, and nil to minimal chronic inflammation. If present, the inflammation is negligible in comparison to that present in the inflammatory arthritides.
- Multiple cracks and deep fissures
- Chondrocyte clones - try to make more cartilage
- Loss of articular cartilage and joint space
- Subchondral sclerosis
- Subchondral cysts
* if used need to examine the fluid - should not see any inflammatory cells, diff classification.

Question 43

Describe the pathophysiology of osteoarthritis

Answer 43

The sequence of events (pathophysiology) leading to OA is as follows:
i) The earliest change in the articular cartilage is loss of proteoglycans from the extracellular matrix. This can only be appreciated histologically by the use of special stains. This alteration is indicative of abnormal biochemical functioning of the chondrocytes.

ii) Small numbers of chondrocytes die and groups of enlarged chondrocytes (chondrocyte clones) develop in an attempt to replace the damaged cartilage.

iii) As the cartilage weakens, superficial cracks develop (surface fibrillation). With time, these cracks become quite deep (fissures). These cracks may be vertical or horizontal and may result in the breaking off of fragments of the articular cartilage which may float freely within the joint space (joint mice, loose bodies). The chondrocytes within the loose bodies remain viable as they get sufficient nutrition from the synovial fluid. The lost hyaline cartilage is often replaced to some extent by fibrocartilage. (Space becomes irregular/ abnormal)
-> Cartilage tries to make new cartilage - not very good at this - makes fibrous cartilage and does not make enough

iv) Loss of articular cartilage exceeds replacement resulting in exposure of the underlying (subchondral) bone. This bone remodels, becoming thickened (sclerotic - subchondral sclerosis) in an attempt to handle the transmitted forces and often becomes smooth and polished in appearance (eburnated - eburnation = smooth and polished).

v) The subchondral bone cracks (microfractures), allowing synovial fluid to enter into the bone marrow cavity and form subchondral cysts. - fluid comes in and expands

vi) The loss of articular cartilage and retransmission of forces results in osteophyte formation at the lateral portion of the joint. These are masses of bone and cartilage formed by the mesenchymal cells of the synovium. They are also called bone spurs. In the fingers they are called Heberden and Bouchard’s nodes.
->Get loss of that bone space - very narrowed

Question 44

Describe the pathogenesis of osteoarthritis

Answer 44

Not simply disease of wear and tear - oversimplification
Multifactorial
- Aging
- Cartilage dysfunction
- Subchondral bone stress
- Synovium - IL-1, TNF-a
- Microvascular disease
End stage of multiple processes
- Fracture, congenital abn, metabolic, etc.

Question 45

What is the etiology of osteoarthritis? What is secondary vs primary OA?

Answer 45

Secondary OA = called this when we know what the cause is
Primary OA = don’t know the cause of the OA
- Many underlying conditions may result in the development of secondary OA including congenital hip dysplasia, fracture, infection, avascular necrosis, metabolic diseases, etc.
- More commonly, however, the exact etiology is unknown (primary OA). While OA increases with increasing age, OA is not an inevitability of aging. On the contrary, many joints remain essentially normal even into extreme old age.
- OA is not simply a result of wear and tear, although this may play a significant role. OA may result from any condition that affects the articular surfaces of the joint, the bones of the joint, or the tissues supporting the joint (ligaments, tendons, capsule).

Question 46

What is the treatment of osteoarthritis?

Answer 46

Removal and replacement of the joint with prosthesis.

Question 47

Describe rheumatoid arthritis

Answer 47

RA is the most common of the inflammatory arthritides. RA is a chronic, systemic disease of unknown etiology that primarily attacks the synovial lining of the peripheral joints. The synovitis results in the secondary destruction of the articular cartilage. RA is characterized by bouts of remission and exacerbation and affects women more than men (3:1).
- Often multiple joints symmetrically, and of the hands and the feet. Also large, load bearing joints - but very common hands.
- Inflammatory - very prominent
- Chronic disease
- Non-suppurative - not an infectious cause
- Systemic
- Joint destruction, deformity
- 1% of population
- Affects all races
- Women : men - 3-5: 1 (like most autoimmune diseases)
- Peak incidence 20-40 yrs

Question 48

What are the clinical features of Rheumatoid Arthritis (RA)?

Answer 48

• Extra-articular features are common and include arteritis, neuropathy, pericarditis, pleuritis, lymphadenopathy, and rheumatoid nodules.
• Patients complain of malaise, and pain and stiffness of the joints which is typically worse in the morning and improves throughout the day.
• RA usually involves multiple joints, bilaterally and symmetrically. Although any joint may be involved, the small joints of the hands and feet are most commonly affected.
• The joints are usually swollen, painful, hot, and red.
• Synovial fluid analysis of an acute joint frequently reveals neutrophils however, no organisms grow on culture = inflammation but no infection

Question 49

What are the radiographic features of RA?

Answer 49

The typical findings are: periarticular loss of bone (osteopenia), bone erosion, narrowing of the joint space, subluxations, dislocations, and soft tissue swelling.

Question 50

What are the pathologic features of RA? gross and microscopic

Answer 50

Gross Features:
- One sees joint destruction but, unlike OA, there is little reparative activity, and osteophytes and new bone formation are not prominent.
- The synovium is hyperplastic and thickened and extends over the articular surface (pannus).
- Get loss of articular cartilage - exposed underlying bone which is rubbed/ smoothed / polished / ebarnated
Microscopic Features:
- The synovial lining cells increase in number (hyperplasia) and size (hypertrophy).
- The synovium is expanded by edema, increased numbers of blood vessels (angiogenesis), and chronic inflammatory cells (lymphocytes and plasma cells – not neutrophils) which frequently form lymphoid follicles with germinal centres. This expansion causes the synovium to form finger-like extensions (papilla/villi) that extend into the joint space and over the surface of the articular cartilage (pannus).

Question 51

What is the pathophysiology of RA?

Answer 51

• Initial injury - goes away tho
• Target tissue = synovial epithelial cells (diff from OA which is the articular cartilage)
• Immune-mediated - inflammation in synovial lining
• Leaky vessels (blood), edema - causing expansion of tissues
• Influx of lymphocytes, histiocytes, and plasma cells - inflammatory cells (not neutrophils)
• Neovascularization (new blood vessels grow)
• Synovial hyperplasia + hypertrophy - increase in size and number - synovium expands into joint space - Synovium is thick due to hyperplasia - forms finger-like projections (pannus - forms blanket and smothers the articular cartilage) that can extend/ encroach on the cartilage. Often find lymphocytes in pannus.
• The pannus destroys the underlying cartilage by several mechanisms: 1) The pannus physically covers the cartilage thereby preventing it from receiving adequate nutrition from the synovial fluid, 2) The pannus releases enzymes that directly destroy cartilage and, 3) The pannus releases inflammatory mediators that activate osteoclasts which destroy bone and cartilage. The end result is destruction of the articular surface and loss of bone with joint subluxation and instability.
• Fibrin begins to coat the surface - Can get fibrin depositions. Fibrin bodies - labelled as rice bodies, based off what they look like
• Lymphocytes arranged in many prominent lymphoid nodules
• Iron deposition gives brown colour
• Pannus grows in joint space
• Burrows into bone
• PMNs in synovial fluid
• Covers and destroys the cartilage (releases degradative enzymes)
• Can have neutrophils within the fibrin - not within pannus (exception - otherwise, neutrophils not involved)
• Joint destroyed by fibrosis
• Loss of articular cartilage
• Loss of periarticular bone
• Fusion occurs = ankylosis (fusion of the joint - pannus extends across the joint and becomes bony = bony ankylosis). Can also have fibrous ankylosis.
• deformities/ misshapen hands - bend towards ulnar side, away from the thumbs due to forces transmitted from the muscles in the hand which tend to pull toward ulnar side = ulnar deviation.
  Fixed flexion of the hands - very difficult to function normally

Question 52

What is the etiology of RA?

Answer 52

RA is believed to be an immune mediated disease. Most patients have rheumatoid factor (auto-antibodies to autologous IgG). Rheumatoid factor complexes with IgG and deposits in the synovium where an immune reaction takes place inciting damage via released enzymes and pro-inflammatory mediators.

Question 53

What is the pathogenesis of RA?

Answer 53

1. Microbial agents - EBV, parvovirus, retrovirus, mycobacteria
   -> Potentially initial virus damages joint, then molecules of the synovial fluid which are not normally present on the outside are - body recognizes as foreign and attacks (theory)
2. Genetic susceptibility - familial, twin studies, HLA-D
   -> Proven - very complex
3. Autoimmunity - cellular (CD4+), humoral (RF)
   -> The CD4+ T-helper cell is a main player in the process. Targets tissue.
   – > Humoral arm - Activates B cells which are antibody factories - produce auto-antibodies - one called rheumatoid factor is common (antibody against IgG). Circulates and forms complexes, precipitate out of blood - causing problems outside of the joints (can lead to inflammation of the lining of the heart or lungs, pleuritis, nodules in soft tissue (around joints often in connective tissue) - necrosis
   –> Nodule = firm, non tender. Round / oval nodule. Micro: central fibrinoid necrosis surrounded by histiocytes, and plasma cells (chronic inflammatory cells - not neutrophils). Rheumatoid necrosis.
   –> Cellular arm - activate macrophages, release cytokines. Activate synovial cells to proliferate - will release enzymes that cause direct damage. Endothelial cell activation which allows inflammation more readily to get to synovial lining cells.
   - All contribute to the creation of pannus. Leads to non functioning joint.