B3192 - Musculoskeletal: Bone Disorders Pt.1

What are the three factors involved in controlling osteoblast and osteoclast activity?

RANK

RANKL

Osteoprogeterin (OPG)

Function of RANKL

RANKL: A protein produced by osteoblasts that bind to RANK receptors on osteoclasts. Once it's bound, it promotes and activates osteoclast activity while inhibiting osteoblasts

Function of RANK?

A receptor on the osteoclasts; activates osteoclasts when RANKL binds to RANK

Function of OPG?

A "decoy" receptor for RANKL and is produced by osteoblasts. It essentially soaks up RANKL and prevents it from binding onto RANK, inhibiting osteoclasts while promoting osteoblast activity

T/F: Does OPG compete with RANKL to bind to RANK receptors?

F: OPG does not compete with RANKL; it competes with RANK receptors by soaking up RANKL, preventing RANKL from binding onto RANK and activating osteoclast activity

RANK ___ osteoclast activity whereas OPG ___osteoclast activity

promotes

inhibits

Significance of Wnt signalling?

It plays a key role in bone formation by inhibiting osteoclast activity and promoting osteoblast activity

Sclerostin (SOST)

a Wnt inhibitor = promotes osteoclast activity and inhibits osteoblasts, results in decreased bone formation

Effects of Sclerostin on osteoclast, osteoblast, RANKL, and OPG

Osteoclast = increased

Osteoblast = decreased

OPG = decreased

RANKL = increased

These overall results in decreased bone formation and increased turnover

Results of sclerostin inhibitor

Inhibits the effects of SOST and promotes bone formation by increasing osteoblast and OPG activity while inhibiting osteoclast and RANKL

What nutrients are required for bone health? How are they important? (7)

Calcium and Phosphate (minerals): aids in the formation of the inorganic matrix of the bone; required for bone formation and growth

Vitamin D: enhances the absorption of calcium in the GI tract

Vitamin C: required for collagen synthesis, which forms the organic components of the bone

Vitamin A: stimulates osteoblast activity during bone remodelling

Vitmain K and B12: synthesis of bone proteins

Hormonal factors required for bone health

GH and Insulin-like GH factors: promote osteoblast activity and protein synthesis

Thyroid hormones: stimulate osteoblast

sex hormones:

- Slows bone resorption by osteoclasts

- promotes bone deposition by osteoblasts

- sex hormones cause osteoblasts to produce more OPG, inhibit osteoclasts, and induce apoptosis of osteoclasts

Calcitonin: inhibits osteoclasts

PTH:

- promotes osteoclast activity

- formation of calcitriol in the kidneys

-calcium reabsorption from urine

Bone fracture

Break in the continuity of a bone that occurs when stress > force bone can absorb

How fractures are classified

Pattern along fracture line

Degree of break in continuity

Communication with external environment

Character of fracture pieces

Three major causes of fractures

Acute injury

Fatigue or stress

Pathologic (weakened bones)

Patterns along fracture lines

-Transverse

-Longitudinal

-Spiral

-Oblique

-Greenstick

Degree of breaks in continuity

-Complete

-Incomplete/partial

Complete fracture

Parts of the bone are completely separated

Incomplete/partial fracture

Break is incomplete, ex. greenstick fracture

Communication with external environment

-Open (compound)

-Closed (simple

Open fracture

Broken bones protrude through skin

Closed fracture

Broken bones do not break skin

character of fracture pieces

-Comminuted

-Compression

-Impacted

-Stress

-Avulsion

Comminuted fracture

Bone in broken into two or more pieces

Compression fracture

Bones are crushed or squeezed together

Impacted fracture

One end of fractured bone is driven into interior of the other end

Stress fracture

Failure of one external surface of the bone

Avulsion fracture

Separation of small bone piece at site of ligament or tendon

Pathogenesis of bone fractures

Broken bones cause damage to the surrounding tissues, periosteum, and the blood vessels in the cortex and bone marrow

- Broken blood vessels lead to hematoma formation

The damage to the bone tissue triggers an inflammatory response

Cause of fracture manifestations

Inflammatory response

This is because a fracture causes DAMAGE to the surrounding tissue, periosteum, and blood vessels in the cortex and bone marrow

Manifestations of fractures

-Pain

-Unnatural alignment

-Swelling

-Loss of function

-Blood loss

-Impaired sensation

Diagnosis of fractures

-X-ray

For fractures that are difficult to detect (occult fractures):

-CT

-MRI

What type of fracture may not be initially visible using X-rays? And why is it good to have more than two angles when imagining a fracture?

Stress fracture

Having two angles when imaging a fracture allows for a complete picture of the fracture, which can help differentiate oblique and spiral fractures

Tx of fractures?

Reduction: Align the bones close to their anatomical position - helps regain normal function

Immobilization: Maintain proper alignment during the healing process (casts, splints, traction, etc.)

Closed manipulation: NON-SURGICAL, bones are manipulated back into place (Pushing ends of bones into their correct position)

Open manipulation: SURGICAL, surgical realignment of bone (screws, nails, plates, wires, glue, cement, etc.)

RICO treats fractures

Bone readily regenerates via _____

processes involved in embryogenesis

Four steps of fracture repair

Hematoma formation

Fibrocartilaginous callus formation

Bony callus formation

Remodeling

Hematoma formation (fracture repair)

Torn blood vessels bleed into and around bone to form a hematoma, facilitating formation of fibrin meshwork

Fibrin meshwork

Aids in fracture repair by sealing off site and providing a framework for healing processes

Fibrocartilaginous callus formation (fracture repair)

Fibroblasts proliferate, creating granulation tissue forms to connect the bone fragments

Procallus

Granulation tissue

Bony callus formation

Callus ossifies and osteoprogenitors develop into osteoblasts to produce spongy bone

Ossification

Conversion of soft cartilage to bony callus

Bone remodeling (fracture repair)

Compact bone replaces spongy bone and osteoclasts remove dead portions of bone

Complications of fracture healing (9)

-Delayed union

-Malunion

-Nonunion

-Osteonecrosis

-Infection

-Compartment syndrome

-Fat emboli

-DVT/PE

-Osteoarthritis

Delayed union - why does this happen? (Complications of fracture healing)

Failure of the fracture to heal within the predicted time

Due to infection, smoking, malnutrition, corticosteroid use, and decreased vascularization; common underlying lesson is due to IMPAIRED IMMUNE FUNCTION

Adverse effects of corticosteroids in bone remodelling?

Corticosteroids can cause an increase in RANKL and a decrease OPG, which leads to an increase in bone resorption

Malunion - why does this happen? (Complications of fracture healing)

Deformity at the fracture site

Could potentially be due to misalignment or immobilization

Nonunion - why does this happen? (Complications of fracture healing)

Failure of the bone to heal

Due to a lack of nutrients, osteoblast dysfunction, or hormonal imbalance

Osteonecrosis - why does this happen? (Complications of fracture healing)

Death of bone tissue due to ischemia

- Fractures can damage or block blood vessels; The bones are not being actively perfused

Compartment syndrome - why does this happen? (Complications of fracture healing)

Increased pressure in the muscle comparment leading to poor blood flow and damage to the muscle/nerves

muscles are enclosed in fascia, when bones and muscles are damaged = inflammation = which puts more pressure and more damage to tissues and compresses blood vessles = ischemia, necrosis, and nerve damage

Fat emboli - why does this happen? (Complications of fracture healing)

Yellow bone marrow contains a lot of fat, which, when released into the bloodstream due to a fracture, can cause an occlusion and impair perfusion.

DVT and PE - why does this happen? (Complications of fracture healing)

Inflammation increases the risk of clotting (hypercoagulability), which is a crucial factor in the development of DVT and PE.

What to watch out for

PE:

-sudden shortness of breath

-sharp chest pain that worsens with breathing

- rapid or irregular heartbeat

-coughing that may produce bloody mucus.

DVT:

- swelling in the affected limb

- pain or tenderness

- warmth to the touch

- skin discoloration (redness or blueness)

- The majority may be asymptomatic due to the formation of collateral blood vessels

Osteoarthritis - why does this happen? (Complications of fracture healing)

Wear and tear of joints, damage to the joint.

Fractures can cause osteoarthritis if they do not heal properly. Fractures alter the joint's weight distribution and increase pressure on the joint, leading to damage and inflammation that can result in osteoarthritis.

Dislocation (mechanical alteration in bones)

Temporary displacement of two bones with complete loss of contact between articular cartilage

Subluxation (mechanical alteration in bones)

Contact between joint surfaces is only partially lost

Osteomyelitis

Pyogenic inflammation of bone and bone marrow due to infection

Hallmark: bone infection is PUS-PRODUCING

Manifestations of osteomyelitis

Inflammation

Fever

Pain

Necrotic bone

Infection origins of osteomyelitis

-Spread from open wound

-Hematogenous

-Spread from skin infections

Common causative agents of osteomyelitis

S. aureus

S. pneumonia

E. coli (in immunocompromised patients)

Pathogenesis of osteomyelitis

Pathogens enter bone and cause inflammation. Thrombosis of local blood vessels causes ischemic necrosis and fibrosis

Complications of osteomyelitis

Septicemia

Arthritis

Pathologic fractures

Sequestra

Sequestra

Necrotic bone that is a medium for continued bacterial proliferation

Diagnosis of osteomyelitis

- Xrays or bone scans

- Bone biopsy and culture

Tx of osteomyelitis

- IV abx - FIRST LINE OF TX

- Debridement

- Amputation

- Hyperbaric oxygen therapy (enhances bone and soft tissue healing)

Skeletal tuberculosis? How does it spread?

Extrapulmonary form of TB, where pathogen spreads from the lungs to the bone

It spreads to the bone via the blood stream or lymphatic drainage

Common sites of skeletal TB infections

- Weight-bearing joints

- Vertebrae

Pott disease

TB of the spine

Result of TB in the vertebrae

- Neurological impairment

- paraplegia from vertebral necrosis and collapse

Tx of skeletal TB

- Anti-TB drugs

Origin cells of bone tumours

From ANY SKELETAL COMPONENT including bone cells, cartilage, fibroblasts, and bone marrow

Note: tumour cells are MONOCLONAL

T/F: Tumours are more likely to form in well-differentiated cells (e.g. osteocytes). Why?

False: Tumours are likely to occur in LESS-differentiated cells because these cells are either stem cells or progenitor cells that naturally divide more frequently, increasing the chance for accumulating genetic mutations that drive uncontrolled growth

Sarcoma

Malignant bone tumour

Osteoid osteoma? Location? S/S? Tx? Demographics affected?

Small BENIGN tumour found on the surface of long bones, flat bones, or the skull

- well localized, increasingly sever pain

- surgical excision, radiofrequency ablation

- Young adults

Composition of osteoid osteoma

Core contains osteoblasts, osteoclasts, and granulation tissue surrounded by sclerotic bone

Osteoblastoma

Larger, more lytic version of osteoid osteoma

Giant cell tumour (osteoclastoma)? Location? Tx? Demographics affected? Metastasis?

BENIGN Tumour of multinucleated giant osteoclasts is usually located at the junction of the metaphysis and epiphysis of long bones. 50% chance of metastasis after surgical disruption of og. tumour

- locally aggressive

- overexpresses RANK

Tx:

-curettage (scraping and scooping)

- bone grafts

Demographic:

- common in adults (20-40), esp. females

Effect of RANK overexpression in osteoclastoma

Hemorrhage from bone cortex thinning and rupturing

Osteosarcoma? Location? S/S? Tx? Demographics affected? Metastasis?

Highly MALIGNANT and most common primary bone cancer. Occurs around the knee - can metastasize to lung

S/s:

- painful, progressively enlargin mass, subject to sudden fracture

Tx:

- chemo

-radiation

- surgery

Demographics:

- young (10-25)

-elderly (>60)

Pathogenesis of osteosarcoma

Mutations in retinoblastoma or p53 gene lead to malignant osteoblasts

Chrondrosarcoma? Location? S/S? Tx? Demographics affected?

Primary MALIGNANT bone tumour of cartilage. Affects shoulder, pelvis, and ribs

S/s:

- painful, progressively enlarging mass (but slow growing)

Tx:

- chemo

- surgical excision

Demographics:

- males (40-70)

Pathogenesis of chrondrosarcoma

Cartilage expands and destroys bone, which stimulates osteoclasts to break down bone

Ewing sarcoma? Location? S/S? Tx? Demographics affected? Metastasis?

RARE and highly MALIGNANT tumour composed of undifferentiated cells that arise from long bones and pelvis

invades soft tissues and metastasizes widely

S/s:

- pain, fractures, and systemic signs of infection

Tx:

- chemo

- combined surgery

- radiation

Demographics:

- Children and young adults aged

Pathogenesis of Ewing sarcoma

Involves reciprocal translocation between chromosomes 11 and 22

invades soft tissues and metastasizes widely, leading

to pain, fractures, and systemic signs of infection

Fibrosarcoma? Location? Metastasis?

Fibrous mass of collagen, malignant fibroblasts, and osteoclast-like cells. Affects the metaphysis of femur or tibia

Metastasizes to the lungs

What is secondary bone cancer? Why is metastasis in bone common?

Secondary (metastatic) bone tumours - arise from a different organ and spread via lymph or blood

Bone is a common site for metastasis as its is highly vascularized - also why it is often MULTIFOCAL

Types of secondary bone tumours

Osteolytic

Bone-forming

Mixed

Osteolytic secondary bone tumour

Leads to pathological fractures from bone weakening

Bone-forming secondary bone tumour

Leads to overly dense bone foci

Osteogenesis imperfecta

Group of hereditary disorders caused by abnormal synthesis of type I collagen

Other name for osteogenesis imperfecta

Brittle bone disease

Manifestations of osteogenesis imperfecta (6)? Why?

- Basic morphological change: due to osteopenia, collagen is a key protein that provides strength and structural support to bones. This defective collagen makes bones abnormally weak, reducing bone density to a level below average (osteopenia)

- Fractures and dislocation: bone slack tensile strength due to osteopenia

- Blue sclera: lack of collagen, appears blue as it is thin

- Abnormal tooth development

- Deafness: an abnormality in the formation of bones in ars, causing irregularity in sound conduction

- Short stature

All of these are primarily due to defective collagen makeing bones abnormally weak, reducing bone density to a level below average (osteopenia)

Diagnosis of osteogenesis imperfecta

-Analysis of collagen production by fibroblasts

-Genetic testing

-Imaging

Tx of osteogenesis imperfecta

-Surgical correction of abnormalities

-Physiotherapy, orthotic supports, mobility devices

-Bisphosphonates

-Sclerostin inhibitors

Biphosphonates

Used in osteogenesis imperfecta to increase bone density by inhibiting osteoclast activity

Marfan syndrome

Autosomal dominant disorder of connective tissue - impaired crosslinking of collagen and elastic fibres

Pathogenesis of Marfan syndrome

Mutation of the FBN1 gene that results in impaired cross-linking of collagen and elastic fibers in the ECM

Skeletal manifestations of Marfan syndrome

-Excessive height

-Long extremities

-Arachnodactyly

-Laxity of joint ligaments

-Pectus excavatum/pectus carinatum

-Kyphosis and scoliosis

Ocular manifestations of Marfan syndrome

-Ectopia lentis

-Retinal detachment

-Severe myopia

The lenses are not directly held in place due to an abnormality in the crosslinking of collagen and elastic fibres (impaired structural integrity of connective tissue)

CVS manifestations of Marfan syndrome

-Mitral valve prolapse

-Dissection and rupture of aorta

Diagnosis of Marfan syndrome

-Genetic testing

-Imaging of bones and eyes

-ECG (for heart)