Bone pathology Flashcards
What are the basic functions of bone?
•MECHANICAL
–support and site for muscle attachment
•PROTECTIVE
–vital organs and bone marrow
•METABOLIC
–reserve of calcium
Bone and the struts and levers it forms is adapted to resist stress, support the body and provide leverage for movement. Macroscopically it is white and dense.
Describe the composition of bone
•INORGANIC - 65%
–calcium hydroxyapatite (10Ca 6PO4 OH2)
–is storehouse for 99% of Ca in the body
–85% of the phosphorous, 65% Na & Mg
•ORGANIC - 35%
– bone cells and protein matrix
Bone matrix is 60-70% inorganic salts (Ca &PO4) 30-40% collagen (Type 1 mostly with some type V) 10-20% water and ~5% non-collagenous protein & carbohydrate. Certain cations rg radium strontium and lead are ‘bone seeking’. They can be radioactive or toxic and cause bone marrow failure.
Describe basic bone geography
Bones display articular surfaces at synovial joints. If small these are called facet joints or fovea. Condyles are knuckle shaped and a trochlea is grooved like a pulley ( ref Grays anatomy).
Compare and contrast the following types of bone
- Cortical
- Cancellous
Cortical:
- Long bones
- 80% of skeleton
- Appendicular
- 80-90% calcified
- mainly mechanical and protective
Cancellous:
- Vertebrae & pelvis
- 20% of skeleton
- Axial
- 15-25% calcified
- mainly metabolic
- Large surface
What does this image show?
Cortical bone stained
What does this image show?
Cancellous bone stained
Define the function of the following bone cells
- Osteoblasts
- Osteoclasts
- Osteocytes
- Osteoblasts - build bone by laying down osteoid
- Osteoclasts - multinucleate cells of macrophage family resorb or chew bone
- Osteocytes - osteoblast like cells which sit in lacunae
Describe what is important for bone cells and their processes
Hormones, cytokines, growth factors, and signal-transducing molecules are instrumental in their formation and maturation, and allow communication between osteoblasts and osteoclasts. Bone resorption and formation in remodeling are coupled processes that are controlled by systemic factors and local cytokines, some of which are deposited in the bone matrix. BMP, bone morphogenic protein; LRP5/6, LDL receptor related proteins 5 and 6
What regulates osteoblast formation and function?
Paracrine molecular mechanisms
Describe the role of RANKL and OPG in osteoclast formation and function
Osteoclasts are derived from the same mononuclear cells that differentiate into macrophages. Osteoblast/stromal cell membrane-associated RANKL binds to its receptor RANK located on the cell surface of osteoclast precursors. This interaction in the background of macrophage colony-stimulating factor (M-CSF) causes the precursor cells to produce functional osteoclasts. Stromal cells also secrete osteoprotegerin (OPG), which acts as a “decoy” receptor for RANKL, preventing it from binding the RANK receptor on osteoclast precursors. Consequently, OPG prevents bone resorption by inhibiting osteoclast differentiation.
- What is metabolic bone disease?
- What is the overall effect?
- Disordered bone turnover due to imbalance of various chemicals in the body (vitamins, hormones, minerals etc)
- Overall effect is reduced bone mass (osteopaenia) often resulting in fractures with little or no trauma
What are the three main categories of metabolic bone disease?
- Non-endocrine (e.g. age related osteoporosis)
- Related to endocrine abnormality (Vit D; Parathyroid hormone)
- Disuse osteopaenia
How is metabolic bone disease diagnosed?
•Histology requires bone biopsy from iliac crest,
processed un-decalcified for histomorphometry
•‘Static’ parameters include
–cortical thickness & porosity
–trabecular bone volume
–thickness, number & separation of trabeculae
- Bone mineralisation is studied using osteoid parameters
- ‘Histodynamic parameters’ are obtained from fluorescent tetracycline labelling
What are the most common causes of osteoporosis?
•Aetiology – 90% cases due to insufficient Ca intake and post-menopausal oestrogen deficiency
–1º - age, post-menopause
–2º - drugs, systemic disease
What is the difference between ‘high turnover’ and ‘low turnover’ osteoporosis?
- ‘High turnover’ OP results from ↑ bone resorption
- ‘Low turnover’ OP results from ↓ bone formation
What are the risk factors for osteoporosis?
- Advanced age
- Female sex
- Smoking
- XS Alcohol
- Early menopause
- Long-term immobility
- Low body mass index
- Poor diet ↓vit D, ↓Ca2+
- Malabsorption
- Thyroid disease
- Low testosterone
- Chronic renal disease
- Steroids
Describe what happens to the following bone cells when there is glucocorticoid excess
- Osteoclast
- Osteoblasts
- Osteocytes
How do osteoporosis patients commonly present?
Patients commonly present with back pain and fracture
- Wrist fracture (Colles’)
- Hip (NOF and intertrochanteric)
- Pelvis
All may be the first sign of disease
What investigations should be done for osteoporosis?
Lab investigations:
- Serum calcium, phosphorous & alk phos (usually N)
- Urinary calcium
- Collagen breakdown products
Imaging
Bone Densitometry
- T score between 1 & 2.5 SD below normal peak bone mass= osteopaenia
- T score >2.5 SD below normal peak bone mass = osteoporosis
Which four organs are directly/indirectly affected by PTH and between them control Ca metabolism?
- Parathyroid glands
- Bones
- Kidneys
- Proximal small intestine
What does Vitamin D deficiency do to PTH?
Vitamin D deficiency leads to increased PTH release and subsequent bone resorption.
What is the commonest cause of hypocalcaemia?
Vitamin D deficiency
How does hypocalcaemia present?
- Muscle twitching
- Spasms
- Tingling
- Numbness
What is the action of PTH on the following:
- Kidney
- Bone
- GI tract
- Kidney:
- Ca reabsorption
- Vitamin D activation
- Bone
* Osteoclast activity/resorption - GI Tract
* Ca absorption
- What is Osteomalacia?
- What are the two types?
- Defective bone mineralization
- 2 types
- Deficiency of vitamin D
- Deficiency of PO4
What happens to bone as a consequence of osteomalacia?
- bone pain/tenderness
- fracture
- proximal weakness
- bone deformity
What is osteomalacia called in children?
Rickets
What does this image show?
Horizontal fracture in Looser’s zone
What happens when there is excess PTH?
–increased Ca + PO4 excretion in urine
–hypercalcaemia
–hypophosphataemia
–skeletal changes of osteitis fibrosa cystica
What are the causes of:
- Primary hyperparathyroidism
- Secondary hyperparathyroidism
- Primary hyperparathyroidism
- Parathyroid adenoma (85-90%)
- Chief cell hyperplasia
- Secondary hyperparathyroidism
- Chronic renal deficiency
- Vitamin D deficiency
- Malabsorption
What is the symptoms Mneumonic for hyperparathyoidism?
- Stones (Ca oxalate renal stones)
- Bones (osteitis fibrosa cystica, bone resorption)
- Abdominal groans (acute pancreatitis)
- Psychic moans (psychosis & depression)
What does this X ray show?
X ray showing features of osteitis fibrosa cystica affecting the tibia
What is a brown cell tumor of hyperparathyroidism?
The brown tumor is a bone lesion that arises in settings of excess osteoclast activity, such as hyperparathyroidism
What happens to the skeleton in renal osteodystrophy?
Comprises all the skeletal changes of chronic renal disease:-
- Increased bone resorption (osteitis fibrosa cystica)
- Osteomalacia
- Osteosclerosis
- Growth retardation
- Osteoporosis
What is Paget’s disease?
Disorder of bone turnover
Stages:
- Osteolytic phase - increased osteoclast activation caused increased osteolysis
- Osteolytic-osteosclerotic - mixed phase, presence of osteoblasts and osteoclasts, with some new bone formation
- Quiescent osteosclerotic - becomes dominated by osteoblasts
What is the epidemiology of Paget’s disease?
- Onset > 40y
- M=F
- Rare in Asians and Africans
- Mono-ostotic 15%
- Remainder polyostotic
What is the aetiology of Paget’s disease?
- Aetiology is unknown
- Familial cases show autosomal pattern of inheritance with incomplete penetrance (mutation 5q35-qter - sequestosome 1 gene)
- Parvomyxovirus type particles have been seen on EM in Pagetic bone
What is the clinical presentation of Paget’s disease?
- pain
- microfractures
- nerve compression (incl. Spinal N and cord)
- skull changes may put medulla at risk
- +/- haemodynamic changes, cardiac failure
- Development of sarcoma in area of involvement 1%
What does this image show?
Paget’s disease affecting tibia
What are the 5 types of fractures?
What are the 4 stages of fracture repair?
- Organisation of haematoma at # site (pro-callus)
- Formation of fibrocartilaginous callus
- Mineralisation of fibrocartilaginous callus
- Remodelling of bone along weight-bearing lines
What factors influence fracture healing?
- Type of fracture
- Presence of infection
- Pre-existing systemic condition :-
–Neoplasm
–Metabolic disorder
–Drugs
–Vitamin deficiency
What are the most common sites for osteomyelitis?
- Vertebrae
- Jaw (2º to dental abscess)
- Toe (2º to diabetic skin ulcer) (>3mm)
- Long bones (usually metaphysis)
What are the clinical features of osteomyelitis
- General
- Local
- General - malaise, fever , chills , leucocytosis
- Local - pain, swelling and redness
60% positive blood cultures
What does an X ray of osteomyelitis show?
Mixed picture, eventually lytic
- What is the most common cause of osteomyelitis?
- What are the common routes of infection?
- Almost always bacterial, rarely fungal
- Routes of infection
- haematogenous (blood bourne)
- Direct extension
- Traumatic (line surgery)
What are the most common causative organisms of osteomyelitis?
Adults
- Staph Aureus(90%)
- E. Coli
- Klebsiella
- Salmonella (associated with sickle cell disease)
- Pseudomonas (IVDA)
Neonates
- Haemophilus influenzae
- Group B Streptococcus
- Occasionally enterobacter
What are some of the X-ray changes that appear in osteomyelitis?
- Usually appear 10 days or so post onset
- Mottled rarefaction and lifting of periosteum
- >1week - irregular sub-periosteal new bone formation called involucrum
- Later - irregular lytic destruction (takes 10-14days)
- Some areas of necrotic cortex may become detached called sequestra (takes 3-6 weeks)
What does this image show?
Osteomyelitis
Involucrum -An involucrum (plural involucra) is a layer of new bone growth outside existing bone.
Sequestrum -a piece of dead bone tissue formed within a diseased or injured bone, typically in chronic osteomyelitis.
What is Pott’s disease?
Spinal disease caused by TB, may result in psoas abscess and severe skeleteal deformity
What are the giant cells called in this picture of TB osteomyelitis?
a) Megakarocytes
b) Osteoclasts
c) Langerhans-type giant cells
c) Langerhans-type giant cells
Syphilis is another rare cause of osteomyeltitis
What are the congenital or acquired skeletal lesions that can occur?
Congenital skeletal lesions:-
- Osteochondritis
- Osteoperiostitis
- Diaphyseal osteomyelitis
Aquired – late skeletal lesions:-
- Non-gummatous periostitis
- gummatous inflammation of bone and joints
- Neuropathic joints (Tabes Dorsalis)
- Neuropathic shaft fractures
- Define lyme disease
- What is the organism?
- What is the Tick species?
Definition:-
- Inflammatory arthropathy as part of a complex multisystem illness resulting from tick bite.
- It is the most prevalent vector bone disease in temperate Northern hemisphere
Organism:-
- Borrelia burgdorferi
Tick Species:-
- Ixodes dammini
What skin rash is associated with a tick bite?
Erythema chronicum migrans
Describe what happens in the following stages of Lyme disease?
- Early localized
- Early disseminated
- Late, persistent
- Early localised
- Characterised by rash (90%) usually within 7-10 days and between 1 & 50cm diameter.
- Often thigh, groin, axilla (earlobe in children)
Early Disseminated
- Affects many organs, musculoskeletal, heart, nervous system.
Late, persistent
- Dominated by arthritis.
What is the treatment for lyme disease?
- Treatment is based on prevention.
- Vaccines are available.
- Antibiotics for proven disease.
- No effective prophylaxis.
- Diagnosis is clinical. No specific histological features.
- Define osteoarthritis
- Define the difference between Primary and secondary OA
- Osteoarthritis is a degenerative joint disease
- Primary OA:
- Age related
Secondary OA:
- Any age
- Previously damaged or congenitally abnormal joint affected
What is the suspected aetiology of osteoarthritis?
- Biochemical factors
- Biomechanical factors
- Ageing
- Genetic
What does osteoarthritis result in?
- cartilage degeneration
- fissuring
- abnormal matrix calcification
- osteophytes
What are the main sites for Osteoarthritis?
Main sites vertebrae hips and knees
+/-DIPJ PIPJ of the hand
+/- carpometacarpal and metatarsophalangeal joints
What does this image show?
Inflamed synovium in osteoarthritis
- Define rheumatoid arthritis
- What is the epidemiology?
- What is the aetiology?
- RA is a severe chronic relapsing synovitis
- 3 F: 1M
Age 30-40years
- Aetiology
–most likely autoimmune
–genetic predisposition (risk alleles TNFA1P3, STAT4)
- Increased incidence amongst first degree relatives
- Associated with HLA DR4 & DR1 (Chr 6p21)
What are 80% of people with rheumatoid arthritis positive for?
•80% patients RF +ve
–RF mostly IgM
–RF forms immunocomplexes with IgG
What are the clinical features of rheumatoid arthritis?
- Mild anaemia
- Raised ESR
- RF+ve(80%)
- +/- rheumatoid nodules (25%)
*can be multisystem disease
- What are the sites of rheumatoid arthritis?
- What are the characteristic deformities that can occur in rheumatoid arthritis?
Sites:-
- Small joints, hands and feet, sparing DIPJ
- Wrists elbows ankles and knees
Characteristic deformities include:-
- Radial deviation of wrist
- Ulnar deviation of fingers
- ‘Swan neck’ & ‘Boutonniere’ deformity of fingers
- ‘Z’ shaped thumb
What is the histology of rheumatoid arthritis?
Proliferative synovitis with
- Thickening of synovial membranes ( villous)
- Hyperplasia of surface synoviocytes
- Intense inflammatory cell infiltrate
- Fibrin deposition and necrosis
Pannus formation with exuberant inflamed synovium
overlying the articular surface
What are Grimley-Sokoloff cells?
Grimley–Sokoloff Giant Cells The hyperplasia and hypertrophy of both intimal and subintimal synovial lining cells is dramatic in RA
What is the diagnosis here?
- Rheumatoid arthritis
- Osteoarthritis
- Gout
- Pseudogout
- Normal
Gout
Describe where gout usually affects and the lesions
- Affects any joint but great toe in 90%
- Usually limited to lower extremities
- Precipitate of needle shaped crystals into joint
- Tophus is the pathognomic lesion
What does this image show?
Acute gout
What does this image show?
Gout tophus
A tophus is a deposit of uric acid crystals, in the form of monosodium urate crystals, in people with longstanding hyperuricemia (high levels of uric acid in the blood). Tophi are pathognomonic for the disease gout.
Describe Calcium crystal deposition disease
- Pseudogout
- Usual age > 50y
- Crystals of
- Calcium pyrophosphate - mainly knees or
- Calcium phosphates (hydroxyapatite) - knees and shoulders
What does this image show?
Ca pyrophosphate crystals
What are the 4 distinct subsets/types of pseudogout?
a) Sporadic (8% pts <75; 22%>85 ?F>M)
b) Metabolic (haemochromatosis, primary HPT, hypoMg; low PO4)
c) Hereditary (autosomal dominant) (ANKH mutn – transmembrane glygoprotein. Chr 8q, 5p, younger age 18% OA knee; 10% hip)
d) Traumatic
What is the commonest malignant bone tumor?
Commenest malignant bone tumor is metastatic
Which cancers metastasize to bone in:
- Adults
- Children
- Adults:
- Breast
- Prostate
- Lung
- Kidney
- Thyroid
- Children
- Neuroblastoma
- Wilm’s tumour
- Osteosarcoma
- Ewings
- Rhabdomyosarcoma
What are the primary malignant bone tumors?
- Osteosarcoma
- Chondrosarcoma
- Ewing’s sarcoma/PNET (primitive peripheral neuroectodermal tumour)
Osteosarcoma is the commonest primary bone sarcoma
- What is most common age affected?
- What is the most common site?
- What does the X-ray show?
- What would the histology show?
- What is the prognosis?
- Age: peak in adolescence (75% patients are <20y)
- Site: 60% occur around the knee, 15% in the hip
- X-ray: usually metaphyseal, lytic, permeative, elevated periosteum (Codman’s Triangle)
- Histo: malignant mesenchymal cells +/- bone and cartilage formation
- Prognosis: poor- 60% 5 year survival. Treatment is usually chemo and limb salvage surgery
- What is a chondrosarcoma?
- What is most common age affected?
- What is the most common site?
- What does the X-ray show?
- What would the histology show?
- What is the prognosis?
- Malignant cartilage producing tumour
- Age: 40y and over, M:F = 5:4
- Site: pelvis, axial skeleton, prox femur, prox tibia
- X-ray: lytic with fluffy calcification
- Histo: malignant chondrocytes +/- chondroid matrix may dedifferentiate to high grade sarcoma
- Prognosis: 70% 5y survival (depends on grade & size)
- What is a Ewing’s sarcoma/PPNET?
- What is most common age affected?
- What is the most common site?
- What does the X-ray show?
- What would the histology show?
- What is the prognosis?
- What is the specific chromosome translocation?
- Highly malignant small round cell tumour
- Age: usually < 20y (80%) M:F = 4:3
- Site: diaphysis/metaphysis of long bones, pelvis
- X-ray: onion skinning of periosteum, lytic +/- sclerosis
- Histo: sheets of small round cells
- Prognosis : - 75% 5y survival 50% longterm
- Specific chromosome translocation 11:22 (EWS/Fli1)
t(11;22)(q24;q12) which results in a EWSR1-FL11 fusion protein
