Musculoskeletal Flashcards
What are the functions of bone?
• STRUCTURE
– give structure and shape to the body • MECHANICAL
– sites for muscle attachment, allowing movement
• PROTECTIVE
– vital organs and bone marrow
• METABOLIC
– reserve of calcium and other minerals
What is the composition of bone?
Inorganic (65%)
- calcium hydroxyapatite
- is storehouse for 99% of calcium in the body
- 85% of phosphorus, 65% sodium, magnesium
Organic (35%)
-bone cells and protein matrix
Collagen fibres, linking proteins
Describe bone geography.
Diagram
Epiphysis —> metaphysis —> diaphysis (shaft) —> metaphysis —> epiphysis
Describe the bone types and the classification of bone.
Anatomical bones
-flat, long (support weight, facilitate movement, allow linear growth), short/cuboid (carpels, tarsals, stabilise and facilitate movement) irregular (vertebrae, pelvis, protect specific organs), sesamoid (patella, embedded in tendon for protection)
Macroscopic structure
- trabecular/ cancellous/ spongy - criss cross through the medullary cavity
- cortical/ compact- surrounded by periosteum
Microscopic structure
- woven bone (immature) - weak, disorganised bone, developing skeleton, rapid growth, pathological high bone turnover
- lamellar bone (mature)
Classification
Cortical
-long bones
-80% of skeleton
-appendicular skeleton
-80-90% calcified -low turnover, not very active/metabolising
-mainly structural, mechanical and protective
Cancellous
- vertebrae and pelvis
- 20% of skeleton
- axial
- 15-25% calcified
- mainly metabolic
- large surface area
Describe the cortical bone micro anatomy.
Diagram
Circumferential lamellae - in periosteum
Concentric lamellae
Interstitial lamellae - in between osteoblast
Trabecular lamellae - not surrounding osteons but in layers
Each circle is an osteoblast - 0.2 mm diameter. Surround Haversian canal - contain blood vessels
Each * = osteocytes canalicular network - allows bone to signal for repair and replacing
Describe bone cells.
Osteoclasts
-mutlinuclear cells that resorb/remove bone
Osteoblasts
-produce osteoid to form new bone
Osteocytes
-mechanosensory network embedded in mature bone
Describe the bone remodelling cycle.
RANKL and M-CSF from osteoblasts cause osteoclast differentiation
Osteocytes sense damage and stress, apoptose and release RANKL, signal to osteoclast, resorb, then osteoblast recruited to produce osteoid
Why should you perform a bone biopsy?
What are the types of bone biopsy?
• Confirm the diagnosis of a bone disorder
• Find the cause of or evaluate ongoing bone pain or
tenderness
• Investigate an abnormality seen on X-ray
• For bone tumour diagnosis (benign vs malignant)
• To determine the cause of an unexplained infection
• To evaluate therapy performance
Types
-closed: needed , core biopsy (Jamshidi needle)
-open: for sclerotic/ inaccessible lesions
Osteosclerosis, can’t access with needed/ require larger bone sample
Transiliac bone biopsy - can sense all the different types of bone at this site
Describe histological staining of bone?
H and E - on decalcified samples (need to decalcify sample)
Masson - Goldner Trichrome - see amount of mineralised/ unmineralised bone (calcified)
- mineralised = green, unmineralised = orange eg. Osteoid
- useful in osteomalacia
Tetracycline/Calcein binding - measure rate of bone turnover and formation (calcified)
-lay down fluorescent line through injection, after few days another line laid down then measure amount of mineralisation within that distance (mineral acquisition rate), bone formation rate = overall bone formation .
What is metabolic bone disease?
What are the common metabolic bone diseases?
- A group of diseases that cause reduced bone mass and reduced bone strength
- Due to imbalance of various chemicals in the body (vitamins, hormones, minerals, etc)
- Cause altered bone cell activity, rate of mineralisation, or changes in bone structure
Common diseases • Osteoporosis • Osteomalacia/Rickets • Primary hyperparathyroidism • Renal osteodystrophy • Paget’s disease
Explain osteoporosis.
Defined as a bone mineral density T-score of -2.5 or lower
-standard deviations different from mean peak bone mass BMD
Primary: age, post -menopause
Secondary: drugs, systemic disease (endocrine, metabolic) - pathological
High turnover: turnover > formation. Both increase but turnover higher
Low turnover: turnover > formation. Both decrease but formation decreases more
Loss of trabecular bone, holes, thinner, thinking of corticoid bone, compression in spine .etc. = decrease in strength
Osteoclasts > osteoblasts
Decreased quantity of bone mass Microstructure normal
Fragility fractures
Deformity
Pain
Describe osteomalacia/ rickets.
Defective mineralisation of normally synthesised bone matrix
Rockets in children
2 types:
-deficiency of vitamin D - hypocalcaemia
-deficiency of PO4 - phosphate wasting syndromes
Vitamin D:
-absorption in small intestine
-reabsorption in kidneys
(Endocrinology pathway)
Sequelae
- bone pain/tenderness
- fracture
- proximal weakness
- bone deformity
Rickets
- widening of growth plates and bowing of legs
- bones try to remodel and deform
Horizontal fracture in Looser’s zone - looser zone fractures at high tensile stress areas
Decreased bone mineral
Osteopenic bone
Soft bones
Too much un-mineralised osteoid:
Looser’s zone
Compensatory: secondary hyperparathyroidism may be superimposed if
calcium stays low
Vitamin D deficiency
Biochemistry: vit d low, calc: N/low, PTH up Inadequate or delayed mineralisation
Explain hyperparathyroidism.
Excess PTH • increased Ca + PO4 excretion in urine • hypercalcaemia • hypophosphatemia • skeletal changes of osteitis fibrosa cystica = resorption of bone and replacement with fibrous tissue
4 organs are directly or indirectly affected by PTH and between them control calcium metabolism:
Parathyroid glands, bones, kidneys, proximal small intestine
Feedback mechanism lost PTH increases, calcium increases
Primary
- parathyroid adenoma (85-90%)
- chief cell hyperplasia
Secondary
- chronic renal deficiency: cannot excrete PO43-
- Vit D deficiency
Mnemonic: Stones (Ca oxalate renal stones) Bones (osteitis fibrosa cystica, bone resorption) Abdominal groans (acute pancreatitis) Psychic moans (psychosis and depression)
Tunnelling resorption: centre of trabeculae lost
Periosteum bone erosions
Brown cell tumour
Repaired with giant cell granuloma, resemble brown cell tumours
Form of osteitis fibrosa cystica
Primary (due to parathyroid adenoma)
-PTH up, calc down, phosphate down
-Bone resorption
Secondary (due to other systemic biochemical imbalance, chronic kidney disease,rickets/osteomalacia)
-PTH up, calc down, phophate normal or down
-Bone resorption AND increased density Tertiary (autonomous)
-PTH up, calc up, phosphate down
Bone resorption
- subperiosteal
- subchondral
- intracortical
- brown tumours
Describe renal osteodystrophy.
Comprises all the skeletal changes resulting from chronic renal disease:
– Increased bone resorption (osteitis fibrosa cystica)
– Osteomalacia
– Osteosclerosis
– Growth retardation
– Osteoporosis
(Failure to excrete PO42- and make Vit D so secondary hyperparathyroidism may result)
What can bone imaging do?
What are the types of imaging used.
Reveal structural failures such as fractures and ligament outs injuries
Also serves as proxy to metabolic dysfunction
- x-rays: density
- CT: density
- bone densitometry: density
- MRI: biochemical composition
- radionuclelotide bone scans - nuclear medicine bone scans: bone turnover
Define radiological sign and pathology.
What pathologies can be seen on imaging?
Pathology: a disease process that gives rise to symptoms, signs, biochemical disturbances and changes in imaging appearance
Radiological sign: a change in imaging appearance, whether structural or functional, that may point towards a pathological
Pathologies
- osteoporosis
- osteomalacia and rickets
- primary hyperparathyroidism
- secondary hyperparathyroidism (renal osteodystrophy)
- Paget’s disease
Describe the diagnosis for osteoporosis, including the radiology
Diagnosis is with bone densitometry (aka dual-energy absortiometry, DEXA)
A measure of bone mineral density (BMD)
Compares BMD to normal reference databases
and gives
▪ T-score (ref database white adult premenopausal females)
▪ Z-score (ref database age and sex matched)
T-score -1.5 to -2.5 = osteopenia; less than -2.5 = osteoporosis
Radiology
-loss of cortical bone/ thinning of cortex
-loss of trabeculae
-insufficiency fractures: stress fractures due to:
Normal stress on abnormal bones
Common sites - sacrum, underside of femoral neck, vertebral bodies, pubic rami
Insufficiency fractures seen in imaging:
X-ray
-initially normal
-can get periosteal reaction and callus
-more commonly increased sclerosis around fracture lines
MRI
-bone oedema .i.e low signal on TI, high signal on T2 and STIR
-increased osteoblastic activity i.e. increased uptake
Describe the radiology in osteomalacia/ rickets?
Radiology depends on age and closure of growth plate
Osteomalacia
- Mature skeleton
- Osteopenia
- Looser’s zones
- Codfish vertebrae
- Bending deformities
Rickets
- Before growth plate closure
- Radiological signs centred mainly to growth plates
- Changes of osteomalacia
Looser’s zones Pseudo/insufficicnecy fractures at high tensile stress areas: -Medial proximal femur -Lateral scapula -Pubic rami -Posterior proximal ulna -Ribs
Biconcave deformity of vertebrae seen in:
- Osteoporosis
- Osteomalacia
Rickets Indistinct/frayed metaphyseal margin Widened growth plate without calcification Cupping/splaying metaphyses due to weight bearing Enlargement of anterior ribs Osteopenia
Describe diagnosis of renal osteodystrophy.
Osteomalacia and osteoporosis
Secondary hyperparathyroidism
-Subperiosteal erosions, brown tumours
-Sclerosis – vertebral endplates giving a rugger jersey spine
-Soft tissue calcification (vessels, cartilages)
Explain Paget’s disease.
Disorder of bone turnover
Divided into 3 stages:
1) osteolytic - focal bone loss and bone loss in specific regions, thickened cortices
2) osteolytic-osteosclerotic - reactive stage, respond to loss, osteoclasts and active resorption
3) quiescent osetosclerotic - osteoblasts react- mosaic pattern
Onset > 40y (affects 3-8% Caucasians > 55y) M>F Rare in Asians and Africans Mono-ostotic 15% (one bone) Remainder polyostotic
Aetiology is unknown
Familial cases show autosomal pattern of inheritance with incomplete penetrance (mutations in SQSTM1 or RANK)
Parvomyxovirus type particles have been seen on EM in Pagetic bone – some doubt this is cause.
Overuse or previous bone injury.
Clinical symptoms:-
– pain
– microfractures
– nerve compression (incl. Spinal N and cord)
– skull changes may put medulla at risk
– deafness
– +/- haemodynamic changes, cardiac failure
– hypercalcaemia
– Development of sarcoma in area of involvement 1%
Disease of bone remodelling
Lytic phase
Mixed lytic/sclerotic phase
Sclerotic phase
Bone pain, deformity, spontaneous fractures May get nerve entrapment, spinal stenosis and deafness
Osteogenic sarcoma
Raised serum alk phos, urinary hydroxyproline, pyridinoline cross-links
Describe radiology in Paget’s.
Cortical thickening
Bone expansion
Coarsening of trabeculae
Osteolytic, osteoclerotic and mixed lesions Osteoporosis circumscripta
What is metabolic bone disease? What are the common metabolic bone disorders?
What are the common symptoms?
What makes a bone strong?
A group of diseases that cause a change in bone density and bone strength by:
1) increasing bone resorption
2) decreasing bone formation
3) altering bone structure
And may be associated with disturbances in mineral metabolism
Common:
- primary hyperparathyroidism
- rickets/ osteomalacia
- osteoporosis
- Paget’s disease
- renal osteodystrophy
Symptoms:
Metabolic - hypocalcaemia, hypercalcaemia, hypo/hyperphosphataemia
Specific to bone - bone pain, deformity, fractures
Mass, Material properties (matrix and mineral) - collagen crosslinking, microarchitecture -trabecular thickness, macro architecture -diameter
What are the ways in which we can access bone structure and function?
How does growth and exercise change peak bone mass?
What is meant by bone remodelling?
Bone histology
Biochemical tests
Bone mineral densitometry e.g. osteoporosis
Radiology
Growth and exercise:
Change in bone dimensions, change in bone shape, change in trabecular volumetric BMD
Bone remodelling:
Process by which areas are repaired, each osteomalacia represents a previous remodelling event
What are the biochemical investigations used in bone disease?
Explain them for each disease?
Serum
Bone profile: Calcium Corrected calcium (albumin) Phosphate Alkaline phosphatase
Renal function:
Parathyroid hormone
25-hydroxy vitamin D
Urine:
Calcium/phosphate
NTX
(Diagram)
Explain calcium balance.
Uses 3 main systems: GI tract, bone, kidney
Total calcium can be complexed, ionised (free) which then undergoes alkalosis to be protein bound
PTH
- Mg dependent
- 8 min T1/2
- PTH receptor activated also by PTHrP
PTH drives active calcium absorption in distal tubule of the kidney
PTH causes bone resorption through the RANK system
Explain primary hyperparathyroidism.
50s, female: male 3:1
Causes: parathyroid adenoma (most common), parathyroid hyperplasia, parathyroid CA
Familial syndromes - MEN 1 2%
An elevated total/ionised calcium (hypercalcaemia) with PTH levels elevated or in the upper half of normal range
Non-suppressed
Clinical features: Thirst, polyuria, tiredness, fatigue, muscle weakness “Stones, abdominal moans and psychic groans” Renal colic, nephrocalcinosis, CRF Dyspepsia, pancreatitis Constipation, nausea, anorexia Depression, impaired concentration Drowsy, coma
Patients may also suffer fractures secondary to bone resorption
High serum calcium causes a diuresis
Chronically elevated PTH increases stone risk
Chronically elevated PTH causes increased cortical bone resorption (increased bone turnover, acute/pulsed PTH: anabolic, chronic: catabolic, cortical > cancellous (light poreless bone)
Chronically elevated PTH increases fracture risk
Biochemical findings
1) increased serum calcium by absorption from bone/ gut
2) decraesed serum phosphaterenal excretion in proximal tubule
3) PTH in the upper half of the normal range or elevated
4) increased urine calcium excretion
5) Cr may be elevated
Explain metabolism and actions of vitamin D.
Vitamin D is metabolised by liver and kidney (pathway from endo)
Vit D binding protein (DBP): t1/2 3 days filtered by kidney
Activated vitamin D increases gut calcium absorption - 1,25(OH)VitD
Vit D actions
Intestine: activates Ca and P absorption in duodenum
Bone: synergies with PTH acting on osteoblasts to increase formation of osetoclasts through RANKL
Increases osteoblasts differentiation and bone formation
Kidney: facilitates PTH action to increase Ca reabsorption in distal tubule
Feedback: parathyroid directly to reduce PTH secretion and increase FGF-23 production in bone
Deficiency of Vit D effects:
Inadequate Vit D leads to defective mineralisation of the cartilaginous growth plate (before a low calcium)
Symptoms
Bone pain and tenderness (axial)
Muscle weakness (proximal)
Lack of play
Signs Age depended deformity Myopathy Hypotonia Short stature Tenderness on percussion
Explain the causes of rickets/ osteomalacia including the biochemical findings.
Vitamin D related
Dietary
Gastrointestinal: small vowel malabsorption/bypass, pancreatic insufficiency, liver/biliary disturbance, drugs -phenytoin, phenobarbitone
Renal: chronic renal failure
Rare hereditary: type I: deficient of 1a hydroxylase, II: defective VDR for calcitriol
Biochemistry Serum: Calcium N/low Phosphate N/low Alk phos High 25(OH)Vit D Low PTH High (secondarily to compensate)
Urine:
Phosphate high
Glucosuria, aminoaciduria, high pH, proteinuria
FGF-23 cause PCT phosphate loss as well as PTH
Produced by osteoblasts
Like PTH causes P loss, unlike PTH inhibits action of Vit D by 1 a OHase
Osteomalacia and phosphate
Kidney forced to lose phosphate
“Isolated” hypophosphatemia: X-lined hypophosphataemic rickets, high levels of FCF-23
Autosomal dominant hypophosphataemic rickets (ADRR) - cleavage site for FCF-23 mutated so high FGF-2
Oncogenically osteomalacia: mesenchymal tumours produce FGF-23
Therefore FGF-23 excess can cause rickets/ osteomalacia
Also:
Kidney proximal tubule damage causes phosphaturia and stops 1a hydroxylation of Vit D (normally PCT only reabsorbs P so this is problem because no reabsorption)
Fanconi syndrome: multiple myeloma, heavy metal poisoning (lead, Mercury), drugs e.g. gentamicin, congenital disease e.g. Wilsons
Explain osteoporosis including biochemical findings.
Causes:
1) High turnover - increased bone resorption greater than increased bone formation eg. Oestrogen deficiency, hyperparathyroidism, hyperthyroidism, hypogonadism
2) Low turnover - decreased bone formation more than decreased bone resorption: liver disease, heparin, age above 50
3) increased bone resorption and decreased bone formation - glucocorticoids
Oestrogen deficiency
Causes remodelling balance with increased bone resorption compared to bone formation (enhanced osteoclast survival and activity)
Trabecular perforation
Increased fracture rates
Biochemistry in osteoporosis used to exclude other causes Serum biochemistry should all be normal 1. Check for Vit D deficiency 2. Check for secondary endocrine causes Primary hyperparathyroidism PTH high Primary hyperthyroidism free T3 high, TSH suppressed Hypogonadism Testosterone low 3. Exclude multiple myeloma 4. May have high urine calcium
BMD measured in osteoporosis
DEXA measures transmissions brought the body of Xrays of two different photon energies
Enables densities of two different tissues to be inferred, i.e. bone mineral, soft tissue
T-score:
Osteoporosis = -2.5
Osteopenia = -1 to 2.5
Normal = > -1
FRAX uses hip BMD (2nd commonest fracture after vertebral)
Bone markers
Unlike BMD they are dynamic, insight into activity of bone cycle. Divided into markers of formation and resorption
Formation markers:
o P1NP – Procollagen type 1 N-terminal Propeptide.
In production of collagen (2a1, 1a2), extension polypeptides (P1NP) are cleaved.
Resorption markers:
o Serum CTX – Cross-linked C-telopeptides.
o Urine NTX – Cross-linked N-telopeptides.
3 hydroxylysine molecules condense out to form a pyridinium ring linkage on resorption of bone.
Resorption markers are used to monitor osteoporosis treatment.
o Bone reabsorption markers fall in 4-6 weeks.
o Expect a 50% drop of urine NTx by 3 months.
o Problems though:
-Hard to reproduce.
-Positive association with age anyway.
-Need to correct for creatinine.
-Diurnal variation in urine markers.
Formation markers:
o Only one formation marker is in common use – ALP.
Used in diagnosis/monitoring of:
• Paget’s disease of bone.
• Osteomalacia.
• Bony metastasis.
BSAP – Bone-Specific Alkaline Phosphatase:
• Types – tissue-specific (bone) form of ALP.
• Roles – essential for mineralisation of bone and regulates concentrations of phosphate.
• Uses – T1/2 40 hours. Increased in Paget’s, osteomalacia, bone metastasis, HPT, HT.
NOTE that ALP varies with age (younger people have more).
o P1NP is being used as a predictor of response to anabolic treatments – e.g. PTH treatment.
