MSK; Lecture 1, 2 and 3 - Intro and biochemistry, Histopathology and Radiology Flashcards
What is metabolic bone disease?
Group of diseases that cause change in bone density and strength -> by increasing bone resorption, decreasing bone formation and altering bone structure (ass.. w/disturbances in mineral met)
What are the 5 common metabolic bone disorders?
1ry hyperPTHism, Rickets/osteomalacia, osteoporosis, Paget’s disease, renal osteodystrophy
What are the symptoms of the common metabolic bone disorders?
Met: hypo/hypercalcaemia, hyper/hypophosphataemia. Bone specific: deformity, fractures causing bone pain
What Ca is present in bone?
Hydroxyapatite; cancellous bone is met active
Which processes occur in the bone?
Remodelling -> 5% anytime with the total skeleton over 7y; continuous exchange of ECF with bone fluid reserve
What makes bone strong?
Mass, Material properties (matrix and mineral), Microarchitecture, Macroarchitecture
How can bone structure and function be assessed?
Bone histology, biochemical tests, BMD, radiology
How does bone mass change with age?
Peak in 20s with men and women decreasing after their 40s, women much faster in early menopause
What is the function of bone?
Mechanical (support and site for muscle attachment); protective (vital organs and bone marrow); metabolic (reserve of calcium)
What is bone composed of?
Inorganic (65%) - Ca hydroxyapatite, storehouse for 99% of Ca in body, 85% of PO4 and 65% in Na/Mg; organic 35% (bone cells and protein matrix)
What are cortical bones?
Skull and long bones, 80% of skeleton, appendicular, 80-90% calcified and mainly mechanical/protective
What are cancellous bones?
Vertebrae and pelvis; 20% of skeleton, axial, 15-25% calcified; mainly metabolic with large SA to allow for easy release of Ca
Why would you take a bone biopsy?
Indications -> evaluate bone pain/tenderness, investigate an abnormality seen on xray; for bone tumour diagnosis (benign/malignant); determine cause of unexplained infection; evaluate therapy
What types of bone biopsy available?
Usually in anterior superior iliac crest for marrow; closed: needle core biopsy; open: for sclerotic/inaccessible lesions
What are osteoblasts?
Build bone by laying down osteoid
What are osteoclasts?
Multinucleate cells of macrophage family; resorb/chew bone
What are osteocytes?
Osteoblast like cells which sit in lacunae in bone
How do you form an osteoblast?
RANK and RANKL
What is RANK?
Receptor activator for nuclear factor kB
What is osteoprotegerin?
Inhibits RANK/L binding and therefore inhibits osteoclastogenesis
What are the types of bone?
Anatomically flat/long/cuboid bones (intramembranous ossification (flat) and endochondral ossification (long)); trabecular (cancellous); compact bone (cortical); woven bone (immature), lamellar bone (mature)
What are reversal lines?
You can see where there has been resorption and building up of bone - like a fossil
What is metabolic bone disease?
Disordered bone turnover due to imbalance of various chemicals in the body (vit, hormones, minerals); overall effect is reduced bone mass (osteopoenia) often resulting in fractures with little/no trauma
What are the 3 main categories of metabolic bone disease?
Related to endocrine abnormality (vit D, PTH); non-endocrine (Age related osteoporosis); disuse osteopoenia (in bed for a long time/space)
What can cause osteoporosis?
1ry: age, post menopause; 2ry: drugs, systemic disease
What features do patients present with?
Bone pain, pathological fracture; weakness in bone
What is the pathological bone in osteoporsis?
Less dense bone
What happens to mineralisation of bone in osteoporosis?
Mineralisation is the same
What is osteomalacia?
Defective bone mineralisation -> 1ry from deficiency of vit D; 2ry from deficiency of PO4
What are the functions of Vit D?
Bone metabolism, intestinal/renal Ca absorption, cell proliferation, cell differentation, immune regulation
What are the symptoms of osteomalacia?
Sequelae; bone pain/tenderness, fracture, proximal weakness, bone deformity
What occurs in rickets?
The growth plates expand but aren’t strong enough to support soft tissue weight, so bow to the side.
Cupping of metaphyses and fraying/splying of the bones occurs.
What are Looser’s zone?
Horizontal fractures in osteomalacia
What is hyperPTHism?
- Excess PTH;
- increased Ca/PO4 excretion in urine hyperCa,
- hypoPO4;
- skeletal changes of osteitis fibrosa cystica (pain as bone is broken down too quickly, and holes are forming in the bone)
- 1ry due to pit adenoma -> BONE RESORPTION
- 2ry due to other systemic background -> BONE RESORPTION AND BONE MINERALISATION (higher PO4 in 2ry)
What is osteitis fibrosa cystica?
Pain as bone is broken down too quickly, and holes are forming in the bone - cysts seen in xray and fibrous tissue in bone where it is breaking
What are the organs affected by hyperPTHism?
PTH glands, bones, kidneys, proximal small intestine
What are the causes of Hyperpthism?
1ry: PTH adenoma; chief cell hyperplasia; 2ry chronic renal deficiency/ vit D deficiency
What is a simple diagnosis method of HyperPTHism?
X-ray of hand; causes small lesion in bones of hand -> brown cell tumours (bone broken down and replaced by fibrous tissue)
What is renal osteodystrophy?
Comprises all skeletal changes of chronic renal disease,->
- increased bone resorption (OFC);
- osteomalacia;
- osteosclerosis;
- growth retardation;
- osteoporosis
What are the features of renal osteodystrophy?
- PO4 retention – hyperphosphataemia
- Hypocalcaemia as a result of ↓vit D
- 2ry hyperparathyroidism
- Metabolic acidosis
- Aluminium deposition
- subperiosteal erosions,
- brown tumours,
- sclerosis
- soft tissue calcification (vesels, cartilage)
What is Paget’s disease?
Disorder of bone turnove -> 3 stages:
- osteolytic;
- osteolytic-osteosclerotic;
- Quiescent osteosclerotic
What is the pathogenesis of Paget’s?
Onset: >40y mainly in caucasians; M=F; rare in asians and africans; mono-ostotic (15%) and rest polyostotic; Familial cases show autosomal patter of inheritance with incomplete penetrance; parvomyxovirus type particles found
What is the site predilection in Paget’s disease?
x
What are the symptoms of paget’s?
Pain; microfractures; nerve compression (incl. Spinal N and cord); Skull changes may put medulla at risk; deafness; +/-haemodynamic changes, cardiac failure haemodynamic changes, cardiac failure • hypercalcaemia • Development of sarcoma in area of involvement 1%
How does each substance in biochem investigations change in each of the 5 main metabolic diseases of bone?
What is normal Ca homeostasis?
How is Ca distributed in the body and how is it corrected?
How does PTH regulate sCa levels?
Has predominant role in minute regulation -> highest regulation from kidneys
What is relevant about PTH?
84a.a. peptide but N1-34 active; Mg dependent (low in alcoholics); T1/2: 8min; PTH receptor activated by PTHrP
Slide 23
x
What is the function of PTH in the kidney?
What is the function of PTH in the bone?
Bone resorption through RANK system
What are the causes of 1ry HyperPTHism?
50s; 3F:1M; Parathyroid adenoma 80%; Parathyroid hyperplasia = 20%; Parathyroid CA = <1%. Familial Syndromes: MEN 1 = 2%; MEN 2A = rare; HPT-JT = rare
How do you diagnose hyperPTHism?
An elevated total/ionised calcium with PTH levels frankly elevated or in the upper half of the normal range’; (ie. Corrected Calcium > 2.60 mmol/l with PTH > 3.9 pmol/l (nr 1.0 - 6.8)). Subjects with hypercalcaemia and a PTH in the upper half of the normal range are physiologically not normal. It is important to note that such ‘non-suppressed’ concentrations are entirely compatible with the diagnosis of Primary HPT
What is the clinical features of 1ry HyperPTHism due to high Ca?
Thirst, polyuria, Tiredness, fatigue, muscle weakness, Renal colic, nephrocalcinosis, CRF, Dyspepsia, pancreatitis, Constipation, nausea, anorexia, Depression, impaired concentration, Drowsy, coma. Patients may also suffer fractures secondary to bone resorption
How does high sCa cause diuresis?
Ca >3 is medical emergency as they become acutely dehydrated
What does chronically elevated PTH increase the risk of?
Renal stones; cortical bone resorption (Increased bone turnover; Acute/ pulsed PTH; anabolic; Chronic: catabolic (Cortical > cancellous)
What are the biochemical findings in 1ry hyperPTHism?
- Increased serum calcium - by absorption from bone/gut 2. Decreased serum phosphate - renal 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 NB: FHH needs to be ruled out before
How is Vit D metabolised?
Metabolised by liver and kidney -> vit D binding protein: t1/2 = 3d, filtered by kidney but reabsorbed by PCT (activates it too); if you have too much then it is converted into 24,25 D and this is inactive;
Where is Ca absorbed?
Activated Vit D increases gut Ca absorption; 20-60% load DDM/JJM and colon; passive in paracellular space (linear with diet); active (up to 40% saturable DDM)
What are the actions of Vit D?
x
What is the definition of Vit D deficiency?
At a nadir 25 OH D = 30 ng/ml (75nmol/l) PTH levels start to rise. Muscle function optimal >70nmol/l. Gut Ca absorption increases up to 80 nmol/l
What is rickets?
Inadequate Vitamin D activity leads to defective mineralisation of the cartilagenous growth plate (before a low calcium)
What are the S+S of rickets?
Symptoms: Bone pain and tenderness (axial); Muscle weakness (proximal); Lack of play Signs:Age dependent deformity; Myopathy; Hypotonia; Short stature; Tenderness on percussion
What are the causes of rickets/osteomalacia?
Lack of sunlight
What is the biochem of rickets/osteomalacia?
x
What is FGF-23 and where is PTH reabsorbed?
FGF-23; 32KD protein Produced by osteoblast, lineage cells, long bones. LIKE PTH causes P loss UNLIKE PTH inhibits activation of Vit D by 1 α OH ase; PO4 fully filtered and reabsorbed ony in PCT
*Describe this picture and explain why 2 systems are needed for PO4
- PTH activates vit D in kidney and causing increase absorption of Ca and PO4;
- which then causes PTH to shut down
- which causes increased Ca and PO4 in blood
- which would lead to crystals forming (not good) so bones detect this and FGF-23 is produced to release it
How is osteomalacia and phosphate linked and what are the causes?
Can also get with renal phosphate loss, when calcium and Vitamin D levels are usually normal
How can FGF-23 excess cause rickets/osteomalacia?
What happens if the PCT is damaged?
Causes phosphaturia and stops 1α hydroxylation of Vit D. Fanconi syndrome: multiple myeloma, heavy metal poisoning: lead, mercury; drugs: tenofovir, gentamycin; congenital disease: Wilsons, glycogen storage diseases
What is osteoporosis and the causes?
Low bone density
How does oestrogen deficiency cause menopausal bone loss?
How does cancellous bone loss differ in men vs women?
Disproportionate loss of cancellous bone in women
What does osteoporosis do to fracture rates?
Increased -> hip fracture has a mortality rate of 3months in elderly
How do you exclude other causes using biochem in osteoporosis?
How do you asses osteoporosis?
Bone density - single best predictor of fracture risk; BMD represents 70% of total risk
What is DEXA?
Uses t-score = BMD - young adult mean BMD/ young adult s.d. -> how many SD off the average for 25yo -> -2.5 = osteoporosis; -1 to -2.5 osteopaenia; >-1 normal; 1SD is a 2.5 increase risk of fracture
Why would you use central measurements to measure osteoporosis?
Risk over 20% - leads to treatment recommendations
What are bone markers?
Give insight into activity (resoption and formation); dynamic (unlike BMD); divided into markers of formation and resorption
How is collagen synthesised?
x
What bone resorption markers are used in monitoring osteoporosis treatment?
Monitoring of response to treatment with anti- resorptive drugs (BMD change 18mnths); bone resorption markers fall in 4-6 weeks; expect a 50% drop of urine NTx by 3 months
What are the problems with cross-links in osteoporosis?
What are the clinical use of bone formation markers?
What is BSAP?
What happens to alkaline phosphatase with age?
What is CKD-MBD?
- Skeletal remodeling disorders caused by CKD contribute directly to to heterotopic calcification, especially vascular.
- The disorders in mineral metabolism that accompany CKD are key factors in the excess mortality caused by CKD.
- CKD impairs skeletal anabolism, decreasing osteoblast function and bone formation rates .
What is the biochemistry of renal osteodystrophy?
How does secondary hyperparathyroidism progress?
What is the difference between osteopenia, osteoporosis and osteomalacia?
Osteopenia is poverty of the bone -> seen in both osteoporosis and osteomalacia. Porosis is decreased bone mass; malacia decreased mineralisation
What are the radiological signs of osteomalacia (and rickets)?
Vit D deficiency -> vit D and Ca are decreased, PTH is increased -> Radiology = age/growth plate closure -> codfish vertebra (biconcave, loss of height, osteopenic and pencilled-in margin)
How can you describe osteomalacia?
Too little mineral = osteopenic. too much osteiod = Looser’s zones
What are Looser’s zones and where are they found?
Narrow lucency, perpendicular to bone cortex -> pubic rami, proximal femur, scapula, lower ribs
What is the difference between osteomalacia and osteoporosis?
Malacia: less mineral, osteopenia, bend and bow before breaking, codfish vertebra with uniform spine deformity. Porosis: less bone, osteopenia, break and anterior wedging
What is the difference between osteomalacia and rickets?
Malacia: changes in mature bone, osteopenia, Looser’s zones, codfish vertebrae and bending vertebrae. Rickets: Before growth plate closure, changes related to growth plates (MAINLY), changes of osteomalacia co-exist
Where are the most obvious changes seen in rickets?
Metaphysis is where the most rapid growth occurs, so where the most obvious changes will be -> indistinct frayed metaphyseal margin, with widened growth plate (no calcification) -> cupping/splaying of metaphyses due to weight bearing
What are the radiological findings in rickets?
Indistinct frayed metaphyseal margin, with widened growth plate (no calcification) -> cupping/splaying of metaphyses due to weight bearing. Rickety rosary (splayed and cupped ends of ribs), bowing of weight bearing bones
What is the radiological finding of primary hyperparathyroidism?
Bone resorption
Where are the main sites of bone resorption in hyperPTHism?
Subperiosteal (radial aspect middle and ring finger phalanges), subchondral (distal clavicle and pubis), intracortical (pepper-pot skull), brown tumours (bigger, shows increased osteoclastic activity)
What are the 2 types of bone loss and which disease have each type?
SLOW: involutional osteoporosis, bone has time to remodel/bone loss occurs according to mechanical needs. FAST: HyperPTHism/Disuse osteoporosis, bone loss is too rapid, so loss doesn’t cater to mechanical needs
What are the radiological findings in renal osteodystrophy?
Osteomalacia, Osteoporosis, 2ry HPTH -> sub-periosteal erosions, brown tumours, sclerosis, axial skeleton/vertebral end plates, rugger jersey spine, and soft tissue calcification (arteries and cartilage)
What are the mediators of bone metabolism?
Ca/P/Vit D/ PTH/calcitonin; other hormones: T4, GH, glucocorticoids, oestrogens, androgens, insulin; other factors: vit c and other nutrients, cytokines, prostaglandin, several GF
What are codfish vertebrae?
Biconcave deformity of vertbrae seen in osteoporosis and osteomalacia
