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What is compact bone?

Bone has 2 gross anatomical forms. Compact bone is seen in long bone shafts. It contributes rigidity to bone and forms the dense outer shell (cortex).

The basic unit of compact bone is the Haversian systems (osteons) arranged in vertical columns. The periosteum is on the outside and the medullary cavity forms the inner portion of bone.


Where is cancellous bone found?

Cancellous bone along with marrow occupies the medullary cavity. Unlike compact bone, the basic unit of cancellous bone is the trabecula that is arranged along lines of stress.


What is meant by the term lamellar structure?

Both types of lamellar bone contain a layered structure.

In compact bone, a single Haversian system has a central canal with capillaries and concentric lamellae containing osteocytes in lacunae. Osteocytes are fairly inactive but communicate through canaliculi in the matrix.

Trabeculae have parallel lamellae of osteocytes in lacunae. There may be occasional osteocytes on the trabecular surface with capillaries present in marrow tissue.


What is the difference between endochondral and membranous ossification?

In endochondral ossification, seen at the metaphyseal ends of long bones, the cartilage of the growth plate dies and is invaded by osteoblasts which "build" bone to replace it.

In membranous ossification, seen in certain flat bones, the osteoblasts appear in an immature connective tissue matrix. This type is rarely seen in pathological processes.


What is woven bone?

Woven or non-lamellar bone, is a primitive form laid down during foetal development. It has irregular trabeculae in a primitive matrix that contain osteocytes. There is also an abundance of collagen. In adult life, this type is seen in bone regeneration and tumours. It may later be replaced by lamellar bone.


What hormones control bone homeostasis?

There are 3 hormones that control bone turnover. These hormones are termed calciotropic hormones as they affect serum calcium.

1) PTH - raises plasma calcium and lowers plasma phosphate
2) Calcitonin - produced by parafollicular C cells of the thyroid gland lowers plasma calcium
3) vitamin D - stimulates calcium and phosphate absorption in the gut and promotes bone mineralisation


What is the normal serum calcium concentration? What is corrected calcium?

Normal serum calcium is between 2.1-2.6mmol/L. Labs usually measure total plasma calcium of which 40% is bound to albumin and the rest is free ionized calcium which is the physiologically important amount. Therefore there is a need to "correct" the calcium concentration to take into account the portion that is bound to albumin.

0.1mmol/L is added to calcium levels for every 4g/L that albumin is below 40g/L. 99% of body calcium and 80% of body phosphorus is found in bone.


What 3 cell types control bone turnover?

1) Osteoblasts synthesize and secrete collagen fibres and promote deposition of calcium phosphate crystals (they "build").

2) Osteoclasts are specialised macrophages and cause bone resorption. Bone resorption depends on the destruction of collagen by lysosomal enzymes and phagocytosis, and the dissolution of bone mineral by an increase in lactate and citrate production.

3) Osteocytes are the most numerous cells in mature bone and are formed from osteoblasts, once surrounded by calcified matrix.


What is the main role of osteocytes?

Osteocytes sense mechanical forces imposed on the bone, specifically mechanical distortion which initiates bone remodelling.

They also play a role in the exchange of calcium between extracellular fluid and bone. This depends on the activity of PTH, calcitriol (1,25 dihydroxy vitamin D), and calcitonin. Only about 1% of the calcium and phosphate of bone is in equilibrium with the ECF through the activity of osteocytes - this is the so called exchangeable pool of bone mineral which acts to buffer short term changes in blood calcium concentrations. The remaining 99% comprises the non-exchangeable pool from which mineral can be released only by osteoclastic resorption


What is RANK?

Osteoblasts also send signals to osteoclasts as part of normal bone remodelling. These signals are required for the full differentiation and activity of osteoclasts.

RANK is a membrane receptor on osteoclasts that binds to RANK ligand (RANKL) on the surface of osteoblasts. This promotes osteoclast activation. However, if a soluble product of osteoblasts and other cell types (e.g. bone stromal cells, monocytes etc) termed osteoprotegrin (OPG) is also present, it competes with RANK for binding to RANK ligand on osteoblasts. In this way soluble OPG inhibits osteoclast activity and bone resorption.


Why does PTH increase osteoclast activity?

PTH and activated vitamin D up-regulate RANKL on osteoblast cell membranes thereby promoting osteolysis. This liberates some of the non exchangeable pool of calcium in bone mineral.


What is the effect of steroids and oestrogen on bone remodelling?

Bone remodelling is a continuos process that is usually under steady-state conditions. If bone resorption exceeds bone formation osteoporosis occurs.

Glucocorticoid excess, occurring in Cushing syndrome or during long term steroid therapy causes bone resorption. Osteoporosis developing in these situations is due to suppressed formation of soluble OPG and increased expression of RANKL.

Oestrogens have the opposite effect. Oestrogens inhibit the secretion of osteoclast activating cytokine production by osteoblasts and also OPG synthesis which conserves bone mass.


Describe bone turnover in cancellous bone. Is it different in cortical bone?

Osteoclasts derived from marrow precursors lie on the bone surface and resorb bone.

This leads to the formation of a Howship's lacunae. Release of cytokines from bone matrix stimulates osteoblasts which lay down osteoid that is then mineralised.

The process is essentially the same in cortical or compact bone. Osteoclasts "crush" and remove bone to form a cutting zone. Osteoblasts then fill in the defect in layers.


Where is the active form of vitamin D synthesised?

Vitamin D is essential for proper bone development. A deficiency in children leads to Ricketts, whilst in adults this is called osteomalacia. Vitamin D is a lipid soluble steroid like compound and exists in 2 forms. The most important form is cholecalciferol that is synthesised from 7-dehydrocholesterol in the skin.

Vitamin D needs to be metabolised into its active form called 1,25 dihydroxycholecalficerol. Cholecalciferol from the skin is converted to 25-hydroxyvitamin D in the liver.

In the kidney this intermediate compound is converted into calcitriol (1,25 dihydroxyvitamin D), if the extracellular concentration of calcium and phosphate are low. The renal enzyme 1 alpha hydroxylase catalyses this conversion and is stimulated by PTH and low plasma phosphate.


Why does vitamin D synthesis have its own negative feedback loop?

Renal 1 alpha hydroxylase is suppressed by calcitriol when it is converted from 25 dihydroxyvitamin D. It also upregulates 24 alpha hydroxylase activity which increases conversion into inactive metabolites that prevents vitamin D toxicity.


What is osteoporosis?

Osteoporosis is THE commonest disorder of bone and is a systemic disease characterised by:
1) low bone mass
2) microarchitectural deterioration of bone, with
3) increase in bone fragility and susceptibility to fracture

Osteoporosis can either be primary (age related) or secondary to other conditions or drugs


What are the clinical features of osteoporosis?

Osteoporosis is predominantly a disease of post-menopausal females, but men are also affected. Clinical features include:
- compression (collapse) of vertebral bodies (usually preceded by gradual loss of height and kyphosis); often associated with sudden pain on weight lifting

- fracture of the neck of femur or other long bones (especially Colles' fracture of distal radius)


What are the risk factors for osteoporosis?

For age related (primary) - parental history (maternal hip fracture), alcohol >4 units/d, RA, obesity, untreated menopause

Use the mnemonic "SHATTERED" for primary and secondary
- Steroid use of >5mg/d of prednisolone
- Hyperthyroidism, hyperparathyroidism, hypercalciuria
- Alcohol and tobacco use
- Thin
- Testosterone reduced (e.g. antiandrogen ca prostate)
- Early menopause
- Renal or liver failure
- Erosive inflammatory bone disease (e.g. myeloma or RA)
- Dietary Ca decreased/ malabsorption, DM type 1


What is the gold standard investigation for osteoporosis?

DEXA scan is the gold standard. It is better to scan the hip than the lumbar spine. Bone mineral density is compared with that of a young healthy adult. The "T" score is the number of standard deviations the bone mineral density (BMD) is from the youthful average. Osteoporosis is diagnosed when BMD is >2.5 standard deviations from that of young subjects.

T score of -1 to - 2.5 suggests the patient has osteopaenia and is at risk of later osteoporortic fractures.


Is serum biochemistry changed in osteoporosis?

No. PTH, Ca, and alk phos (osteoblasts and a marker of bone formation) are all normal in osteoporosis which helps to distinguish this from other metabolic bone diseases.


What are the pathological features of osteoporosis?

Macroscopically - vertebral bodies are porotic with wide honey-comb spaces. IVDs can be seen bulging into bone.

Microscopically, trabeculae appear thin and disconnected. Bone loss is most marked in calcellous bone with its high turnover, but cortical bone is also affected.


Why is peak bone mass important in osteoporosis and what determines it?

Peak bone mass is the bone mass of a typical healthy young adult and is slightly lower for females than males. A high peak bone mass makes osteoporosis less likely.

This depends on factors including:
a) genetic predisposition - polymorphisms of vitamin D receptor gene, type I collagen gene etc
b) nutrition - especially calcium
c) exercise


How is osteoporosis managed?

Pharmacological therapy is guided by risk stratification tool - FRAX. This takes into account age, risk factors and DEXA scan results. It calculates a 10yr risk of osteoporotic fracture in untreated patients. So it is useful for patients who fall into the osteopaenia category of T scores.

Management includes i) lifestyle measures and ii) pharmacological measures.

Lifestyle measures include:
- quit smoking and reduce alcohol consumption
- weight bearing exercise may increase BMD
- calcium and vit D rich diet


What pharmacological measures are important in osteoporosis?

- Bisphosphonates: alendronate is 1st line (but not if eGFR is <35). Instruct patient to drink with plenty of water and sit upright for 30mins after. Inhibits osteoclasis. (SE: photosensitivity, GI upset)

- Calcium and vitamin D: offer if evidence of deficiency, rarely used alone for prophylaxis

- Strontium ranelate: helps decr. fracture rates and is an alternative to those intolerant of bisphosphonates. May promote new bone formation

- Teriparatide: (synthetic PTH) inhibits osteoclasts and upregulates osteoblasts. Offered to patients who suffer from further fractures despite treatment with other agents. Small risk of renal malignancy


What are the actions of calcitriol (vitamin D)?

Vitamin D acts on the small intestine to promote the absorption of calcium and phosphate, both of which are necessary for bone formation.

It also facilitates bone mineralisation by increasing the extracellular fluid concentration of calcium and phosphate.


What cell type produces PTH? Why is removal of this gland potentially dangerous?

PTH is produced by chief cells in the parathyroid gland. It circulates and is then rapidly metabolised in the liver and kidney.

Removal of the parathyroid glands causes plasma calcium levels to fall and leads to hypocalcaemia tetany. This is characterised by extensive spasms of skeletal muscle and can lead to asphyxiation due to laryngeal spasm.


What are the actions of PTH?

PTH increases ionized plasma calcium and lowers plasma phosphate concentrations. It does this by acting on the kidney, bone and indirectly via the GIT.

PTH increases the rate of bone resorption by stimulating the activity of osteocytes and osteoclasts. Within a lag time of about 2-3 hours PTH increases the permeability of osteocytes, enabling their calcium uptake from the bone interstitial fluid and release of Ca towards the capillaries. A slower effect of PTH is the upregulation of RANKL on osteoblasts and subsequent increases in osteoclast activity. Osteoclasts dissolve bone matrix and release Ca and phosphate into capillaries.

PTH decreases the reabsorption of phosphate in the proximal tubule. Phosphate ions bind calcium and therefore the fall in plasma phosphate concentration increases the ionized fraction of plasma Ca. PTH also increases Ca reabsorption in the distal tubule.

PTH induces 1 alpha hydroxylase activity in the kidney which converts 25 dihydroxy vitamin D into 1,25 dihydroxy vitamin D. So, the absorption of calcium in the GIT is increased as a consequence of an increase in calcitriol.


What controls PTH secretion?

PTH secretion is regulated by plasma calcium acting on parathyroid glands. The chief cells of the parathyroid gland express a Ca binding receptor. This is a GPCR.

Hypocalcaemia is the main stimulus for PTH secretion. High serum calcium and calcitriol are the main inhibitors of PTH secretion, but calcitriol takes longer to exert its negative feedback effect.


What is calcitonin? Where is it produced? What are its main actions?

Calcitonin is polypeptide hormone produced by the parafollicular C cells of the thyroid gland. The C cells have calcium sensing receptors, similar to chief cells of the parathyroid gland.

High serum Ca stimulates calcitonin secretion by C cells. Calcitonin decreases plasma Ca and phosphate levels by inhibiting bone resorption. Calcitonin is probably the only hormone to act directly on osteoclasts - it inhibits their function. It also increases urinary loss of Ca and phosphate by decreasing their reabsorption in the kidney.


What is osteomalacia or rickets?

Osteomalacia and rickets are disorders of bone in which the essential defect is a failure of calcification in newly formed osteoid, caused by vitamin deficiency in most cases.

Osteomalacia occurs in adult life and affects the osteoid which is being continually laid down in the normal remodelling of bone.

Rickets affects growing children and serious additional disturbances are seen the growing ends of long bones.


What are the signs and symptoms of osteomalacia or rickets?

Rickets: growth retardation, hypotonia, knock knees (valgus), bow legged (varus) and deformities of metaphyseal-epiphyseal junction. Features of hypocalcaemia are often mild, but children with rickets are ill.

Osteomalacia: bone pain and tenderness; fractures (esp femoral neck); proximal myopathy (waddling gait).


What are the causes of osteomalacia or rickets?

The main cause is a deficiency of vitamin D that is needed for bone mineralisation.

1) Vitamin D deficiency: malabsorption, poor diet or reduced sunlight
2) Renal osteodystrophy: renal failure (CKD) leads to 1,25 dihydroxy vitamin D deficiency due to failure of 1 alpha hydroxylase activity
3) Drug induced: anticonvulsants may induce liver enzymes leading to an increased breakdown of active vitamin D
4) Liver disease due to reduced hydroxylation of vitamin D to 25 dihydroxy vitamin D and malabsorption of vitamin D (fat soluble)
5) Vitamin D resistance: inherited conditions
6) Tumour induced osteomalacia (oncogenic hypophosphataemia): mediated by raised tumour production of phosphatonin fibroblast growth factor 23 (FGF-23) which causes hyperphosphaturia and decreased serum phos.


What are the effects of vitamin D deficiency (regardless of the source) on bone in osteomalacia and rickets?

Vitamin D deficiency causes reduced gut absorption of Ca and reduced gut absorption of phosphate. This leads to hypocalcaemia and hypophosphataemia.

Low serum calcium promotes PTH secretion, but there is reduced Ca and phosphate product which leads to failure of bone bone mineralisation.

Bone trabeculae are of NORMAL size but there is a thick osteoid layer that gets deposited due to delayed calcification. The calcified bone that is present can be stained by Von Kossa's method and appears black. Serum alkaline phosphatase is raised.

NB - PTH activity tends to restore Ca towards normal levels


What investigations should be performed in suspected osteomalacia and rickets?

- mildy decreased Ca
- decreased phos
- raised alk phos
- high PTH
- serum vitamin D levels: 25 dihydroxy vitamin D is low in vitamin D defiency but may otherwise be normal; 1,25 - dihydroxy vitamin D is low (defiency, renal failure, vitamin D dependent rickets type I)

- incomplete mineralisation, muscle biopsy (if proximal myopathy) is normal

X ray:
- generalised osteopenia with cortical thinning with multiple fractures
- pseudofractures (Looser's zones) are translucent bands perpendicular to the surface of bone extending from the surface inwards
- widened or irregular metaphysis in rickets


How can vitamin D be elevated in rickets when it is normally caused by a deficiency?

Vitamin D dependent (or resistant) rickets exists in 2 forms. Type I has low renal 1 alpha hydroxylase activity, and type II has end organ resistance to 1,25 dihydroxycholecalciferol due to a point mutation in the receptor.

So active vitamin D levels are low in type I but elevated in type II.


How is rickets or osteomalacia treated?

This somewhat depends on the cause.
- if dietary deficiency give supplementary vitamin D as simple ergocalciferol; this can be metabolised normally
- in malabsorption or hepatic disease give vitamin D2 (ergocalciferol) in large doses (up to 1mg/d); ergocalciferol is an active form of vitamin D and is a water-soluble product that can be absorbed by the small intestine
- if due to renal disease or vitamin D resistance give alfacalcidol (1 alpha hydroxycholecalciferol)

Serum Ca should be monitored closely.


What bone changes are seen in hyperparathyroidism?

Hyperparathyroidism means an increase in PTH production that can either be primary, secondary or tertiary. Bone changes are more likely if the hyperparathyroidism has been long standing.

The essential change is increased bone resorption due to greatly increased osteoclastic activity; usually osteoblastic activity is also increased by the net effect is bone loss.

Histologically, there are numerous osteoclasts attacking trabecular bone. There are numerous giant cells (osteoclasts) and spindle cells occupying the marrow tissues.


What is osteitis fibrosa cystica?

This is a condition associated with hyperparathyroidism. The effects of increased osteoclast activity although generalised, may be locally very severe causing cystic spaces to appear in bone.

In some cases giant cell tumour of bone may be mimiked (so called BROWN TUMOUR of hyperparathyroidism).


What is the classic serum biochemistry of primary hyperparathyroidism?

Primary hyperparathyroidism is most common in females and in the >45 group. In most cases the result is a single autonomous parathyroid adenoma (90%).

Classically there is:
- raised serum Ca
- decreased or low normal serum phos
- serum alk phos may be normal or raised (reflecting increased bone turnover)
- raised PTH


Under what conditions does hypertrophy of bone occur?

1) In acromegaly the enlargement of the jaws, hand and feet is due to subperiosteal osteoblastic proliferation and bone formation under the influence of pituitary growth hormone (other soft tissues are also thickened)

2) Hypertrophic osteoarthropathy (including finger clubbing) affects the digits, distal ends of long bones and the distal joints; mechanism is unknown but the condition is associated with chronic lung disease, lung cancer, cyanotic heart disease and chronic intestinal inflammatory conditions
- there is oedema and increase of vascular connective tissues under nail bed
- periosteal new bone formation


What is fibrous dysplasia of bone? What are its complications?

This disorder may affect a single (monostotic) or several bones (polystotic). The lesion is of well demarcated fibrous tissue containing small abnormal bone trabeculae (often resemble "lobster claws"). The normal bone is gradually replaced; small cysts may be present.

Over expression of a proto oncogene is responsible for the polystotic form.

Fracture or deformity of the weakened bone is the main complication.


What is Paget's disease? What is the aetiology?

This disease of unknown aetiology usually presents after the age of 50 years and affects males predominantly.
It is fairly common but only in its more sever forms are there clinical symptoms. There is increased bone turnover associated with increases numbers of osteoblasts, and osteoclasts with result remodelling, bone enlargement, deformity and weakness.

Paget's disease is focal: the bones particularly affected are the pelvis, lower vertebrae, skull and lower limbs. A viral infection (e.g. measles, distemper) of osteoclasts is responsible.


What are the clinical features of Paget's disease?

Initially, there is a localised increase in osteoclastic activity causing bone resorption; soon there is also marked osteoblastic reaction with bone resorption and deposition proceeding chaotically so that irregular bone trabeculae with mosaic cement lines are formed. The bone may be thickened, but its structure is defective and weak.

It is asymptomatic in 70% of patients; deep, boring pain and bony deformity and enlargement (classically there is a bowed sabre tibia).


What is the serum biochemistry in Paget's disease?

Calcium and phosphate are normal but biochemical changes reflect the cellular activity at a trabecular level:
- raised alk phos (osteoblastic)
- raised urinary hydroxyproline (collagen destruction, osteoclastic)


What are the important complications of Paget's disease?

1) Fracture of weakened bones (including partial long bone fracture and vertebral compression)
2) Osteoarthritis of joints due to abnormal stresses caused by bony deformity
3) Increased risk (x30) of development of bone sarcoma
4) Increased circulatory load through the vascular stroma may cause high output cardiac failure in patients with compromised cardiac function
5) Nerve entrapment due to bone outgrowth


How is Paget's disease managed?

If analgesia fails, alendronate may be tried to reduce pain and / or deformity.


What bones are commonly associated with avascular necrosis? Other than trauma what are some important associations?

The femoral neck and scaphoid bones are common sites for avascular necrosis due to the anatomical arrangement of their blood supply.

Trauma is not always a factor in some cases of osteonecrosis. Noted associations are:
- decompression in those working in increased atmospheric pressure (Caisson disease)
- alcoholism
- Gaucher's disease
- sickle cell anaemia
- prolonged corticosteroid therapy

In these cases local ischaemia may be due to sludging of blood in arteries to bone.


What causes subperiosteal haematoma formation?

In scurvy, the lack of vitamin C is the cause of abnormal collagen synthesis and there is a bleeding tendency due to capillary fragility.

In very young children, large haematomas may form under the periosteum in response to relatively minor trauma. The osteoblasts on the undersurface proceed to form irregular bone.


What causes achondroplasia?

This disease causes a particularly striking dwarfism. Short, deformed limbs cause a waddling gait. The bones at the skull base are underdeveloped.

The basic abnormality is defective, irregular development of cartilage cells, particularly at growing epiphyseal growth plates. The result is stunted long bones.

It is caused by a mutation of the fibroblast growth factor receptor.


What is osteogenesis imperfecta? What are the important clinical features?

This is a disease characterised by thin and brittle bones. Bones fracture easily and a history of multiple fractures with minimal cause is the usual presentation.

The basic defect is in the osteoblasts which fail to synthesise collagen properly. The defects are due to mutations affecting Type I collagen genes on chromosomes 7 and 17. The severity of the disorder depends on the type of mutation.

Associated conditions are:
- very thin blue sclera
- abnormal tooth development


What is osteopetrosis?

(Also known as marble bone disease of Albers-Schonberg) is a disorder in which osteoclasts are absent or defective. This results in failure of bone remodelling and abnormal conversion of cartilage to bone. The whole skeleton becomes dense and the bones thickened.

Complications are:
- anaemia due to marrow replacement
- fractures
- cranial nerve compression


What are osteochondroses?

The osteochondroses are a group of conditions characterised by the abnormal endochondral ossification of epiphyseal growth during childhood.

Osteochondrosis occurs in the wrist, elbow, knee, hip, ankle, fingers, toes and spine. All osteochondroses undergo an interruption of blood supply to the epiphysis, followed by bone and cartilage necrosis, revascularisation and regrowth of bone.