Rheumatology - Metabolic bone disease Flashcards
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.
