Bone Disease Therapy

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  • Created by: LBCW0502
  • Created on: 25-01-19 18:42
Describe features of cortical compact bone
80%. Provides strength when torsion is the dominant force. Dense. Main component of long bones
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Describe features of trabecular bone
20%. Resists compressive forces. Less dense, found at the ends of long bones (growing or ends of bones, iliac crest/hip bone). Makes up the major component of the vertebral body. Metabolically more active
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90% of the body's calcium is found in the skeleton and exists in what form?
Calcium hydroxyapatite - provides hard tissue with its strength
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What is the osteoid?
Organic matrix of bone. Made up of collagen, proetoglycans and matrix proteins including osteocalcin, osteonectin, osteopotin
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What is the function of the osteocalcin?
Involved in regulation of bone density
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What is the function of the osteonectin?
Involved in regulating calcium and organising mineral in matrix
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What is the function of the osteopotin?
Cell-binding protein
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Describe the synthesis and metabolism of vitamin D (1)
Vitamin D3 (cholecalciferol) is synthesised in the skin on exposure to UV B (less absorbed from diet). Converted to 25(OH)D3 calcifediol in the liver by 25-hydroxylase. Calcifediol is converted to biologically active metabolite calcitriol
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Describe the synthesis and metabolism of vitamin D (2)
(1,25 (OH)D3 in the kidney by 1 alpha-hydroxylase
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What are the functions of vitamin D (calcitriol) in calcium levels and bone health
Secreted in the blood where it enhances cell differential and activation of osteoblasts. Promotes intestinal absorption of Ca 2+. Increases Ca 2+ from bone
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What is the daily turnover of bone minerals?
700 mg/day
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Which food and drink in our diet contains calcium?
Milk, cheese, orange juice, tofu, salmon, broccoli
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Which hormones raise plasma calcium levels?
Parathyroid hormone (PTH) and calcitriol (1, 25 (OH2)D3))
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Which hormone reduces plasma calcium levels?
Calcitonin
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Fall in plasma calcium levels induces the secretion of which hormone?
PTH from parathyroid glands
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PTH has the most significant effects in which organ?
The kidneys - increases calcium reabsorption, decreases calcium urinary excretion, promotes calcitriol formation from calcefediol (increase calcium reabsorption in intestine, increases osteoclast activity - bone loss)
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What happens if the body senses calcium loss?
PTH and calcitrol levels rise to stimulate calcium mobilisation from bones
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Describe features of osteomalacia/rickets (1)
Caused by vitamin deficiency. This results in both low and high concentrations of vitamin D3, promotion of resorption (bone loss). Mouse KO models show that VDR KO mice have increased bone density
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Describe features of osteomalacia/rickets (2)
Decreased bone calcium mineralisation (due to decrease calcium/phosphate absorption). No loss of osteoid tissue. Abnormal bone development in children (rickets). Decreased bone strength, susceptible to fractures (osteomalacia)
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What is osteoporosis?
Reduced quantity of bone (thinning of bone with age)
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What are the factors which accelerate bone loss?
Menopause, alcohol, smoking, glucocorticosteroids. GCS inhibits osteoblast/osteoclast activity (promotes bone resorption)
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Which hormone inhibits osteoclastic activity?
Oestrogen (promotes mineralisation - more calcium and phosphate present)
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State features of meta-analysis
Combine studies, identify which one favours treatment (RHS of line), past 0 line (means that the study is unclear). E.g. effects on vitamin D supplements on bone mineral density (overall - just able favours treatment) - diagram
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State the four stages of Paget's Disease of Bone
Osteoclastic activity, mixed osteoclastic-osteoblastic activity, osteoblastic activity, malignant degeneration
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Describe features of Paget's Disease of Bone (1)
Initial stages see increase in rate of bone resorption in localised areas by increased osteoclast activity (osteolysis)
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Describe features of Paget's Disease of Bone (2)
Osteolysis is followed by a compensatory increase in bone formation induced by increased osteoblast activity. Associated with accelerated deposition of lamellar bone in a disorganised fashion
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Describe features of Paget's Disease of Bone (3)
Resorbed bone is replaced and marrow spaces filled with excess of fibrous connective tissue. Latter stages - replacement of normal bone marrow with highly vascular fibrous tissue
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Which drugs are used in the treatment of bone disorders?
Anti-resorptive - bisphosphonates, selective estrogen receptor modulators (SERMs), salmon calcitonin, denosumab, calcium, strontium. Anabolic agents that increase bone formation - teriparatide, strontium
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Describe features of bisphosphonates (1)
Enzyme resistant analogues of pyrophosphate. Reduces resorption of bone (inhibit recruitment of OC, apoptosis of OC). Incorporated in bone matrix (months-years)
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Describe features of bisphosphonates (2)
Administered orally (poor absorption, impaired by milk products, food and calcium supplements). GI disturbances which can be severe (can induce peptic ulcers), oesophagitis (unable to swallow tablets, ulcers), osteonecrosis of jaw (used in cancer)
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Give examples of bisphosphonates
Etidronate. Clodronate. Tiludronate. Pamidronate. Alendronate. Risedronate. - Increasing potency (causes osteomalacia if given continuously). Prevention/treatment of osteoporosis, Paget's disease of bone
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Describe features of oestrogen and related compounds (1)
E.g. estrone sulphate, micronised estriadiol-20 beta, phytoestrogens. Inhibits effect of OC on bone resorption. Administered with progesterone to suppress endometrial hyperplasia induced by estrogen
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Describe features of oestrogen and related compounds (2)
Estrogen binds to receptors bound to specific DNA sequences and alters gene transcription. Reduces incidence of osteoporosis in women
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Describe features of Selective Estrogen Receptor Modulators (SERMs) (1)
E.g. tamoxifen (pro-drug), raloxifene. Decreased risk fo breast cancer, increased risk of endometrial cancer (with tamoxifen), protection against osteoporosis (decrease OC activity)
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Describe features of Selective Estrogen Receptor Modulators (SERMs) (2)
Protection against CVD, venous thromboemolism. Alpha/beta estrogen receptors (agonist/antagonist)
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Describe features of calcium supplements
Used in dietary deficiency, hypocalaemia (hyperthyroidism or malaborption). Gluconate, lactate used in combination with oestrogen, bisphosphonates and vitamin D in osteoporosis. Carbonate (antacid) binds phosphate used in hyperphosphataemia
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Describe features of vitamin D (vitamin D2, ergocalciferol)
Deficiency states (Rickets, oesteomalacia, malabsorption and liver disease). Promotes absorption of Ca from GIT. Hypocalaemia due to hypoparathyroidism. Renal failure (give calcitriol instead)
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Describe features of calcitonin for Paget's disease (1)
Produced in thyroid gland, opposite effect to PTH/calcitriol on bone resorption. 32 amino acid peptide that binds directly to OC and reduces resorption of bone. Inhibits re-absorption of Ca 2+/PO4 from GI/kidney
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Describe features of calcitonin for Paget's disease (2)
Binds to cell surface receptor which couples to adenylyl cyclase raising cAMP which has an inhibitory action on OC activity. Nasal calcitonin spray (metabolised in GIT by aminopeptidases and proteases)
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Describe features of calcitonin for Paget's disease (3)
Malignancy with long term use, no longer used in post-menopausal osteoporosis (can be used in Paget's when all else fails)
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Why is marine salmon (salcatonin) or eel calcitonin used for treatment of Paget's disease instead of human calcitonin?
Due to being more potent
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Describe features of PTH (1)
Human recombinant PTH, 84 amino acid peptide. Teriparatide (recombinant fragment of PTH 1-34, sc, od). Low doses stimulate OB activity (PHT1/2 receptors) and enhance bone formation. Used in post-menopausal osteoporosis
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Describe features of PTH (2)
Also used in osteroporosis in mean at risk of fractures and corticosteroid-induced osteroporosis
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Describe features of strontium ranelate (1)
Inhibits bone resorption and promotes bone formation. Increased risk of CVD (blocks K+ channels, hypokalaemia, abnormal arrhythmias), venous thromboembolism. Absorbed in GIT. Stimulates differentiation of OB, secrete OPG (inhibit OC differentiation)
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Describe features of strontium ranelate (2)
Low incidence of nausea and diarrhoea. Used in post-menopausal women and men at risk of osteoporosis (in patients where bisphosphonates are contra-indicated or not tolerated)
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Describe features of denosumab (1)
First biological (anti-RANKL) for treatment of osteoporosis (post-menopausal, men with prostate cancer because of hormone ablation, bone metastases). Calcium/vitamin D deficiencies need to be corrected. Dental work needs to be undertaken
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Describe features of denosumab (2)
Risk of osteonecrosis of the jaw. Diarrhoea, hypocalaemia, hypophosphataemia
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Describe features of gout (1)
(Crystal arthritis), asymptomatic hyperuricemia, acute intermittent gout, chronic gout
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Describe features of gout (2)
Tissue uric acid levels - balance between production and secretion of purines. If production > secretion, urate precipitates to form crystals
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Outline the mechanism for the formation of gout
Adenine, guanosine - nucleic acids - hypoxanthine - xanthine - (xanthine oxidase) - uric acid - crystals - inflammation (synovial tissue of joints)
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Which drugs are used to treat acute gout
NSAIDs (indomethacin, diclofenac, naproxen, ketoprofen, etoricoxib - aspirin not indicated). Colchicine if NSAIDs are CI (microtubule inhibitor - stops leukocyte migration). Glucocorticosteroids (prednisolone, oral, IV, intra-articular)
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Which drugs are used in the prophylaxis of gout? (1)
Start when patient is asymptomatic. Allopurinol (prevents formation of uric acid, febuxostat - same MOA for management of hyperuricaemia in patients intolerant to allopurinol - rashes). Probenecid, sulfinpyrazone
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Which drugs are used in the prophylaxis of gout? (2)
(urosiric drugs for those allergic to allopurinol)
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How can serum uric acid levels be reduced?
Changes in lifestyle. Low purine diet (red meat, seafood). Avoid drugs like low dose aspirin, thiazide diuretics, cyclosporin - these reduce urate clearance
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Outline the mechanism of action of allopurinol (long term control of gout) (1)
Allopurinol - alloxanthine (non-competitive inhibitor to enzyme xanthine oxidase) - prevents conversion of xanthine to uric acid. Promotes uric acid excretion. Decrease levels of insoluble urates and uric acid in tissue/plasma/urine
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Outline the mechanism of action of allopurinol (long term control of gout) (2)
Absorption of uric acid by the kidneys is prevented by uricosuric agents (probenecid, sulfinpyrazone)
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What is spasticity?
A symptom of neurological disorders (cerebral palsy, multiple sclerosis, stroke)
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What is baclofen?
GABA-B agonist acts presynaptically on spinal afferents and inhibits activation of motor neurones
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What is diazepam?
GABA-A receptor (on sensory nerve) and promotes action of GABA released inhibitory interneuron
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What is dantrolene?
Inhibits calcium release from SR (skeletal muscle)
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What is botulinum toxin?
Inhibits ACh release from motor neurones (destroys SNAP-25 protein, interferes with exocytosis)
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Other cards in this set

Card 2

Front

Describe features of trabecular bone

Back

20%. Resists compressive forces. Less dense, found at the ends of long bones (growing or ends of bones, iliac crest/hip bone). Makes up the major component of the vertebral body. Metabolically more active

Card 3

Front

90% of the body's calcium is found in the skeleton and exists in what form?

Back

Preview of the front of card 3

Card 4

Front

What is the osteoid?

Back

Preview of the front of card 4

Card 5

Front

What is the function of the osteocalcin?

Back

Preview of the front of card 5
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