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Block 4 AR > Bone Physiology > Flashcards

Bone Physiology Flashcards

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1
Q

What are dietary recommendations for calcium? And which patients require higher levels?

A

UK RDA is 700 mg

Higher in older adults, children, pregnant and lactating women

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2
Q

Where is most of the body’s calcium found?

A

Skeleton

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3
Q

What is normal plasma calcium?

A

2.5 mmol/l (range 2.12 - 2.6)

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4
Q

What are physiological roles of phosphate?

A

Intracellular metabolism: ATP synthesis
Phosphorylation: enzyme activation
Phospholipids in membranes

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5
Q

What 5 tissues and hormones are involved in calcium and phosphate homeostasis?

A

Parathyroid glands: sense low plasma Ca, make PTH
Kidney: regulated Ca reabsorption, PO4 excretion and vitamin D activation (1alpha hydroxylase enzyme)
Gut: site of Ca uptake and PO4 uptake regulated by vitamin D
Thyroid: makes calcitonin
Bone: body store of Ca and PO4, makes FGF-23

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6
Q

Which cells secrete parathyroid hormone?

A

Chief cells

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7
Q

What can allow preservation of parathyroid function after thryoidectomy?

A

Different blood supplies

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8
Q

Describe parathyroid hormone and its receptor

A

Peptide hormone (half life is minutes)
Acts via GPCR: multiple isoforms, PTHR1 – binds and is activated by PTH and PTH-related peptide (PTHrP)
Enough is stored for 60-90 min release

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9
Q

What does sustained release of PTH require?

A 
Gene expression ( hours - days) 
Proliferative activity of PT cells (days - weeks/ longer)
Eventually gland size increases
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10
Q

What are primary and secondary effects of PTH?

A

PTH acts on kidney to: increase Ca2+ reabsorption, promote PO4 excretion, increase active vitamin D by 1alpha hydroxylase action
PTH acts on bone to: mobilise calcium
Secondary effects- due to increased vitamin D production

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11
Q

Where is calcium re absorbed in the kidney? And what effect does PTH have?

A

Usually most calcium is reabsorbed from tubular fluid
Range of different sites in nephron
Distal tubule reabsorption enhanced by PTH

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12
Q

What is Parathyroid Hormone-Related Peptide (PTHrP)?

A

Made by many tissues, normal role not fully understood
Mimics PTH, elevating plasma Ca2+
Produced by some cancers, causes hypercalcaemia associated with malignancy
Concentration normal in hyperparathyroidism and other non-malignant hypercalaemias
Does not increase vitamin D levels

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13
Q

What are the kidneys 3 roles in calcium and phosphate homeostasis?

A

Ca2+ reabsorption: passive, active (regulated by PTH and calcitonin)
Phosphate excretion regulated by PTH
Makes 1,25(OH)2D3 (calcitriol), active vitamin D

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14
Q

What role does vitamin D have in calcium homeostasis? And what problem do people with kidney disease have?

A

Calcium poorly absorbed from the GI tract
Absorption mediated by active form of vitamin D, calcitriol
Kidney produces 1α-hydroxylase which converts inactive precursor into active form of vitamin D
Patients with kidney disease develop renal bone disease due to failure to produce this enzyme and inability to absorb adequate calcium from diet

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15
Q

Describe the synthesis of active vitamin D

A

7 dehydro cholesterol from UV light converted in body into inactive d3
This and d2 from diet converted by 25-hydroxylase in liver into calcidiol
Kidney releases 1alpha hydroxylase which converts this into active vitamin D, calcitriol

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16
Q

How does vitamin D exert its effects and what are these effects?

A

Binds to a nuclear receptor - acts like steroid hormone
Cell membrane and intracellular transport proteins
Endocrine and local paracrine/autocrine actions
Increases Ca2+ uptake from gut - increases expression of TRPV6, CaBP and CaATPase
Increases Ca2+ and PO4 reabsorption in the kidney
Increases bone resorption, which releases Ca2+ and PO4 into plasma

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17
Q

Where does calcium intake come from?

A

All our calcium intake comes from the intestine

uptake is regulated by vitamin D

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18
Q

What are the 3 methods of calcium absorption in the gut?

A

Active uptake and extrusion: TRPV6 at brush border, CaATPase and Ca/3Na exchanger at basolateral surface
Paracellular transport: with Ca binding protein via tight junctions
Exocytosis of Ca2+-CaBP complex: TRPV6 at brush border, packaged into vesicles

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19
Q

Where is calcitonin synthesised?

A

Thyroid gland C cells

neuroendocrine, parafollicular cells

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20
Q

What are the actions of calcitonin?

A

On bone (primary site): inhibits bone resorption (decreases Ca2+release from bone)
On kidney: decreases reabsorption of PO4 and Ca2+
Opposes PTH

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21
Q

What is mineral component of bone?

A

Hydroxyapatite

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22
Q

What hormonal control is bone under?

A

PTH: bone resorption, increasing plasma Ca2+ and PO4 levels
Vitamin D: bone resorption, increasing Ca2+ and PO4 levels
Calcitonin suppresses bone resorption

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23
Q

What does phosphate homeostasis depend on?

A

Diet and uptake from gut: absorption from gut is 80-90% efficient
Intracellular : extracellular movement
Urinary excretion: actively reabsorbed in proximal convoluted tubule

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24
Q

What hormonal controls are PO4 levels under?

A

PTH increases plasma Ca2+ and decreases plasma PO4

Vitamin D increases plasma Ca2+ and increases plasma PO4

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25
How is phosphate reabsorbed? And what inhibits it?
Most phosphate in diet absorbed from GI tract & passes into filtrate Phosphate is reabsorbed by a sodium phosphate co-transporter Transporter usually reaches Tm from dietary phosphate ∴excess phosphate spills over into urine PTH (& fibroblast growth factor-23 (FGF-23)) inhibit the sodium phosphate co-transporter, thus reducing phosphate reabsorption
26
What is the homeostatic response to low PO4?
Stimulates 1alpha hydroxylase to form active vitamin D which acts to increase PO4 absorption in gut, reabsorption in kidney and bone resorption
27
What is the body's response to high PO4?
Klotho in kidney and FGF23 in bone are obligate partners to inhibit 1alpha hydroxylase so less active vitamin D is formed FGF23 also provides negative feedback to the secretion of PTH
28
What is FGF23?
Fibroblast growth factor 23 Predominantly made by osteocytes and osteoblasts Prevents vitamin D mediated hyperphosphataemia Phosphaturic hormone (increase PO4 in urine, decrease PO4 in plasma) Inhibits 1alpha hydroxylase (prevents vitamin D activation) Inhibits type II sodium-phosphate co- transporters FGF-23 signalling: Cell surface receptor Klotho: obligate receptor partner for FGF-23
29
What are symptoms of hypocalcaemia?
Neuromuscular irritability Muscle cramps/tetany: As extracellular Ca falls the peripheral nerve fibres discharge spontaneously, leading to muscle contractions Hypocalcaemic tetany in the hand (carpopedal spasm) Seizures Severe cases: prolonged QT interval on ECG
30
What are symptoms of hypercalcaemia?
Nausea/vomiting/constipation/anorexia Tiredness, confusion, depression, headaches Muscle weakness Kidney stones/ectopic calcification Loss of bone Polyuria/polydipsia Severe cases: shortened QT interval on ECG
31
What can cause hypercalcaemia?
Primary hyperparathyroidism - Usually caused by a benign tumour (adenoma) on one of parathyroid glands. Individual cells respond normally to Ca2+, but increased numbers mean that more PTH is produced Tertiary hyperparathyroidism
32
What can cause hypocalcaemia?
Primary hypoparathyroidism: loss of parathyroid gland function Pseudohypoparathyroidism: target tissue resistance to effects of PTH Secondary hyperparathyroidism: low serum Ca2+ stimulates PTH production & secretion, usually associated with kidney disease: kidneys can’t respond to PTH, can’t make vitamin D, can’t increase absorption of Ca2+ from gut or kidney, can’t increase PO4 excretion only place Ca2+ can come from is bone, renal osteodystropy (renal bone disease), Generally, plasma Ca2+ decreases, plasma PO4 increases, Gland enlarges & produces unregulated amounts of PTH
33
What is the management for Hypercalcaemia?
``` >3-3.5mmol/l must treat as emergency Fluids (normal saline) Loop diuretic (furosemide) Calcitonin Bisphosphonates Oral phosphate Long term ? parathyroid gland surgery ```
34
What is management for hypocalcaemia?
Acute: neuromuscular symptoms! IV calcium gluconate Chronic: oral calcium, vitamin D (form depends where the defect is)
35
Describe the difference between woven and lamella bone
Woven: (weak) rapid osteoid production, collagen haphazard Disorganised, Expanded in size, More vascular, Weaker - more susceptible to fracture / deformity Lamella: (strong) parallel collagen (lamellae - sheets) To convert woven to lamella requires bone remodelling
36
What determines the brittle or bendiness of a bone?
Hard but brittle - Mineral Hydroxyapatite (~65%) Ca10(PO4)6(OH)2 Soft but bendy - Collagen – osteoid is 90% type 1 collagen
37
What is Paget's disease?
Excessive breakdown and remodelling of bone which results in disorganised woven bone predominating Localised defect: doesn’t spread beyond original affected area Common sites femur, spine, skull, tibia Fractures Deformity (bowing, increased skull size, spinal curvature) Pain (bone or pressure on nearby nerves) Deafness/disturbed vision Arthritis Cardiac, neurological and neoplastic (osteosarcoma) complications Common disorder, generally > 40 years old Significant genetic component
38
How can bone structure be assessed?
Calcium homeostasis: Ca, phosphate, vitamin D, PTH, urinary calcium Bone turnover: alkaline phosphatase, osteocalcin, collagen breakdown Imaging: X-ray, Radionucleotide scans (technetium), CT/MRI/USS Bone biopsy: histology Bone density: DEXA (Dual Energy X-Ray Absorptiometry)
39
What is osteogenesis imperfecta?
Group of disorders: defective production of type I collagen due to genetic mutations in collagen genes Four main types - severity and age of onset varies between types Brittle bones (fractures) 50% may have hearing loss Sclera have blue, purple or grey tint Problems with teeth (dentinogenesis imperfecta, brownish teeth) Sometimes growth retardation
40
What could multiple fractures relating to osteogenesis imperfecta be confused with?
Child abuse
41
What treatment is used for Paget's disease?
Bisphosphonates to inhibit osteoclast activity
42
What is Rickets disease?
Affects children Defective mineralisation at the growth plate mainly due to vit D deficiency e.g. diet / UV exposure / malabsorption / chronic kidney disease resulting in low phosphate +/- calcium levels Growth retardation and bony deformities (weight bearing limbs) Imaging shows widening of the epiphyseal growth plate/ metaphysis
43
What is osteomalacia?
``` Affects adults & children Defective mineralisation of osteoid mainly due to vitamin D deficiency e.g. diet / UVexposure / malabsorption / chronic kidney disease resulting in low phosphate +/- calcium levels may be asymptomatic Muscle weakness (proximal) Bone pain Fractures ```
44
What are most common tumours of bone?
Primary malignancies of bone rare (osteosarcoma most common) Metastatic deposits mainly: lytic lesions from bronchial, breast, thyroid or renal carcinomas (multiple myeloma), sclerotic lesions from prostate Focal abnormality of bone structure predisposing to pathological fracture Metastases (ectopic secretion of PTHrP) may result in hypercalcaemia
45
What is osteoporosis?
Low bone density and micro-architectural defects in bone tissue, increased bone fragility and susceptibility to fracture Asymptomatic until fracture from weakened bone (fragility fracture) which is major cause of morbidity, mortality and financial cost Typical fracture sites: Wrist (distal radius), Hip (proximal femur), Vertebral column (compression fractures) Pain Kyphosis
46
What are risk fractures for osteoporosis?
Older age, Female, White ancestry, Low BMI, Family Hx, Fragility fracture, Postmenopausal (oestrogen loss), Smoking, Excessive alcohol use, Glucocorticoid excess / corticosteroid use, Hypogonadism (male and female), Immobility, Vitamin D and Ca2+ deficiency
47
Describe the pathology of osteoporosis
Loss of balance between bone formation & bone resorption during remodelling Osteoclasts make deeper holes Osteoblasts not as efficient
48
What determines whether you develop osteoporosis?
Genetics Lifestyle Age Peak bone mass (genetics, diet, exercise, environment)
49
What can be used to risk assess for fractures?
FRAX and Qfracture | Algorithms that give the 10-year probability of fracture
50
Describe the WHO diagnostic criteria for osteoperosis and osteopenia
Based on T scores from a DEXA scan | Normal: BMD 2.5 SD below the young adult mean
51
What are management steps for osteoperosis
Diet & lifestyle Fall prevention Calcium and vitamin D supplements Oral bisphosphonates are first line in most cases Other agents: SERMs (selective oestrogen receptor modulators), PTH, Denusomab (anti RANKL monoclonal antibody)
52
How do Bisphosphonates work?
Absorbed onto hydroxyapatite crystals (analogues of pyrophosphate) and slow down rate of bone remodelling (long half life) Taken up by osteoclasts and interfere with their function Most inhibit mevalonate pathway and thereby prevent attachment of osteoclast to bone (therefore unable to resorb bone)
53
Name 2 Bisphosphonate drugs to treat osteoperosis
Alendronic acid (alendronate), risedronate
54
How are Bisphosphonates administered any why does this mean many patients do not adhere to their therapy?
Most orally administered but have to be standing up, first thing in morning whilst fasting as it causes oesophageal irritation and its absorption is affected by Ca Usually prescribed once daily or once weekly
55
In what disease should Bisphosphonates be prescribed with caution?
Chronic kidney disease as they are not metabolised, excreted unchanged in urine
56
What are problems with long term treatment with Bisphosphonates?
Revaluate / limit to 5 years treatment – maybe have a ’holiday’ and then restart Long term effects - atypical femoral fractures due to toughening of affected parts of bone but lack of remodelling in unaffected parts which are then susceptible to fracture
57
What are side effects of Bisphosphonates?
Asymptomatic hypocalcaemia General GI disturbances / oesophageal reactions Osteonecrosis of the jaw (dental check up prior to treatment)
58
What is Raloxifene?
Selective estrogen receptor modulator (SERM) Mixed antagonist/agonist function - tissue specific Bone ER agonist, good for osteoporosis Does not stimulate uterine or breast tissue Usually prescribed for postmenopausal osteoporosis if bisphosphonates not tolerated
59
How is PTH used in the treatment of osteoperosis?
Continuous PTH causes bone loss Intermittent peaks promote production trabecular bone (anabolic) Recombinant PTH has to be injected (subcutaneous)
60
What is Teriparatide?
Recombinant fragment of PTH used in treatment of osteoperosis Maximum duration of treatment is 24 months due to risk of bone malignancy
61
What is Denusomab?
Monoclonal antibody that inhibits RANKL and thus inhibits osteoclast bone resorption (acts like OPG – osteoprotegerin the normal ‘decoy’)
62
How do you manage hypocalcaemia?
Acute (neuromuscular symptoms): IV calcium gluconate | Chronic: oral calcium, vitamin D
63
What is pharmacological vitamin D used to treat?
Correct a vitaminD deficiency e.g. rickets / osteomalacia or as a supplement to ensure adequate levels (+/- calcium) e.g. osteoporosis
64
Name 2 active pharmacological forms of vitamin D
Alfacalcidol | Calcitriol
65
What are ergocalciferol and cholecalciferol?
Vitamin D2: ergocalciferol | Vitamin D3: cholecalciferol
66
Which form of vitamin D is required for CKD patients?
Activated forms - calcitriol and alfacalcidol because they cannot product sufficient 1alpha hydroxylase to activate vit D themselves
67
How do drugs like furosemide act to reduce calcium reabsorption?
Act on thick ascending limb of Loop of Henle Inhibit the Na+K+2Cl- co- transporter (compete with Cl- binding) Indirectly reduce calcium reabsorption by reducing the electrochemical gradient; therefore calcium excreted in urine (calciuric effect)
68
When is calcitonin used to reduce calcium levels?
Hypercalcaemia associated with malignancy and Paget’s disease if other treatments ineffective No longer used for osteoporosis due to links with long term use and malignancy
69
How does calcitonin work?
Counteracts the effects of PTH to prevent Ca reabsorption in kidney and prevent mobilisation of Ca from bone
70
Describe secondary hyperparathyroidism in kidney disease
Low serum Ca2+ normally stimulates PTH production In kidney disease: kidneys can’t respond to PTH, can’t make vitamin D can’t increase absorption of Ca2+ from gut or kidney, can’t increase PO4 excretion, only place Ca2+ can come from is bone - renal osteodystropy (renal bone disease) Plasma Ca2+ decreases, plasma PO4 increases Gland enlarges & produces unregulated amounts of PTH Serum Ca2+ begins to rise – Tertiary hyperparathyroidism
71
What is cinacalcet? And what is it used for?
Calcimimetic Partial agonist at CaR (chief cells parathyroid) Increase sensitivity of CaR to Ca - effective reduction in PTH secretion Indicated only for specific groups of patients with secondary hyperparathyroidism (renal osteodystrophy receiving dialysis)
72
What are 5 roles of bone?
``` Support Protection Movement Haematopoiesis Mineral homeostasis ```
73
What are the roles of synovial fluid?
Metabolic support for articular cartilage | Lubrication of joint
74
What is synovium? And what are its layers?
Mesenchymal origin Synovocytes Lympho-vascular rich supporting tissue No basement membrane
75
What are tissue types of synovium?
Depend on components of supporting tissue Areolar Fibrous Adipose
76
What are types of synovocytes? And what is their job?
Type A (akin to macrophages) Type B (akin to fibroblasts), maintain ECM Normally no more than 4 cell layers thick, commonly 1 cell layer thick Produce synovial fluid
77
What is synovial fluid?
Secreted: hyaluronic acid rich, Glycoproteins Transudate from capillaries, Very occasional leukocytes Lack of basement membrane facilitates ease of movement between tissue and synovial fluid
78
What are the physiological roles of Calcium?
Bone and teeth formation: growth and remodelling Muscle contraction: initiate attraction between actin and myosin filaments, causes them to slide over each other Nerve function: Na+ permeability, release acetylcholine Enzyme co-factor: clotting Intracellular second messenger Stabilisation of membrane potentials

Block 4 AR (8 decks)

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