Bone Physiology Flashcards
What are dietary recommendations for calcium? And which patients require higher levels?
UK RDA is 700 mg
Higher in older adults, children, pregnant and lactating women
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
Where is most of the body’s calcium found?
Skeleton
What is normal plasma calcium?
2.5 mmol/l (range 2.12 - 2.6)
What are physiological roles of phosphate?
Intracellular metabolism: ATP synthesis
Phosphorylation: enzyme activation
Phospholipids in membranes
What 5 tissues and hormones are involved in calcium and phosphate homeostasis?
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
Which cells secrete parathyroid hormone?
Chief cells
What can allow preservation of parathyroid function after thryoidectomy?
Different blood supplies
Describe parathyroid hormone and its receptor
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
What does sustained release of PTH require?
Gene expression ( hours - days) Proliferative activity of PT cells (days - weeks/ longer) Eventually gland size increases
What are primary and secondary effects of PTH?
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
Where is calcium re absorbed in the kidney? And what effect does PTH have?
Usually most calcium is reabsorbed from tubular fluid
Range of different sites in nephron
Distal tubule reabsorption enhanced by PTH
What is Parathyroid Hormone-Related Peptide (PTHrP)?
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
What are the kidneys 3 roles in calcium and phosphate homeostasis?
Ca2+ reabsorption: passive, active (regulated by PTH and calcitonin)
Phosphate excretion regulated by PTH
Makes 1,25(OH)2D3 (calcitriol), active vitamin D
What role does vitamin D have in calcium homeostasis? And what problem do people with kidney disease have?
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
Describe the synthesis of active vitamin D
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
How does vitamin D exert its effects and what are these effects?
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
Where does calcium intake come from?
All our calcium intake comes from the intestine
uptake is regulated by vitamin D
What are the 3 methods of calcium absorption in the gut?
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
Where is calcitonin synthesised?
Thyroid gland C cells
neuroendocrine, parafollicular cells
What are the actions of calcitonin?
On bone (primary site): inhibits bone resorption (decreases Ca2+release from bone)
On kidney: decreases reabsorption of PO4 and Ca2+
Opposes PTH
What is mineral component of bone?
Hydroxyapatite
What hormonal control is bone under?
PTH: bone resorption, increasing plasma Ca2+ and PO4 levels
Vitamin D: bone resorption, increasing Ca2+ and PO4 levels
Calcitonin suppresses bone resorption
What does phosphate homeostasis depend on?
Diet and uptake from gut: absorption from gut is 80-90% efficient
Intracellular : extracellular movement
Urinary excretion: actively reabsorbed in proximal convoluted tubule
What hormonal controls are PO4 levels under?
PTH increases plasma Ca2+ and decreases plasma PO4
Vitamin D increases plasma Ca2+ and increases plasma PO4
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
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
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
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
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
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
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
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
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
What is management for hypocalcaemia?
Acute: neuromuscular symptoms! IV calcium gluconate
Chronic: oral calcium, vitamin D (form depends where the defect is)
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
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
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
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)
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
What could multiple fractures relating to osteogenesis imperfecta be confused with?
Child abuse
What treatment is used for Paget’s disease?
Bisphosphonates to inhibit osteoclast activity
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
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
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
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
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
Describe the pathology of osteoporosis
Loss of balance between bone formation & bone resorption during remodelling
Osteoclasts make deeper holes
Osteoblasts not as efficient
What determines whether you develop osteoporosis?
Genetics
Lifestyle
Age
Peak bone mass (genetics, diet, exercise, environment)
What can be used to risk assess for fractures?
FRAX and Qfracture
Algorithms that give the 10-year probability of fracture
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
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)
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)
Name 2 Bisphosphonate drugs to treat osteoperosis
Alendronic acid (alendronate), risedronate
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
In what disease should Bisphosphonates be prescribed with caution?
Chronic kidney disease as they are not metabolised, excreted unchanged in urine
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
What are side effects of Bisphosphonates?
Asymptomatic hypocalcaemia
General GI disturbances / oesophageal reactions
Osteonecrosis of the jaw (dental check up prior to treatment)
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
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)
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
What is Denusomab?
Monoclonal antibody that inhibits RANKL and thus inhibits osteoclast bone resorption (acts like OPG – osteoprotegerin the normal ‘decoy’)
How do you manage hypocalcaemia?
Acute (neuromuscular symptoms): IV calcium gluconate
Chronic: oral calcium, vitamin D
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
Name 2 active pharmacological forms of vitamin D
Alfacalcidol
Calcitriol
What are ergocalciferol and cholecalciferol?
Vitamin D2: ergocalciferol
Vitamin D3: cholecalciferol
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
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)
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
How does calcitonin work?
Counteracts the effects of PTH to prevent Ca reabsorption in kidney and prevent mobilisation of Ca from bone
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
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)
What are 5 roles of bone?
Support Protection Movement Haematopoiesis Mineral homeostasis
What are the roles of synovial fluid?
Metabolic support for articular cartilage
Lubrication of joint
What is synovium? And what are its layers?
Mesenchymal origin
Synovocytes
Lympho-vascular rich supporting tissue
No basement membrane
What are tissue types of synovium?
Depend on components of supporting tissue
Areolar
Fibrous
Adipose
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
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
