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LCRS2: Endocrinology > Calcium and bone > Flashcards

Calcium and bone Flashcards

1
Q

Using a labelled diagram, demonstrate the synthesis of vitamin D, including vitamin D metabolites and their actions on calcium metabolism.

A
  • (2 vitamin inactive D inputs: a) diet (US fortification) and b) sunshine
  • Kidney; 1a hydroxylase which is stimulated by PTH to make calcitriol 1,25 (OH)2D3)
  • UV acts on 79dehydrocholesterol in the skin to form cholecalciferol (vitamin D3)
  • The other source of vitamin D is from the diet in the form of ergocalciferol

(vitamin D2)

  • Cholecalciferol gets converted to 25Khydroxycholecalciferol in the liver
  • Then it goes to the kidneys where it is converted to the active and powerful

1,25 dihydroxycholecalciferol via the action of 1ahydroxylase

  • 1a hydroxylase is stimulated by PTH
  • Effects of calcitriol (1,25 dihydroxycholecalciferol):
  1. ### Increased calcium absorption in the intestines (MAIN EFFECT)
  2. ### Increased calcium maintenance in bone
  3. ### Negative feedback on PTH
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2
Q

Discuss vitamin D metabolites and their actions on calcium metabolism.

A

Vitamin D Metabolites

  • 1,25 dihydroxycholecalciferol (CALCITRIOL)
    • Normally, this is the most important product of vitamin D metabolism
    • Its precursor, 25 hydroxycholecalciferol can have calcitriol like effects when produced in large amounts (Vitamin D intoxication)

o1) PRINCIPLE EFFECT: STIMULATES INTESTINAL ABSORPTION OF CALCIUM (and magnesium) AND PHOSPHATE

  • This intestinal absorption provides the ions necessary for normal bone mineralisation
  • 2) Renal Effects -> increased calcium reabsorption + decreased phosphate reabsorption via FGF23
  • 3) Monitors active form of vitamin D, under the control of PTH, production of calcitriol is affected
  • It also stimulates osteoclast formation from precursors in the bone and stimulates their activity
  • It also stimulates osteoblasts (to produce osteoclast activating factors (OAFs), matrix protein synthesis (e.g. osteocalcin) or repression (e.g. type 1 collagen)
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3
Q

Vitamin D deficiency

A

Vitamin D Deficiency States

  • Definition: lack of mineralisation in bone
  • This results in:
    • Softening of bone 9 you are unable to bear the weight of the rest of the body so you get the characteristic bowing of the legs
    • Bone deformities
    • Bone pain
    • Severe proximal myopathy
  • Vitamin D deficiency is referred to by different names:
    • In children = Rickets
    • In adults = Osteomalacia

Causes of Vitamin D Deficiency

  • Diet
  • Lack of sunlight
  • Gastrointestinal malabsorptive states
  • Renal failure
  • Receptor defects (autosomal recessive)
  • NOTE: this is re9emerging as a problem in the UK due mainly to inadequate diet and lack of sunlight
  • Causes of Vitamin D Deficiency
  1. Diet issues (coeliac disease which causes absorptive issues)
  2. Some elderly people may lack exposure to sunlight and have insufficient ergocalciferol in the diet
  3. Liver Disease can be a problem because this is where 259hydroxycholecalciferol is produced and stored in the liver ( because you can’t do the first step in the pathway)
  4. Renal Disease is a problem because this is where the second hydroxylation takes place to convert the 259hydroxycholecalciferol to the more active form
  5. The causes are all associated with steps in the synthesis of calcitriol or problems with the action of calcitriol

Diagnosis of Vitamin D Deficiency

  • NOTE: generally 259hydroxycholecalciferol is measured as a gage of the amount of calcitriol in the patient because calcitriol is difficult to measure. This is only a good measure of calcitriol if there is normal renal function (so that the second hydroxylation can take place)

·Plasma 25Khydroxycholecalciferol = usually LOW (in vitamin D deficiency)

  • Plasma Calcium = LOW
    • However, if the plasma calcium is low it will stimulate the release of PTH from the parathyroid gland
    • This is secondary hyperparathyroidism
    • If more PTH has been released then this will attempt to increase the plasma calcium and hence would mask the hypocalcaemia due to vitamin D deficiency

·PTH = HIGH

  • This is the secondary hyperparathyroidism that can make plasma calcium appear normal

·Plasma Phosphate = LOW

  • Radiological Findings (variable)
    • E.g. widened osteoid seams
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4
Q

Treatment of vitamin D deficiency

A

Treatment of Vitamin D Deficiency

NOTE: if patients have normal renal function they will be able to activate 259 hydroxycholecalciferol perfectly fine (because they have functioning 1a hydroxylase)

·In patients with NORMAL RENAL FUNCTION

  • Give 259hydroxy vitamin D
  • Patient can convert this to calcitriol via 1ahydroxylase
  • Supplements are in the form of:
    • Ergocalciferol 9 259hydroxy vitamin D2
    • Cholecalciferol 9 259hydroxy vitamin D3

·In patients with RENAL FAILURE

  • Don’t have their own 1a hydroxylase activity
  • So they can’t activate 259hydroxy vitamin D preparations

Give ALFACALCIDOL 9 1Khydroxycholecalciferol

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5
Q

Vitamin D excess

A

Vitamin D Excess (Intoxication)

  • Can lead to hypercalcaemia and hypercalciuria due to increased intestinal absorption of calcium
  • REMEMBER: increasing the intestinal absorption of calcium is the MAIN EFFECT of calcitriol
  • Vitamin D excess can occur as a result of:
    • Excessive treatment with active metabolites of vitamin D, as in patients with chronic renal failure
    • Granulomatous Disease 9 e.g. sarcoidosis, leprosy and tuberculosis
      • Granulomatous tissue can convert 259hydroxycholecalciferol to the active metabolite 1,259dihydroxycholecalciferol
      • This is because granulomatous tissues have 1a hydroxylase
      • So this is ectopic production of calcitriol
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6
Q

Calcium regulation: explain the hormonal regulation of blood calcium ion concentration

A

Overview on Calcium Storage

  • Bone is the largest store of calcium in the body and it consists of:

oInorganic mineral component

  • 65% of bone mass
  • Consists of calcium hydroxyapatite crystal
  • It fills the space between collagen fibrils

oOrganic component (osteoid)

  • 35% of bone mass
  • Collagen fibres (95%)
  • Only a tiny amount of the body’s collagen is intracellular
  • Plasma calcium range = 2.2K2.6 mmol/L
  • Hormones that INCREASE plasma calcium:

oParathyroid Hormone (PTH)

  • Vitamin D (Calcitriol)
  • Hormone that DECREASES plasma calcium:

oCalcitonin

  • Doesn’t have a particularly important role in humans

Calcium Homeostasis: Interaction between PTH and Vitamin D

Phosphate is regulated:

  • There is an interactive system between PTH and vitamin D
  • As serum calcium falls, you get an increase in PTH
  • PTH mobilises calcium from bone to increase plasma calcium
  • It has another direct effect on the kidneys to increase reabsorption of calcium in the kidneys
  • It also stimulates an increase in plasma calcium indirectly via the activation of vitamin D
  • PTH stimulates the kidneys to make 1ahydroxylasewhich converts the precursor, 259hydroxycholecalciferol, to the active1,25K dihydroxycholecalciferol (calcitriol)
  • Calcitriol then has two main effects to increase serum calcium:
    • Increased calcium absorption in the intestines
    • Increased calcium mobilisation in bone
      • They do this by acting on osteoblasts and making them release RANKL, which, in turn, activates osteoclasts
  1. In the kidney: reabsorbed from urine, PTH inhibits NA+/PO43- and so there is phosphate loss in the urine because it cannot be reabsorbed by the transporter
    High PTH – low phosphate because reabsorption is inhibited
    1. FGF 23 – like PTH also inhibits the reabsorption of phosphate in the kidney - net result of that more phosphate in the urine and hence serum phosphate is lower
  3. Also, FGF 23 inhibits calcitriol production , and less active vitamin D, less phosphate reabsorption from the gut

PTH receptor – when Ca is very high that binds to the receptor on the PTH cell and that inhibits the stimulation of the release of PTH secretion (high Ca prevents PTH secretion – suppression)

Hypocalcaemia- no binding of calcium to calcium sensing receptor and hence there is no inhibition and more PTH is secreted

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7
Q

List the causes and clinical features of hypocalcaemia

A

Hypocalcaemia

NORMAL RANGE = 2.292.6 mmol/L

·Signs and Symptoms

  • Parasthesia (hands, mouth, feet and lips)

oArrhythmias

  • Convulsions
  • Tetany
  • This can be remembered a CATs go numb
  • IMPORTANT: hypocalcaemia sensitises excitable tissues leading to muscle cramps/tetany, tingling

Chvostek’s Sign

  • Tap the facial nerve just below the zygomatic arch
  • POSITIVE response = twitching of the facial muscles
  • Indicates neuromuscular irritability due to hypocalcaemia

Trousseau’s Sign

  • Inflation of the blood pressure cuff for several minutes induces carpopedal spasm

This is also caused by neuromuscular irritability due to hypocalcaemia

Causes of Hypocalcaemia

  • Vitamin D Deficiency
  • Low PTH Levels = Hypoparathyroidism
    • Surgical 9 neck surgery (e.g. parathyroidectomy)
    • Auto9immune
  • PTH resistance (e.g. pseudohypoparathyroidism)

·Renal Failure

  • Impaired 1a9hydroxylase
  • Leads to decreased production of calcitriol
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8
Q

List the causes and clinical features of hypercalcaemia and hypocalcaemia

A

Hypercalcaemia

Tends to lead to reduced neuronal excitability and atonal muscles

  • Signs and Symptoms 9 ‘Stones, abdominal moans and psychic groans’
    • Stones 9 renal effects
      • Polyuria + Thirst
      • Nephrocalcinosis (deposition of calcium in the kidneys), renal colic, chronic renal failure
    • Abdominal moans 9 GI effects
      • Anorexia, nausea, dyspepsia, constipation, pancreatitis
    • Psychic groans 9 CNS effects
      • Fatigue, depression, impaired concentration, altered mentation, coma (the last three only tend to occur when calcium concentration is > 3 mmol/L)

Causes of Hypercalcaemia

The first two causes are responsible for 90% of cases of hypercalcaemia

·PRIMARY HYPERPARATHYROIDISM

  • E.g. due to a parathyroid adenoma which becomes too busy and produces excessive amounts of PTH

·MALIGNANCY K TUMOURS/METASTASES

  • Can be due to bone metastases where increased bone turnover causes an increase in serum calcium
  • Tumours can also produce PTHKrelated peptide

·Conditions with high bone turnover

  • Hyperthyroidism
  • Paget’s disease of bone 9 immobilised patient

·Vitamin D excess (rare)

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9
Q

Diagnostic Approach to Hypercalcaemia

A

Primary Hyperparathyroidism

  • Normally, there is negative feedback on PTH by calcium so if serum calcium rises, PTH will decrease
  • In the case of Primary Hyperparathyroidism (above), there is a parathyroid adenoma in the bottom right parathyroid gland
  • This parathyroid adenoma is secreting PTH autonomously and is not responding to negative feedback
  • So if you look at the serum calcium and PTH you will see:

oCalcium K HIGH

  • PTH K HIGH (unsuppressed)

Primary hyperparathyroidism: high PTH and high Ca because there is no negative feedback loop

Hypercalcaemia of Malignancy

  • This is also a common cause of hypercalcaemia
  • You can get increased bone turnover due to the presence of bony metastases
  • The calcium rises but the negative feedback is still intact so the PTH is switched off in this case
  • The blood results will show:

oCalcium K HIGH

  • PTH K LOW

Releasing too much calcium from bones: nothing wrong with parathyroid glands, Hypercalcemia of malignancy: raised calcium and suppressed PTH

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10
Q

Discuss the process of osteoclast differentiation

A
  • RANKL expressed on osteoblast surface
  • RANKL binds to RANK-R to stimulate osteoclast formation and activity
  • Osteoblasts express receptors for PTH & calcitriol (1,25 (OH)2 vit D) – regulate balance between bone formation & resorption

RANKL:

  • This is an important molecule that increases the activation of osteoclasts
  • Stimulates the maturation of osteoclasts from osteoclast precursors
  • If there are more mature osteoclasts then you get more bone resorption
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11
Q

Recall the clinical features of vitamin D deficiency and its effects on bone

Recall how renal dysfunction leads to bone disease; explain the mechanism

A

VITAMIN D DEFICIENCY:
EFFECTS ON BONE

  • Inadequate mineralisation of newly formed bone matrix (osteoid)
  • Children – RICKETS
    • affects cartilage of epiphysial growth plates and bone
    • skeletal abnormalities and pain, growth retardation, increased fracture risk
  • Adults – OSTEOMALACIA
    • after epiphyseal closure, affects bone
    • skeletal pain, increased fracture risk, prox myopathy
  • Normal stresses on abnormal bone cause insufficiency fractures - Looser zones
  • Waddling gait – typical
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12
Q

Discuss predisposing factors for vitamin D deficinecy

A
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13
Q

Outline the effects of hyperparathyroidism on bone

A

HYPERPARATHYROIDISM:
EFFECTS ON BONE

  1. Adenoma (Primary Hyoeroarathyroidism)
    Over-active parathyroids and increase in PTH increase in Calcium – Impaired negative feedback PTH doesn’t come down
  2. In Vitamin D deficiency calcium is low or low/normal
    Calcium falls – appropriate response is to make more PTH
    PTH goes up (SECONDARY hyperparathyroidism) -> it’s usually a response to vitamin D deficiency
  3. Chronic low plasma

Parathyroidis become autonomous because of chronic kidney disease -> increased PTH and hypercalcaemia

TERTIARY hyperparathyroidism

Renal failure and Bone disease

  • Renal Disease is a problem because this is where the second hydroxylation takes place to convert the 259hydroxycholecalciferol to the more active form
  • The causes are all associated with steps in the synthesis of calcitriol or problems with the action of calcitriol

Decreased renal function, you can’t have calcitriol secretion and Phosphates decrease too

Increase of phospahate which is binding to calcium and hypocalcaemia

Reduction in PTH -???? Xamooos rewatch

Osteitis fibrosa cystica (hyperparathyroid bone disease) – rare

= XS osteoclastic bone resorption 2o to high PTH

‘Brown tumours’ = radiolucent bone lesions

TREATMENT OF OSTEITIS FIBROSA CYSTICA (HYPERPARATHYROID BONE DISEASE)

  • Hyperphosphataemia
    • Low phosphate diet
    • Phosphate binders – reduce GI phosphate absorption
  • Alphacalcidol – ie calcitriol analogues
  • Parathyroidectomy in 3o hyperparathyroidism
    • Indicated for hypercalcaemia &/or hyperparathyroid bone disease
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14
Q

Osteoporosis: define osteoporosis, recall the risk factors and treatment options.

A

OSTEOPOROSIS

  • Loss of bony trabeculae, reduced bone mass, weaker bone predisposed to fracture after minimal trauma
  • Bone mineral density (BMD) > 2.5 standard deviations below the average value for young healthy adults (usually referred to as a T-score of -2.5 or lower)
  • BMD predicts future fracture risk
  • A condition of reduced bone mass and a distortion of bone microarchitecture which predisposes to fracture after minimal trauma

·CLINICAL DEFINITION: having a bone mineral density (BMD) that is 2.5 standard deviations (SD) or more below the average value for young healthy adults (usually referred to as a TEscore of E2.5 or lower)

  • BMD is measured by DualKEnergy XKray Absorptiometry (DEXA)

Osteoporosis: Predisposing Conditions

  • Post-menopausal Oestrogen Deficiency
    • Oestrogen deficiency leads to a loss of bone matrix
    • Subsequent increase in risk of fracture
  • ### Age-related deficiency in bone homeostasis (men and women) E.g. osteoblast senescenc
  • ### Hypogonadism in young men and women
  • Endocrine conditions
    • Cushing’s syndrome
    • Hyperthyroidism
    • Primary hyperparathyroidism
  • ​Iatrogenic
    • Prolonged use of glucocorticoids
    • Heparin

Measuring BMD

  • Dual Energy X-ray Absorptiometry (DEXA) - femoral neck and lumbar spine
  • Mineral (calcium) content of bone measured, the more mineral, the greater the bone density (bone mass)

OSTEOPOROSIS VS. OSTEOMALACIA

Both predispose to fracture

OSTEOMALACIA

  • Vitamin D deficiency (adults) causing inadequately mineralised bone
  • Serum biochemistry abnormal (low 25(OH) vit D, low/low N Ca2+, high PTH (2o hyperparathyroidism)

OSTEOPOROSIS

  • Bone reabsorption exceeds formation
  • Decreased bone MASS
  • Serum biochemistry normal
  • Diagnosis via DEXA scan
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15
Q

Osteoporosis Treatment

A

Osteoporosis Treatment Options Overview

  1. Oestrogen/Selective Oestrogen Receptor Modulators
  2. Bisphosphonates
  3. Denusomab
  4. Teriparatide
  5. (Strontium ranelate)

1. Oestrogen (HRT)

  • Treatment of post-menopausal women with pharmacological doses of estrogen
  • This has an anti-resorptive effect one bone
  • This prevents bone loss
  • Women with an intact uterus (i.e. no hysterectomy) will need additional progestogen to prevent endometrial hyperplasia/cancer

The use of oestrogen in HRT is limited largely due to concerns regarding:

  • Increased risk of breast cancer
  • Venous thromboembolism

2. Bisphosphonates

  • These are analogues of pyrophosphate
  • Examples: alendronate, sodium etidronate
  • Binds avidly to hydroxyapatite and is ingested by osteoclasts
  • It impairs the ability of osteoclasts to resorb bone
  • It also decreases maturation of osteoclasts from their precursors (decreased progenitor development and recruitment)
  • It promotes osteoclast apoptosis

NET RESULT = REDUCED BONE TURNOVER

Use of Bisphosphonates

  • Osteoporosis 9 first line treatment
  • ·Malignancy
  • Associated hypercalcaemia
  • Reduced bone pain from metastases
  • Paget’s Disease -> reduces bony pain
  • Severe hypercalcaemic emergency
  • I.V. saline initially to REHYDRATE
  • Then you give bisphosphonates

Pharmacokinetics of Bisphosphonates

  • Orally active but poorly absorbed
  • Must be taken on an empty stomach (food (milk in particular) reduces drug absorption)
  • Accumulates at the site of bone mineralisation and remains part of the bone until it is resorbed
  • This could be months or years
  • It is still not certain what the impact would be of this accumulation of bisphosphonates

Unwanted Actions of Bisphosphonates

  1. Oesphagitis
    • May require switch from oral to IV preparations
  2. FluKlike Symptoms (IV)
    • Often this is only limited to the first dose
  3. Osteonecrosis of the Jaw
    • Greatest risk in cancer patients receiving IV bisphosphonates
  4. Atypical Fractures
    • May reflect over-suppression of bone remodelling in prolonged bisphosphonate use

3. Denusomab

  • This is a human monoclonal antibody
  • ·It binds to RANKL and inhibits osteoclast formation and activity
  • Hence it inhibits osteoclast-mediated bone resorption
  • It is given subcutaneously every 6 or 12 months
  • This is the second-line treatment to bisphosphonates

Teriparatide

  • Recombinant fragment of PTH
  • This is consists of 34 amino acids
  • Increases bone formation and bone resorption, but formation outweighs resorption
  • This is the thirdKline treatment for osteoporosis
  • Daily subcutaneous injection
  • Very EXPENSIVE

Strontium Ranelate (not used any more)

  • Accumulates in bone 9 especially areas of active remodelling
  • Stimulates bone formation and reduces bone resorption
  • Use is limited by increased risk of myocardial infarction and thromboembolis
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16
Q

Paget’s disease of bone: recall the clinical, biochemical and radiological features of Paget’s disease and treatment options.

A

Paget’s Disease

·Definition: very active (increased), localised but disorganised bone metabolism E usually slowly progressive

  • Characterised by abnormal, large osteoclasts
  • NOTE: increased bone metabolism means that there is increased breakdown and increased synthesis of bone matrix
  • Significant genetic component (up to 30% of cases are autosomal dominant)
  • Evidence of viral origin (e.g. measles virus)
  • Men and women are affected equally (though men may be more symptomatic)
  • Disease is usually not apparent until around 50K60 years
  • More than 10% of over 60s are affected (but majority will experience no symptoms)
  • Apparently more common in the UK than anywhere else
  • So in Paget’s disease you get breakdown of bone and then bone being formed in excessive amounts too 9 this is all disorganised so the bone ends up being weaker than it should be
  • Symptoms include:
    • Increased vascularity 9 you get warmth over the affected bone

oIncreased osteoclast/osteoblast activity

  • Initially increased osteoclast activity (increased deformity and fracture risk)
  • Followed by increased osteoblast activity (thickening of deformed bone)
  • Most commonly affected bones:
    • Pelvis
    • Femur
    • Spine
    • Skull (associated with hearing loss)
    • Tibia

oIncreased incidence of fractures

  • Bone Pain
    • As a consequence of the deformed bone, the nerves can become trapped, joints can be involved and this manifests as pain

Paget’s Disease X-ray

Diagnosis of Paget’s Disease

  • Plasma Calcium = NORMAL
  • Plasma Alkaline Phosphatase (ALP) = usually HIGH
    • ALP increases when there is increased bone activity
  • Radiology demonstrating variable features including:

oLoss of trabecular (spongy/cancellous) bone

  • Increased density
  • Deformity
  • Radioisotope (Technetium) scanning can be performed to indicate the areas of involvement

TREATMENT OPTIONS FOR PAGET’S DISEASE

  • Bisphosphonates – very helpful for reducing bony pain and disease activity
  • Simple analgesia

LCRS2: Endocrinology (9 decks)

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