Disorders of Calcium Metabolism

Question 1

What are the biological functions of calcium?

Answer 1

-Intracellular Ca2+ is maintained at very low
concentrations (less than 1 μmol/L).
=Reversible increases allow Ca2+ ions to bind to
proteins to influence many key cell processes (proliferation, cell migration and differentiation and apoptosis)
-Extracellular Ca2+ is present at much higher
concentration (about 1 mmol/L).
=To allow normal bone mineralisation
=To maintain normal activity of excitable tissue (neuromuscular tissues have contractility)

Question 2

What phase of blood is extracellular calcium measured in?

Answer 2

-Liquid (non-cellular) phase of blood i.e. either
o Serum (the liquid phase obtained after blood has
clotted) OR
o Plasma (the liquid phase of non-clotted blood where
the blood sample taken includes an anti-coagulant)

Question 3

Describe plasma (or serum) calcium (what are the components and concentration)

Answer 3

The concentration measured in plasma (or serum) is within a well defined normal range
• This range is typically 2.1-2.6 mmol/L
• This calcium concentration is made up of 2 components:
o Ionised Ca2+ which is physiologically active
o Ca2+ which is ‘bound’ mainly to albumin and
is not physiologically active
• It is the ionised Ca2+ which is actively regulated

Question 4

What is the link between albumin and calcium?

Answer 4

• Albumin is the major Ca2+ binding protein in plasma (or serum)
• Abnormal albumin concentration (which is quite common, more likely down than up in infection/inflammation/malignancy) will alter the Ca2+ bound
• Measuring both albumin and total calcium is required to assess extracellular ionised Ca2+ status

Question 5

How does albumin affect interpretation of plasma calcium?

Answer 5

• Ionised calcium constant
• Bound calcium not constant
• Albumin not constant (less= less capacity to bind calcium)

Question 6

Describe calcium balance

Answer 6

-Net absorption and excretion both 5mmol/24h
=Diet 25 mmoles
=10 mmoles absorbed from gut
=5 mmoles excreted, other excreted through kidneys
=Bone exchange and turnover (dynamic organ)

Question 7

How does calcium balance alter throughout life?

Answer 7

• Growth (new bone formation) requires a positive Ca2+ balance
• Adulthood would ideally be associated with neutral balance (Ca2+ in = Ca2+ out)
• The ageing process is associated with a slow phase of negative Ca2+ balance leading to loss of bone density (may lead to osteoporosis)
• Bone loss accelerated after menopause

Question 8

What is the morphology and function of bone?

Answer 8

• The skeleton makes up ±17% by body weight
• Bone functions
o Support of the body
o Protection of organs
o Leverage system for movement
o Site for haematopoiesis
o Endocrine function (fibroblast growth factor-23;
osteocalcin= basal metabolic rate)
o Regulation of mineral homeostasis
• Bone morphology
o Trabecular Bone (narrow rods, internal)
o Cortical Bone (thicker, outside, strength)

Question 9

What are the types of bone cells?

Answer 9

• Osteoblasts= cells that make bone
• Osteoclasts= cells that resorb bone
• Osteocytes= most abundant cell type in bone, mechanosensor cell

Question 10

Describe bone formation by osteoblasts

Answer 10

• Ob precursor
• Ob (osteoblast)
• Osteoid (uncalcified bone matrix, fibrils and collagen, adjacent to osteoblast)
• Calcified bone matrix (phosphate)
• Cell process from osteocyte
• Osteocyte (internal, cell processes for pressure sensing)

Question 11

Describe bone matrix mineralisation

Answer 11

• Several day delay before osteoid mineralises
• Skeleton contains ~98% of body calcium
• Mineral component is hydroxyapatite: Ca10(PO4)6(OH)2
o Tiny crystals surround collagen fibres
o Provides rigidity, resistance to compression
• Mineralisation of osteoid dependent on calcitriol (active vitamin D);
o Deficiency results in failure to mineralise
o Leads to rickets in children, osteomalacia in adults
• Full mineralisation takes several months

Question 12

Describe the role of Alkaline phosphatase (ALP) in mineralisation

Answer 12

• Expressed on surface of differentiated osteoblasts; also released into extracellular fluid and circulation (bone formation marker), liver function test
• Releases inorganic phosphate ions (PO4 3-) from diverse molecules (hydrolysis)
• ALP promotes mineralisation (i.e., precipitation of calcium phosphate/ hydroxyapatite) in 2 ways:
o by increasing the local concentration of inorganic phosphate ions
o by hydrolysing pyrophosphate, a key endogenous inhibitor of mineralisation

Question 13

What is the role of osteoclasts in bone resorption?

Answer 13

o Multinucleate, motile bone-resorbing cells
o Formed by fusion of promonocytic precursors present in marrow and circulation
o “Ruffled border” adjacent to bone surface secretes H+
and enzymes
o Express high levels of carbonic anhydrase II required for H+ generation

Question 14

Describe the role of RANK-RANKL in osteoclast biology and function

Answer 14

-Bone marrow stromal cell (expresses RANKL) communicates with osteoclast precursor through RANK-RANKL interaction ligands
=Activation of osteoclast precursor
=Mature osteoclast

Question 15

How do osteoclasts resorb bone?

Answer 15

• Pits on flat surface of bone

- Osteoclast highly motile

Question 16

What clues indicate osteopetrosis?

Answer 16

• Also known as: ‘Marble bone disease’/ stone bone
• Inherited bone disease
=shorter
• Increased bone mass
• Caused by dysfunctional osteoclasts
=flat pits

Question 17

What is the cause of osteopetrosis?

Answer 17

-Failure of matrix degradation by osteoclasts
=CA 2 mutations (carbonic anhydrase)
=TCIRG1 mutations (proton pumps through ruffled border)
=CLCN7 mutations (chloride channel defects, so no HCl)
=Cat K mutations (other protein pumps)

Question 18

Overview of bone remodelling cycle

Answer 18

• Quiescence of lining cells
• Osteoclast resorption (10 days)
• Osteoblast reversal (osteoblast lays down new osteoid)
• Osteocytes= formation
• Mineralisation 3 months

=4-6 months

Question 19

Why do we need bone metabolism?

Answer 19

o To grow
o Respond to altered mechanical requirements
o Repair damage (macro / micro fractures)
o Maintenance (failure prevention)
o Calcium deficit
• Skeleton is renewed every ± 7 years
• In health, bone formation and resorption are
balanced
• For bone growth, formation exceeds resorption

Question 20

Describe bone turnover and metabolism in disease

Answer 20

• Pathological imbalance between formation and
resorption leads to disease
• Most common bone diseases reflect this
imbalance
• Osteoporosis (late stages in life, oestrogen influence, smoking, reduced bone density)
o Most common cause: low oestrogen after menopause
o Main cause of bone loss: increased bone resorption
• Paget’s disease
o Due to overactive osteoclasts (thickened bone, skull can affect neuro-processes, hearing problems and pain)

Question 21

How is ionised Ca2+ regulated?

Answer 21

• This regulation is endocrine, requiring the
participation of 2 key hormones called
parathyroid hormone (PTH) and calcitriol which
show typical endocrine feedback loops
• PTH is a peptide hormone
• Calcitriol is a steroid hormone which is
synthesised from dietary factor (vitamin D)
• The principal organs involved are gut, bone and
kidney (liver and skin)

Question 22

What is the physiology of PTH?

Answer 22

• A peptide hormone required for the minute-byminute regulation of ionised calcium levels in
blood
• PTH is secreted as a single chain polypeptide
(84 amino acids) from the parathyroid glands
• PTH secretion is increased in response to falling
Ca2+ and its actions are directed at restoring
Ca2+ levels
• Rising Ca2+ feeds back to the parathyroid glands
and suppresses PTH secretion (negative
feedback loop)

Question 23

How is PTH secretion regulated?

Answer 23

• PTH secretion is tightly
regulated to maintain Ca2+ in physiological range
• Calcium receptors on cell
sense Ca2+ levels to regulate PTH secretion
• G-protein coupled receptor is activated by binding of calcium

Question 24

What are the actions of PTH?

Answer 24

oStimulates efflux of Ca2+ from bone
oStimulates renal tubular reabsorption of Ca2+
(distal tubule)
oStimulates formation of calcitriol (indirectly)
promoting intestinal absorption of Ca2+
oPromotes phosphate and bicarbonate loss from
the kidney (proximal tubule, inhibits reabsorption)

Question 25

Describe calcium, PTH and vitamin D feedback loops

Answer 25

-Rising blood Ca2+ =Suppress PTH =Decreased bone resorption, increased urinary calcium loss, decreased active vitamin D production -Falling blood Ca2+ =Stimulate PTH =Increased bone resorption, decreased urinary calcium loss, increased active vitamin D production

Question 26

Describe calcitonin

Answer 26

• 32 amino acid polypeptide secreted in response to rising Ca2+ from parafollicular or C-cells of the thyroid gland • Principal action is to reduce osteoclast activity • No clear role in calcium homeostasis (e.g. neither total thyroidectomy nor calcitonin-secreting tumours alter calcium homeostasis) • May be used therapeutically to treat high serum calcium levels • Also serves as a ‘tumour marker’ (certain thyroid tumours; some breast cancers)

Question 27

Describe cholecalciferol

Answer 27

• Fat soluble vitamin (vitamin D) • Steroid structure • Produced endogenously by the action of UV light on skin precursor, 7-dehydrocholesterol • Dietary sources include oily fish, eggs, butter, margarine (fortified)= 30% • Cholecalciferol requires activation by liver and kidney to produce the active hormone, calcitriol

Question 28

Describe vitamin D physiology

Answer 28

• Calcitriol is a hormone: it is synthesised in one location (kidney) and acts at many sites • Vitamin D is distinct from other “classical” vitamins, such as vitamin C, B vitamins, etc., which act as cofactors in biochemical reactions • Calcitriol is required for the longer-term maintenance of calcium (and phosphate) levels and is required for normal bone growth and mineralisation

Question 29

How is vitamin D synthesised (precursor to D3)?

Answer 29

-The precursor for vitamin D synthesis is a sterol in the cholesterol biosynthetic pathway, 7- dehydrocholesterol which is found in skin • Ultraviolet light (UVB) transforms 7- dehydrocholesterol to vitamin D3 (cholecalciferol)

Question 30

How is vitamin D synthesised (D3 to 25(OH) vitamin D)?

Answer 30

• Vitamin D3 circulates to the liver, where the microsomal enzyme 25-hydroxylase hydroxylates it to 25-hydroxy vitamin D (25(OH)vitamin D)= calcidiol • 25-hydroxylase functions constitutively without input from blood calcium status or PTH (all the time) • 25(OH)vitamin D is the best screening test for vitamin D adequacy

Question 31

How is vitamin D synthesised (to active form)?

Answer 31

• 25(OH)vitamin D circulates to the kidneys where it is hydroxylated by 1α-hydroxylase to 1,25(OH)2 vitamin D (calcitriol) = ‘active’ vitamin D • Renal 1α-hydroxylase is regulated by PTH which stimulates its activity. PTH is the principle physiologic regulator, although calcium can affect the activity • Other hydroxylations possible (e.g. at the 24- position= inactivates vitamin D)

Question 32

Describe vitamin D metabolism

Answer 32

- 7-DHC= Vitamin D3= 25(OH)D3= 1,25(OH)D3 - Increases calcium and phosphate absorption in gut through calbindin - Increases bone resorption

Question 33

What is the mechanism of calcitriol action

Answer 33

• Calcitriol binds to a single vitamin D receptor (VDR) • The VDR-calcitriol complex acts through a vitamin D-responsive element (new protein synthesis= gene transcription) o In the intestine, a calcium-binding protein (calbindinD9k) is synthesised which promotes absorption of both calcium and phosphate o In bone, stimulates osteoblast differentiation and osteoclast activation via RANK ligand (RANKL) formation in osteoblasts

Question 34

What are the actions of calcitriol?

Answer 34

• Calcitriol promotes gut absorption of calcium and phosphate (requires new protein synthesis) • Calcitriol, in concert with PTH, stimulates osteoclasts and efflux of Ca2+ from bone • Calcitriol, in concert with PTH, increases renal Ca2+ reabsorption • Maintenance of both calcium and phosphate levels essential for hydroxyapatite formation and normal bone mineralisation • Calcitriol deficiency has major effects on bone mineralisation (low calcitriol, high PTH- secondary hypoparathyroidism)

Question 35

Compare and contrast calcitriol with PTH

Answer 35

* Both maintain ionised Ca2+ * PTH responsible for minute-by-minute plasma Ca2+ regulation * Calcitriol responsible for longer term plasma Ca2+ regulation * PTH tends to decrease plasma phosphate * Calcitriol raises plasma phosphate

Question 36

What are the effects of 25(OH)D deficiency on calcium metabolism?

Answer 36

- Phosphate wasting (lost from urine) - Bone resorption - Reduced calcium absorption from gut

Question 37

Describe the interactions between PTH and calcitriol

Answer 37

• Co-operativity o PTH promotes 1α-hydroxylase activity o PTH and calcitriol both required in vivo for osteoclast activation and distal tubular Ca2+ reabsorption o Calcitriol deficiency may impair PTH action • Limitation of action – Calcitriol stimulates 24-hydroxlase (promotes its own inactivation) – Calcitriol can switch off PTH gene transcription via VDR in parathyroid cells, limiting PTH action

Question 38

Describe regulation of ionised calcium by PTH

Answer 38

-Fall in Ca2+ stimulates parathyroid hormone -Restores Ca2+ by =Increasing bone release of Ca2+ =Increasing renal reabsorption of Ca2+ =Stimulating formation of calcitriol -Rising Ca2+ suppresses PTH

Question 39

What are the clinical manifestation of hypercalcaemia?

Answer 39

*‘Stones, bones, abdominal moans and psychic groans’ • Muscle weakness (striated and smooth); possible competition with inward Na+ movement • Central effects (anorexia, nausea, mood change, depression) • Renal effects (impaired water concentration, frequent urination; renal stone formation) • Bone involvement (cause-dependent) • Abdominal pain • ECG changes (shortened QT interval= 3-4.5 mmol/L, cardiac arrhythmias and arrest)

Question 40

What is Factitious hypercalcaemia?

Answer 40

``` -Non-pathological, clinically fine • Raised [calcium] due to high plasma [albumin] e.g. o Venous stasis (tourniquet applied too long, blood leaks out from vessels to tissues, increase in protein so albumin increases) o Dehydration o IV albumin ```

Question 41

Describe the epidemiology of primary hyperparathyroidism

Answer 41

• 1 in 500 to 1 in 1000 • Most common in 6th decade • Most common aetiology in outpatients • Women > men, 3:2 ratio (hormonal influence?) • Many patients found on routine screening with minimal symptoms • 90% solitary adenoma; hyperplasia; carcinoma (rare)= growths in parathyroid gland produces too much PTH

Question 42

What are the types of hyperparathyroidism?

Answer 42

• 1y hyperparathyroidism is an autonomous and inappropriate overproduction of PTH leading to hypercalcaemia =high PTH, high calcium, low phosphate • 2y hyperparathyroidism is an appropriate increase in PTH in response to hypocalcaemia, chronic kidney disease =high PTH, low/normal calcium, high phosphate (CKD) • 3y hyperparathyroidism is rare but refers to the situation where a 2y overactive gland becomes overactive (now autonomously so from appropriate to inappropriate) =very high PTH, high calcium, high phosphate

Question 43

Describe the histology of parathyroid adenoma

Answer 43

- No spaces between clusters of cells - Homogenous - Overproduction of cell types

Question 44

Describe the radiology of hyperparathyroidism

Answer 44

- Bones brittle, fragile - Dark- less bone matrix - Calculi

Question 45

How do we diagnose 1y hyperparathyroidism?

Answer 45

• Raised Ca2+ with inappropriately increased PTH • Phosphate and bicarbonate tend to be low in serum (increased renal excretion) • Alkaline phosphatase normal or moderately increased in more severe disease • Further investigations: o Parathyroid imaging scan (Sestamibi, 99mTc-MIBI, adenoma and hyperplasia, isotope scans)

Question 46

What is the treatment of 1y hyperparathyroidism?

Answer 46

• Acutely, patients may need treatment of their high ionised calcium: – re-hydration – drugs • Definitive treatment is removal of parathyroid adenoma (surgery- complete removal or adenoma removal) • Mild cases may be managed by repeated follow-up of serum calcium/PTH • Where surgery may be difficult (e.g. poor operative risk) drugs to lower calcium levels may be required

Question 47

What are the available drugs to treat hypercalcaemia?

Answer 47

``` o Bisphosphonates (inhibit osteoclast action and bone resorption as analogues of pyrophosphate, reduce recruitment and promote apoptosis); after re hydration this is key drug for longer-term control o Furosemide (inhibits distal Ca2+ reabsorption; requires care and patient must be hydrated first) o Calcitonin (inhibits osteoclast action); tolerance may develop but useful for immediate, short-term management- side effects o Glucocorticoids (inhibit vitamin D conversion to calcitriol; can prolong calcitonin action) ```

Question 48

What are the new drugs that treat hypercalcaemia?

Answer 48

o Calcimimetic drugs which bind to Ca2+ sensor receptor and inhibit PTH release. Restricted use (e.g. parathyroid carcinomas, CKD) =Cinacalcet

Question 49

What is the link between malignant disease and hypercalcaemia?

Answer 49

• Commonest cause of hypercalcaemia in hospitalised patients • Up to 20-30% cancer patients may develop hypercalcaemia during course of illness • Two broad reasons: o Endocrine factors secreted by malignant cells acting on bone o Metastatic tumour deposits in bone locally stimulating bone resorption via osteoclast activation

Question 50

What is the frequency of different malignancies as causes of hypercalcaemia?

Answer 50

- Lung= 35% - Breast= 25% - Haematological (including myeloma)= 14% - Head and Neck= 6% - Renal= 3% - Prostate= 3% - Unknown primary= 3% - Others= 3%

Question 51

What are the endocrine factors in malignant hypercalcaemia?

Answer 51

• Solid tumours may secrete PTH-related peptide (or PTHrP) (e.g. breast; squamous tumours of lung, head and neck) • PTHrP shows structural homology to PTH and shares similar actions but is distinct (PTH itself is suppressed due to feedback) • Where PTHrP is the cause this is known as humoral hypercalcaemia of malignancy • Some tumours (esp. Hodgkin’s lymphoma) possess 1-OHase activity and synthesise calcitriol

Question 52

Describe how malignant hypercalcaemia is associated with bony metastases

Answer 52

• Approx. 20% cases malignant hypercalcaemia • Most commonly associated with breast and lung cancers, multiple myeloma • Secretion of osteoclast activating cytokines or other factors into the bone micro-environment is key element • Metastatic breast tumour may locally produce PTHrP • Myeloma cells produce cytokines that activate osteoclasts (RANKL, IL-3, IL-6)

Question 53

Describe the findings of multiple myeloma

Answer 53

-Bone marrow biopsy =Increase in plasma cells (abundance, more than 10%) -Pepper pot skull= lesions in skull, punched out holes

Question 54

How do we diagnose malignant hypercalcaemia?

Answer 54

• Raised Ca2+ with suppressed PTH o Phosphate tends to be high o Alkaline phosphatase may be very high (liver or bone metastases) o Often clear from previous history of malignant disease

Question 55

What are the principles of treatment of malignant hypercalcaemia?

Answer 55

• Re-hydrate the patient • If required, use drugs which lower calcium in the blood • Treat underlying malignancy (surgery, chemotherapy)

Question 56

What are other causes of hypercalcaemia?

Answer 56

* Granulomatous disease e.g. sarcoidosis * Exogenous vitamin D excess * Familial hypocalciuric hypercalcemia * Drugs (e.g. Li, thiazide diuretics) * Some endocrine diseases (thyrotoxicosis, Addison’s disease) * Immobilization

Question 57

What is sarcoidosis?

Answer 57

``` • Granulomatous disease • Usually affects lung (90%) and skin (10%) • ↑[calcium] with n[PTH] • Hydroxylation of vit D in granulomas =Marker is ACE =Relapsing and remitting pattern ```

Question 58

Describe Familial hypocalciuric hypercalcaemia (FHH)

Answer 58

• Rare but interesting • Ca2+ sensor on parathyroid glands less sensitive to Ca2+ suppression of PTH • Altered ‘set-point’ for PTH/Ca2+ interaction • PTH levels tend to be high normal or slightly raised • Plasma ionised calcium increased (mild) • Urine Ca2+ excretion low (relative to plasma Ca2+)

Question 59

What are the clinical manifestations of hypocalcaemia?

Answer 59

``` • Predominantly due to an increase in neuromuscular excitability (increased inward Na+ movement?) • Neuromuscular o Numbness and paraesthesia (‘tingling’) in fingertips, toes, around mouth o Anxiety and fatigue o Muscle cramps, carpo-pedal spasm, bronchial or laryngeal spasm o Seizures • Mental state o Personality change o Mental confusion, psychoneurosis o Impaired intellectual ability • ECG changes, eye problems ```

Question 60

What are the signs of hypocalcaemia?

Answer 60

- Chvostek's sign= tapping facial nerves causes twitching of eye - Trousseau's sign= blood pressure inflated so brachial artery completely occluded and makes pinching sign

Question 61

What is factitious hypocalcaemia?

Answer 61

Consequence of low plasma [albumin] e.g.: • Acute phase response (low albumin) • Malnutrition or malabsorption (protein deficiency in diet) • Liver disease (reduced liver synthesis albumin) • Nephrotic syndrome (albumin lost in urine)

Question 62

What are the causes of active vitamin D deficiency (amount or action)?

Answer 62

* Lack of sunlight * Inadequate dietary source * Malabsorption (crohns, coeliac) * Chronic renal disease (relatively common) * Chronic liver disease (rare) * Defective 1-OHase (v. rare) * Defective 1,25- D3 receptor (v.rare)

Question 63

Describe vitamin D deficiency

Answer 63

• Historically, in the UK, poor diet and inadequate sunlight exposure led to many cases of deficiency in children • Although food (milk, cereals, margarine) is fortified with vitamin D, the action of sunlight on skin is the main source of vitamin D • Current risk factors where supplementation may be required: o Those confined indoors (e.g. elderly) o Dark skinned individuals at high latitudes o Lack of sunlight exposure through dress, high factor sunscreen etc.

Question 64

What are the biochemical and clinical features of vitamin D deficiency?

Answer 64

-Symptoms related to low Ca2+ -Osteomalacia (bone pain, fractures, disordered growth in children as a consequence of defective mineralisation) • Low 25-D3 (measured) and 1,25-D3 (usually) • Low Ca2+ (may be normal in early stages) • High PTH (2y hyperparathyroidism) • Phosphate tends to be low • Often raised ALP (defective mineralisation)

Question 65

Describe Osteomalacia

Answer 65

* Pathological bone problem classically associated with vitamin D deficiency * Osteoid laid down by osteoblasts is not adequately calcified * Osteoid content in bone increases at the expense of normal calcified osteoid (bone matrix) * Bones are softened, weak and susceptible to fracture

Question 66

Describe Rickets

Answer 66

- Bone deformity (bowing of long bones widening of cartilage at growth plate) - Bone pain - Weakness

Question 67

What are the inherited causes of osteomalacia/ rickets?

Answer 67

• Deficient 1-hydroxylase (vitamin D-resistant rickets type 1, VDRR type 1) • Defective receptor for calcitriol (Vitamin D- Resistant rickets type 2, VDRR type 2) • Other inherited causes of rickets: o Hypophosphatemic rickets  Low serum phosphate  Impaired mineralisation  Excessive urine phosphate loss  Phosphaturic hormone (FGF23)/PHEX mutations o Hypophosphatasia (low alkaline phosphatase)

Question 68

Overall, what are the causes of hypoparathyroidism?

Answer 68

-Acquired • Surgical damage or removal (relatively common; usually transient) • Suppressed secretion (e.g. low Mg2+, maternal hypercalcaemia) -Inherited • Developmental parathyroid problems • Genetic/familial disorders e.g. DiGeorge syndrome

Question 69

What is the biochemistry of hypoparathyroidism?

Answer 69

• Low Ca2+ • Inappropriately low PTH • Phosphate may be increased

Question 70

What are the principles of treatment of hypocalcaemia?

Answer 70

• In acute situations IV calcium may be required • Normally oral calcium and vitamin D are given (Mg sometimes) • Vitamin D may be given in various forms: – By injection (IM) if malabsorption is present or stores require to be replete more quickly – As the 1OH form if renal function is impaired • Close monitoring of plasma calcium concentration necessary

Question 71

Describe osteoporosis

Answer 71

``` • Commonest bone disease (up to 30% women and 12% men) • Reduced bone mineral density; disruption of microarchitecture • Increased risk of fracture • Routine biochemistry unaffected ```

Question 72

How do we assess bone mineral density?

Answer 72

Dual-energy X-ray absorptiometry (DEXA) =Scores, average estimate of bone density

Question 73

Compare and contrast osteoporosis and osteomalacia

Answer 73

``` Osteoporosis: • Loss of calcified matrix and reduced bone density •‘Less’ bone but histologically normal • Susceptibility to fracture • Essentially normal biochemistry • Defined by bone densitometry (less than 2.5 SD than bone from a young adult) ``` ``` Osteomalacia: • Abnormal histology with wide seams of uncalcified osteoid • Loss of calcified matrix and reduced bone density • Susceptibility to fracture • Abnormal biochemistry ```

Question 74

What is the formula for corrected calcium?

Answer 74

corrected [Ca2+] = measured [Ca2+] + (40 - [albumin] * 0.02)

Question 75

Why might total serum calcium not represent patient's ionised calcium status?

Answer 75

-Hypoalbuminaemia -Acid-base balance disorders can affect the binding of calcium to albumin and inorganic ions. =In acidosis, albumin becomes protonated which prevents it from binding calcium as effectively, therefore unbound calcium increases. = On the other hand, in alkalosis albumin can bind calcium more easily, resulting in a reduction in unbound calcium. -In these situations, there is a change in the proportions of calcium bound and unbound, but the total calcium remains unchanged

Question 76

How is calcium transported across the intestinal epithelia?

Answer 76

1. Calcium diffuses paracellularly (between cells) down its concentration gradient. This occurs only when the concentration of calcium in the gut lumen is greater than the concentration of calcium in the extracellular fluid. 2. When calcium levels in the gut lumen are low, calcium can diffuse transcellularly (across cells). First calcium diffuses into the cell (because the intracellular concentration is much lower than the concentration in the gut lumen. =However, this diffusion cannot go on forever, because calcium is dangerous to the cell. Also, the concentration gradient would be lost, so no more calcium would diffuse in once an equilibrium is reached. 3. Therefore the cell has calcium binding proteins (such as calbindin) within it. Calcium binds to the proteins. This maintains the concentration gradient of free calcium so more can diffuse into the cell. 4. Calcium is then pumped out of the basal membrane of the cell. The Na+/Ca2+ exchange protein pumps calcium out of the cell by using the sodium gradient created by the Na+/K+ pump.

Question 77

Where is calcium absorbed in the kidney?

Answer 77

- 60% PCT - 25% ascending limb - 10% DCT, amount modifiable by hormones

Question 78

Features of primary hyperparathyroidism progression

Answer 78

-Subperiosteal bone erosion in phalanges -Osteitis fibrosa cystica =chronic overstimulation of osteoclasts= excessive bone resorption =brown tumours (weak patches of immature bone, connective tissue and bone stroma)

Question 79

How would humoral hypercalcaemia of malignancy present compared to osteolytic bone metastases?

Answer 79

-HHoM =high calcium, high PTHrP, low PTH, low phosphate -Bone metastes =high calcium, low PTH, high phosphate and high alkaline phosphatase

Question 80

Describe Multiple Myeloma

Answer 80

-Cancer of plasma cells (mature immunoglobulin producing cells that differentiate from B cells) =secrete paraproteins (abnormal immunoglobulin/ IgG) causes tissue damage -Common in black elderly people, incurable

Question 81

What are the symptoms of Multiple Myeloma?

Answer 81

-CRAB -Calcium= hypercalcaemia =Renal= kidney damage from paraproteins and hypercalcemia -Anaemia= disrupt haematopoiesis in marrow -Bone= resorption

Question 82

What is Milk-alkali syndrome?

Answer 82

- caused by excess dietary intake of calcium and alkali, for example taking calcium supplements alongside calcium carbonate antacids. - This can cause hypercalcaemia, a metabolic alkalosis and kidney damage

Question 83

What symptoms present in chronic hypocalcaemia?

Answer 83

- Cataracts - Basal ganglia calcification - Extrapyramidal disorders

Question 84

What are the causes of hypocalcaemia?

Answer 84

- Vitamin D deficiency - Hypoparathyroidism - Chronic kidney disease - Hypomagnesemia - Acute pancreatitis

Question 85

How do we treat secondary hyperparathyroidism?

Answer 85

- Treat CKD - Ergocalciferol - Low phosphate diet - Phosphate binders