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Mechanisms of Disease 2 > Calcium and Bone Disease > Flashcards

Calcium and Bone Disease Flashcards

1
Q

Describe the features of bone turn over

A

Bone is an active tissue - turns over several times in a lifetime

  • Increased rate of growth in childhood and puberty
  • In adults rates of bone formation and resorption are coupled and matched
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2
Q

List the functions of calcium

A

Structural
– e.g. bone, teeth

Neuromuscular
– e.g. control of excitability, release of neurotransmitters, initiation of muscle contraction

Enzymic
– e.g. coenzyme for coagulation factors, trypsin

Signalling
– e.g. intracellular second messenger

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3
Q

Describe the distribution of plasma calcium

A

Ionised Calcium - around 1.0mmol/l
– Physiologically active fraction
• Cellular Effects
• Control of PTH

Bound Calcium - around 0.95mmol/l
– Physiologically inactive
– Albumin main binding protein (50%)

Complexed Calcium - around 0.05mmol/l
– Salts - calcium phosphate

Total Calcium = Ionised + Bound + Complexed = around 2.0mmol/l

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4
Q

Describe the laboratory measurement of calcium

A

Usual measurement is Total Calcium
– Cheaper
– More convenient

Doesn’t necessarily reflect ionised calcium
because:
– Total Ca affected by albumin concentration
because of protein binding
– pH influences ionised Ca more H+ ions inhibit Ca2+
binding

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5
Q

How does acidosis effect plasma calcium levels?

A

Bound calcium dissociates into ionised calcium

From around 0.95mmol/l to around 0.55mmol/l

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6
Q

How does alkalosis effect plasma calcium levels?

A

Ionised calcium changes to bound calcium

From around 1.00mmol/l to around 0.60mmol/l

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7
Q

Describe the evidence and clinical implications of the relationship between calcium and pH

A
  • Direct measurement with ion specific electrodes confirms the relationship
  • Alkalosis can precipitate tetany – eg carpopedal spasm (hyperventilation)
  • Hypocalcaemic patients with acidosis don’t develop symptoms
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8
Q

Describe the pathophysiology of calcium

A

Disorders of homeostatic regulators
–Parathyroid hormone
–vitamin D

Disorders of the skeleton
–bone metastases

Disorders of effector organs
–gut - malabsorption
–kidney

Diet

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9
Q

List the calcium-regulating hormones

A

Parathyroid hormone
Calcitriol
Calcitonin

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10
Q

How does parathyroid hormone effect calcium homeostasis?

A

84 and 34 residue forms
• release stimulated by decrease [Ca2+]

Actions:
– bone:
• increased osteoclast activity
• rapid calcium release
• increased plasma [Ca2+]
– kidney:
• increased calcium reabsorption
– increased plasma [Ca2+]
• decreased  phosphate reabsorption
– decreased plasma [Pi]
• increased 1α-hydroxylase activity (calcitriol formation in kidney)
– increased gut absorption Ca & Pi
• decreased bicarbonate reabsorption
– acidosis
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11
Q

Describe the actions of calcitriol

A

Intestine:
• increased synthesis of calcium-binding protein - calbindin D - in enterocytes
• increased uptake of dietary calcium & phosphate
• increased ECF calcium & phosphate, hence  bone
mineralization

Bone:
• Binding to receptors in osteoblast -  alkaline
phosphatase & osteocalcin (Ca-binding protein,
unknown function)
• High concs stimulate osteoclast activity & bone
resorption

Kidney
• Inhibits 1α-hydroxylase
• Small permissive effect with PTH on Ca reabsorption

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12
Q

Give examples of bone diseases related to calcium levels

A

Hypercalcaemia
– Metastatic disease
– Hyperparathyroidism

Hypocalcaemia
– Osteomalacia / Rickets
– Hypoparathyroidism

Eucalcaemia, but impaired bone mineralization
– Osteoporosis
– Paget’s Disease

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13
Q

How is bone disease investigated?

A

Gross Structure
– X-ray

Bone Mass / Density
(Calcium)
– DEXA (dual energy X-ray absorptiometry)

Cellular Function / Turnover
– Biochemistry - e.g. enzymes - AP

Microstructure / Cellular Function
– Biopsy

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14
Q

Describe clinical features of hypercalcaemic bone diseases

A 
Common:
– malignant disease
• metastatic
– tumour may actively dissolve bone
• no apparent metastases
– tumour may secrete PTH-related peptides
– hyperparathyroidism (primary)

Rarer:
– thyrotoxicosis, vitamin D intoxication, thiazide diuretics etc

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15
Q

Describe the effects hyperparathyroidism

A

Commonest overall cause of hypercalcaemia

Primary / Secondary / Tertiary forms seen
• Secondary due to decreased calcitriol and plasma Ca (e.g. chronic renal disease, vitamin D deficiency)
• Tertiary - renal transplant patients

Parathyroid adenomas common - less often diffuse hyperplasia - rarely parathyroid carcinoma

Results in:
• Increased bone turnover / resorption
• Hypercalcaemia / Hypophosphataemia
• Alkaline Phosphatase raised
• Long standing damage : Osteitis Fibrosa Cystica
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16
Q

Give examples of hypocalcaemic bone diseases

A

Osteomalacia/Rickets (Vitamin D deficiency)

Renal failure

Hypoparathyroidism
– congenital (+/- immune deficiency)
– acquired (idiopathic, autoimmune, surgery (thyroidectomy) etc.

Pseudohypoparathyroidism
– failure of cAMP signalling
– increased PTH, but ineffective

17
Q

Describe osteomalacia

A

Due to vitamin D deficiency
– dietary &/or lack of sunlight

Adult form - widened osteoid seams with lack of
mineralisation

Classic childhood rickets (before epiphyseal closure) - widened epiphyses & poor skeletal growth

Failure of vitamin D metabolism or effectiveness e.g. in renal / liver disease and some rare genetic
forms

Results in:
– Hypocalcaemia with secondary hyperparathyroidism
– Raised alkaline phosphatase

18
Q

What is osteomalacia?

A

Rickets disease

19
Q

What is the biochemistry in osteomalacia?

A 
Low vitamin D
Low calcium
Increased PTH
Low/N phosphate
Increased Alkaline phosphatase
20
Q

Give examples of metabolic bone diseases with normal plasma calcium

A

Osteoporosis

Paget’s disease

21
Q

Describe the features of osteoporosis

A
  • Common disease especially of elderly
  • Generalised loss of bone with propensity to fractures - spine, hip
  • Aetiology is largely unknown though current major research efforts are providing some clues - includes oestrogen deficiency
  • No abnormalities are seen in routine biochemical tests perhaps because they are too insensitive
  • Diagnosis relies almost exclusively on DEXA/X-Ray
22
Q

Describe how sex hormones effect bone disease

A

Women who lose bone fastest post menopause have the lowest endogenous sex hormone (oestrogen) levels

  • Mechanism: Osteoclast and osteoblast cells have oestrogen receptors. The binding of oestrogens causes a cytokine mediated reaction that promotes bone re-modelling.
  • Changes are reversed during Oestrogen therapy
23
Q

Describe how calcium levels effect bone disease

A
  • Recommended daily allowance of Calcium is 700mg/day
  • Most adults only achieve 500 mg/day
  • Post menopausal women require 1400 mg/day
  • Negative calcium balance and reduced intestinal absorption have been demonstrated in post menopausal women
  • Studies have shown that calcium supplementation has beneficial skeletal effects in post menopausal women. It is NOT a replacement for HRT.
24
Q

Describe the use of biochemistry tests in bone disease

A

Normal biochemical profile except a raised alkaline
phosphatase

Osteocalcin (bone formation)

Pyridinoline cross-links (marker of bone turnover/resorption):
• cross-links in collagen released on breakdown of collagen
during bone turnover
• Measurements include:
– Urinary total pyridinoline (PYD)
– Urinary free deoxypyridinoline (DPD)

25
Q

Describe the use of DEXA/X-ray in the investigation of bone disease

A
  • Dual energy X-ray absorptiometry (DEXA)
  • Used to measure bone mass of the spine and the femoral neck
  • Low radiation dose
  • Preferred technique of measurement of bone mass at fracture sites
26
Q

Describe Paget’s disease

A

Common disorder - 5% of over 50’s

Possible slow virus aetiology

Disordered bone growth often isolated to a single bone

Causes:
– Raised alkaline phosphatase
– Calcium / Phosphate normal except in immobilised

Mechanisms of Disease 2 (6 decks)

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