Endocrine Bone Disorders Flashcards
What is the most important vitamin D metabolite?
1, 25-dihydroxycholecalciferol (calcitriol)
What is the principle effect of calcitriol?
Increase calcium, magnesium and phosphate absorption in the small intestines
What are the other effects of calcitriol?
Increased reabsorption of calcium and decreased phosphate reabsorption in the kidneys (via FGF23)
Stimulates osteoclast formation from precursors
Stimulates osteoblasts to make osteoclast-activating factors (OAFs e.g. RANKL)
What does vitamin D deficiency cause? State some symptoms.
Lack of bone mineralisation Softening of bone (can lead to bowing of the legs) Bone deformities Bone pain Severe proximal myopathy
What are the different names for vitamin D deficiency in children and adults?
Children – Rickets
Adults – Osteomalacia
State some causes of vitamin D deficiency.
Inadequate dietary intake Lack of sunlight Receptor defects Renal failure Gastrointestinal malabsorptive states
Which step, in vitamin D metabolism, required UV light?
The conversion of 7-dehydrocholesterol in the skin to cholecalciferol (vitamin D3) requires UV light
Describe the two hydroxylation reactions in vitamin D metabolism.
Cholecalciferol is firstly hydroxylated to form 25-hydroxycholecalciferol in the Liver
It then goes to the kidneys where it undergoes its next hydroxylation (by 1-hydroxylase) to form 1, 25-dihydroxycholecalciferol (calcitriol)
What can stimulate 1-hydroxylase in the kidneys?
Parathyroid Hormone (PTH)
How can lack of sunlight cause vitamin D deficiency?
It will mean that less 7-dehydrocholesterol is being converted to cholecalciferol
How can liver disease cause vitamin D deficiency?
The liver is where the first hydroxylation takes place and where 25-hydroxycholecalciferol is stored so liver disease can interfere with this step in vitamin D metabolism
How can renal failure cause vitamin D deficiency?
The second hydroxylation step takes place in the kidneys (via 1-alpha-hydroxylase) so renal failure can interfere with 1-alpha-hydroxylase activity
What is usually measured to gage the level of calcitriol? Whatcondition must be fulfilled for this to be a good measure of calcitriol?
25-hydroxycholecalciferol
This is only a good measure in the case of normal renal function
Describe how you would diagnose vitamin D deficiency.
Plasma Calcium = LOW
Plasma 25-hydroxycholecalciferol = LOW
Plasma PTH = HIGH (secondary hyperparathyroidism stimulated by the hypocalcaemia)
Plasma Phosphate = LOW
Radiological findings e.g. widened osteoid seams
What would you expect the plasma phosphate level to be in someone with renal failure and why?
HIGH – because there is a decrease in plasma excretion via the kidneys
What would you expect the plasma calcium level to be in someone with renal failure and why?
LOW – because they are not producing as much calcitriol (due to renalfailure interfering with 1-alpha hydroxylase) so there is less calcium absorption in the small intestines
What are the consequences of hypocalcaemia caused by renal failure?
There is a decrease in bone mineralisation and an increase in bone resorption (because of an increase in PTH) leading to osteitis fibrosa cystica
The imbalance in calcium and phosphate can also lead to the formation of salts that can be deposited in extra-skeletal tissue causing extra-skeletal calcification
What can vitamin D excess lead to?
Hypercalcaemia and hypercalciuria (due to increased intestinal absorption of calcium)
What can vitamin D excess result from?
Excessive treatment with active metabolites of vitamin D, as in patients with chronic renal failure
Granulomatous disease – granulomatous tissue has 1-hydroxylase so it can be a source of ectopic calcitriol
What is Paget’s disease?
Very active (increased), localised but disorganised bone metabolism –usually slowly progressive. There is increased bone breakdown and bone formation.
What is Paget’s disease characterised by histologically?
Abnormal, large osteoclasts
State some symptoms of Paget’s disease.
Increased vascularity (warmth over affected bone)
Increased osteoblast/osteoclast activity
Initially increased osteoclast activity
Followed by increased osteoblast activity (leading to thickening of deformed bone)
Most commonly affected bones are: pelvis, femur, tibia, skull, and spine
Increased incidence of fracture
Bone pain
Describe how you would diagnose Paget’s disease.
Plasma calcium = NORMAL
Plasma ALP (alkaline phosphatase) = HIGH
Radiological findings:
Loss of trabecular (spongy) bone
Increased bone density
Deformity
Radioisotope (technetium) scanning can be performed to indicate areas of involvement
What are the two components of bone in which 95% of the body’s calcium is stored?
Inorganic mineral component –65%
Stored as calcium hydroxyapatite crystals between the collagen fibrils
Organic (osteoid) component –35%
Collagen fibres (95%)
What is the normal plasma calcium range?
2.2-2.6 mmol/L
State 2 hormones that increase plasma calcium concentration.
Calcitriol
PTH
State a hormone that decreases plasma calcium concentration.
Calcitonin
What are the 2 direct effects of PTH?
Increased mobilisation of calcium in bone
Increased calcium reabsorption in the kidneys and stimulation of 1a-hydroxylase
What are the 2 direct effects of calcitriol?
Increased calcium absorption from the small intestine
Increased mobilisation of calcium in bone
What can stimulate PTH release?
Hypocalcaemia
State 4 signs of hypocalcaemia.
Parasthesia
Arrhythmias
Convulsions
Tetany
What effect does hypocalcaemia have on excitable tissues?
It sensitises excitable tissue –> neuromuscular excitability
State 2 clinical signs of neuromuscular irritability due to hypocalcaemia.
Chvostek’s Sign
Tap the facial nerve just below the zygomatic arch
Positive = twitching of facial muscles
Trousseau’s Sign
Pump the blood pressure cuff for several minutes
Induces carpopedal spasm
State 4 causes of hypocalcaemia.
Hypoparathyroidism (e.g. due to surgery) Vitamin D deficiency Pseudohypoparathyroidism Renal failure (impaired 1-alpha hydroxylase)
Describe the effect of hypercalcaemia on neuronal excitability.
It reduces neuronal excitability and you get atonal muscles
What are the main signs and symptoms of hypercalcaemia?
Stones, abdominal moans and psychic groans
Stones – renal effects
Polyuria + polydipsia
Nephrocalcinosis = deposition of calcium in the kidneys (can cause renal colic)
Abdominal moans – GI effects
Anorexia, nausea, constipation, pancreatitis, dyspepsia
Psychic groans – CNS effects
Fatigue, depression, impaired concentration, altered mentation, coma
What are the 2 main causes of hypercalcaemia?
Primary Hyperparathyroidism (e.g. parathyroid adenoma) Malignancy (e.g. bone tumours/metastases –> increased bone turnover –> increased plasma calcium; tumours can also produce PTH-like peptide)
State 2 other causes of hypercalcaemia.
Conditions of increased bone turnover (e.g. hyperthyroidism, Paget’s) Vitamin D excess (rare)
Describe how you would differentiate between primary hyperparathyroidism and malignancy causing hypercalcaemia.
In primary hyperparathyroidism there is no negative feedback because the parathyroid adenoma will be producing PTH autonomously
Plasma Calcium = HIGH
PTH = HIGH
In malignancy, the negative feedback will be intact as it is due to increased bone turnover due to bony metastases
Plasma Calcium = HIGH
PTH = LOW
Describe the treatment of vitamin D deficiency in the case of normal renal function.
Give 25-hydroxy vitamin D
This can be in the form of:
Ergocalciferol = 25-hydroxy vitamin D2
Cholecalciferol = 25-hydroxy vitamin D3
Describe the treatment of vitamin D deficiency in the case of renal failure.
Alfacalcidol = 1-hydroxycholecalciferol
What do osteocytes produce?
Type 1 collagen and other extracellular matrix components
What is RANK ligand?
An osteoclast-activating factor – it increases the activation of osteoclasts
It stimulates the maturation of osteoclasts from osteoclast precursors
If there are more mature osteoclasts, you get more bone resorption
Define osteoporosis.
Having a bone mineral density (BMD) that is 2.5 standard deviations (SD) or more below the average for young healthy adults (usually referred to as a T-score of -2.5 or lower)
BMD is measured using Dual Energy X-ray Absorptiometry (DEXA)
State some predisposing conditions for osteoporosis.
Post-menopausal oestrogen deficiency Age-related deficiency of bone homeostasis Hypogonadism in young men and women Endocrine conditions (e.g. Cushing’s syndrome, hyperthyroidism, primary hyperparathyroidism) Iatrogenic (e.g. prolonged use of glucocorticoids, heparin)
What are the benefits of oestrogen replacement to prevent osteoporosis in post-menopausal women?
It has an anti-resorptive effect in bone and, hence, prevents bone loss
What are some cautions and risks of oestrogen replacement?
In patients with a uterus (i.e. not had a hysterectomy), you must give additional progestogen to prevent endometrial hyperplasia and reduce the risk of endometrial carcinoma
Risks:
Breast cancer
Venous thromboembolism
Name 2 selective oestrogen receptor modulators and their effects.
Selective oestrogen receptor ANTAGONISTS – Tamoxifen
Antagonises ERs in the breast
Oestrogenic activity in bone
But, oestrogenic activity in uterus, which limits its use in osteoporosis
Selective oestrogen receptor AGONIST – Raloxifene
Oestrogenic in bone
Anti-oestrogenic in breast and uterus
But there is a risk of stroke and venous thromboembolism
What are the 1st, 2nd and 3rd line treatments for osteoporosis?
Bisphosphonates
Denusomab
Teriparatide
What are bisphonates analogues of?
Pyrophosphate
Give 2 examples of bisphosphonates.
Alendronate
Sodium etidronate
Describe how bisphosphonates work.
They bind avidly to hydroxyapatite crystals in the bone and are ingested by osteoclasts
They impair the ability of osteoclasts to resorb bone
It also decreases the maturation of osteoclasts and promotes osteoclast apoptosis
State some uses of bisphosphonates.
Osteoporosis Malignancy – reduces bony pain Paget’s disease – reduces bony pain Severe hypercalcaemic emergency I.V. saline to rehydrate Then bisphosphonates
Describe the pharmacokinetics of bisphosphonates.
They are orally active but poorly absorbed
Must be taken on an empty stomach
Accumulates at the site of bone mineralisation and remains a part of the bone until it is resorbed
State 4 unwanted actions of bisphosphonates.
Oesophagitis
Flu-like symptoms
Osteonecrosis of the jaw (greatest risk in cancer patients receiving IV bisphosphonates)
Atypical fractures (due to over-suppression of bone remodelling)
What is denusomab and how often does it need to be given?
It s a human monoclonal antibody
It binds to RANKL and inhibits osteoclast formation and activity
It is given subcutaneously every 6-12 months
What is teriparatide and how often does it need to be given?
Recombinant fragment of PTH
Increases bone resorption and formation – but formation exceeds resorption
Daily subcutaneous injections
EXPENSIVE
What is strontium ranelate?
Not used anymore
Stimulates bone formation and reduces bone resorption
Increased risk of MI and thromboembolism
