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
