Endocrine bone disorders Flashcards
What is the most important product of vitamin D metabolism?
1,25 dihydroxycholecalciferol -calcitriol
What is the principal effect of calcitriol?
Stimulates intestinal absorption of calcium and phosphates (and magnesium)
What is the precursor of calcitriol?
25 hydroxycholecalciferol
What effect can 25 hydroxycholecalciferol have?
In high concentrations, it can have calcitriol effects
Why is the intestinal absorption of ions important?
Provides ions necessary for bone mineralisation
What other effects does calcitriol have?
Stimulates osteoclast formation from precursors in bone and their activity
Stimulates osteoblasts
Renal effects- increased calcium reabsorption and decreased phosphate reabsorption
What is the definition of vitamin D deficiency?
Lack of mineralisation in the bone
What does vitamin D deficiency result in?
Softening of bone
Bone deformities
Bone pain
Severe proximal myopathy
What is vitamin D deficiency referred to as in children?
Ricket’s
What is vitamin D deficiency referred to as in adults?
Osteomalacia
What are the causes of vitamin D deficiency?
Diet Lack of sunlight Gastrointestinal malabsorptive states Liver disease Renal failure Receptor defects
How is vitamin D formed by UV light?
UV acts on 7-dehydrocholesterol in the skin to form cholecalciferol (vitamin D3)
What is the other source of vitamin D?
Diet- ergocalciferol (vitamin D2)
What happens to cholecalciferol once it is formed?
It gets converted to 25-hydroxycholecalciferol in the liver, then it goes to the kidneys where it is converted to the active and powerful 1,25 dihydroxycholecalciferol in the kidneys via the action of 1 alpha hydroxylase which is stimulated by PTH
How do you gage the amount of calcitriol in a patient?
25-hydroxycholecalciferol is measured as a gage of the amount of calcititrol because calcitriol is difficult to measure however this method is reliant on good renal function
If you were to diagnose vitamin D deficiency what would you look for?
Plasma 25-hydroxycholecalciferol would be low
Plasma calcium would be low
PTH= high
Plasma phosphate would be low
Why is PTH high?
Secondary hyperparathyroidism- plasma calcium is low so stimulates release of PTH, which will attempt to increase plasma calcium and could potentially mask hypocalcaemia
How does decreased renal function make bone disease worse?
Decrease in renal function =
Decrease production of calcitriol because 1alpha hydroxylase is required
Decreased phosphate excretion so plasma phosphate increases
Decreased calcitriol will cause decreased calcium absorption from the intestines leading to hypocalcaemia which will stimulate PTH
PTH will break down bone matrix to restore calcium and will lead to osteoporosis
What can vitamin D excess lead to?
Hypercalcaemia and hypercalciuria due to increased intestinal absorption of calcium (main effect of calcitriol)
What can vitamin D excess occur as a result of?
Excess treatment with active metabolites of vitamin D
Granulomatous disease- sarcoidosis, leprosy and tuberculosis
Why is granulomatous disease a cause of vitamin D excess?
Granulomatous tissue can convert 25 hydroxycholecalciferol to active metabolite 1,25- dihydroxycholecalciferol because granulomatous tissue have 1 alpha hydroxylase so this is ectopic calcitriol production
What is Paget’s disease?
Very active (increased), localised but disorganised bone metabolism - usually slowly progressive
What is Paget’s characterised by?
Abnormal large osteoclasts
What are the causes of Paget’s disease?
Significant genetic component
Evidence of viral origin
What percentage of over 60s are affected by Paget’s?
More than 10% (but majority will experience no symptoms)
What are the symptoms of Paget’s disease?
Increased vascularity
Increased osteoclast/osteoblast activity (osteoclast first)
Increased incidence of fractures
Bone pain
Which bones are most commonly affected by Paget’s disease?
Pelvis Femur Spine Skull Tibia
How do you diagnose Paget’s disease?
Plasma calcium= normal Plasma alkaline phosphate= usually high Radiology demonstrating variable features including: Loss of trabecular bone Increased density Deformity
What is the largest (65%) component of bone mass?
Inorganic mineral component
What does the inorganic mineral component contain?
Calcium hydroxyapatite crystal
What does the inorganic mineral component do?
Fills the space between the collagen fibres
What makes up 95% of the organic component (osteoid)?
Collagen fibres
What is the normal plasma calcium range?
2.2-2.6mmol/l
What hormones increase plasma calcium?
Parathyroid hormone
Vitamin D
What hormone decreases plasma calcium?
Calcitonin (not specifically important in humans)
What are the effects of increased PTH in response to low calcium?
Mobilises calcium from bone to increase plasma calcium
Direct effect to increase reabsorption of calcium in the kidneys
Stimulates activation of vitamin D which leads to increase in calcium
Stimulates kidneys to make 1alpha hydroxylase
What responds to the increase in calcium due to PTH?
Parathyroid gland- decreases PTH secretion
What are the signs and symptoms of hypocalcaemia?
Parasthesia Arrhythmia Convulsions Tetany (CATs go numb)
What is parasthesia?
Abnormal sensation such as numbness or tingling without a cause
Why do you experience muscle cramps and tetany with hypocalcaemia?
Hypocalcaemia senstises excitable tissues
What signs are used to check for hypocalcaemia?
Chvostek’s signs
Trousseau’s sign
What are Chvostek’s signs?
Tap the facial nerve just below the zygomatic arch
A positive response= twitching of the facial muscles indicates neuromuscular excitability
What is Trousseau’s sign?
Inflation of the blood pressure cuff for several minutes induces carpopedal spasm due to neuromuscular excitability
What are the causes of hypocalcaemia?
Vitamin D deficiency Hypoparathyroidism (Low PTH) Surgical- neck Autoimmune PTH resistance Renal failure
What are the signs and symptoms of hypercalcaemia?
Stones and Polyuria- Nephrocalcinosis, renal colic and chronic renal failure
Abdominal moans- GI effects e.g. Anorexia, nausea, dyspepsia, constipation and pancreatitis
Psychic groans- CNS effects e.g. Fatigue, depression, impaired concentration, altered mentation and coma
(Stones, abdominal moans and psychic groans)
What are the causes of hypercalcaemia?
Primary hyperparathyroidism (parathyroid adenoma)
Malignancy (Tumours/metastases)- bone metastases lead to increased calcium
Conditions with high bone turnover- Hyperthyroidism, Paget’s disease and vitamin D excess
If you were diagnosing primary hyperparathyroidism, what would you expect to see?
Calcium- high
PTH- high (parathyroid adenoma doesn’t respond to negative feedback of calcium)
If you were diagnosing hypercalcaemia of malignancy, what would you expect to see?
Calcium- high
PTH- low
Increased bone turnover due to bony metastases, calcium rises but negative feedback still in place so PTH is suppressed
When treating a patient for vitamin D deficiency, what affects their treatment choice?
Renal function
How would you treat someone with vitamin D deficiency with normal kidney function?
Give 25-hydroxy vitamin D
Patient can convert this to calcitriol via 1alpha hydroxylase
Supplements are ergocalciferol or cholecalciferol
How would you treat someone with vitamin D deficiency with renal failure?
Don’t have 1alpha hydroxylase activity
So can’t activate 25-hydroxy vitamin preparations
Give alfacalcidol- 1,hydroxycholecalciferol
What does RANK ligand (RANKL) do?
Important molecule that increases the activation of osteoclasts
Stimulates maturation of osteoclasts from osteoclast precursors which stimulates bone resorption
What do osteoblasts do?
Synthesise osteoid and participate in mineralisation/calcification of osteoid
What do osteoclasts do?
Release lysosomal enzymes which break down bone
What is osteoporosis?
Condition of reduced bone mass and distortion of bone microarchitecture which predisposes to fracture after minimal trauma
What is the clinical definition of osteoporosis?
Having a bone mineral density that is 2.5 standard deviations or more below the average value for young healthy adults
How is bone mineral density measured?
Dual-energy X-ray absorptiometry
What conditions predispose you to osteoporosis?
Post-menopausal oestrogen deficiency
Age-related deficiency in bone homeostasis
Hypogonadism in young men and women
Endocrine conditions- cushing’s, hyperthyroidism and primary hyperparathyroidism
Iatrogenic- prolonged use of glucocorticoids and heparin
How can you treat osteoporosis?
Oestrogen/selective oestrogen receptor modulators (SERMs)
Bisphosphonates
Denusomab
Teriparatide
Why is the use of oestrogen therapy limited?
Increased risk of breast cancer and venous thromboembolism
What are the two types of selective oestrogen receptor modulators?
Tissue selective ER antagonists and agonists
What is a common example of a tissue selective ER antagonist/anti-oestrogen?
Tamoxifen
What do ER antagonists do?
Antagonise ERs in breast
Oestrogenic activity in the bone and endometrium
Use is limited because of effects on endometrium
What is a common example of a tissue selective ER agonist?
Raloxifene
What do ER agonists do?
Oestrogenic activity in bone
Anti-oestrogenic activity in breast and uterus
How do bisphosphonates work?
Binds avidly to hydroxyapatite and is ingested by osteoclasts- it impairs osteoclasts ability to resorb bone, it also decreases maturation of osteoclasts from their precursors
Net result- reduced bone turnover
What are bisphosphonates used for?
Osteoporosis
Malignancy
Paget’s disease
Severe hypercalcaemic emergency after saline
What are the unwanted actions of bisphosphonates?
Oesophagitis
Flu-like symptoms
Osteonecrosis of the jaw
Atypical fractures
What is denusomab?
A human monoclonal antibody
How does denusomab work?
Binds to RANKL and inhibits osteoclast formation and activity so inhibits resorption (second line treatment to bisphosphonates)
What is teriparatide?
Recombinant fragment of PTH
What does teriparatide do?
Increases bone formation and resorption (formation more)
(Third line treatment)
Very expensive
