endocrine and metabolic bone disorders Flashcards by Stephanie Dunn

what is the composition of bone?

65%: inorganic minerals (Ca hydroxyapatite)

- 35%: organic components (type 1 collagen)

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what do osteoblasts do?

build up bone (synthesise, mineralise and calcify osteoid)

- express receptors for PTH and calcitrol

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what do osteoclasts do?

break down/resorb bone

lysosomal enzymes

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What do osteocytes do?

make type 1 collagen and other EC matrix components

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describe osteoclast differentiation

RANKL expressed on osteoblast membrane
RANK-R binds RANKL
this stimulates osteoclast formation and activity

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what is osteoprotegerin?

acts as a competitive inhibitor for RANKL

- inhibits

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describe the first and second hydroxylation steps

calcidiol is made in liver (1st)

- calcitriol is made in kidneys (2nd)

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what does PTH/calcitrol cause?

causes bone to release Ca and phosphates

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what does PTH do?

causes kidneys to inc. calcitrol synthesis and dec. excretion of Ca

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what does calcitriol do?

inc absorption of dietary Ca

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what does high EC calcium/ low EC calcium cause?

High EC Ca - Ca blocks Na influx so LESS membrane excitability
Low EC Ca - enables greater influx of Na so more membrane excitability

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what are the symptoms of hypocalcaemia?

too much excitability (PCAT):

parathesia
convulsions
arrhythmias
tetany
signs: Chovstek’s sign, Trousseau’s sign

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what is Chovstek’s sign?

tap facial nerve below zymgomatic arch, face twitch

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what is Trousseau’s sign?

inflate BP cuff for minutes

- induces carpopedal spasm

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what are the causes of hypocalcaemia?

Vit D def (low calcitriol)
renal failure (impaired 1 alpha-hydroxylase activity so low calcitriol)
low PTH levels
PTH resistance (pseudohypoparathyroisism)

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what are the symptoms of hypercalcaemia?

stones, abdo maons and psychic groans (slows down)
Stones: renal stones
Abdo moans: GI effects
Psychic groans: CNS effects

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what are the causes of hypercalcaemia?

primary hyperparathyroidism (benign adenoma of parathyroid, PTH high, Ca high)
malignancy (tumours ofen secrete PTH-RP, PTH low, PTH-RP high, Ca high)
Paget’s disease (condition w/ high bone turn over)
Vit D toxicosis

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what is the active form of Vit D?

calcitriol

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what are the effects of calcitriol?

intestinal absorption of Ca, Mg, PO4
regulates osteoblast differentiation
renal effects (inc. Ca reabsorption, dec. PO4 reabsorption)

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what happens when there is a Vit D def?

softening of bone
bone deformities
bone pain
severe proximal myopathy

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what is Vit D def called in children and adults?

children - rickets

adults - osteomalacia

what s Vit D3 and Vit D2 called?

Vit D3 - cholecalciferol

Vit D2 - ergocalciferol

what are the causes of Vit D def?

block in UVB light catalysation
malsabsorption or bad diet
liver disease (no 1st hydroxylation)
renal disease (no 2nd hydroxylation)
receptor defects

what is primary hyperparathyroidism?

autonomous PTH production due to adenoma

produces a hypercalcaemia

what is secondary hyperparathyroidism?

no calcitriol so lower Ca so more PTH production to try and normalise serum Ca not hypercalcaemia

what is needed in a diagnosis of Vit D def?

Low - calctriol, Ca, PO4 High - PTH Radiological findings: widened osteoid seams (bone lesions showing excessive osetoclastic bone resorption)

what is the treatment of Vit D def?

- normal renal function: give synthetic Vit D (kidney hydroxylates futehr) - impaired renal function (give ready hydroxylated Vit D)

how does low renal function lead to extra-skeletal deposition?

- low renal function can lead to dec. calcitriol and PO4 excretion - leads to higher serum phosphate that binds Ca in blood - leads to extra-skeletal deposition

what can Vit D toxicosis lead to?

- hypercalcaemia and hypercalciuria due to inc, intestinal absorption of Ca

what can Vit D toxicosis occur because of?

- excessive treatment of Vit D def | - granulomatous disease (macrophaes in granuloma produce 1 alpha-hydroxylase which overproduces Vit D)

what is osteoporosis?

- condition of reduced bone mass and a distortion of bone microarchitecture which predisposes to fracture after minimal trauma

what is the definition of osteoporosis?

BMD < 2.5 SDs or more

what is BMD measured by?

DEXA

what are the risk factors for osteoporosis?

- post-menopausal oestrogen def - age related def in bone homeostasis - hypogonadism in young people - endocrine conditions (Cushing's, hyperthyroisism, primary hyperparathyroidism) - iatrogenic

what are the different drug classes for the treatment of osteoporosis?

- oestrogen receptor modulators (oestrogen HRT, SERMS) - bisphosphonates - denosumab - teriparatide

what is the effect of oestrogen HRT?

- oestrogen has anti-absorptive effects on skeleton - women with intact uterus need progestogens to prevent endometrial hyperplasia - used limited, concerns with breast cancer

what are SERMs?

selective oestrogen receptor modulators - tissue selective ER antagonists e.g. Tamoxifen - tissue selective ER agonists e.g. Raloxifene

how does Tamoxifen work?

antagonises ERs in breast but has oestrogenic activity in bone

how does Raloxifene work?

oestrogenic activity in bone and anti-oestrogenic activity on breast and uterus

what is the MoA of bisphosphonates?

- bind to hydroxyapatite crystals and are absorbed by osteoclasts (impair ability to resorb bone) - dec. osteoclast development/ recruitment and promotes osteoclast apoptosis

what are the uses of bisphosphonates?

- first line for osteoporosis | - also used for malignancy, Paget's and severe hypercalcaemic emergencies

what are the pharmacokinetics of bisphosphonates?

- orally active, porrly absorbed (eat on empty stomach) | - remains at site of action for YEARS so mainly used in elderly

what are the side effects of bisphosphonates?

- oesophagitis - flu like symptoms - osteonecrosis of jaw - atypical fractures

what is denosumab and what does it do?

- human monocloncal antibody - binds to RANKL and so inhibits osetoclast activation and bone resorption - taken bi-yearly - 2nd line drug for osteoporosis

what is teriparatide?

- recombinant PTH fragments - inc. bone formation and bone resorption - formation outweighs resoprtion - 3rd line treatment - expensive

what happens in Paget's disease?

- accelerated, localised and disorganised bone remodellung - excessive bone resorption followed by compensatory inc in bone formation - leads to formation of woven bone - bone fragility - bone hypertrophy and deformity

what are the features of Paget's disease of bone?

- genetic - possible viral origin - affects men and women equally - disease not apparent under 50yo - most pt asymptomatic

what is Paget's characterised by?

- abnormal, large and numerous osteoclasts

which bones are most commonly affected in Paget's?

- skull - thoracolumbar spine - pelvis - femur - tibia

what are the clinical features of Paget's?

- arthritis - fractures - pain - bone deformity - inc. vascularity (warm to touch) - deafness - radiculopathy (due to nerve compression)

what could be used to diagnose Paget's?

- Ca normal - ALP inc (due to over activity of bones secreting ALP) - plain X-rays show lytic lesions (early), thickened, enlarged and deformed bones (later)

how do you treat Paget's?

- bisphosphonates | - analgesia