Endocrine Bone Disorders Flashcards
What are the other effects of calcitriol?
Increased reabsorption of Ca2+ 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 is Paget’s disease?
Accelerated, localised but disorganised bone remodelling
Excessive bone resorption followed by a compensatory increase in bone formation
New bone = woven bone
What is Paget’s disease characterised by histologically?
Abnormal, large osteoclasts excessive in number
State 8 clinical features of Paget’s disease and the most commonly affected bones
Increased vascularity (warmth over affected bone) Increased incidence of fracture Arthritis Bone pain Bone frailty Bone hypertrophy + deformity Deafness (cochlear involvement) Radiculopathy (due to nerve compression) Skull, thoracolumbar spine, pelvis, femur + tibia most commonly affected
Describe how you would diagnose Paget’s disease.
Plasma calcium = NORMAL
Plasma ALP = HIGH
Plain X-ray: Lytic lesions (early), thickened, enlarged, deformed bones (later)
Radionuclide bone scan demonstrates extent of skeletal involvement
What are the 2 components of bone in which 95% of the body’s calcium is stored?
Inorganic mineral component (65%):
Stored as calcium hydroxyapatite crystals between collagen fibrils
Organic (osteoid) component (35%):
Type 1 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 calcitriol?
Increased calcium absorption from the small intestine
Increased mobilisation of calcium in bone
What do osteocytes produce?
Type 1 collagen + other extracellular matrix components
Define osteoporosis. What is the consequence of osteoporosis? How is it diagnosed?
Bone mineral density (BMD) >,2.5 SD below the average for young healthy adults (T-score of -2.5 or lower)
Loss of bony trabeculae, reduced bone mass, weaker bone, predisposed to fracture after minimal trauma
Diagnosed via DEXA scan
State 5 predisposing conditions for osteoporosis.
Post-menopausal oestrogen deficiency Age-related deficiency of bone homeostasis Hypogonadism in young men + 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?
Anti-resorptive effect in bone, hence, prevents bone loss
What are the cautions and risks of oestrogen replacement?
Women with an intact uterus need additional progestogen to prevent endometrial hyperplasia + reduce the risk of endometrial carcinoma
Increased risk of breast cancer + 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.
Bind avidly to hydroxyapatite crystals in bone + are ingested by osteoclasts
Impair ability of osteoclasts to resorb bone
Decrease osteoclast progenitor development + recruitment Promote osteoclast apoptosis
Result= reduced bone turnover
State 4 uses of bisphosphonates.
Osteoporosis
Malignancy: hypercalcaemia- reduces bone pain from metastases
Paget’s disease: reduces bony pain
Severe hypercalcaemic emergency (I.V. saline to rehydrate + then bisphosphonates)
Describe the pharmacokinetics of bisphosphonates.
Orally active but poorly absorbed
Must be taken on an empty stomach
Accumulates at site of bone mineralisation + remains a part of the bone until it is resorbed (months/ years)
State 3 unwanted actions of bisphosphonates.
Oesophagitis
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?
Human monoclonal antibody
Binds to RANKL, inhibits osteoclast formation + activity
Inhibits osteoclast-mediated bone resorption
Given subcutaneously every 6-12 months
What is teriparatide and how often does it need to be given?
Recombinant PTH fragment
Increases bone resorption + formation– but formation exceeds resorption
Daily subcutaneous injections
EXPENSIVE
What is the role of osteoblasts?
Synthesise osteoid + participate in mineralisation/ calcification of osteoid
= Bone formation
What is the role of osteoclasts?
Release lysosomal enzymes which break down bone
= Bone resorption
Describe osteoclast differentiation
RANKL expressed on osteoblast surface
RANKL binds to RANK-R to stimulate osteoclast formation + activity
What are the 2 types of bone in the body?
How are they formed?
Cortical (hard) bone
Trabecular (Spongy) bone
Formed in a lamellar pattern: collagen fibrils laid down in alternating orientations, mechanically strong
What are the characteristics of woven bone?
Disorganised collagen fibrils
Mechanically weaker
Describe how rickets effects children
Affects cartilage of epiphyseal growth plates + bone
Skeletal abnormalities + pain
Growth retardation
Increased fracture risk
Describe how Osteomalacia effects adults
After epiphyseal closure, affects bone
Skeletal pain
Increased fracture risk
Proximal myopathy
What causes primary hyperparathyroidism? Describe PTH and Ca2+ levels
Adenoma
High PTH (no negative feedback)
High Ca2+
What causes secondary hyperparathyroidism? Describe PTH and Ca2+ levels
Low plasma Ca2+, e.g. renal failure, Vitamin D deficiency High PTH (appropriate physiological response) Low/ normal Ca2+
What causes tertiary hyperparathyroidism? Describe PTH and Ca2+ levels
Chronic low plasma Ca2+ e.g. CKD- can’t 1-alpha hydroxyls, can’t make calcitriol, causes secondary hyperparathyroidism, parathyroids increase in size + become autonomous
High PTH
High Ca2+
Describe the epidemiology of Paget’s disease
Often +ve FH Some evidence of viral origin M + F equally affected Usually >50s Most patients are asymptomatic
What are the treatment options for Paget’s disease?
Bisphosphonates (reduce bony pain + disease activity)
Simple analgesia
What receptors do osteoblasts express? Why?
PTH + Calcitriol receptors
To regulate balance between bone formation + resorption
What does Vitamin D deficiency result in for both children and adults?
Inadequate minerilastion of newly formed bone matrix (osteoid)
Describe 2 observed effects resulting from vitamin D deficiency
Looser zones: Fractures from inadequately mineralised bone baring the weight of the skeleton
Waddling gait: Caused by proximal myopathy + pain
How does the ineffective excretion of phosphate in CKD effect calcium levels?
Phosphate binds to calcium, further reducing serum calcium levels
What are the consequences of tertiary hyperparathyroidism causing high circulating phosphate levels?
Calcification, particularly in blood vessels
What is Osteitis fibrosa cystica? What is it caused by?
Cysts in the bone
Caused by extremely high PTH driving excess osteoclast bone resorption
=”Brown tumours” (radiolucent bone lesions)
Describe treatment for Osteitis fibrosa cystica
Low phosphate diet
Phosphate binders to reduce GI phosphate absorption
Calcitriol analogues (as can’t alpha hydroxylase)
Parathyroidectomy in tertiary hyperparathyroidism
How is BMD measured? Why?
DEXA SCAN
Predicts fracture risk
Calcium content of bone measured- the more mineral, the greater the bone density, the greater the bone mass
What is osteomalacia? How is it diagnosed? Why?
Vitamin D deficiency (adults) causing inadequately mineralised bone Diagnosed via blood test low 25(OH) vit D low/low N Ca2+ high PTH (secondary hyperparathyroidism)
What is the difference in presentation between osteomalacia and osteoporosis?
Malacia: can be painful
Porosis: only painful if you fracture
