Endocrine and Metabolic Bone Disorders Flashcards
Identify and describe the 2 components of bone
- Osteoid - organic component - unmineralised bone made up of type 1 collagen
- Calcium hydroxyapatite crystals - inorganic component - fill the space between collagen fibrils
What 2 types of cells are involved in bone turnover and outline their function in bone turnover
- Osteoblasts - synthesise bone (osteoid component)
- Osteoclasts - enzymatic bone resorption
What happens if there is imbalances in bone turnover
- There is constant remodelling of bone by bone turnover
- If there is imbalance with too much bone resorption and inadeqaute bone synthesis then this can lead to weakened bone structure and make the bone prone to fracture
Describe how PTH has its actions on osteoblasts and osteoclasts
- PTH directly binds osteoblasts bu acting on PTH receptors on osteoblasts
- It has indirect effects on osteoclasts as osteoblasts release OAFs (osteoclast activating factors)
Give an example of an OAF (osteoclast activating factor)
- RANKL
Describe osteoblast-osteoclast interaction leading to osteoclast differentiation and thus bone resorption and what modulates the interaction between osteoblasts and osteoclasts
- Calcitiriol and PTH bind osteoblasts to promote OAF release by osteoblasts
- Osteoblasts express RANKL (an OAF)
- Osteoclast precursors have RANK receptors which bind the RANKL (RANK-ligand) and become activated
- Thus osteoclast differentiation and fusion occurs to form the activated osteoclast and thus bone resorption
Describe the layers and then the arrangement of bone
- Cortical bone on outside - very hard
- Trabecular bone on inside - spongy
- Lamellar arrangement of collagen fibrils to give the maximum mechanical strength
What is the type of bone which is weaker and why is it weaker than normal bone?
Woven bone - due to irregular thus weak arrangement of collagen fibrils - not in the lamellar arrangement as occurs in normal bone which otherwise give the bone high mechanical strength
How does vitamin D deficiency manifest bone problems in the child - what is the name of the condition, what is the pathophysiology including where it affects it and what are the clinical signs and symptoms?
- Rickets
- Inadequate mineralisation of newly formed osteoid bone matrix
- Affects cartilage of epiphyseal plates and bone
- Skeletal abnormalities (tibia bowing), pain, growth retardation, increased fracture risk
How does vitamin D deficiency manifest bone problems in the adult - including the name of the condition, the pathophysiology and the clinical signs?
- Osteomalacia
- Inadequate bone mineralisation of newly formed osteoid bone matrix
- After epiphyseal closure, affects bone
- Skeletal pain, increased fracture risk, proximal myopathy
- No bone deformities as in rickets in children
What are the differences in the manifestation of inadequate vitamin D in the child and in the adult?
- Child - rickets vs Adult - osteomalacia
- In children it affects them prior to epiphyseal closure and in adults it affects them after epiphyseal closure
- Thus you have skeletal deformities in rickets in children whereas there are no skeletal deformities in osteomalacia in adults as development has already occured
1) Why does vitamin D deficiency lead to increased risk of bone fracture, what type of fracture is this and where does it manifest?
2) How do patients change their gait in response and why?
1)
- Vitamin D promotes calcium maintenance within the bone and also osteoblast activation
- Insufficiency fractures at sites of high bone loading and stress
2)
- Waddling gait due to pain from abnormal bone fractures
What happens pathophysiologically in primary hyperparathyroidism?
- Autonomous PTH secretion which does not respond to negative feedback by serum calcium
- So high PTH and high serum calcium (hypercalcaemia)
What happens pathophysiologically in secondary hyperparathyroidism?
- Low plasma [Ca2+] due to renal failure or vitamin D deficiency
- This leads to increased PTH due to less negative feedback
What happens pathophysiologically in tertiary hyperparathyroidism?
- Chronic low plasma [Ca2+]
- So there is autonomous secretion of PTH to try and compensate to increase plasma [Ca2+] again
Give 2 ways in which renal failure can lead to hypocalcaemia
- Decreased formation of calcitriol (1,25-(OH)2-D3) because there is decreased conversion of 25-OH-D3 using renal 1α-hydroxylase. This causes reduced Ca2+ absorption at the gut, leading to hypocalcaemia
- Decreased PO43- excretion so there is increased serum phosphate and this phosphate binds calcium so it further decreases bioavailable serum calcium so leads to hypocalcaemia
Why would impaired renal function lead to osteitis fibrosis cystica - outline the pathophysiology of it
- Less calcitriol formation so less Ca2+ absorption at the gut so there is hypocalcaemia and also decreased phosphate excretion and increased plasma phosphate which binds calcium so further decreases serum calcium levels
- SO hypocalcaemia
- This leads to decreased bone mineralisation
- Also the lower serum calcium levels leads to PTH increase due to less negative feedback
- This leads to increased bone resorption
- SO hypocalcaemia → decreased bone mineralisation AND high PTH → increased bone resorption BOTH lead to osteitis fibrosis cystica
1) Why does renal failure lead to vascular calcification and increased risk of macrovascular disease?
2) So how is hyperphosphataemia managed in patients with renal failure?
1)
- Renal failure leads to decreased PO43- so there is increased serum phosphate level causing hyperphosphataemia
- Hyperphosphataemia contributes to vascular calcification
- Vascular calcification leads to increased risk of macrovascular disease
2)
- Diet mamagement - low phosphate diet
- Phosphate binders - collate phosphate at the gut to reduce absorption at the gut
What signs might we see that indicate osteitis fibrosis cystica on an X-ray?
- Radioluscency at points of high bone resorption at where hyperparathyroidism has resulted in high osteoclast activity
- ‘Pepper pott skull’
3 things you can do to treat osteitis fibrosis cystica?
- Alphacalcidol - active vitamin D drug (1,25-(OH)2-D3 to combat hypocalcaemia
- Parathyroidectomy - in tertiary hyperparathyroidism
- Hyperphosphataemia - low phosphate diets or phosphate binders
1) What is the pathophysiology of osteoporosis?
2) In what kind of people would you see osteoporosis?
1)
- Reduction in bone mineral density resultin in increased risk of bone fracture and increased risk of fracture after minimal trauma
- Trabecular meshwork loss - weaker bone
2)
- Older women (post-menopausal) - oestrogen loss which normally preserves normal bone turnover
- Everyone as they age due to loss of bone mineral density
1) How do we measure bone mineral density?
2) How can we use it to diagnose osteoporosis - at what level?
1)
- DEXA scans measure bone mineral density
- T-scores are given - normal range is 1.0 - 0.0
- The femoral neck and lumbar spine are scanned
2)
- T-scores >2.5 standard deviations below the average range - usually -2.5 or lower are indicative of osteoporosis
In what ways is the serum biochemistry abnormal in osteomalacia?
- Low 25-OH-Vit D3
- Low Ca2+
- High PTH - secondary hyperparathyroidism
Give 5 types of predisposing conditions, including examples where they are subcategories, or explanations where necessary
- Postmenopausal oestrogen deficiency - leads to loss of bone matrix
- Age-related deficiency in bone haemostasis - e.g. osteoblast senescense
- Hypogonadism
- Endocrine conditions - Cushing’s syndrome, Hyperthyroidism, Primary hyperparathyroidism
- Iatrogenic - prolonged use of glucocorticoids, heparin
List 5 different treatment options for osteoporosis
- Oestrogen / selective oestrogen receptor modulators
- Teriparatide
- Bisphosphonates
- Denosumab
1) Why is oestrogen given as treatment for osteoporosis, and to whom?
2) What should be co-administered with it and why?
3) 2 possible side-effects of oestrogen therapy
1)
- Anti-resorptive effects on the skeleton preventing bone loss in post-menopausal women
2)
- Progestogen to prevent uncontrolled endometrial hyperplasia in women with an intact uterus
3)
- Increased risk of breast cancer
- Venous thromboembolism
Give 2 types (with one example for each) of selective estrogen receptor modulators (SERMs) and say how they work to treat osteoporosis and 1 possible side effect for each
- Selective oestrogen antagonists e.g. Tamoxifen
- Antagonises ER in breast but weirdly has oestrogen effects in bone
- Side effect: oestrogenic effects on endometrium limits its use in osteoporosis management
- Selective oestrogen agonists e.g. Raloxifene
- Oestrogenic activity in bone, but weirdly anti-oestrogenic effect in breast and uterus
- Side effect: reduces breast cancer risk but increases risk of venous thromboembolism
What is the mechanism by which bisphosphonate works?
- Bind to hydroxyapatite
- Ingested by osteoclasts, impairing the osteoclast ability to carry out bone resorption
- Decreases osteoclast progenitor development and recruitment
- Promote osteoclast apoptosis
- Net result = decreased bone turnover
4 times when bisphophonates are used?
- Osteoporosis - first line treatment
- Malignancy - associated hypercalcaemia and reduce bone pain from metastases
- Paget’s disease - reduce bony pain
- Severe hyperglycaemic emergency - i.v. initially (+++re-hydration first)
Describe the pharmacokinetics of bisphophonates
- Orally active but poorly absorbed so taken on an empty stomach
- Accumulates at sites of bone mineralisation and remains part of bone until it is resorbed - takes a long time
3 possible unwanted effects of bisphosphonates and ways to manage these where applicable and one general way to avoid unwanted effects?
- Oesophagitis (heart burn) - can switch from oral to i.v. administration
- Osteonecrosis of the jaw - greatest risk in cancer patients recieving i.v. bisphosphonates
- Atypical fractures - due to prolonged suppression of bone remodelling
- Bisphosphonate holidays so bone can recover from the treatment
1) What is the mechanism for how Denusomab works to treat osteoporosis?
2) How is Denosumab administrated?
3) When is it used in treatment?
1)
- Human monoclonal antibodies
- Binds RANKL, inhibiting osteoclast activity and formation
- Hence inhibit osteoclast mediated bone resorption
2)
- Subcutaneous injection
3)
- 2nd line treatment to bisphosphonates due to price
1) What is the mechanism for how Teriparatide works to treat osteoporosis?
2) How is Teriparatide administrated?
3) When is it used in treatment?
1)
- It is a recombinant parathyroid fragment - 34 A.A. part of the amino terminal of PTH
- It induces both bone formation and resorption, but induces more formation than resorption
2)
- Daily subcutaneous injection
3)
- 3rd line treatment for osteoporosis as it is very expensive
What is the pathophysiology of Paget’s disease?
- Accelerated, localised but disorganised bone remodelling
- Excessive bone resorption (XS osteoclast activity) but then compensatory bone formation by osteoblast activity, but the new bone being formed is woven bone
- Woven bone is structurally disorganised, therefore weaker than normal adult lamellar bone, leading to bone frailty and bone hypertrophy / deformity
In terms of the origins of Paget’s disease, how is the FHx and what is the possible evidence of its origin?
- Positive family history
- Evidence for viral origin (e.g. measles virus)
What bones are most commonly affected by Paget’s disease?
- Skull
- Thoracolumbar spine
- Pelvis
- Femur
- Tibia
List 7 clinical signs of Paget’s disease?
- Arthritis
- Fracture
- Pain
- Bone deformity
- Increased vascularity so warmth over affected bone
- Deafness (cochlear involvement)
- Radiculopathy - due to compressed nerve
4 findings for diagnosis of Paget’s?
- Plasma [Ca2+] is normal
- Plasma [alkaline phosphatase] (the bone isoenzymes) is usually increased
- Plain x rays = Lytic lesions (early), thickened, enlarged, deformed bones (later)
- Radionucleide bone scan demonstrates extent of skeletal involvement
2 treatments for Paget’s?
- Bisphosphonates – very helpful for reducing bony pain and disease activity
- Simple analgesia
