Endocrine and metabolic bone disease Flashcards
Where is most of the calcium in the body found
Bone
Stores >95% of body’s Ca2+
Describe the inorganic component of bone
Organic components
(osteoid – unmineralised bone)
(35% bone mass)
Type 1 collagen fibres (95%)- the other 5% is ground substance- being composed of proteoglycans.
Describe the inorganic mineral component of bone
Inorganic mineral component
(65% bone mass)
Calcium hydroxyapatite crystals
fill the space between collagen fibrils
Whta is osteoid
Bone is generally compromised of a calcified matrix called osteoid.
Describe osteoblasts
synthesise osteoid and participate
in mineralisation/calcification
of osteoid
(bone formation)
Describe osteoclasts
release lysosomal enzymes
which break down bone
(bone resorption)
large, multi-nucleated cells- similar to macrophages and monocytes.
What is a key feature of bone remodelling
Bone remodelling
ie a DYNAMIC process- constantly resorbed and formed depending on the activity of osteoblasts and osteoclasts.
Outline osteoclast differentiation
Osteoclasts are activated by osteoclast-activating factors (OAFS)
These include two cytokines released from osteoblasts and their precursors: receptor activator of nuclear kappa B ligand (RANKL) and M-CSF. IL1B is also important.
RANKL binds to RANK on osteoclast progenitors, resulting in their differentiation and fusion into osteoclasts.
In contrast, osteoprotegrin acts as a decoy receptor for RANKL, preventing its binding to RANK.
What do osteoblasts express receptors for
Osteoblasts express receptors for PTH & calcitriol (1,25 (OH)2 vit D) – regulate balance between bone formation & resorption
Describe the structure of bone
Cortical (hard) bone
Trabecular (spongy or trabecular) bone
Both formed in a lamellar pattern = collagen fibrils laid down in alternating orientations, mechanically strong
Describe woven bone
Woven bone – disorganised collagen fibrils, weaker
What happens in vitamin D deficiency
Inadequate mineralisation of newly formed bone matrix (osteoid)
Explain the effects of vitamin D deficiency in children
Children – RICKETS
affects cartilage of epiphysial growth plates and bone- less bendy and flexible joints
skeletal abnormalities and pain, growth retardation, increased fracture risk
Explain the effects of vitamin D deficiency in adults
Adults – OSTEOMALACIA
after epiphyseal closure, affects bone
skeletal pain, increased fracture risk, prox myopathy
What are the key bone presentations of vitamin D deficiency
Normal stresses on abnormal bone cause insufficiency fractures - Looser zones- not due to trauma- just weakness of the bone.
Waddling gait - typical- due to pain and proximal myopathy
Describe primary hyperparathyroidism
Parathyroid adenoma
Increases PTH (autonomous production from tumour)
This will therefore increase Ca2+ (via increased kidney reabsorption, increased calcitriol and increased resorption from bone).
Phosphate will therefore also be low
PTH will stay high- as Ca2+ no longer has negative feedback (tumours are autonomous).
Describe secondary hyperparathryoidism
Renal failure or vitamin D deficiency
Results in a low Ca2+
This stimulates release of PTH
But the Ca2+ will stay low or normal, as we have no calcitriol to reabsorb Ca2+ from the gut
If vitamin D deficient, phosphate will be low.
Describe tertiary hyperparathyroidism
Chronic low Ca2+- due to kidney failure and vitamin D deficiency.
Hyperplasia of the parathyroid (becomes autonomous), leading to increased PTH (no longer under negative feedback) and increased Ca2+
Describe the relationship between renal failure and bone disease
Decline in glomerular filtration rate (GFR) results in
Less phosphate excreted in the urine, hence, a rise in serum phosphate. Reduced calcitriol (1,25(OH)2D3) formation – due to less one alpha hydroxylation of 25[OH]D3
Hypocalcaemia develops due to precipitation of calcium with phosphate (due to high phosphate) in tissues and due to impaired intestinal absorption of calcium due to reduced calcitriol.
The hypocalcaemia increases PTH release, leading to increased bone resorption
The hypocalcaemia and reduced calcitriol will lead to decreased bone mineralisation
The increased bone resorption and decreased bone mineralisation will lead osteitis fibrosa cystica
The high serum phosphate will inhibit calcitriol synthesis (via FGF23) and will lead to vascular calcification.
Describe osteitis fibrosa cystica
Osteitis fibrosa cystica (hyperparathyroid bone disease) – rare
= XS osteoclastic bone resorption 2o to high PTH
‘Brown tumours’ = radiolucent bone lesions
Describe the treatment of osteitis fibrosa cystica (hyperparathyroid bone disease)
Hyperphosphataemia
Low phosphate diet
Phosphate binders – reduce GI phosphate absorption
Alphacalcidol – ie calcitriol analogues
Parathyroidectomy in 3o hyperparathyroidism
Indicated for hypercalcaemia &/or hyperparathyroid bone disease
What is osteoporosis
Loss of bony trabeculae, reduced bone mass, weaker bone predisposed to fracture after minimal trauma
Describe the threshold for increased risk of fractures and the fracture threshold
Increased risk of fractures- bone mass below 70%
Fracture threshold- bone mass below 40%
Bone mass decreases after around the age of 24
Rapid decrease in post-menopausal women unless put on HRT
Describe how osteoporosis is diagnosed
Bone mineral density (BMD) > 2.5 standard deviations below the average value for young healthy adults (usually referred to as a T-score of -2.5 or lower)
BMD predicts future fracture risk
Between -1.0 and -2.5- osteopenia- weaker bones- may become osteoporosis.
How do we measure BMD
Dual Energy X-ray Absorptiometry (DEXA) - femoral neck and lumbar spine
Mineral (calcium) content of bone measured, the more mineral, the greater the bone density (bone mass)
Low dose radiation (less than a CXR)
Define osteoporosis
A condition of reduced bone mass and a distortion of the bone microarchitecture which predisposes to fracture after minimal trauma.
WHO Definition: a T-score of -2.5 or less in healthy postmenopausal women and men aged 50 years and older.
T-score represents a comparison of the patient’s bone mineral density (BMD) with that of a young adult reference population.
What is important to remember about osteomalacia and osteoporosis
Both predisposes to fractures
Osteomalacia painful, osteoporosis- not painful
What are the key features of osteomalacia
Vitamin D deficiency (adults) causing inadequately mineralised bone
Serum biochemistry abnormal (low 25(OH) vit D, low/low N Ca2+, high PTH (2o hyperparathyroidism)
What are the key features of osteoporosis
Bone reabsorption exceeds formation
Decreased bone MASS
Serum biochemistry normal
Diagnosis via DEXA scan
What is the most common pre-disposing condition for osteoporosis
Postmenopausal oestrogen deficiency
Oestrogen deficiency leads to a loss of bone matrix
Subsequent increased risk of fracture
Describe some other pre-disposing conditions for osteoporosis
Age-related deficiency in bone homeostasis (men and women) eg osteoblast senescence Hypogonadism in young women and in men Endocrine conditions Cushing’s syndrome Hyperthyroidism Primary hyperparathyroidism Iatrogenic Prolonged use of glucocorticoids Heparin
Describe the consequences of hip fractures
20% dead within one year
30% permanent disability
40% unable to walk independently
80% unable to carry out a least one independent activity of daily living
Describe the use of oestrogen (HRT) to treat osteoporosis
Treatment of post-menopausal women with pharmacological doses of oestrogen
- Anti-resorptive effects on the skeleton
- Prevents bone loss
Women with an intact uterus need additional progestogen to prevent endometrial hyperplasia/cancer
Use limited largely due to concerns re:
- Increased risk of breast cancer
- Venous thromboembolism
Can’t really be used for long periods of time.
What needs to be excluded in osteoporosis
Biochemistry profile is normal. Co-existent vitamin D deficiency should be excluded (and vitamin D supplementation should be given if suboptimal [vitamin D]).
Summarise the management of osteoporosis
Adequate intake of calcium and vitamin D
Ensure lifestyle has been reviewed eg smoking, alcohol intake, exercise, falls prevention advice (elderly), avoidance of glucocorticoids if possible.
Treat underlying endocrine condition; sex hormone replacement should improve BMD in pre-menopausal women and in men (oestrogen/progesterone therapy for women, testosterone for men).
Describe the action of bisphosphonates
Bind avidly to hydroxyapatite and ingested by osteoclasts – impair ability of osteoclasts to reabsorb bone
Decrease osteoclast progenitor development and recruitment
Promote osteoclast apoptosis (programmed cell death)
Net result = reduced bone turnover.
Describe the different formulations of bisphosphonates
eg. Alendronate (oral), Zolendronic acid (intravenous) The bisphosphonates bind avidly to hydroxyapatite, the crystalline form of calcium and phosphate in bone, and are ingested by osteoclasts, inhibiting osteoclast-mediated bone resorption.
Describe the different uses of bisphosphonates
Osteoporosis (1st line treatment)
Hypercalcaemia associated with malignancy (and effective in reducing bone pain from metastases)
Paget’s disease (effective in reducing bony pain)
Life-threatening hypercalcaemic emergency- i.v. initially (+++ re-hydration first)
Describe the pharmacokinetics of bisphosphonates
Orally active but poorly absorbed; take on an empty stomach (food, especially milk, reduces drug absorption generally)- take with water- to prevent accumulation on oesophagus
Accumulates at site of bone mineralisation and remains part of bone until it is resorbed - months, years- bad in young patients- disrupts bone remodelling- bone becomes adynamic
Explain why a short course of i.v bisphosphonates can be effective for long periods of time
Prolonged skeletal storage (months to years) explains why single/short course of intravenous bisphosphonates in patients with high bone turnover eg Paget’s disease of bone, can be effective for a long time.
Describe the unwanted actions of bisphosphonates
Oesophagitis (adverse GI side effects may warrant switch from oral to intravenous)
‘flu like symptoms’ including bone pain, often limited to first dose
Osteonecrosis of the jaw – greatest risk in cancer patients receiving iv bisphosphonates, instruct patients to have any remedial dental work before starting treatment and to maintain good oral hygiene.
Atypical fractures of femur have been described (very small risk) – may reflect oversuppression of bone remodelling in prolonged bisphosphonate use. ‘Bisphosphonate holiday’ recommended after 5y of treatment.
Describe denosumab to treat osteoporosis
Human monoclonal antibody
Binds RANKL, inhibiting osteoclast formation and activity
Hence inhibits osteoclast-mediated bone resorption
SC injection 6/12ly
2nd line to bisphosphonates
Describe teriparatide to treat osteoporosis
Recombinant PTH fragment - amino-terminal 34 amino acids of native PTH
Increases bone formation and bone resorption, but formation outweighs resorption - differs to action of PTH because of dose used
3rd line treatment for osteoporosis
Daily s.c. injection
£££
What is strontium ran elate
Not used anymore
Stimulates bone formation and reduces bone resorption
Increased risk of MI and thromboembolism
Define Paget’s disease of bone
Definition: very active (increased), localised but disorganised bone metabolism; usually slowly progressive (abnormal, large osteoclasts).
What is the issue in Paget’s disease of bone
Accelerated, localised but disorganised bone remodelling
Excessive bone resorption (osteoclastic overactivity) followed by a compensatory increase in bone formation (osteoblasts)
New bone formed = WOVEN bone
structurally disorganised
mechanically weaker than normal adult lamellar bone
What are the two key problems in Paget’s disease of bone
BONE FRAILTY
BONE HYPERTROPHY & DEFORMITY
What is Paget’s disease of bone characterised by
Characterised by abnormal, large osteoclasts – excessive in number
As a result of osteoclast and osteoblast overactivity- we see ‘mosaic’ bone
Describe the different risk factors for Paget’s disease of bone
Significant genetic component (up to 30% cases, autosomal dominant)
Evidence for viral origin (e.g. measles virus)
Men and women equally affected
Disease usually not apparent under age 50-60y
More than 10% of over-60s affected (but majority have no symptoms)
Prevalence
Highest in UK, N America, Australia and NZ
Lowest in Asian and Scandinavia
So higher in 1st world countries
Describe the clinical features of Paget’s disease of bone
Skull, thoracolumbar spine, pelvis, femur and tibia most commonly affected
Arthritis
Fracture
Pain
Bone deformity
Increased vascularity (warmth over affected bone)
Deafness – cochlear involvement
Radiculopathy – due to nerve compression- nerve entrapment of spinal nerve roots.
Explain the bone deformity in Paget’s disease of bone
Increased osteoclast/osteoblast activity; initially osteoclast activity (increased deformity and fracture risk), followed by increased osteoblast activity (thickening of deformed bone)
Describe the biochemical diagnosis of Paget’s disease
Plasma [Ca2+] normal
Plasma [alkaline phosphatase] usually increased- liver and bone isotopes
Urine Ca elevated initially, later normal or low- stones in 20% of cases
Describe the typical presentation of a patient with Paget’s disease
Enlargement of head Deafness (cn8) Blindness (cn2) Kyphosis Increased cardiac output Bowing of limbs- due to irregularity of bone reformed- not weakness as in osteomalacia. Increased warmth and tenderness of bones
Describe the radiological diagnosis of Paget’s disease
Plain x rays =
Lytic lesions (early), thickened, enlarged, deformed bones (later)
Radionuclide bone scan demonstrates extent of skeletal involvement - technetium used
Fissure fractures
Advancing edge of bone
Great thickening of bones of skull, with areas of demineralisation.
Summarise the different treatment options for Paget’s disease
Bisphosphonates – very helpful for reducing bony pain and disease activity
Simple analgesia
Describe some different risk factors for secondary hyperparathyroidism
Risk factors:
Skin pigmentation (means reduced skin synthesis of VitD)
Vegetarian
Reduced sun exposure e.g. UK
What is the difference between microscopic and macroscopic haematuria that may result form Paget’s disease of bone
Microscopic haematuria: blood detected with dipstick
Macroscopic haematuria: blood visible in urine
Explain the consequences of Hypercalcaemia
Hypercalcaemia: can lead to renal stones and hence renal cholic; Sx:
Stones - kidney stones (and hence dehydrated so give fluids); high calcium leads to nephrogenic DI (ADH resistance) - need to give fluids to dilute the blood
Abdominal moans - nausea, pain from kidney stones, constipation
Psychic groans - confusion, depression, tiredness
Cardiac - dysrhythmmias as affects QT interval
What is the treatment for hypercalcaemia of malignancy
a. Fluids via oral or IV route. Give bisphosphonates.
No caffeine
Summarise the discrimination between the different types of hypoparathyroidism
Hypopara: \/ PTH, /\ phosphate
Pseudo-hypopara: /\ PTH, /\ phosphate
VitD def: /\ PTH, \/ phosphate
Describe the production and role of calcitonin.
Thyroid parafollicular cells produce pre-procalcitonin
Stimulated by an increase in plasma Ca2+
Inhibited by somatostatin and Calcitriol
Also stimulated by gut hormones (gastrin0, B-receptor agonists and glucocorticoids.
Describe the actions of calcitonin
Decreased Na+ and Ca2+ reabsorption in the kidney
Increased osteoblast activity, decreased osteoclast activity.
What else can stimulate release of PTH
Catecholamines
