13. Endocrine Bone Disorders Flashcards
Role and composition of bone
Provides a skeleton, but also acts as a resevoir for calcium and phosphate
Composed of calcium hydroxyapatide cyrstals and the organic osteoid formed from type 1 collagen
Osteoblast role
Synthesises osteoid and participates in mineralisation/ calcification of osteoid (formation)
Osteoclast role
Release lysosomal enzymes which break down bone
Control of osteoclast activity and formation
Controlled in part by osteoblasts (needed to become active)
RANKL is expressed on osteoblast surface
RANK-R expressed on the osteoclast precursor surface must bind to RANKL to allow activation.
Osteoblasts in turn express receptors for PTH and calcitriol which regulate the process.
Classification of bone types
- Cortical (hard bone)
- Trabecular (spongy)- meshwork of trabeculae
- Woven bone- disorganised collagen fibres, weaker
Cortical and trabecular bone is formed in a lamellar pattern- mechanically strong
Effects of 1,25 dihydroxycholecalciferol (calcitriol)
Principle effect: stimulates intestinal absorption of calcium and phosphate
Stimulates osteoclast formation (from prcursors)
Stimulates osteoblasts to produce osteoclast activity
Renal Effects - increased calcium reabsorption + decreased phosphate reabsorption via FGF23
How renal failure causes bone disease
Decreased renal function leads to a decrease in the production of calcitriol (since 1a hydroxylase is required)
Will also be a decrease in phosphate excretion so plasma phosphate increases
Decreased calcitriol production causes a decrease in calcium absorption leading to hypocalaemia:
Hypocalaemia causes increased PTH secretion: PTH will break down bone matrix leading to osteoperosis
Lack of calcium also decreases bone mineralisation
The combination leads to osteitis fibrosa cystica
Appearance of osteitis fibrosa cystica in x-rays
‘brown tumours’ radiolucent bone lesions- has a risk of fracture and is painful
Treatment of osteitis fibrosa cystica
- Low phosphate diet ( to account for hyperphosphataemia)
- Alphacidol- calcitriol analogues
- Parathyroidectomy
Osteoperosis and BMD
A condition of reduced bone mass and a distortion of bone microarchitecture which predisposes to fracture after minimal trauma
BMD- Bone mineral density (2.5 standard deviations lower in osteoperosis)
BMD predicts fracture risk and is calculated using Dual X-ray Absorptiometry (DEXA) in the femoral head and lumbar spine
Osteoperosis vs Osteomalacia
Osteomalacia is caused by vitamin D deficiency causing inadequately mineralised bone- biochemistry abnormal (how you diagnose)
VS
In Osteoperosis the serum biochemistry is normal, bone reabsorption exceeds formation, diagnosied via DEXA scan
BOTH predispose fracture
Predisposing conditions of osteoperosis
- Post-menopausal oestrogen deficiency
- Age-related deficiency in bone homeostasis (osteoblast senescence)
- Hypogonadism in young men and women
-
Endocrine conditions:
- Cushing’s
- Hyperthyroidism- increased bone turnover
- Hyperparathyroidism
- Latronergic- herparin, use of glucocorticoids
Osteoperosis treatment options
- Oestrogen/Selective Oestrogen Receptor Modulators (see HRT lecture)
- Bisphosphonates
- Denusomab
- Teriparatide
Action of bisphosphonates
Analogues of pyrophosphate
E.g alendronate, sodium etidronate
Binds to hydroxyapatite and is ingested by osteoclasts- impairs the ability of oestoclasts to resorb bones and decreases maturation, promotes apoptosis
NET RESULT= REDUCED BONE TURNOVER
Treatment of severe hpercalcaemic emergency
I.V saline used initially to REHYDRATE
Then use bisphosphates
How are bisphosphates taken
- Orallt active but poorly absorbed
- Must be taken on an empty stomach
- Accumulates at the site of bone mineralisation and remains at the site until it is resorbed
- LONG TERM EFFECTS OF ACCUMULATION UNCERTAIN
Unwanted effects of bisphosphonates
- Oesphagitis- may require switch from oral to IV preparation
- Flu-like symptoms
- Osteonecrosis of the jaw- bone hardens and dies- risk in cancer patients
- Atypical fractures- over supression of bone remodelling
Denusomab
A human monoclonal antibody which binds to RANKL and inhibits osteoclast formation and activity
Given subcutaneosly every 12 months as a second line treatment to bisphosphonates
Teriparatide
Recombinant fraction of PTH which increases bone formation and bone resorption (formation outweighs)
Daily subcutaneous injection- very expensive- third line treatment
Paget’s Disease characteristics
A very active, localised but disorganised bone metabolism- usually slowly progressive
- Characterised by abnormal, large osteoclasts
- Significant genetic component as well as evidence of viral origin
- Men and women effecetd equally (though men may be more symptomatic)
- Disease not apparent for 50-60 years
- Get breakdown of bone and then bone being formed again in a disorganised manner- weakened
Padget’s disease symptoms
- Increased vascularity- warmth over affected bone
- Increased osteoclast/blast activity- osteoclast followed by osteoblast so deformity then thickening of deformed bone
- Increased fracture incidence
- Bone pain (can get trapping of nerves)
- Arthritis
- Fracture
- Deafness
Diagnosis of Paget’s disease
- Plasma Calcium = NORMAL
- Plasma Alkaline Phosphatase (ALP) = usually HIGH- increases when there is increased bone activity
Radiology demonstrating variable features including:
- Loss of trabecular (spongy/cancellous) bone
- Increased density
- Deformity
Radioisotope (Technetium) scanning can be performed to indicate the areas of involvement
Treatment of Padget’s disease
Bisphosphonates- reduce bone pain and disease progression
Simple analgesia
