Endocrine and metabolic bone disorders

Question 1

What proportion of the body’s calcium is stored in bone?

Answer 1

> 95%

Question 2

What are the 2 main components of bone?

Answer 2

Organic component (osteoid- unmineralised bone).

Inorganic mineral component.

Question 3

What proportion of bone mass do the organic components (osteoid) of bone make up?

Answer 3

35% of bone mass.

Question 4

What do the organic components (osteoid) of bone consist of?

Answer 4

Unmineralised bone.

Type 1 collagen fibres (95%).

Question 5

What proportion of bone mass does the inorganic mineral component of bone make up?

Answer 5

65%

Question 6

What does the inorganic mineral component of bone consist of?

Answer 6

Calcium hydroxyapatite crystals fill the space between collagen fibrils.

Question 7

What are the many types of bone cells?

Answer 7

Osteoblasts (synthesise osteoid and participate in mineralisation/calcification of osteoid- bone formation).

Osteoclasts (release lysosymal enzymes which break down bone- bone resorption).

Question 8

What is bone remodelling?

Answer 8

An ongoing dynamic process, involving bone resorption and formation.

Question 9

Where is RANKL expressed?

Answer 9

Osteoblast surface.

Question 10

How do osteoclasts differentiate?

Answer 10

RANKL expressed on osteoblast surface.

RANKL binds to RANK-R to stimulate osteoclast formation and activity.

Osteoblasts express receptors for PTH and calcitriol (1,25-(OH)2-vitamin D).

Regulate balance between bone formation and resorption.

Question 11

What are the different types of bone?

Answer 11

Lamellar (collagen fibrils laid down in alternating orientations, mechanically strong, cortical (hard) or trabecular (spongy) bone).

Woven bone (disorganised collagen fibrils, weaker, immature bone).

Question 12

What are the effects of vitamin D deficiency on bone?

Answer 12

Inadequate mineralisation of newly formed bone matrix (osteoid).

Children- rickets:

• affects cartilage of epiphyseal growth plates and bone.
• skeletal abnormalities and pain, growth retardation, increased fracture risk.

Adults- osteomalacia:

• after epiphyseal closure, affects bone.
• skeletal pain, increased fracture risk.
• proximal myopathy

Normal stresses on abnormal bone cause insufficiency fractures- looser zones

Waddling gait- typical

Question 13

What is osteitis fibrosa cystica?

Answer 13

Hyperparathyroid bone disease.

Rare.

Excess osteoclastic bone resorption secondary to high PTH.

Brown tumours = radiolucent bone lesions.

Question 14

What is the connection between renal failure and bone disease?

Answer 14

Low renal function results in low calcitriol and low phosphate excretion.

Low calcitriol leads to reduced calcium absorption and hypocalcaemia.

Reduced phosphate excretion leads to increased plasma phosphate concentration, leading to hypocalcaemia and vascular calcification.

Hypocalcaemia leads to decreased bone mineralisation and high PTH concentrations.
Decreased bone mineralisation leads to osteitis fibrosa cystica.

High PTH concentration leads to increased bone resorption, leading to osteitis fibrosa cystica.

Question 15

What are the 3 types of hyperparathyroidism?

Answer 15

Primary: parathyroid adenoma- high PTH, high calcium, no negative feedback by calcium on parathyroids.

Secondary: normal physiological response to low plasma [Ca], e.g renal failure (can’t make vitamin D), vitamin D deficiency- high PTH, low or normal calcium, more PTH released to raise calcium.

Tertiary: chronic low plasma [Ca] e.g. in chronic renal failure- high PTH, high calcium concentration, no active calcitriol made, autonomous parathyroids due to hyperplasia.

Question 16

How is osteitis fibrosa cystica (hyperparathyroid bone disease) treated?

Answer 16

Hyperphosphataemia: low phosphate diet; phosphate binders- reduce GI phosphate absorption.

Alphacalcidol- i.e. calcitriol analogues.

Parathyroidectomy in tertiary hyperparathyroidism- indicated for hypercalcaemia and/or hyperparathyroid bone disease.

Question 17

What is osteoporosis?

Answer 17

Loss of bony trabeculae

Reduced bone mass

Weaker bone predisposed to fracture after minimal trauma

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)

Question 18

How is bone mineral density (BMD) measured?

Answer 18

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).

Question 19

What are the similarities and differences between osteoporosis and osteomalacia?

Answer 19

Both predispose to fracture.

Osteomalacia:

• vitamin D deficiency (adults) causing inadequately mineralised bone
• serum biochemistry abnormal (low 25(OH) vitamin D, low/ low normal Ca2+, high PTH (secondary hyperparathyroidism)

Osteoporosis:

• bone reabsorption exceeds formation
• decreased bone mass
• serum biochemistry normal
• diagnosis via DEXA scan

Question 20

What conditions can predispose people to osteoporosis?

Answer 20

Postmenopausal oestrogen deficiency: oestrogen deficiency leads to a loss of bone matrix- subsequent increased risk of fracture.

Age-related deficiency in bone homeostasis (men and women), e.g. osteoblast senescence.

Hypogonadism in young women and in men.

Endocrine conditions:

• Cushing’s syndrome
• hyperthyroidism
• primary hyperparathyroidism

Iatrogenic: prolonged use of glucocorticoids; heparin.

Question 21

What are the treatment options for osteoporosis?

Answer 21

Oestrogen/ selective oestrogen receptor modulators.

Bisphosphonates.

Denosumab.

Teriparatide.

Question 22

Why is oestrogen (HRT) used to treat osteoporosis?

Answer 22

Anti-resorptive effects on the skeleton.

Prevents bone loss.

Question 23

Why are selective oestrogen receptor modulators (SERMS) used to treat osteoporosis?

Answer 23

Tissue selective ER antagonists/ anti-oestrogens, e.g. tamoxifen: antagonises ERs in breast but has oestrogenic activity in bone; oestrogenic effects on endometrium limit its use in osteoporosis management.

Tissue selective ER agonist raloxifene has been further developed for its selectivity on bone: oestrogen activity in bone; anti-oestrogenic at breast and uterus; reduces breast cancer risk (anti-oestrogen) but increases risk of venous thromboembolism.

Question 24

What are the actions of bisphosphonates in treating osteoporosis?

Answer 24

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.

Question 25

What are bisphosphonates used to treat?

Answer 25

Osteoporosis- first line treatment.

Malignancy: associated hypercalcaemia; reduce bone pain from metastases.

Paget’s disease- reduce bony pain.

Severe hypercalcaemic emergency- i.v. initially (+++ re-hydration first).

Question 26

Describe the pharmacokinetics of bisphosphonates.

Answer 26

Orally active but poorly absorbed.

Take on an empty stomach (food, especially milk, reduces drug absorption generally).

Accumulates at site of bone mineralisation and remains part of bone until it is resorbed- months, years.

Question 27

What is denosumab?

Answer 27

Human monoclonal antibody.

Binds RANKL, inhibiting osteoclast formation and activity.

Hence inhibits osteoclast-mediated bone resorption.

SC injection 6/12ly.

Second line to bisphosphonates.

Question 28

What is teriparatide?

Answer 28

Recombinant PTH fragment- amino-terminal 34 amino acids of native PTH.

Increases bone formation and bone resorption, but formation outweighs resorption.

Third line treatment for osteoporosis.

Daily s.c. injection.

Expensive.

Question 29

What is Paget’s disease of bone?

Answer 29

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.

Bone frailty.

Bone hypertrophy and deformity.

Characterised by abnormal, large osteoclasts- excessive in number.

Question 30

What are the clinical features of Paget’s disease of bone?

Answer 30

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.

Question 31

How is Paget’s disease of bone diagnosed (biochemical and radiological features)?

Answer 31

Plasma [Ca2+] normal.

Plasma [alkaline phosphatase] usually increased.

Plain x-rays = lytic lesions (early), thickened, enlarged, deformed bones (later).

Radionuclide bone scan demonstrates extent of skeletal involvement.

Question 32

What are the treatment options for Paget’s disease of bone?

Answer 32

Bisphosphonates- very helpful for reducing bony pain and disease activity.

Simple analgesia.

Question 33

Discuss the epidemiology of Paget’s disease of bone.

Answer 33

Often positive family history- genetic cause?

Evidence of viral origin, e.g. measles virus?

Prevalence- highest in UK, N America, Australia and NZ; lowest in Asia and Scandinavia.

Men and women affected equally.

Disease usually not apparent under age 50y.

Most patients are asymptomatic.