Metabolic Bone Disease

Question 1

What kind of conditions arise from imbalances in osteoclast and osteoblast activity?

Answer 1

Too much osteoclast too little osteoblast = Osteoporosis

Opposite = stone bone (osteopetrosis) and sclerosteosis (caused by mutation in sclerostin gene)

Question 2

What part of the bone declines most rapidly with age?

Answer 2

Trabecular bone

cortical bone does thin too

Question 3

What is osteoporosis?

Answer 3

Skeletal disorder characterised by compromised bone strength predisposing to increased risk of fracture.

Reduced skeletal mass and progressive discontinuity in bone microarchitecture leading to structural failure and fracture

Question 4

What does bone strength refer to in relation to bone metabolism and pathology?

Answer 4

Bone density + bone quality

Quality = architecture, turnover, damage, etc

Question 5

How common is osteoporosis?

Answer 5

Most common metabolic bone disease with over 1.2 million sufferers in Australia (5% of WAians)

1 in 2 women and 1 in 3 men over 60 years and costs 2.75 billion dollars a year

Question 6

When is a fracture considered osteoporotic-related?

Answer 6

If it results from a fall from standing height or less

Question 7

What are the most common sites of osteoporotic fractures?

Answer 7

Hip

Vertebrae

Wrist

Question 8

What is the rate of survival 5 years after hip or vertebral fracture?

Answer 8

80% of men and women of similar age without fracture

Hip fracture mortality is higher in men than women.

Death not directly attributed to the fracture but other chronic diseases associated that lead to the fracture.

Question 9

When is the risk of death greatest following a fracture of the hip or vertebrae?

Answer 9

It is greatest immediately after the fracture

Question 10

What percentage of fracture survivors have some degree of permanent disability?

Answer 10

7%

Question 11

What are the factors that determine risk for osteoporosis?

Answer 11

Peak bone mass

Rate of bone loss

Imbalance resorption and formation

Calcium metabolism

Hormonal status

Age related changes

Physical activity

Question 12

What are the types of osteoporosis?

Answer 12

Type I: Post menopausal, trabecular, forearm, and spinal fractures

Type II: Age related, cortical and trabecular, hip fractures

Secondary: Caused by endocrine diseases, drugs, glucocorticoids, malabsorption, and rheumatological diseases

Question 13

What are the clinical features of osteoporosis?

Answer 13

Could be asymptomatic but presents with complications like pain, microfractures, deformities

Question 14

What happens to bone and bone marrow morphology in osteoporosis?

Answer 14

Trabeular and cortical thinning

Bone width doesn’t change

Bone marrow loses cellularity with replacement of fat cells in it

Question 15

How is a clinical diagnosis made for osteoporosis?

Answer 15

Serum biochemistry:

Alkaline phosphatase (ALP, bone formation marker)

Carboxy terminal telopeptide of type-1 collagen (CTX, Bone resorption marker)

Serum calcium and serum phosphate

X-ray: not a very good method because it has low sensitivity

X-ray would show decreased bone density, cortical thinning, and fractures

Question 16

When is a DEXA score said to be Normal, osteopenic, osteoporotic, and severely osteoporotic?

Answer 16

Normal >= -1

Osteopenia -1 to -2.5

Osteoporosis

Question 17

What does T score represent?

Answer 17

Number of SD a patient is above or below the mean BMD of a young adult

Question 18

How is osteoporosis treated?

Answer 18

Bisphosphonates

Denosumab (anti-RANKL)

PTH/PTHrH (despite stimulating production of osteoclasts in daily intermittent doses it stimulates osteoblasts to work)

Calcium + VitD (at older ages it isn’t very useful usually given in combination with other stuff)

Anti-resorptives

Question 19

How do bisphosphonates work?

Answer 19

Binds bone surface and bones uptake that and induces apoptosis of osteoclasts.

Question 20

How does Denosumab work?

Answer 20

Works like OPG to block osteoclast formation by preventing RANKL from binding osteoclast RANK receptor.

Question 21

What is the problem with use of antiresorptives?

Answer 21

It is often administered late where patients are already osteopenic/osteoporotic

Poor compliance

Undesirable effects such as atypical subtrochanteric femoral fractures and osteonecrosis of the jaw

Question 22

What are the downsides of using anabolics?

Answer 22

Expensive

Usually administered late after patients are severely osteoporotic

Require daily injection and peak levels of circulating PTH to control levels within 3 hours

Osteosarcoma risk seen in rats

Question 23

What is osteomalacia?

Answer 23

aka Ricketts, is defective mineralisation of organic matrix, excess osteoid, deficiency of minerals

Question 24

What does osteomalacia do to bone?

Answer 24

Lack of mineralisation affects both quality and quanitity of bone. Reduced stiffness and strength make them susceptible to compressive forces with deformities of weight-bearing bones and pathological fractures

Question 25

What is the cause of osteomalacia/ricketts?

Answer 25

VitD deficiency (dietary or sunlight lack/malabsorption) VitD resistance (phosphate wasting, end organ insensitivity and renal tubular acidosis) Hypophosphataemia (Renal tubular disorders, antacids) Drugs (Phenytoin, aluminium, heavy metals) Neoplasia (Oncogenic osteomalacia)

Question 26

What are the clinical features of osteomalacia?

Answer 26

May be asymptomatic Bone is soft / fragile (fractures) Bone pain / tenderness Proximal muscle weakness Radiology shows generalised osteopenia (multiple bilateral and symmetrical cortical lucencies) Alterations in the serum concentrations of calcium, phosphorous, vitamin D. (tend to show low to normal serum calcium, low phosphate and high ALP)

Question 27

What are histological features of osteomalacia?

Answer 27

Osteoid is increased in amount of surfaces of bone trabeculae

Question 28

What happens in growing bones if a child suffers from osteomalacia?

Answer 28

Defective growth Deformity Metaphyses near growth plates Fracture

Question 29

What is the cause of primary hyperparathyroidism?

Answer 29

Primary from a parathyroid adenoma (80%) Parathyroid hyperplasia (15 - 20%)

Question 30

What is the cause of secondary hyperparathyroidism?

Answer 30

Chronic hypocalcaemia Lack of negative feedback Hypersecretion of PTH

Question 31

What is the result of hyperparathyroidism?

Answer 31

Excessive PTH stimulates osteoclastic resorption which results in marked hypercalcaemia Mobilisation of Ca2+/PO4(2-) Diffuse osteopenia Cysts Marrow fibrosis 'osteitis fibrosa cystica' Brown tumours in large localised areas of resorption such as the jaw, the skull, and in long bones

Question 32

What are the clinical symptoms of hyperparathyroidism?

Answer 32

Asymptomatic (biochemical abnormality detected incidentally) Signs and symptoms of hypercalcaemia: Abdominal cramps, constipation, muscle fatigue, peptic ulceration, renal calculi Bone related disease

Question 33

How is hyperparathyroidism diagnosed?

Answer 33

Pathology/radiology of primary/secondary bone changes (Bone changes is essentially identical) Dissecting / tunnelling bone resorption Thinning cortical and trabecular bone Irregular new bone formation X-rays: Diffuse osteopenia and/or circumscribed lucencies subperiosteal Microscopic examination shows increased osteoclast number and activity (characteristic tunnelling or dissecting pattern Mesenchymal cells proliferate in the marrow space and fibrous tissue replaces lost bone

Question 34

How many phases does paget's disease have?

Answer 34

3 phases: Osteolytic (lots of osteoclasts present and active) Mixed (lytic and blastic) Osteoblastic

Question 35

What is the result of paget's disease?

Answer 35

Results in thick, soft, porous bone, prone to compression and deformity

Question 36

What causes paget's disease?

Answer 36

Idiopathic disorder Relatively common Late adult life Virus (Paramyxovirus inclusions?) Genetic (p62/sequestosome) May involve: 1 bone or multiple bones Most commonly pelvis and skull but virtually any bone can be affected

Question 37

What are the clinical symptoms of paget's disease?

Answer 37

Greatly variable, depend upon sites and extent of disease Can be asymptomatic Can have complications or no complications Pain, swelling, deformity, enlargement of bones Also associated with high output congestive heart failure due to shunting of blood through skin (bone is hypervascular and hot)

Question 38

How is paget's disease diagnosed?

Answer 38

Often asymptomatic X-ray Elevated serum ALP and urinary hydroxyproline Radiology: Early: radiolucency Late: Increased bone density, increased microfractures, loss of distinction between cortex and medulla, may have sharp demarcation between normal and affected bone, may extend into soft tissue if florid disease

Question 39

What kind of historlogical features indicate paget's disease is the likely diagnosis?

Answer 39

Chaotic turnover (Extensive resorption and appositional new bone) Increases in both Osteoclastic and osteoblastic activity with supportive radiologic findings Disorganized and purposeless changes Acute: Primarily woven bone; focal mosaic pattern of lamellar bone, resembles jigsaw puzzle with prominent irregular cement lines, osteoclasts present at surface of bone but don't tunnel and in osteolytic phase osteoclasts may have up to 100 nuclei Chronic: Thick trabeculae and thicker bones; fine fibrosis of marrow.