2. Metabolic bone disease

Question 1

Types of metabolic bone diseases

Answer 1

1. Osteoporosis
2. Osteomalacia & Rickets
3. Hyperparathyroidism
4. Paget’s disease
5. Osteopetrosis

Question 2

Definition of osteoporosis

Answer 2

Systemic skeletal disease characterised by low bone mass & microarchitectural deterioration of bone tissue with consequent increase in bone fragility & susceptibility of fracture

WHO Quantitative Criteria

• Bone density study using dual energy X-ray absorptiometry
  i. Osteoporosis: bone mass > 2.5 SD below young normal mean
  ii. Osteopenia: 2.5 SD > bone mass > 1 SD below young normal mean

Question 3

Causes of osteoporosis

Answer 3

Primary causes:

1. Old age (senile osteoporosis)
   - Decreased replicative ability of osteoprogenitor
   - Decreased synthetic ability of osteoblasts
   - Decreased biologic activity of matrix-bound growth factors
   - Reduced physical activity (as mechanical forces are needed to induce bone remodeling)
2. Menopause
   - Decreased serum estrogen levels
   - Increased RANK & RANKL expression which increases osteoclast generation & activity

Secondary causes:

1. Endocrine causes
   - Cushing syndrome
   - Hyperparathyroidism
   - Hyperthyroidism
   - Hypogonadism
   - Type I diabetes mellitus
2. Gastrointestinal causes (malnutrition)
   - Vitamin C & D deficiency
   - Liver insufficiency
3. Drugs
   - Corticosteroids
   - Chemotherapy
4. Immobilization
5. Bone diseases
   - Multiple myeloma
   - Osteogenesis imperfecta

Question 4

Sites affected in osteoporosis

Answer 4

1. Spongy bone of vertebral bone
   - Affected first (high surface area for osteoclast action)
   - Causes loss of vertebral height in elderly, leading to
   dowager’s hump
2. Cortex in hip & wrist
   - Thinning of cortex (subperiosteal & endosteal resorption with widening of haversian systems)

Question 5

Morphology of osteoporosis

Answer 5

Histologically:

• Thin trabeculae disconnected from one another
• Normal mineralization

Question 6

Management of Osteoporosis

Answer 6

1. Prevention:
   - Maximize peak bone mass attained during early adulthood by ensuring adequate calcium intake during adolescence
   - Regular exercise to promote bone remodelling
2. Treatment:
   - Hormone replacement therapy
   - Bisphosphonates (binds to bone to inhibit osteoclast)
   - Vitamin D + calcium supplementation

Question 7

Definition of Osteomalacia & Rickets

Answer 7

Defect in matrix mineralization often due to Vitamin D deficiency; rickets is the clinical manifestation seen in children whereas osteomalacia is its adult counterpart

Question 8

Causes of Osteomalacia & Rickets

Answer 8

1. Vitamin D deficiency
   - Dietary insufficiency, malabsorption
   - Reduced skin synthesis due to insufficient exposure to sunlight
2. Abnormal Vitamin D metabolism
   - Increased degradation (drugs)
   - Chronic liver disease (diminished 25-hydroxylation)
   - Renal failure (diminished 1-hydroxylation)
3. Causes with normal Vitamin D levels
   - End organ resistance (type 2 Vitamin D resistant
   rickets)
   - Hypophosphatemia (renal tubular disorders such as
   in Fanconi syndrome)
4. Abnormal bone mineralization
   - Low bone alkaline phosphatase (hypophosphatasia)
   - Chemical drugs (aluminium toxicity)

Question 9

Morphology of Osteomalacia & Rickets

Answer 9

1. Excessive osteoid forming thickened seams (due to delay in mineralization of bone matrix)
2. Deficient calcification front (lack of effective endochondral ossification)
3. Irregular thickening of the hypertrophic zone of the
   epiphyseal growth plate in rickets (due to failure to mineralize, which prevents osteoclastic resorption of the cartilage)
   - Loss of normally orderly columns of cells
   - Marked increase in axial height
   - Disorderly proliferation of cells with only a small amount of intervening matrix

Question 10

Clinical Features of Osteomalacia & Rickets

Answer 10

1. Presentation:
   - Rickets: bowing of legs, lumbar lordosis
2. Xray findings:
   - ‘Looser zone’ or pseudofracture (a thin tranverse band of rarefaction; also seen in Paget’s disease)
   - Incomplete stress fractures which heal with callus lacking in calcium

Question 11

Definition of hyperparathyroidism

Answer 11

Overactivity of the parathyroid glands leading to increased osteoclastic activity which results in bone disease

Question 12

Causes of Hyperparathyroidism

Answer 12

1. Primary Hyperparathyroidism
   - Parathyroid adenomas
   - Parathyroid hyperplasia (seen in MEN I & IIa)
2. Secondary Hyperparathyroidism
   - Physiological response to hypocalcemia in various conditions (chronic renal failure, deficient calcium intake, Vitamin D deficiency)
3. Tertiary Hyperparathyroidism
   - Autonomous hyperplastic nodule in long standing secondary hyperparathyroidism

Question 13

Morphology of hyperparathyroidism

Answer 13

Histologically:

• Increased number of osteoclasts
• Dissecting osteitis (osteoclasts boring through the centre of bony trabeculae) due to increased osteoclastic resorption
• Bone loss & replacement by immature woven bone & fibrous tissue
• Brown tumour (mass formed due to extensive accumulation of osteoclastic giant cells with hemorrhage & fibrous tissue; can mimic giant cell tumours)

Question 14

Clinical features of hyperparathyroidism

Answer 14

Location: affects entire skeleton, cortical bone more so than medullary bone

Presentation:
1. Presents in young to middle-aged adults
2. Only 25% have bone disease:
- Typically presents as bone pain
- Recklinghausen disease (aka osteitis fibrosa
cystica; a combined picture of increased bone cell activity, peritrabecular fibrosis & cystic brown tumour formation) rarely seen nowadays due to early detection
3. Recurring kidney stones, peptic ulcer, nausea,
vomiting, weakness & headaches

Lab findings: Marked hypercalcemia & hypophosphatemia

Xray findings:

1. Expansile lytic lesions with occasional intralesional trabeculations
2. Surrounding periosteum produces reactive bone & margins of the tumour may be well-defined or indistinct

Question 15

Definition of Paget’s disease

Answer 15

Bone disease characterized by excessive turnover of bone resulting in disorganization of its architecture; not to be confused with Paget’s disease of the breast

Question 16

Epidemiology of Paget’s disease

Answer 16

1. 90% are over age 55, rare before age 40

2. Common in white, rare in blacks, China, Japan & Africa

Question 17

Pathogenesis of Paget’s disease

Answer 17

1. Inciting agent postulated to be due to slow infection by paramyxovirus
2. Some areas of bone experience increased activity of both osteoclasts & osteoblasts
   - Increases rate of bone resorption & laying
   - Results in high turnover & remodeling of bone
   - Enlarges these areas of bone
3. However, rate of turnover is very rapid, hence quality of remodeled bone is low
   - Despite overreactive areas enlarging, they are structurally abnormal and weak

Question 18

Morphology of Paget’s disease

Answer 18

Histologically: collage of matrix madness (3 phases)
1. Osteolytic phase: osteoclastic bone resorption

2. Mixed osteoclastic/osteoblastic phase: hectic bone
   formation
3. Burnt-out osteosclerotic phase (gain in bone mass,
   but bone is disordered in architecture)
   - Characteristic mosaic pattern of lamellar bone,
   resembling jigsaw puzzle with prominent & irregular cement lines

Question 19

Clinical features of Paget’s disease

Answer 19

Xray findings:

1. Early stage: radiolucency
2. Late stage: increased bone density (white & patchy)
3. Increased microfractures
4. Loss of distinction between cortex & medulla

Question 20

Complications of Paget’s disease

Answer 20

1. Leontiasis ossea
   - Bone overgrowth in the craniofacial skeleton
   - Cranium becomes so heavy that it becomes difficult
   for the patient to hold the head erect
2. Severe secondary osteoarthritis
   - Due to anterior bowing of femurs distorting the femoral head
3. Fractures & nerve compression injury
   - Vertebrae
   - Long bones (chalkstick-type fractures)
4. Arteriovenous shunt
   - Hypervascularity of Pagetic bone acts as an arteriovenous shunt
   - Leads to high-output cardiac failure or the exacerbation of underlying cardiac disease
5. Development of tumours or tumour-like conditions
   - Giant cell tumour & giant cell reparative granuloma
   - Extraosseous masses of hematopoiesis
   - Sarcoma (0.7-0.9% of cases)

Question 21

Definition of osteopetrosis

Answer 21

Also known as Marble Bone Disease or Albers-Schönberg disease; a heterogenous group of disorders characterized by defective osteoclast function leading to reduced bone resorption

Question 22

Causes of osteopetrosis

Answer 22

1. Deficiency of carbonic anhydrase (required for H+ production within osteoclasts)
2. Deficient osteoclastic H+ ATPase function (required for bone resorption)
   - Mutations in components of the H+ ATPase
   - Mutations in Cl- channel gene which interferes with H+ ATPase function
3. RANKL mutation (required for stimulation of osteoclast progenitors to differentiate into osteoclasts)

Question 23

Pathogenesis of osteopetrosis

Answer 23

1. Decreased osteoclastic bone resorption results in increased bone density (stone-like quality)
2. However, lack in bone remodeling results in deficient replacement of immature (woven) bone with mature (lamellar) bone
   - Bone is hard but brittle
   - Prone to pathologic fractures

Question 24

Clinical features of osteopetrosis

Answer 24

1. Xray findings:
   - Erlenmeyer flask deformity (ends of long bones are
   bulbous & misshapened)
2. Treatment:
   - Bone marrow transplantation (to give rise to functional osteoclast progenitor cells)

Question 25

Complications of osteopetrosis

Answer 25

1. Pathologic fractures
2. Failure of bone marrow formation leading to anemia
   - Due to lack of involution of primary spongiosa to create a medullary cavity for hematopoietic maturation
3. Cranial nerve palsies
   - Blindness, deafness, facial paralysis etc
   - Due to narrowing of exit foramina of cranial nerve branches in the skull