Metabolic Bone Disease

Hyperparathyroidism

overproduction by the parathyroid glands

Paget's disease

- bone disease of unknown cause characterised by the excessive breakdown of bone tissue, followed by abnormal bone formation

- incidence ~3% 40+

- some clustering in families

Osteoporosis

a condition in which the bones become fragile & break easily

Osteomalacia

abnormal softening of bones in adults

- Bone weakness due to defective mineralisation of osteoid matrix

– On biopsy see increased surface osteoid plus decreased mineralisation

– Can get increased osteoid w/ normal mineralisation during rapid bone turnover eg.Pagets, HPT, near fracture site

Normal bone remodelling - Bone Remodelling Unit

- coordinated sequence of events (3-4 months)

- bone removal

- bone formation

Bone removal:

- osteoclast activation (via osteoblasts)

– resorption of bone matrix & mineral

Bone formation:

- activation of osteoblasts

– formation of new bone matrix (osteoid)

– mineralisation of bone matrix (delay of 6-12 days)

– reversal (cement) lines mark the limits of each BRU

What controls bone formation?

- local physical factors act as the trigger for remodelling

– parathormone receptors found on osteoblasts

– vitamin D

Control of bone formation: Local physical factors

- sensed by osteocytes within bone lacunae

- release cytokines or other substances

Control of bone formation: Parathormone receptors

net effect of actions is to increase blood calcium

Control of bone formation: Vitamin D

- needed for the resorbing action of PTH in bone

- 1,25 diOH vitD

> increases intestinal calcium absorption

> promotes bone mineralisation

What is parathormone?

- Hormone secreted by parathyroid glands

- Controls imbalanced levels of calcium & phosphate in the blood & tf

- Influences levels of excitability

What is the action of parathormone: Bone?

– increases numbers of osteoblasts & osteoclasts

– activates osteoblasts which, in turn, activate osteoclasts (probably via PGE)

– inhibits matrix production by osteoblasts

– stimulates production of proteases by osteoblasts

What is the action of parathormone: Kidney?

- increased calcium resorption by tubules

- increased phosphate excretion

Primary hyperparathyroidism:

raised hyperparathyroid hormone

- 80% due to solitary adenoma

– typically F, peak age 45y

– usually asymptomatic

– detected on biochemical screening (raised Ca & low PO4 raised ALP)

– if severe: bone pain & fractures muscle weakness & renal calculi

Where are the two places in the body alkaline phosphatase is found?

- liver

- osteoblasts

Secondary hyperparathyroidism:

– raised PTH in response to persistent hypocalcaemia (renal failure, vit.D deficiency, hypophosphataemia)

– all glands enlarged & hyperplastic

Tertiary hyperparathyroidism:

- secondary HPT plus autonomous nodules

- tx of cause does not reverse parathyroid changes

What are bone changes which can be seen through radiology in hyperparathyroidism?

Hands:

- resorption of tufts of terminal phalanges

– subperiosteal erosions of sides of phalanges

- localised lytic areas in shafts of long bone, ribs, jaw & skull (brown tumours)

Bone pathology of hyperparathyroidism: Bone (oesteitis fibrosa)

- excessive osteoclastic activity, lacunae & tunnelling resorption

- excessive osteoblastic activity

- marrow fibrosis

- lytic lesions

Bone pathology of hyperparathyroidism: Soft tissue

metastatic calcification: vessel walls, alveoli, skin, renal tubules, renal calculi

What is the aetiology of Paget's?

– unknown, but may be related to virus infection of bone cells

– paramyxovirus-like inclusion found in osteoclasts

– viral antigens shown by IHC

– measles virus & RSV possibilities

? canine distemper virus implicated (unproven)

How does Paget's disease present radiographically?

– Mainly sacrum & pelvis, spine, skull & femur

– In long bones starts at end of bone & spreads towards diaphysis

Spectrum of changes:

– initially osteolytic (flame defect)

– osteoblastic phase: increased endosteal & periosteal new bone (bone scans useful)

– inactive phase: residual increased bone

Pathology of Paget's disease:

– increased osteoclastic resorption plus fibrosis affecting cortical & trabecular bone

– increased osteoblastic activity produces woven bone

– random replacement causes mosaic appearance of cement lines

- late phase: thickened, mosaic bone, little activity

What are the general clinical presentations of Paget's?

– Usually no symptoms, signs or biochemical abnormalities

Focal manifestations:

– bone expanded (skull enlargement)

– bone softened: deformities – spine curves forward, femur & tibia bow anteriorly & laterally, pelvic deformities

– nerve compression: cranial nerves in foramina, sc (thoracic) causes lower limb signs

What are the clinical presentations of Paget's? Local complications

- fracture (particularly femur & tibia)

- tumours (osteosarcoma - pelvis, skull, femur, humerus)

What are the systemic manifestations of Paget's disease?

- cardiovascular: increased CO if extensive dx

- biochemical:

> raised ALP due to osteoblastic activity

> raised urinary hydroxyproline due to bone breakdown

> occasionally get hypercalcaemia & hypercalciuria, hyperuricaemia & gout

What are the effects of osteoporosis on bone?

– Reduction in trabecular bone mass (i.e. trabecular thickness & number)

– Bone remains qualitatively normal (i.e. proportions of mineralised & unmineralised bone remain normal)

When does bone mass peak in adults with osteoporosis?

30-40y, then decreases particularly in F

> Osteoporosis = 1SD or 2SD below normal for age & sex

> Trabecular bone volume (TBV) <11% then likely to get vertebral fractures

What are possible causes of decreased bone mass?

– decreased bone formation

– increased bone resorption

– any combination of (a) & (b)

N.B. different cellular mechanisms may be important when considering tx

What is an idiopathic aetiological cause of osteoporosis?

idiopathic/involutional

– postmenopausal loss of oestrogens

– decreases Ca absorption

– increases Ca excretion

– accompanied by increased bone remodelling activity (net BL)

What are some other aetiological causes of osteoporosis?

– Immobilisation: increases osteoclastic activity

– Malabsorption of calcium

– Collagen disturbances: scurvy, OI

– Homocystinuria

– Endocrine: Cushing's, steroid therapy (increased resorption)

– Hyperthyroidism, acromegaly

– Hypogonadism

– Cellular proliferation: mast cells, haemopoietic cells, neoplasia

What is a clinical manifestation for osteoporosis?

- predominantly a dx of postmenopausal, elderly F

– fractures

> in <70 mainly trabecular loss (vertebral # (L thoracic & U lumbar spine. Loss of height))

> in >70 (cortical & trabecular loss – femoral # (37500 hip # per year))

> also proximal humerus & distal radius often after trivial trauma

How is a diagnosis of osteoporosis formed?

– bone biopsy of iliac crest

– correlates well w/ vertebral loss

– needs good standardisation

– single photon or dual photon absorptiometry (Dexascan)

How is osteoporosis treated?

- Oestrogen replacement

– Exercise to increase preMP bone mass (?postMP)

– Ca, vitamin D – probably little effect

– Fluoride: increases trabecular bone mass but decreases cortical mass (only used for severe vertebral OP - 1/3 don't respond)

– Etidronate (blocks osteoclasts to decrease resorption)

What is the aetiology of osteomalacia?

vitamin D related

- Vitamin D deficiency: diet, sunlight

– Vitamin D malabsorption: ileal/pancreatic disease

– Impaired vitamin D metabolism: liver/renal disease

– Increased vitamin D catabolism: enzyme induction

– Phosphate depletion & hypophosphataemia: increased PTH, congenital, metabolic acidosis, Fanconi syndrome

– Inhibition of mineralisation: diphosphonates, F-, aluminium (dialysis pts)

– Hypophosphatasia

What are general clinical manifestations of osteomalacia in adults?

– bone pain & tenderness

– deformities - bowing of limbs, pigeon chest, spinal

– muscle weakness (type 2 fibre atrophy)

– X-ray: density of bone may be increased or decreased (osteoid is denser than marrow)

– pseudofractures (Looser's zones)

– cortical microfractures w/ poorly-formed callus

What are general clinical manifestations of osteomalacia in children?

rickets

- failure of calcification of epiphysial cartilage

– disordered, continued cartilage proliferation

– widened & irregular growth plate

– flaring of the metaphysis.