Metabolic Bone Disease

Metabolic Bone Disease

·        Osteoporosis: bone matrix reduced in amount but normally mineralised (ie ¯bone mass due to loss of both protein matrix and Ca in equal proportions) 

·        Osteomalacia: normal amount of bone matrix but deficient mineralisation (ie ¯Ca)

·        Both will appear on x-ray as osteopenia (poverty of bone)

Bone Metabolism

·        Osteoblasts: 

o  Synthesise osteoid: normally this is a thin layer as the time between matrix deposition and mineralisation is short. If either ­osteoid or delayed mineralisation ® thick layer (hyperosteoidosis), eg: 

§  ­Bone formation: fracture callus, Paget‟s disease, hyperparathyroidism

§  ¯Calcium, phosphorous, or vitamin D

§  Blocked mineralisation due to inhibitory/toxic substances (eg aluminium, iron, fluoride)

o  Mediate osteoclast activity

o  Flat when inactive, plump when active.  Become buried in cortex (then called osteocytes)

o  ­Activity due to physical activity, ­PTH, growth factors, fluoride. Suppressed by inactivity and steroid hormones

·        Osteoclasts:

o   Regulated by PTH and osteoblasts

o   Large cells containing 2 – 4 nuclei 

o   Adhere to bone and are seen in depressions referred to as Howship‟s lacunae or resorption bays ® scalloped appearance of resorbed bone

·        Woven bone: immature bone laid down by osteoblasts in a callus (eg healing of a fracture)

·        Lamellar bone: parallel and organised

·        Tetracycline:

o   Give pulses before bone biopsy

o   Binds to actively mineralising surfaces and fluoresces in UV light under the microscope

o   Shows the extent of mineralisation and amount of bone formed over a given time

Osteoporosis

·        Normal bone composition – just less of it.  Either primary or secondary

·        Epidemiology: 

o   Often presents with a hip fracture. 3 per 1000 in men and 6 per 1000 in women over 65 per year. Number of vertebral fractures and resulting disability unknown 

o   ¼ of those > 80 going to hospital with a fracture don‟t return to their previous residential status

·        Pathogenesis:

o   Bone is constantly turning over. From the 3^rd decade, resorption exceeds bone formation – the two become uncoupled. In women, this accelerates post menopause (oestrogen is protective). Around menopause will loose 6 – 10% of bone mass, then returns to gradual decline 

o   Trabecular bone (20% of skeleton) turnover 8 times that of cortical bone (80% of skeleton). Femoral head has lots of trabecular bone Þ good place to measure loss. Use Singh Index of number of trabecular groups present (6 = good, 1 = bad) 

o   Also thinning and attenuation of the cortices

o   Fracture risk a combination of density (which we can measure) and structure (which we can‟t)

o   By the time they present with a fracture, osteoporosis is usually advanced

·        Severity depends on: 

o   Peak bone mass. Peaks at around age 30. Largely determined by type of inherited vitamin D receptor. Also calcium intake in teens, etc

o   Sex: peak bone mass of males > females

o   Age: men affected later than women

o   Also physical activity positive (disuse ® localised osteoporosis), smoking negative, calcium intake

·        Distribution:

o   Osteoporotic vertebrae (most common fracture):

§  Loose secondary trabeculae 1^st (leaves vertical lines of primary trabeculae) ® clear glass appearance

§  Changes in shape: wedge, biconcave, planar (ie flat)

§  Anterior of vertebrae reduced

§  May occur with trivial trauma or lifting 

§  Small fractures don‟t cause immediate pain – comes on after several days. If no scoliosis then can heal

o   Fractures affecting proximal femur, proximal humerus, distal radius resulting from falls

o   Look for insufficiency factors in the sacrum, pubis, and supra acetabular

·        Differential of osteoporosis:

o   Male: hypogonadism (® ¯testosterone), excess alcohol

o   Female: ¯Ca and Vit D post menopause

·        Scanning for osteoporosis:

o   Plain x-ray insensitive: don‟t show changes until 30 – 40% of bone mass lost. Radiodensity varies due to exposure, developing, and patient‟s build

o   Dual Energy X-ray Absorbiometry = DEXA:

§  Measures bone density (ie Ca density) by firing X-rays of 2 different wave lengths – one maximally absorbed, the other absorbed as much as carbon, and subtract the two

§  Number of standard deviations from the mean (of 30 year old women) more important than actual density. T < -2.5 standard deviations = Osteoporosis. Osteopenia: -1 < t < -2.5

·        Management:

o   Prevention: 

§  Physical exercise (® ­bone laid down)

o   Adequate Ca (prevents bone resorption)

o   Vitamin D if house bound (a small amount of sun is sufficient)

o   Rocaltrol: 1,25(OH)2D3 

o   HRT: most stop before 5 years – compliance problem. Can start at any age – but if elderly need to build up gradually

·        Treatment: alendronate (or Fosamax) ® ¯osteoclast action ® ¯turnover ® gain bone

Osteomalacia

·        Osteomalacia in adults = Rickets in kids

·        Present with bone pain, fractures (eg neck of femur) or waddling gait (proximal myopathy)

·        Aetiology:

o  Deficiency or abnormal metabolism of vitamin D

o  Calcium deficiency

·        Pathology:

o  Intracortical tunnelling (due to secondary hyperPTH)

o  Coarsened indistinct trabecular pattern (due to seams of osteoid) ® frosted glass appearance

o  Looser‟s zones: the hallmark of osteomalacia: lateral margin of scapula, ribs, pubic rami, proximal femur, proximal ulna

o  Micro: ­­ in unmineralised bone (up to 40 – 50%) + disorganisation of trabecular architecture

·        In children: changes around metaphyses of most rapidly growing bones (knee and wrist), with irregular and broadened epiphyseal growth plates

·        Investigations: 

o  X-rays: generalised osteopenia + multiple, bilateral, symmetrical partial linear fractures (stress fractures)

o  May be ­ALP, ¯vitamin D 

o  PTH assay not very helpful: normal range is too wide (0.5 – 5) so can mask an increase. Mild increase ® ­osteoclastic activity, but serum Ca normal so remineralising normally ® osteopenia and not osteomalacia

Increased Bone Resorption

·        Hyperparathyroidism:

o  Old term: osteitis fibrosa cystica 

o  ­PTH (either primary of secondary) ® ­Ca and ¯PO4 

o  Presentation: kidney stones, peptic ulcer, bone pain, nausea, vomiting, weakness, headaches, depression (bones, stones, groans). Now rare – usually picked up as an incidental finding of hypercalcaemia 

o  Affects cortical bone more than cancellous/trabecular bone 

o  ­Osteoclast and osteoblast activity 

o  May ® reactive fibrosis tissue (eg following microfractures and secondary haemorrhages) ® mass called a „Brown tumour‟ 

o  X-ray: generalised osteopenia and tufts on end of distal phalanges

o  Differential: 

§  Blood sample with dehydration or tourniquet ® ­Ca

§  Malignant disease and/or neoplastic syndrome with PTHrH secretion

§  Sarcoidosis

§  Vit D intoxication

§  Diuretic therapy

o  Treatment: neck exploration for parathyroid adenoma

·        Renal Osteodystrophy:

o  = All skeletal changes resulting from chronic renal disease, including: 

§  ­Osteoclast resorption (mimicking hyperPTH)

§  Delayed matrix mineralisation (osteomalacia)

§  Osteosclerosis

§  Growth retardation

§  Osteoporosis

o  Due to: 

§  PO4 retention ® Secondary HyperPTH ® ­Osteoclast activity

§  Metabolic acidosis ® bone resorption

§  ¯ Conversion of 1,25(OH)2D3 in kidneys ® hypocalcaemia 

§  Aluminium deposition (from antacids, dialysis fluid) at the site of mineralisation ® ¯mineralisation 

o   Similar impact to osteomalacia: ­PTH ® osteoclastic bone resorption

o   Investigations:

§  X-ray and bone densitometry

§  Bloods: Ca, albumin, phosphate, PTH, ALP, Vitamin D3 levels

§  Urine Ca usually low and faecal Ca high

·        Paget’s Disease:

o   Common in northern Europeans, rare in Blacks/Asians, M = F, usually old

o   Presentation:

§  Monostotic, asymptomatic and incidental finding on x-ray (doesn‟t spread) 

§  In a small number, widespread, polystotic lesions with bone pain (worse at night), fracture, arthritis or development of a sarcoma

§  Usually axial skeleton (spine, skull, pelvis) and femur 

o   Pathogenesis: ?viral infection (paramyxovirus) of osteoclasts ® ­­ osteoclast activity ® ­­ osteoblast activity ® disorganised, woven bone. Normal bone mineralisation. Also genetic and geographic predisposition

o   Gross: enlarged bone with thick cortices

o   Micro: irregular trabeculae with numerous osteoclasts and plump osteoblasts, jigsaw pattern

o   Prognosis: 

§  Progressive bone deformity and micro fractures, anterior bowing of the femur. Arthritis due to deformed joints

§  Osteosarcoma in 5 – 10% of those with severe disease

o   Investigations: 

§  X-ray: early radiolucency. Late: loss of distinction between cortical and cancellous bone (may be confused with primary bone tumour) 

§  ­Bone formation ® ­­ALP but Ca and PO4 normal.  ­Urinary hydroxyproline

o   Treatment:

§  Mild: NSAIDs – indicated if pain

§  Severe: biphosphonates (alendronate), calcitonin

o   Complications:

§  Fractures 

§  Spinal stenosis ® nerve compression

§  Osteosarcoma

§  Enlargement of the skull, femur, clavicle, tibia („Sabre Tibia‟)

§  Neural deafness due to bone overgrowth 

§  High output heart failure (due to ­ blood flow to bone)