PATH 23 METAB BONE Ds

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njards
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174409
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PATH 23 METAB BONE Ds
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2012-09-30 11:33:19
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Metabolic Bone Disease Pathology
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METABOLIC BONE DISEASE
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  1. METABOLIC BONE DISEASE 
    Some disturbance in formation and/or breakdown of bone matrix.

    Usu manifest as Ds of skeleton, but other organ systems may also be affected.

    Examples:

    • osteoporosis
    • osteomalacia / ricketts
    • hyperparathyroidism
    • Paget’s disease
  2. NORMAL BONE HISTOLOGY AND METABOLISM 
    • Bones comprise - external shell/cortex
    • & internal medullary cavity - comprising cancellous bone and bone marrow.

    Cortical bone in adults = dense compact cylindrical units, (osteons or haversian systems)

    Cancellous bone formed by avascular plates (trabeculae).

    Bone composed of extracellular matrix (Type I collagen, crystal – calcium hydroxyapatite) and cellular elements.

    • Collagen --> tensile strength (resist forces of tension, torsion and shear).
    • Calcium hydroxyapatite -->"stiffness" (resist compression).
  3. Osteoblasts 
    produce bone matrix and control its mineralisation, and are found at the surfaces of bone.

    The non-mineralised matrix synthesised by osteoblasts is referred to as osteoid.

    Normal skel mineralisation rests upon the presence of sufficient calcium and phosphate at the mineralization sites, together with normal cellular function and absence of inhibitory / deleterious metabolic factors.

    When osteoblasts become incorpd into the substance of the bone --> referred to as osteocytes, and occupy lacunar spaces within the matrix.

    Osteocytes maintain cellular contact w each other via interconnecting canaliculi.
  4. Osteoclasts 
    cells responsible for the removal of bone matrix

    Found in surface depressions at bone surfaces referred to as Howship’s lacunae.
  5. Lamellar v Woven bone?
    Lamellar bone has an org'd & layered structure =  mature bone.

    Woven bone = immature and disorgd precursor of lamellar bone. Collagen fibres in matrix are irregularly arranged.
  6. The regulation of bone metabolism is a....
    • complex process involving interactions between:
    • minerals (e.g. calcium and phosphate),
    • hormonal and other regulatory proteins
    • and a number of mechanical and environmental stimuli.
  7. Calcium and bones...
    Bone contains 99% of the Ca in body, stored as hydroxyapatite crystals.

    • Calcium has # of physiol fntns....
    • delicate homeostatic mechanisms which maintain [serum Ca] at physiol levels (sometimes at expense of skel mass).

    • Calcium absorption occurs in the small bowel
    • Facilitated by parathyroid hormone (PTH) and vitamin D.

    Excretion of calcium occurs via the bowel and kidney.

    PTH is the primary regulator of extracellular calcium, and is secreted in response to low serum [calcium].

    Prolonged PTH --> increases osteoclastic bone absorption.

    Vit D absrbd in gut from diet/synthd in liver.

    Calcitonin inhibits osteoclastic resorption of bone. Other systemic hormones may influence bone metabolism, and both deficiency and excess states may result in bone alterations.
  8. Phosphate and bones...
    Bone contains about 85% of phosphate in the body.

    • Phosphate absorption occurs in lower small bowel.
    • Excretion occurs by bowel and kidney.

    Both Ca and phosphate regd primarily by PTH & Vit D, which act either directly or indirectly on the gut, kidney and bone.
  9. Bone remodelling
    = continuous process involving both formation & resorption.

    • 2 principal functions;
    • 1) allows repair of microscopic areas of damage withn bone --> maintain skeletal strength,
    • 2) To release Ca -->  maintain serum [Ca]

    Control and regul of bone remodelling is intricate. Production, removal, and maintenance of bone is a couple and control process, in which osteoblasts and osteoclasts are the effector cells of turnover.

    • Ideally, resorbed bone = newly formed bone ---> maintenance of skeletal mass.
    • But, there is age related loss of bone, --> commence earlier and proceed more rapidly in women,
    • accelerates before & during menopause.

    Trabecular bone loss occurs in the spine and distal radius in women and involves both the spine and hips in both women and men.
  10. OSTEOPOROSIS 
    - diminished bone mass and progressive discontinuity of bone microarchitecture --> structural failure --> susceptibility to fracture.

    = skeletal fragility assocd w ic risk of fracture.

    • Osteoporosis = reduction in bone mass due to imbalance in  processes influencing acquisition and maintenance of skeletal mass.
    • No underlying abnormality in either the mineral or organic matrix of the bone, or their relative proportions within the osteoporotic bone.

    Osteoporosis may be categorized by etiology as either primary or secondary, depending upon whether the bone loss can be attributed to a known cause.

    In addition to osteoporosis affecting the entire skeleton, the basis of the discussion below, localized and transient regional forms are also recognized.

    Localized osteoporosis may result from disuse or in vasomotor responses associated with injury.

    W ageing however resorption and new bone formation become imbalanced, with resorption predominating, this reflecting either an increase in the osteoclastic activity and or a decreasing osteoblastic activity. An imbalance between resorption and new bone formation may become manifest at different ages and in different sites of the skeleton.
  11. Osteoporosis is a major....
    ...... health problem worldwide.

    Effectively, = inadequate amount of normally mineralised bone.

    Bone is structurally normal and contains a normal amount of mineral, but is reduced in amount.

    • Age-related osteopenia --> fractures at sites such as vertebral bodies (crush fractures),
    • Colles’ fractures
    • femoral neck fractures.

    • The development of osteoporosis is related to:
    • peak bone mass achieved in the skeleton,
    • rate of bone loss (imbalance between resorption and formation),
    • number of other factors related to changes in calcium metabolism, hormonal status (especially estrogens), changes in physical activity level, and possibly age related changes.

    Peak skel mass & density usu achieved earlier in life, and a number of factors (nutrition, life style and genetic factors) determine peak skeletal mass and density.
  12. Primary (involutional) osteoporosis has 2 types...
    • Type 1, (post-menopausal) related to the loss of protective effects of estrogen on the skeleton.
    • Bone loss is predominantly from cancellous bone, is assoc w ic bone turnover after menopause and typically results in spinal and forearm fractures.

    • Type 2, (age-related osteoporosis)
    • usu occurs at ages greater than 70 years,
    • with females more commonly affected than males. Proportionate loss from both cortical and cancellous bone occurs, and the typical clinical manifestation is hip fracture.

    Aside from the effects of menopause and aging, several disorders can lead to ‘secondary’ osteoporosis:

    • endocrinological diseases (Cushing’s, thyrotoxicosis, hypogonadism, hyperparathyroidism etc.)
    • drugs (corticosteroids, heparin, anticonvulsants), malabsorption
    • rheumatological (Rheumatoid arthritis, anklyosing spondylitis).
  13. Osteoporosis and fractures...
    .... will not in itself cause symptoms unless fracture occurs, though height loss and back pain may result from verterbral changes.

    • Common fracture sites =  
    • hip,
    • verterbral bodies (mid-lower thoracic, upper lumbar), forearm,
    • proximal humerus,
    • ribs and pelvis.

    • Preventative strategies:
    • maxmise peak bone mass during growth,
    • avoid/ modfy risk factors
    • prevention of post menopausal bone loss.
  14. Osteoporosis tests...
    • Lab studies usu wthn normal limits
    • - normal serum calcium, phosphate & alkaline phosphatase.

    Radiologically evidence of decreased bone density, loss of horizontal trabeculae, cortical thinning and possibly fractures. Estimation of bone density based on plain X-rays is inaccurate and densitometry techniques are preferred.

    Osteopenia = radiolol appearance of decreased bone density. For osteopenia to be detectable on plain X-ray the density of bone must be usually reduced by about 30%.

    • Histologically, the bone is essentially unremarkable but is decreased in quantity. Decreased quantity of bone, thin trabeculae and loss of trabecular interconnections may be observed in cancellous bone, cortical bone demonstrates enlargement of haversian canals and close spacing of cement lines.
    • Cellularity, osteoid seam width and marrow space are normal.
    • Morphometric analysis may be necessary to identify subtle / early cases.
  15. OSTEOMALACIA/RICKETS 
    • defective mineralisation of the organic matrix of bone.
    • In both rickets and osteomalacia the lack of mineralisation affects both the quality and quantity of bone formed.

    Osteomalacic bone ... sig reduced  'stiffness' --> may deform by compression --> deformities of weight-bearing bones and pathological fractures may result.

    In rickets the growing skeleton is involved, and because the defective mineralization involves both bone and the cartilage matrix of the growth plates, normal bone growth and development becomes deranged, and a variety of distinctive skeletal abnormalities may develop.

    In osteomalacia in adults, the defective/inadequate matrix mineralisation results in osteopenia (reduced overall skeletal mass) and a predisposition to insufficiency fractures.
  16. The process of normal skeletal mineralization activity.... 
     rests upon the presence of sufficient calcium and phosphate at the mineralization sites, together with normal cellular function and absence of inhibitory / deleterious metabolic factors.

    Rickets / osteomalacia results when osteoblast activity produces matrix that cannot be adequately mineralized.

    When this occurs, the production of organic matrix / osteoid also gradually decreases, but as a result of the mineralization abnormality, --> overall increase in fraction of bone forming surface covered by incompletely mineralized osteoid.
  17. Causes of defects in matrix mineralisation:
    • Various dietary deficiencies – (of Vit D, Ca, phosphate),
    • GI disorders (gastric or hepatobiliary disease, malabsorption syndromes etc)
    • Vit D resistance – (phosphate wasting, enzymatic deficiency, end organ insensitivity and renal tubule acidosis)
    • drug associated (phenytoin, aluminium, heavy metals etc.), tumour associated
    • chronic renal disease.

    • In Rickets and osteomalacia, the underlying cause is most often related to either a lack of vit D, or some disturbance in vit D metab.
    • The principal fntn of vit D = maintain normal serum [calcium] and [phosphorus].

    Adequate vit D levels and function are therefore important to prevent bone disease (rickets in children, osteomalacia in adults), and also to prevent hypocalcaemia (which may be complicated by hypocalcaemic tetany).
  18. Ricket chars...
    • Growth is disturbed,
    • cartilage formation continues in the epiphyses,
    • but because of the lack of mineralisation, epiphyseal growth and new bone formation is delayed and retarded.

    Epiphyseal plates --> thickened and may be distorted, and deformities can result.

    • Reduction in the length of  long bones.
    • Bones susceptible to fracture.

    • Clinically, Rickets may present w:
    • weakness and hypotonia,
    • skeletal deformities
    • fractures
    • disturbances in growth.
  19. Osteomalacia chars...
    Presentation of osteomalacia in adults often dominated by the clin features of the underlying disorder.

    • Symptoms, when they occur include:
    • skeletal pain
    • bone tenderness
    • proximal muscular weakness.

    Radiological features may be difficult to distinguish from osteoporosis, as the dc in bone density is assoc w loss of trabecular bone and cortical thinning.

    Classically, multiple bilateral and symmetric lucencies involve the cortex. These areas represent stress or pseudofractures where repair occurs with poorly mineralised osteomalacic bone, and are a finding that suggests on osteomalacia.

    • Lab studies - vary according to the underlying cause of the disease process, but tend to show:
    • low to normal serum calcium,
    • low phosphate,
    • high alkaline phosphatase

    Histol- osteomalacic bone has ic amounts of osteoid (unmineralised matrix) on surfaces of bone trabeculae.
  20. HYPERPARATHYROIDISM 
    • 2 major forms
    • 1°, 2° and much less commonly, a 3° form.
  21. 1° hyperparathyroidism = 
    = Excessive and uncontrolled production of parathyroid hormone from neoplastic or hyperplastic parathyroid tissue.

    • Usu (+95%) caused by sporadic parathyroid adenoma / sporadic parathyroid hormone hyperplasia. 
    • Various genetic syndromes assoc with familial 1° hyperparathyroidism, (including MEN-1 and MEN-2) account for only a small proportion of cases.

    Excessive PTAH -->  osteoclastic resorption -->  marked hypercalcemia.

    • Patients may be:
    • asymptomatic
    • present with signs and symptoms related to hypercalcemia or in a small proportion of cases, present with bone related changes.

    In asymptomatic presentations, condition is detected as hypercalcaemia on blood testing for unrelated conditions.

    (It should be remembered that there are a number of other causes of hypercalcaemia, including hypercalcaemia associated with malignancy, vitamin D toxicity, immobilisation, some diuretics, and sarcoidosis).

    Symptomatic primary hyperparathyroidism reflects both hypercalcaemia and inappropriate and excessive parathyroid hormone secretion.

    In addition to osseus disease, described below, there are renal (renal calculi, chronic renal insufficiency), gastro-intestinal (constipation, nausea, peptic ulcers, pancreatitis and gallstones), CNS (depression, lethargy, seizures), neuromuscular (weakness and fatigue) and cardiac (valve calcifications) complications.
  22. Secondary hyperparathyroidism,
    Most commonly assocd w chronic renal disease (though occasionally with other disease processes), results from chronic parathyroid stimulation by low serum calcium.

    • Clinical features usu dominated by those of chronic renal failure.
    • In general, the osseous pathology is less severe than that seen in primary hyperparathyroidism.
    • Metastatic calcification occurs in the secondary form, and the vascular calcification may result in significant ischaemic damage, a process referred to as calciphylaxis.
  23. Tertiary hyperparathyroidism
     =  autonomous and continuing PTH secretion in the absence of low serum calcium.
  24. Features of hyperparathyroidism
    Radiological and histolol features of hyperparathyroidism are similar in both primary and secondary forms of the disease, though the microscopic features of the bone pathology in the secondary form may be modified by the underlying disease process.

    The earliest osseous change in hyperparathyroidism consists of a fibrovascular proliferation in the marrow space, which is gradually accompanied by increased numbers of osteoclasts.

    The osseous trabeculae, which are normally smooth surfaced, become ragged and scalloped, and lined by the increased osteoclast population.

    Tunneling resorption is chard by fibrosis and osteoclastic activity from the inside of the trabeculae. Haversian systems of the cortex are expanded and demonstrate irregular scalloping of their walls with a characteristic pattern of "dissecting resorption".

    New bone formation as a result of osteoblastic activity does not keep pace with the rapid rate of bone destruction, and the net effect is a loss of bone mass. The "brown tumour" of hyperparathyroidism represents a large localised area of bone resorption, which, although uncommon, may mimic other bone neoplasms.

    Radiological examination may reveal diffuse osteopenia and/or circumscribed areas of lucency (particularly in the phalanges) and spine deformities may occur secondary to weakening or fracture.
  25. RENAL OSTEODYSTROPHY
    = Range of skel abnormalities seen in assoc w long standing renal disease and haemodialysis.

    • Clinical and radiol manifestations of renal osteodystrophy: osteopenia,
    • osteomalacia,
    • secondary hyperparathyroidism
    • osteosclerosis.

    Chronic renal failure is assocd w phosphate retention, hypocalcaemia and sometimes a metabolic acidosis.

    The hypocalcaemia may trigger secondary hyperparathyroidism, the acidosis promotes osteoporosis / osteopenia, and there is a relative or absolute decrease in   [active Vit D].

    • Various manifestations ie
    • osteitis fibrosa cystica,
    • osteomalacia,
    • osteosclerosis
    • and osteopenia can occur in varying combination.
  26. PAGET’S DISEASE OF BONE 
    = idiopathic disorder which may involve one bone (monostotic) or multiple bones (polyostotic).

    Derangement of bone remodelling and turnover, described as occurring in three phases:

    • i) accelrtn of resorption (osteolytic phase).
    • ii) followed by efforts at replacement of resorbed bone by appositional new bone formation, whilst bone reosrption continues (mixed osteolytic / osteblastic phase)
    • iii) ultimately is followed by continuing bone formation with diminished resorption (osteoblastic / sclerotic phase).

    Pagetic bone = structurally disorganised, and is more susceptible to deformity and fracture.

    Usu involves pelvis and skull but virtually any bone may potentially be affected.

    Aetiology unknown... possib genetic/viral.

    Clinical manifestations vary greatly... depend upon the extent of the disease, the particular bone or bones involved and the presence or absence of assocd complictns.

    • May notice:
    • swelling/deformity of long bone
    • enlargement of the size (eg by increasing in hat size)
    • pain (which may relate to the disease itself, or to distortion and degenerative changes in joints etc).

    Asymptomatic patients-  often ID'd by elevated alkaline phosphatase level identified on serum biochemistry, or  incidental abnormality identified on x-ray.

    Pain = most common presenting symptom, and may reflect increased blood flow within bone, expanding and lytic bone lesions, fractures or deformities.

    • Dx usu based on radiol & biochemistry.
    • Bone scans are more sensitive that plain x-ray for disease detection.
    • Classic radiological manifestations include bone deformity, thickening of cortical bone and coarsely of the bone trabeculae.
  27. Pagets Disease Histol...
    Histologically, extensive bone resorption and osteoclastic activity are followed by efforts at new bone formation (osteoblasts).

    Disordered and thickened bone = mosaic patterns of cement lines, reflecting chaotic and disorganised remodelling.

    • Bones commonly affected:
    • spine
    • skull
    • pelvis
    • long tubular bones.

    The disease may be asymptomatic, be detected biochemically (raised alkaline phosphatase as a result of osteoblastic activity) or radiologically as an incidental finding or present with pain, increasing bone size, deformity or fracture.

    Normal bone architecture is lost, the bone becomes soft, thickened, porous and disorganised and is susceptible to stress related deformation and fracture.

    Other complications include pathological fracture, high output cardiac failure and sarcomatous degeneration.

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