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Metabolic Bone Diseases

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Title: Metabolic Bone Diseases


1
Metabolic Bone Diseases
By Dr Walaa F. El Bazz Professor Of Internal
Medicine Al Azhar University
2
Metabolic Bone Disease
  • Definition
  • Is an umbrella term referring to abnormalities of
    bones caused by a broad spectrum of disorders
  • Abnormalities of minerals such as ca, Ph, Mg, or
    Vit D.
  • These disorders are commonly reversible once the
    underlying defect has been treated.
  • It should be differentiated from larger group of
    genetic disorders, where there is a defect in the
    specific signalling ystem or cell type..

3
Conditions considered to be metabolic bone
disorders
  • Osteoporosis.
  • Rickets or osteomalacia.
  • Vit D deficiency
  • Hypophosphatemia.
  • Hyperparathyroidism
  • Primary Hyperparathyroidism.
  • Secondary Hyperparathyroidism
  • Renal osteodystrophy
  • Corticosteroid overuse
  • Pagets disease of bone

4
Pagets disease
  • It is a localized progressive disorder
    characterized by increase bone remodeling, bone
    hypertrophy with abnormal structure (osteitis
    deformans).
  • Common in Europe ? 3 of general population gt 50
    years old (2nd disease gt osteoporosis)
  • Prevalance decrease in last 30 years. Rare in
    arabs, Black and Asian.
  • Diagnosis gt 40 years, males gt females.
  • Genetic factors ( FH), abnormal gene on
    chromosome 18q.

5
Pathophysiology
  • Bone turnover increase at certain sites of
    skeleton.
  • Increase in local remodeling modeling.
  • The cause ?? A slow paramyxovirus infection
    (inclusion in osteoclast ? nucleocaspids,
    positive reaction with antisera against measles
    virus).
  • Initially, marked increase of bone resorption due
    to increase IL-6 production by marrow and bone
    cells ? osteolytic lesions.
  • Compensatory increase in bone formation ?
    abnormal positive bone balance with sclerotic
    lesions local deformaties.

6
C/O
  • Asymptomatic, discovered accidentally.
  • Increased Alk. Phos.
  • X ray with lytic, sclerotic foci.
  • Scintigraphy Ex ? hot spots
  • Pelvis, vertebrae, scapula, long bones
  • Bone deformity.
  • 5 ? symptomatic.
  • Pain may be intense, back, hip, long bone
    (fissure fracture) or 2ry to joint disease.
  • Bone deformity
  • Bending of long bones, spine.
  • Enlargement of bones, skull
  • Neurovascular syndromes vertebro-basilar artery
    syndrome, spinal cord dysfunction, deafness.
  • Increased vascularization of affected bone ?
    cardiac failure.
  • 1 or less ? osteosarcoma.

7
Laboratory features
  • Increase Alk. Phos. (total bone specific)
  • S. osteocalcin ? poorly correlates to disease.
  • Increase fasting urinary hydroxyproline, urinary
    pyridinium cross links. (C- and N terminal
    teopeptides)
  • X ray ?
  • osteous deformities.
  • Increase size of certain bone.
  • Local areas of increase bone density / lytic
    lesions.
  • Sclerotic vertebrae DD skeletal metastasis.
  • Tc 99 ? hot spots.

8
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9
Histology of Pagets disease
  • Features of extremely rapid turnover
  • Mosiac structure of areas of resoption with many
    osteoclasts and formation sites, osteoblasts ?
    increase amount of bone matrix.

10

11
Follow-up of disease treatment
  • Assess symptoms.
  • X rays.
  • S Alk Phos., Pyridinium cross links.
  • Best is least expensive.

12
Treatment
  • For all asymptomatic symptomatic patients with
    affection of bone liable for complications.
  • Calcitonin
  • Effective decrease bone turnover.
  • Improve clinical manifestations.
  • Less effective than bisphosphonates.
  • Resistance can develop.
  • Bone turnover relapse earlier after
    discontinuation

13
  • Bisphosphonates
  • Drug of choice.
  • Decrease bone turnover.
  • Concentrated in affected areas ? log lasting
    effect.
  • All alendronate, Clodronate, etidronate,
    Pamidronate, Risedronate, Zoledronate.
  • Their effects are qualitatively similar, differ
    in potency side effects.
  • Decrease both bone resorption bone formation,
    that is later on, 2ry to physiologic coupling
    between two processes.
  • Decrease S ionized ca, P, increase PTH, 1, 25
    (OH)2 D may occur in patients with very active
    osteolysis

14
  • So Ca 0.5 1 g, vit D 400 800 U/day may be
    used.
  • Only Etidronate increase renal tubular absorption
    of P when given at daily oral dose of 300 mg.
  • Decrease bone pain or disappear except arthritic
    pain may decrease or not respond.
  • Neurological spinal syndromes as well as
    scintigraphic scans ? improved.
  • Therapeutic effect on bone can last for long time
    (years) after stopping treatment.
  • Aim to normalize turnover as assessed e.g. Alk.
    Phos. (6 ms or more) stop treatment, resumed when
    symptoms recur or Alk. Phos. increases.
  • Patients with more severe disease needs higher
    doses.

15
Morphologicaly
  • Decrease bone turnover.
  • Decrease number of osteoclats.
  • Bone formed during treatment ? lamellar
    organization (not woven).

16
3.2 - 6
17
  • Alendronate (Fosamax) 40 mg / 6 ms PO.
  • Clodronate (Ostac) 1600 mg / 6 ms PO IV.
  • Pamidronate (Aredia) 30 mg / 3 day IV, infusion
    180 mg / 3 days.
  • Risedronate (Actonel) 30 mg / day ? 12 weeks PO,
    may be repeated.
  • Zolendronate (Aclasta).

18
Osteomalacia
  • Soft bone result from impaired mineralization
    in matrix bone.
  • Causes
  • Inadequate concentration of extrcellular fliud
    phosphate /or calcium or from circulatory
    inhibitor of mineralization.
  • Deficiency of vit. D dietary plus inadequate
    sunlight exposure.
  • Malabsorption gastric surgery, coeliac disease,
    defect bile salt production.
  • Renal disease decrease conversion of 25 (OH) D ?
    1, 25 (OH)2 D.
  • Hepatic disease less common ? decrease 1, 25
    (OH)2 D.
  • Due to phenytoin, barbiturate.

19
  • Vit. D resistance Rickets. (Familial
    hypophosphataemia) X linked disease, increase
    renal tubular P loss, hypophosphataemia, Rickets.
  • Congenital 1 alpha hydroxylase deficiency
    (genetic mutation) ? decrease renal activation ?
    decrease absorption of Ca P.
  • Congenital vit D receptor abnormality (gene
    mutation).

20
Clinical manifestation
  • Bone pain, deformities, fracture.
  • Muscle weakness, growth retardation.
  • Muscle pain tenderness (subclinical fracture).
  • Proximal myopathy ? waddling gait.
  • In children ? characteristic picture of rickets.

21
Biochemical changes
  • Low S. Ca /or phosphate.
  • Increase Alk. Phos.
  • Low Ca \ Po4 is useful as a screening test.
  • Decrease 1,25 OH Vit. D.
  • Low urinary Ca excretion.
  • X rays ? defect mineralization of bone especially
    long bone, pelvis, ribs with loosers zones,
    milkmans fracture.
  • Definite diagnosis bone biopsy ? increase
    osteoid, decrease mineralization.

22
Treatment
  • Simple nutritional deficiency vit D 5000 u/day
    with maintenance 400/day.
  • Malabsorption vit D 50,000 100,000 u/day.
  • Renal disease vit D 50,000 100,000 u/day,
    calcitrol 0.25 1 ug.
  • Hypophosphatemic rickets Calcitrol 0.25 1 ug
    oral P.
  • Vit D resistance vit D 100,000 200,000 u/day,
    Calcitrol 5 60 ug/day or IV Ca infusion.

23
Hypercalcaemia(hyperparathyroidism)
  • Hypercalcamia ? may be detected accidently.
  • Asymptomatic ? 0.1 hyperparthyrodism
  • Causes
  • Excess PTH 1ry, 2ry, terteriary.
  • Excess Vit D Iatrogenic, Sarcoidosis
  • Excess intake of Ca (Milk alkali syndrome).
  • Drugs thiazide
  • Malignancy ? secondaries, production of
    osteoclast factors, myeloma.
  • Other endocrine disease ? thyrotoxicosis,
    addisons disease.
  • Miscellaneous
  • Long term immobility.
  • Familial hypocalcuric hypercalcaemia.

24
1ry hyperparathyrodism
  • Parathyroid adenoma 80 single, 5 ? multiple
    adenoma.
  • Hyperplasia ? 10.
  • Parathyroid carcinoma 2 ? severe hypercalcaemia.
  • 2ry hyperparathyroid
  • Compensatory hypertrophy of parathyroid 2ry to
    hypocalcaemia e.g. renal failure, vit D
    deficiency.
  • PTH increase, S ca low or normal, decrease PTH
    after correction of the cause.

25
Tertiary hyperparathyroidism
  • Long standing 2ry hyperparathyroidism ?
    autonomous parathyroid hyperplasia.
  • Common in RF.
  • Increase S ca increase PTH ? later more increase.

26
Clinical picture
  • Mild hypercalcaemia S Ca lt 3 mmol/ml ?
    asymptomatic.
  • Severe hypercalcaemia ? symptomatic.
  • General malaise, fatigue, depression.
  • Renal pains colics ? stone formation ? polyuria,
    nocturia, hematuria, hypertension.
  • Hypercalcaemia ? decrease renal tubules
    concentrating ability ? form of nephrogenic DI.
  • Bone ? pains, fracture, bone cyst (5 10).
  • Abdominal pains, peptic ulcer, constipation.
  • Corneal calcification ? long standing cases.
  • CVS arrhythmia ECG changes.

27
Malignancy induced hypercalcaemia
  • Bone metastasis of 1ry malignancies e.g.
    bronchogenic carcinoma, breast, myeloma,
    oesophagus, thyroid, prostate, lymphoma, renal
    cell carcinoma.
  • Hypercalcaemia is due to increase bone osteolysis
    ? release of Ca ? circulation.
  • Increase tubular reabsorption of Ca in kidney due
    to production of PTH-related peptide ?
    PTH-receptor.
  • Local bone resorbing cytokines, PGs ? bone
    osteolysis.
  • Dehydration with malignant disease due to
    increase Na excretion, impaired water
    reabsorption by hypercalcaemia.

28
  • Severe hypercalcaemia gt 3 mmol/L is usually with
    malignant disease
  • Hyperparathyroidism.
  • Renal dialysis.
  • Vit D administration.
  • 1ry hypercalcaemia ? only 5 10 ? show definite
    bone disease, 20 40 ? renal involvement.

29
Investigation
  • S. Ca increase S. P decrease (1ry
    hyperparthyroidism urinary Ca).
  • PTH increase increase Ca ? hyperparathyroidism.
  • Abd, X ray, renal caluli nephrocalcinosis, renal
    function.
  • Hand x ray ? subperiosteal bone erosions in
    terminal phalanges.
  • Hydrocortison suppression test 10 40 tid ? -ve
    test in hyperparathyroidism some malignancies.

30
  • PTH if undetected or normal
  • Protein electrophoresis, T3, T4, TSH, skin biopsy
    for sarcoidosis, ACE level.
  • High resolution CT of neck
  • More sensitive ? MRI.
  • Radioisotope subtraction scan, Thalium 201,
    Technitium 99
  • Other investigation for underlying malignancy.
  • Bone isotope scan (secondaries).

31
Treatment
  • 1ry hyperparathyroidism ? surgery.
  • Renal disease.
  • Bone disease.
  • Young lt 50 years.
  • Severe hypercalcaemia.
  • Attack of acute hypercalcaemia.
  • Asymptomatic or mild symptoms ? observation.
  • Malignancy induced hypercalcaemia ? treatment of
    1ry turmour, surgery, chemotherapy,
    hormonotherapy.
  • Plicamycin inhibitor of RNA synthesis ? high
    toxicity, not used nowadays.
  • Bisphosphonates are drug of chocie.
  • They decrease often normalize plasma Ca, this
    effect depend on type of tumour.

32
  • They inhibit bone resorption ? decrease pain,
    prevent new osteolytic lesions ? decrease risk of
    fractures ? improve quality of life.
  • Alendronate, Clodronate, pamidronate, Residronate
    are drugs of choice in treatment of acute and
    chronic hypercalcaemia.
  • Pamidronate 30 90 mg IV infusion repeated with
    increase S Ca again may be used monthly.
  • Alendronate 10 mg / day.
  • Risendronate decrease bone resorption 30 mg / day
    ? 6 months.
  • Zolendronate IV infusion of 0.02 0.4 ng/kg ?
    decrease S Ca.

33
Acute hypercalcaemia
  • Emergency.
  • Severe nausea, vomiting, polyurea.
  • Drowsiness, confusion
  • S Ca 3 5 mmol/L.
  • Adequate rehydration 3 4 L /day, saline 2
    3days.
  • Prednisolone 30 60 mg/day effective
    (Sarcoidosis, Myloma, some malignancies, Vit D).
  • IV bisphosphonate e.g. Etidronate, Pamidronate 15
    60 mg IV infusion.
  • Calcitonin 200 unit / 6 h IV.
  • Oral phosphate Na cellulose phosphate 5 gm/day.

34
Thank You
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