Metabolic Bone Diseases

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Metabolic Bone Diseases
By Dr Walaa F. El Bazz Professor Of Internal
Medicine Al Azhar University
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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..

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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

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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.

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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.

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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.

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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.

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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.

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Follow-up of disease treatment

• Assess symptoms.
• X rays.
• S Alk Phos., Pyridinium cross links.
• Best is least expensive.

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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

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• 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

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• 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.

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Morphologicaly

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

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3.2 - 6
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• 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).

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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.

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• 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).

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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.

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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.

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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.

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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.

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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.

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Tertiary hyperparathyroidism

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

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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.

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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.

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• 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.

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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.

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• 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).

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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.

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• 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.

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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.

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Thank You