METABOLIC BONE DISEASES

METABOLIC BONE DISEASES

Mona A Fouda Neel Mona A Fouda Neel MBBS,MRCP(UK),FRCPEMBBS,MRCP(UK),FRCPE

Associate professor of medicineAssociate professor of medicine

Cosultant EndocrinologistCosultant Endocrinologist

1.1. Provide rigid support to extrimities and Provide rigid support to extrimities and body cavities containing vital organs.body cavities containing vital organs.

2.2. Provide efficient levers and sites of Provide efficient levers and sites of attachment of muscles which are all crucial attachment of muscles which are all crucial to locomotion.to locomotion.

3.3. Provide a large reservoir of ions such as Provide a large reservoir of ions such as calcium, phosphorus, magnesium and calcium, phosphorus, magnesium and sodium which are critical for life and can be sodium which are critical for life and can be mobilized when the external environment mobilized when the external environment fails to provide themfails to provide them

Bone has three major functionsBone has three major functions::

Types of BoneTypes of Bone

The compact bone of Haversian systems The compact bone of Haversian systems such as in the shaft of long bones.such as in the shaft of long bones.

I. Cortical Bone:I. Cortical Bone:

II. Trabecular Bone:II. Trabecular Bone:

The lattice – like network of bone found in The lattice – like network of bone found in the vertebrae and the ends of long bones.the vertebrae and the ends of long bones.

The difference pattern of bone loss The difference pattern of bone loss affecting trabecular and cortical bone affecting trabecular and cortical bone results in two different fracture syndrome.results in two different fracture syndrome.

Disorders in which cortical bone is Disorders in which cortical bone is defective or scanty lead to fractures of long defective or scanty lead to fractures of long bones whereas disorders in which bones whereas disorders in which trabecular bone is defective or scanty lead trabecular bone is defective or scanty lead to vertebral fractures and also may help in to vertebral fractures and also may help in fractures of lone bones because of the loss fractures of lone bones because of the loss of reinforcement.of reinforcement.

Bone is resorbed and formed continuously Bone is resorbed and formed continuously throughout life and these important throughout life and these important processes are dependent upon three major processes are dependent upon three major types of bone cells.types of bone cells.

The bone forming cells which are actively The bone forming cells which are actively involved in the synthesis of the matrix component involved in the synthesis of the matrix component of bone (primarily collagen) and probably facilitate of bone (primarily collagen) and probably facilitate the movement of minerals ions between the movement of minerals ions between extracellular fluids and bone surfaces.extracellular fluids and bone surfaces.

I. Osteoblasts:I. Osteoblasts:

II. Osteocytes:II. Osteocytes:

The are believed to act as a cellular syncytium The are believed to act as a cellular syncytium that permits translocation of mineral in and out of that permits translocation of mineral in and out of regions of bone removed from surfaces.regions of bone removed from surfaces.

III. Osteoclasts:III. Osteoclasts:The bone resorption cells.The bone resorption cells.

OsteomalaciaOsteomalacia

Failure of organic matrix (osteoid) of bone Failure of organic matrix (osteoid) of bone to mineralize normally.to mineralize normally.A number of factors are critical for normal A number of factors are critical for normal bone mineralization. An absence or a bone mineralization. An absence or a defect in any one of them may lead to defect in any one of them may lead to osteomalaciaosteomalacia, the most common , the most common biochemical causes are a decrease in the biochemical causes are a decrease in the product of concentrations of calcium and product of concentrations of calcium and phosphate in the extra-cellular fluid so that phosphate in the extra-cellular fluid so that the supply of minerals to bone forming the supply of minerals to bone forming surfaces is inadequate.surfaces is inadequate.

OsteomalaciaOsteomalacia

Other causes include abnormal or defective Other causes include abnormal or defective collagen production and a decrease in the collagen production and a decrease in the PH at sites of mineralization.PH at sites of mineralization.

Etiology of OsteomalaciaEtiology of Osteomalacia

1.1. Inadequate sunlight exposure without dietary Inadequate sunlight exposure without dietary supplementation.supplementation.

House- or institution bound people.House- or institution bound people. Atmosphere smog.Atmosphere smog. Long term residence in far northern & far southern Long term residence in far northern & far southern

latitudes.latitudes. Excessive covering of body with clothing.Excessive covering of body with clothing.

2.2. Gastrointestinal diseases that interrupts the Gastrointestinal diseases that interrupts the normal enterohepatic recycling of vit. D & its normal enterohepatic recycling of vit. D & its metabolites, resulting in their fecal loss.metabolites, resulting in their fecal loss.

Chronic steatorrhea (pancreatic)Chronic steatorrhea (pancreatic) Malabsorption (gluten-sensitive enteropathy)Malabsorption (gluten-sensitive enteropathy) Surgical resection of large parts of intestine.Surgical resection of large parts of intestine. Formation of biliary fistulas.Formation of biliary fistulas.

Vitamin D deficiencyVitamin D deficiency::


3.3. Impaired synthesis of 1,25(OH)2D3 by the kidney.Impaired synthesis of 1,25(OH)2D3 by the kidney. Nephron loss, as occurs in chronic kidney diseaseNephron loss, as occurs in chronic kidney disease Functional impairment of 1,25(OH)2D3 hydroxylase Functional impairment of 1,25(OH)2D3 hydroxylase

(eg. In hypoparathyroidism)(eg. In hypoparathyroidism) Congenital absence of 1,25(OH)2D3 hydroxylase (vit. Congenital absence of 1,25(OH)2D3 hydroxylase (vit.

D-dependency rickets type I).D-dependency rickets type I). Suppression of 1,25(OH)2D3 production by Suppression of 1,25(OH)2D3 production by

endogenously produced substance (cancer).endogenously produced substance (cancer).

4.4. Target cell resistance to 1,25(OH)2D3 e.g. Target cell resistance to 1,25(OH)2D3 e.g. absent, or diminished number of 1,25(OH)2D3 absent, or diminished number of 1,25(OH)2D3 receptors, as in vit.D-dependency rickets type II.receptors, as in vit.D-dependency rickets type II.

Vitamin D deficiencyVitamin D deficiency::


DietaryDietary Low intake of phosphate.Low intake of phosphate. Excessive ingestion of aluminum hydroxide.Excessive ingestion of aluminum hydroxide.

Impaired renal tubular reabsorption of Impaired renal tubular reabsorption of phosphatephosphate

X-linked hypophosphataemia.X-linked hypophosphataemia. Adult-onset hypophosphataemia.Adult-onset hypophosphataemia. Other acquired & hereditary renal tubular Other acquired & hereditary renal tubular

disorders associated with renal phosphate loss disorders associated with renal phosphate loss (Fanconi’s sydnrome, Wilson’s disease).(Fanconi’s sydnrome, Wilson’s disease).

Tumor-associated hypophosphataemiaTumor-associated hypophosphataemia

Phosphate deficiencyPhosphate deficiency::


• Chronic renal failureChronic renal failure

• Distal renal tubular acidosisDistal renal tubular acidosis

• UreterosigmoidoscopyUreterosigmoidoscopy

• Chronic acetazolamide & ammonium Chronic acetazolamide & ammonium chloride administrationchloride administration

Systemic Acidosis:Systemic Acidosis:

Drug induced Osteomalacia:Drug induced Osteomalacia:

Laboratory & Radiological FindingsLaboratory & Radiological Findings

Patients with osteomalacia go through Patients with osteomalacia go through three phases of development characterized three phases of development characterized by unique changes in the serum by unique changes in the serum concentration of calcium, phosphate, PTH concentration of calcium, phosphate, PTH and vit D3 levels and the radiographically and vit D3 levels and the radiographically assessed bone lesions.assessed bone lesions.


The underlying defect leading to these The underlying defect leading to these changes is changes is the decrease in the production the decrease in the production of 1,25(OH)2D3 which is due to diminished of 1,25(OH)2D3 which is due to diminished availability of the major circulating availability of the major circulating metabolites of vit D 25OHD3.metabolites of vit D 25OHD3. The decreased 1,25(OH)2D3 results in The decreased 1,25(OH)2D3 results in decreased intestinal calcium absorbtion, decreased intestinal calcium absorbtion, decreased bone resorption, hypocalcaemia, decreased bone resorption, hypocalcaemia, increased PTH secretion and increased PTH secretion and hypophosphataemia .hypophosphataemia .


The resulting decreased CaxPho. Product The resulting decreased CaxPho. Product in serum is insufficient for the normal in serum is insufficient for the normal mineralization of bone and the mineralization of bone and the osteomalacic process is initiated. osteomalacic process is initiated.

The increased PTH secretion and The increased PTH secretion and hypophosphataemia occur at the expense hypophosphataemia occur at the expense of osseous demineralization caused by of osseous demineralization caused by hyperparathyroidism.hyperparathyroidism.

Clinical FeaturesClinical Features

The clinical manifestations of osteomalacia in The clinical manifestations of osteomalacia in adults usually go unrecognized because of the adults usually go unrecognized because of the non-specific skeletal pain and muscular non-specific skeletal pain and muscular weakness. Only when the disease is extensive, weakness. Only when the disease is extensive, deformities occur with fractures of ribs, vertebrae deformities occur with fractures of ribs, vertebrae and long bones.and long bones.Clinically patients with osteomalacia have a Clinically patients with osteomalacia have a characteristic waddling gait, that is due to the characteristic waddling gait, that is due to the proximal muscle weakness and to the pain and proximal muscle weakness and to the pain and discomfort during movements of the limbs. discomfort during movements of the limbs. Some patients have severe muscular hypotonia Some patients have severe muscular hypotonia and paradoxically brisk deep tendon reflexes.and paradoxically brisk deep tendon reflexes.

TreatmentTreatment

Patients with osteomalacia due to simple dietary Patients with osteomalacia due to simple dietary deficiency of vit D or lack of exposure to sunlight will deficiency of vit D or lack of exposure to sunlight will respond well to small daily doses of ergocalciferol and respond well to small daily doses of ergocalciferol and calcium.calcium.Administration of oral doses of ergocalciferol(D2) or Administration of oral doses of ergocalciferol(D2) or cholecalciferol (D3)(2000 IU daily) for several months will cholecalciferol (D3)(2000 IU daily) for several months will heal the bone disease and restores biochemical and heal the bone disease and restores biochemical and hormonal values to normal in most cases.hormonal values to normal in most cases.1,25(OH)2D3 (calcitriol) has also been successful in the 1,25(OH)2D3 (calcitriol) has also been successful in the treatment of simple osteomalacia.treatment of simple osteomalacia.Decrease in serum calcium have been described Decrease in serum calcium have been described secondary to rapid movement of calcium from the secondary to rapid movement of calcium from the extracellular fluids into bone as a result of vit D induced extracellular fluids into bone as a result of vit D induced mineralizationmineralization

TreatmentTreatment

Therefore it is important to administer calcium to Therefore it is important to administer calcium to prevent this phenomenon and to provide prevent this phenomenon and to provide adequate calcium for bone mineralization (1-2 gm adequate calcium for bone mineralization (1-2 gm of elemental calcium daily).of elemental calcium daily).Serum ALP and PTH decrease slowly over Serum ALP and PTH decrease slowly over several weeks but improvement in radiological several weeks but improvement in radiological appearences may take several months.appearences may take several months.Other forms of osteomalacia may need different Other forms of osteomalacia may need different preparations and doses of treatment e.g., preparations and doses of treatment e.g., osteomalacia secondary to malabsorption may osteomalacia secondary to malabsorption may require huge doses of vit D (200,000 IU orally) require huge doses of vit D (200,000 IU orally) because of the poor absorbtion of the drug or because of the poor absorbtion of the drug or even I.V./I.M. vit D (40,000-80,000 IU).even I.V./I.M. vit D (40,000-80,000 IU).

OsteoporosisOsteoporosis

““THE SILENT THE SILENT THIEF”THIEF”

DefinitionDefinition

Decrease in bone mass and strength Decrease in bone mass and strength associated with an increased tendency to associated with an increased tendency to fracturesfractures


It is usually an asymptomatic disease until It is usually an asymptomatic disease until fractures occur. The first manifestation of reduced fractures occur. The first manifestation of reduced bone mass is usually a wrist fracture or a bone mass is usually a wrist fracture or a vertebral crush fracture caused by a small vertebral crush fracture caused by a small amount of force which produces severe localized amount of force which produces severe localized pain.pain.Subsequent vertebral fractures may contribute to Subsequent vertebral fractures may contribute to chronic back pain.chronic back pain.In well established osteoporosis dorsal Kyphosis In well established osteoporosis dorsal Kyphosis and loss of height occurs.and loss of height occurs.Hip fractures with its fatal complications also Hip fractures with its fatal complications also occur commonly as osteoporosis become more occur commonly as osteoporosis become more severe. severe.

Type I: OsteoporosisType I: Osteoporosis(Post Menopausal)(Post Menopausal)

Fractures of bones composed mainly of Fractures of bones composed mainly of Trabecular bone.Trabecular bone.

e.g., Distal Radiuse.g., Distal Radius -- Colle’s fractureColle’s fracture

VertebraVertebra -- Crush & Crush & Wedge Wedge fracturesfractures

Usually affects woman within 15 years of Usually affects woman within 15 years of menopause.menopause.

Type II: OsteoporosisType II: Osteoporosis(Senile)(Senile)

Fractures of bones composed of both Fractures of bones composed of both cortical & Trabecular bone.cortical & Trabecular bone.

e.g., Hipe.g., Hip -- Femure neck fractureFemure neck fracture

Usually affects individual over age of 70 Usually affects individual over age of 70 years.years.


ALP and PTH are within normal in patients with ALP and PTH are within normal in patients with osteoporosis due to sex hormones deficiency and osteoporosis due to sex hormones deficiency and aging.aging.X-rays of skeleton do not show a decrease in X-rays of skeleton do not show a decrease in osseous density until at least 30% of bone mass osseous density until at least 30% of bone mass has been losthas been lost. X-ray of lumbothoracic vertebrae . X-ray of lumbothoracic vertebrae show prominent trabeculae and prominent end show prominent trabeculae and prominent end plates of the vertebral bodies.plates of the vertebral bodies.Cod fish appearance indicates protrusion of the Cod fish appearance indicates protrusion of the disk into the body of the vertebrae secondary to disk into the body of the vertebrae secondary to mechanical failure.mechanical failure.X-ray of the upper part of the femur may also be X-ray of the upper part of the femur may also be helpful in assessing reduced bone mass and helpful in assessing reduced bone mass and calculating the risk for hip fracture.calculating the risk for hip fracture.

Assessment of bone mass Assessment of bone mass available methodsavailable methods

• Single-Photon absorptiometrySingle-Photon absorptiometry SPASPA• Dual-Photon absorptiometryDual-Photon absorptiometry DPADPA• Computed TomographyComputed Tomography CTCT• Dual-Energy X-ray AbsorptiometryDual-Energy X-ray Absorptiometry DEXADEXA

They measure bone mass by the ability of the They measure bone mass by the ability of the tissue to absorb the photons emitted from the tissue to absorb the photons emitted from the radionuclide source or the X-ray tube.radionuclide source or the X-ray tube.

Age related bone loss particularly trabecular bone Age related bone loss particularly trabecular bone in the spine begins in women before menopause.in the spine begins in women before menopause.

Assessment of bone mass Assessment of bone mass available methodsavailable methods

It is appropriate to begin to look for risk factors It is appropriate to begin to look for risk factors that predispose a person to osteoporosis and that predispose a person to osteoporosis and develop a rational prevention program tailored to develop a rational prevention program tailored to person’s risk before the menopause.person’s risk before the menopause.e.ge.g., Women with thin light frame, history of low ., Women with thin light frame, history of low calcium intake, decreased physical activity, high calcium intake, decreased physical activity, high alcohol or caffein cumsumption, smoking, family alcohol or caffein cumsumption, smoking, family history of osteoporosis, history of prior menstrual history of osteoporosis, history of prior menstrual disturbances or history of drug like antiepileptics disturbances or history of drug like antiepileptics or steroidsor steroids are all high risk groups and in the are all high risk groups and in the presence of one or more of such risk factors presence of one or more of such risk factors measurement of BMD provides further information measurement of BMD provides further information to the risk of fractures. to the risk of fractures.

Strategy for Management of Strategy for Management of OsteoporosisOsteoporosis

• Prevent OsteoporosisPrevent Osteoporosis

• Detect and treat early to decrease further Detect and treat early to decrease further progressionprogression

• Limit disability and provide rehabilitationLimit disability and provide rehabilitation

TreatmentTreatment

““Senile Osteoporosis is a pediatric Senile Osteoporosis is a pediatric disease”.disease”.

• A calcium intake of 1200 mgm/day is recommended.A calcium intake of 1200 mgm/day is recommended.• Adequate sun exposure or vit D supplementation to Adequate sun exposure or vit D supplementation to

ensure adequate level.ensure adequate level.• A reasonable exercise program is recommended.A reasonable exercise program is recommended.• ? Genetic influence on peak bone mass attainment. ? Genetic influence on peak bone mass attainment.

II. The Adolescent Female II. The Adolescent Female (Peak bone mass attainment)(Peak bone mass attainment)

TreatmentTreatment

A.A. Adequate calcium intake; 1000-1500 mgm/day disease.Adequate calcium intake; 1000-1500 mgm/day disease.

B.B. Adequate sun exposure or vit D supplementationAdequate sun exposure or vit D supplementation

C.C. A reasonable exercise program is recommended, but not to the point of A reasonable exercise program is recommended, but not to the point of amenorrhea.amenorrhea.

D.D. Avoidance of osteopenia-producing conditions/medications/lifestyles:Avoidance of osteopenia-producing conditions/medications/lifestyles:

1.1. Smoking & excessive alcohol intake, excessive caffeine/protein intake.Smoking & excessive alcohol intake, excessive caffeine/protein intake.

2.2. Amenorrhea/oligomenorrhea.Amenorrhea/oligomenorrhea.

3.3. Cortisone, excessive thyroid hormone replacement (?), loop diuretics, Cortisone, excessive thyroid hormone replacement (?), loop diuretics, prolonged heparin exposure.prolonged heparin exposure.

III. The Premenopausal Female III. The Premenopausal Female (Maintenance of bone mass)(Maintenance of bone mass)

TreatmentTreatment

Consideration of estrogen replacement Consideration of estrogen replacement therapy (conjugated equine estrogen therapy (conjugated equine estrogen (CEE) or its equivalent, 0.625 mgm daily (CEE) or its equivalent, 0.625 mgm daily or cycled, or transdermal estrogen by or cycled, or transdermal estrogen by patch 0.05-0.1 mgm/day daily or cycled).patch 0.05-0.1 mgm/day daily or cycled).

If intact uterus, consideration of If intact uterus, consideration of medroxyprogesterone 5-10 mgm daily or medroxyprogesterone 5-10 mgm daily or cycledcycled

IV. The Immediately Postmenopausal IV. The Immediately Postmenopausal Female (Prevention of bone mass loss)Female (Prevention of bone mass loss)

TreatmentTreatment

Other modalities of therapyOther modalities of therapy1.1. Nasal spray calcitoninNasal spray calcitonin

2.2. BisphosphonatesBisphosphonates

3.3. SERMS (Selective estrogen receptor SERMS (Selective estrogen receptor modulators) e.g., Evista, Livialmodulators) e.g., Evista, Livial

4.4. ProtelosProtelos

5.5. PTHPTH

IV. The Immediately Postmenopausal IV. The Immediately Postmenopausal Female (Prevention of bone mass loss)Female (Prevention of bone mass loss)

Paget’s DiseasePaget’s Disease

Paget’s disease of the bone is disorder of bone Paget’s disease of the bone is disorder of bone remodelling characterized by histological and remodelling characterized by histological and gross osseous deformities due to local gross osseous deformities due to local uncontrolled bone resorption which is caused by uncontrolled bone resorption which is caused by excessive numbers of osteoclasts and excessive numbers of osteoclasts and osteoblasts and ultimately leads to formation of osteoblasts and ultimately leads to formation of structurally fragile osseous tissuestructurally fragile osseous tissue..Any bone in the body can be involved but the Any bone in the body can be involved but the most frequent sites are the femur, tibia, skull, most frequent sites are the femur, tibia, skull, lumbosacral spine and pelvis.lumbosacral spine and pelvis.The disease is common in Germany and England, The disease is common in Germany and England, less common in North America and is rare in less common in North America and is rare in Scandinavia, Africa and in the near and far east.Scandinavia, Africa and in the near and far east.


Relatively few patients with radiologically proven Relatively few patients with radiologically proven Paget’s disease have significant symptoms. It is a Paget’s disease have significant symptoms. It is a disease of middle age and the diagnosis is often disease of middle age and the diagnosis is often made as an incidental findings on x-rays taken for made as an incidental findings on x-rays taken for other reasons.other reasons.The chief symptom is bone pain over lesions as The chief symptom is bone pain over lesions as well as joint pains which are difficult to distinguish well as joint pains which are difficult to distinguish from arthritis.from arthritis.Deafness can occur and is related to bony Deafness can occur and is related to bony abnormalities of the internal and external auditory abnormalities of the internal and external auditory apparatus.apparatus.Vertebral fractures occur frequently and fractures Vertebral fractures occur frequently and fractures of the long bones may occur & usually heal of the long bones may occur & usually heal rapidly.rapidly.


Serum calcium, phosphate, magnesium & Serum calcium, phosphate, magnesium & PTH are usually normal. Abnormalities PTH are usually normal. Abnormalities could be due to a superimposed condition could be due to a superimposed condition e.g., immobilization or a coexisting primary e.g., immobilization or a coexisting primary hyperparathyroidismhyperparathyroidism. Serum ALP is . Serum ALP is markedly elevated and acid phosphatase markedly elevated and acid phosphatase may be increased.may be increased.


Thickness of long bones and vertebrae Thickness of long bones and vertebrae occur frequently and crush fractures cause occur frequently and crush fractures cause varying degree of Kyphosis.varying degree of Kyphosis.

Radionuclide bone scars using Tc99m or Radionuclide bone scars using Tc99m or others aid greatly in documenting the extent others aid greatly in documenting the extent of the disease and reveal lesions that may of the disease and reveal lesions that may not be apparent radiologically.not be apparent radiologically.

TreatmentTreatment

Only patients with symptoms should be treated. Only patients with symptoms should be treated. The available drugs are calcitonin, The available drugs are calcitonin, diphosphonates and mithramycin. They all diphosphonates and mithramycin. They all suppresses the number and activity of the suppresses the number and activity of the abnormal bone cells by acting through different abnormal bone cells by acting through different mechanisms.mechanisms.Calcitonin decreases bone resorption by Calcitonin decreases bone resorption by decreasing the number of active osteoclasts.decreasing the number of active osteoclasts.The diphosphonates inhibit both bone resorbtion The diphosphonates inhibit both bone resorbtion and formation.and formation.Mithramycin is a cytotoxic drug that inhibits bone Mithramycin is a cytotoxic drug that inhibits bone resorbtion and should only be used under the resorbtion and should only be used under the most desperate conditions e.g., spinal cord most desperate conditions e.g., spinal cord compression.compression.

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METABOLIC BONE DISEASES