Metabolic bone disorders

Dr Kshitij Srivastava

Metabolic bone disorders

• Bone has an obvious mechanical function as well as

it serves an equally imp role as a mineral reservoir.

• Bone is in continuous state of flux i.e. its internal

shape and structure changing from moment to

moment in concert with normal variation in

mechanical function and mineral exchange.

Alterations in mineral ion conc.

Regulates hormones and local factors

Controls cellular Activity

Modulates bone structure and composition

The metabolic bone disorders are conditions in which generalized

skeletal abnormalities result from disruption of the complex

interactive system

Outline• Normal bone structure

• Normal calcium/phosphate metabolism

• Presentation and investigation of bone metabolism disorders

• Common disorders of bone metabolism in children

Normal Bone Structure

• What are the normal types of bone?• Woven The collagen fibres are arranged

haphazardly and the cells have no specific orientation. It acts as a temporary weld before being replaced by mature bone.

It is laid down in fibrous tissue unlike lamellar bone which forms only on existing bone surfaces. – Immature– Healing

Normal Bone Structure• Lamellar(mature bone)• Collagen fibres are arranged parallel to

each other to form multiple layers with osteocytes in between

• It is laid only on existing bone surface• It occurs in two structurally different forms

:– Cortical : made up of compact units –

haversion system( osteons) These compact units consist of haversion canals having blood vessels, lymphatics and nerves and surrounded by concentric lamellae of bone with the osteocytes lying in between.

• Cancellous bone – present in internal meshwork of all bones, ends of tubular bones, vertebral bodies.

• It has a honeycomb appearance, the structural units comprising of flattened sheets that can be thought of as unfolded osteons. These units are arranged according to the mechanical needs of the structure i.e. thickest and strongest along trajectories of compressive stress and thinnest in plane of tensile stress

• The spaces between the trabeculae are the opened out vascular spaces containing the marrow and fine sinusoidal vessels

• This comprises only 1/4th of the bone mass but 2/3rd of the bone surface area.

• It is covered with marrow and that’s why the effect of metabolic disorders are first seen here.

• What is the composition of bone?– 60% inorganic

• Calcium hydroxyapatite Interface between the bone and osteoid can be

labelled by administering tetracycline which is taken up avidly in newly mineralised bone and shows a fluorescent band on U-V light microscopy

– 40% organic( non mineralised matrix is known as osteoid )

• Type 1 collagen (tensile strength)• Proteoglycans (compressive strength)• Osteocalcin/Osteonectin( bone forming protein )• Growth factors/Cytokines/Osteoid

Mineralization CalcificationMineralization Calcification

The cellsOsteoblast : concerned with bone formation, derived from

mesenchymal precursors & from row of cells along free surface of trabeculae.

These are rich in alk phosphatase and responsible for prod of type I collagen

At the end of bone remodelling cycle they either remain on newly formed surface as lining cell or enveloped in matrix as resting osteocyte.

Osteocyte : spent osteoblast, communicate with each other with cytoplasmic process. They are sensitive to mechanical stimuli & communicate information about changes in stress and strain to active osteoblast.

under the influence of PTH they participate in bone resorption and Ca ion transport

Osteoclast : principle mediators of bone resorption. Derived from monocyte precursors in marrow ( osteblast and T

lymphocyte express RANK ligand that on chemotactic stimuli bind to RANKL receptors on monocyte and release M-CSF & convert monocyte to osteoclast. Osteoprotegrin is competitve inhibitor of this process )

By chemotactic stimuli they come and attach to specific regions on cell surface – ruffled border and release lysozyme.

with the resorption of organic matrix osteclast come and left in shallow excavations called Howship lacunae

Bone turnover• It goes on throughout life and its rate depends upon – demands of

growth endocrine activity mechanical stress biochemical exchange • How does normal bone grow……..

– In length – by endochondral ossification– In width - by subperiosteal opposition– Medullary cavity is expanded by endosteal bone resorption

• How does normal bone remodel? it proceeds by coordinated phases of osteoclastic resorption and

osteoblastic proliferation it serves a crucial purpose in the preservation of skeletal

structure each bone remodelling cycle takes around 4-6 months, annual rate of turnover is 4% for cortical and 25% for trabecular

bone

• During growth - turnover high, During growth - turnover high,

formation> resorption formation> resorption net bone gain net bone gain

• During adulthood - turnover moderate, During adulthood - turnover moderate, formation< resorption formation< resorption net bone loss net bone loss

Bone turnover• What happens to bone……• Puberty to 30 yrs : haversion canal and intertrabecular

spaces are filled in & cortices increase in overall thickness – bones become heavier and stronger.

bone mass is increased 3% every yr and attains peak bone mass in 3rd decade ( affected by genetic, hormonal, dietary, environmental factors) the greater the peak bone mass the less will be the effect of inevtible depletion of bone.

• >30yrs : slow inexorable loss of bone starts i.e. haversion space enlarge, trabeculae becomes thinner, endosteal surface resorbed, medullary space expands.

Bone loss occurs at the rate of 0.3% per yr in men & 0.5%per yr in women

• After menopause in women : phase of rapid bone loss 3% per yr for the next 10 yrs predominantly in

trabecular bone this is as a result of increased osteoclastic activity due

to loss of inhibition of gonadal hormones • 60 – 75 yrs : rate of bone loss decreases and becomes

steady at 0.5% ( this phase is due to decreased osteoblastic activity

0.4

0.6

0.8

1.0

1.2

1.4

0 10 20 30 40 50 60 70 80

BMD, g/cm2

Age

TOTAL BODY

Change in BMD (mean ± 1SD) with age in healthy male (--) and female (--)

• Bone strength is lost disproportionately to bone mass because of :

1. bone mass is not the only factor responsible

2. gaps appear in trabecular bone and not all defects are repaired

3. old age – slow remodelling rate

Calcium metabolism• What is the recommended daily intake?• 1000mg( for avg adult)• Total body calcium?• 1100gm( skeleton-99% & plasma-1%)• What is the plasma concentration?• 2.2-2.6mmol/L• How is calcium excreted?• Kidneys - 2.5-10mmol/24 hrs• How are calcium levels regulated?• PTH and vitamin D (+others)

• Fn of Ca : coagulopathy, nerve fn, contraction of muscle.

• Ca in bone occurs in two forms : readily exchangeable (500mmol/day) and slowly exchangeable (7.5mmol/day) which is more stable form and concerned with bone remodelling by constant resorption & deposition

• A large amount of Ca is filtered in kidneys & 98-99% is reabsorbed ( 60% in prox tubule and rest in ascending limb of loop of henle and regulated in turn by PTH)

• Ca absorbed from the GI tract is actively transported out of the intestine by system in brush border involving Ca dependent ATPase and regulated by 1,25-DHCC. Some absorption also occurs by passive diffusion.

• When Ca intake is high – 1,25-DHCC level falls and increase with deficient Ca intake.

Phosphate metabolism

• Normal plasma concentration?• 0.9-1.3 mmol/L (total Phosp – 500-

800gm) 85-90%in skeleton• Absorption and excretion?• Gut and kidneys• Regulation• Not as closely regulated as calcium but

PTH most important ( causes inhibition of active transport in proximal tubule which accounts for majority of the phosphorus reabsorption)

PTH• Physiological role• Production related to plasma calcium

levels• Control of calcium levels

– target organs• bone - increased Ca/PO4

3- release

• kidneys– increased reabsorption of Ca

– increased excretion of PO43-

• gut - indirect increase in calcium reabs by stimulting activation of vitamin D metabolism

Calcitonin

• Physiological role

• Levels increased when serum Ca >2.25mmol/L

• Target organs– Bone - suppresses resorption– Kidney - increases excretion

Vitamin D (cholecalciferol)

• Sources of vit D• Diet• u.v. light on precursors in skin• Normal daily requirement• 400 IU/day• Target organs

– bone - increased Ca release– gut - increased Ca absorption

Factors affecting bone turnover

• Other hormones• Oestrogen

– gut - increased absorption– bone - decreased resorption

• Glucocorticoids– gut - decrease absorption / increased

excretion– bone - increased resorption/decreased

formation• Thyroxine

– stimulates formation/resorption– net resorption

Factors affecting bone turnover

• Local factors• Insulin-Like Growth Factor I (somatomedin C)

– increased osteoblast proliferation,regulated by growth hormone

• TGF– increased osteoblast activity, accounts for

coupling and resorption• IL-1/Osteoclast Activating Factor

– increases osteoclast activity• PG’s

– increased bone turnover (in fractures & inflammn)

– Causes hypercalcaemia in metastatic bone disease

• BMP– bone formation

Factors affecting bone turnover

• Other factors• Local stresses• Electrical stimuln• Environmental

– Increased temp inc bone formation– Dietary phosphates & pyrophosphate

inhibits resorption – Fluoride stimulation of osteoblastic

activity– acid/base balance

Bone metabolic disorders• Presentation?• Skeletal abnormality

– osteopenia – rickets/osteomalacia/osteoporosis

– osteitis fibrosa cystica - replacement of bone with fibrous tissue usually due to PTH excess

• Hypercalcaemia(anorexia, abdominal pain, depression, metastatic calcification)

• Underlying hormonal disorder

Bone metabolic disorders• Assessment• History

– duration of sx– drug rx– causal associations

• Examn: Features of underlying endocrine disorder- moon face(hypercortisonism), hairless skin(testicular atrophy) , physical underdevelopment (rickets)

• X-rays - plain and specialist • - shows loss of horizontal trabeculae in osteoporosis • - stress fractures(prox tibia and femur), compression fractures in vertbrae.

• Biochemical tests• Bone biopsy

• nm

Methods of measuring Bone Mineral Density

• PRINCIPLE: a beam of energy is attenuated as it passes through bone and the degree of attenuation is related to the mass of the bone and its mineral content.

• Radiographic absorptiometry: by comparing values with aluminium reference wedge.

• Single energy X-ray absorptiometry: measures the attenuation of collimated photon bem

• Quantitative C T : measures mineral content per unit volume of bone.

• Dual energy X-ray absorptiometry it’s the method of choice, precision and accuracy are excellent, x-ray exposure is also not excessive

Indications for using bone densitometry

• To assess the degree and progress of bone loss in diagnosed patients of metabolic bone disease

• Screening procedure for perimenopausal women

• To monitor the effect of treatment for osteoporosis

Biochemical tests• Which investigations?

• Serum Ca/PO43- measured in fasting state and it’s the

ionised fragment that is imp • Alkaline phosphatase (osteoblastic activity)• Osteocalcin (GIa protein):more specific marker of

osteoblastic activity• PTH • Vit. D activity (measured by 25-HCC conc) • Urinary hydroxyproline excretion: measure of bone

resorption (less sensitive)• Excretion of pyridinium compounds : derived from

collagen cross links, much more sensitve for bone resorption, useful in monitoring the progress of hyperparathyroidism and osteoporosis

Metabolic Bone DiseasesMetabolic Bone Diseases

• Loss of MineralizationLoss of Mineralization : osteomalacia/rickets : osteomalacia/rickets• Low bone massLow bone mass : osteoporosis,Osteogenesis : osteoporosis,Osteogenesis

ImperfectaImperfecta• High bone massHigh bone mass : osteopetrosis : osteopetrosis• High bone turnoverHigh bone turnover : pagets, : pagets,

hyperparathyroidism, thyrotoxicosishyperparathyroidism, thyrotoxicosis• Low bone turnoverLow bone turnover : adynamic disease, : adynamic disease,

hypophosphatasiahypophosphatasia

Diseases of Mineralization: Diseases of Mineralization: Osteomalacia and RicketsOsteomalacia and Rickets

• If the mineralization is defective at growth plate, bone If the mineralization is defective at growth plate, bone growth slows and bone age is retarded – ricketsgrowth slows and bone age is retarded – rickets

• Poor mineralization of trabecular bone resulting in Poor mineralization of trabecular bone resulting in greater amount of unmineralised osteoid – greater amount of unmineralised osteoid – osteomalaciaosteomalacia

• Rickets is found only in growing children before Rickets is found only in growing children before fusion of epiphysis whereas osteomalacia is present fusion of epiphysis whereas osteomalacia is present in all ages.in all ages.

• All patients with rickets have osteomalacia but not all All patients with rickets have osteomalacia but not all patients with osteomalacia have ricketspatients with osteomalacia have rickets

• These features occur in a no. of other conditions so These features occur in a no. of other conditions so these term are restricted to those due to vit D these term are restricted to those due to vit D metabolismmetabolism

Pathophysiology • Defective bone growth results from retardation of normal

epiphyseal cartilage growth and calcification. Cartilage cells fail to complete their normal cycle of proliferation and degeneration, with subsequent failure of capillary penetration and it occurs in patchy manner, result is frayed irregular epiphyseal line at the end of shaft. Failure of osseous and cartilage matrix to mineralize in the zone of preparatory calcification, followed by newly formed uncalcified osteoid results in wide irregular frayed zone of nonrigid tissue (the rachitic metaphysis)

• Normally the epiphyseal line of long bone is well defined narrow strip of cartilage(2mm deep) is widened in rickets because the cartilage zone is hyperplastic but the normal palisade arrangement of cells is lost.

• Mineralization is also defective in subperiosteal bone, preexisting cortical bone is resorbed in normal manner, but replaced by unmineralized osteoid and the shaft loses rigidity casing distortion and fractures.

• With healing the degeneration of cartilage cell along the diaphyseal metaphyseal border occurs, capillary penetration in resultant spaces is resumed and calcification in the zone of prep calcification takes place producing a line visible on radiographs.

Rickets • Clinical features?1. Large head,open fontanelles, craniotabes,

frontal bossing2. Prominent abdomen3. Separation of recti muscles over the

protuberant abdomen4. Narrow chest (pigeon chest, harrison sulcus)5. Enlarged epiphysis6. Beaded ribs – the rickety rosary7. Bowing of the long bones with genu valgum8. Delayed dentition with irregular soft

decaying teeth9. Pale skin, flabby subcut tissue, typical

wizened lok

Radiological appearances• The radiographic changes are described into 4

stages :• The acute stage : cloudy epiphysis, splayed out

metaphysis, thickened periosteum• Second stage : epiphysis is mottled irregular, ill

defined shadow, ragged and broader, periosteal thickening disappaear and bowing occurs

• Third stage : Stage of repair. dense line appears in metaphysis due to deposition of calcium. Most characteristic feature is marked diff in size between the ends of shaft and the epiphysis

• Fourth stage : metaphyseal broadening still present, bone shows normal Ca content. This stage marks the end of the proccess.

Biochemistry

• Investigation Ca – normal or low Ph – low Alk phosphstase – increased Urinary cyclic AMP level – elevated Urinary Ca – lowered • 24-hydroxylase assay is used in diag of vit D

dependency rickets • Serum 25 hydroxy vitamins levels are

monitored before and after treatment ( their value is lowered, normal is 3-30micro gm)

• Bone biopsy

Treatment

• Medical treatment : milk n cheese diet, low cereals

50-150ug of vit D3 daily or 0.5-2ug of 1,25- DHCC or 15000ug single dose of vit D • Prevention of deformity : by controlling

movements and splinting.• Treatment of established deformity : - by splinting - by ostotomy the osteotomies to be done only after third

stage of rickets has reached.

Types of Rickets

• Rickets – Nutritional rickets – Congenital rickets – Rickets of prematurity – Genetic rickets – Neoplastic rickets – Hypophosphatemic rickets – Drug-induced rickets

• Renal causes - Renal osteodystrophy, Fanconi syndrome

• Tumor-induced osteomalacia • Other causes

– Hypophosphatasia – McCune-Albright syndrome – Osteogenesis imperfecta with mineralization defect

(syndrome resembling osteogenesis imperfecta)

Nutritional ricketsNutritional rickets

• Vitamin D DeficiencyVitamin D Deficiency

• Impaired 25 OH Vitamin D productionImpaired 25 OH Vitamin D production

• Impaired 1,25 OHImpaired 1,25 OH22 Vitamin D production Vitamin D production

• Defective Vitamin D receptor Defective Vitamin D receptor

Vitamin D DeficiencyVitamin D Deficiency

• EnvironmentalEnvironmentalhousebound; frail elderly; housebound; frail elderly;

immigrant from low to high altitude; immigrant from low to high altitude; gastrectomy; malabsorptiongastrectomy; malabsorption

• GeneticGeneticdark skin pigmentationdark skin pigmentation

• BiochemistryBiochemistryvitD low; 25(OH)D low; vitD low; 25(OH)D low;

1,25(OH)1,25(OH)22D low to normal ; Ca D low to normal ; Ca low; PTH low; PTH

high; Alk Ph high; P low high; Alk Ph high; P low

Impaired 25(OH)vit D productionImpaired 25(OH)vit D production

• EnvironmentalEnvironmentalhepatic failure; drugs affecting hepatic failure; drugs affecting

CYP liver CYP liver enzymesenzymes• BiochemistryBiochemistry

vit D normal; 25(OH)D low; 1,25 vit D normal; 25(OH)D low; 1,25 (OH)(OH)22D low to normal; D low to normal; Ca low; PTH high; Alk Ca low; PTH high; Alk ph high; P lowph high; P low

Impaired 1,25 (OH)Impaired 1,25 (OH)22D productionD production

• EnvironmentalEnvironmentalchronic renal failurechronic renal failure

• GeneticGeneticmutations in 25(OH)D 1 alpha mutations in 25(OH)D 1 alpha

hydroxylase hydroxylase (D dependent rickets type 1)(D dependent rickets type 1)• BiochemistryBiochemistry

vitD normal; 25(OH)D normal; vitD normal; 25(OH)D normal; 1,251,25(OH)(OH)22D D low; Ca low; low; Ca low; PTH high; Alk PTH high; Alk

Ph high; P high in CRF and Ph high; P high in CRF and low in D low in D dependent ricketsdependent rickets

Defective vit D receptor (VDR)Defective vit D receptor (VDR)

• The clinical picture consists of rickets with The clinical picture consists of rickets with severe hypocalcemia and alopecia, severe hypocalcemia and alopecia, although a variant without alopecia exists. although a variant without alopecia exists. Patients without alopecia appear to Patients without alopecia appear to respond better to treatment with vitamin D respond better to treatment with vitamin D metabolitemetabolite

• GeneticGeneticmutations in calcitriol receptor ( D mutations in calcitriol receptor ( D

dependent rickets type 2) dependent rickets type 2) • BiochemistryBiochemistry

vitD normal; 25(OH)D normal; 1,25vitD normal; 25(OH)D normal; 1,25(OH)(OH)22D D high; Ca high; Ca low; PTH high; Alk Ph high; P lowlow; PTH high; Alk Ph high; P low

Hypophosphataemic rickets• Hypophosphataemic ( due to impaired renal tubular

absorption of phosphate)1. Familial ( vit D resistant) - commonest form

– growth decr +++ and severe deformity with wide epiphyses

– x-linked dominant– Gene Xp22.1 (termed PHEX), it also has aut dominant

form linked to mutation in fibroblast growth factor, F6F23.– decreased tubular reabsorption of PO4

3- – They present with bow legs, pulp deformities and lesions

of intraglobular dentin are characteristic tooth abnormalities

– Ca normal but low PO43- and elevated alk ph.

– Rx : PO43- and vit D. oral phos atleast 5 times a

day( young child 0.5-1g/24hr & older 1-4g/24hr )– s/e diarrhoea (resolves spontaneously)– Vit D is given as dihydrotachysterol 0.02mg/kg/24hr

Adult onset hypophosphotasia : cause of unexplained bone loss in adults responding dramatically to vit D.

• Both autosomal recessive and autosomal dominant (FGF 23) inheritance have been found and have been associated with the same clinical phenotype. In approximately one third of patients, the disease appears to occur as a consequence of a new mutation. Clinical findings are similar to those of nutritional rickets, but without proximal myopathy.

• Because calcium levels remain normal, neither tetany nor secondary hyperparathyroidism are present.

Vitamin D dependent rickets

• Also known as Pseudovitamin D deficiency rickets.

• Inborn error of vit D metabolism• Most severe deforming type of

rickets• Autosomal recessive• gene is located on band 12q13.3• Ca is low

Rickets of PrematurityRickets of Prematurity

• Dietary Phosphate insufficiencyDietary Phosphate insufficiency milk phosphate intake inadequate for milk phosphate intake inadequate for the requirements of a rapidly the requirements of a rapidly developing skeleton in a premature developing skeleton in a premature babybaby

Renal rickets(osteodystrophy)

• Kidneys fail to excrete phosphate – phosphate rise in blood – excess phosphate excreted into gut – phosphorus combines with Ca in gut – Ca level falls – PTH released – ca withdrawn from bone – rickety changes.

• Osteodystrophy (ie, renal rickets) is the only variety of rickets with a high serum phosphate level. It can be adynamic (a reduction in osteoblastic activity) or hyperdynamic (increased bone turnover).

Renal rickets

• Bone changes are aggravated by aluminium retention.

• Children are stunted, pasty faced, have marked rachitic deformity and myopathy

• X-ray : widened & irregular epiphyseal plate, displacement of epiphysis, osteosclerosis in axial skeleton (rugger jersy spine)

• Biochemistry : low Ca, high PO43- , high alk

ph, high PTH.• Treatment : high doses of vit D(50,000

IU/day), epiphyseolysis needs internal fixation.

Drugs and ToxinsDrugs and Toxins

• EnvironmentalEnvironmentalEtidronate; Fluoride; AluminumEtidronate; Fluoride; Aluminum

• BiochemistryBiochemistry Alk ph normal ; vitD normal; Alk ph normal ; vitD normal;

25(OH)D normal; 25(OH)D normal; 1,25(OH)1,25(OH)22 D D

normal; Ca normal; PTH normal; Ca normal; PTH normal; P normal; P normalnormal

Osteoporosis

• Childhood osteoporosis may be primary : idiopoathic juvenile osteoporosis, osteoporosis-pseudo glioma syndrome, osteogenesis imperfecta OR secondary : klinefelter syndrome, turner syndrome, leukaemia, homocystinuria.

• Onset prior to puberty, long bones and metatarsal fractures, vertebral fractures, washed out appearance of spine and long bones improving after puberty.

• Blood inv are normal, DEXA shows markedly reduced bone mineral content and bone density

• Spontaneous recovery occurs after puberty.

• SCURVY : vit C deficiency, defect of collagen synthesis, marked in juxtaepiphyseal region

X-ray : generalized bone rarefaction, ring sign in juxtaepiphyseal region.

• HYPERVITAMINOSIS A : increased density in metaphyseal region and subperiostal calcification.

• HYPERVITAMINOSIS D : Ca is withdrawn from bones but metastatic calcification occurs.

• FLUOROSIS : >2-4ppm causes mottling of teeth, >10ppm causes fluorosis, inc osteoblastic activity (fluoroapatite crystals get deposited and are resistant to resorption)

subperiosteal new bone accretion, osteosclerosis, hyperostosis (of bony ligaments,tendons &fascia) backache, bone pain, joint stiffness.

X-ray : osteosclerosis, osteophytosis, ossification of ligaments (most marked in spine, pelvis)

Endocrine disorders

• Cushings – generalised osteoporosis

• Hypopituitarism - GH def - prop dwarf

or Frohlich adiposogenital syndrome

• Hyperpituitarism - gigantism or

acromegaly

• Hypothyroidism - cretinism or

myxoedema

• Hyperthyroidism - o’porosis

Thank You