• Bone contains largely – collagenous matrix, – impregnated with mineral salts – populated by cells.

BONE COMPOSITION

BONE MINERAL

• Half the bone volume is mineral matter– calcium and phosphate in the form of

crystalline hydroxyapatite• laid down in osteoid (newly formed bone which is

unmineralised) at the calcification front

• In mature bone,– calcium and phosphate are firmly bound to

collagen

BONE CELLS• Osteoblasts

– bone formation– derived from local mesenchymal precursors– rich in alkaline phosphates– responsible for production of type I collagen, non-collagenous bone proteins,

mineralization of bone matrix– initiates and controls osteoclastic activity

• Osteocytes– resting bone cells which may have a function in communicating information about

local stresses and strains to the other bone cells.– function is obscure; may under the influence of parathyroid hormone participate

in bone resorption (osteocytic osteolysis) and calcium transport• Osteoclasts

– large multinucleated cells derived from monocytic precursors in marrow– principal mediators of bone resorption– once activated, carries out resorption by lysozomal enzymes

BONE STRUCTURE

• Immature bone– woven bone

• collagen fibres are arranged haphazardly and cells have no specific orientation

• Mature bone – lamellar bone

• collagen fibres are arranged in parallel fashion forming multiple layers with osteocyes in between the lamellae

• exist in two structurally different forms, compact (cortical) bone and cancellous (trabecular) bone

• Compact bone– Found where support matters

most : outer walls of all bones especially shafts of tubular bones, subchondral plates supporting articular cartilage

– Made up of compact units – haversian systems or osteons

– Each consists of Central canal (haversian canal) containing blood vessels,lymphatics and nerves enclosed by concentric lamellae of bone.

– They are connected extensively with each other and with endosteal and periosteal surfaces surfaces by smaller channels called Volksmann’s canals

• Cancellous bone– Or trabecular bone, has a

honeycomb appearance; makes up the interior meshwork of all bones

– Looks like flattened sheets or unfolded osteons, interconnected and arranged according to the mechanical needs of the structure

– More porous than cortical bone

– Though it makes up only 1/4th of the total skeletal mass, the trabaculae provides 2/3rds of the total bone surface, thus the effects of metabolic disorders are seen first in trabecular bone

Regulation of Bone Turnover and Mineral Exchange

CALCIUM• Essential for normal cell function and physiological process

– nerve conduction, muscle contraction.

• Normal conc : 8.8-10.4mg/dL (2.2-2.6mmol/L)

• Much of this – bound to protien, – about half is ionised and effective in cell metabolism and regulation of calcium

homeostasis.

• Recommended daily intake : 800-1000mg (20-25mmol) and 1500mg during pregnancy and lactation.

• 50% of dietary calcium is absorbed (mainly in upper gut), much of that secreted back into the bowel and only about 200mg (5mmol) enters the circulation.

• Calcium absorption – mediated by vitamin D metabolites and– inhibited by excessive intake of phosphates, oxalates, phytates,

fats and administration of corticosteroid and malabsorption disoders of the bowel.

• Urinary excretion of calcium is 100-200mg (2.5-5mmol)/24hrs

• If calcium intake reduced, – urinary excretion adjusted by increasing tubular reabsorption. – If persistently reduced, calcium drawn from skeleton by

increased bone resorption.

• These compensatory shifts in intestinal absorption, renal excretion and bone remodelling are – regulated by PTH and vit D metabolites.

PHOSPHORUS

• Needed for many important metabolic process.• Plasma conc : 2.8-4.0 mg/dL (0.9-1.3mmol/L) almost

entirely in the form of ionised inorganic phosphates.• Abundantly available in diet and absorbed in small

intestine.• Absorption reduced in the presence of antacids;

aluminium hydroxide which binds phosphorus in the gut.• Excretion extremely efficient, 90% reabsorbed in

proximal tubules.• Tubular reabsorption decreased ( and overall excretion

increased) by PTH

VITAMIN D• Through its active metabolites, concerned with

– Calcium absorption, transport and act with PTH in bone remodelling.

• Target organs are small intestine and bone.

• Distribution – Diet

• Naturally occuring vit D3 – cholecalciferol derived from – Diet and – indirectly from the action UV light on the precursor 7-dihydrocholesterol in the skin.

• Dietary sources- Fish liver oil, Fish, egg yolk• Normal requirement – 400 IU per day

• Vitamin D is in inactive form. Conversion to active metabolites takes place first in the liver by 25-hydroxylation to form 25-hydroxycholecalciferol,

• And then in the kidneys by further hydroxylation mediated by PTH to 1,25 – dihydroxycholecalciferol.

Cholicalciferol skin 7-Dehydrocholesterol

Liver 25-Hydroxylase

25-OH Cholicalciferol

Kidney 1α-Hydoxylase

1,25-Di OH Cholicalciferol (Calcitriol- Active vitamin D)

The terminal metabolite 1,25 – dihydroxycholecalciferol and to a lesser extent 25-hydroxycholecalciferol act on the lining cells of the small intestine, stimulating the absorption of calcium and phosphate.

In bone they assist PTH to promote osteoclastic bone resorption, also enhance calcium transport across the cell membrane and indirectly promote process of mineralisation.

PARATHYROID HORMONE• Fine regulator of calcium exchange.

• Maintains extracellular calcium conc between narrow limits; – production and release are stimulated by a fall and – supressed by a rise in plasma ionised calcium.

• Target organs :– kidneys, bone and indirectly the gut.

• Acting on the renal tubules, – PTH increases phosphate excretion by restriction its reabsorption and conserves

calcium by increasing its reabsorption.– This response rapidly compensate for any change in plasma ionised calcium.

• Acting on kidney parenchyma, – it controls hydroxylation of vitamin D metabolite 25-hydroxycholecalciferol.

• In bone PTH – promotes osteoclastic resorption and the release of calcium and phosphate into the

blood. This is much slower way of maintaining calcium levels.

Calcium homeostasis

• Serum Ca falls increased PTH

Increased tubular Reabsorption of Ca

Increased 1,25-DHCIncreased osteoclasticactivity

Increased intestinal Absorption of Ca

Bone resorption

Serum Ca restored

• Calcitonin – secreted by C cells of the thyroid, opposite action to

PTH, supresses osteoclastic bone resorption and increases renal calcium excretion.

• Oestrogen – stimulate calcium absorption and protect bone from

unrestrained action of PTH.

• Adrenal corticosteroid – administered in excess cause a pernicious type of

osteoporosis due to combination of increased bone resorption, diminished bone formation, decreased intestinal calcium absorption and increased calcium excretion.

METABOLIC BONE DISEASES

OsteoporosisRickets and osteomalacia

HyperparathyroidismPaget’s disease

• Most of the common metabolic disorders are associated with depletion of bone tissue.

• They fall into 3 groups :– Osteoporosis ( quantity of bone mass is

abnormally low)– Osteomalacia (osteoid is present but

insufficiently mineralised.– Osteitis fibrosa ( PTH overproduction leads to

bone resorption and replacement by fibrous tissue)

OSTEOPOROSIS (porous bone)

• Systemic skeletal disease characterized by low bone mass and micro architectural deterioration with consequent increase in bone fragility and susceptibly to fracture.

• Occurs when rate of bone resorption exceeds the rate of bone formation.

• WHO definition of osteoporosis in women :– A bone mass density of 2.5 std deviation below peak

bone mass as measured by DEXA.

• F:M – 4:1• Localised osteoporosis

– is usually due to disuse (including paralysis) or nearby inflammation.

• Generalised osteoporosis – may be physiological (age related or primary),

systemic disorders (secondary).• Age related osteoporosis

– Bone mass decreases slowly but steadily from age of 40. this process accelerated around the menopause due to estrogen withdrawal and less restrained osteoclastic activity resorption.

– From about 70 yrs onward, there is gradual decrease in the rate of bone formation and bone loss due to diminished activity, chronic illness and dietary deficiencies.

Secondary osteoporosis• Endocrine disorders:

– Hypercortisonism ( ↑ bone resorption ,↓ bone formation)– Cushings– thyrotoxicosis

• Drug induced :– Alcohol abuse

• Malignant :– Multiple myeloma

• Nutritional:– Malnutrition– scurvy

• Non malignant– Rheumatoid arthritis– Ankylosing spondylosis

• Idiopathic – Juvenile osteoporosis

• RISK FACTORS– Non modifiable :

• advanced age, • gender (women)• Ethnicity : white, hispanic

– Modifiable :• Alcohol, soft drinks• Tobacco• Vitamin D deficiency• Malnutrition• Low BMI• Too much/ little physical activity• Heavy metal

• CAUSES:– Senility– Post immobilization ; bed ridden patient– Post menopausal– Protien deficiency

• Inadequate intake – old age, illness• Malnutrition• Malabsorption• Excess protien loss; 3rd degree burns, CRF

– Endocrinal• Cushing’s disease• Cushing’s syndrome• Hyperthyroid state

– Drug induced• Long term steroid theraphy• Phenobarbitone theraphy

• CLINICAL FEATURES– Postmenopausal osteoporosis

• Women between age of 55 and 65 may presents with acute back pain due to vertebral compression; with repeated minor fractures, develop progressive kyphosis.

• Liable to fracture when they fall ; long bones, usually the distal end of radius (colles’ fracture)

– Involutional osteoporosis• Over the age of 70, patients (women and men) are more likely to be

seen with a fracture of the femoral next or proximal end of humerus.• May already have previous history of fracture or obvious vertebral

osteoporosis.– Radiological features :

• Typical osteoporotic fracture• General reduction in radiographic bone density • Abnormal thinning of the cortices• Loss of vertical height of a vertebra due to collapse• Cod fish appearance : disc bulges into the adj vertebral bodies so

that disc becomes bi-convex• Ground glass appearance of the bones, conspicuous in bones like

the pelvis

• Investigations :– Biochemistry

• Serum calcium, phosphates, ALP (normal)• Total plasma protiens and plasma albumin (may be low)

– Densitometry :• method to quantify osteoporosis; where absorption of photons

emitted from gamma emiting isotopes by the bone calcium is measured.

• Two types of bone densitometry is available – ultrasound based and xray based.

• DEXA scan is xray based bone densitometry and is the gold standard in quantification of bone mass. Done every 2 years, T score > -1 normal.

– Neutron activation analysis : • calcium in the bone is activated by neutron bombarding and its

activity is measured.

– Bone biopsy

• PREVENTION :– Bone densitometry can be used to identify women are

at more than usual risk of suffering fracture at the menopause.

– Women approaching menopause advised to maintain adequate levels of dietary calcium and vitamin D, keep up high level of physical activity and avoid smoking and excessive consumption of alcohol.

– Estrogen medication (HRT) • Maintain bone density and reduce risk of fracture after

menopause• Risk of recurrent uterine bleeding and increased incidence of

breast and uterine cancer.– Biphosphonates

• Alternatives to HRT• Alandronate prevent bone loss and reduce risk of vertebral

and hip fractures• GI side effects

• TREATMENT– Medical

• Antiresorptive drug– Bisphosphonates : alendronates (10mg/day)– Risedronate (5mg/day)

• Selective estrogen receptor modulator– Roloxifine, tamoxifen

• Tibolone• HRT

– Increase bone formation• Teriparatide (recombinant PTH)

– Give daily inj– Very low BMD, intolerable to bisphosphonate

– Others : • high protien diet, calcium supplementation, vitamin D, Calcitonin.

– Orthopeadic treatment• Exercises : weight bearing is a major stimulus to bone formation• Bracing : prophylactic bracing of the spine by using an ASH brace or

Taylor brace maybe useful in prevention of pathological fractures in a severely osteoporotic spine.

RICKETS & OSTEOMALACIA

• Diseases where organic matrix of bone fails to calcify properly, leaving large osteoid seams.

• Rickets – growing bones of children• Osteomalacia – bones of adults

• Bone conditions are primarily due to deficiency of vitamin D or a disturbance in its metabolism secondary to renal disease.

RICKETS• Failure of normal mineralisation• Seen prominently at the growth plates• Resulting in softening of bones and development of deformities.• 2 types of rickets : I and II.• Type I : deficiency of vitamin D or a defect in its metabolism.• Type II : deficiency of phosphates in the extra cellular fluid because

of defective tubular resorption or diminished phosphate intake.

• Nutritional deficiency continues to be the commonest cause of rickets in developing countries because of poor socio-economic conditions.

• TYPE I :– Deficiency of vitamin D

• Diminished intake : malnutrition• Diminished absorption

– Malabsorption syndrome– Gastric abnormalities– Biliary diseases

• Lack of exposure to sunlight– Disturbance of vitamin D metabolism

• Hepatic factor– Lack of 25 hydroxylation of vit D– Increased degradation of vit D in patients on prolonged anti convulsant theraphy

• Renal factor– Lack of 1 hydroxylation (autosomal recessive)

• Unresponsiveness of target cells to 1,25-dihydroxy vit D• Renal osteodystrophy

• TYPE II– Defective absorption of phosphates through renal tubules

• Hypophosphataemic rickets ( x linked dominant)• Fanconi syndrome• Renal tubular acidosis• Oncogenic rickets

– Diminished intake or absorption of phosphates

• CLINICAL FEATURES– Craniotabes

• Manifestation of rickets seen in young infants• Pressure over the soft membranous bones of the skull gives the feeling of a ping pong ball

being compressed and released.– Bossing of the skull

• Bossing of the frontal and parietal bones becomes evident after the age of 6 months– Broadening of the ends of long bones

• Seen most prominently around wrists and knees• Seen around age of 6 months

– Delayed teeth eruption in infants– Harrison’s sulcus

• Horizontal depression along the lower part of the chest, corresponding to insertion of the diaphragm.

– Pigeon chest• Sternum is prominent

– Rachitic rosary• The costochondral junctions on the anterior chest wall become prominent• Giving rise to appearance of a rosary.

– Muscular hypotonia• The child’s abdomen becomes protuberant (pot-belly)• Because of marked muscular hypotonia; visceroptosis and lumbar lordosis occurs

– Deformities• Deformities of the long bone resulting in knock knees or bow legs common presentation once

the child start walking.

– Radiological features :• Delayed apperance of epiphysis• Widening of epiphysial plates due to excessive

accumulation of uncalcified osteoid at the growth plate (normal is 2-4mm)

• Cupping of the metaphysis : – normally metaphysis meets the epiphysial plate as a smooth

line of sclerosis (zone of provisional calcification).

– In rachitic bones, this line is absent and the metaphyseal end appears irregular.

– The cartilage cells accumulating at the growth plate create a depression in the soft metaphyseal end giving rise to cup shaped appearance.

• Splaying of the metaphysis / rarefaction of diaphyseal cortex

• Bone deformities

Lab investigations

• Serum calcium, is low or normal

• Serum phosphates low

• But, serum ALP is high

• Urinary calcium excretion is diminished

Treatment

• Untreated patients develop long bone deformities which may later require corrective osteotomy

• Responds rapidly to vitamin D administration in form of calciferol 400-1000 IU per day

• Residual deformities are usually slight.

OSTEOMALACIA

• Adult counterpart of rickets• Results from defects anywhere along the

metabolic pathway for vitamin D– Nutritional lack of vitamin D– Underexposure to sunlight– Intestinal malabsorption– Defective conversion to active metabolites in liver or

kidney• This results in failure to replace the turnover of

calcium and phosphorus in the organic matrix of bone, hence, bone content is dimineralised and bony substance replaced by soft osteoid tissue.

Clinical features

• Bone pains– Backache diffuse bone pain

• Muscular weakness

• Spontaneous fractures– Usually spine and may result in kyphosis

RADIOLOGICAL FEATURES

• Generalised rarefaction of bone and signs of previous fracture of the vertebrae, ribs, pubic rami or long bones

• Looser zone (pseudo fractures)– Radio lucent zones occurring at sites of stress

Other INVESTIGATIONS

• Serum calcium level is low

• Phosphates are high

• ALP high

• Bone biopsy : from iliac crest confirms diagnosis. (excessive uncalcified osteoid)

TREATMENT

• Vitamin D supplements, in daily mantenance doses of 400 IU is sufficient.

• Calcium supplements also given

• Underlying disorders of gut, liver and kidney must be treated.

HYPERPARATHYROIDISM

• Primary : usually due to parathyroid adenoma or hyperplasia

• Secondary : due to persistent hypercalcemia

• Tertiary : when secondary hyperplasia leads to autonomous over activity.

Action of parathyroid hormone

• Acts directly on the bone to RELEASE CALCIUM INTO THE EXTRA CELLULAR FLUID by stimulating osteoclastic resorption.

• Also, enhances calcium conservation by stimulating tubular resorption and intestinal absorption.

CLINICAL FEATURES

• Middle aged (40-65yrs)• Women twice as affected as often as men

• Anorexia, nausea, abdominal pain, depression, fatigue, muscle weakness

• Polyuria, kidney stones or nephrocalcinosis (due to chronic hypercalcuria)

• Joint symptoms due to chondrocalcinosis

• Only 10% present with bone disease (generalised osteoporosis)

RADIOLOGICAL FEATURES• Typical features of osteoporosis

• Brown’s tumor is an expansile lytic lesion, which appears like a bone tumor, generally affecting the maxilla / mandible

• Areas of cortical erosions

• Subperiosteal cortical resorption of the middle phalanges (diagnostic feature)

• Subperiosteal resorption of lateral end of clavicle

• Salt-pepper appearance– Skull bones show well marked stippling, but the opaque areas are small

pin-head sizes

• Renal calculi, nephrocalcinosis and chondrocalcinosis

Other INVESTIGATIONS

• Serum calcium high• Phosphates low• ALP high

• Urinary excretion of calcium is low and that of the phosphates is high

• CT scan of the neck for parathyroid and, of other organs for ectopic secretion of parathyroid hormones

TREATMENT

• Usually conservative and includes adequate hydration and decreased calcium intake.

• If adenoma is present, should be removed.

• Postoperatively, there is danger of severe hypocalcemia due to brisk formation of new bone (hungry bone syndrome) – treated with fast acting Vitamin D metabolites.

PAGET’S DISEASE (OSTEITIS DEFORMANS)

• Characterised by enlargement and thickening of the bone, but the internal architecture is abnormal and the bone is unusually brittle.

• It is relatively common in north america, britain, germany and australia but rare in asia, africa and the middle east.

Pathology

• Any bone may be involved• Due to the alternating phases of rapid bone resorption

and formation, cortices are thickened but irregular , at one stage more porous than usual and at another more sclerotic.

• While resorption predominates, the bones are easily deformed.

• In the late stage, bones becomes brittle and sclerotic.

• Characteristic cellular change : increase in osteoblastic and osteoclastic activity.

CLINICAL FEATURES • Increasingly common in patients above 50yrs

of age.• Commonest sites : pelvis and tibia, followed

by the femur, skull, spine and clavicle.• Most patients are asymptomatic. • Usually, diagnosed by incidental x ray

findings or raised serum ALP.• When pain occurs, dull and aching in nature.• Deformities are seen in lower limbs.

– Limb looks bent, and feels thick and skin is unduly warm

• There may be kyphosis (patient becomes short and ape like with bent arms and legs)

• Skull may enlarge and skull base flattened (platybasia)

• Cranial nerve compression may lead to impaired vision, facial palsy, trigeminal neuralgia or deafness).

• Vertebral thickening, may lead to spinal cord compression or nerve root compression.

RADIOLOGICAL FINDINGS

• Resorptive phase : localised areas of osteolysis

• Later : bones become thick and scleoritc , with coarse trabeculations

LAB INVESTIGATIONS

• Serum calcium and phosphates normal

• Serum ALP correlates with activity of bone, and extent of disease.

• 24 hr urine excretion of pyridinoline crosslink

TREATMENT• Most patients never have symptoms nor do they

require treatment

• CALCITONIN and BISPHOSPHONATES can control the disease by suppressing bone turnover.– Calcitonin : reduces bone resorption by decreasing activity

and number of osteoclasts. Urinary hydroxyproline and serum ALP are lowered.

– Bisphosphonates : bonds to hydroxyapatite crystals and inhibit growth and dissolution (eg alandronate)

• Patients should be examined regularly for signs of increased bone activity– Local tenderness– Warmth– Rise in ALP

• Indications for specific treatment

1. Persistent bone pain

2. Repeated fractures

3. Neurological complications

4. High output cardiac failure (due to prolonged and increased bone blood flow)

5. Hypercalcemia due to immobilization

6. Preparation for bone surgery, where there is a risk for hemorhage.