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
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?
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.
Normal Bone Structure
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 1/4 th of the bone mass but 2/3 rd 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?
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 )
Osteoblast : 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
It goes on throughout life and its rate depends upon – demands of growth
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,
formation> resorption net bone gain
During adulthood - turnover moderate, formation< resorption net bone loss
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 3 rd 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
BMD, g/cm 2 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 :
bone mass is not the only factor responsible
gaps appear in trabecular bone and not all defects are repaired
old age – slow remodelling rate
What is the recommended daily intake?
1000mg( for avg adult)
Total body calcium?
1100gm( skeleton-99% & plasma-1%)
What is the plasma concentration?
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.
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.
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
Serum Ca/PO 4 3- 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
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 Diseases
Loss of Mineralization : osteomalacia/rickets
Low bone mass : osteoporosis,Osteogenesis Imperfecta
High bone mass : osteopetrosis
High bone turnover : pagets, hyperparathyroidism, thyrotoxicosis
Low bone turnover : adynamic disease, hypophosphatasia
Diseases of Mineralization: Osteomalacia and Rickets
If the mineralization is defective at growth plate, bone growth slows and bone age is retarded – rickets
Poor mineralization of trabecular bone resulting in greater amount of unmineralised osteoid – osteomalacia
Rickets is found only in growing children before fusion of epiphysis whereas osteomalacia is present in all ages.
All patients with rickets have osteomalacia but not all patients with osteomalacia have rickets
These features occur in a no. of other conditions so these term are restricted to those due to vit D metabolism
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.
Large head,open fontanelles, craniotabes, frontal bossing
Separation of recti muscles over the protuberant abdomen
Narrow chest (pigeon chest, harrison sulcus)
Beaded ribs – the rickety rosary
Bowing of the long bones with genu valgum
Delayed dentition with irregular soft decaying teeth
Pale skin, flabby subcut tissue, typical wizened lok
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.
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)
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.
Biochemistry vit D normal; 25(OH)D low; 1,25 (OH) 2 D low to normal; Ca low; PTH high; Alk ph high; P low
Impaired 1,25 (OH) 2 D production
Environmental chronic renal failure
Genetic mutations in 25(OH)D 1 alpha hydroxylase (D dependent rickets type 1)
Biochemistry vitD normal; 25(OH)D normal; 1,25 (OH) 2 D low; Ca low; PTH high; Alk Ph high; P high in CRF and low in D dependent rickets
Defective vit D receptor (VDR)
The clinical picture consists of rickets with severe hypocalcemia and alopecia, although a variant without alopecia exists. Patients without alopecia appear to respond better to treatment with vitamin D metabolite
Genetic mutations in calcitriol receptor ( D dependent rickets type 2)
Biochemistry vitD normal; 25(OH)D normal; 1,25 (OH) 2 D high; Ca low; PTH high; Alk Ph high; P low
Hypophosphataemic ( due to impaired renal tubular absorption of phosphate)
Familial ( vit D resistant)
- commonest form
growth decr +++ and severe deformity with wide epiphyses
Gene Xp22.1 (termed PHEX), it also has aut dominant form linked to mutation in fibroblast growth factor, F6F23.
decreased tubular reabsorption of PO 4 3-
They present with bow legs, pulp deformities and lesions of intraglobular dentin are characteristic tooth abnormalities
Ca normal but low PO 4 3- and elevated alk ph.
Rx : PO 4 3- 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
gene is located on band 12q13.3
Ca is low
Rickets of Prematurity
Dietary Phosphate insufficiency milk phosphate intake inadequate for the requirements of a rapidly developing skeleton in a premature baby
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).
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 PO 4 3- , high alk ph, high PTH.
Treatment : high doses of vit D(50,000 IU/day), epiphyseolysis needs internal fixation.
Drugs and Toxins
Environmental Etidronate; Fluoride; Aluminum
Biochemistry Alk ph normal ; vitD normal; 25(OH)D normal; 1,25(OH) 2 D normal; Ca normal; PTH normal; P normal
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)