Metabolic bone diseases

1. Metabolic Bone DiseasesMetabolic Bone Diseases

2. BONE STRUCTURE AND METABOLISMBONE STRUCTURE AND METABOLISM
Specialised connective tissue.Specialised connective tissue.
Mineralised organic matrix in which living cells are dispersed.Mineralised organic matrix in which living cells are dispersed.
Bone
Mineralised bone matrix
Bone matrix or organicBone matrix or organic
fraction (30 per cent)fraction (30 per cent)
Collagen andCollagen and
ground substanceground substance
Inorganic portionInorganic portion
(70 per cent)(70 per cent)
Cells of mesenchymalCells of mesenchymal
originorigin
crystalline hydroxyapatitecrystalline hydroxyapatite
(Ca(Ca1010 (PO(PO44))66OHOH22))

4. Growth in lengthGrowth in length of bones is dependent uponof bones is dependent upon
proliferation of cartilage cells and on the endochondralproliferation of cartilage cells and on the endochondral
sequence at the growth plate.sequence at the growth plate.
Growth in widthGrowth in width and thickness is achieved by formationand thickness is achieved by formation
of bone at the periosteal surface and by resorption atof bone at the periosteal surface and by resorption at
the endosteal surface, with the rate of formationthe endosteal surface, with the rate of formation
exceeding that of resorption.exceeding that of resorption.
ModellingModelling refers to the cellular-based process thatrefers to the cellular-based process that
alters the shape, contour and amount of bone,alters the shape, contour and amount of bone,
primarily in response to biochemical factors.primarily in response to biochemical factors.
Bone modelling activity subsides at skeletal maturityBone modelling activity subsides at skeletal maturity
around the age of 18 years.around the age of 18 years.

5. RemodellingRemodelling continues throughout life.continues throughout life.
Old bone is replaced with an equal amount of newOld bone is replaced with an equal amount of new
bone, by the coordinated (coupled) actions ofbone, by the coordinated (coupled) actions of
osteoclasts and osteoblasts.osteoclasts and osteoblasts.
Remodelling almost exclusively takes place in theRemodelling almost exclusively takes place in the
cortical (intracortical or Haversian), endosteal andcortical (intracortical or Haversian), endosteal and
trabecular bone surfaces.trabecular bone surfaces.
A typical boneA typical bone remodelling cycleremodelling cycle has 3 major events:has 3 major events:
activation, resorption and formation, and this occursactivation, resorption and formation, and this occurs
at basic multicellular units (BMU)at basic multicellular units (BMU)

7. OsteoclastsOsteoclasts are giant multinucleated cells derivedare giant multinucleated cells derived
from a haematopoietic cell related to thefrom a haematopoietic cell related to the
mononuclear-phagocyte series. They remove bone.mononuclear-phagocyte series. They remove bone.
OsteoblastsOsteoblasts synthesise and secrete the organicsynthesise and secrete the organic
matrix and regulate its mineralisation. The matrix ismatrix and regulate its mineralisation. The matrix is
composed of type I collagen and non collagenouscomposed of type I collagen and non collagenous
proteins.proteins.
OsteocytesOsteocytes are the osteoblasts which secrete matrix.are the osteoblasts which secrete matrix.
This is then mineralised.This is then mineralised.
Lining cellsLining cells separate bone from bone marrow andseparate bone from bone marrow and
from systemic ECF.from systemic ECF.

9. RANKL is secreted by osteoblasts, synovial fibroblasts,
stromal cells, T cells.
The osteoclast receptor for this protein is referred to as
RANK.
OPG binds and neutralizes RANKL, leading to a block in
osteoclastogenesis and decreased survival of
preexisting osteoclasts.

10. Bone remodeling also is regulated by several
circulating hormones, including estrogens,
androgens, vitamin D, and parathyroid hormone
(PTH), as well as locally produced growth factors
such as IGF-I and immunoreactive growth
hormone II (IGH-II), transforming growth
factor β (TGF-β), parathyroid hormone–related
peptide (PTHrP), interleukins (ILs),
prostaglandins, and members of the tumor
necrosis factor (TNF) superfamily.

11. OsteoporosisOsteoporosis
Osteoporosis is defined as a reduction in the strength of bone
that leads to an increased risk of fractures.
Normal homeostatic bone remodeling is altered – the rate of bone
resorption is greater than the rate of bone formation.

12. The World Health Organization (WHO) operationally defines osteoporosis
as a bone density that falls 2.5 standard deviations (SD) below the mean
for young healthy adults of the same sex—also referred to as a T-score of
–2.5.

19. Measurement of Bone Mass
Dual-energy x-ray absorptiometry (DXA),
Single-energy x-ray absorptiometry (SXA),
Quantitative CT,
Ultrasound (US).

20. DXA
Highly accurate x-ray technique
Standard for measuring bone density
Clinical determinations usually are made of the lumbar spine and hip.
Two x-ray energies are used to estimate the area of mineralized tissue, and the
mineral content is divided by the area, which partially corrects for body size.
Cannot estimate the depth or posteroanterior length of the bone.
Small people tend to have lower than average bone mineral density (bmd).
Bone spurs, which are common in osteoarthritis, tend to falsely increase bone density
of the spine.
Because DXA instrumentation is provided by several different manufacturers, the
output varies in absolute terms.
Consequently, it has become standard practice to relate the results to "normal" values
by using T-scores, which compare individual results to those in a young population that
is matched for race and sex. Z-scores compare individual results to those of an age-
matched population that also is matched for race and sex.

23. CT
Primarily to measure the spine and, more recently, the hip.
Peripheral CT is used to measure bone in the forearm or tibia.
Technique is three-dimensional and can provide a true density (mass of bone tissue
per unit volume).
CT also can specifically analyze trabecular bone and cortical bone content and
volume separately.
CT remains expensive, involves greater radiation exposure, and is less reproducible
than DXA.
A new technique employing high-resolution CT scanning called Xtreme CT also can
provide information on skeletal architecture, including cancellous connectivity

24. When to Measure Bone Mass

25. When to Treat Based on Bone Mass Results
BMD is >2.5 SD below the mean value for young adults (T-score ≤–2.5).
Postmenopausal women with fracture risk factors even if BMD is not in
the osteoporosis range.
Risk factors (age, prior fracture, family history of hip fracture, low body
weight, cigarette consumption, excessive alcohol use, steroid use, and
rheumatoid arthritis) can be combined with BMD to assess the likelihood
of a fracture over a 5- or 10-year period.

26. Elements of osteoporosis preventionElements of osteoporosis prevention

27. Treatment Osteoporosis
History and physical examination should be performed to identify
risk factors for osteoporosis.
A low Z-score increases the suspicion of a secondary disease.
Height loss >2.5–3.8 cm (>1–1.5 in.) is an indication for
radiography or vertebral fracture assessment by DXA to rule out
asymptomatic vertebral fractures, as is the presence of significant
kyphosis or back pain, particularly if it began after menopause.
For patients who present with fractures, it is important to ensure
that the fractures are not caused by an underlying malignancy.

28. OP fracturesOP fractures

31. Routine Laboratory Evaluation
Complete blood count
Serum and 24-h urine calcium
Renal and hepatic function tests
serum calcium level hyperparathyroidism or malignancy
serum calcium level malnutrition and osteomalacia.
Serum PTH level differentiates between hyperparathyroidism (PTH )↑
and malignancy (PTH ), and a high PTHrP level can help document the↓
presence of humoral hypercalcemia of malignancy.
Urine calcium (<50 mg/24 h) suggests osteomalacia, malnutrition, or
malabsorption;
Urine calcium (>300 mg/24 h) is indicative of hypercalciuria
Hypercalciuria in three situations: (1) a renal calcium leak (2) absorptive
hypercalciuria, which can be idiopathic or associated with increased
1,25(OH)2D in granulomatous disease; or (3) hematologic malignancies
or conditions associated with excessive bone turnover such as Paget's
disease, hyperparathyroidism, and hyperthyroidism.

32. Measurement of serum 25(OH)D level.
Hyperthyroidism should be evaluated by measuring thyroid-
stimulating hormone (TSH).
Urinary free cortisol levels or a fasting serum cortisol should be
measured after overnight dexamethasone.
When bowel disease, malabsorption, or malnutrition is suspected,
serum albumin, cholesterol, and a complete blood count should be
checked.
Myeloma commonly presents with bone pain and characteristic
"punched-out" lesions on radiography. Serum and urine
electrophoresis and evaluation for light chains in urine are
required to exclude this diagnosis.

34. Nutritional Recommendations
Calcium
Vitamin D
Salt
High animal protein intakes
Vitamin K
Pharmacologic Therapies
Estrogens
Progestins
SERMs
Bisphosphonates
Calcitonin
Denosumab
Parathyroid Hormone
Fluoride

37. Estrogens
For oral estrogens,0.3 mg/d esterified estrogens,
0.625 mg/d for conjugated equine estrogens,
5 μg/d for ethinyl estradiol.
For transdermal estrogen, 50 μg estradiol per day.
Hormone therapy reduces the risk of hip and clinical spine fracture by 34% and that of
all clinical fractures by 24%.
The majority of estrogen (and androgen) effects on bone resorption are mediated
indirectly through paracrine factors produced by osteoblasts.
These actions include (1) increasing IGF-I and TGF-β and (2) suppressing IL-1 (α and
β), IL-6, TNF-α, and osteocalcin synthesis. The indirect estrogen actions primarily
decrease bone resorption.
Combined estrogen-progestin treatment increased risk of fatal and nonfatal myocardial
infarction by 29%,40% increase in stroke, a 100% increase in venous thromboembolic
disease, and a 26% increase in risk of breast cancer.

38. SERMs
Two SERMs are used currently in postmenopausal women:
Raloxifene for the prevention and treatment of osteoporosis
Tamoxifen for the prevention and treatment of breast cancer.
Tamoxifen reduces bone turnover and bone loss in postmenopausal women.
Tamoxifen acts as an estrogenic agent in bone. Breast Cancer Prevention
study indicated a possible reduction in clinical vertebral, hip, and Colles'
fractures.
Raloxifene (60 mg/d) has effects on bone turnover and bone mass that are
very similar to those of tamoxifen, indicating that this agent is also estrogenic
on the skeleton.
The effect of raloxifene on bone density (+1.4–2.8% versus placebo in the
spine, hip, and total body) is somewhat less than that seen with standard
doses of estrogens.
Raloxifene reduces the occurrence of vertebral fracture by 30–50%, depending
on the population; however, there are no data confirming that raloxifene can
reduce the risk of nonvertebral fractures over 8 years of observation.

39. Bisphosphonates
Alendronate, risedronate, and ibandronate are approved for the prevention
and treatment of postmenopausal osteoporosis.
Risedronate and alendronate are approved for the treatment of steroid-
induced osteoporosis.
Risedronate also is approved for prevention of steroid-induced osteoporosis.
Both alendronate and risedronate are approved for treatment of osteoporosis
in men.
Alendronate treatment (5 mg/d for 2 years and 10 mg/d for 9 months
afterward) reduces vertebral fracture risk by about 50%, multiple vertebral
fractures by up to 90%, and hip fractures by up to 50%.
Once-weekly therapy generally is preferred because of the low incidence of
gastrointestinal side effects and ease of administration.
Alendronate should be given with a full glass of water before breakfast.
Patients remain upright for at least 30 min after taking the medication to
avoid esophageal irritation.

40. Risedronate demonstrated 40–50% reduction in vertebral fracture risk over 3 years,
accompanied by a 40% reduction in clinical nonspine fractures.
Etidronate was the first bisphosphonate to be approved, initially for use in Paget's
disease and hypercalcemia. Its not approved by the FDA for treatment of osteoporosis.
Ibandronate doses of 150 mg/month PO or 3 mg every 3 months IV had greater
effects on turnover and bone mass than did 2.5 mg/d.
Zoledronic acid (5 mg as a single IV infusion annually) reduced the risk of vertebral
fractures by 70%, nonvertebral fractures by 25%, and hip fractures by 40%.
Bisphosphonates specifically impair osteoclast function and reduce osteoclast number,
in part by inducing apoptosis.

41. Calcitonin
Calcitonin preparations are approved by the FDA for Paget's disease,
hypercalcemia, and osteoporosis in women >5 years past menopause.
A nasal spray containing calcitonin (200 IU/d) is available for treatment of
osteoporosis in postmenopausal women.
Calcitonin suppresses osteoclast activity by direct action on the osteoclast
calcitonin receptor

42. Denosumab
A novel agent that was given twice yearly by SC administration in a randomized
controlled trial in postmenopausal women with osteoporosis has been shown to
increase BMD in the spine, hip, and forearm and reduce vertebral, hip, and
nonvertebral fractures over a 3-year period by 70, 40, and 20%, respectively.
Denosumab was approved by the FDA in 2010 for the treatment of postmenopausal
women who have a high risk for osteoporotic fractures, including those with a
history of fracture or multiple risk factors for fracture, and those who have failed or
are intolerant to other osteoporosis therapy.
Denosumab is a fully human monoclonal antibody to RANKL.
Denosumab binds to RANKL, inhibiting its ability to initiate formation of mature
osteoclasts from osteoclast precursors and to bring mature osteoclasts to the bone
surface and initiate bone resorption. Denosumab also plays a role in reducing the
survival of the osteoclast.

43. Teriparatide
An exogenous PTH analogue (1-34hPTH; teriparatide) that has been approved for the
treatment of established osteoporosis in both men and women.
The first randomized controlled trial in postmenopausal women showed that PTH, when
superimposed on ongoing estrogen therapy, produced substantial increments in bone
mass (13% over a 3-year period compared with estrogen alone) and reduced the risk
of vertebral compression deformity.
20 μg PTH(1–34) daily by SC injection reduced vertebral fractures by 65% and
nonvertebral fractures by 45%.
Treatment is administered as a single daily injection given for a maximum of 2 years.
Strontium Ranelate
Strontium ranelate is approved for the treatment of osteoporosis. It increases bone
mass throughout the skeleton; in clinical trials, the drug reduced the risk of vertebral
fractures by 37% and that of nonvertebral fractures by 14%.

44. OsteoporosisOsteoporosis
Surgical intervention for vertebralSurgical intervention for vertebral
fracturesfractures
–VertebroplastyVertebroplasty
High pressure injection of boneHigh pressure injection of bone
cement through pedicles tocement through pedicles to
vertebral bodyvertebral body
Contraindicated in severeContraindicated in severe
vertebral body collapsevertebral body collapse

45. OsteoporosisOsteoporosis
Surgical intervention for vertebralSurgical intervention for vertebral
fracturesfractures
–KyphoplastyKyphoplasty
Bone tamp through corticalBone tamp through cortical
windowwindow
Inflation of bladder in vertebralInflation of bladder in vertebral
bodybody
Injection of bone cement underInjection of bone cement under
LOW PRESSURELOW PRESSURE

46. Rickets and OsteomalaciaRickets and Osteomalacia
Rickets and osteomalacia describe disorders in which there is failure of orRickets and osteomalacia describe disorders in which there is failure of or
defective mineralisation of newly formed organic matrix of the skeleton.defective mineralisation of newly formed organic matrix of the skeleton.
In rickets, the growing skeleton is involved and defective mineralisationIn rickets, the growing skeleton is involved and defective mineralisation
occurs not only in bone but also in the cartilaginous matrix of the growthoccurs not only in bone but also in the cartilaginous matrix of the growth
plate.plate.
Osteomalacia is the adult counterpart of rickets.Osteomalacia is the adult counterpart of rickets.
Deficiency of vitamin D, or ineffective formation or action of one of its activeDeficiency of vitamin D, or ineffective formation or action of one of its active
metabolites, leads to decreased concentrations of circulating calcium andmetabolites, leads to decreased concentrations of circulating calcium and
phosphate and to impaired mineralisation of bone.phosphate and to impaired mineralisation of bone.

49. Vitamin D deficiencyVitamin D deficiency
Deficiency of vitamin D is the commonest cause of rickets and osteomalacia inDeficiency of vitamin D is the commonest cause of rickets and osteomalacia in
our country.our country.
Inadequate exposure to ultraviolet light is the critical factor in the causationInadequate exposure to ultraviolet light is the critical factor in the causation
of rickets and osteomalacia.of rickets and osteomalacia.
Dietary calcium deficiency alone does not cause rickets or osteomalacia.Dietary calcium deficiency alone does not cause rickets or osteomalacia.
Repeated pregnancies and lactation impose a considerable drain on the boneRepeated pregnancies and lactation impose a considerable drain on the bone
mineral reserves and vitamin D stores of the mother, causing osteomalacia.mineral reserves and vitamin D stores of the mother, causing osteomalacia.
Age-related impaired intestinal absorption of calcium and deficient synthesisAge-related impaired intestinal absorption of calcium and deficient synthesis
and supply of vitamin D precipitate osteomalacia in elderly women.and supply of vitamin D precipitate osteomalacia in elderly women.
Congenital (neonatal) rickets may occur in babies born to osteomalacicCongenital (neonatal) rickets may occur in babies born to osteomalacic
mothers who had completely exhausted their bone mineral and vitamin Dmothers who had completely exhausted their bone mineral and vitamin D
reserves.reserves.

50. Muscular hypotoniaMuscular hypotonia
Skeletal deformities such as widening of the epiphyses at theSkeletal deformities such as widening of the epiphyses at the
wrists and ankles and of the costochondral junctionswrists and ankles and of the costochondral junctions (rickety(rickety
rosary)rosary) are characteristic of rickets.are characteristic of rickets.
Between 6 and 12 months, softening of the skullBetween 6 and 12 months, softening of the skull (craniotabes,(craniotabes,
frontal bossing)frontal bossing) and later deformities of the thorax and spineand later deformities of the thorax and spine
(kyphosis or lordosis)(kyphosis or lordosis),, knock-kneesknock-knees,, bowing of legsbowing of legs andand waddlingwaddling
gaitgait develop and result indevelop and result in short statureshort stature ..
TeethTeeth show irregular pits and grooves. Enamel hypoplasia andshow irregular pits and grooves. Enamel hypoplasia and
caries are frequent and severe in rachitic children.caries are frequent and severe in rachitic children.
The softened lower ribs may be pulled in at the site of attachmentThe softened lower ribs may be pulled in at the site of attachment
of the diaphragm, formingof the diaphragm, forming Harrison’s grooveHarrison’s groove..
The abdomen, due to hypotonia of the muscles, is markedlyThe abdomen, due to hypotonia of the muscles, is markedly
protuberantprotuberant (rachitic potbelly)(rachitic potbelly)..
Spontaneous carpopedal spasmsSpontaneous carpopedal spasms, laryngeal stridor and even, laryngeal stridor and even
convulsions suggestive ofconvulsions suggestive of tetanytetany (positive Chvostek’s and(positive Chvostek’s and
Trousseau’s signs) may occur if the calcium level drops below 6Trousseau’s signs) may occur if the calcium level drops below 6
mg/dl.mg/dl.

51. Muscular weakness, bone pains and tenderness, backache, waddlingMuscular weakness, bone pains and tenderness, backache, waddling
gait, difficulty in walking or climbing, and deformities of the spinegait, difficulty in walking or climbing, and deformities of the spine
and pelvis are the most common features of osteomalacia.and pelvis are the most common features of osteomalacia.
Inability to stand unaided or the tendency to prop on self while risingInability to stand unaided or the tendency to prop on self while rising
up from the floor is an important clue to the diagnosis ofup from the floor is an important clue to the diagnosis of
osteomalacia.osteomalacia.
Severe and long-standing cases may develop ankylosis andSevere and long-standing cases may develop ankylosis and
generalised forward flexion at the spinegeneralised forward flexion at the spine

52. The most diagnostic biochemical feature of rickets and osteomalacia isThe most diagnostic biochemical feature of rickets and osteomalacia is lowlow
25 (OH)D concentration in plasma25 (OH)D concentration in plasma in the presence of secondaryin the presence of secondary
hyperparathyroidism.hyperparathyroidism.
Treatment of vitamin D-deficiency rickets consists of intake ofTreatment of vitamin D-deficiency rickets consists of intake of 1-2 g of1-2 g of
elemental calcium per dayelemental calcium per day. This can be obtained by adding. This can be obtained by adding 1 litre milk1 litre milk toto
the diet or 1 g as calcium supplements.the diet or 1 g as calcium supplements.
Vitamin D in a dose ofVitamin D in a dose of 60,000 IU (1.5 mg of D60,000 IU (1.5 mg of D33)) is givenis given orallyorally andand
repeated atrepeated at 2-42-4 week intervalsweek intervals. In mild cases 1 to 3 doses, in moderate. In mild cases 1 to 3 doses, in moderate
cases 3 to 6 doses, and in severe cases 6 to 10 such doses may becases 3 to 6 doses, and in severe cases 6 to 10 such doses may be
necessary for raising the circulating concentration of 25 (OH)Dnecessary for raising the circulating concentration of 25 (OH)D33 into theinto the
normal range and for complete healing of bone disease.normal range and for complete healing of bone disease.
Vitamin D administered to patients with secondary hyperparathyroidism isVitamin D administered to patients with secondary hyperparathyroidism is
quickly converted to 1,25 (OH)quickly converted to 1,25 (OH)22DD33. The. The response to treatment usuallyresponse to treatment usually
appears after 2-3 weeks and bone lesions heal completely in 8 to 12appears after 2-3 weeks and bone lesions heal completely in 8 to 12
weeks.weeks.
Vitamin D can be replaced by use of vitamin D metabolites such as 25Vitamin D can be replaced by use of vitamin D metabolites such as 25
(OH)D(OH)D33 (calcifediol)(calcifediol) 50µg daily or 1,25 (OH)50µg daily or 1,25 (OH)22DD33 (calcitriol)(calcitriol) or its analogueor its analogue
(1-aD) 0.25 to 0.5 µg daily for 4-8 weeks.(1-aD) 0.25 to 0.5 µg daily for 4-8 weeks.

53. Vitamin D-dependent rickets (Pseudo vitamin DVitamin D-dependent rickets (Pseudo vitamin D
deficiency)deficiency)
Type IType I
Autosomal recessive disorder.Autosomal recessive disorder.
Deficiency of or presence of a biologically inactive form of renalDeficiency of or presence of a biologically inactive form of renal 25 (OH) D-la-25 (OH) D-la-
hydroxylase.hydroxylase.
Affected persons develop early onset (less than one year of age) vitamin D deficiencyAffected persons develop early onset (less than one year of age) vitamin D deficiency
(low serum 1,25 (OH)(low serum 1,25 (OH)22DD33).).
The resultant rickets is unresponsive to usual doses of calciferol and 25-hydroxy D.The resultant rickets is unresponsive to usual doses of calciferol and 25-hydroxy D.
Complete cure is obtained on continuous treatment with 1,25 (OH)Complete cure is obtained on continuous treatment with 1,25 (OH)22DD33 or high doses ofor high doses of
vitamin D.vitamin D.
Rickets recurs if therapy is withdrawn.Rickets recurs if therapy is withdrawn.
Type IIType II
Vitamin D-dependency rickets.Vitamin D-dependency rickets.
Serum 1,25 (OH)Serum 1,25 (OH)22DD33 levels are normal.levels are normal.
There is deficiency inThere is deficiency in the target tissue cytosol receptorthe target tissue cytosol receptor for 1,25 (OH)for 1,25 (OH)22DD3.3.
10-25 µg of 1,25 (OH)10-25 µg of 1,25 (OH)22DD33 or 1-a-OHDor 1-a-OHD33 per day may be required for cure.per day may be required for cure.

54. Anticonvulsant - induced osteomalaciaAnticonvulsant - induced osteomalacia
Anticonvulsant drugs, especially phenobarbitone and phenytoin, induce liverAnticonvulsant drugs, especially phenobarbitone and phenytoin, induce liver
enzymes, resulting in diminished 25 (OH)Denzymes, resulting in diminished 25 (OH)D33 that leads to rickets andthat leads to rickets and
osteomalacia.osteomalacia.
Calcium supplements of 1-2 g per day and calciferol in doses varying from 0.1Calcium supplements of 1-2 g per day and calciferol in doses varying from 0.1
to 1.0 mg correct and prevent the biochemical and radiographic abnormalitiesto 1.0 mg correct and prevent the biochemical and radiographic abnormalities
of osteomalacia.of osteomalacia.
Renal tubular disordersRenal tubular disorders
Increased renal clearance of inorganic phosphorus and hypophosphataemiaIncreased renal clearance of inorganic phosphorus and hypophosphataemia
with normal glomerular filtration rate.with normal glomerular filtration rate.
X-linked familial hypophosphataemia (phosphate diabetes) is the commonestX-linked familial hypophosphataemia (phosphate diabetes) is the commonest
form ofform of hereditary vitamin D-resistant rickets (VDRR)hereditary vitamin D-resistant rickets (VDRR) and is characterised byand is characterised by
X-linked dominant inheritance, progressively severe skeletal deformities andX-linked dominant inheritance, progressively severe skeletal deformities and
dwarfism.dwarfism.
The bone disease is more severe in males, and females often exhibit onlyThe bone disease is more severe in males, and females often exhibit only
hypophosphataemia.hypophosphataemia.
In other patients, the tubular dysfunction may be part of Fanconi’s syndrome.In other patients, the tubular dysfunction may be part of Fanconi’s syndrome.
Rickets may also occur in proximal renal tubular acidosis.Rickets may also occur in proximal renal tubular acidosis.
Treated with large doses ofTreated with large doses of calciferol (2.5 to 10 mg per day) and oralcalciferol (2.5 to 10 mg per day) and oral
supplements of inorganic phosphate (1.4 g per day).supplements of inorganic phosphate (1.4 g per day). In renal tubular acidosis,In renal tubular acidosis,
sodium bicarbonate (5 to 15 mEq/kg per day) reverses the acidosis, improvessodium bicarbonate (5 to 15 mEq/kg per day) reverses the acidosis, improves
serum phosphate levels, heals the bone disease and with maintenance use ofserum phosphate levels, heals the bone disease and with maintenance use of
alkali, recurrence is prevented.alkali, recurrence is prevented.

55. In children with rickets, failure of cartilage
calcification is radiologically manifested by
frayed or irregularly widened and "cupped"
ends of growing metaphyses at the wrists,
knees and ankles
Characteristic shaft deformities of the legs
(genu valgum, genu varum, coxa vara)
may be present. Secondary
hyperparathyroidism usually manifests as
coarse cystic trabeculations and irregular
lacy subperiosteal erosions, especially
about the metaphyses of long bones at the
wrists, knees and ankles .
Vitamin D deficiency rickets around puberty
often shows a characteristic radiolucent
band in the submetaphyseal region,
especially at the wrists.

56. The pathognomonic radiological feature of
osteomalacia is the presence of
pseudofracture, a straight, transverse,
ribbon-like band of rarefaction representing
unmineralised bone. Pseudofractures, also
known as Looser’s zones or Milkman’s
fractures, are often bilateral and
symmetrical (Fig. 18.7). Common sites are
the concave side of the femoral necks and
shafts of long bones, ischio-pubic rami,
clavicles, ribs, scapulae, metacarpals and
metatarsal bones. In severe cases, the
vertebrae become biconcave and the
spaces at the symphysis pubis and
sacroiliac joints are widened. Narrowing of
the pelvic cavity from inward pressure of
the hips may lead to a triradiate pelvis

57. HyperparathyroidismHyperparathyroidism
Primary hyperparathyroidism:Primary hyperparathyroidism:
– Often an incidental findingOften an incidental finding
– May be part of MEN I, MEN IIMay be part of MEN I, MEN II
Secondary hyperparathyroidismSecondary hyperparathyroidism
– Compensates for chronic low Ca eg. Renal failure orCompensates for chronic low Ca eg. Renal failure or
malabsorptionmalabsorption
– [Ca[Ca2+2+
] and [PO] and [PO44
2-2-
] normal PTH high] normal PTH high
Tertiary hyperparathyroidismTertiary hyperparathyroidism
– Hyperplasia in longstanding secondary diseaseHyperplasia in longstanding secondary disease

58. Solitary Adenomas
A single abnormal gland is the cause in 80% of patients.∼
In 15% of patients, all glands are hyperfunctioning;∼ chief cell parathyroid hyperplasia
is usually hereditary and frequently associated with other endocrine abnormalities.
Hereditary Syndromes and Multiple Parathyroid Tumors
MEN 1 (Wermer's syndrome) consists of hyperparathyroidism and tumors of the
pituitary and pancreas, often associated with gastric hypersecretion and peptic ulcer
disease (Zollinger-Ellison syndrome).
MEN 2A is characterized by pheochromocytoma and medullary carcinoma of the
thyroid, as well as hyperparathyroidism.
MEN 2B has additional associated features such as multiple neuromas but usually lacks
hyperparathyroidism.
Each of these MEN syndromes is transmitted in an apparent autosomal dominant
manner.
The hyperparathyroidism jaw tumor (HPT-JT) syndrome occurs in families with
parathyroid tumors (sometimes carcinomas) in association with benign jaw tumors.

59. One-half or more of patients with hyperparathyroidism are asymptomatic.
Manifestations of hyperparathyroidism involve primarily the kidneys and the
skeletal system. Kidney involvement, due either to deposition of calcium in the
renal parenchyma or to recurrent nephrolithiasis, was present in 60–70%.
Nephrocalcinosis may also cause decreased renal function and phosphate retention.
The distinctive bone manifestation of hyperparathyroidism is osteitis fibrosa cystica,
which occurred in 10–25% of patients.Histologically, the pathognomonic features
are an increase in the giant multinucleated osteoclasts in scalloped areas on the
surface of the bone (Howship's lacunae) and a replacement of the normal cellular
and marrow elements by fibrous tissue.
X-ray changes include resorption of the phalangeal tufts and replacement of the
usually sharp cortical outline of the bone in the digits by an irregular outline
(subperiosteal resorption). In recent years, osteitis fibrosa cystica is very rare in
primary hyperparathyroidism, probably due to the earlier detection of the disease.

64. Renal OsteodystrophyRenal Osteodystrophy
Effect on bone of disordered calciumEffect on bone of disordered calcium
homeostasishomeostasis
May be osteomalacia, hyperparathyroidismMay be osteomalacia, hyperparathyroidism
Leads toLeads to
– Bone painBone pain
– Skeletal deformitySkeletal deformity
– Muscular weaknessMuscular weakness
– Ectopic calcificationEctopic calcification
– Growth retardationGrowth retardation

66. The clinical manifestations include bone pains and tenderness, fractures, growthThe clinical manifestations include bone pains and tenderness, fractures, growth
retardation, joint disease and abnormal calcification of cartilage.retardation, joint disease and abnormal calcification of cartilage.
Both osteomalacia and osteitis fibrosa cystica (OFC) may cause bone pain,Both osteomalacia and osteitis fibrosa cystica (OFC) may cause bone pain,
tenderness and muscle weakness.tenderness and muscle weakness.
Pain in the lower limbs, pelvis and back is particularly common and may worsenPain in the lower limbs, pelvis and back is particularly common and may worsen
on exercise.on exercise.
Proximal muscle weakness is common. Fractures are uncommon with OFC, butProximal muscle weakness is common. Fractures are uncommon with OFC, but
are a feature of aluminium-induced bone diseaseare a feature of aluminium-induced bone disease

67. The radiological features of renal
osteodystrophy are those of rickets and
osteomalacia and/or hyperparathyroidism .
Secondary hyperparathyroidism causes
subperiosteal erosions and small
subperiosteal cysts, endosteal resorption
and a reduction in the cortical width of long
bones.
In very severe cases, periosteal new-bone
formation may occur and the phalangeal
tufts may show marked acro-osteolysis.
The hyperparathyroid features usually do
not occur in low-turnover aluminium-related
bone disease.
In the late stages, rugger-jersey spine may
occur. Patients on long-term dialysis may
reveal pathologic bone cysts, destructive
arthritis and erosive spondyloarthropathy.

68. Control of hyperphosphataemia and acidosisControl of hyperphosphataemia and acidosis ::
Dietary phosphate is restricted to 700-900 mg per day with protein restriction to 40Dietary phosphate is restricted to 700-900 mg per day with protein restriction to 40
g/day and avoidance of dairy products.g/day and avoidance of dairy products.
Additionally, administration of calcium and aluminium compounds to bind intestinalAdditionally, administration of calcium and aluminium compounds to bind intestinal
phosphate is necessary.phosphate is necessary.
Aluminium compounds to bind phosphate in the intestine are almost always necessary;Aluminium compounds to bind phosphate in the intestine are almost always necessary;
these include aluminium hydroxide either as tablet/powder or in gel form. Thesethese include aluminium hydroxide either as tablet/powder or in gel form. These
preparations may lead to aluminium toxicity. The use of an anion exchange resin maypreparations may lead to aluminium toxicity. The use of an anion exchange resin may
be a better alternative.be a better alternative.
Oral vitamin DOral vitamin D22 and Dand D33 dose of 0.5 - 12 mg/day.dose of 0.5 - 12 mg/day.
Di hydro tachysterol (DHT)Di hydro tachysterol (DHT) is a synthetic compound which does not require prior renalis a synthetic compound which does not require prior renal
1-alpha hydroxylation for biological activity. A daily dose of 250-370 µg is sufficient to1-alpha hydroxylation for biological activity. A daily dose of 250-370 µg is sufficient to
cure osteitis fibrosa and osteomalacia in a majority of cases.cure osteitis fibrosa and osteomalacia in a majority of cases.
25(OH)D25(OH)D33 (dose 40-125 µg/day)(dose 40-125 µg/day) bypasses hepatic hydroxylation and is less likely to bebypasses hepatic hydroxylation and is less likely to be
stored in body fat or muscles.stored in body fat or muscles.

69. Paget’s DiseasePaget’s Disease
Osteitis DeformasOsteitis Deformas
↑↑ Bone resorptionBone resorption →→ ↑↑ bonebone
formationformation →→
develop large irregularly shapeddevelop large irregularly shaped
bones with poor mineralizationbones with poor mineralization →→
thick brittle bonesthick brittle bones
EtiologyEtiology
– Slow progressing diseaseSlow progressing disease
– Often occurs between 50-70 yearsOften occurs between 50-70 years
– Familial tendency in malesFamilial tendency in males
– Usually asymptomaticUsually asymptomatic

70. Paget’s DiseasePaget’s Disease
Clinical PresentationClinical Presentation
– Deep aching sensationDeep aching sensation ↑↑ with weightwith weight
bearingbearing
– Pain - mild to severe unrelated toPain - mild to severe unrelated to
activityactivity
– May have bony deformities – skullMay have bony deformities – skull
– Loss of heightLoss of height
Physical ExaminationPhysical Examination
– Kyphosis / Bowing of long bonesKyphosis / Bowing of long bones
– Conductive hearing lossConductive hearing loss
– Fracture healing is impairedFracture healing is impaired
– Complications – CHF / Paget’sComplications – CHF / Paget’s

71. Paget’s DiseasePaget’s Disease
DiagnosticsDiagnostics
– Serum alkaline phosphatase -Serum alkaline phosphatase -↑↑
– Urinary hydroxyproline -Urinary hydroxyproline - ↑↑
– Serum/ urinary citrate –Serum/ urinary citrate – ↑↑
– Serum uric acid –Serum uric acid – ↑↑in < 50%in < 50%
– X-RaysX-Rays
Early localized demineralizationEarly localized demineralization
Later bony overgrowth – irregularLater bony overgrowth – irregular
Mosaic patternMosaic pattern
– Bone scanBone scan
Metabolic activity-Metabolic activity- ↑↑

72. Paget’s DiseasePaget’s Disease
Clinical ManagementClinical Management
– AsymptomaticAsymptomatic
Monitor patientMonitor patient
– SymptomaticSymptomatic
NSAIDsNSAIDs
Calcitonin – relieve bone painCalcitonin – relieve bone pain
BisphosphonatesBisphosphonates
– Ambulation with assistive devicesAmbulation with assistive devices
Surgical InterventionSurgical Intervention
– Correction of malalignment /Correction of malalignment /
fracturesfractures

74. OSTEOGENESIS IMPERFECTAOSTEOGENESIS IMPERFECTA
Osteogenesis imperfecta is a heritable disorder of connectiveOsteogenesis imperfecta is a heritable disorder of connective
tissue due to defect intissue due to defect in synthesis of type I collagensynthesis of type I collagen interferinginterfering
with bone function.with bone function.
The usual clinical features include multiple fractures, blueThe usual clinical features include multiple fractures, blue
sclerae, deafness, high-pitched voice, deformities of longsclerae, deafness, high-pitched voice, deformities of long
bones, joint hyperextensibility, pectus deformity, dentalbones, joint hyperextensibility, pectus deformity, dental
abnormalities, thin skin and generally normal intelligence.abnormalities, thin skin and generally normal intelligence.
Many types have been identified; the congenital (newbornMany types have been identified; the congenital (newborn
type) is the most severe.type) is the most severe.
Routine biochemical investigations are typically normal;Routine biochemical investigations are typically normal;
elevations in serum alkaline phosphatase and urineelevations in serum alkaline phosphatase and urine
hydroxyproline levels occur with fractures.hydroxyproline levels occur with fractures.

75. Characteristic radiological
findings include generalised
osteopenia, deformities of long
bones from recurrent fractures,
collapsed vertebrae, defective
periosteal bone formation, thin
cortices and disordered
maturation of growing plates
(popcorn calcification).

76. OSTEOPETROSISOSTEOPETROSIS
Osteopetrosis is rare developmental disorder of bone characterised byOsteopetrosis is rare developmental disorder of bone characterised by
osteosclerosis and fractures. It results from insufficient resorption ofosteosclerosis and fractures. It results from insufficient resorption of
primary bone trabeculae.primary bone trabeculae.
Two distinct forms of the disease:Two distinct forms of the disease:
Malignant osteopetrosisMalignant osteopetrosis, of autosomal recessive inheritance,, of autosomal recessive inheritance,
presenting at birth or early infancy, is severe and death due topresenting at birth or early infancy, is severe and death due to
pancytopenia or obliteration of marrow cavity occurs in the firstpancytopenia or obliteration of marrow cavity occurs in the first
decade of life.decade of life.
Anaemia, hepatosplenomegaly, lymph node enlargement, cranialAnaemia, hepatosplenomegaly, lymph node enlargement, cranial
nerve palsies, hydrocephalus and death due to infection ornerve palsies, hydrocephalus and death due to infection or
haemorrhage are common.haemorrhage are common.
Flask-shaped swelling of bone ends, particularly around long bones,Flask-shaped swelling of bone ends, particularly around long bones,
and fractures may cause angulation and deformity.and fractures may cause angulation and deformity.
Mild form, is inherited as autosomal dominant, and is variable in ageMild form, is inherited as autosomal dominant, and is variable in age
of onset and severity. This is often discovered incidentally.of onset and severity. This is often discovered incidentally.

77. Plasma biochemistry is normal except for rise inPlasma biochemistry is normal except for rise in
alkaline phosphatase with fractures. Secondaryalkaline phosphatase with fractures. Secondary
hyperparathyroidism with elevated PTH and calcitriolhyperparathyroidism with elevated PTH and calcitriol
levels is often seen. Acid phosphatase is oftenlevels is often seen. Acid phosphatase is often
increased. In severe cases there is an excessiveincreased. In severe cases there is an excessive
positive calcium balance.positive calcium balance.
Radiologically, long bones are uniformly dense .Radiologically, long bones are uniformly dense .
Within the bone, particularly the spine and longWithin the bone, particularly the spine and long
bones, sclerotic foci are seen. Around this there is abones, sclerotic foci are seen. Around this there is a
more lucent region and peripheral to this is moremore lucent region and peripheral to this is more
sclerotic bone (bone within bone appearance).sclerotic bone (bone within bone appearance).

78. CARBONIC ANHYDRASE II DEFICIENCYCARBONIC ANHYDRASE II DEFICIENCY
Carbonic anhydrase II deficiency is characterised by osteopetrosis,Carbonic anhydrase II deficiency is characterised by osteopetrosis,
renal tubular acidosis and cerebral calcification.renal tubular acidosis and cerebral calcification.
Failure to thrive, developmental delay, short stature, frequentFailure to thrive, developmental delay, short stature, frequent
fractures, impaired vision from compression atrophy of optic nerve,fractures, impaired vision from compression atrophy of optic nerve,
and dental malocclusion are frequent problems.and dental malocclusion are frequent problems.
There may be hypotonia, apathy and muscle weakness. LifeThere may be hypotonia, apathy and muscle weakness. Life
expectancy appears to be normal.expectancy appears to be normal.
The radiologic findings are similar to those in osteopetrosis.The radiologic findings are similar to those in osteopetrosis.
Cerebral calcification appears around 2-5 years of age andCerebral calcification appears around 2-5 years of age and
complicatescomplicates onlyonly this type of osteopetrosis. Metabolic acidosisthis type of osteopetrosis. Metabolic acidosis
(proximal or distal renal tubular acidosis) may be present.(proximal or distal renal tubular acidosis) may be present.
The impact of correcting acidosis is not known since treatment couldThe impact of correcting acidosis is not known since treatment could
conceivably block the protective effect of acidosis on bone density.conceivably block the protective effect of acidosis on bone density.
Bone marrow transplantation is under evaluationBone marrow transplantation is under evaluation

79. HYPOPHOSPHATASIAHYPOPHOSPHATASIA
Hypophosphatasia is an inherited metabolic bone disease (rickets andHypophosphatasia is an inherited metabolic bone disease (rickets and
osteomalacia) characterised by generalised decrease in tissue nonspecificosteomalacia) characterised by generalised decrease in tissue nonspecific
(liver, bone, kidney) alkaline phosphatase (ALP); placental and intestinal(liver, bone, kidney) alkaline phosphatase (ALP); placental and intestinal
ALP activity is normal.ALP activity is normal.
Hypophosphatasia affects importantly only the skeleton and dentition.Hypophosphatasia affects importantly only the skeleton and dentition.
Four clinical types - perinatal (lethal), infantile, childhood and adult - areFour clinical types - perinatal (lethal), infantile, childhood and adult - are
known.known.
Rickets occurs in the infantile and childhood forms.Rickets occurs in the infantile and childhood forms.
In adults the disorder may be recognised in middle age. Osteomalacia andIn adults the disorder may be recognised in middle age. Osteomalacia and
calcium pyrophosphate disease may present in the adult form.calcium pyrophosphate disease may present in the adult form.
In the infantile form skeletal radiographs may reveal progressive skeletalIn the infantile form skeletal radiographs may reveal progressive skeletal
demineralisation and rickets. Radiolucent tongues may extend fromdemineralisation and rickets. Radiolucent tongues may extend from
growth plate cartilage into the metaphyses in the childhood form, andgrowth plate cartilage into the metaphyses in the childhood form, and
osteomalacia with pseudofractures may be present in adults.osteomalacia with pseudofractures may be present in adults.

80. Fibrodysplasia Ossificans Progressiva
Also called myositis ossificans progressiva;
Rare autosomal-dominant disorder.
Congenital deformities of the hands and feet and episodic soft tissue swellings
that ossify.
Ectopic bone formation occurs in fascia, tendons, ligaments, and connective
tissue within voluntary muscles. Tender, rubbery induration, sometimes
precipitated by trauma, develops in the soft tissue and gradually calcifies.
Heterotopic bone forms at these sites of soft tissue trauma.
Mortality is usually related to restrictive lung disease caused by an inability of
the chest to expand. Laboratory tests are unremarkable.
Bisphosphonates, glucocorticoids, and a low-calcium diet have largely been
ineffective in halting progression of the ossification.
Surgical removal of ectopic bone is not recommended.