Congenital Achondroplasia* Osteogenesis imperfecta* Osteopetrosis * Metabolic bone diseases Osteoporosis* Osteitis fibrosa cystica* Rickets and osteomalacia Renal osteodystrophy Disease caused by osteoclast dysfunction Paget’s disease* Osteonecrosis (avascular necrosis) ** Infections* Fractures Miscellaneous

1. 11
Non-neoplastic disorders of bone
1. Congenital
1. Achondroplasia*
2. Osteogenesis imperfecta*
3. Osteopetrosis *
2. Metabolic bone diseases
1. Osteoporosis*
2. Osteitis fibrosa cystica*
3. Rickets and osteomalacia
4. Renal osteodystrophy
3. Disease caused by osteoclast dysfunction
1. Paget’s disease*
4. Osteonecrosis (avascular necrosis) **
5. Infections*
6. Fractures
7. Miscellaneous

2. 22
Congenital disorders of bone
1. Achondroplasia
• (long bones not formed properly)
2. Osteogenesis imperfecta
• (Defective synthesis of type I
collagen)
3. Osteopetrosis:
• (Replacement of marrow cavity by
bone due to defective osteoclast
function)

3. 33
Achondroplasia
• An autosomal dominant condition in which
– there is impaired formation of the long
bones due to
– Impaired proliferation of cartilage at growth
plate.
• Is one of the MC causes of dwarfism
• Clinical findings:
– Normal sized head and vertebral column
– Shortened arms and legs (dwarfism)
– Normal intelligence, life span and
reproductive ability.
– Normal GH and insulin growth factor -1
levels.

4. 44
Achondroplasia
• Molecular basis:
– point mutation in gene
coding for fibroblast
growth factor
receptor 3 (FGFR3)
– Inhibits cartilage
synthesis at growth
plate
– Decreased growth of
long bones

5. 55
Osteogenesis imperfecta
• AKA "brittle bone diseases“ or fragilitas
ossium.
• A group of diseases having in common defective
synthesis of type I collagen.
– Due to mutations in genes coding for α1 & α2
chains of collagen.
• Pathology:
– Generalized osteopenia (brittle bone)
• Resulting in recurrent fractures and
skeletal deformity.
– Disease affects skeleton and other tissues
rich in type I collagen.

6. 66
Osteogenesis imperfecta
• Types: Several types are known (Type I-IV)
– Most are autosomal dominant***.
• Clinical findings:
– pathological fractures** at birth
– blue sclera** : due to reflection of underlying
choroidal veins.
– Deafness : involvement of bone of inner and
middle ear
– Thin dermis  easy bruising.
– Dental imperfections.
– Type II is lethal in utero

7. 77
Blue sclera
Osteogenesis imperfecta

8. 88

9. 99
Osteogenesis imperfecta

10. 1010
Osteopetrosis ("marble bone disease")
• Group of genetic diseases characterized by:
– decreased osteoclast function, leading to
• Decreased resorption, and
• Greatly increased density* of bone.
• Pathology:
– Increased bone density and thickening of
bone cortex
– Marrow cavity replaced by bone
– The thickened bones are brittle and fracture
easily.

11. 1111
Dense bones
of the
lower extremities
Obliteration of the
marrow space
Absence of marrow

12. 1212
Osteopetrosis
X-ray findings:
Osteosclerosis
Broadened metaphysis
Erlenmeyer
flask
shaped
deformity

13. 1313
• Occurs in two forms
– autosomal dominant (usually mild) or
– autosomal recessive (usually severe).
• Clinical findings:
– Pathologic fractures
– Pancytopenia and leukoerythroblastic blood
picture:
• Replacement of marrow cavity by bone.
– Extramedullary hematopoiesis:
hepatosplenomegaly
– Cranial nerve compression:
• Due to narrowing of cranial foramina
• May result in blindness, deafness and facial
nerve palsies.
• Treatment: bone marrow transplant

14. 1414
Metabolic diseases of bone

15. 1515
Osteoporosis
• Refers to increased porosity of skeleton.
• Occurs due to:
– Loss of organic bone matrix and minerals.
• Resulting in :
– decreased bone mass and density.
– decreased thickness of cortical and
trabecular bone.
• Osteoporotic bones:
– thin and fragile and are susceptible to
fracture.

16. 1616
Osteoporosis
• Pathogenesis:
– Osteoporosis results from a slight excess
of bone resorption over bone deposition,
continuing over many years.
• Epidemiology:
– Is the most common metabolic
abnormality of bone.
– MC occurs in postmenopausal Caucasian
women and the elderly.

17. 1717
TYPES of osteoporosis
A: Localized : e.g. disuse OP of a limb
B: Generalized: involves entire skeleton. Two types
1. Primary:
– Old age (Senile)
• Osteoblasts with diminished capacity to
make new bone
• Physical inactivity
– Estrogen deficiency (postmenopausal)
2. Secondary: due to underlying disease
– Cushing’s disease (hypercortisolism)
– Drugs (heaprin and steroids)
– Space travel

18. 1818
Postmenopausal osteoporosis
Pathogenesis
• Is secondary to estrogen deficiency.
• Normally Estrogen:
– Stimulates OPG production
– Decreases production of M-CSF
– Decreases response of osteoclasts to RANK
ligand.
– Net result:
• Decreased formation of osteoclasts
• Decreased bone resorption

19. 19
Postmenopausal osteoporosis
Pathogenesis………
• Estrogen deficiency results in:
• ↑production of IL1 and TNF by monocytes

• Increased activity of RANK ligand and M-
CSF
• ↑ osteoclast activity  bone loss.

20. 2020
Peak bone mass
Osteoporosis
Menopause
↓ estrogen
↑ IL1,TNF
↑ RANK ligand, M-CSF
↑ osteoclast activity
Aging
↓ activity of
Osteoprogenitor cells
↓ activity of osteoblasts
↓ physical activity
Physical activity Nutrition
Genetic factors

21. 2121

22. 2222
Osteoporotic
vertebral body
Normal
Vertebral body

23. 2323
FractureOsteoporosis

24. 2424
N L K

25. 25
Osteoporosis
• Clinical findings:
– Bone pain
– Weight bearing bones predisposed to #
• Compression # of vertebral bodies
(most common)
• Colles’ # of distal radius.
• # femoral neck.
– Loss of height and kyphosis
25

26. 2626

27. 2727
Pathology
• thin cortical bone and thin trabecular bone

28. 2828
• Diagnosis:
– Dual energy X ray absorptiometry (DEXA)
• evaluate bone density.
• Prevention of postmenopausal osteoporosis:
– weight bearing exercises: walking, not swimming
– calcium, vitamin D supplements
– estrogen replacement therapy
• Unopposed estrogen increases the risk of
endometrial Ca.
• Prevented by addition of progesterone.
• Treatment:
– Bisphosphonates: inhibit bone resorption.
– Calcitonin: inhibits osteoclasts
– SERM: selective estrogen receptor modulators

29. 2929
Osteitis Fibrosa Cystica
( von Recklinghausen disease of bone)
• The cause is primary or secondary hyperparathyroidism
1. Primary hyperparathyroidism :
– Parathyroid adenoma  ↑ PTH
– Parathyroid hyperplasia  ↑ PTH
2. Secondary hyperparathyroidism :
– prolonged hypocalcemia (renal failure) increased
PTH.
• Increased levels of PTH
– Activates osteoblasts, which in-turn activates
osteoclasts resulting in bone resorption and
hypercalcemia.

30. 3030
Osteoclasts Fibrosis Osteoclasts in a fibrous stroma
“Brown tumor” of hyperparathyroidism

31. 3131

32. 3232
• Characterized by:
– Wide spread osteolytic lesions.
– Predisposing to Deformity , microfractures
and
– Secondary hemorrhages with formation of
cysts.
– OFC can manifest as “Brown tumor” of bone
characterized by:
• Cystic spaces lined by multinucleated
osteoclasts, filled with fibrous tissue, and
with brown discoloration resulting from
hemorrhage.
Osteitis Fibrosa Cystica

33. 3333
Rickets and osteomalacia
• Both diseases characterized by
– Decreased mineralization of newly formed
bone.
– Usually caused by deficiency or abnormal
metabolism of vitamin D.
• Osteomalacia:
– Cause is Vitamin D deficiency in adults
• Rickets:
– Cause is vitamin D deficiency in children
• See nutrition lectures***.

34. 3434
Renal osteodystrophy
• Osteomalacia secondary to chronic renal
disease.
• Pathogenesis: Chronic renal failure causes
– Hypocalcemia
• Due to lack of conversion of inactive
vitamin D into active vit.D
– Hypocalcemia results in secondary
hyperparathyroidism
– PTH secretion stimulates osteoclast
activity

35. 3535
Paget’s disease of bone
OSTEITIS DEFORMANS

36. 3636
Paget disease of bone (osteitis deformans)
• Skeletal disease characterized by episodes of:
– Excessive and disordered bone resorption by
osteoclasts followed by
– Exuberant but disorganized bone formation,
producing
• thickened but weak bone that is
• susceptible to deformity and #.
• Epidemiology:
– Primarily occurs in elderly men (>40 yrs).
• Etiology:
– Cause unknown ( ? paramyxovirus)

37. 3737

38. 3838
Paget disease of bone
• Forms of involvement:
– Monostotic: involving one bone
– Polystotic : involving multiple bones.
– Common bones include:
• pelvis >skull> femur.

39. 3939
Pathogenesis
• Three stages of Paget disease:
1.Osteolytic stage
2.Mixed osteolytic-osteoblastic stage
3.Osteosclerotic (burnt out stage)

40. 4040

41. 4141
Paget disease of bone : Stages
• Osteolytic Stage:
– osteoclastic resorption of bone predominates
• Mixed osteolytic and osteoblastic stage: characterized
by
– Osteolytic and increased osteoblastic bone formation
(usually woven bone).
– New bone: poorly mineralized, soft and weak.
• vulnerable to # and deformation.
• the bone is deposited in a tile like or mosaic
pattern which is pathognomonic of Paget disease.
• increased alkaline phosphatase levels.
• Osteosclerotic stage:
– Osteoblastic activity predominates

42. 4242
• Clinical findings:
– Asymptomatic in most cases
– Elevated alkaline phosphatase*
– Bone pain from Pathologic fractures*
– Skeletal deformities* (tibial bowing, skull
enlargement; increased hat size)
– Hearing loss:* narrowing of foramina
– Warmth of overlying skin due to bone
hypervascularity.
– High output cardiac failure (due to AV
connections in vascular bone)*
– Increased risk of osteogenic sarcoma*.

43. 4343
Pathology
• Microscopic features:
– Haphazard arrangement of cement lines
creating a “mosaic pattern” .

44. 4444Normal bone

45. 4545
Mosaic pattern of lamellar bone

46. 4646Paget's disease of bone: Mosaic pattern

47. 4747
Osteonecrosis (Avascular necrosis)
• Ischemic infarction of bone & bone marrow.
• Causes of ischemia:
– Vascular interruption (fracture)
• (femoral neck #  bleeds into capsule 
compromise medial femoral circumflex
artery  avascular necrosis)
– Corticosteroids* (most common) (SLE
patients)
– Sickle cell disease, Caisson disease.
• Common sites include
– femoral head
– Scaphoid bone.

48. 4848
Osteonecrosis: Morphology
• Osteonecrosis: Can involve
– The medullary cavity or
– The subchondral region
• Medullary infarct:
– involves marrow and the cancellous bone.
– usually clinically silent.
– Remains stable
• Subchondral infarct:
– Involves the subchondral bone
• Wedge shaped area of necrosis with viable overlying
articular cartilage
– Causes chronic pain
– Collapse  predispose to osteoarthritis

49. 4949
Osteonecrosis

50. 5050

51. 5151
Osteonecrosis in children
• May involve characteristic sites:
• Legg-Calve-Perthes disease:
– Aseptic necrosis involving the ossification
center in the femoral head.
– Occurs most often in boys 3-10 years of
age.
– Pain in knee or limp
– secondary osteoarthritis is common.
• Kohler bone disease:
– Aseptic necrosis of navicular bone

52. 5252
Osgood-Schlatter disease
• Inflammation of
proximal tibial
apophysis at insertion
of patellar tendon.
• Affects physically
active boys 11-15 yrs
of age
• Produces permanent
knobby appearing
knees.