This document provides an overview of bone structure, function, development, and disorders. It discusses the normal structure and cellular components of bone, including osteoblasts, osteocytes, and osteoclasts. It describes developmental disorders like osteogenesis imperfecta and osteopetrosis. Acquired disorders covered include osteopenia, osteoporosis, Paget's disease, rickets, hyperparathyroidism, and renal osteodystrophy. Fractures and the healing process are also summarized. The document is intended to teach pathology of bone and cartilage disorders.

1. BONES I
Dr Venugopal Rao MD
1
PATHOLOGY II

2. Learning objectives
•To learn about the Developmental and acquired
bone and cartilage disorders.
•To learn indetail about the pathology of
osteoporosis, osteopenia, rickets , osteomalacia.

3. Bone – Structure and Function
• adult human skeleton is composed
of 206 bones and accounts for
approximately 12% of body weight.
• functions of bone include
mechanical support, transmission
of forces generated by muscles,
protection of viscera, mineral
homeostasis, and providing a niche
for production of blood cells.
• constituents of bone include an
extracellular matrix and specialized
cells responsible for production
and maintenance of the matrix.

4. Bone – Structure and Function – Extracellular Matrix
• Bone matrix is the extracellular
component of bone.
• it is composed of an organic
component known as osteoid
(35%) and a mineral component
(65%).
• osteoid is made up of
predominantly type I collagen with
smaller amounts of
glycosaminoglycans and other
proteins, which are grouped
according to function (Table 26-1)

5. Bone - Extracellular Matrix
• the unique feature of bone matrix,
its hardness, is imparted by the
inorganic moiety hydroxyapatite
[Ca10(PO4)6(OH)2]
• hydroxyapatite also serves as a
repository for 99% of the body’s
calcium and 85% of its phosphorus
• the bone matrix is synthesized in
one of two histologic forms, woven
or lamellar
Woven bone (A) is more cellular and
disorganized than lamellar bone (B)

6. Bone – Structure and Function – Cells
• the cellular component of
mature bone consists of
bone synthesizing
osteoblasts, osteocytes,
and bone-resorbing
osteoclasts
• osteoblasts, located on the
surface of the matrix,
synthesize, transport and
assemble the matrix and
regulate its mineralization A, Active osteoblasts synthesizing bone matrix. The
surrounding spindle cells represent osteoprogenitor cells

7. Bone – Structure and Function – Cells
• osteocytes are interconnected by
an intricate network of dendritic
cytoplasmic processes through
tunnels known as canaliculi.
• osteocytes help to control
calcium and phosphate levels in
the microenvironment
• osteocytes also detect
mechanical forces and translate
them into biologic activity—a
process called
mechanotransduction.
Osteocyte in Lacuna

8. Bone – Structure and
Function – Cells
• osteoclasts: specialized
multinucleated macrophages
derived from circulating
monocytes - responsible for bone
resorption
• by means of cell surface integrins,
osteoclasts attach to bone matrix
and create a sealed extracellular
trench (resorption pit).
• secretion of acid and neutral
proteases (predominantly matrix
metalloproteases, [MMPs]) into
the pit results in dissolution of
the inorganic and organic
components of bone.
B, Two osteoclasts resorbing bone.

9. Bone
Cells

10. Bones - Developmental Disorders of Bone and Cartilage
• abnormalities in a
single bone or a
localized group of
bones are called
dysostoses - arise
from defects in the
migration and
condensation of
mesenchyme.
- they manifest as
absent,
supernumerary or
abnormally fused
bones
Mandibulofacial dysostosis: A syndrome that includes various
malformations of specialized structures in the head and neck, including
notched eyelid fissures, hypoplasia of the mandible, enlarged mouth
with high or cleft palate and incorrectly positioned teeth, and atypical
hair growth. Franceschetti – Klein Syndrome

11. Bones - Developmental Disorders of Bone and Cartilage
• global
disorganization
of bone and/or
cartilage is called
a dysplasia
• developmental
abnormalities
can be
categorized by
the associated
genetic defect.

12. Bones -
Dysplasia

13. Bones - Developmental Disorders of Bone and Cartilage
Defects in Extracellular
Structural Proteins:
• mutations in the genes for
type I collagen underlie
most types of
osteogenesis imperfecta
(brittle bone disease) -
characterized by defective
bone formation and skeletal
fragility.
• the fundamental
abnormality in OI is too
little bone

14. Bones - Osteogenesis Imperfecta
• the result is extreme skeletal fragility
other findings include:
• blue sclerae caused by decreased collagen
content, making the sclera translucent and
allowing partial visualization of the
underlying choroid;
• hearing loss related to both a
sensorineural deficit and impeded
conduction due to abnormalities in the
bones of the middle and inner ear
• dental imperfections (small, misshapen,
and blue-yellow teeth) secondary to a
deficiency in dentin

15. Developmental Disorders of Bone and Cartilage - OI

16. Bones - Osteogenesis Imperfecta

17. Bones - Developmental Disorders of Bone and Cartilage
Defects in Metabolic Pathways (Enzymes,
Ion Channels, and Transporters):
• Osteopetrosis aka: marble bone disease and
Albers-Schönberg disease, refers to a group of
rare genetic diseases that are characterized by
reduced bone resorption and diffuse symmetric
skeletal sclerosis due to impaired formation or
function of osteoclasts.
• the term osteopetrosis reflects the stone-like
quality of the bones.
• However, the bones are abnormally brittle and
fracture easily, like a piece of chalk.
Figure 26-7 Radiograph of the upper extremity in
an individual with osteopetrosis. The bones are
diffusely sclerotic, and the distal metaphyses of the
ulna and radius are poorly formed

18. Bones - Developmental Disorders of Bone and Cartilage
Defects in
Metabolic
Pathways
(Enzymes, Ion
Channels, and
Transporters):
Osteopetrosis
Figure 26-8 Section of proximal tibial diaphysis from a fetus with
osteopetrosis. The cortex (1) is present, but the medullary cavity
(2) is filled with primary spongiosa, which replaces the
hematopoietic elements.

19. Developmental Disorders of Bone and Cartilage - Osteopetrosis

20. Bones - Acquired Disorders of Bone and Cartilage
Osteopenia and Osteoporosis:
• osteopenia refers to decreased bone mass
• osteoporosis is osteopenia that is severe enough to significantly increase the
risk of fracture.

21. Bones - Acquired Disorders of Bone
and Cartilage
Osteopenia and
Osteoporosis:
• the disorder may
be localized to a
certain bone or
region, as in
disuse
osteoporosis of a
limb
• may involve the
entire skeleton, as
a manifestation of
a metabolic bone
disease

22. Bones - Acquired Disorders of Bone and Cartilage
Osteopenia
and
Osteoporosis:
• generalized
osteoporosis
may be
primary or
secondary to
a large
variety of
conditions

23. Bones - Acquired Disorders of Bone and Cartilage
Osteopenia and
Osteoporosis:
• the disease is very
common with marked
morbidity and mortality
from fractures.
• multiple factors including
peak bone mass, age,
activity, genetics,
nutrition and hormonal
influences contribute to
its pathogenesis.

24. Bones - Acquired Disorders of Bone and Cartilage
Osteopenia and
Osteoporosis:

25. Bones - Acquired Disorders of Bone and Cartilage
Osteopenia and
Osteoporosis:

26. Bones - Acquired Disorders of Bone and Cartilage
Osteopenia and
Osteoporosis:

27. Bones - Acquired Disorders of Bone and Cartilage
• Paget disease is a disorder of locally
increased but disordered bone.
• genetic and possibly viral infectious
etiologies have been proposed.
• relatively common in whites: England,
France, Austria, regions of Germany,
Australia, New Zealand, the USA
• rare in the native populations of
Scandinavia, China, Japan, and Africa.
• the exact incidence is difficult to
determine because many affected
individuals are asymptomatic

28. Acquired Disorders of Bone and Cartilage – Paget Disease
• the disease shows remarkable
histologic variation over time
and from site to site.
• the hallmark is a mosaic
pattern of lamellar bone,
seen in the sclerotic phase.
• this jigsaw puzzle-like
appearance is produced by
unusually prominent cement
lines, which join haphazardly
oriented units of lamellar bone

29. Bones - Acquired Disorders of
Bone and Cartilage – Paget Disease
• This unique skeletal disease can
be divided into three sequential
phases:
(1) an initial osteolytic stage
(2) a mixed osteoclastic-
osteoblastic stage, which ends with
a predominance of osteoblastic
activity and evolves ultimately into
(3) a final burned-out quiescent
osteosclerotic stage

30. Paget
Disease

31. Macroscopic observation of internal
structural changes in the right clavicle
(Left) compared with the normal
cortical and trabecular structure of an
unaffected right clavicle (Right).

32. Rickets and Osteomalacia
• manifestations of vitamin D deficiency or its
abnormal metabolism (Chapter 9).
• fundamental defect is an impairment of
mineralization - result is accumulation of
unmineralized matrix. (unlike osteoporosis, in
which the mineral content of the bone is normal and
the total bone mass is decreased).
• Rickets - the disorder in children -
interference with the deposition of bone in
the growth plates.
• Osteomalacia - adult counterpart -bone
formed during remodeling is undermineralized
- predisposition to fractures. Rickets: note bowing of legs due to
formation of poorly mineralized bones.

33. Acquired
Disorders of
Bone and
Cartilage
Rickets and
Osteomalacia
Rickets. A, Normal costochondral junction of a young child illustrating formation of cartilage palisades and orderly
transition from cartilage to new bone. B, Detail of a rachitic costochondral junction in which the palisades of cartilage is
lost. Darker trabeculae are well-formed bone; paler trabeculae consist of uncalcified osteoid

34. Rickets and Osteomalacia
Vitamin D deficiency – effects on bone
There is inadequate substrate for the renal
1α-hydroxylase (1), yielding a deficiency of
1,25(OH)2D (2), and deficient absorption
of calcium and phosphorus from the gut
(3), with consequently depressed serum
levels of both (4). The hypocalcemia
activates the parathyroid glands (5),
causing mobilization of calcium and
phosphorus from bone (6a).
Simultaneously, the parathyroid hormone
(PTH) induces wasting of phosphate in the
urine (6b) and calcium retention. As a
result, the serum levels of calcium are
normal or nearly normal, but phosphate
levels are low; hence, mineralization is
impaired (7).

35. Bones - Acquired Disorders of Bone and Cartilage
Hyperparathyroidism
• arises from either
autonomous or
compensatory
hypersecretion of PTH
• can lead to osteoporosis,
brown tumors, and
osteitis fibrosa cystica.
• in developed countries,
where early diagnosis is the
norm, the above
manifestations are rarely
seen.

36. Parathyroid hormone
(PTH) plays a central role in
calcium homeostasis via:
• osteoclast activation,
increasing bone
resorption and calcium
mobilization. PTH
mediates the effect
indirectly by increased
RANKL expression on
osteoblasts.
• increased resorption of
calcium by the renal
tubules
Hyperparathyroidism

37. Parathyroid hormone (PTH)
plays a central role in calcium
homeostasis via: ctd.
• increased urinary excretion
of phosphates
• increased synthesis of active
vitamin D, 1,25(OH)2-D, by
the kidneys, which in turn
enhances calcium
absorption from the gut and
mobilizes bone calcium by
inducing RANKL on
osteoblasts
Hyperparathyroidism

38. Hyperparathyroidism

39. Bones - Acquired Disorders of Bone and Cartilage
Renal Osteodystrophy
• describes collectively the
skeletal changes that occur
in chronic renal disease,
including those associated
with dialysis.
• represents the constellation
of bone abnormalities
(osteopenia, osteomalacia,
hyperparathyroidism, and
growth retardation) from
chronic renal failure.

40. Bones - Acquired Disorders of Bone and Cartilage
Renal
Osteodystrophy
• The mechanisms
are complex but
stem from
decreased
tubular,
glomerular, and
hormonal
functions of the
kidney

42. Fractures
• Defined as a loss of
bone integrity due to
mechanical injury
and/or diminished bone
strength.
• fractures are some of
the most common
pathologic conditions
affecting bone

43. Fractures
Fracture types -
affect treatment:
• Simple: the
overlying skin is
intact.
• Compound: the
bone communicates
with the skin
surface.

44. Fractures
• Comminuted:
the bone is
fragmented.
•Displaced: the
ends of the
bone at the
fracture site
are not aligned.

45. Fractures
• Stress: a slowly
developing fracture that
follows a period of
increased physical
activity in which the
bone is subjected to
repetitive loads
• “Greenstick”: extending
only partially through the
bone, common in infants
when bones are soft
• Pathologic: involving
bone weakened by an
underlying disease
process, such as a tumor
Stress fracture of the
second metatarsal
bone

46. Fractures - HEALING
• vessel rupture –
hematoma – fibrin mesh
– framework for
inflammation,
fibroblasts, capillaries
• release of PDGL, TGF-β,
FGF – activation of
osteoprogenitor cells –
osteoblastic &
osteoclastic activity
stimulated
• at end of first week soft
tissue callus / procallus
formed – ends of bone …
some anchorage

47. Fractures - HEALING
• bony callus forms at end of 2nd or 3rd
week - woven bone, chondrocytes,
fibro and hyaline cartilage formed –
fracture site stabilized
• cartilage undergoes endochondral
ossification – newly deposited
trabeculae – fractured ends bridged –
mineralizes – controlled weight
bearing may be tolerated
• mature callus subject to weight –
bearing - excess tissues not physically
stressed are resorbed
• lamellar bone and medullary cavity
formed

48. Fractures - HEALING
Sequence of events in the
healing of a fracture can be
easily impeded or even
blocked
• displacement,
comminuted fractures:
some deformity
• inadequate mobilization
– callus movements:
delayed union / nonunion
– pseudoarthrosis
• infection, esp open
fractures
• malnutrition, skeletal
dysplasia

49. Fractures - HEALING
• children / young adults: usually near perfect union
• older adults: usually assoc. w. osteoporosis, osteomalacia – surgery usually needed

50. Thank you all