1. Metabolic Bone Disease
Brian G Caserto DVM DACVP
S2116 Schurman Hall
3‐4125
bgc7@cornell.edu

2. Anatomy Review
2

3. Bone Organ

4. Bone‐Histology
• Periosteum
•CoTcal bone
‐ Osteons
‐ Haversian systems
‐ Volkmanns canals
‐ Canaliculi
•Endosteum
•Cancellous/
Trabecular Bone
•Marrow
Current Opinion in Rheumatology 2006, 18 (suppl
1):S3–S10

5. Bone Histology
CorTcal bone‐ Cancellous bone‐Woven when newly
compact osteonal (adult). Can be formed, but remodeled to lamellar later
formed as woven bone in large
animals, and later remodeled into
lamellar

6. Bone‐ Osteoid Pa[erns
• Pa%erns of Osteoid
‐Lamellar
•Slowly produced
•Mature/remodeled
‐Woven
•rapidly produced
•immature/new bone
Woven Lamellar

7. Bone Cells
• Osteoblasts
• Chondrocytes • Osteoclasts
• Osteocytes • monocyte/macrophage
• Blood vessels
• HematopoieTc cells lineage
• Osteoprogenitor cells
• Stromal fibrous and
adipose Tssue

8. Blood Supply of Bone
• Blood Supply
– Nutrient artery
• Mid diaphysis, anastomoses with metaphyseal arteries
– Metaphyseal arteries‐ proximal and distal
• Penetrate the cortex and anastomose with branches of the nutrient artery
(protect against infarcTon)
• Supply the chondrocytes nearest the metaphysis and parts of the cortex
– Make hairpin loops and are predisposed to bacterial emboli
– Periosteal arteries
• Sites of fascial a[achment and supply outer cortex
– Epiphyseal arteries
• Supply the chondrocytes nearest the epiphysis, and the epiphysis

9. Bone Growth, FormaTon and
Remodeling
9

10. Bone FormaTon (modeling)
• Endochondral • Intramembranous
– CarTlage precursor – Mesenchymal cells
differenTate directly
– CarTlage is removed and
into osteoblasts
replaced by osteoid
which lay down
– Long bones cancellous bone
– Base of the skull – Horizontal ramus of
– Ribs, vertebrae, hips the mandible
– Dorsal bones of the
skull
– Osseous metaplasia

11. Endochondral OssificaTon
• Long bones
• Vertebrae
• Base of the skull
• Pelvis

12. Intramembranous ossificaTon
• Direct differenTaTon of mesechymal cells into
osteoblasts (no carTlage model)
• Calvaria
• Mandible
• Hard palate
• Maxilla 12

13. Bone Remodeling
• AcTvaTon ‐‐> ResorpTon ‐‐> FormaTon
• Bone Metabolic Unit
• AcTvaTon of Osteoblasts/Osteoclasts
• Osteoclast ResorpTon of bone
• FormaTon of bone by Osteoblasts
• Osteoclast resorpTon of woven osteoid and deposiTon
of lamellar bone
• Enlargement of the medullary cavity during growth
• ResorpTon of bone in pathologic disease

14. Bone Remodeling‐ Howships Lacunae
Osteoclasts
Howships lacunae
Howships lacunae
14

15. Ac4va4on of Remodeling Osteoclast
differenTaTon and OC binding to OC acid
PTH, Vit D OB acTvaTon RGD ligand producTon
RANK receptor
ODF/RANK
Osteoblast ligand
Osteoclast
Bound or TGF
diffusible RGD ligand in
osteoid
H+ into
ECM
Osteoprotegrin
Cessa4on of Remodeling
CollagenolyTc
NegaTve feedback on OC via TGF‐beta
Enzymes
and Osteoprotegrin inhibiTng ODF

16. Osteoclasts and Bone
Resorp4on
Sealing zone
Bone surface
Howships lacunae
Carbonic
Anhydrase
Mineral + H+  HPO4 and Ca++ H2O + CO2 Lysosome
Osteoclast H2CO3 Enzymes
Demineralized Collagen + MMP/
Collagenase  Bone resorpTon
ECM/Bone H+ (pH 4‐5) MMP/ Collagenase

17. Bone Remodeling Units (BRU’s)
Cujng Cone
Osteon‐
cortex
Haversian
canal
Woven Bone or lamellar bone
BRU‐ Lamellar
trabeculae bone

18. Metabolic Bone Disease in
Veterinary Medicine
18

19. What is metabolic bone disease?
• Any systemic condiTon • Examples:
that results in: – Hyperparathyroidism
–Reduced bone strength – Vit D imbalance
– Altered mineralizaTon – Calcium/Phosphorus
imbalance
or composiTon
– Copper deficiency
– Protein deficiency

20. Calcium Homeostasis
Hormones:
•PTH
•Increased renal absorpTon of Calcium
•Decrease renal reabsorp4on of
phosphorus in the PCT
•Increase renal conversion of 25‐OH D3
to 1,25‐(OH)2 D3
•increased osteoclast bone resorpTon
•Vit D Serum Ionized Calcium
•Increases intesTnal absorpTon of
calcium (upregulate calbindin)
•Increase renal resorpTon of calcium
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21. EvaluaTon of Bones
• Disorders of mineraliza4on • Disorders of Bone forma4on
– Osteoid – Osteopenia
• Osteomalacia – Osteoporosis
– Physeal Car4lage – Resopr4on > Forma4on
• Rickets – Scurvy
• Osteochondrosis • abnormal osteoid
– Fibrous Osteodystrophy formaTon
21

22. MineralizaTon Balance
– Decreased MineralizaTon ‐Increased MineralizaTon
– Vit D Deficiency – Vit D Toxicity (son Tssue
mineralizaTon)
– Calcium Deficiency
– Mild Bone Changes
– Phosphorus deficiency
– inhibiTon of Bone resorpTon
(sclerosis)
So3 Bones, Growth Plate problems Mild bone sclerosis/systemic problems
Osteomalacia MetastaTc son Tssue
Rickets mineralizaTon
Osteochondrosis
22

23. ResorpTon/FormaTon Balance
ResorpTon > FormaTon FormaTon > ResorpTon
Decreased Bone Mass Increased Bone Mass
Hyperostosis/ New bone
Osteopenia/Osteoporosis
Osteosclerosis
Osteopetrosis
23

24. Osteopenia/ Osteoporosis
Bone resorpTon > Bone formaTon
– Age related
– Hormone related
– NutriTonal
24

25. Osteopenia
Osteopenia and
serous atrophy of
fat, from
Normal bone starvaTon
25

26. Osteopenia of trabecular bone
Normal Medullary bone (trabecular/ Osteopenia‐ thin trabeculae, reduced bone
cancellous bone) mass

27. Osteopenia of corTcal bone
Normal Cortex Osteopenia‐ “CancellozaTon” of
the cortex

28. Osteopenia in a growing animal
Osteopenia
• Loss of hypertrophic zone of
carTlage
• Transient arrest of physeal
growth
• Transverse trabeculae of
bone= Growth Arrest Lines
‐ Causes
‐ starvaTon, illness

29. Growth Arrest Lines

30. T-score”.
“A skeletal disorder characterized by compro-
Osteoporosis
mised bone strength predisposing to an increased
risk of fracture”.
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manifest as bone pain, pathologic fractures and malformaTon
Normal Osteopenia Osteoporosis
Fig. 3.1. Progressive architectural deterioration of cancellous bone: increased osteoclastic resorption cavities and marked attenu-
Bartl…. Pathogenesis of Osteoporosis. Osteoporosis (2009)
ation of cancellous bone (osteopenia); disconnected trabeculae, no longer a network (established osteoporosis)

31. o a Question of Quality! Osteoporosis 33
Bone strength
OCl
e OB
y,
re- Bone density Bone architecture Bone remodelling Bone material
erial (DXA method) (x-ray, CT, biopsy)) (marker, biopsy)) (marker, biopsy))
• In Osteoporosis the quality of bone is compromised
M‐
Strength
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• Due to changes in bone mineralizaTon, or
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resorpTon/formaTon imbalance
(2009)
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32. Bones affected by Osteoporosis
• Bones with lots of • Architecture
trabeculae compared to ‐ Horizontal lines
corTcal bone disappear first
–Vertebral bodies ‐ VerTcal lines have
–Ribs more load
–Femoral neck
–Heel (humans)

33. Scurvy (Vit C Deficiency)
Abnormal Osteoid/Collagen formaTon
Bone formaTon < bone resorpTon
33

34. Scurvy‐Vitamin C Deficiency
• Pathophysiology
– Ascorbic acid
• component of lysyl and
prolyl hydroxylase
• HydroxylaTon of
procollagen
• parTcipates in cross linking and
helix formaTon
Fragile helixes, and highly
soluble, easily degraded,
decreased secreTon
34

35. Scurvy
• GULO oste
ASC
–L‐gulonolactone
EXP
oxidase M
con
• Non‐funcTonal eats
vita
mutaTon TD.
C in
–Primates dose
Vita
–Humans vide
anti
–Guinea Pigs mg/
that
FIGURE 1. Ascorbic acid synthesis pathway. Conversion of glucuronate to of p
L-gulonate occurs mainly through GR. AR is a minor contributor. GULO con-
J Biol Chem (2010) vol. 285 (25) pp. 19510‐20
verts L-gulonate to ASC. Gene knockouts in our mouse lines are numbered
info
1–3. Primates, guinea pigs, and the sfx congenic mouse have deletions of the
35 A
GULO gene (5) and are unable to synthesize ASC. An AR/GR double knock-out

36. Scurvy‐ Gross Lesions
• Gross
– Joint swelling
– Sub‐periosteal and periarTcular
hemorrhage
– Fragile metaphyses, with
hemorrhage, and separate easily
from adjacent physes
– Bones are osteopenic, fragile
– Guniea pigs with subclinical
scurvy‐ diarrhea, weight loss,
dehydraTon
• Radiographically‐ carTlage spicules
of the scorbuTc lajce are highly
mineralized and appear as
radiodense bands in the metaphysis.
Primate‐ cephalohematoma (top) and costo‐vertebral hemorrhage

37. Guinea Pig Scurvy
• Enlarged costochondral junc4on
‐ Differs from rickets (in rickets the
enlargement is in the metaphysis
above the costochondral juncTon
• Periar4cular Hemorrhage
‐ Weak blood vessels from poorly
formed collagen
37

38. Scurvy‐ Histopath
• Histopath
– ScorbuTc lajce (SL)‐ Mineralized carTlage
in the primary spongiosa
– Myelofibrosis
– Fractures of trabeculae, hemorrhage (FX)
FX
SL
Normal Scurvy
38

39. Rickets/Osteomalacia
Bone mineralizaTon < Bone formaTon
Results in poorly mineralized osteoid
39

40. Rickets/Osteomalacia
• What is required for bone mineralizaTon?
–Vitamin D , Calcium, Phosphorous
• SuscepTbility
–Llama > Sheep‐ hypophosphatemic rickets
–Ca[le, Horses Rare, no inherited forms
–Pigs‐ nutriTonal and inherited forms
–Dogs and cats‐ rare‐ Phosphorous is plenTful in meat
diets, however high phosphorus, low calcium diets
can cause rickets and osteomalacia
40

41. Rickets
•Pathophysiology
•Impaired mineraliza4on
•Growth carTlage
•Physeal abnormaliTes, failure of endochondral
ossificaTon
•AccumulaTon of unmineralized osteoid
•Onen seen in combinaTon with osteopenia if the cause is
nutriTonal (StarvaTon)
41

42. Inherited Rickets in Corriedale Sheep
• Skeletal deformiTes
• Irregular, enlarged physis
• Parathyroid hyperplasia
42

43. Phytase Deficiency in Broiler Chickens
• Phytase extracts • Hypophosphatemia
phosphorpus from ‐ Rickets or
phytate for use by osteomalacia
animals
–Chickens
–Pigs

44. Osteomalacia in StarvaTon
Ribs, Osteomalacia = son bones
•Causes
•Inadequate Vit D
•Inadequate Calcium
•Inadequate protein
•Onen seen in combinaTon
with osteopenia if the
cause is nutriTonal
(StarvaTon)
Femur, Osteopenia and serous atrophy 44

45. Fibrous Osteodystrophy
Bone mineralizaTon < Bone formaTon
combinaTon of Osteomalacia and
Fibrous Dysplasia
45

46. Fibrous Osteodystrophy
PTH funcTon during hypocalcemia
Decrease Calcium
excreTon
PTH Normalizes serum
Increased Vitamin calcium
D acTvaTon
Small IntesTne Calcium
AbsorpTon
72 HRs
Ostoclasts resorb
bone

47. Fibrous Osteodystrophy
• Bone is replaced by fibrous 4ssue
– Excess PTH causes osteoprogenitor cells to differenTate into fibroblasts
– Osteoclasts demineralize and resorb osteoid to try to restore normal serum calcium
levelsSoLening of bone
– Paradoxically there is onen new poorly mineralized bone formaTon in response to
the weakened skeleton
• Causes
– Secondary Hyperparathyroidism
• Nutri0onal
– Low Calcium High Phosphorus Diets‐ Meat Only (carnivores)
– Excess phosphorus‐ Reduces serum Ca++ (Grains/Bran)
– Hypovitaminosis D‐ Reduces intesTnal absorpTon of Ca++
– High oxalate diet in horses
• Renal
– Decreased Vitamin D acTvaTon (25‐Hydroxycholecalciferol1,25
Dihydroxycholecalciferol)
– Hyperphosphatemia
– Primary hyperparathyroidism (Parathyroid neoplasia)
• Persistent increase in PTH

48. Fibrous Osteodystrophy‐
Persistently elevated PTH
Vit D deficiency
Hypocalcemia
High Phosphorous
Diet
•Excessive resorpTon of
Renal Failure calcium from bones
Increased PTH
•STmulates
differenTaTon of
fibroblasts in bones
(Fibrous Osteodystrophy)
Parathyroid tumor

49. Fibrous Osteodystrophy
• Dogs
–Rubber jaw
• Rep4les
–Low calcium high
phosphorus diets
–Low UV light
–Vitamin D deficiency

50. Fibrous Osteodystrophy
• Simian Bone
Disease
• Bran Disease
(Horse‐ Ca:P = 1:3
or more)
• Bighead (Rams)
50

51. Fibrous Osteodystrophy
• Osteoclast
resorpTon
• Fibrous Tssue
filling marrow
spaces
• New bone
formaTon
51

52. Osteochondrosis
Failure of endochondral ossificaTon
Epipyseal CarTlage necrosis
Failure of physeal mineralizaTon or
vascularizaTon
52

53. Osteochondrosis
• ArTcular ‐ Epiphyseal Complex
–Necrosis of epiphyseal carTlage (ischemia)
• failure of endochondral ossificaTon
• Physeal CarTlage
–Inadequate mineralizaTon of hypertrophic
chondrocytes
• failure of endochondral ossificaTon
–Vascular disorder prevenTng localized vascular invasion
–Resembles rickets
53

54. ArTcular Osteochondrosis
Vet Pathol 44:4, 2007 Osteochondrosis 433
Vet Pathol 44:4, 2007 Osteochondrosis
lamellar
cartilage
• Ischemic necrosis of removal a
The rate
epiphyseal carTlage progress,
dimensio
• NecroTc carTlage cant process t
genetic, n
mineralize and vessels cant al), and
invade computer
been des
growth a
stress (te
stress (co
Several
Schipani9
provide e
drocytes
a local
temporal
volves th
chondroc
tide (PTH
forming
feedback
chondroc
irreversib
Fig. 2. Cartilage canals in the articular–epiphyseal cartilage complex of the medial femoral condyle of a 7- hypertrop
Veterinary Pathology Online (2007) vol. 44 (4) pp. 429 image is from a 5-mm-thick cut frontal slab from an animal
week-old piglet viewed with transillumination. The 54
Fig. 1. Schematic cross-section of an articular–
perfused with barium sulphate in which the tissues were cleared with methyl-salicylate (see Ytrehus134 for full
with hom

55. Physeal Osteochondrosis
• Zone of
Mineralized
chondrocytes
Normal • Vascular invasion
• Failure of
mineralizaTon or
OC vascularizaTon
55

56. QuesTons?
56

57. Osteogenesis imperfecta
• Impaired Osteoid FormaTon, similar to scurvy
57

58. Copper Deficiency
• Abnormal Osteoid ProducTon
• Osteochondrosis
• Enzyme Lysyl oxidase‐ cross‐linking of pro‐
collagen to collagen molecules
58

59. Vitamin A toxicity
• Spondylosis of the cervical vertebrae and other
joints
• Can be seen with all meat diets, excessive liver
diets
• FYI‐ (Vit A Deficiency= opTc nerve damage, thick dura mater,
poor bone growth and remodeling, squamous metaplasia)
59

60. Vitamin D Toxicity
• MetastaTc mineralizaTon, mild bone sclerosis
• Causes:
• rodenTcide, chronic granulomatous diseases,
excess supplementaTon
60