metabolic disease study for pahtology post graduate students.

1. Metabolic Bone Diseases
Presenter: Dr. Animesh Debbarma
Moderator: Assoc. Prof. Gayatri Pukhrambam
8/28/2017 1

2. Basic structure and function of bone
• Adult human skeleton is composed of 206 bones and responsible for 12% of
body weight.
• Functions of bone:
1. Mechanical support
2. Transmission of forces generated by muscles.
3. Protection of viscera.
4. Mineral homeostasis.
5. Providing niche for formation of blood cells.
8/28/2017 2

3. Constituents of bone
• It includes specialized cells responsible for the production and maintenance of
matrix; and extracellular matrix.
• Cellular compartment of the mature bone consists of bone synthesizing osteoblasts
and osteocytes; and bone resorbing osteoclasts.
• Extracellular matrix is made up of 70% inorganic salts (mineral component) and
30% organic component (osteoid) by weight.
• Inorganic component mainly consists of calcium and phosphate in the form of
hydroxyapatite crystals.
8/28/2017 3

4. • Collagen (type I) make up 90% of the organic component, remainder being
ground substance proteoglycans and non-collagen molecules which appear
to regulate bone mineralization.
• Ground substance proteoglycans contribute a much smaller portion of the
matrix than in cartilage and mainly consists of chondroitin sulfate and
hyaluronic acid in the form of proteoglycan aggregates.
• Remaining non-collagen molecules include osteocalcin, osteonectin and
sialoproteins.
8/28/2017 4

5. 8/28/2017 5

6. • Osteoblasts: synthesize osteoid and mediates its mineralization. Found
lined up along bone surfaces.
• Osteocytes: inactive osteoblasts trapped within formed bone. Assist in the
nutrition of bone.
• Osteoclasts: phagocytic cells capable of eroding bone. Important along
with osteoblasts, in the constant turnover and refashioning of bone.
• Osteoblasts and osteocytes are derived from primitive mesenchymal (stem)
cell called osteoprogenitor cell.
8/28/2017 6

7. • Osteoclasts are multinucleate phagocytic cells derived from
macrophage-monocyte cell line.
• Most bone have a dense rigid outer shell of compact bone (cortex) and
a central medullary (cancellous) zone of thin interconnecting narrow
bone trabeculae.
• Space in the medullary bone between trabeculae is occupied by
hematopoietic bone marrow.
8/28/2017 7

8. 8/28/2017 8

9. • Bone exists in two main forms: woven bone and lamellar bone.
• Woven bone is an immature form with randomly arranged collagen fibers.
• Lamellar bone is composed of regular parallel bands of collagen arranged
into sheets.
• Rapidly formed woven bone is eventually remodeled to form lamellar bone,
which is physically stronger and more resilient. Virtually all bone in a
healthy adult is lamellar.
8/28/2017 9

10. 8/28/2017 10

11. Bone development and growth
• Fetal development of bone occurs in two ways, both of which involve
replacement of primitive collagenous supporting tissue by bone.
• Resulting woven bone is then extensively remodeled by resorption and
appositional growth to form the mature adult skeleton, which is made up of
lamellar bone.
• Lone bones, vertebrae, pelvis and bones of the base of the skull are
preceded by the formation of a continuously growing cartilage model which
is progressively replaced by bone (endochondral ossification).
• Bone of the vault of the skull, the maxilla, and most of the mandible are formed by
deposition of bone within primitive mesenchymal tissue (intramembranous
ossification).
8/28/2017 11

12. Bone homeostasis and remodeling
• Adult skeleton appears static but is constantly turning over in a tightly
regulated process: remodeling.
• Approximately 10% of the skeleton is replaced annually.
• This process can repair microdamage and change the shape of the bones in
response to structural and mechanical demands.
8/28/2017 12

13. • Remodelling takes place at a microscopic locus known as bone (or basic)
multicellular unit (BMU), it consists of a unit of coupled osteoclast and
osteoblast activity on the bone surface.
• Events at the bone multicellular unit are regulated by cell-cell interactions
and cytokines.
• Exact control mechanism are not known completely, but there are several
signaling pathways of particular importance:
1. RANK signaling pathway:
 3 factors are involved. (i) transmembrane receptor RANK (receptor
activator for NF-κB) expressed on osteoclast precursors; (ii) RANK
ligand (RANKL) expressed on osteoblast and marrow stromal cells; and
(iii) osteoprotegerin (OPG), receptor made by osteoblast and several
other types of cells that can bind RANKL and thus prevent its interaction
with RANK.8/28/2017 13

14.  When stimulated by RANKL, RANK signaling activates the transcription
factor NF-κB, which is essential for the generation and survival of osteoclasts.
2. Second: monocyte colony stimulating factor (M-CSF) produced by
osteoblast.
 Activation of M-CSF receptor on osteoclast precursors stimulates a tyrosine
kinase cascade that is also crucial for the generation of osteoclasts.
3. WNT/β-catenin pathway:
 WNT proteins produced by osteoprogenitor cells, bind to the LRP5 and LRP6
receptor on osteoblasts and thereby trigger the activation of β-catenin and the
production of OPG.
8/28/2017 14

15.  Conversely, sclerostin, produced by osteocytes, inhibits the WNT/β-catenin
pathways.
8/28/2017 15

16. • Balance between net bone formation and resorption is modulated by
the signals that connect to the RANK and WNT signaling pathways.
• Systemic factors that affect this balance include hormones (PTH,
estrogen, testosterone and glucocorticoids), vitamin D, inflammatory
cytokines (e.g., IL-1), and growth factors (e.g., bone morphogenetic
factors).
• Parathyroid hormones, glucocorticoids and IL-1 promote osteoclast
differentiation.
• In contrast bone morphogeneic protein, sex hormones they block
osteoblast differentiation or their activity.
• Another level of control involves paracrine cross talk between
osteoblast and osteoclast.
8/28/2017 16

17. METABOLIC BONE
DISEASES
8/28/2017 17

18. • Any systemic condition that results in reduced bone strength, altered
mineralization or composition.
8/28/2017 18
Abnormal formation of
the organic matrix
Abnormal mineralization Abnormal resorption
Osteogenesis imperfecta Osteomalacia and rickets
Hypophosphatasia
Metal toxicity
Hyperparathyroidism
Paget disease
osteoporosis
Osteopetrosis.

19. Calcium homeostasis
First line of defense: Buffer function of the exchangeable calcium in bones.
Second line of defense: Hormonal control of calcium ion concentration.
1)Parathyroid hormone:
Mobilizes calcium and phosphate from the bone.
Decreases calcium excretion and increases phosphate excretion by the
kidneys.
Increases calcium and phosphate absorption by the kidney (by
converting 25-OH D3 to 1,25-(OH)2D3).
8/28/2017 19

20. 8/28/2017 20

21. 2)Vitamin D:
Promote intestinal calcium and phosphate absorption.
Decreases renal calcium and phosphate excretion.
Extreme quantities of vitamin D causes resorption of bone and
smaller quantities promote bone calcification.
3)Calcitonin:
Decreases plasma calcium concentration and has opposite effects of
those of PTH.
8/28/2017 21

22. DISEASES DUE TO ABNORMAL
FORMATION OF THE
ORGANIC MATRIX
8/28/2017 22

23. Osteogenesis imperfecta (Brittle bone disease)
• One of the most common congenital connective tissue matrix diseases.
• Caused by deficiency of type I collagen (that’s why also known as type I
collagen disease).
• Comprises of several distinct syndromes, some inherited as an autosomal
dominant trait and others as recessive trait; still others occur as spontaneous
mutations.
• Patients with these various syndromes have in common a short stature and a
propensity for #.
• Fractures are more common in the lower limbs and in a significant no. of
cases, involve the growth plates around the knee joints, giving rise
eventually to growth plate fragmentation.
8/28/2017 23

24. • Subsequent independent growth of the cartilage fragment causes
swelling of the epiphyseal end of the bone. The deformed bone end
filled with nodules of cartilage, appear on X-ray as a “bag of
popcorn”.
8/28/2017 24

25. • Microscopy:
 Severe cases bone lack an
organized trabecular pattern.
 Osteocytes are crowded with in the
bone, reflecting diminished
collagen synthesis by the crowded
osteoblast at the surface.
 Frequently large areas of woven
bone are seen.
 Less severe cases bone is generally
lamellar in pattern, although even
in these bone, osteocytes are
crowded and the lamellae may be
thinner than those in age-matched
controls.
8/28/2017 25

26. DISEASES DUE TO ABNORMAL
MINERALIZATION
8/28/2017 26

27. Osteomalacia and rickets
• Caused by deficiency of vit. D, abnormality in the metabolism of vit.
D or deficiency of calcium in the diet.
• C/F:
8/28/2017 27
Osteomalacia Ricket
 Bone pain, usually generalized, vague.
 Low calcium level- muscle weakness.
 X-ray: generalized osteopenia with
multiple bilateral and symmetric partial
linear # of the bone (insufficiency #).
 Anatomic changes are most characteristic
around the epiphysis of the most rapidly
growing bone i.e. around the knee and
wrist joint.
 X-ray: epiphyseal growth plates are
irregular, broadened and cup shape.

28. 8/28/2017 28

29. MICROCOPY:
8/28/2017 29
Osteomalacia Ricket
 Massive increase in the amount of
unmineralized bone (40-50% of the
total bone volume) and disorganization
of the trabecular architecture.
 Mineralization front is very irregular,
granular and fuzzy.
 In addition to increase in osteoid
volume, bone volume is often
increased over all as a consequence of
increased osteoblastic activity.
 Growth plate is thickened and poorly
defined, especially on its metaphyseal
side, tongues of uncalcified cartilage
can be seen extending into the
metaphysis.
 Increase in osteoid mass.

30. Hypophosphatesia
• Rare genetic disease characterized by disturbance in the synthesis of
alkaline phosphatase.
• 2 forms:
 Inherited as an autosomal recessive trait- severe disease in infants.
 Autosomal dominant- may not become evident until adulthood; less
severe and often asymptomatic.
• Disease is characterized by:
 Decreased level of alkaline phosphatase in the blood, bone, intestine,
liver and kidneys.
 Serum calcium and phosphatase level- normal.
 Childhood h/o ricket like disorder.
 Short stature and deformed extremities.
8/28/2017 30

31. • Microscopic examination:
 Infants: increased osteoid and irregular epiphyseal cartilage with
lengthened chondrocyte columns.
 Adult: osteomalacic picture with increased quantities of unmineralized
bone. Unlike osteomalacia of vit. D deficiency, there is paucity of
osteoblasts.
8/28/2017 31

32. Metal toxicity
• Many patients undergoing renal dialysis are treated with high doses of
antacids to bind dietary phosphate to prevent hyperphosphatemia.
• Aluminum of the antacids become deposited in the bone and other
body tissues of the patients.
• Usually suffer from aluminum induced encephalopathy and aluminum
induced bone disease.
• In aluminum induced bone disease, the amount of osteoid in the
skeleton may be considerably increased. However unlike that of vit. D
deficiency, the mineralization front is well demarcated and the
osteoblastic activity is minimal.
8/28/2017 32

33. • ‘Aurintricarboxylic acid stain’ may be used to demonstrate
aluminum along the mineralization front.
8/28/2017 33

34. DISEASES DUE TO ABNORMAL
RESORPTION
8/28/2017 34

35. Osteopenia/ Osteoporosis
• Osteopenia: decreased bone mass.
• Osteoporosis: osteopenia severe enough to significantly increase the risk of
#
• Radiographically:
 Osteoporosis: bone mass at least 2.5 SD below the mean bone peak mass
in young adults
 Osteopenia: 1-2.5 SD below the mean.
• Presence of an atraumatic or vertebral compression # signifies osteoporosis.
8/28/2017 35

36. 8/28/2017 36

37. • Disorder may be localized to a certain bone or region or may involve
the entire skeleton(generalized).
• Generalized osteoporosis: 1O or 2O
• Most common form of osteoporosis: senile and postmenopausal type.
• Pathogenesis:
8/28/2017 37
 Genetic factors.
 Reduced physical activity.
 Nutrition.
 Menopause.
 Aging.

38. 8/28/2017 38

39. Morphology:
• Hallmark: histologically normal bone that decrease in quantity.
• Postmenopausal osteoporosis:
 Increase in osteoclast activity mainly affects bones or portions of the
bones that have increased surface area, such as cancellous compartment
of vertebral bodies.
 Trabecular plates become perforated, thinned and lose their
interconnections leading to progressive microfractures and eventual
vertebral collapse.
• Senile osteoporosis:
 Cortex is thinned by subperiosteal and endosteal resorption and the
Haversian system are widened.
 In severe cases the Haversian system are so enlarge that the cortex
mimics cancellous bone.
8/28/2017 39

40. 8/28/2017 40

41. • Clinical features:
 Vertebral # (T & L) are painful.
 When multiple: significant loss of height and various deformities,
including lumber lordosis and kyphoscoliosis.
• Diagnosis:
 Can’t be readily detected by plain radiograph until 30-40% of the
bone mass is lost, and measurement of blood calcium, phosphorous
and alkaline phosphatase are not diagnostic.
 Best estimates of bone loss, aside from biopsy (rarely performed),
are specialized imaging techniques: dual energy X-ray
absorptiometry and quantitative computed tomography.
8/28/2017 41

42. • Prevention and treatment of senile and postmenopausal osteoporosis:
 Exercise
 Appropriate calcium and vit D intake.
 Pharmacologic agents:
• Bisphosphonates (reduce osteoclast activity and induce
apoptosis).
• Menopausal hormone therapy (complications- deep venous
thrombosis & stroke).
• Denosumab, an anti-RANKL antibody, for treating PMO.
8/28/2017 42

43. Osteopetrosis/ Marble bone disease/
Alber’s-Schonberg disease
• Group of rare genetic diseases, characterized by reduced bone
resorption and diffuse symmetric skeletal sclerosis due to impaired
formation or function of osteoclasts.
• Term Osteopetrosis: stone like quality of the bones.
• However, bones are abnormally brittle and # easily like a piece of
chalk.
8/28/2017 43

44. Pathogenesis:
• Most of the mutations interfere with the process of acidification of
osteoclast resorption pit, required for dissolution of the calcium
hydroxyapatite within the matrix.
• Examples:
 Autosomal recessive defects in the gene for the enzyme carbonic
anhydrase 2 (CA2).
 Mutations in the CLCN7.
8/28/2017 44

45. Morphology:
• Bones lack a medullary canal and the ends of the long bone are
bulbous and misshapen.
• Neural foramina are small and compress exiting nerves.
• Microscopy:
 Primary spongiosa persists and fills the medullary cavity leaving
no room for the hematopoietic marrow and preventing the
formation of mature trabeculae.
 Deposited bone is not remodeled and tends to be woven in
architecture.
8/28/2017 45

46. 8/28/2017 46

47. Clinical features:
• Severe form is autosomal recessive and usually becomes evident in
utero or soon after birth.
• Fracture, anemia and hydrocephaly are often seen, resulting in
postpartum mortality.
• Affected individuals who survive during their infancy have cranial
nerve defects and repeated infections.
• Mild form is autosomal dominant, may not be detected until
adolescence or adulthood, when it is discovered on X-ray studies
performed because of repeated #.
8/28/2017 47

48. Treatment:
• Hematopoietic stem cell transplantation.
8/28/2017 48

49. Paget disease (Osteitis deformans)
• Disorder of increased, but disordered and
structurally unsound, bone mass.
• 3 sequential phases:
a. Initial osteolytic stage
b.Mixed osteoclastic and osteoblastic stage
c. Final burned out quiescent osteosclerotic
stage.
• Begins in late adulthood (avg. 70Y) and
become progressively more common thereafter.
8/28/2017 49

50. Pathogenesis:
• Uncertain.
• Current evidence suggest both genetic and environmental factors
contribute.
• 40-50% of familial Paget disease, and 5-10% of sporadic cases harbor
mutations in the SQSTM1 gene. Net effect- increase activity of NF-
κB, which increases osteoclast activity.
• Activating mutation in RANK and inactivating mutation in OPG
account for some cases of juvenile Paget disease.
8/28/2017 50

51. Morphology:
• Hallmark: mosaic pattern of lamellar bone, seen in sclerotic stage.
• Jigsaw puzzle like appearance is produced by unusually prominent
cement lines, which join haphazardly arranged units of lamellar bone.
• Initial lytic phase: increase osteoclast activity and increase no. of
resorption pits.
• Osteoclast are abnormally large and have many nuclei upto 100.
• Mixed phase: osteoclast persists but many of the bone surfaces are
lined by prominent osteoblast.
8/28/2017 51

52. 8/28/2017 52

53. • Marrow adjacent to the bone forming surface is replaced by loose
connective tissue that contain osteoprogenitor cells and numerous
blood vessels.
• Newly formed bone may be woven or lamellar, but eventually all of it
is remodeled into lamellar bone.
• As the mosaic pattern unfolds and the cell activity decreases, the
periosseous fibrovascular tissue recedes and is replaced by normal
marrow.
• In the end bone is composed of coarsely thickened trabeculae and
cortices that are soft, porous and lack structural stability.
8/28/2017 53

54. Clinical features:
• Monostotic in 15% of cases and polyostotic in
the remainder.
• Axial skeleton and proximal femur are
involved in about 80% of cases.
• Pain usually localized to the affected bone.
• Enlargement of the craniofacial skeleton may
produce leontiasis ossea (lion face) and a
cranium so heavy that is difficult for the person
to hold the head erect.
• Weight bearing causes anterior bowing of the
femur and tibia and distorts the femoral head,
resulting in the development of secondary
osteoarthritis.
8/28/2017 54

55. • Chalk-stick type # in long bone of lower extremities.
• Compression # of the spine: spinal cord injury and kyphosis.
• Variety of tumor and tumor like conditions develop:
 Benign lesions: giant cell tumor, giant cell reparative granuloma,
extraosseous masses of hematopoietic tissue.
 Malignant lesions: osteosarcoma, fibrosarcoma.
8/28/2017 55

56. Diagnosis:
• X-ray: enlarged bone with thick, coarsened cortices and cancellous
bone.
• Elevated serum alkaline phosphatase and normal serum calcium and
phosphorous.
Treatment:
• In the absence of malignant transformation: calcitonin and
bisphosphonates.
8/28/2017 56

57. Hyperparathyroidism
• PTH causes elevation in serum calcium, which under normal circumstances,
inhibits further PTH production.
• However, excessive levels of PTH can result from autonomous parathyroid
secretion (1O hyperparathyroidism) or can occur in the setting of underlying
renal disease (2O hyperparathyroidism).
• In either cases hyperparathyroidism causes significant skeletal changes
because of unabated action of osteoclast.
• PTH is directly responsible for bone changes in 1O hyperparathyroidism,
but additional alterations contribute to the development of bone disease in
2O hyperparathyroidism.
8/28/2017 57

58. • In chronic renal insufficiency:
 Inadequate active vit D formation, which ultimately affects
gastrointestinal calcium absorption.
 Hyperphosphatemia due to renal failure also suppresses renal α1-
hydroxylase, further impairing vit D synthesis.
 Additional influences include- metabolic acidosis and aluminum
deposition in bone.
• As bone mass decreases, affected patients are increasingly susceptible
to #, bone deformation and joint problems.
8/28/2017 58

59. • Marrow spaces around the affected
surfaces are replaced by
fibrovascular tissue.
• Bone loss predispose to
microfractures and secondary
hemorrhages which causes influx of
macrophages and an ingrowth of
reparative fibrous tissue, creating a
mass of reactive tissue (brown
tumor).
• Brown color is due to vascularity,
hemorrhage and hemosiderin
deposition, and the lesion may
undergo cystic degeneration.
8/28/2017 59

60. • Combination of increased bone cell activity, peritrabecular fibrosis and
cystic brown tumors is the hallmark of severe hyperparathyroidism
and is known as generalized osteitis fibrosa cystica (von
Recklinghausen disease of bone).
8/28/2017 60

61. OTHER METABOLIC DISEASES
8/28/2017 61

62. Renal osteodystrophy
• Skeletal changes that occur with chronic renal disease, including those
associated with dialysis.
• Manifestations are-
a. Osteopenia/osteoporosis.
b. Osteomalacia.
c. 20 hyperparathyroidism.
d. Growth retardation.
8/28/2017 62

63. • Histologic changes in bone in end stage renal disease can be divided
into 3 major types:
1. High-turnover osteodystrophy: increase osteoclast and osteoblast
activity with the former predominating.
2. Low-turnover or aplastic disease: adynamic bone (little
osteoclastic and osteoblastic activity), and less commonly,
osteomalacia.
3. Mixed pattern of disease with areas of high-turnover and low-
turnover.
8/28/2017 63

64. Pathogenesis:
• Kidney disease causes skeletal abnormalities through 3 mechanisms:
1. Tubular dysfunction: Major tubular disease that affect the skeleton is
renal tubular acidosis. The associated low pH dissolves hydroxyapatite,
resulting in demineralization of the matrix and osteomalacia.
2. Generalized renal failure: affecting glomerular and tubular function,
leads to reduced phosphate excretion, chronic hyperphosphatemia,
hypocalcemia and, ultimately secondary hyperparathyroidism. Resulting
metabolic state is not analogous to primary hyperparathyroidism in that
bone volume, turnover and mineralization can vary independently.
8/28/2017 64

65. 3. Decreased production of secreted factors:
 A hormonal feedback loop between kidney and bone that regulate
calcium and phosphate homeostasis involved secreted BMP-7, and
FGF-23 and the membrane protein Klotho.
 BMP-7 produced by renal tubular cells causes osteoblast
differentiation and proliferation.
 FGF-23 produced by osteocytes act on the kidney to regulate
phosphate homeostasis and vit D production, which are dependent
on production of membrane protein Klotho.
 Levels of this signals change in chronic renal disease resulting in
osteopenia and osteomalacia.
8/28/2017 65

66. 8/28/2017 66

67. References:
1. Robbins and Cotran Pathologic basis of disease- 9th edition.
2. Wheater’s functional histology- 6th edition.
3. Sternberg’s diagnostic surgical pathology- 5th edition.
4. Guyton and Hall Textbook of medical physiology- 13th edition.
8/28/2017 67

68. 8/28/2017 68

69. Evaluation of bones
Disorders of mineralization
Rickets
Osteomalacia
Fibrous osteodystrophy
Metastatic soft tissue mineralization
Disorders of bone formation
Osteopenia
Osteoporosis
Scurvy
Hyperostosis
Osteosclerosis
OsteopetrosisDecreases
mineralization
Increases
mineralization
Vit D deficiency
Calcium deficiency
Phosphorous deficiency
Vit D toxicity (soft tissue
mineralization).
Mild bone changes:
inhibition of bone
resorption (sclerosis).
8/28/2017 69