This document discusses various metabolic bone diseases including: - Calcium and phosphate regulation by parathyroid hormone, vitamin D, and calcitonin - Primary hyperparathyroidism caused by parathyroid adenomas, hyperplasia, or carcinomas leading to hypercalcemia and bone loss - Hypoparathyroidism and pseudohypoparathyroidism caused by parathyroid deficiency or resistance, leading to hypocalcemia - Nutritional rickets/osteomalacia caused by vitamin D or calcium deficiency impairing bone mineralization

1. Metabolic Bone
Diseases

2. Metabolic Bone Diseases
 Calcium, phosphate metabolism
 Primasry hyperparathyoidism
 Hypo & pseudohypoparathyoidism
 Rachitic syndromes and renal osteodystrophy
 Scurvy
 Gaucher’s disease
 Gout and pseudo gout
 Alkaptonuria - Ochronosis
 Osteoporosis
 Thyroid disorders
 Paget’s disease
 Misc.

3. Calcium & phosphate Regulation
Before we launch a discussion of the metabolic diseases the
student must have a basic knowledge concerning the regulation
of calcium and phosphate metabolism. To help in this discussion
I refer you to the Frank Netter schematic from Ciba seen on the
next slide.
The three hormonal regulators include parathormone (PTH)
produced by the four parathyroid glands on the back side of the
thyroid gland, the active form of vitamin D produced in the
proximal renal tubule 1,25(OH)2, and calcitonin produced by the
parafollicular cells in the thyroid gland.
The major function of PTH is to prevent the dangerous
reduction in the serum calcium level by increasing the pro-
duction of 1,25,(OH)2 vitamin D in the kidney which then
increases the absorption of calcium from the gut and renal
tubule. PTH also activates osteoclastic mobilization of calcium
from bone mineral. A second role of PTH is to promote urinary

4. excretion of phosphorous.
The major function of 1,25,(OH)2 vitamin D is to activate the
absorption of calcium from the gut and bone.
The least important calcium regulator is calcitonin which is
designed to prevent an increase of serum calcium by inhibiting
the osteoclastic mobilization of calcium at the bone level.

5. Hormonal regulation
of calcium and phosphate

6. Calcium and Phosphate Regulation
The next slide is another Ciba schematic that helps one to
understand the role of vitamin D in calcium regulation.
The crude inactive form of vitamin D comes from the gut
and the skin that is exposed to sun light which is then trans-
ported to the liver for its first phase of activation by a
hydroxylation process at the 25 position of the sterol ring.
This still inactive form then goes to the kidney for its finial
activation by a hydroxylation process on the 25 position of the
sterol ring. This now activated vitamin D acts as a hormone
similar to PTH to help absorb calcium from the gut and bone.

7. Calcium and phosphate
metabolism

8. Mobilization of Ca from Bone
The following slide will help you to understand the mech-
anism for the mobilization of calcium from bone mineral.
When the serum calcium level drops below normal the para-
thyroid gland puts out PTH which then activates resting bone
cells to differentiate into an active lytic osteoclast as seen in the
following schematic. On the bone surface the active brush
border of the cell secrets collagenase enzyme which dissolves
bone mineral thus liberating calcium and phosphorous ions
which are then transported across the cell to its outer membrane
where a 1,25,(OH)2 pumping mechanism transports the
calcium and phosphorous into the blood stream.

10. Primary Hyperparathyroidism
As you will see in the following Ciba schematic there are three
types of primary hyperparathyroidism. The most common 80%
is a solitary adenoma found in the posterior capsule of the
thyroid gland or ectopically further down the neck or into the
mediastinum. The next most common is the 18% hyperplasia
cases involving all four parathyroid glands. The least common
is the 2% parathyroid carcinoma cases. As you can see in the
schematic the major affect of the elevated PTH level is a state
of hypercalcemia second to increased osteoclastic activity in
bone and an increased flow of calcium into the blood from the
renal tubule and gut. The bone is weakened by the osteolytic
process and the kidneys may become calcified. Initially the serum
phosphorous level is depressed from phosphate loss in the
renal tubule but may reverse if the kidney fails second to
nephrocalcinosis. The secondary forms of hyperparathroidism
will be discussed later under rachitic syndromes including
renal osteodystrophy.

11. Primary
hyperparathyroidism

12. Case #1 Primary Hyperparathyroidism
43 yr female with acute onset of elbow pain

13. X-ray showing generalized
osteomalacia with a
specific lysis of the outer
end of clavical

14. Resected adenoma
Lump in throat Chief cells

15. Reversal line
Osteolysis Cutting cone

16. Salt and pepper granular osteolysis of the skull

17. Digital clubbing Subperiosteal osteolysis

18. Another case of
of early hand
hyperparathroidism

19. Case #1.1 Primary Hyperparathroidism
2008
56 year female with anterior knee pain for 2 years

20. Sag T-2 PD FS

21. Axial PD FS Cor PD FS

22. 2009 2011
Two new aneurysmal lesions in foot two years apart
with bone graft to 3rd metatarsal ABC in 2009

23. 2011
Osteomalacic looking bones

24. Bell shaped chest cage Dorsal kyphosis

25. 2011
T-5
Sag T-2
Axial T-2
at T-5
CT and MRI images of spinal defects with paraparesis

26. Post op spinal decompression
and posterior stabilization

27. Case #2 Healed hyperparathyroidism
40 year female with parathyroid adenoma removed 8 yrs ago

28. Chronic deformation of the skull bones

29. Chronic bell shaped deformity of rib cage

30. X-ray
Pseudo clubbing

31. Case #3 Primary hyperparathyroidism
48 yr female with multiple brown tumors of hyperparathyroidism

32. CT scan sacroiliac area
Iliac biopsy shows
increased osteoclastic
activity

33. Case #4 Primary hyperparathyroidism
39 yr female with right hip and left hand pain for 6 mos

34. Case #5 Brown Tumor of Hyperparathyroidism
25 yr female
Pain 3 mos

35. Biopsy specimen showing benign giant cells

36. Trabecular bone with with thick pink staining osteoid seams

37. Case #6 Brown tumors of hyperparathyroidism
49 yr female with
parathyroid adenoma
with bilateral leg pain

38. Case #7 & 8 Brown tumors of tibia
41 year old female 43 yr female

39. Case #9 Brown tumor tibia
Axial T-2
Sag T-2
46 yr male with pain in leg for 6 months

40. Case #10 Brown tumor hand
30 year old female with
hyperparathyroidism and
a secondary brown tumor
of the index finger

41. Case #11 Nephrocalcinosis 2nd to parathyroid CA
43 yr male with history of primary hyperparathyroidism 2nd
to a parathyroid carcinoma

42. Hypoparathyroidism
As you will see in the following Ciba schematic, the most
common form of hypoparathyroidism is second to the
inadvertant removal of the parathyroid glands during a
thyroid surgery. The rare idiopathic form is either sporadic,
familial or the result of an autoimmune destructive mechanism
which can result in chronic mucocutaneous candidiasis.
The lack of PTH results in hypocalcemia second to a decrease
of calcium absorption from the gut, renal tubule and bone.
The serum phosphorous is increased because of an increased
absorption from the renal tubule. Although the reduction of
PTH inhibits calcium absorption from bone, the formation of
bone is reduced which results in a normal or slightly increased
bone mass. The blood calcium deficiency is treated with comb-
inations of oral calcium and the 1,25(OH)2 form of vitamin D.
The symptoms of chronic hypocalcemia include mental
lassitude, irritability, depression and even psychosis.

43. Despite their hypocalcemia, these patients may develop
calcification in their lens and basal ganglion of the brain.
Hypocalcemia can also result in spotty alopecia and neuro-
musculular excitability resulting in hyper-reflexia, stridor due
to laryngeal spasm and seizures.

44. Pathologic physiology of
hypoparathyroidism

45. Pseudohypopararthyroidism
(Seabright Bantum’s Disease)
The cause for this disorder is due to a failure of response of the
kidney and bone to elevated PTH levels. Because the renal tubule
is unable to activate vitamin D there is a lack of absorption of
calcium from the gut. The resultant hypocalcemia stimulates
the increased output of PTH from hyperplastic parathyroid
glands. Because the blood calcium and phosphorous levels
are the same as in hypoparathyroidism, the signs and symptoms
are the same. An additional finding in pseuohypoparathroidism
includes a variant of multiple epiphyseal dysplasia known as
Albright’s hereditary osteodystrophy which includes short stature,
obesity, round facies, mental retardation and specific shortening
of the fourth and fifth digits of the hands and feet.
In rare cases where the bone responds to the elevated PTH we
have a condition known as pseudohypohyperparathyroidism.

46. Pathophysiology of
pseudohypoparathyroidism

47. Pseudohypoparathyroidism
Case #1
40 year old male with short
stature, round face and mental
retardation
Blood chemistries included a
low calcium, high phosphorous
and high PTH

48. Short metatarsals & metacarpals
Short lateral digits

49. Calcified basal ganglion

50. Case #2 Pseudohypoparathyroidism
18 yr female with short stature, round face and calcification
in basal ganglion plus a low serum calcium & high phosphorous

51. Shorting of the ulnar digits
of the hand

52. Shortening of the fibular
digits of the feet

53. Rachitic Syndromes & Renal
Osteodystrophy
 Nutritional - deficiency rickets
 Renal tubular syndromes
Vit D resistant rickets (prox tubule)
Vit D resistant (prox and distal tubule)
Vit D resistant (renal tubular acidosis)
 Renal failure rickets (renal osteodystrophy)
 Vit D dependent (pseudodeficiency rickets)
 Hypophosphatasia

54. Vitamin D metabolism
In order to discuss the rachitic syndromes one needs to under-
stand the metabolism of vitamin D by referring to the following
schematic. The major source of crude inactive vit D is from the
upper two thirds of the GI tract. The second and least common
source is from the skin which is activated by UV light. Both of
these inactive forms then travel to the liver where a partial
activation occurs by a hydroxylation process on the 25 position
of the sterol ring. The final activation occurs in the kidney with
the help of PTH by a hydroxylation process on the 1 position of
the sterol ring to form the active form of vit D known as 1-25
dihydroxycholecalciferol. This final renal activation is regulated
by the serum calcium and phosphorous level which must be low
at the time in order to activate the needed PTH stimulus. If the
serum calcium and phosphorous level is high, then the PTH
level drops and instead we see an activation of calcitonin (CT)

55. which switches the second hydroxylation to the 24 position
which results in an inactive form of vit D thus decreasing the
transfer of calcium to the blood from the gut, bone and renal
tubule. Notice that despite the increased absorption of P2
from the gut and bone with increased PTH and 1,25 D-3
activation, the resultant P2 blood level will be down because
of the dominating loss if P2 at the renal tubular level.
From all this discussion it becomes apparent that 1,25
dihydroxycholecalciforal is acting as a hormonal regulator
of calcium and phosphorous metabolism along with PTH and
calcitonin.

57. Nutritional - Deficiency Rickets
The following Ciba schematic helps to understand the patho-
physiology of the pediatric nutritional or intestinal deficiency
rickets and the adult osteomalacia. The classic form of rickets
is due to the lack of sunshine and vit D intake. Other deficiency
disorders include liver damage or bile duct stenosis: dilantin
medication which blocks the formation of 25(OH)3; lack of
digestive enzymes and bile; high intake of P2, phytate or
oxalate; gastectomy patients; intestinal sprue (malabsorption
diseases); and patients on steroids will block calcium absorption
at the gut level. Pregnancy and lactation can cause a calcium
deficiency.
The result of all these conditions results in a decreased calcium
level which then stimulates the production of PTH by the
parathryroid chief cells. The PTH then helps to reabsorb calcium
from the renal tubule and at the same time cause a loss of P2

58. from the blood into the glomerular filtrate. The PTH then
activates the formation of 1,25 D3 in the kidney which then
causes the gut to absorb Ca and P2 from the gut. At the bone
level we see the activation of dormant bone cells to become
active osteoclasts that digest bone mineral to mobilize Ca
and P2 into the blood stream. As the result of bone destruction
there is a responsive osteoblastic healing process that causes
an increase of alkaline phosphatase in the blood serum.
The clinical manifestations of rickets include short stature,
frontal bossing, dental defects, chest deformities, enlarged ends
of long bones and bowing of the lower extremities. Radiographic
findings include widening and a fuzzy appearing growth
plate next to a widened and cupped metaphysis. In adult
osteomalacia we find symptoms of generalized bone pain
and muscle weakness. Bowing of the lower extremities is seen
along with x-ray evidence of cortical thinning and multiple
stress fractures thru Looser’s zones (Milkman’s syndrome)

59. seen in the medial aspect of weight baring long bone
metaphyses.
Treatment consists of a correction of the nutritional defect
that caused the disease.

60. Nutritional - deficiency
rickets & osteomalacia

61. Case #1 Vit D deficient rickets
One year old with bowing of the lower extremities

62. More knee x-rays

63. Case #2 Terminal rickets
Epiphyseal
bone
X
Macro section and radiology
of autopsy specimen
Microscopic growth plate

64. Chest deformity
Rachitic rosery nodularity at costochondral junctures

65. Case #3
Rickets at the wrist
Rachitic swelling at the wrists
second to metaphyseal flaring

66. Case #4 Intestinal rickets
6 month old with congenital bile duct atresia

67. Case #5 Deficiency rickets
4 year old rachitic
child with knock-
knee deformity

68. Case #6 Healing rickets
2 yr male with epiphyseal rings second to treated rickets

69. Case #7 Jan 6 Feb 2
Adult Intestinal
Osteomalacia
49 yr female with
severe obesity and
gastric bypass 2 yr
ago and now recent
gradual onset of
pain in leg without
trauma

70. Isotope bone scan

71. Cor T-1 T-2 Gad
Increased alkaline phosphatase and PTH levels

72. Sag T-1 T-2

73. Case #7 Physiologic bowing (pseudorickets)
2 year old male with
physiologic bowing of
the lower extremities
that looks like rickets

74. Case #7 Jansen’s disease (pseudorickets)
3 yr male with bowing of lower extremities and wide plates

75. Vitamin D Resistant Rickets & Osteomalacia Second
To Proximal Renal Tubular Defects
(Hypophosphatemic Rickets)
By far the most common form of rickets or adult osteomalcia in
the USA is the proximal renal tubular defect condition known
as hypophosphatemic vitamin D resistant rickets (phosphate
diabetes). This condition is transmitted as a sex-linked dominant
trait seen more common in males. There is an oncogenic form of
hypophosphatemic rickets that is induced by certain low grade
soft & bone tumors. The defective proximal renal tubule is unable
to reabsorb P2 from the glomerular tubular filtrate resulting in
severe hypophosphatemia. The serum calcium and PTH levels
are usually normal but at times the calcium is slightly depressed,
resulting in an elevated PTH with resultant loss of bone mineral
and resultant increased alkaline phosphatase activity. In more
severe cases there can be a loss of glucose and even amino acids
(proximal Fanconi syndrome).

76. The clinical picture and radiologic findings are like those of
nutritional rickets except the renal forms do not respond to
normal intake of vitamin D. The treatment consists of an in-
creased intake of P2 and vitamin D.

77. Vitamin D Resistant
Rickets & osteomalcia
Second to Proximal Renal
Tubular Defects
(Hypophosphatemic
Rickets)

78. Case #1 X-linked Hypophosphatemic Rickets
10 year happy female with short stature and bowed legs

79. Case #2 X-linked Hypophosphatemic Rickets
7 year male from a family of short
stature and bowed lower extremities

80. Tibial bowing with mild growth plate changes

81. Case #3 X-linked hypophosphatemic Osteomalacia
54 yr 5’2” male with low serum P and life time of universal bone pain

82. He had a subtotal parathyroid resection for high PTH levels

83. Case #4 Hypophosphatemic Osteomalcia
26 yr female with short
stature and bowed lower
extremities since childhood
Looser’s zone or stress
Fracture in bowed femur

84. Microscopic picture of
osteomalcia showing
thickened and poorly
mineralized osteoid seams

85. Case 5 Hypophosphatemic osteomalacia
25 yr male with recent onset of
pain in the feet and proximal
right tibia with x-ray evidence
of multiple Looser’s zones

86. Photomicrographs of
osteomalacic bone with
thickened poorly calcified
osteoid seams

87. Case #6
Non Familial Hypophosphatemic Osteomalacia

88. Stress fractures of foot and tibia

89. Vitamin D Resistant Rickets & Osteomalcia second
To Proximal & distal Tubular Defects
(Fanconi syndrome)
This form of vitamin D resistant rickets includes a defect in
both the proximal and distal renal tubules resulting in a loss of
calcium, P2, glucose, amino acids, protein, water, fixed base, (Na
& K) and bicarbinate (hyperchloremic acidosis). The calcium loss
causes secondary hyperparathyroidism which along with
acidosis results in a severe form of rickets or osteomalcia with
Looser’s zones and cystic brown tumors seen on x-ray. The
serum P2 is very low. The low K can result in severe muscle
weakness. The serum vitamin D levels are normal.
The Lignac-Fanconi syndrome is a rare variant that includes a
generalized cystine metabolic disorder with resultant deposits
of cystine crystals in the macrophages of the liver, spleen, bone
marrow and lymph nodes. Cystine crystals are seen in the
cornea of the eye.

90. Other variants including oculocerebrorenal syndrome
(Lowe’s disease) and superglycine syndrome all have a poor
prognosis because of severe renal tubular defects.

91. Vitamin D resistant
Rickets & Osteo-
malcia Second to
Proximal & Distal
Tubular Defects
(Fanconi syndrome)

92. Case #1 Fatal case of Fanconi’s Syndrome
X-ray Macrosection
Autopsy specimen of the upper femur in a young child who died
of severe renal disease with advanced hyperparathyroidism

93. Vitamin D Resistant Rickets & Osteomalacia 2nd to
Renal Tubular Acidosis
This is another severe form of renal tubular rickets involving
the entire tubule. This can be genetic in origin or can result from
acquired pyelonephritis or heavy metal poisoning. There is a
renal tubular loss of calcium, P2, Na, K, water and bicarbinate
resulting in hyperchloremic acidosis. The calcium loss results
in secondary hyperparathroidism which along with acidosis,
results in severe rickets or osteomalacia with associated X-ray
evidence of stress fractures and cystic brown tumors of hyper-
parathyroidism. The hypokalemia results in severe muscle weak-
ness. The excessive loss of calcium in the kidney can result in
nephrocalcinosis. All of these metabolic problems can result in
a poor prognosis for survival.

94. Vitamin D Resistant Rickets & Osteomalcia
Renal Tubular Acidosis

95. Vitamin D Dependent (pseudodefciency)
Rickets & Osteomalacia
This rare form of rickets is usually inherited and has the same
clinical, radiographic findings and chemistries as vitamin
deficient rickets but is not cured with a normal intake of
vitamin D in the diet. The primary cause for this condition
is due to either a renal failure to convert 25(OH)2D to 1,25(OH)2D
or a failure of the gut to respond to 1,25(OH)2D both of which
result in hypocalcemia and secondary hyperparathyroidism
which then results in hypophosphatemia and osteoclastic
resorption of bone with its osteomalacic appearance on x-ray
(bowing, cytic changes and Looser’s zones) with a responsive
elevation of serum alkaline phosphatase. This condition
responds well to treatment with 1,25(OH)2D.

96. Vitamin D Dependent
(pseudodeficiency) Rickets
& Osteomalcia

97. Renal Failure Rickets & Osteomalacia
(Renal Osteodystrophy)
All the previous types of renal rickets resulted from a defect
in the renal tubule, whereas in renal failure rickets or its adult
osteomalacic form results from a complete failure of the entire
nephron including the tubule and glomerulus. Glomerular
tubular nephritis is a common cause of chronic renal failure. The
kidney’s failure to produce 1,25(OH)2D3 results in hypocalcemia
which then results in secondary hyperparathroidism which
along with renal tubular acidosis causes severe osteolysis with
resultant osteitis fibrosa cystica, brown tumors, pseudofractures
and slipped proximal femoral epiphyses. Compared to most
forms of renal rickets which have hypophosphatemia, in renal
osteodystrophy we have hyperphosphatemia second to the
damaged glomerulus. The high serum P2 results in a high
Ca - P2 product which causes calcification of vessels, deposition
of calcium about joints (tumoral calcinosis) and nephrocalcinosis.
Treatment consists of oral aluminum hydroxide to absorb P2

98. in the gut, 1,25(OH)2D3 to restore serum calcium, subtotal
parathroidectomy to reduce PTH levels and the ultimate
replacement of the damaged kidney.

99. Renal failure Rickets
(Renal Osteodystrophy)

100. Case #1 Renal Osteodystrophy
13 yr female with past history of glomular tubular nephritis &
now shows deformities of extremities with hyperphosphatemia

101. X-ray evidence of bowed long bones
of forearm and wide fuzzy growth
plates of distal radius and ulna

102. Slipped prox femoral epiphysis is
common in renal failure rickets
along with bowing of the femur

103. Osteitis fibrosa cystica
with active cutting cone
Osteolysis at the outer
end of clavicle

104. Case #2 Renal Osteodystrophy
10 year old female with
chronic renal failure 2nd to
myelomeningocele and
paraplegia with multiple
pathologic fractures

105. Case #3 Terminal Renal Osteodystrophy
Female child died of severe renal failure rickets and 2ndary
hyperparathyroidism with path fracture distal femur and
rachitic rosary and subperiosteal osteolysis of ribs

106. Case #4 Terminal Renal Osteodystrophy
Autopsy x-ray specimen of a
child with wide growth plates
and severe metaphyseal end
plate osteolysis from severe
secondary hyperparathyroidism

107. Autopsy macrosection prox femur
Cutting cone of 2ndary
hyperparathytoidism
Wide and weakened growth plate
made up of excessive hypertrophic
cartilage and no zone of provisional
calcification or osteoid

108. Case #5 Renal Osteodystrophy
Juxtra articular and vascular calcification in adult

109. Case #6 Renal Osteodystrophy with Brown Tumor
63 yr male with renal failure rickets and brown tumor of tibia
resulting from secondary hyperparathyroidism

110. T-1 MRI T-2
Hemorrhagic cysts seen in T-2 image of brown tumor

111. Hypophosphatasia
Hypophosphatasia is a rare rachitic like syndrome that is
inherited as either an autonomic recessive or dominant trait.
It results from a deficient alkaline phosphatase which is
required to allow for normal minineralization of young osteoid
recently formed off a growth plate or on a trabecular bone surface.
Pyrophosphate in newly formed osteoid inhibits calcium
deposition thus creating an excess of calcium in the serum and
urine that can result in nephrocalcinosis, renal failure and death.
The normal role of alkaline phosphatase is to remove pyro-
phosphate from young osteoid so as to allow for normal mineral-
ization. In hypophosphatasia, serum pyrophosphate, phospho-
ethanolamine and phosphoserine are excreted by the kidney.
Serum P2 is normal compared to the changes seen in all other
forms of rickets. The clinical picture and x-ray abnormalities of
bone is the same as in other more common forms of rickets
except for cranial stenosis that can result in an elevated

112. intracranial pressure. The autosomal recessive pediatric forms
have a worse prognosis compared to the adult autosomal
dominant forms.

113. Hypophosphatasia

114. Case #1 Hypophosphatasia
Infant female with short stature
and rachitic deformities of the
extremities
High serum calcium with normal
P2 and no alkaline phosphatase

115. Cranial stenosis
Rachitic lower extremities with
bowing, shortening and wide
fuzzy looking growth plates

116. Rib macrosection X microscopic image
X
Macro and microscopic changes at rib growth plate

117. Hyperphosphatasia
Juvenile Paget’s Disease
2 year old female with
Short stature bowed
extremities with osteopenic
bones and heart shaped
pelvis similar to rickets
Deformed bell shaped rib
cage with osteopenia like
rickets
All chemistries normal
except for elevated alkaline
phosphatase

118. Thickened calvarium

119. Scurvy

120. Scurvy
Scurvy is a well know nutritional disorder second to a lack of
vitamin C (ascorbic acid) which is necessary for the production
of collagen fiber, osteoid, dentine and intercellular cement
substance in the vascular endothelium. Vitamin C acts as a
catalyst for the hydroylation of proline to hydroxyproline in the
synthesis of collagen of bone and soft tissue structures. The
clinical end result is osteoporosis and ligamentous weakness.
The intercellular cement substance deficiency results in increased
capillary fragility with ecchymoses, bleeding gums, hemorrhagic
periostitis and painful hemarthoses. The painful hemorrhagic
periostitis can produce radiographic changes similar to those
seen in congenital lues, Caffey’s disease, leukemia and hyper-
vitaminosis A. Enlargement of the costochondral rib junctures
can result in a scorbutic rosary similar to that seen in rickets.
The classic radiographic changes seen in a scorbutic growth plate
include a dense white band across the distal end of the

121. metaphyseal face that represents excessive calification in the
zone of provisional calcification known as Frankel’s white line.
At the peripheral edge of the physeal line one may see the so-
called Pelkan’s spur which is second to callous formation
resulting from repeated stress fracture thru the osteopenic
bone on the metaphyseal side of the physis. A thin white line
can be seen around the epiphyseal ossification center which
is known as Wimberger’s ring which is second to the excessive
calcification in the zone of provisional calcification as we see
in Frankel’s line. On the metaphyseal side of Frankel’s line one
will see a radiolucent band second to a deficiency of osteoid
formation and is an area thru which pathologic fractures
can be seen. This same radiolucent band can be seen in
leukemia patients. The diaphyseal bones have a osteopenic
look with a ground glass appearance with thin cortices second
to a bone volume deficiency.

122. Case #1 Scurvy
Osteoid deficient
Radiolucent zone
Frankel’s
line
8 mo female with scurvy comparing radiographic and
pathologic findings

123. Case #2 Hemorrhagic Periostitis in Scurvy
periostium
cortex
15 mo female with severe thigh pain from scurvy

124. Case #3 Slipped epiphyses in Scurvy
1 year old child with multiple
slipped epiphyses second to
scurvy

125. Case #3 Scorbutic Rosary
1 year old child with
widened costochondral
rib junctures as in
rickets

126. Gaucher’s Disease

127. Gaucher’s Disease
Gaucher’s disease is the more common of a group of familial
diseases in which there is a metabolic disturbance of lipid
metabolism resulting in an abnormal accumulation of sphingo-
lipids in the macrophage system of organs such as the liver,
spleen and bone marrow. Along with Gaucher’s disease, the
other spingolipidoses include Tay-Sachs disease, Niemann-
Pick’s disease, metachromatic leukodystrophy and Fabry’s disease
many of which are found in Jewish families. The specific sphingo-
lipid found in Gauchers disease is kerasin found in the foamy
cytoplasm of large foam cells found on bone marrow biopsy
known as Gaucher cells.
There are two clinical forms of Gaucher’s disease. The infantile
form is the least common and die early from acute neurologic
manifestations. The more common chronic adult form is often
times asymptomatic until early adult life when they are found
with a large liver and spleen and perhaps a pathologic fracture

128. or collapse of a femoral head second to weakened bone from
foam cell infiltration. Generalized bone marrow replacement
and hypersplenism can result in anemia, thrombocytopenia
and leukopenia that increases the chance for post op infection
in these patients. The most common bone deformity in
Gaucher’s disease include flatening of the proximal femoral
epiphysis producing a Perthes’ like syndrome, a widened distal
femoral metaphysis producing an Erlenmeyer flask deformity
like fibrous dysplasia, flatened vertebral bodies and similar
changes seen in the tibia and skull.
Currently, these lipid storage disorders can be treated with
the specific deficient enzymes that are required to catabolize
the excessive sphingolipids. Cerezyme is the specific enzyme
used for Gaucher’s disease at a cost of $200,000 per year.

129. Case #1 Gaucher’s Disease
29 yr male with pathologic fracture femur and family history
of Gaucher’s disease

130. R L L
X-ray both humeri and L elbow with prior fracture R humerus

131. Case #2 Gaucher’s Disease
9 yr male with a Perthes like
collapse of the right femoral head
and an Erlenmeyer flask deformity
of the distal femori second to
Gaucher’s disease

132. Case #3 Gaucher’s Disease
17 year male with path fracture right humerus & Gaucher’s

133. Case #4 Gaucher’s Disease
45 yr male with Gaucher’s of the long bones

134. Case #5 Gaucher’s Disease
55 yr male with Gaucher’s of humerus, femur and tibia

135. Gaucher’s Disease
Epiphyseal lesions
looking like GCT

136. Gout & Pseudo Gout

137. Gout
Gout is a well known clinical condition resulting from hyper
uricemia due to a purine metabolic disorder with an over
production of uric acid or a decrease in renal excretion of uric
acid which is usually familial but more common in older males
then females. The hyperuricemia is present early in life but the
clinical symptoms related to the deposition of Na urate crystals
in and around joints does not occur until the fifth decade. The
most common location for gouty arthritis is the great toe MP joint
followed by the intertarsal joints, ankle and knees. The diagnosis
can be made by viewing the needle shaped Na urate crystals
in synovial fluid which show strong negative birefringence under
polarized light. The typical radiographic finding is that of juxta-
articular bony erosion with minimal evidence of chondrolysis
even though urate deposits can be seen on the joint surface with
arthroscopic viewing. 50-60% of gout patients will develop
tophi consisting of visible deposits of chalky white Na urate in

138. synovial linings and other juxta-articular soft tissues which can
go on to calcify similar to patients with tumoral calcinosis
second to renal failure. Tophi are common in the ear pinna and
in bursae about the elbow, knee, hand and foot.
There are many medical conditions that can result in hyper
uricemia such as myeloproliferative disorders, bone marrow
neoplasms, and inflammatory renal disease. However, the
clinical diagnosis of gout can only be made with the discovery
of Na urate crystals in synovial fluid or juxta-articular tissue.
medical treatment includes symptomatic relief with colchicine,
Anti inflammatory agents or allopurinol which blocks the
formation of Na urate at the cellular level.

139. Case #1 Tophaceous Gout
45 yr male with painful lump medial 1st MP joint foot 2 yrs

140. Case #2 Tophaceous Gout Foot
Early disease age 40 Older disease age 65

141. Case #3 Tophaceous Gout Hand
Late changes
Early changes

142. Case #4 Gouty Changes in Hand
58 yr male with advanced gouty
changes in hand with macro section
of metacarpal head with early
subchondral gouty granuloma

143. Case #5 Tophaceous Gout of Hand with Amputation
Two advanced cases of tophaceous
gout with secondary infection of
ulcerating tophi resulting in
amputation

144. Case #6 Tophaceous gout
synovial sarcoma pseudotumor
51 year male with tender prepatellar lump for three years

145. Axial T-1 T-2
Gad

146. Sag T-1 T-2
Gad

147. Case #7 Gouty Arthritis of Ankle
Sag T-1
Cor T-2
80 year old female with
large subchondral gouty
granulomas

148. Case #8 Soft Tissue Changes in Gout
Olecranon Bursa Ear Pinna Deposits
Cutaneous deposits Photomicrograph

149. Pseudo Gout
Calcium Pyrophosphate Dihydrate Crystal Deposition
Disease (CPPD) - Chondrocalcinosis
Pseudo gout is a clinical condition that presents in mid and
older aged patients with painful arthritic pains similar to patients
with true gouty arthritis. In both conditions, the inflammatory
synovitis is induced by an irritating crystal which in the case of
gout is the Na urate crystal and in the case of pseudo gout it is
calcium pyrophosphate. In the Pseudo gout patients the most
commonly involved joint is the knee which on radiographic
exam will show evidence of chondrocalcinosis of the joint surface
and menisci. Calcium pyprophosphate crystals must be found
in the synovial fluid and confirmed with polarized light micro-
scopy with a weakly positive birefingence compared to the
strongly negative birefringence seen with the Na urate crystals
of gout. Many cases of chondrocalcinosis second to CPPD disease

150. will have no painful pseudo gout symptoms but those that do
have painful synovitis will experience destructive chondrolysis
induced by proteolytic enzymes produced by the inflammatory
synovitis. The most common cause for CPPD deposition
disease is degenerative osteoarthritis but can also be seen in
diabetic patients, hyperparathyroidism, hemochromatosis,
Wilson’s disease, neuropathic arthropathy, ochronosis, and
even true gout patients can have CPPD crystal deposition
disease.

151. Pseudo Gout - Chondrocalcinosis
62 year old male with painful
synovitis of knee and x-ray
evidence of chondrocalcinosis

152. Common Crystal Origin of Gout and Pseudo Gout

153. Alkaptonuria
Ochronosis

154. Alkaptonuria - Ochronosis
Alkaptonuria is a rare autosomal recessive hereditary
metabolic disorder created by an absence of homogentistic acid
oxidase which is required for the normal catabolism of phenyl-
alanine and tyrosine. As a result, excessive homogentistic acid in
urine becomes oxidized to a melanin-like product that turns the
urine dark. In the third decade the dark pigmented form of
homogentistic acid will appear in various mesenchymal
structures such as the intervertebral disc space, articular cartilage,
laryngeal, trachial, bronchial and rib cartilage, eye sclera and
cornea, heart valves, prostate gland and kidneys. The articular
cartilage deposition over time leads to early chondromalacia and
chondrocalcinosis. The pigmented chondromalacic articular
cartilage flakes off the joint surface and is picked up by the
synovial lining producing a secondary pigmented synovial
chondromatosis. In the intervertebral disc space one sees early
calcification of the pigmented disc material with resultant loss of
disc height and hypertrophic spur formation.

155. Case #1 Ochronosis Knee
62 yr male with ochronosis
resulting in TKA

156. 2ndary Synovial Osteochondromatosis in Ochronos
Macrosection knee Synovial microscopic

157. Case #2 Ochronosis Hip
Autopsy specimen
Microscopic joint surface chondromalcia

158. Case #3 Spinal Ochronosis
X-ray and autopsy specimen of ochronosis of spine

159. Case #4 Spinal Ochronosis
71 year male with spinal ochronosis with autopsy specimen

160. Case #5 Facial changes with Alkaptonuria
54 year old male
Dark pigmentation in the ears, nose
and sclera of the eye

161. Osteoporosis
(Osteopenia)

162. Osteoporosis
Osteoporosis is a condition of bone resulting from an
abnormal decrease in total bone volume taking in a consider-
ation of normal variation second to body size, age, sex and
genetic background. In contrast, osteomalcia is a specific loss
of the mineral component of bone second to a metabolic
disturbance affecting the normal remodeling process which if
lasts over a long period of time will lead to an osteoporotic
state of total bone volume deficiency. The loss of bone volume
in osteoporosis is not homogenous throughout the entire
skeletal system and usually starts in the less radiodense areas
of cancellous trabecular bone with a large surface area located
in the meta-epiphyseal areas at the ends of long bones and
in vertebral bodies. As the condition becomes more chronic
with age one will see loss of bone volume in dense cortical
bone. The disabling problem with more advanced symptomatic
osteoporosis is pathologic fracture of the spine associated with

163. kyphotic axial shortening and fractures of the proximal femur
and distal radius. There are a multitude of conditions and
disease states that can lead to osteoporosis as listed in the
following slide Cibagram.
Disuse osteoporosis is a common problem in any age or
sex group which can be generalized as in any illness that
forces inactivity or can be localized as in the case of a fracture
that requires a cast fixation. Paralytic conditions such as para-
plegia will cause osteoporosis in the lower extremities that
become inactive. Astronauts in a weightless environment run
a risk of loosing bone volume from lack of gravitational pull.
Nutritional osteoporosis which may start out as osteo-
malacia can result from a lack of calcium, vitamin C and D and
protein. Alcoholism is frequently associated with poor
nutrition.
Drug related osteoporosis can be seen in patients on

164. heparin, methotrexate and glucocorticoids.
Familial or congenital forms of osteoporosis are
common in patients with genetic defects that regulate the
synthesis of collagen fiber including osteogenesis inperfecta,
Marfan’s disease, epiphyseal and spondyloepiphyseal
dysplasias and in mucopolysacharidosis patients.
Chronic illness such as rheumatoid arthritis, hepatitis,
nephritis, and myelogenous sarcomas such as myeloma,
leukemia and lymphomas can cause generalized osteoporosis.
Endocrine disorders associated with osteoporosis include
pituitary adenomas, adrenal cortical hyperplasia or adenoma,
ovarian deficiency such as post menopausal osteoporosis,
testicular deficiency from disease or aging, and over active
thyroid and parathyroid conditions.
Treatment of osteoporosis depends on the cause of bone loss
which can be extremely varied as seen above. However, in the

165. case of type I post menopausal osteoporosis the therapeutic
focus is on prevention including increased physical activity,
nutritional supplements of vitamin D and calcium, early
replacement estrogen therapy in high risk cases with a strong
familial background, and diphosphonate therapy for those
patients with abnormal bone mineral densitometry findings of
the spine and hip areas.

166. Causes of Osteoporosis

167. Advanced Spinal Osteoporosis
disc
75 year female with multiple biconcave codfish vertebrae

168. Spinal Osteoporosis vs Metastatic CA
80 yr female with 64 yr female with
Osteoporotic collapse Metastatic CA collapse

169. Sacral Osteoporotic
Stress Fracture
71 year old female with
LBP for 4 weeks

170. T-1 MRI study to rule
out metastatic disease

171. Axial CT scan
Isotope bone scan
The CT scan clearly shows the
symmetric stress fracture lines
with a bridge across at S-2
The isotope scan shows the
diagnostic Honda sign

172. 20 yr Normal Vertebral Body Aging 56 yr
Coronal CT scans of normal
vertebral bodies at early,
middle and late adulthood
autopsy specimens
80 yr

173. 30 yr Normal Vertebral Body Aging
50 yr
Axial CT scans thru vertebral
bodies in normal young and
mid aged adults - autopsy

174. Normal Femoral
Cortex Aging
I - Axial CT scan of normal
femoral cortex in 20 yr old
II - age 40 yr with early sub-
endosteal loss of bone
III - 60 yr old with progressive
lateral porotic changes
IV - 80 yr old with only 2 mm
of cortical bone remaining
l

175. Histology of Cortical Osteoporosis
Advanced Osteoporosis
Moderate Osteoporosis

176. Histology of Osteoporosis vs Osteomalacia
Osteomalcia
Advanced Osteoporosis
Von Kossa stain

177. Hyperadrenalism of Bone (Cushing’s Syndrome)
42 yr male with low turnover osteoporosis from an
adrenal cortical adenoma resulting in stress fractures

178. Thyroid Disorders

179. Thyroid Disorders
Thyroid deficiency in infants and young children results in
cretinism associated with mental retardation, retarded growth,
lethargy, abdominal distention, enlarged and protruding tongue,
hypotonic, dry hair and skin and delayed dentition. Radio-
graphic features of cretin bones include retarded and irregular
maturation of ossification centers and delayed closure of growth
plates and cranial suture lines. One may find transverse sclerotic
metaphyseal bands in tubular hand bones second to a deficiency
of osteoclastic remodeling similar to that seen in osteopetrosis
patients and in patients with phosphorous, arsenic, lead, or
fluoride toxicity. Hypothyroidism in older children and adults
can result in soft tissue myxedema.
Hyperthyroidism or thyrotoxicosis is seen in adult patients
with toxic diffuse goiter (Graves’ disease) and toxic nodular goiter
produced by a single thyroid adenoma. Symptoms include
fatigue, nervousness, increased sweating, weight loss, diarrhea

180. and tachycardia. Bony abnormalities seen on x-ray include
osteoporsis and can be seen in patients who take thyroxine
over a long period of time to control obesity.

181. Case #1 Cretinism
8 year old female with mental
retardation and dwarfism
second to retarded epiphyseal
maturation in cretinism

182. Hand Cretinism
8 yr old
X-ray of hand showing
retarded epiphyseal
ossification and sclerotic
metaphyseal bands

183. Teen-age Hypothyroidism
12.5 yr male at time of first
diagnosis of hypothyroidism
with delayed closure of
growth plates & osteoporosis
One year later after treatment
with thyroxine with rapid
closure of growth plates and
return of normal bone
density

184. Paget’s Disease
(Osteitis Deformans)

185. Paget’s Disease (osteitis deformans)
Paget’s disease is seen in 3% of middle aged humans but in
10% in the ninth decade. It is rare under forty years and more
common in males in colder climates such as England, USA, New
Zealand and Australia. Paget’s is not really a metabolic disease
because of its patchy involvement but has features similar to
hyperparathyroidism. The early phase of the disease results from
increased osteoclastic activity and bone resorption followed by a
coupling osteoblastic response with increased alkaline phos-
phatase found in the blood serum. Hydroxyproline will be found
in the urine as a result of increased bone break down. Inflam-
matory hyperemia and bone pain is associated with the early
osteolysis. The etiology of this condition still remains unknown
but in some cases, intranuclear inclusions have been found in the
pagetic osteoclasts suggesting a slow viral infectious etiology. The
most common form of Paget’s disease is the monostotic form in
older patients. However, the more aggressive symptomatic form

186. is a painful polyostotic disease involving the skull, spine, pelvis
and lower extremities. The cranial involvement can cause
cranial nerve entrapment resulting in visual and hearing
problems. Bowing of the lower extremities with increased
warmth and tenderness results from early inflammatory
osteolysis. Later complications result from transverse pathologic
fractures, early degenerative osteoarthritis, and pagetic sarcomas
seen in less than 1% of patients.
Paget’s presents as a focal osteolytic process that looks more
like a lytic tumor such as a hemangioma, giant cell tumor,
metastatic tumor or a myelogenous sarcoma. As the healing
osteoblastic phase appears we see extensive reparative osteo-
blastic activity with patchy sclerotic changes and an increased
course stress line oriented trabecular pattern as the bone
becomes enlarged and deformed.
Treatment is only required for the more aggressive early
symptomatic phase of the disease which is focused on inhibiting

187. early osteoclastic activity. The two agents that inhibit osteoclastic
activity include human calcitonin for the more severe cases and
diphosphonates for the less severe cases. Care must be exercised
when using these agents for more than six months for fear of
creating a remodeling deficiency osteomalacia that can increase
the incidence of pathologic fracture.
For a discussion of pagetic sarcomas, refer to Vol #3 under
osteosarcoma variants.

188. Case #1 Paget’s of Femur
68 year female with Paget’s of femur with pain

189. MRI Study of Paget’s
Cor T-1 Sag T-1

190. Gross and microscopic changes
similar to hyperparathyroidism
with increased osteoclastic and
osteoblastic activity along with
a reversal line mosaic pattern

191. Late changes in Paget’s with Stress Fractures
Case #2
68 year old male with multiple stress fracture lines
in lateral femoral cortex with macroscopic specimen

192. Case #3 Path Fracture Femur in Paget’s
59 yr male Paget’s patient with transverse femur fracture
treated with IM nail

193. Case #4 Early vs Late Changes in Paget’s
54 yr male with early lytic changes L compared to late changes
R with multiple convex cortical stress fracture lines 15 yrs later

194. Case #5 Early Paget’s of Pelvis
32 year male with early pelvic deformity from Paget’s

195. Case #6 Late Paget’s of Pelvis
70 year old patient with late burned out pelvic changes

196. Case #7 Early vs Late Paget’s of Skull
Blastic phase 20 yrs later
40 yr female with early
lytic phase Paget’s with
a headache known as
osteoporosis circumscripta

197. Case 8 & 9 Early vs Intermediate Paget’s Skulls
48 yr male with moderate
blastic response to Paget’s
of the skull
41 yr male with early lytic
phase Paget’s of skull
osteoporosis circumscripta

198. Case #10 Paget’s Lumbar Spine
CT scan
51 year old male with early
Paget’s L-5 and CT scan
looking like hemangioma
After diphosphonate therapy

199. Case #10.1 Early Paget’s of L-2
49 yr old male with LBP for 6 months

200. Sag STIR Gad

201. Case #11 & 12 Asymptomatic Paget’s
68 yr male with monostotic 60 yr male with C-2 &
Paget’s of os calcis C-4 incidental Paget’s

202. Miscellaneous
 Pituitary disorders
 Hypogonadism
 Hypervitaminosis D
 Hypervitaminosis A
 Hypercholesterolemia
 Phosphorous poisoning

203. Pituitary Disorders
Pituitary gigantism is usually the result of an adenoma of
the anterior portion of the pituitary gland which becomes active
during the growing years of a child that results in over growth
of the entire musculoskeletal system which by age 16 years
produces a seven to eight foot giant with strong muscles and long
strong bones. This form of gigantism is easily separated from a
eunuchoid giant with testosterone insufficiency because the
eunuch’s seven to eight foot height is not reached until the
early twenties as the result of delayed growth plate closure.
Eunuchs also have weak muscles and long frail bones. As
pituitary giants get older their pituitary glands atrophy with
associated adrenal insufficiency leading to physical weakness,
osteoporosis and decreased resistance to infections that leads to
an early demise.
Acromegaly is usually the result of a pituitary adenoma that

204. doesn’t become active until after the normal closure of the
growth plates. The clinical manifestations include a bull dog
face with a protruding jaw plus abnormal thickness of arms and
legs with soft tissue hypertrophy of enlarged hands and feet.
The skull x-rays will show an enlarged sell tursica from enlarge-
ment of the pituitary gland and one will notice a hyperostosis
frontalis interna along with a prominent external occipital
protuberance. Hand x-rays will show early hypertrophic osteo-
arthritis of the IP joints along with prominent tufts of the distal
phalanges.

205. Acromegaly Skull and Face
45 year male with a pituitary adenoma in enlarged sella tursica
a Dick Tracy jaw, hyperostosis frontalis interna & large sinuses

206. Acromegaly Hand and Foot
Prominent tufts on distal
phalanges with early distal IP
joints OA & soft tissue hypertrophy
Thick heal pads

207. Hypogonadism (eunuchoid giant)
21 yr testosterone deficient
7 foot tall male with long
fingers and persistent growth
because of open growth plates

208. Hypervitaminosis D
This young child was given a large
amount of vitamin D resulting in
dense bone in calvarium similar to
that of osteopetrosis
Dense sclerotic bands seen in
metaphyses similar to cretinism
and phosphorous poisoning

209. Hypervitaminosis A
Comparison of subperiosteal seroma of long bone in a cat vs
human with macrosection of cat specimen

210. Soft Tissue Cholesteotomas
Second to Hypercholesterolemia
45 yr female with familial
hypercholesterolemia and
secondary cholesteotomas
Hand specimen with micro
evidence of cholesteral cleft

211. Cholesteotomas of Knees
Same case with subQ lesions
of both knees

212. Bilateral Heel Cord Cholesteotomas
Surgical result from resection
of both heel cords

213. Phosphorous Toxicity Lines
12 yr male with multiple growth arrest lines second to repeated
ingestion of phosphorous in match heads.