Metabolic Bone

Diseases

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.

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

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.

Hormonal regulation

of calcium and phosphate

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.

Calcium and phosphate

metabolism

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.

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.

Primary

hyperparathyroidism

Case #1 Primary Hyperparathyroidism

43 yr female with acute onset of elbow pain

X-ray showing generalized

osteomalacia with a

specific lysis of the outer

end of clavical

Lump in throat

Resected adenoma

Chief cells

Reversal line

Osteolysis Cutting cone

Salt and pepper granular osteolysis of the skull

Digital clubbing Subperiosteal osteolysis

Another case of

of early hand

hyperparathroidism

Case #1.1

56 year female with anterior knee pain for 2 years

2008

Primary Hyperparathroidism

Sag T-2 PD FS

Axial PD FS Cor PD FS

2009 2011

Two new aneurysmal lesions in foot two years apart

with bone graft to 3rd metatarsal ABC in 2009

2011

Osteomalacic looking bones

Bell shaped chest cage Dorsal kyphosis

Sag T-2

Axial T-2

at T-5

CT and MRI images of spinal defects with paraparesis

2011

T-5

Post op spinal decompression

and posterior stabilization

Case #2 Healed hyperparathyroidism

40 year female with parathyroid adenoma removed 8 yrs ago

Chronic deformation of the skull bones

Chronic bell shaped deformity of rib cage

Pseudo clubbing

X-ray

Case #3

48 yr female with multiple brown tumors of hyperparathyroidism

Primary hyperparathyroidism

CT scan sacroiliac area

Iliac biopsy shows

increased osteoclastic

activity

39 yr female with right hip and left hand pain for 6 mos

Case #4 Primary hyperparathyroidism

25 yr female

Pain 3 mos

Case #5 Brown Tumor of Hyperparathyroidism

Biopsy specimen showing benign giant cells

Trabecular bone with with thick pink staining osteoid seams

Case #6 Brown tumors of hyperparathyroidism

49 yr female with

parathyroid adenoma

with bilateral leg pain

Case #7 & 8 Brown tumors of tibia

41 year old female 43 yr female

Case #9 Brown tumor tibia

46 yr male with pain in leg for 6 months

Sag T-2 Axial T-2

Case #10 Brown tumor hand

30 year old female with

hyperparathyroidism and

a secondary brown tumor

of the index finger

Case #11 Nephrocalcinosis 2nd to parathyroid CA

43 yr male with history of primary hyperparathyroidism 2nd

to a parathyroid carcinoma

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.

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.

Pathologic physiology of

hypoparathyroidism

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.

Pathophysiology of

pseudohypoparathyroidism

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

Short lateral digits

Short metatarsals & metacarpals

Calcified basal ganglion

Case #2 Pseudohypoparathyroidism

18 yr female with short stature, round face and calcification

in basal ganglion plus a low serum calcium & high phosphorous

Shorting of the ulnar digits

of the hand

Shortening of the fibular

digits of the feet

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

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)

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.

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

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)

seen in the medial aspect of weight baring long bone

metaphyses.

Treatment consists of a correction of the nutritional defect

that caused the disease.

Nutritional - deficiency

rickets & osteomalacia

Case #1 Vit D deficient rickets

One year old with bowing of the lower extremities

More knee x-rays

Epiphyseal

bone

Case #2

Macro section and radiology

of autopsy specimen

Terminal rickets

Microscopic growth plate

X

Chest deformity

Rachitic rosery nodularity at costochondral junctures

Rickets at the wrist

Rachitic swelling at the wrists

second to metaphyseal flaring

Case #3

Case #4 Intestinal rickets

6 month old with congenital bile duct atresia

Case #5 Deficiency rickets

4 year old rachitic

child with knock-

knee deformity

Case #6 Healing rickets

2 yr male with epiphyseal rings second to treated rickets

Jan 6 Feb 2 Case #7

49 yr female with

severe obesity and

gastric bypass 2 yr

ago and now recent

gradual onset of

pain in leg without

trauma

Adult Intestinal

Osteomalacia

Isotope bone scan

Cor T-1 T-2 Gad

Increased alkaline phosphatase and PTH levels

Sag T-1 T-2

Case #7 Physiologic bowing (pseudorickets)

2 year old male with

physiologic bowing of

the lower extremities

that looks like rickets

Case #7 Jansen’s disease (pseudorickets)

3 yr male with bowing of lower extremities and wide plates

that looks rachitic but is Jansen’s disease

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).

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.

Vitamin D Resistant

Rickets & osteomalcia

Second to Proximal Renal

Tubular Defects

(Hypophosphatemic

Rickets)

Case #1 X-linked Hypophosphatemic Rickets

10 year happy female with short stature and bowed legs

Case #2 X-linked Hypophosphatemic Rickets

7 year male from a family of short

stature and bowed lower extremities

Tibial bowing with mild growth plate changes

Case #3 X-linked hypophosphatemic Osteomalacia

54 yr 5’2” male with low serum P and life time of universal bone pain

He had a subtotal parathyroid resection for high PTH levels

Hypophosphatemic Osteomalcia

26 yr female with short

stature and bowed lower

extremities since childhood

Looser’s zone or stress

Fracture in bowed femur

Case #4

Microscopic picture of

osteomalcia showing

thickened and poorly

mineralized osteoid seams

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

Photomicrographs of

osteomalacic bone with

thickened poorly calcified

osteoid seams

Case #6 Non Familial Hypophosphatemic Osteomalacia

Stress fractures of foot and tibia

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.

Other variants including oculocerebrorenal syndrome

(Lowe’s disease) and superglycine syndrome all have a poor

prognosis because of severe renal tubular defects.

Vitamin D resistant

Rickets & Osteo-

malcia Second to

Proximal & Distal

Tubular Defects

(Fanconi syndrome)

Case #1 Fatal case of Fanconi’s Syndrome

Autopsy specimen of the upper femur in a young child who died

of severe renal disease with advanced hyperparathyroidism

X-ray Macrosection

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.

Vitamin D Resistant Rickets & Osteomalcia

Renal Tubular Acidosis

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.

Vitamin D Dependent

(pseudodeficiency) Rickets

& Osteomalcia

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

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.

Renal failure Rickets

(Renal Osteodystrophy)

Case #1 Renal Osteodystrophy

13 yr female with past history of glomular tubular nephritis &

now shows deformities of extremities with hyperphosphatemia

X-ray evidence of bowed long bones

of forearm and wide fuzzy growth

plates of distal radius and ulna

Slipped prox femoral epiphysis is

common in renal failure rickets

along with bowing of the femur

Osteolysis at the outer

end of clavicle

Osteitis fibrosa cystica

with active cutting cone

Case #2 Renal Osteodystrophy

10 year old female with

chronic renal failure 2nd to

myelomeningocele and

paraplegia with multiple

pathologic fractures

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

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

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

Case #5 Renal Osteodystrophy

Juxtra articular and vascular calcification in adult

Case #6 Renal Osteodystrophy with Brown Tumor

63 yr male with renal failure rickets and brown tumor of tibia

resulting from secondary hyperparathyroidism

T-1 MRI T-2

Hemorrhagic cysts seen in T-2 image of brown tumor

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

intracranial pressure. The autosomal recessive pediatric forms

have a worse prognosis compared to the adult autosomal

dominant forms.

Hypophosphatasia

Case #1 Hypophosphatasia

Infant female with short stature

and rachitic deformities of the

extremities

High serum calcium with normal

P2 and no alkaline phosphatase

Rachitic lower extremities with

bowing, shortening and wide

fuzzy looking growth plates

Cranial stenosis

Rib macrosection X microscopic image

X

Macro and microscopic changes at rib growth plate

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

Thickened calvarium

Scurvy

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

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.

Scurvy

Osteoid deficient

Radiolucent zone

Frankel’s

line

Case #1

8 mo female with scurvy comparing radiographic and

pathologic findings

Case #2 Hemorrhagic Periostitis in Scurvy

15 mo female with severe thigh pain from scurvy

periostium

cortex

Case #3 Slipped epiphyses in Scurvy

1 year old child with multiple

slipped epiphyses second to

scurvy

Scorbutic Rosary

1 year old child with

widened costochondral

rib junctures as in

rickets

Case #3

Gaucher’s Disease

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

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.

Case #1 Gaucher’s Disease

29 yr male with pathologic fracture femur and family history

of Gaucher’s disease

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

R L L

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

Case #3 Gaucher’s Disease

17 year male with path fracture right humerus & Gaucher’s

Case #4 Gaucher’s Disease

45 yr male with Gaucher’s of the long bones

Case #5 Gaucher’s Disease

55 yr male with Gaucher’s of humerus, femur and tibia

Gaucher’s Disease

Epiphyseal lesions

looking like GCT

Gout & Pseudo Gout

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

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.

Tophaceous Gout

45 yr male with painful lump medial 1st MP joint foot 2 yrs

Case #1

Tophaceous Gout Foot

Early disease age 40 Older disease age 65

Case #2

Tophaceous Gout Hand

Early changes

Late changes

Case #3

Gouty Changes in Hand Case #4

58 yr male with advanced gouty

changes in hand with macro section

of metacarpal head with early

subchondral gouty granuloma

Tophaceous Gout of Hand with Amputation Case #5

Two advanced cases of tophaceous

gout with secondary infection of

ulcerating tophi resulting in

amputation

Case #6

51 year male with tender prepatellar lump for three years

Tophaceous gout

synovial sarcoma pseudotumor

Axial T-1 T-2

Gad

Sag T-1 T-2

Gad

Case #7 Gouty Arthritis of Ankle

80 year old female with

large subchondral gouty

granulomas

Sag T-1

Cor T-2

Case #8 Soft Tissue Changes in Gout

Olecranon Bursa Ear Pinna Deposits

Cutaneous deposits Photomicrograph

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

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.

Pseudo Gout - Chondrocalcinosis

62 year old male with painful

synovitis of knee and x-ray

evidence of chondrocalcinosis

Common Crystal Origin of Gout and Pseudo Gout

Alkaptonuria

Ochronosis

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.

Ochronosis Knee Case #1

62 yr male with ochronosis

resulting in TKA

2ndary Synovial Osteochondromatosis in Ochronosis

Macrosection knee Synovial microscopic

Case #2 Ochronosis Hip

Autopsy specimen

Microscopic joint surface chondromalcia

Case #3 Spinal Ochronosis

X-ray and autopsy specimen of ochronosis of spine

Case #4 Spinal Ochronosis

71 year male with spinal ochronosis with autopsy specimen

Case #5 Facial changes with Alkaptonuria

Dark pigmentation in the ears, nose

and sclera of the eye

54 year old male

Osteoporosis

(Osteopenia)

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

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

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

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.

Causes of Osteoporosis

Advanced Spinal Osteoporosis

disc

75 year female with multiple biconcave codfish vertebrae

Spinal Osteoporosis vs Metastatic CA

80 yr female with

Osteoporotic collapse

64 yr female with

Metastatic CA collapse

Sacral Osteoporotic

Stress Fracture

71 year old female with

LBP for 4 weeks

T-1 MRI study to rule

out metastatic disease

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

Normal Vertebral Body Aging 20 yr 56 yr

80 yr

Coronal CT scans of normal

vertebral bodies at early,

middle and late adulthood

autopsy specimens

Normal Vertebral Body Aging 30 yr

50 yr

Axial CT scans thru vertebral

bodies in normal young and

mid aged adults - autopsy

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

Histology of Cortical Osteoporosis

Moderate Osteoporosis

Advanced Osteoporosis

Histology of Osteoporosis vs Osteomalacia

Advanced Osteoporosis

Von Kossa stain

Osteomalcia

Hyperadrenalism of Bone (Cushing’s Syndrome)

42 yr male with low turnover osteoporosis from an

adrenal cortical adenoma resulting in stress fractures

Thyroid Disorders

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

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.

Case #1 Cretinism

8 year old female with mental

retardation and dwarfism

second to retarded epiphyseal

maturation in cretinism

Hand Cretinism

X-ray of hand showing

retarded epiphyseal

ossification and sclerotic

metaphyseal bands

8 yr old

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

Paget’s Disease

(Osteitis Deformans)

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

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

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.

Case #1 Paget’s of Femur

68 year female with Paget’s of femur with pain

MRI Study of Paget’s

Cor T-1 Sag T-1

Gross and microscopic changes

similar to hyperparathyroidism

with increased osteoclastic and

osteoblastic activity along with

a reversal line mosaic pattern

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

Case #3 Path Fracture Femur in Paget’s

59 yr male Paget’s patient with transverse femur fracture

treated with IM nail

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

Case #5 Early Paget’s of Pelvis

32 year male with early pelvic deformity from Paget’s

Case #6 Late Paget’s of Pelvis

70 year old patient with late burned out pelvic changes

Case #7 Early vs Late Paget’s of Skull

40 yr female with early

lytic phase Paget’s with

a headache known as

osteoporosis circumscripta

Blastic phase 20 yrs later

Case 8 & 9 Early vs Intermediate Paget’s Skulls

41 yr male with early lytic

phase Paget’s of skull

osteoporosis circumscripta

48 yr male with moderate

blastic response to Paget’s

of the skull

Case #10 Paget’s Lumbar Spine

51 year old male with early

Paget’s L-5 and CT scan

looking like hemangioma

After diphosphonate therapy

CT scan

Case #10.1

49 yr old male with LBP for 6 months

Early Paget’s of L-2

Sag STIR Gad

Case #11 & 12 Asymptomatic Paget’s

68 yr male with monostotic

Paget’s of os calcis 60 yr male with C-2 &

C-4 incidental Paget’s

Miscellaneous

Pituitary disorders

Hypogonadism

Hypervitaminosis D

Hypervitaminosis A

Hypercholesterolemia

Phosphorous poisoning

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

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.

Acromegaly Skull and Face

45 year male with a pituitary adenoma in enlarged sella tursica

a Dick Tracy jaw, hyperostosis frontalis interna & large sinuses

Acromegaly Hand and Foot

Prominent tufts on distal

phalanges with early distal IP

joints OA & soft tissue hypertrophy

Thick heal pads

Hypogonadism (eunuchoid giant)

21 yr testosterone deficient

7 foot tall male with long

fingers and persistent growth

because of open growth plates

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

Hypervitaminosis A

Comparison of subperiosteal seroma of long bone in a cat vs

human with macrosection of cat specimen

Soft Tissue Cholesteotomas

Second to Hypercholesterolemia

45 yr female with familial

hypercholesterolemia and

secondary cholesteotomas

Hand specimen with micro

evidence of cholesteral cleft

Cholesteotomas of Knees

Same case with subQ lesions

of both knees

Bilateral Heel Cord Cholesteotomas

Surgical result from resection

of both heel cords

Phosphorous Toxicity Lines

12 yr male with multiple growth arrest lines second to repeated

ingestion of phosphorous in match heads.