Metabolic and Endocrine Abnormalities

Calcium plays a crucial role in the irritability,
conductivity, and contractility of smooth and skeletal muscle, and in
the irritability and conductivity of nerves. Small changes in
extracellular and intracellular calcium levels lead to dysfunction of
these cells. In the case of neurons, cellular activity is inversely
proportional to calcium ion concentration, whereas for cardiac myocytes
there is a direct proportionality. Therefore, decreases in ionic
calcium concentration can lead to tetany, convulsions, or diastolic
death. Conversely, increases in the concentration of calcium can lead
to muscle weakness, somnolence, and ventricular fibrillation. It is
obviously important for the body to guard the concentration of ionized
calcium, thereby providing a rationale for the overriding importance of
calcium homeostasis in modulating bone density (8,9).

Calcium is absorbed from the gut, stored in the bone,
and excreted primarily by the kidney. Therefore, diseases that affect
gut absorption or renal function have the potential to dysregulate
normal calcium homeostasis and bone mass. In addition, some conditions
that cause massive loss of bone mass, such as widespread metastatic
disease or prolonged bed rest, can also alter serum calcium levels.
Almost all of the body’s calcium is stored in the bones and is held in
the form of hydroxyapatite, a salt that is composed of calcium,
phosphorus, hydrogen, and oxygen (CaHPO) in very tiny crystals embedded
in the collagen fibers of the cortical and cancellous bone (10,11,12,13).
The small size of the crystals provides an enormous surface area, and
this factor, combined with the reactivity of the crystal surface and
the hydration shell that surrounds it, allows a rapid exchange process
with the extracellular fluid (ECF). This process converts the
mechanically solid structure of bone into a highly interactive
reservoir for calcium, phosphorus, and a number of other ions (12,14).

Hydroxyapatite is not freely soluble in water. At the pH
of body fluids, calcium and phosphate concentrations in serum exceed
the critical solubility product, and are predicted to precipitate into
a solid form. It is thought that various plasma proteins act to inhibit
the precipitation and

keep
these ions in solution. This metastable state is important for bone
structure, as it allows the deposition of hydroxyapatite with a minimal
expenditure of energy during bone formation. Unfortunately, it also
makes the occurrence of ectopic calcification and ossification easy,
because of increments in the levels of either or both of these ions.

Calcium cannot passively diffuse across mammalian cell
membranes, and requires an active transport machinery to move it into
or out of cells (8,12,14,15,16).
Although the mechanism to control this transport is regulated, in large
part, by the action of the active form of vitamin D, PTH, and the
concentration of phosphate (14,17,18),
a variety of other cell-signaling pathways also play their roles in
transporting calcium across cell membranes. These other cell-signaling
pathways, however, seem to act in specialized cell types under specific
physiologic states and, as such, are likely to play only a small role
in regulating the total serum calcium level. Therefore, PTH, vitamin D,
and phosphate are the three factors that play the most crucial roles in
the calcium transport process and, consequently, in maintaining the
normal extracellular soluble calcium level.

PTH is produced by cells of the parathyroid glands, and
the expression level of PTH is regulated by the serum level of ionized
calcium. When serum calcium levels are low, there is an increase in PTH
expression and protein production, leading to increased PTH levels in
the serum. There are four parathyroid glands, and any one gland has the
potential to produce enough PTH to maintain calcium homeostasis. This
fact is of importance in the surgical management of thyroid neoplasia,
in which it is preferable to maintain the viability of at least one
parathyroid gland. PTH binds to a family of cell membrane receptors
called parathyroid hormone receptors (PTHR) that activate a number of
cell-signaling pathways. The pathway that has been studied the most in
the control of calcium is the one that regulates adenyl cyclase
activity, resulting in an increased cellular level of cyclic adenosine
monophosphate (cAMP). cAMP renders the cell membrane more permeable to
ionic calcium, and it induces the mitochondria, which are intracellular
storehouses for calcium, to release their calcium. These actions
increase the intracellular concentration of calcium, but do not promote
transport to the extracellular space, a function that also requires
vitamin D. PTH acts with 1,25-dihydroxyvitamin D to facilitate cellular
calcium transport in the gut, the renal tubule, and in the lysis of
hydroxyapatite crystals (16,17,19).
PTH directly stimulates osteoblasts to begin to degrade the surrounding
calcium-rich osteoid. Osteoclasts do not contain receptors for PTH, but
are stimulated by PTH activation in osteoblasts through induction of
the expression of RANKL, which activates osteoclasts (19,20).
Another action of PTH is to diminish the tubular reabsorption of
phosphate, thereby causing the renal excretion of phosphate (19,21,22).

Active vitamin D is produced from provitamins through conversion steps in the skin, liver, and kidney (Fig. 7.2). The provitamins are ingested from animal fats (ergosterol) or synthesized by the liver (7-dehydrocholesterol) (10,16,23),
and are converted to calciferol and cholecalciferol by ultraviolet
light, a process that occurs in the skin. In the absence of ultraviolet
light, this conversion cannot occur; this explains why vitamin D
deficiency is associated with prolonged periods indoors away from
ultraviolet light sources, such as in chronically ill individuals, or
in individuals living in extremely cold climates (10,24). The compounds are then transported to the liver, where they are converted to 25-hydroxyvitamin D by a specific hydrolase (25,26,27,28,29).
Severe liver disease or the intake of drugs that block hydrolase
activity will inhibit the production of 25-hydroxyvitamin D, also
potentially leading to vitamin D deficiency. The final conversion
occurs in the kidney. In the presence of specific hydrolases and a
number of biochemical cofactors, 25-hydroxyvitamin D is converted to
either 24,25-dihydroxyvitamin D or 1,25-dihydroxyvitamin D. The latter
serves as the potent calcium transport promoter (30–32). A low serum
calcium level and a high PTH level cause conversion to the 1,25 analog,
whereas a high serum calcium level, a higher serum phosphate level, and
a low PTH level favor formation of 24,25-dihydroxyvitamin D, which is
less potent in activating calcium transport (Fig. 7.3) (30,33,34,35,36).
Serum phosphate also plays an important role here, because a high
concentration of phosphate shunts the 25-hydroxyvitamin D into the
24,25-dihydroxy form. Although the 24,25-dihydroxy form is less active
in regulating calcium levels, it has an important role in growth-plate
chondrocytes. This crucial role of the kidney in converting vitamin D,
as well as its important role in excreting excess calcium and
phosphorus, explains the particularly deleterious effect of renal
failure on bone homeostasis, causing vitamin D deficiency as well as
directly dysregulating normal calcium excretion. Because of the crucial
role of vitamin D in calcium metabolism, the National Academy of
Sciences and the American Academy of Pediatrics recommends 200 IU per
day of vitamin D (37). This dose will prevent
physical signs of vitamin D deficiency and maintain serum
25-hydroxyvitamin D at or above 27.5 nmol per L (11 ng per mL). The
generic name of 1,25-dihydroxyvitamin D is calcitriol.
Recent studies found that vitamin D also plays a variety of
extra-skeletal roles, including in modulation of the immune response,
and as a chemoprotective agent against certain cancers (38).

Dietary calcium is crucial for the maintenance of bone mass. Daily requirements vary depending upon the need

for calcium during periods of rapid bone growth. Recommendations from the American Academy of Pediatrics are summarized in Table 7.1 (8,24,39,40).
Adequate calcium in the diet during adolescent years is important for
the maintenance of bone mass over the long term, and orthopaedists
should counsel their patients about the importance of including
appropriate amounts of calcium, as well as vitamin D, in their diet.
Several dietary factors alter calcium absorption. Calcium salts are
more soluble in acid media; therefore the loss of the normal
contribution of acid from the stomach reduces the solubility of the
calcium salts and decreases the absorption of the ionized cation. A
diet rich in phosphate may decrease the absorption of calcium by
binding the cation to HPO^2-₄ and precipitating most of the ingested calcium as insoluble material (12,41).
Ionic calcium can be chelated by some organic materials with a high
affinity for the element, such as phytate, oxalate, and citrate.
Although these materials may remain soluble, they cannot be absorbed (12,41,42,43). Calcium, in the presence of a free fatty acid, forms an insoluble soap that cannot be absorbed (41,44).
Disorders of the biliary or enteric tracts, associated with
steatorrhea, are likely to reduce the absorption of calcium because it
forms an insoluble compound and because the fat-soluble vitamin D that
is ingested is less likely to be absorbed under these circumstances (45).

Phosphate (PO₄) is absorbed lower in the
gastrointestinal (GI) tract than is calcium, and is freely transported
across the gut cell to enter the extracellular space, in which it
represents a major buffer system. Transport into and out of the bone is
passive and is related to the kinetics of the formation and breakdown
of hydroxyapatite crystals. Tubular reabsorption of phosphate, however,
is highly variable, with reabsorption ranging from almost 100% to less
than 50%. The principal factor that decreases tubular reabsorption of
phosphate is PTH.

The most potent endocrine regulator of bone density is
estrogen. Most of the clinical and experimental data on the role of
estrogen in bone have been generated from studies of postmenopausal
women. However, clinical data from children with deficiencies in sex
hormones, such as in Turner syndrome, also show that a lack of estrogen
in growing girls is responsible for profound loss of bone density. The
exact mechanism by which estrogen regulates bone formation and loss is
unknown. Estrogen receptors are present on both osteoblasts and
osteoclasts, yet the cellular mechanism by which estrogen alters the
behavior of

these
cells is not clear. Studies in animals suggest that estrogen exhibits
at least some of its effects through the regulation of pleuripotential
stromal cells in the bone marrow, a process that may be mediated by
interleukin-6. Estrogen also suppresses the activation of osteoclasts
by inhibiting the activation of RANK in the precursor cells (46,47).

Androgens also seem to regulate bone mass, although the
mechanism is less well understood than it is in the case of estrogen.
Idiopathic hypogonadotropic hypogonadism is associated with decreased
bone mass, and there is an association between delayed puberty and low
bone mass in boys, suggesting a positive role for androgens in
regulating bone mass (48).

Thyroid hormones act in the cell nucleus, interacting
with nuclear proteins and DNA to increase the expression of a variety
of genes, ultimately regulating cell activity positively. Thyroid
hormone activates both osteoblasts and osteoclasts. The actual effect
on bone mass depends on the body’s balance between these two cell
types, and how well the normal control of the calcium level is able to
counteract their heightened activity. In general, the balance is in
favor of the osteoclast and, very often, increased thyroid hormone
levels lead to bone loss (49,50).

Corticosteroids have a variety of effects on cells; they
inhibit cellular activity in general, potentially decreasing the
ability of osteoblasts to lay down new bone. Corticosteroids also have
profound effects on the skeleton because of their effect on calcium
regulation in the kidney, where they increase calcium excretion; this
leads, secondarily, to elevated PTH levels, with consequent negative
effects on bone density (51,52).

CT is produced by parafollicular thyroid cells. Although
CT causes inhibition of bone resorption by osteoclasts and osteoblasts,
and decreases reabsorption of calcium and phosphate in the kidneys in
animal models and cell cultures, it seems to play a minor role in
humans (53,54).

Rickets is described as a
clinical condition in which there is inadequate mineralization of
growing bone. Severe nutritional rickets was endemic in early
industrialized societies, particularly where sunlight was scarce.
Accordingly, severe rachitic deformities were commonly seen in the
early days of orthopaedics (60,61). In developed countries nutritional rickets is now a rarity, although it may present de novo to pediatric orthopaedists for diagnosis. Inherited forms of rickets are still commonly seen in the United States (62).
The surgeon should also be familiar with renal tubular abnormalities
that can result in rickets, as well as with the clinical entity of
renal osteodystrophy, which describes the bone disease associated with
end-stage renal disease and includes features of rickets as well as
secondary hyperparathyroidism.

The clinical manifestations of all forms of rickets are
similar, and therefore the clinical presentation will be covered first,
prior to a discussion of the various etiologies.

Rickets is failure of or delay in calcification of newly
formed bone at long bone physes. The manifestations include changes in
growth-plate morphology, with decreased longitudinal growth and angular
deformities of the long bones. Osteomalacia, which is the failure of
mineralization of osteoid formed at cortical and trabecular surfaces,
often accompanies rickets in childhood. In the adult, osteomalacia is
the only result of the mechanisms that cause rickets in childhood.

The skeletal abnormalities of severe rickets present in
early childhood and often before the age of 2 years. The child may have
a history consistent with hypocalcemia in infancy, including apneic
spells, convulsions, tetany, and stridor prior to the age of 6 months (63).
The child is often hypotonic with delayed motor activity milestones for
sitting, crawling, and walking. There is proximal muscle weakness and
sometimes profuse sweating. Cardiomyopathy and respiratory and GI
infections may accompany the clinical presentation (64,65,66,67,68,69).

Skeletal deformities may be evident at every physis. The
wrists, elbows, and knees are thickened, and the long bones are short.
Genu varum or valgum may be present, as may coxa vara. Costochondral
enlargement leads to the characteristic rachitic rosary appearance of
the chest. Harrison’s sulcus is an indentation of the lower ribs caused
by indrawing against the soft bone. Kyphoscoliosis may be present.
Closure of the anterior fontanelle is delayed. Frontal and parietal
bossing of the skull is evident. Plagiocephaly may be related to the
effect of positioning on a soft skull. Delayed primary dentition is
common (70,71).

The radiographic hallmark of rickets is widened and indistinct growth plates (Fig. 7.4). In a normal child, the distance between the metaphysis and epiphysis of the distal radius should never be greater than 1 mm (72).

Lateral expansion of the growth plates also occurs,
particularly with weight bearing. One should remember that crawling
children bear weight on their wrists, and this explains the thickened
wrists as well as knees. The metaphysis typically takes on a cupped and
splayed appearance. The long bones are short for age, and show evidence
of coxa vara and genu varum or valgum as described in the preceding
text. Radiography may reveal further evidence of osteomalacia. The
hallmark is Looser zones. These are

transverse
bands of unmineralized osteoid, which typically appear in the medial
aspect of the proximal femur and at the posterior aspect of the ribs.
These are described as pseudofractures and often have an osteosclerotic
reaction area around them. In an adult, they can progress to true
fractures. Acetabular protrusion and pathologic fractures complete the
radiographic signs of rickets (64,70,72,73).

Bone is mineralized by the crystallization of calcium
and phosphate in the presence of alkaline phosphatase enzyme. Calcium
and phosphate are maintained very close to their solubility coefficient
by a complex series of inhibitors. The control mechanisms in the
physiologic state have been discussed in earlier sections of this
chapter.

A useful way of approaching the management of rickets is
to consider those conditions that reduce the availability of calcium,
those conditions that reduce the availability of phosphate, and the
rare condition that reduces the availability of alkaline phosphatase at
the osteoblast-bone junction (Table 7.2).
Nutritional rickets and end organ insensitivity to calcitriol are
problems as far as calcium is concerned. X-linked hypophosphatemia is
the most common form of rickets seen today in the United States. It is
caused by renal tubular phosphate wasting in isolation (74).
Renal tubular abnormalities, including Fanconi syndrome, cause renal
wasting of phosphate, calcium, magnesium, and bicarbonate. Alkaline
phosphatase is deficient only in one rare recessive condition,
appropriately called hypophosphatasia.

Finally, renal osteodystrophy is often discussed with
rickets, and appropriately so because many children with renal
osteodystrophy manifest signs of rickets. However, renal osteodystrophy
classically includes the changes of secondary hyperparathyroidism as
well as those of rickets.

Nutritional rickets had near universal prevalence in
northern industrialized societies in the 19th century. It has now
largely disappeared in developed countries. It remains a significant
clinical problem in the developing world; for example, a 66% prevalence
of clinical rickets was found in preschool children in Tibet in 2001 (75).

The main cause of nutritional rickets is vitamin D deficiency. Vitamin D₃
(cholecalciferol) can be produced in the skin by a process that
requires ultraviolet B radiation, or it can be ingested in the diet.
The peak age of presentation of nutritional rickets is between 3 and 18
months in children who have inadequate exposure to sunlight and no
vitamin D supplementation in the diet (76,77,78). Breast milk is poor in vitamin D, and prolonged breast-feeding is a risk factor (79,80). Vitamin D is supplemented in dairy foods in North America, and diets deficient in dairy foods are therefore a risk factor (80,81,82). Two hundred international units of vitamin D is the recommended daily amount for preventing rickets (37,62).
Exposure to sunlight also prevents rickets. Two hours per week of
summer sunshine at the latitude of Cincinnati (39 degrees north) is
sufficient to produce adequate vitamin D in the skin. However, during
the winter months in Edmonton (52 degrees north), there is insufficient
UVB exposure to allow for adequate intrinsic production of vitamin D (62).

Although vitamin D deficiency is the principal cause of
nutritional rickets, it is possible to get rickets because of a
profoundly calcium-deficient diet, even in the presence of adequate
vitamin D intake (83). Probably much more
common is a subtle combination of calcium deficiency and vitamin D
deficiency interacting to produce dietary rickets (84). This interaction has been described among the modern Asian population in the United Kingdom (85,86) and black populations in the United States (71).
A diet that is low in calcium and high in phytate, oxalate, or citrate
(substances that bind calcium and are found in almost all fresh and
cooked vegetables) means that calcium availability in the diet is poor.
Vegetarians, especially those who avoid dairy products, are
particularly at risk. This lack of calcium produces an increase in PTH,
which in turn increases vitamin D catabolism. Vitamin D status may
already have been marginal because of low exposure to sunlight and poor
dietary intake. The increased catabolism of vitamin D, along with these
factors, results in vitamin D deficiency and the clinical presentation
of rickets. This combination of deficiencies of both calcium and
vitamin D is very prevalent among adolescents who present with rickets
in the United Kingdom and the United States.

Treatment of nutritional rickets involves adequate
provision of vitamin D. A dose of 5000 to 10,000 International Units
(IU) per day for 4 to 8 weeks should be prescribed, along with calcium
to the extent of 500 to 1000 mg per day in the diet (87).
Where daily dosing and compliance pose problems, much larger doses of
vitamin D (200,000 IU to 600,000 IU orally or intramuscularly) have
been given as single doses with good results (88).

Laboratory abnormalities in established nutritional
rickets may include a low-normal or decreased calcium ion
concentration, a low serum phosphate level, a low serum
25-hydroxyvitamin D₃ level, and a high alkaline phosphate level. Alkaline phosphate level drops to normal in response to successful therapy.

Even if adequate calcium and vitamin D are present in the diet, some GI diseases prevent their appropriate absorption (89).
Gluten-sensitive enteropathy, Crohn disease, ulcerative colitis,
sarcoidosis, and short-gut syndromes have been implicated. If liver
disease interferes with the production of bile salts, then fat
accumulates in the GI tract and prevents the absorption of fat-soluble
vitamins including vitamin D. The resulting deficiencies of vitamin D
and calcium cause bone disease in the same way as nutritional
deficiencies do, but the treatments need to be aimed at rectifying the
underlying GI problem as well as at supplementing the deficient vitamin
and mineral.

X-linked hypophosphatemia is the most common inherited etiology for rickets with a prevalence of 1 in 20,000 persons (90).
It is an X-linked dominant disorder; this means the female-to-male
patient ratio is approximately 2:1, and there is no male-to-male
transmission. Approximately one-third

of the cases are sporadic (90).
Individuals in whom the condition has sporadically occurred do transmit
the defect to their offspring. The defect is in a gene called PHEX (91).
This gene product indirectly regulates the transport of renal
phosphates. The defect at the kidney is isolated renal phosphate
wasting, leading to hypophosphatemia. In addition, a low or normal
kidney production of 1,25-dihydroxyvitamin D₃ is observed, which is inappropriate in the hypophosphatemic state.

The clinical presentation includes rickets and mild shortening in stature (92,93). Dental abscesses occur in childhood, even prior to the development of dental caries (94).
Adults with the condition have osteomalacia accompanied by degenerative
joint disease, enthesopathies, dental abscesses, and short stature (95,96,97). The specific treatment for the condition is oral administration of phosphate and the active form of vitamin D₃,
calcitriol, which is 1 α-hydroxylated. Treatment requires careful
metabolic monitoring. Hyperparathyroidism, soft tissue calcification,
and death caused by vitamin D intoxication have been problems with
medical therapy in the past. Calcitriol can be used in much lower doses
than the less-active vitamin D metabolites previously used, and is
thought to be a safer therapy (91,98,99). Angular deformities, particularly genu valgum, may persist after medical treatment, requiring osteotomy (100,101,102).

A small number of patients with McCune-Albright syndrome
also develop hypophosphatemic rickets. This syndrome includes patients
with café au lait spots, precocious puberty, and fibrous dysplasia of
multiple long bones. The syndrome is caused by constitutional
activation of the cyclic adenosine monophosphate-protein kinase A
(AMP-PKA) signaling pathway, and is related to genetic defects in G
signaling proteins (103).

In 1961, Prader et al. described what was initially called vitamin D-dependent rickets (104);
this was because the early patients were treated with very large doses
of vitamin D. It turns out that such patients have 1 α-hydroxylase
deficiency and they can be treated with much smaller quantities of the
biologically active 1 α-hydroxylated calcitriol (105).
Typically, the patients are less than 24 weeks of age with weakness,
pneumonia, seizures, bone pain, and the skeletal bone changes of
rickets. Serum findings include low calcium and phosphorus, high
alkaline phosphatase and PTH, with a normal level of 25-hydroxyvitamin D₃ but a markedly decreased level of 1,25-dihydroxyvitamin D₃. The patients are not able to convert the accumulated 25-hydroxyvitamin D₃ to its biologically active form of 1,25-dihydroxyvitamin D₃ and therefore develop clinical rickets. The autosomal recessive genetic pattern has been described (106) and the specific mutations were initially described in 1997 (107), since which time at least 31 distinct mutations in the 1 α-hydroxylase gene have been identified (105).

Currently, the treatment consists of oral administration of activated vitamin D₃ which is curative.

In 1978, Marx et al. (108)
described two sisters with clinical rickets. The unusual clinical
feature was an exceedingly high circulating level of
1,25-dihydroxyvitamin D₃. In patients having this condition, these levels can be 3- to 30-fold higher than normal (109).
A striking clinical finding is alopecia or near total loss of hair from
the head and body. These patients have an end organ insensitivity to
vitamin ₃ (109). Treatment with
very high doses of vitamin D produces a variable but incomplete
clinical response. Intravenous high doses of calcium followed up with
oral calcium supplementation in large quantities has also been tried,
but as yet this rare form of rickets cannot be completely cured (105).

There are many causes of the Fanconi syndrome. This
syndrome implies failure of tubular reabsorption of the many molecules
smaller than 50 Da. The kidneys lose phosphate, calcium, magnesium,
bicarbonate, sodium, potassium, glucose, uric acid, and small amino
acids. With this renal tubular abnormality, there are multiple
mechanisms by which bone mineral homeostasis is disrupted (89,110).
As a result, such patients are short, with rickets and delayed bone
age. The predominant cause of bone disease is hypophosphatemia from
renal phosphate wasting, very similar to that seen in X-linked
hypophosphatemic rickets. Other mechanisms include calcium and
magnesium loss, metabolic acidosis caused by bicarbonate loss, renal
osteodystrophy (if renal disease is sufficiently advanced that less
1,25-dihydroxyvitamin D₃ is produced), and finally, decreased calcium and phosphate reabsorption.

The treatment is similar to that of X-linked
hypophosphatemia: administration of oral phosphate and vitamin D.
Electrolyte imbalances from other causes need monitoring and treatment,
and the underlying renal disease should also be treated if possible.

Hypophosphatasia is another disease having clinical
overlap with rickets. Hypophosphatasia is caused by alkaline
phosphatase deficiency. Like most enzyme deficiencies, this is a
recessive condition with over 112 mutations described in the alkaline
phosphatase gene in chromosome 1 (111,112,113).
Clinically, alkaline phosphatase deficiency produces abnormal
mineralization of bone with a presentation of rickets in the child or
osteomalacia in the adult (114). Pathologic fractures can occur in children and in adults (115,116).
The fractures are accompanied by abnormal formation of dental cementum,
which causes loss of teeth. The primary teeth are lost early and with
minimal root resorption (117). Additional clinical manifestations may include failure to thrive, increased intracranial pressure, and craniosynostosis.

Hypophosphatasia has an estimated prevalence of 1 per 100,000 people (118).
There is a perinatal lethal form of the condition. A childhood form
presents with rickets at 2 or 3 years of age and remission of the
disease in adolescence. An adult form presents with mild osteomalacia
with pathologic fractures (111).

There is no satisfactory medical treatment for the
underlying defect. Bone marrow transplantation has been used
experimentally in severe cases, with the aim of repopulating the bone
marrow with osteoblasts capable of producing alkaline phosphatase (111).
Surgical treatment of femoral fractures and pseudofractures in the
adult has been reported, with rodding techniques found to be superior
to plating techniques in the abnormal bone (115).

Renal osteodystrophy describes the bony changes
accompanying end-stage renal disease; it is commonly seen in patients
on dialysis. The clinical presentation includes hyperparathyroidism as
well as rickets with osteomalacia in varying combinations (119,120,121,122).

Renal failure leads to inadequate clearance of phosphate
from the blood once the renal function drops below 25% to 30% of
normal. The hyperphosphatemia drives the solubility equilibrium to
produce hypocalcemia, which signals the parathyroid glands to produce
PTH, causing secondary hyperparathyroidism. The bony changes of
hyperparathyroidism then become evident. These include subperiosteal
erosions and brown tumors (Fig. 7.5). The
subperiosteal erosions are described as classically appearing on the
radial margins of the middle phalanges of digits 2 and 3 of the hand in
adults. In children, they can also be seen at the lateral aspects of
the distal radius and ulna and at the medial aspect of the proximal
tibia (Fig. 7.6) (123).
Prolonged stimulation of the parathyroid glands can produce sufficient
hyperplasia to make the glands remain autonomous and maintain a
hyperparathyroid state, even if the end-stage renal disease is treated
by transplantation. In this case, the ongoing hyperparathyroidism is
described as tertiary rather than secondary.

The other aspect of renal osteodystrophy is rickets. If
there is inadequate renal mass to produce sufficient
1,25-dihydroxyvitamin D₃ rickets (clinical and radiographic)
will accompany renal osteodystrophy. The clinical manifestations can
include varus or valgus deformities at the knees or ankles, and
radiographic evidence of widened and deformed growth plates and
rickets/osteomalacia such as Looser zones (Fig. 7.7).

Treatment of renal osteodystrophy includes:

SCFE occurs frequently in patients with renal osteodystrophy but is not common in other presentations of rickets (Fig. 7.8) (124,125,126). The slip occurs through the metaphy-sis (120,127,128)
and occurs at a younger age, in children who are typically small
because of their chronic disease. Therefore, stabilization of the slip
should permit ongoing growth of the proximal femur if possible.
Unstable slips and avascular necrosis are rare in patients with renal

osteodystrophy, but avascular necrosis possibly associated with steroid use posttransplant has been reported (128).
If the child is young, the slip severe, and the bone disease has not
yet been treated medically, then traction plus medical treatment have
shown very good results. When considering surgical treatment of the
slipped epiphyses, the high incidence of bilaterality suggests that
both epiphyses should be stabilized. In young patients, a pinning
technique that allows for growth (smooth pins across the physis) can be
considered (127). Hardware cutout, including
pin protrusion into the joint, is more likely with the soft bone of
renal osteodystrophy, but has generally been associated with inadequate
medical control of hyperparathyroidism (127,128).

The National Institutes of Health (NIH) Consensus Panel
(2000) has defined osteoporosis as “a skeletal disorder characterized
by compromised bone strength predisposing to an increasing risk of
fracture.” The Consensus Panel notes that bone strength includes both
bone density and bone quality. Childhood osteoporosis can come from
numerous primary and secondary etiologies, as summarized in Table 7.3.

There are 10 million individuals in the United States
with osteoporosis, and 18 million more with low bone mass are at risk
for osteoporosis (129). We associate
osteoporosis with senescence, and certainly most of the individuals
currently affected are old and not likely to be consulting pediatric
orthopaedists. However, the NIH emphasizes that “sub-optimal bone
growth in childhood and adolescence is as important as bone loss to the

development
of osteoporosis.” The recommended intake of calcium for children aged 9
to 18 is 1300 mg per day, and it is estimated that only 10% of girls
and 25% of boys meet this minimum requirement (129).
Whereas consumption of dairy-based beverages supplying calcium has
declined, consumption of carbonated beverages has increased (130).
Phosphoric acid is used in cola soft drinks to maintain carbonation,
and teenage girls who drink soft drinks are three to four times more
likely to report fractures than those who do not, the association being
strongest among active girls drinking cola (131).
The pediatric orthopaedic surgeon has at least three reasons to be
interested in osteoporosis. First, osteogenesis imperfecta (OI) is an
example of primary osteoporosis with profound implications for medical
and surgical management during childhood. The understanding of this
condition is advancing rapidly. Second, many children treated by
pediatric orthopaedists already have, or are at risk for, secondary
osteoporosis—especially nonambulatory children with neuromuscular
disorders. Finally, prevention of the most common osteoporosis
associated with aging, and its attendant morbidity, has to include a
focus on acquisition of adequate bone mineral strength in childhood and
adolescence—something pediatric orthopaedic surgeons are ideally
positioned to promote among their patients, in their community, and
nationally (132,133).

OI is a rare condition with an estimated prevalence of 1 in 15,000 to 1 in 20,000 children (134).
The hallmark of OI is brittle bones and the tendency to fracture, with
recurrent fractures occurring in childhood, in particular during the
preschool years. Bone pain is a feature in many patients. It is
described as chronic and unremitting and usually relates to old
fractures. Muscle weakness may be variously present. Ligamentous laxity
and joint hypermobility may be present. Wormian bones are present in
the skull in approximately 60% of patients. Abnormal collagen in the
eye leads to the blue or gray-blue sclerae classically associated with
OI. Abnormal collagen in the teeth leads to dentinogenesis imperfecta
(clinically small, deformed teeth which are “opalescent” due to a
higher ratio of transparent enamel to opaque dentin); this is present
in some, but not all, patients with OI (135–140).

The clinical presentation of OI is heterogeneous across
a very wide spectrum. The clinical classification scheme that is most
commonly used is based on the one first proposed by Sillence et al. in
1979 (140). The Sillence classification has
stood the test of time and is a useful way of dividing the phenotype.
This classification has recently been modified (138,141) to incorporate genetic and biochemical abnormalities (Table 7.4). Greater genetic understanding has led to the addition of extra types to the four OI types initially described by Sillence.

Most presentations of OI are caused by mutations within
the collagen 1A1 gene found on chromosome 7q, or mutations in the
collagen 1A2 gene found on chromosome 17q. The complete list of
mutations found is kept up-to-date at the OI mutation database at http://www.le.ac.uk/genetics/collagen.

Two different types of mutations produce OI. OI type I, which is the mild form, is a quantitative defect in collagen production resulting from a silenced allele of the collagen 1A1 gene (138,153,154).
This is usually the result of a premature stop codon within the gene
and results in the production of nonsense messenger RNA instead of
proper messenger RNA coding for the preprocollagen of the collagen
molecule. The nonsense messenger RNA is detected and destroyed, and the
result is production of a diminished number of α 1 chains, and
consequently a decreased

quantity
of normal collagen being produced. With the decreased quantity of
collagen, the bone is weakened and becomes more susceptible to
microfractures. Bone can sense its mechanical environment, and
microfractures cause a new round of bone removal and reformation,
leading to constant activation of bone remodeling in OI. This process
demands an increased transcriptional activity of type I collagen and
induces more osteoclasts and an increase in the excretion of collagen
degradation of products. Bone turns over rapidly, but remains of poor
quality. When growth ceases at puberty, the transcriptional activity
demand is reduced and bone turnover can slow down; then the bone
strength and architecture become closer to normal, and the fracture
rate drops.

OI types II, III, and IV are usually caused by the production of abnormal types of collagen (138,155).
The collagen molecule is a triple helix formed by spontaneous
self-assembly of three long linear procollagen molecules. These
procollagen molecules have a typical repeating amino acid pattern of
glycine XY-glycine XY-glycine XY. Glycine appears at every third
position because it is the smallest amino acid and can be folded into
the interior of the triple helix. Glycine substitutions place a larger
amino acid where the glycine residue belongs, so that the collagen
triple helix cannot assemble appropriately. The collagen molecule
begins assembling at the C-terminal end and assembles toward the
N-terminal end. If the mutation substitutes for a glycine close to the
C-terminus at the beginning of the molecule, then a very short strand
of abnormal gene product is produced, and the corresponding clinical
diseases are severe. If the glycine substitution mutation is toward the
distal N-terminus end, then a longer partial collagen molecule can be
formed, and the clinical phenotype is less severe.

The primary defect in OI is the osteoporosis produced by
an abnormal quantity or quality of collagen. Mechanically the bone is
more ductile, rather than being more brittle (156).
Secondary osteoporosis caused by immobilization following fractures or
surgery, or by decreased physical activity and weight bearing with
severe deformity, adds to the complications of the primary defect.
Prevention of secondary osteoporosis is an important concept when
treating fractures, planning surgery, or recommending general care.

The clinical approach is the mainstay for the diagnosis
of OI. There is no single laboratory test that distinguishes
individuals with OI from those with normal bone. The clinical features
of severe OI type II and type III are distinct enough that physical
findings and plain radiography are usually sufficient for a diagnosis.
Patients with type I OI have blue or blue-gray sclerae and are readily
identified clinically. Normal babies may have blue sclerae until 1 year
of age, so this finding has diagnostic value only in the older child.
Patients with mild presentations of type IV OI are easy to diagnose if
they have dentinogenesis imperfecta, but those with normal teeth may
benefit from additional investigation, depending on the purpose of
making the diagnosis. Dual energy x-ray absorptiometry (DEXA) scanning
shows low levels of lumbar and femoral bone mineral density (BMD) in
patients with mild OI (157,158). Published values for BMD in healthy normal children are available for comparison (159).
Caution must be exercised in interpreting DEXA scans in children, and
overdiagnosis of osteoporosis is reported to be frequent (160);
this is because DEXA scanning reports BMD per square centimeter surface
area of bone, ignoring the third dimension (thickness of the bone in
the path of the photon), which is larger in adults, thereby leading to
a higher area density even if the true volumetric density were to
remain a constant.

Dozens of individual mutations have been found within
collagen 1A1 and collagen 1A2 genes producing the main phenotypes of
type I, type II, type III, and type IV OI (138,148,149,154,161).
As such, many new patients often have new mutations specific to
themselves. Accordingly, a DNA-based genetic test for OI is not
currently clinically useful. An intermediate level of testing involves
culturing dermal fibroblasts and studying the collagen that they
produce. Quantitatively abnormal collagen production can be detected in
87% of individuals with known OI. Conversely, 13% of individuals with
known OI would be missed by a cultured dermal fibroblast test. One
common question is whether a patient has OI or inflicted trauma. OI is
very rare, and inflicted injury remains significantly more prevalent.
Clinical diagnosis remains a gold standard to distinguish these two
entities, and cultured dermal fibroblast testing is not considered
useful as a routine part of such investigation (162).
In cases with legal implications, positive findings in the past
history, family history, clinical examination, or properly interpreted
DEXA scan may assist in the diagnosis of osteoporosis or OI. OI cannot
be entirely ruled out in patients with negative findings, but is a
highly unlikely diagnosis in the presence of findings suggesting child
abuse (discussed elsewhere). Finally, a diagnosis of OI does not
exclude the possibility of child abuse.

Cyclical administration of intravenous bisphosphonates has recently become popular in the pharmacologic management of severe
OI, but cannot currently be recommended for mild OI. Bisphosphonates
are widely used drugs based on the pyrophosphate molecule, which is the
only natural inhibitor of bone resorption. The exact mechanism of the
drug is unclear, but its primary action is at the level of the
osteoclast. Glorieux et al. reported the effects of bisphosphonate
treatment in an uncontrolled observational study of 30 patients with
severe OI (163). The intravenous dose given was
3 mg per kg of pamidronate per cycle by slow intravenous infusion at
4-month intervals. All patients were given 800 to 1000 mg calcium and
400 international units of vitamin D per day. There was marked

improvement
in the clinical status of the patients. BMD increased at an average
rate of 42% per year. There was an increase in the cortical width of
the metacarpals and in the size of the vertebral bodies. The average
number of fractures dropped from 2.3 per year to 0.6 per year. No
nonunions or delayed unions of any fractures were noted. Patients
reported a marked reduction in bone pain 1 to 6 weeks following
initiation of treatment. The only adverse effect noted was the acute
phase reaction comprising fever, back pain, and limb pain on day two of
the first cycle. This adverse effect was treated with acetaminophen and
did not recur with subsequent infusion cycles. Mobility improved in 16
of the 30 patients treated, with no change in the other 14. Growth
rates increased. Patients younger than 3 years showed a faster and more
pronounced response to the bisphosphonate. The direct effect of the
bisphosphonate is decreasing resorption and turnover of bone. The
resulting decrease in bone pain and fractures led to increased weight
bearing and mobility. It is likely that the increased weight bearing
and mobility would have resulted in further strengthening of bone and
muscle. Bisphosphonate treatment has become a standard for severe OI.
It should be noted that this drug does not address the basic
abnormality underlying OI, but it does alter the natural course of the
disease. Radiographs of patients with OI treated with bisphosphonates
show characteristic dense sclerotic lines that form at the growth
plate, one per treatment cycle (164).

Caution must be exercised in extending the indications
for bisphosphonate treatment to patients with milder forms of OI.
Reported clinical results apply only to patients with severe OI.
Osteopetrosis is a reported complication of bisphosphonates in humans (165). Animal studies suggest reduced longitudinal bone growth with these drugs (166,167,168).
Randomized controlled clinical trials are needed before routine
clinical use of bisphosphonates in milder forms of OI is considered.

Other medical treatments for OI include anabolic agents,
specifically human growth hormone. Human growth hormone is an anabolic
agent, and therefore stimulates increased bone turnover, causing a
higher demand for collagen transcription and perhaps exacerbating the
underlying abnormality while attempting to ameliorate the decreased
stature. Because growth hormone may have both beneficial and negative
effects in OI, clinical research results are required before
indications can be stated. We suggest at present that growth hormone be
used in patients with OI only in the context of clinical research
studies.

Patients with mild (nondeforming) OI require little
modification of standard surgical treatments, whereas those with severe
(deforming) OI require multiple specialized surgical techniques and
implants.

The treatment of fractures in mild OI must be done in
such a way as to minimize disuse osteoporosis. Simple undisplaced
fractures can be treated with plaster cast or splints which should be
removed early to allow prompt return to function. Avulsion fractures of
the olecranon can be treated by tension band wiring and early motion
with good results (Fig. 7.11).

Severe OI requires specialized techniques. Children with
very fragile lower extremities can be supported with vacuum orthoses to
permit protected weight bearing (169).
Eventually, however, children with severe OI will be considered for IM
rodding of the long bones. This IM rodding is best carried out in
conjunction with medical treatment using bisphosphonates in an
interdisciplinary setting. Some centers propose that lower extremity
rodding be considered as soon as the patient stands and before walking
begins, at about the age of 18 months (148).
Upper extremity rodding is indicated if repeated long bone fractures
cause deformity which affects function, in particular, if the use of
crutches or a walker is compromised (148,170).

Rodding techniques have been developed to correct the
bowed long bones typical of severe forms of OI. Rodding allows for
correction of the deformity, puts the weight-bearing line along the
axis of the bone, is effective in soft bone, and allows for continued
growth.

Sofield et al. first described the technique of open
fragmentation and rodding of the long bones in 1952 and reported the
results in 1959 (171). He described a long open
exposure with removal of the entire diaphysis of the bone, division
with multiple transverse osteotomies, and reassembly over a rod.
Williams (172) developed a threaded end rod
that can be attached to an insertor (which simplifies placement of the
rod in the bone) and then detached. Bailey and Dubow developed a rod
with overlapping male and female shafts allowing for expansion of the
rod during normal bone growth (Fig. 7.12). The
rod is anchored into the epiphysis using a t-piece at each end.
Complications of extensible rods are frequent; Nicholas and James (173)
reported 56 roddings in 16 patients, with 6 failed expansions, 12 t-end
loosenings, 4 rod migrations, 6 bent rods, and 5 fractures. Separation
of the rods after growth led to fracture and bowing in every case, and
close radiographic surveillance was proposed. Comparison of
nonelongating to elongating rods has shown slightly higher complication
rates with elongating rods, although crimping the t-piece may reduce
this complication rate. A newer elongating rod design, the Fassier
Duval rod, has cancellous screw threads at either end to provide stable
anchorage in the epiphysis or metaphysis (174).
In one series, the need for revision due to bone growth and rod
migration was reported as being higher for nonelongating rods (175), but in another series it was reported as being approximately equal to that seen with elongating rods (176). Methods of rod exchange through percutaneous techniques have been described (177,178), and a stereotactic device to assist this has been developed (178) but is not in wide clinical use.

Tiley et al. reported on 129 roddings among 13 children, of whom 11 maintained or gained the ability to ambulate (179). Most reports suggest that ambulation is improved by

rodding (180,181,182,183), but one emphasizes the possibility of ambulatory status worsening in a large number of patients (184).
Ultimately, the prognosis with regard to walking is much more strongly
influenced by the subtype of OI than by the treatment (185,186,187),
but modern combinations of medical and surgical treatment combined with
rapid advances in the understanding of the biology of the disease may
one day change this situation.

Scoliosis (Fig. 7.13) can be very challenging to treat in patients with OI (188,189,190,191,192,193,194,195,196,197). Bracing appears to be ineffective at preventing curve progression even when curves are small (194,197).
Patients with large progressive curves may suffer from pulmonary
compromise, and bracing can cause rib deformities that worsen it. It is
unknown whether operative management of the scoliosis leads to improved
pulmonary function, quality of life, and survival. Accordingly,
decision making regarding surgery must be individualized for each
patient. Spinal fusions have a higher complication rate in OI, with 20
patients out of 60 experiencing a total of 33 major complications (194).
The most common complications were blood loss greater than 2.5 L (nine
cases), intraoperative hook pullout (five cases), postoperative hook
pullout (five cases), and pseudarthrosis (five cases). Strategies to
prevent hook pullout include load sharing via segmental
instrumentation, supplementation of hook site bone with methyl
methacrylate, and consideration of fusion without instrumentation.
Preoperative medical treatment (bisphosphonate) to strengthen the bone
is logical but results are not yet reported. Progression of the curve
postoperatively, with or without pseudarthrosis, may occur (194).
The natural history, expectations, likelihood of complications, and
likelihood of success must be carefully assessed for each patient, and
decisions not to embark on surgical reconstruction are sometimes
correct.

The central nervous system exerts direct control over
BMD. The fat-derived hormone leptin acts on hypothalamic neurons that
mediate bone mass via the sympathetic nerves (206,207,208,209).
The clinical significance of this recent finding has not been
elucidated, but it may become important in managing osteoporosis and
related regional conditions such as reflex sympathetic dystrophy. At
present, the management of neuromuscular osteoporosis focuses on the
downstream effects of the neuromuscular abnormalities on load bearing
and nutrition.

Low bone mass is observed in patients with cerebral
palsy (CP) (210–214). Typically, it is nonambulatory patients with the
lowest bone masses who are at risk for pathologic and low energy
fractures, but reduced bone mass has been observed in the affected
limbs of ambulatory hemiplegics also (215,216),
thereby suggesting that both weight bearing and muscle forces play
roles in the establishment and maintenance of bone mass. After absence
of ambulation, undernutrition is the second most important predictor of
low bone mass in patients with CP (214,217).
Fractures and a “fracture cascade” of increasing disuse osteoporosis
from treatment-related immobilization can cause significant problems
for many patients (218,219). Fracture prevalence among children and adolescents with moderate to severe CP was 26% in one study (214).
The orthopaedic surgeon should focus as much on the prevention as on
the treatment of osteoporosis in the CP population. Increasing weight
bearing, optimizing nutrition, and minimizing the extent and duration
of immobilization following surgery are important. A controlled trial
of weight bearing in patients with CP showed significant increases in
femoral neck bone mineral content (220). Medical treatments including vitamin D and calcium (221) or bisphosphonates (222)
have also been reported to increase BMD in patients with CP, although
the precise indications for their prescription are unclear.
Approximately one-third of children without CP suffer a fracture during
childhood, so the 26% fracture prevalence among children with CP does
not seem out of line. Accordingly, if weight bearing is easy to achieve
and enjoyable for the child it can be recommended; but if

extensive
surgery, elaborate standers, and many hours of professional care are
required, then perhaps it is not of benefit to the child.

Patients with Duchenne muscular dystrophy (DMD) lose
bone mass as the lower extremities weaken, with bone densities 1.6
standard deviations below the mean while they are still walking and 4
standard deviations below the mean once they become nonambulatory. Of
41 boys followed, 18 sustained fractures, 12 of which were lower
extremity fractures, and 4 of which caused loss of ambulation (223).
In boys with DMD, BMD has been reported as lower among those who were
treated with steroids (prednisone) than among untreated boys (224).
Deflazacort is a steroid medication which preserves muscle strength,
ambulation, and respiratory function as well as preventing the onset of
scoliosis. Despite being a glucocorticoid analog, it is reported to
have bone-sparing effects (225) and randomized
trial evidence (in juvenile arthritis) shows less bone loss among
patients treated with deflazacort compared with patients treated with
prednisone (226). Vertebral fractures have been reported in patients treated with deflazacort (227), whereas they are rare among untreated patients (223). No trials of bisphosphonates in DMD have been reported yet.

Growth hormone deficiency results in extremely short
stature and low muscle mass. BMD is low in both adults and children,
and adults have a 2.7 times increased fracture rate compared with
normal controls (228). Treating the deficiency
with growth hormone improves longitudinal growth and muscle mass and
also improves calcium absorption, thereby exerting beneficial effects
on the osteoporosis both mechanically and biologically. Improved BMD
with growth hormone treatment has been documented in adults but
requires further study in children (229,230).

It is worth noting that growth hormone deficiency is the
second most common endocrinologic cause of SCFE (after hypothyroidism).
Ninety-two percent of children with growth hormone deficiency and SCFE
present with the slip after growth hormone
treatment has been initiated, perhaps because the growth plate becomes
more active and potentially weaker, mechanically, relative to the
larger size of the body. The prevalence of bilaterality in slips with
endocrinopathies has been reported to be as high as 61%, and therefore
prophylactic pinning of the contralateral side has been suggested by
some specialists (231). Among 2922 children
followed prospectively while receiving growth hormone in Australia and
New Zealand, only 10 slipped epiphyses were reported by clinicians
performing active surveillance for complications (232).

Hyperthyroidism leads to bone loss through increased
bone turnover. T3 directly stimulates osteoblasts, resulting in linked
osteoclast activation and bone resorption. The increase in serum
calcium and phosphate suppresses PTH and 1,25-hydroxy vitamin D
production, which then decreases calcium and phosphate absorption and
increases calcium excretion. The net result is bone resorption in a
high turnover state (133). Treatment of the underlying disease to achieve a euthyroid state is the appropriate management for the osteoporosis.

One third to one half of adult bone mass is accrued
during the pubertal years, and sex steroids are necessary for this
accelerated bone mineral accrual. Mineral accrual lags behind the
longitudinal growth spurt by a year or two, perhaps partially
explaining the increased fracture rate documented during and just after
the growth spurt (233). Over the last 30 years
there has been a statistically significant increase in the incidence of
distal forearm fractures in adolescents, but it is unclear whether this
relates to changes in diet or in physical activity (234).

Precocious puberty results in accelerated growth and
bone mineral accrual. It can be treated with gonadotropin-releasing
hormone analogs to preserve epiphyseal function and allow attainment of
greater final height. Such treatment does not adversely affect peak
bone mass. Constitutionally delayed puberty in boys is associated with

lower BMD, but it is unclear whether testosterone treatment improves overall mineral acquisition (133).

Athletic amenorrhea is common among young women training
for sport. Thirty-one percent of college level athletes who were not
using oral contraceptives reported athletic amenorrhea or
oligomenorrhea (235). Athletic amenorrhea plus disordered eating plus osteoporosis has been dubbed the “female athlete triad” (236,237). The full triad is rare among athletes (238) and was found to be nonexistent among female army recruits (239).
Not all sports are equal in propensity for bone loss. Gymnasts exhibit
higher bone mass than do runners despite similar prevalance of
amenorrhea (240); gymnasts have both higher muscle strength (241) and higher serum insulinlike growth factor 1 (IGF-1) (242)
than do runners, and these are both protective of bone mass. It must be
remembered that for the general population, more exercise means more
bone, as has been demonstrated in randomized trials of physical
activity in prepubescent and pubescent children (243,244).

Untreated anorexia nervosa is associated with 4% to 10% trabecular and cortical bone loss per year (245).
The long-term prevalence of fractures amongst people with anorexia
nervosa is 57% at 40 years follow-up, 2.9 times higher than that in the
general population (246). Estrogen alone is insufficient to restore BMD, particularly if nutrition is compromised (247,248).
Restoration of body mass, provision of adequate calcium and vitamin D,
and correction of the hormonal environment should all occur.

Primary amenorrhea from pure dysfunction of the
hypothalamic–pituitary axis was associated with osteoporosis in 3 and
osteopenia in 10 of 19 girls (ages 16 to 18), compared with 0 among 20
controls with regular cycles (249).

Osteopetrosis is caused by specific osteoclast defects
that prevent the osteoclast from carrying out its normal function in
reabsorption of bone. Many specific defects have been identified. These
include carbonic anhydrase deficiency, which prevents the osteoclasts
from acidifying the extracellular space at the ruffled border. This is
associated with the milder clinical forms and may also be associated
with distal renal tubular acidosis and with intercranial calcifications
that are unique to this form (275,276,277). Fatal infantile forms of osteopetrosis have been associated with defects in the genes coding for proton pump or chloride

channel protein production (278). More recent case reports describe iatrogenic osteopetrosis as being the result of bisphosphonate treatment (165).

All causes of osteopetrosis decrease the function of
osteoclasts in the reabsorption of bone. The histologic hallmark of
osteopetrosis is remnants of primary spongiosa within the bone. These
are areas of calcified cartilage, which are precursors to enchondral
bone formation and are normally removed during the first pass
remodeling in fetal life. The ongoing failure to resolve and remodel
bone leads to the skeletal manifestations of the disease, limits the
narrow space available, contributes to pancytopenia and
hepatosplenomegaly, and is also responsible for the cranial nerve
compression at the base of the skull. The predisposition toward
musculoskeletal infections is thought to be caused by a combination of
the abnormal bony architecture and the insufficiency of white blood
cells.

Bone marrow transplantation for the severe forms of infantile osteopetrosis was first described in 1977 (279) and has since been widely reported (280,281,282).
Successful bone marrow transplantation corrects both the skeletal and
hematologic abnormalities associated with osteopetrosis. However, not
all bone marrow transplantations are successful and not all patients
have survived. Additional medical treatment can include very high doses
of calcitriol to stimulate osteoclastic activity and the administration
of interferon γ to stimulate superoxide production by osteoclasts.
Long-term therapy with interferon γ in patients with osteopetrosis
increases bone resorption and hematopoeisis and improves leukocyte
function (283).

Most patients presenting to pediatric orthopaedists do so because of fractures (284). Most fractures in children with osteopetrosis will heal well if treated with closed means, although healing may be delayed (Fig. 7.17).
The principal exceptions are fractures of the femoral neck and
intratrochanteric region, which can be extremely difficult to manage (Fig. 7.18). Armstrong’s survey of the experience of the Pediatric Orthopaedic Society of North America (284)
described a high incidence of nonunion and varus deformity of the femur
if femoral neck and intertrochanteric fractures were treated by closed
means. The results of early operative treatment of femoral neck and
intertrochanteric fractures were good, but technical difficulties
involved in obtaining fixation in the dense bone were noted. Worn-out
or broken drills and even drivers were reported. Subtrochanteric and
femoral shaft fractures did well with both closed and open management.
Most tibial fractures were managed closed. Multiple fractures of the
tibia were reported in some patients, but could be well managed with
casts.

Cervical spine fractures are rare and involve the
posterior elements. These fractures are treated with immobilization.
Lumbar spondylolysis and listhesis have also been described (284,285)
and have responded well to nonoperative treatment in children and
adolescents, though occasionally requiring spinal fusion in adults.

Acquired coxa vara can be treated with proximal femoral
valgus osteotomies fixed by conventional plates or screws, but with
technical difficulties similar to those encountered in treating femoral
fractures.

Some patients with osteopetrosis get osteoarthritis of
the hip and knee during midlife. These can be treated with total knee
arthroplasty and total hip arthroplasty, although difficulties with
reaming the canal and cutting the bone surfaces have been noted.