2. Introduction
• Rickets is a specific bone disorder of the growing skeleton, thus occurring only in
children and adolescents before the epiphyseal fusion has occurred, and is
associated with characteristic skeletal deformitis
• Osteomalacia is a generalized softening of the bones regardless of age or cause and
therefore occurs in both children and adults
• Rickets is due to defective mineralization of both preosseous cartilaginous and
mature osseous matrix resulting in subnormal linear growth, a consequence of the
involvement of growth plates
• In contrast, osteomalacia is due to defective mineralization of the mature lamellar
bone
3. • Of the four major metabolic bone diseases, osteoporosis is by far the most common,
whereas rickets and osteomalacia combined are a distant second, followed by osteitis
deformans (also known as Paget disease of bone)
• Osteitis fibrosa cystica, the typical bone disease of severe primary, secondary, or
tertiary hyperparathyroidism, is the least common, and is rarely seen in the United States
but still prevalent in other parts of the world where vitamin D deficiency is endemic
• Soon after the discovery of vitamin D, rickets and osteomalacia became synonymous with any
condition that could be cured by vitamin D therapy.
• However, with the recent discovery of fibroblast growth factor 23 (FGF23, several types of both
genetic and acquired forms of rickets and osteomalacia are now better characterized with specific
genotypic and phenotypic features
6. Historical Perspective
Rickets
• The earliest reports of rickets date back to the 17th century, with the first detailed
descriptions by William Glisson and DanielWhistler in 1645.
• Glisson was also the first to recognize rickets as a separate entity from infantile scurvy,
which often coexisted with rickets during that time.
• Even more interesting is that Glisson believed that rickets was neither congenital nor
inherited, although it is now clear that both types of rickets forms can occur.
• As early as in the middle of the 17th century, rickets was attributed to the industrial
revolution and growing urbanization (presumably less sunlight exposure), as
well as to breastfeeding (breast milk has poor vitamin D content)
7. • The temporal relationship between rickets and sunshine was not appreciated until the
19th century, and the “proof of concept” that sunshine can cure rickets did not
occur until the beginning of the 20th century.
• Early 20th-century reports on rickets were exclusively from the regions of the world
where vitamin D deficiency was endemic, numerically the most common, and almost all
cases were due to nutritional vitamin D deficiency.
• With the current policies of routine fortification of milk and other food
products with vitamin D, nutritional vitamin D–deficiency rickets and
osteomalacia all but disappeared from developed countries.
• Consequently, genetic and acquired forms of rickets and osteomalacia are more prevalent
in nonendemic regions of the world.
8. Osteomalacia
• The term osteomalacia originally referred to the generalized softening of
the bones resulting in crippling deformities
• In earlier publications, various descriptive terms, such as mollities ossium,
rheumatic, syphilitic, senile, and even neurotic osteomalacia, were used to
describe osteomalacia, implying that the bone disease was due to either infection or
inflammation.
• Because of the grotesque deformities involving long bones, even more descriptive
terms, such as boomerang bones or osteomalacia sclerotica,were used to describe
a peculiar disease seen rather exclusively in Australian Aborigines and in
Sudanese populations.
• Since osteoporosis was such a frequent accompaniment of osteomalacia, the term
osteoporomalacia was often used in the 20th century.
9. • The distinction between rickets that specifically involved metaphyses,
and to a lesser extent epiphyses, and osteomalacia, which affected all of
the bones, was recognized early in the 18th century, and was
reemphasized by Fuller Albright in his classic monograph.
• The histologic differentiation of osteomalacia from both osteoporosis
and osteitis fibrosa was first made by Pommer in the late 19th century
by examining cadaveric bones and later confirmed in humans by
Fuller Albright
• The first detailed tetracycline-based bone histomorphometric
measurements were made by Harold Frost in 1966.
• Although the original descriptions defined rickets and osteomalacia as
distinct entities, the two terms are often used (and probably can be used,
except that rickets occurs only in children) interchangeably.
11. • Worldwide, nutritional deficiency of vitamin D and calcium is still the
most common cause and type of rickets and osteomalacia.
• Precise estimates for the prevalence of rickets and osteomalacia are lacking.
• Recent reports suggest a rising trend in the prevalence of nutritional rickets
worldwide, including the regions where routine fortification of dairy and other
food products with vitamin D is practiced.
• The most recent estimates of vitamin D–deficiency rickets ranged from 2.2 in
100,000 people in 1980 to 24 in 100,000 people in 2000
• Similarly, the prevalence of osteomalacia in adults due to vitamin D depletion
may be rising because of the increasing rates of bariatric surgery for
morbid obesity, which results in malabsorption of both vitamin D
and calcium
12. • A similar trend was observed following earlier, but now abandoned, intestinal
bypass surgeries for obesity and after gastrectomy (partial or total) for peptic
ulcer disease, which is now performed rarely.
• Rarity of vitamin D deficiency rickets and osteomalacia in developed countries
explains the relatively higher prevalence of genetic and acquired forms of
rickets and osteomalacia in theWestern world.
• It is estimated that the most common genetic form of rickets and osteomalacia
occurs 1 in 20,000 live births.
13. • In the past decade there has been a growing number of reports of osteomalacia
related to the expanding use of the antiretroviral drugs tenofovir and
adefovir.
• Although rickets in children due to antiviral drug therapy has not yet been
reported, it is most likely because of the low prevalence of their use in the
pediatric population.
• In addition, the incidence of rickets and osteomalacia due to anticonvulsants,
antacids, and aluminum toxicity remains very low.
• Thus, rickets and osteomalacia not related to nutrition and drugs are most prevalent
in the developed countries, whereas rickets and osteomalacia related to vitamin D
and calcium deficiency are most common in developing countries
14. • Certain individuals and ethnic groups are particularly susceptible to the
development of nutritional rickets and osteomalacia.
• Both secular and nonsecular tendencies of the populations, geographic
locations, prevailing sunlight, and local dietary habits all contribute to the
development of rickets and osteomalacia related to deficiency of vitamin D
and calcium.
• Immigrants, particularly those with darkly pigmented skin or
specific dietary habits (vegetarians, high phytate intake) moving
to temperate zones with limited or reduced sunlight exposure are at risk
of developing rickets and steomalacia—so-called immigrant
osteomalacia.
• Because of the rarity of rickets and osteomalacia due to vitamin D
deficiency in developed countries, the diagnosis is often missed or delayed.
16. Bone Remodeling and Mineralization
• Bone remodeling is a necessary mechanism by which old bone is replaced by new bone
throughout the life span of an individual
• In the course of normal bone remodeling, a moiety of old bone is removed and replaced
by the same amount of normal lamellar bone in young adults, but in aging and
disease, the replacement mechanism is not as efficient as it is in the young.
• A lesser amount of normal lamellar bone is replaced in osteoporosis, by a
mixture of woven bone and fibrous tissue in osteitis fibrosa due to
hyperparathyroidism, by an abnormal local production of woven bone in
Paget’s disease, and by an unmineralized bone matrix (or osteoid tissue) in
osteomalacia.
• This fundamental difference in the nature of the replaced bone distinguishes osteomalacia from
the most common metabolic bone diseases, as well as from rare bone disorders such as
hypophosphatasia, fibrogenesis imperfecta ossium, and axial osteomalacia that resemble
17. • For proper and optimal mineralization of bone, at a minimum, two
principal requirements must be met: synthesis of mature lamellar
bone matrix by osteoblasts and exposure of this newly
synthesized lamellar bone matrix to optimal calcium ×
phosphate product provided by the mineral homeostatic
system regulated by parathyroid hormone (PTH) and vitamin
D
• Any abnormality in either component will result in defective
mineralization
• In classical osteomalacia, deficiency of minerals, however produced,
results in the accumulation of unmineralized bone matrix or
osteoid
• In contrast,in all other bone disorders that resemble osteomalacia (or
“osteomalacia like”), the osteoid accumulation is a consequence of
abnormalities outside of these two principal components.
18. • In hypophosphatasia, it is the enzyme deficiency, whereas in Paget disease of
bone, fibrous dysplasia, fibrogenesis imperfecta ossium, and possibly osteogenesis
imperfecta, it is the abnormal bone matrix, and in certain drug-induced
osteomalacia (etidronate, fluoride, aluminum, and iron), it is the toxic
effects of the drugs inhibiting matrix mineralization.
• Normal mineralization of bone matrix occurs in two stages.
In the rapid phase, termed primary mineralization,75% to 80% of the maximal
mineral content is deposited within a few days to weeks.
In the second and much slower phase, termed secondary mineralization, the
mineral content of the bone increases further to reach about 90% to 95% over a period
of months.
The remaining 5% to 10% represents the bone matrix that is newly formed but
not yet mineralized
19. • Accordingly, an osteoid surface greater than 15% of the bone
surfaces, sometimes referred to as hyperosteoidosis, can be
seen in conditions with high rates of bone turnover, such as
immediately after estrogen depletion in postmenopausal
women, hyperparathyroidism (primary or secondary),
hyperthyroidism, and osteitis deformans.
21. • Classical vitamin D deficiency osteomalacia, irrespective of its cause, evolves in three
stages.
The first stage is characterized by an increased bone remodeling due to
secondary hyperparathyroidism (2°HPT), associated with increased
osteoid surface and osteoid volume, but not the thickness of osteoid, and
normal mineralization of bone.
• This represents the earliest bone histologic phenotype of vitamin D deficiency,
designated as hypovitaminosis D osteopathy stage I (HVO I) or
preosteomalacia.
• Similar bone histologic features can also be seen in patients with calcium
malabsorption, but without vitamin D deficiency, designated as 2°HPT.
• In both HVO I and 2°HPT, there is evidence of mainly cortical bone loss due to
excess PTH secretion, and the patients are usually asymptomatic at this stage but may
present with fragility fractures.
22. • Serum levels of calcium and phosphate are normal, and the serum level of
alkaline phosphatase is usually, but not always, elevated
• The serum 25-hydroxyvitamin D level is low (<10 ng/mL), and
serum levels of PTH and 1,25-dihydroxyvitamin D are elevated
• The increases in serum levels of alkaline phosphatase and 1,25-
dihydroxyvitamin D respectively are related to increased bone turnover and
increased 1α-hydroxylase activity in the kidney as a consequence of 2°HPT
• In addition, an irreversible PTH mediated cortical bone loss may
have already occurred
23. • In the second stage, designated as HVO II, there is further
accumulation of osteoid with increases in osteoid surface,
osteoid volume, and osteoid thickness but with preservation of
some mineralization as assessed by tetracycline uptake at the
mineralization front.
• Both serum PTH and alkaline phosphatase levels increase further, but
serum 1,25-dihydroxyvitamin D levels may return to normal or low
depending on the degree of vitamin D deficiency (as assessed by its
substrate, 25-hydroxyvitamin D) and PTH elevation.
• The serum calcium level usually declines at this stage with low
normal or frank hypocalcemia, and serum phosphate levels
are usually low.
• Patients may be symptomatic with bone pain, muscle
weakness, and fragility or pseudofractures.
24. • In the third stage, designated as HVO III, the mineralization of bone matrix
ceases and osteoid accumulation continues to cover more than 90% of
the bone surfaces.
• It is at this stage that hypocalcemia is invariable, as the osteoid covered
bone is resistant to osteoclastic bone resorption, which is a necessary
mechanism to maintain normal serum calcium levels.
• The extensive coverage of the bone surfaces with osteoid is perhaps a protective
mechanism” to prevent complete dissolution of bone.
• However, peritrabecular and bone marrow fibrosis, a feature of more
severe hyperparathyroidism, occurs only in HVO III and can be demonstrated
on bone biopsy.
25. • Patients are almost always symptomatic at this stage, with
diffuse bone pain, muscle weakness, and pseudofractures,
although an occasional patient may present primarily with
muscle weakness without bone pain.
• Osteomalacia defined by an osteoid thickness greater than 12.5
μm and a mineralization lag time of more than 100 days
conforms to the conventional clinical and radiologic descriptions of
osteomalacia.
26.
27. Fig. 31.1 Topographic depiction of stages of hypovitaminosis D osteopathy (HVO I, II, and
III), atypical osteomalacia (AOM), and focal osteomalacia (FOM). For comparison, secondary
hyperparathyroidism (2°HPT) without mineralization defect and low turnover osteoporosis
(LTO) are shown. In (A), the location of the seven types of bone lesions is based on the
relationship between osteoid thickness (y-axis) and the extent of bone surface covered by
osteoid (x-axis). In (B), the location is based on the relationship between osteoid thickness (y-
axis) and adjusted appositional rate (x-axis) as determined by tetracycline uptake (x-axis). In
normal subjects, and in patients with 2°HPT, HVO I, and LTO, there is no relationship between
osteoid thickness and osteoid surface until the osteoid surface exceeds greater than 50% to 60%
of the bone surface (straight solid horizontal lines), after which the relationship becomes
hyperbolic (interrupted
curvilinear lines).
By contrast, there is a positive relationship between osteoid thickness and the adjusted mineral
apposition rate (straight interrupted lines) in normal subjects and in patients with 2°HPT, HVO
I, and LTO (B). The oblique interrupted line indicates the reversal of this relationship in
patients with more severe osteomalacia (HVO II and III), the cardinal feature of osteomalacia
unlike all other conditions (2°HPT, LTO, AOM, and FOM). The solid straight line represents a
mineralization lag time of 100 days (MLT, the time delay between matrix deposition osteoblasts
and subsequent mineralization) that separates patients with and without eomalacia. Locations
are shown for clarity and simplicity. Note a significant overlap of 2°HPT, HVO I, and LTO
29. • The three principal mechanisms by which rickets and osteomalacia develop are
vitamin D depletion or deficiency, phosphate depletion or deficiency,
and calcium deficiency—in that order of frequency.
• Hypophosphatemia due to nutritional phosphate deficiency is a very
rare cause of rickets or osteomalacia, although occasional cases have been
reported in patients on prolonged total parenteral nutrition.
• Vitamin D deficiency or depletion, if prolonged or left untreated, ultimately leads to
rickets and osteomalacia.
30. • Phosphate depletion, however caused (genetic, tumor induced, or acquired), is
the second most common cause of rickets and osteomalacia, and the
most prevalent type in parts of the world where vitamin D
deficiency is not endemic.
• The two most common causes of hypophosphatemic rickets and osteomalacia are
hereditary hypophosphatemic syndromes and FGF23-secreting
tumors.
• Other less frequent causes of hypophosphatemic rickets and osteomalacia
include prolonged use of phosphate-binding antacids, as well as
various genetic and acquired renal tubular defects.
• Other causes- toxic effects of drugs such as sodium fluoride, etidronate,
aluminum, and iron, which directly inhibit bone mineralization.
31. • Vitamin D deficiency can be extrinsic or intrinsic.
• Extrinsic vitamin D deficiency is due to deficient endogenous cutaneous
production of vitamin D3 or poor dietary intake
• Inadequate exposure or avoidance of sunlight, use of sunprotective
lotions or sunscreens, darkly pigmented skin, excessive covering of the
body with clothing for cultural reasons, and aging all contribute to the
decreased production of vitamin D3 or cholecalciferol from its precursor 7-
dehydrocholesterol.
32. • Rickets and osteomalacia due to intrinsic vitamin D depletion (the
descriptive term depletion for all intrinsic causes of vitamin D
deficiency is probably more appropriate) is most commonly caused by
impaired gastrointestinal absorption of vitamin D (and calcium as
a result of intestinal disease, resection, or gastric bypass surgery
• Vitamin D deficiency can also result from genetic or acquired causes
of impaired or defective vitamin D 25-hydroxylase in the liver or
impaired or deficient 25-hydroxyvitamin D 1α-hydroxylase in the
kidney and other target tissues
33.
34.
35. • Of all the intrinsic causes of vitamin D depletion, malabsorption of
vitamin D is by far the most common cause of osteomalacia.
• Both gluten enteropathy and Crohn disease have been associated with
osteomalacia due to vitamin D depletion
• Although decreased bone mineral density (BMD), increased fracture risk, and
growth retardation (possibly related to rickets) have been associated with
inflammatory bowel disease, osteomalacia due solely to inflammatory
bowel disease has not been reported.
• Severe calcium malabsorption, malnutrition, or both, as seen in patients with
inflammatory bowel disease, may lead to 2°HPT with the consequent cortical
bone loss and increased risk of fragility fractures but without vitamin D
depletion severe enough to cause osteomalacia.
36. • Total and partial gastrectomy, vagotomy and pyloroplasty, intestinal
resection, and gastric or intestinal bypass surgery for morbid obesity
have all been associated with vitamin D depletion and osteomalacia
• Because of the malabsorption of multiple nutrients, including calcium and
vitamin D, the bone phenotype varies from simple osteopenia detected by
BMD testing to osteoporosis with increased fracture risk, to frank
osteomalacia on bone histomorphometry
• The relative frequency of osteomalacia in patients with various gastrointestinal
disorders or surgeries is not clearly established but may be as high as 50%.
• Prolonged 2°HPT can occasionally lead to bone marrow fibrosis and
hypercalcemic 2°HPT (or tertiary hyperparathyroidism)
37. • By contrast, hepatobiliary and pancreatic disorders are relatively
less common causes of rickets and osteomalacia, although
osteoporosis is very common in both kinds of disorders.
• Most often, additional factors, such as poor dietary vitamin D intake,
antiviral drug therapy for hepatitis and coexistent primary
biliary cirrhosis contribute to severe vitamin D depletion and
osteomalacia
• Immaturity and neonatal hepatitis are also rare causes of rickets in
children and osteomalacia in adults most likely related to defective or
insufficient vitamin D 25-hydroxylase enzyme, although not
conclusively documented.
38. • Despite a significant fat malabsorption and steatorrhea in patients
with exocrine pancreatic insufficiency, rickets and
osteomalacia are uncommon, but both rickets and osteomalacia
have been reported in patients with cystic fibrosis.
• Drugs that interfere with the 25-hydroxylation step in the vitamin
D activation pathway are discussed in the section on drug-induced
rickets and osteomalacia.
39.
40. Calcium-Deficiency Rickets
• Unlike nutritional vitamin D and phosphate deficiency, which cause both rickets and
osteomalacia, only rickets has been convincingly documented as resulting
from nutritional calcium deficiency without associated vitamin D
deficiency.
• No case of osteomalacia in an adult due to calcium deficiency alone has
been reported; the reasons for this discordant effect of calcium nutrition on the
skeleton in children and adults is perplexing
• A more severe 2°HPT over a relatively short period due to severe calcium
malnutrition in a growing child may produce radiologic features similar to rickets—
the so-called short-latency disease.
41. • Calcium malnutrition as a cause of rickets was first suggested in a child from
San Francisco, who responded to calcium infusion
• A similar case of rickets in an Italian child from Toronto, Canada, in whom both
vitamin D deficiency and resistance were excluded with appropriate
biochemical testing
• A daily calcium intake of greater than 200 mg appears to be the lowest
threshold for the risk of developing calcium deficiency rickets independent of
vitamin D nutritional status; “wet-nursing” and prolonged
breastfeeding, practices that are prevalent in some cultures, are other risk
factors for calcium deficiency rickets
42. • Rickets due to calcium deficiency tends to occur later in life than that due
to vitamin D deficiency, with an average age at presentation of 4 years in
Nigeria, but ranging from 4 to 16 years in other series.
• Clinically, calcium deficiency rickets differs from other forms of rickets,
especially in adolescents who may have significant genu valgum without
many end-plate deformities.
• The rarity of calcium-deficiency rickets in developed countries may be related to
a much higher dietary calcium intake and less prolonged breastfeeding.
• Nevertheless, when a child is encountered with rickets and if the serum level of
25-hydroxyvitamin D is normal, think of calcium-deficiency rickets, particularly
if serum calcium is low and PTH is elevated.
43. Phosphate-Deficiency/Depletion Rickets and
Osteomalacia
• Nutritional phosphate deficiency is a very rare cause of rickets and osteomalacia, as
there is abundant phosphate in foods, fruits, vegetables, and dairy
products.
• Since intestinal absorption of phosphate is mostly passive and quite efficient, it is very
difficult to produce true nutritional phosphate deficiency in an otherwise healthy
individual.
• The serum phosphate level is maintained within a narrow range by the kidney under
the control of PTH and FGF23.
44. • Hypophosphatemia, however, is not uncommon in hospitalized patients, in
patients with iron deficiency, and in those receiving phosphate
binders and antacids known to deplete phosphorus in the body.
• Such hypophosphatemic states usually do not last long enough to produce
rickets and osteomalacia.
• Consequently, almost all hypophosphatemic rickets and osteomalacia are either
genetic or acquired.
47. • The symptoms and signs of rickets and osteomalacia are primarily related to the
musculoskeletal system.
• With few exceptions, the clinical manifestations are similar regardless of their
pathogenesis—nutrient deficiencies, genetic or acquired causes, tumor induced, or
drug induced.
• Because rickets involves the growth plates affecting linear growth, short stature
is common.
• In long bones, rickets affects diaphysis (bowing), metaphysis (widening,
fraying, and cupping), and epiphysis (irregular margins), whereas
osteomalacia involves only the diaphysis of the long bones.
• If osteomalacia develops later in life without a history of rickets during infancy and
childhood, the clinical manifestations are subtle and resemble those of
age-related osteoporosis.
48. • In general, the later the onset of osteomalacia, the more easily its clinical clues
are missed and the more likely the symptoms are dismissed as aches and
pains of aging
• The most common presenting clinical symptoms are bone pain, muscle
weakness and difficulty in walking, skeletal deformities, and
fractures.
• Carpal and pedal spasms, muscle cramps, and seizures due to hypocalcemia are
uncommon but mostly seen in children with rickets than in adults
with osteomalacia.
• Triradiate pelvis, a rare complication of osteomalacia due to softening of the
pelvic bones , may cause difficult or obstructed labor in childbearing women
49. Bone Pain
• Bone pain in osteomalacia is diffuse, nondescript, dull aching, deep seated,
and poorly localized, and at times can be debilitating.
• It is felt more in the bones than in the joints and often is bilaterally symmetric.
• Because of its vague nature, bone pain is often misdiagnosed as tension headache
(so-called osteomalacic cephalalgia), “angina” (chest pain due to
pseudofractures in the ribs), rheumatism, and fibromyalgia.
• The pain is persistent and gnawing, is aggravated by weight bearing or muscle
contractions during attempted walking, and is rarely relieved by rest.
• The pain usually begins in the lower back and spreads to the pelvis, hips,
thighs, upper back, and ribs but is nonradiating and is rarely felt below
the knees unless fragility or pseudofractures are present in tibiae and
fibulae.
50. • Bone tenderness can be elicited by pressure or percussion over the
shin bones, squeezing of the forearm with a fist, lateral
compression of the pelvis and rib cage, and posterior
compression of the sternum.
• The propensity of pain to localize to the axial skeleton is probably
related to an earlier and a greater accumulation of osteoid in the
cancellous bone, whereas the appendicular skeleton, rich in
cortical bone, is more subject to fragility fractures.
• The mechanism for bone pain is believed to be related to the stretching of
the periosteum by the overhydrated unmineralized bone matrix.
• Bone pain almost never occurs in patients with osteoporosis in the absence
of a fracture, but in osteomalacia, bone pain occurs with or without a
fracture.
51. MuscleWeakness
• Proximal muscle weakness, especially in the lower extremities, is the
most common muscular manifestation in osteomalacia
• In mild cases, the muscle weakness must be distinguished from the patient’s
reluctance to stand or walk for fear of aggravating the bone pain.
• Difficulty in rising from a sitting position or going up and down stairs without
using the arms is quite specific.
• In advanced cases, classical waddling gait (walking like a duck), the
result of a combination of muscle weakness and bone pain, is observed.
• With prolonged vitamin D depletion of increasing severity, a patient may
become completely immobilized and bed bound because of profound
weakness and excruciating bone pain, sometimes masquerading as a
terminal illness.
52. • Muscle atrophy is uncommon, although mild muscle wasting with atrophy of
the type II fibers has been reported occasionally.
• Hypotonia can be present, but fasciculation and clonus are absent.
• Deep tendon reflexes are normal or increased
• Rarely, dilated cardiomyopathy that responds to vitamin D repletion has been
reported in severe rickets.
• Other muscular symptoms such as muscle cramps and spasms, tingling and
numbness, and seizures (usually in children) occur when the serum
calcium level falls below 6.0 mg/dL.
• Both the muscle weakness and atrophy are commonly attributed to hypocalcemia
and 2°HPT
53. • In general, muscle weakness is more prominent in
hypophosphatemic rickets and osteomalacia, whereas bone pain
is more common in vitamin D–deficiency osteomalacia.
• Interestingly, despite a significant muscle weakness in patients with X-
linked hypophosphatemia (XLH), bone mass, bone size, and
estimated bone strength are normal or increased.
54. Skeletal Deformities and Fractures
• Skeletal deformities are common in children with rickets, vary with the age of
presentation, and may remain permanent, whereas bone deformities are
uncommon in adult-onset osteomalacia unless fractures have occurred.
• Infants present with open fontanelles, dolichocephaly, frontal bossing,
rachitic rosary (due to consecutive pseudofractures of multiple ribs
often bilaterally symmetric), Harrison sulcus (a visible horizontal line
of depression at the level of the diaphragm due to weakness of the
chest muscles), swollen wrist and ankle joints (due to widened
metaphysis), and double malleoli.
• Once the child starts walking, bowing of the long bones, genu valgum, genu
varum, and windswept deformity are seen.
55. • The skeletal deformities are usually more severe in genetic
hypophosphatemic rickets and osteomalacia, and they
predominantly involve lower limbs, resulting in a
disproportionate short stature.
• Fragility fractures are not uncommon, but Looser zones or
pseudofractures, the diagnostic radiologic abnormalities, are more
common in patients with rickets and osteomalacia.
• Pseudofractures are linear radiolucent bands perpendicular to
the long axis of the bones, and are stress fractures that can extend to a
complete fracture, usually in the subtrochanteric region of the femur
or metatarsals—the greatest load-bearing bones.
• Rib fractures also commonly occur.
57. Biochemical Changes
• In all types of rickets and osteomalacia, elevated serum alkaline
phosphatase is the most frequent (∼80–90%) and the earliest biochemical
abnormality.
• In general, hypocalcemia is a late biochemical manifestation, but it
occurs earlier in the course of development of rickets in children than during
the evolution of osteomalacia in adults.
• Mild to moderate hypocalcemia (serum calcium level of 7.0–8.5 mg/dL) is
often asymptomatic unless it falls below the threshold for symptoms (usually
<6.0 mg/dL).
• Like other types of biochemical abnormalities in clinical practice, it is the rate
of change rather than the absolute value that determines the development of
relevant symptoms.
58. • The serum phosphate level is quite variable, lacks specificity, and is subject
to diurnal variation, meal ingestion (and hence should be
measured in the fasting state in the morning), renal function, and
degree of serum PTH elevation—a known regulator of the serum
phosphate level; thus, serum phosphate in nutritional rickets and
osteomalacia can be normal, low, and occasionally high, particularly in
patients with more severe hypocalcemia.
• By definition, the serum phosphate level is less than 2.5 mg/ dL in
all forms of hypophosphatemic rickets and osteomalacia.
59. • Although all patients with nutritional rickets and osteomalacia have low 25-
hydroxyvitamin D levels (usually <10 ng/mL), the vice versa is not true.
• In calcium-deficiency rickets, serum 25-hydroxyvitamin D is either normal or
slightly reduced, although not to the same extent as in vitamin D–deficiency
rickets and osteomalacia.
• An accelerated catabolism of 25-hydroxyvitamin D to its more polar and
biologically active 1,25-dihydroxy vitamin D or to its inert metabolites
contributes to the lower levels of serum 25-hydroxyvitamin D, sometimes referred to
as conditional or obligatory vitamin D insufficiency.
60. • Serum levels of 1,25-dihydroxyvitamin depend on the stage in the evolution of
nutritional rickets and osteomalacia, the availability of its precursor (25-
hydroxyvitamin D), and the degree of PTH elevation; thus, the serum levels of
1,25-dihydroxyvitamin D can be high, normal, or low.
• By contrast, serum 1,25-dihydroxyvitamin D levels are low, although not invariably, in
hypophosphatemic rickets and osteomalacia.
• Serum levels of PTH are always elevated in nutritional-deficiency (both
vitamin D and calcium) rickets and osteomalacia, and the levels are normal in
hypophosphatemic disorders regardless of the pathogenesis, unless vitamin D
deficiency also exists.
• However, serum PTH levels rise progressively over time in patients with
hypophosphatemic rickets and osteomalacia treated with long-term oral phosphate
supplements.
63. • The major radiologic manifestations of nutritional rickets and osteomalacia are
bone structural changes discernible on routine x-rays, generalized decrease in
apparent bone density on x-rays, vertebral deformities , and
pseudofractures (or Looser zones)
• Generalized thinning of cortices in the long bones is probably the earliest
radiologic manifestation due to PTH-mediated endocortical bone resorption.
• Subperiosteal bone resorption (best seen on the radial aspect of the middle
phalanges, metacarpals, and metatarsals) and brown tumors (osteitis fibrosa
cystica) are seen in more advanced cases with severe hyperparathyroidism.
• Symmetrical biconcavity of vertebrae, referred to as cod fish vertebrae because
they resemble vertebrae in cod fish, involves almost all vertebrae.
64. • Fish-mouth” appearance of the intervertebral space is the result of
yielding of the soft vertebral bone to the pressure of the intervertebral discs.
• When present, the cod fish vertebrae–like appearance of the spine is virtually
diagnostic of osteomalacia.
• The generalized apparent decrease in density of the bones on radiographs is
manifested as decreased BMD by dual energy x-ray absorptiometry.
• Looser zones or pseudofractures are lucent border of the scapulae
and less commonly at the inferobands (2–5 mm in width) perpendicular
to the long axis of the bone or periosteum, often bilaterally symmetrical with
sclerotic borders (Milkman syndrome); they occur more commonly in the
ribs, pubic rami, and outer medial region of the proximal femurs and
medial aspect of the shafts of the long bones.
65. • Insufficiency fractures, sometimes inappropriately referred to as
pseudofracture, can be seen in Paget disease of bone, hypophosphatasia,
fibrous dysplasia, and atypical femur fractures due to long-term
bisphosphonate therapy but usually occur (or begin) on the lateral
cortex of long bones.
• Both insufficiency fractures and pseudo-fractures can progress across the shaft
of the bone to a complete fracture.
• Looser zones or pseudofractures are caused by erosion of bone by
nutrient arterial pulsation, which explains their specific medial
cortical location, and represent the unhealed insufficiency type of
stress fracture.
66. • The generalized increase in radionuclide uptake throughout the skeleton,
referred to as super scan, is specific for conditions associated with
increased bone turnover but is more common in osteomalacia.
• Typically, there are no discrete focal abnormalities in the absence of
pseudofractures, and the radionuclide uptake in the kidneys, in the absence of
renal dysfunction, is either faint or absent, as most of the isotope is
retained in the skeleton and very little is available for renal
excretion.
• When present, Looser zones are seen as “hot spots” on nuclear imaging
• With a few exceptions, most radiologic features are similar among the various
type of rickets and osteomalacia.
67. • Cortical thinning in long bones is not seen in XLH, and in fact, thick
cortices are the rule rather than the exception.
• Similarly, enthesopathy is seen exclusively in XLH, but the underlying
mechanisms for its development is not known.
• In most acquired forms of hypophosphatemic osteomalacia (tumor and drug-
induced or renal tubular defects), cortical thinning and decreased BMD
may be seen, most likely the result of age-related bone loss
• Horizontal bands of endplate sclerosis of the vertebrae with relative
lucency in the middle portion of the vertebral bodies (Rugger-
Jersey spine, so named as the appearance resembles jerseys of rugby players)
are sometimes observed in osteomalacia due to renal tubular acidosis but is a
more characteristic feature of renal osteodystrophy
68. • Fig. 31.4 (A) Typical symmetrical biconcave deformities of all the vertebrae,
ometimes referred to as cod fish vertebrae because they resemble the vertebrae of the
fish. When present, it is diagnostic of osteomalacia of all types. (B) Typical random
osteoporotic wedge and compression deformities in a postmenopausal woman with
osteoporosis.
71. Fig. 31.5 Characteristic bone scan in a patient with osteomalacia. Note increased
nuclide uptake throughout the skeleton with very little or no uptake in the kidneys as
the radionuclide is all retained in the high remodeling skeleton. Also see multiple
bilateral symmetrical uptake in the ribs (left) due to pseudofractures, often confused
with metastatic disease
72. Bone Mineral Density
• BMD as assessed by dual energy x-ray absorptiometry is reduced at all of
the relevant sites (lumbar spine, proximal hip, and forearm), usually
with a greater deficit at the site of rich cortical bones in the forearms.
• By contrast, BMD is either normal or even increased at the lumbar
spine in adults with XLH osteomalacia
• A lower BMD in tumor-induced osteomalacia (TIO) is more likely age related.
• Although the patterns of BMD deficits are different in different types of
osteomalacia, the findings are neither sensitive nor specific to
differentiate osteomalacia from osteoporosis.
• Accordingly, in vivo tetracycline-labeled bone histomorphometry is
the gold standard method to conclusively establish the diagnosis of
osteomalacia in suspected cases.
74. Treatment of Nutritional Rickets and
Osteomalacia
• Treatment of rickets and osteomalacia must be based on their pathogenesis.
• In general, there is no “fixed-dose” or “one-size-fits-all” regimen to treat
all varieties of rickets and osteomalacia.
• First, most recommendations are largely based on personal
preferences, clinical experience, and availability of suitable vitamin D
preparations.
• Second, moderate to severe rickets and osteomalacia related to vitamin D and
calcium deficiency, but not the hypophosphatemic variety, are frequently
associated with hypocalcemia and thus require much higher doses of
vitamin D and calcium supplements initially.
75. • Third, it must be kept in mind that patient symptom relief is much faster (a
few weeks to a few months) than the biochemical, radiologic, or
histologic improvements, which may take a few months to years.
• Fourth, even after apparent “cure” of clinical, biochemical, radiologic, and bone
histologic abnormalities, many patients remain at risk for fractures because of
irreversible cortical bone loss.
• In some patients with long-standing vitamin D–deficiency rickets and osteomalacia,
2°HPT may even progress to hypercalcemic 2°HPT (or tertiary
hyperparathyroidism) requiring parathyroidectomy.
• This is analogous to the development of tertiary hyperparathyroidism after long-
term oral phosphate therapy in patients with hypophosphatemic
(genetic or acquired) osteomalacia, and in patients on chronic maintenance
dialysis or after kidney transplantation.
76. • Whichever method is chosen, it must achieve the therapeutic goals
• In symptomatic patients with moderate to severe rickets and
osteomalacia, we recommend 50,000 IU of either ergocalciferol
(vitamin D2) or cholecalciferol (vitamin D3) weekly for 8 to 12
weeks followed by a maintenance dose of 1000 to 2000 units daily.
• Despite the contradictory claims, there is not much difference between
vitamin D2 and vitamin D3 in replenishing depleted vitamin D stores, and
both vitamin D preparations are equally effective in treating rickets and
osteomalacia.
77. • During follow-up, adjustments to the vitamin D dose should be made based on
serum and urine levels of calcium, alkaline phosphatase, PTH, and
achieved serum 25-hydroxyvitamin D levels, with target levels of 25-
hydroxyvitamin D greater than 30 ng/mL and PTH in the reference
range.
• Once achieved, a maintenance dose of 1000 to 2000 IU/day is recommended.
• Several vitamin D formulations (oral, sublingual, and injectable) are
available, and most have comparable therapeutic efficacy, although no
formal studies have been co nducted.
78. • In addition, certain vitamin D metabolites (calcidiol, calcitriol, and
alphacalcidol) are available in other countries, but only calcitriol is available
in the United States.
• Perhaps calcidiol (25-hydroxyvitamin D3), if available, is preferred
because it has a shorter half-life (∼2 weeks), which is an advantage
should hypercalcemia develop during therapy, it can be measured directly
to monitor treatment, and the dose can be adjusted based on serum levels.
• The other active metabolites (calcitriol and alphacalcidol) are
not preferred in treating vitamin D–deficiency rickets and
osteomalacia but have been used.
79. • The use of calcitriol along with vitamin D is suggested in patients
with more severe 2°HPT (PTH levels >500 pg/mL), in some patients
with significant malabsorption of calcium due to celiac sprue or
gastric bypass surgery, in patients with documented bone marrow
fibrosis, or in those with compromised kidney function.
• However, calcitriol should not be either the first-line or sole therapy
for vitamin D–deficiency rickets and osteomalacia.
80. • In malabsorptive states, particularly in patients with small intestinal resection
or gastric bypass surgery, higher doses of vitamin D (10,000–50,000
IU/day) may be required to replete vitamin D stores.
• Compared with parenteral administration, the rise in serum 25-
hydroxyvitamin D levels is rapid with oral preparations.
• Careful close follow- up is essential during the first few months (1–3
months) of treatment to monitor treatment-related adverse events, such as
hypercalcemia, hypercalciuria, and renal dysfunction.
81. • Vitamin D deficiency of sufficient severity to produce osteomalacia is invariably
associated with decreased intestinal calcium absorption and negative
calcium balance.
• Accordingly, oral calcium supplements in the form of calcium carbonate (or
citrate) 1000 to 1500 mg/day in divided doses must be prescribed with
vitamin D administration to accomplish not only clinical and biochemical but also
radiologic and bone histologic responses.
• With effective therapy, symptoms of osteomalacia start improving within a few
weeks, but complete disappearance of symptoms usually takes a few months and
sometimes years.
• Although nutritional rickets is mostly curable, osteomalacia is only treatable
but not curable and requires long-term maintenance therapy largely
dictated by the clinical and biochemical responses.
82. • Complete healing of osteomalacia and resolution of 2°HPT must
be ensured before commencing anti-fracture therapy for the
associated osteoporosis.
• Nonadherence to long-term therapy is not uncommon because both the
patient and sometimes the treating physician might assume that the condition
is “cured” based on clinical symptoms, and therefore there is no need for
continued therapy.
83. Rickets Due to Genetic Disorders ofVitamin D Metabolism
Vitamin D–Dependent RicketsTypes
1A, 1B, and 2
• There are three unique forms of rickets due to genetic disorders, resulting in
the loss of function of the enzymes required for vitamin D biologic activation.
• Severe rickets despite adequate vitamin D intake that responded only to high doses of
vitamin D2 in two siblings was probably the first example of rickets due to a
possible genetic defect in the 25-hydroxylase enzyme.
• Recent genetic studies suggest that mutations in the CYP2R1 gene, the principal
25-hydroxylase in humans, are responsible for the severe atypical form of
vitamin D deficiency and rickets
84. • The genetic transmission appears to be both autosomal dominant and
recessive, and this rare atypical form rickets is now designated as vitamin D–
dependent rickets type 1B VDDR1B).
• The other two types— vitamin D–dependent rickets type 1A (VDDR1A)
and vitamin D–dependent rickets type 2 (VDDR2)—are due either to a
defective 25- ydroxyvitamin D 1α-hydroxylase, the critical enzyme required in the
final step of vitamin D biologic activation, or to an end-organ resistance to vitamin
D action due to loss of vitamin D receptors, respectively.
• Impairment of 1α-hydroxylase enzyme activity can also be acquired, as in
chronic kidney disease, various renal tubular disorders, or excess or
ectopic production of FGF23,known to inhibit 1α-hydroxylase enzyme
activity.
85. • Genetic defect in the 1α-hydroxylase enzyme, VDDR1A, or pseudo–
vitamin D deficiency, is a rare autosomal recessive disorder due to
mutations in the cytochrome P450 (CYP27B1) gene for the 1α-hydroxylase
enzyme located on the chromosome 12q13.3
• Rickets develops during the first year of life, and clinical features include growth
failure, hypotonia, weakness, convulsions, tetany, open fontanels, and
pathologic fractures, as well as oral and dental manifestations.
• As can be predicted, the condition responds to the physiologic doses (0.04
μg/kg per day) of active vitamin D metabolite, 1,25-
dihydroxyvitamin D or calcitriol, but requires much higher doses of the
parent compound vitamin D (∼10,000 units/day) to heal rickets—hence the
name vitamin D– dependent rickets.
86. • Similar to VDDR1A, but even more resistant to vitamin D therapy, is
due to defects in the vitamin D receptor, designated as
VDDR2.
• Children with VDDR2 have alopecia, a very unique feature that
distinguishesVDDR2 from bothVDDR1A andVDDR1B.
• However, the prevalence of alopecia is variable as is its extent of
involvement ranging from alopecia of the head to alopecia of the
entire body—“alopecia universalis.”
• Interestingly, although the biochemical and radiologic abnormalities in
VDDR2 respond to high-dose vitamin D or calcitriol and phosphate
therapy, alopecia does not.
• Vitamin D receptors are lacking in fibroblasts of the skin.
87. • Biochemical and radiologic features of vitamin D–dependent rickets are similar
to those seen in nutritional rickets, except serum 25-hydroxyvitamin
D levels are normal inVDDR1A and DDR2, and low or very low in
VDDR1B .
• Because of the low or very low serum 25-hydroxyvitamin D levels, the
biochemical findings inVDDR1B resemble those of nutritional vitamin D–
deficiency rickets and thus may be misdiagnosed as nutritional rickets.
• Family history, adequate vitamin D intake, lack of clinical and
biochemical response to standard-dose vitamin D therapy, and lack
of rise in serum 25-hydroxyvitamin D levels with vitamin D therapy
should raise suspicion for the possibility of this very rare inborn error of
vitamin D metabolism due to mutations in the CYP27B1 gene.
88. • BothVDDR1A (due to 25-hydroxyvitamin D 1α-hydroxylase deficiency)
andVDDR1B (due to vitamin D 25-hydroxylase deficiency) respond to
physiologic replacement doses of calcitriol (0.04 μg/kg per day), just as
nutritional rickets.
• However, patients withVDDR2 require much higher doses of
vitamin D or calcitriol because of end-organ resistance as a
result of vitamin D receptor defects.
• All children with vitamin D–dependent rickets regardless of the type
require adequate calcium and phosphate supplements during
therapy with calcitriol to achieve healing of the rickets and
suppress 2°HPT.
• Hypercalciuria and hypercalcemia are potential complications during long-
term therapy.
90. • There are several types of hereditary rickets that in the past were collectively
referred to as vitamin D–resistant rickets because of the very high doses
of vitamin D required to cure rickets.
• These rare types of rickets can be distinguished from the other types of rickets by
the pattern of their inheritance, underlying genetic defects, and hypophosphatemia
with normal serum calcium level, and if they are FGF23 dependent or
independent.
• The most common type of rickets and osteomalacia among them and clinically
most relevant is XLH rickets and osteomalacia.
91. Autosomal Dominant and Recessive
Rickets
• Autosomal dominant hypophosphatemic rickets (ADHR) is caused by
mutations in the FGF23 gene
• Inactive mutations in the dentin matrix protein (DMP1) and the
ectonucleotide pyrophosphatase/phosphodiesterase 1
(ENPP1) genes are responsible for autosomal recessive
hypophosphatemic rickets (ARHR) type 1 and type 2,
respectively.
• In patients with ADHR, there are mutations in several amino
acids (Arg176 or Arg179) resulting in resistance to
proteolytic processing.
92. • In addition, the degree of hypophosphatemia correlates with the intact FGF23
levels.
• In patients with FGF23-dependent hypophosphatemia due to mutations in the
DMP1 gene, there are deformities of the legs and short stature in
childhood, similar to the clinical phenotype of nutritional rickets.
• ARHR typically manifests during childhood with characteristic clinical features of
rickets; however, in adulthood, ARHR patients may manifest with bone pain,
fatigue, muscle weakness, and repeated bone fractures.
93. X-Linked Recessive Hypophosphatemic
Rickets
• X-linked recessive hypophosphatemic rickets— a rare genetic form of
hypophosphatemic rickets also known as the Dent disease complex— comprises
of a group of heterogeneous inherited disorders characterized by a proximal renal
tubular reabsorptive disorder of the Fanconi type.
• It is caused by missense, nonsense, frameshift, and splicing mutations in
genes located on the chromosome Xp11.22 and X25.
• Two subtypes are known to exist: type 1 (∼50–60% of cases), caused by an
inactivating mutations in the chloride channel 5 (CLCN5) gene that codes
for a chloride-proton exchanger, and type 2 (∼15% of cases), by
inactivating mutations in the oculocerebrorenal syndrome (OCRL) gene
located on an X chromosome that codes for inositol polyphosphate 5-
94. • Dent disease is associated with hypercalciuria with variable other
proximal renal tubular dysfunction, nephrocalcinosis or
nephrolithiasis, low-molecular-weight proteinuria, and
progressive renal insufficiency, but only a minority of patients
manifest rickets.
• In addition to hypercalciuria and proteinuria, the disease may be associated
with defective renal tubular reabsorption of one or more of the
following solutes: glucose, phosphate, uric acid, potassium,
bicarbonate, and amino acids.
95. X-Linked Hypophosphatemic Rickets and
Osteomalacia
• XLH (OMIM #307800) is an X-linked dominantly inherited disorder with an
estimated prevalence of about 1 in 20,000 live births.
• It is the most common form of hereditary hypophosphatemic rickets,
caused by an inactivating mutation in the phosphate-regulating gene with
homologies to endopeptidases on the X chromosome (PHEX).
• PHEX is expressed on the cell surface of bones and teeth.
• More than 300 types of mutations in the PHEX gene have been reported in patients
with XLH, and the mutations may be de novo in some patients.
96. • The prevailing hypothesis is that the mutations found in the PHEX
gene in patients with XLH are likely to enhance the
production of FGF23 in bones, but the pathogenic implications to the
clinical expression of the disorder are unclear
• Although TIO, XLH, and ADHR all have overlapping phenotypical
features, all three types of rickets share a common biochemical
phenotype— hypophosphatemia as a result of defective renal tubular
reabsorption of phosphate.
• Current evidence supports the notion that under normal physiologic
conditions, the concentration of FGF23 in serum (and possibly other
tissues) is regulated by PHEX-dependent proteolysis.
97. • Conditions with excess circulating FGF23 concentrations or activity are
associated with a marked depression in the proximal renal
tubular reabsorption of phosphate and hypophosphatemia.
• When PHEX is inactive, as in patients with XLH, FGF23 is not
degraded and accumulates in the circulation.
• In ADHR, missense mutations replace the key amino acids in
FGF23 and render the protein resistant to proteolysis, thereby
leading to increased circulating FGF23 concentrations or action.
• Similarly, ectopic overproduction of FGF23 by tumors causing
TIO may saturate the capacity of endogenous proteolytic
enzymes, such as PHEX, to degrade FGF23
98. • The clinical features of XLH are variable, with most patients presenting
with rickets during childhood.
• In childhood- onset XLH, skeletal deformities such as bowed legs and
short stature are common.
• In adults, XLH may be discovered during a routine biochemical work-up
revealing hypophosphatemia.
• Symptoms in adults resemble those seen in osteomalacia, such as bone
pain, insufficiency fractures, muscle weakness that is often
disabling, neurologic complications related to enthesopathy,
and ectopic calcifications.
• In addition, dental disease, such as root abscesses, often develop due to a
defect in dentin and enamel microdefects.
99. Radiologic and Biochemical Findings
• The radiologic features of all hereditary rickets are similar to those seen in
nutritional rickets, except metaphyseal involvement is slightly
asymmetrical and bowing is slightly more common.
• As adults, most patients are obese and manifest a disproportionate
short stature with greater shortening of the lower extremities.
• Enthesopathy occurs almost exclusively in XLH and is almost never seen in other
types of rickets and osteomalacia.
• The most common and consistent biochemical findings are
hypophosphatemia, renal phosphate wasting as assessed by tubular
reabsorption of phosphate or tubular maximum for phosphate
reabsorption adjusted for glomerular filtration rate (GFR; TmP/
dlGFR), and elevated serum alkaline phosphatase levels.
100. • Serum calcium, 25-hydroxyvitamin D, and PTH levels are characteristically
normal in the untreated state.
• Serum FGF23 levels are inappropriately elevated in the context of chronic
hypophosphatemia.
• The differential diagnosis of XLH includes nutritional rickets, metaphyseal
dysplasia, physiologic bowing, and other forms of renal phosphate
wasting disorders.
• Considering the possibility of de novo mutations in the PHEX gene, an absence
of family history of rickets does not necessarily exclude XLH.
• Genetic testing is not a prerequisite for a clinical diagnosis of XLH.
101.
102. Treatment of Hereditary Hypophosphatemic
Rickets and Osteomalacia
Standard Treatments
• The standard of practice for the treatment of XLH in children includes a
combination of active vitamin D metabolites (calcitriol or
alphacalcidol) and oral phosphate supplementation.
• Skeletal deformities and growth retardation may improve with treatment but do
not completely resolve.
• In adults, these same medications are used for symptom management and to
improve impaired bone mineralization.
• In one observational study, treatment of adult patients with XLH reduced pain
symptoms and improved fracture healing following orthopedic
surgery but did not prevent or reverse enthesopathy.
103. Novel Treatments
• Recently, the use of burosumab, a recombinant human immunoglobulin
G1 monoclonal antibody that binds to the FGF23 receptor and inhibits
its activity, was evaluated in a phase 1 double-blind, placebo-controlled
randomized clinical trial.
• With a single dose, burosumab increased the TmP/GFR, and serum
levels of phosphate and 1,25-dihydroxyvitamin D.
• The peak serum phosphate concentration achieved was between 8 and 15 days
and returned to the baseline within 50 days after the initial
subcutaneous injection.
• In a subsequent phase 1/2 open label, dose-escalation study, monthly burosumab
resulted in a sustained improvement in TmP/GFR, and in serum phosphate and
1,25-dihydroxyvitamin D levels, with a favorable safety profile.
104. Long-Term Management
• Treatment with active vitamin D metabolite, calcitriol, and oral
phosphate supplements -adverse effects over the long term.
• Hypercalciuria with or without hypercalcemia may develop and may lead to
nephrolithiasis, nephrocalcinosis, and impaired renal function.
• Use of oral phosphate supplements causes diarrhea and abdominal pain
• An unintended consequence of long-term (usually years) oral phosphate
therapy is the development of 2°HPT, which may evolve into
hypercalcemic 2°HPT (also referred to as tertiary
hyperparathyroidism).
• Cinacalcet, radiofrequency ablation of the tumor to reduce
ectopic production of FGF23, and deliberate total
parathyroidectomy have all been tried with variable success.
105. Tumor-Induced Osteomalacia
• TIO was first reported by Robert McCance in 1947,but the first “proof of
concept” was provided by Andrea Prader in 1959, who postulated the
production of a “rachitogenic substance” by a “giant cell reparative
granuloma of bone,” the removal of which cured the young patient’s
rickets.
• Interestingly, the discovery of FGF23 and characterization of its function as
a major phosphate regulating hormone did not occur until a few decades
later.
• The condition is conventionally referred to as osteomalacia, as most cases
are detected in adults, but rickets in children has been reported.
• Nearly 500 cases of TIO have been reported in the literature; the majority
are adults with a mean age of 45 years at the time of diagnosis
and a wide age range, and there does not appear to be any gender
predilection.
106. • TIO is a rare paraneoplastic syndrome that clinically manifests with diffuse
nonspecific bone pain, profound muscle weakness, and fractures
• The pathogenesis is related to the ectopic production of FGF23—a
phosphatidic hormone secreted by small mesenchymal tumors.
• The biochemical hallmark of TIO is the triad of hypophosphatemia due
to renal phosphate wasting, inappropriately low or normal serum
1,25-dihydroxyvitamin D level, and elevated or inappropriately
normal serum FGF23 level.
• The kidney is the principal target for FGF23, where it regulates renal tubular
reabsorption of phosphate and production of 1,25-dihydroxyvitamin D.
107. • FGF23 inhibits both sodium-dependent phosphate reabsorption and 1α-
hydroxylase activity in the proximal tubule, leading to hypophosphatemia and
aberrant production and inappropriately low levels of 1,25-dihydroxyvitamin D.
• The combination of hypophosphatemia and “low” 1,25-dihydroxyvitamin D
causes muscle weakness and mineralization defect, respectively.
• TIO is usually caused by tumors of mesenchymal origin, referred to as
phosphaturic mesenchymal tumor of mixed connective tissue
variant, and rarely by other types of tumors, such as osteosarcoma,
giant cell tumor, glomus tumor, small cell carcinoma of the lung,
and adenocarcinoma of the colon.
108. • These tumors tend to be small (often escaping clinical detection), slow growing,
and difficult to localize
• Histology of the tumors reveals neoplastic spindled and stellate-shape
cells with low nuclear and mitotic activity that stain for FGF23.
• Other phosphatonins such as frizzled-related protein 4, FGF7, and
matrix extracellular phosphoglycoprotein have been described.
• Patients with TIO usually present with long standing and progressive debilitating
symptoms that go undiagnosed for years
• Symptoms can be nonspecific, and the most common complaints are bone pain,
fatigue, muscle weakness, and multiple fractures
109. • Laboratory evaluation of a patient suspected of having TIO should begin
with measurement of serum phosphate, preferably in the fasting
state.
• Since hypophosphatemia is uncommon in the ambulatory nonhospitalized
patient, a serum phosphate level less than 2.5 mg/dL should raise
suspicion in the right clinical setting
• Elevated serum alkaline phosphatase supports the clinical suspicion.
• Once hypophosphatemia is detected and confirmed, further assessment of
the renal tubular handling of phosphate (tubular reabsorption
of phosphate and TmP/GFR: tubular maximum for phosphate
reabsorption per unit of GFR should be performed, and a low value for
either measurement clinches the diagnosis of a phosphate-wasting condition
110. • As in genetic hypophosphatemic disorders, serum levels of calcium, 25-
hydroxyvitamin D, and PTH are normal in TIO, but similar to
genetic disorders, 1,25-dihydroxyvitamin D levels are either
inappropriately “normal” or low.
• Interestingly, serum levels of alkaline phosphatase are elevated in all varieties of
hypophosphatemic rickets and osteomalacia
• Serum FGF23 levels are elevated in the majority of, but not all,
patients with TIO and depend on the type of assay used (intact vs. C-
terminal fragment).
• A normal serum FGF23 level does not exclude the diagnosis.
• A positive family history of rickets or osteomalacia, or presence of metabolic
acidosis, makesTIO unlikely.
111. • Radiologic and radionuclide manifestations of TIO are similar to those
seen in other types of rickets and osteomalacia with some exceptions:
unlike genetic hypophosphatemic but similar to nutritional
deficiency disorders, BMD is low, most likely the result of some
combination of age-related bone loss and impaired bone mineralization
due to hypophosphatemia.
• Enthesopathy is not seen inTIO, but fractures are common.
• Except for higher osteoid volume, which may remain high even
after clinical “cure,” bone histologic features are similar to other types
of osteomalacia.
112. • Localization of the tumor can be quite challenging because most are small
tumors, often found in obscure locations
• Since somatostatin receptors are expressed in many phosphaturic mesenchymal
tumors of mixed connective tissue variant, an octreotide scan can help
with tumor localization in about 50% of cases
• 18F-fluorodeoxyglucose positron emission tomography is quite
sensitive in localizing tumors but can lead to false-positive results.
• Gallium-DOTATATE positron emission tomography is an emerging
imaging modality for tumors producing TIO, is now the imaging method of
choice.
• Functional imaging can be supported by selective venous sampling with
measurement of FGF23 to confirm the location of the tumor in cases
114. • The treatment of choice for TIO is resection of the tumor, which results in
clinical, biochemical, radiologic, and bone histologic improvements.
• Wide surgical resection is essential to avoid tumor recurrence.
• Levels of serum phosphate and FGF23, which has a half-life of ∼45
minutes, return to normal rapidly, often within 24 hours, after tumor
resection, but healing of osteomalacia may take several months.
• Rarely, recurrences with metastasis can occur.
• If the tumors are not readily identifiable, or not amenable to surgical removal,
lifelong medical therapy with oral phosphate and calcitriol is required.
115. • Oral phosphate in three to four divided doses with meals and
calcitriol 0.5 to 1.0 μg/day in divided doses to maintain serum
phosphates level at the lower end of the age-appropriate reference range is
recommended.
• However, long-term oral phosphate therapy may lead to secondary and
occasionally hypercalcemic 2°HPT (tertiary hyperparathyroidism) that
requires surgical intervention.
• Other potential treatment options in situations where the tumor cannot be
surgically removed or localized, use of calcium-sensing receptor
agonists, radiofrequency ablation of the tumor, or deliberate total
parathyroidectomy can be considered.
116. Drug-Induced Osteomalacia
• Several drugs have been implicated in the pathogenesis of rickets and
osteomalacia
• Among them, nucleoside reverse transcriptase inhibitors
(NRTIs), tenofovir and adefovir, are currently the most common
causes of drug-induced rickets and osteomalacia.
• Other drugs that cause rickets or osteomalacia include anticonvulsants,
aluminum containing antacids, non-nitrogen containing
bisphosphonates, and sodium fluoride.
• Fanconi syndrome has also been reported with NRTI
117. • Serum FGF23 levels are characteristically normal in NRTI-related
hypophosphatemia.
• Sudies have shown that a time interval between initiation of NRTI
treatment and the development of Fanconi syndrome varies from 1 to
26 months, and the prevalence of osteomalacia is about 0.5% in patients
receiving the drugs.
• Concomitant use of ritonavir-boosted protease inhibitor increases NTRI
toxicity because protease inhibitors increase intracellular concentrations of the
drugs.
• The exact mechanism of tenofovir-induced nephrotoxicity is not well
understood, but it appears to be due to mitochondrial damage and
alterations in human organic anion transporter 1.
118. • Proximal renal tubular mitochondrial injury due to the inhibition of
mitochondrial DNA polymerase results in decreased mitochondrial
DNA replication and impairs molecular transport, vitamin D
activation, and urinary acidification.
• Discontinuation of the causative drug promptly corrects hypophosphatemia
and renal dysfunction if detected early, but additional therapy with oral
phosphate and vitamin D or its metabolites is required for patients with
osteomalacia.
119. • Anticonvulsants, phenytoin, primidone, phenobarbital, and rifampin
induce the hepatic cytochrome P450 oxidase enzyme system, which increases the
conversion of vitamin D to polar inactive metabolites in the liver,
reducing the bioavailable 25-hydroxyvitamin D.
• The resulting conditional vitamin D deficiency, if prolonged and severe, ultimately
leads to rickets and osteomalacia.
• The clinical manifestations, biochemical changes, and radiologic and bone histologic
features are similar to those seen in patients with nutritional vitamin D deficiency and
defective genetic 25-hydroxylase orVDDR1B.
• Treatment with vitamin D and calcium in the recommended doses for
nutritional vitamin D deficiency is usually effective.
• Unlike in the case of NRTIs, there is no need to discontinue the drugs that caused the
problem in the first place.
120. • Although both isoniazid and ketoconazole inhibit 1α-hydroxylase enzyme
in the kidney, cases of rickets and osteomalacia have not been reported.
• In earlier times, a unique form of “vitamin D–resistant” osteomalacia related to the
use of tap water in dialysate solution and aluminum-containing
phosphate binders was seen in patients on maintenance hemodialysis.
• Aluminum is preferentially deposited at the interface of mineralized and
unmineralized (osteoid) bone, and uncouples matrix synthesis and its
subsequent mineralization, resulting in excess osteoid accumulation.
• With the use of deionized water, reverse osmosis, and abandonment of aluminum-
containing phosphate binders, aluminum- induced osteomalacia has all but
disappeared.
• A similar form of osteomalacia has been reported with sucralfate, another
121. • Osteomalacia due to iron deposition is more complex.
• Interestingly, both aluminum and iron co-localize in bone at the
mineralized bone–osteoid interface, and some patients receiving iron infusions
develop FGF23-mediated hypophosphatemic osteomalacia.
• Drug-induced osteomalacia has rarely been reported with the use of
etidronate and sodium fluoride, usually in high doses and over long
periods, but no currently approved second-generation nitrogen-containing
bisphosphonates have been reported to cause osteomalacia.
• In addition, etidronate is used in high doses (up to 20 mg/kg per day) to treat
rare bone and mineral disorders such as fibrous dysplasia, heterotopic
ossification, and myositis ossificans with some success.
122. • Bone histologic features of drug-induced mineralization defects due to
aluminum, iron, etidronate, and sodium fluoride differ substantially
from the osteomalacia as defined earlier due to vitamin D and phosphate
deficiency.
• Defective bone mineralization due to aluminum overload, the
osteoid accumulation is generalized, as in vitamin D
deficiency and hypophosphatemic osteomalacia, but osteoid
thickness is not increased and may even be thinner.
• This type of bone histologic abnormality is designated as atypical
osteomalacia.
123. • Bone turnover is extremely low, staining for aluminum is
positive at the osteoid-mineralized bone interface establishing the
diagnosis, and the bone lesion does not respond to vitamin D
therapy.
• Osteoid accumulation in etidronate- and sodium fluoride–
related osteomalacia is patchy with very thick osteoid
seams randomly distributed throughout bone (both on
bone surfaces and within the interstitial bone), which is
designated as focal osteomalacia
124.
125.
126. Conditions That Resemble Rickets and
Osteomalacia
• Pathogenesis of many of these rare bone disorders is currently poorly
understood.
• The mechanism for the development of radiologic abnormalities and
mineralization defect is different from that of classical rickets and osteomalacia.
• The abnormalities are either due to the effects of PTH excess on bone or to the
defects in bone collagen matrix structure that does not mineralize normally.
• In children with primary hyperparathyroidism, metaphyseal abnormalities
resemble rickets or a child might have rickets due to both vitamin D deficiency
and masked primary hyperparathyroidism.
• The radiologic abnormalities respond to parathyroidectomy.
127. • In severe 2°HPT in children with end-stage renal disease, both “rickets” and
“osteomalacia” have been noted.
• Any condition that increases bone remodeling inevitably increases the extent of
osteoid surface (usually <50% of the bone surface) and by extension osteoid
volume (usually >3–5% of bone volume), but osteoid thickness, the hallmark
of mineralization defect in traditional osteomalacia, is always normal (<12
μm).
• Some have used the term hyperosteoidosis to describe this type of histologic
abnormality, which is seen in conditions associated with increased bone
remodeling, such as renal osteodystrophy, hyperthyroidism,
primary hyperparathyroidism, and osteitis deformans (Paget
disease of bone)
• However, the use of such a descriptive term as hyperosteoidosis does not serve
any useful purpose
128. • In certain very rare disorders, such as fibrogenesis imperfecta ossium and
axial osteomalacia, various degrees of defective mineralization are seen, but
they are due to abnormal collagen structure.
• Hypophosphatasia is now reasonably well characterized, and enzyme
replacement therapy with asfotase alfa was recently approved for childhood
onset of the disease.
• It is due to “loss of function” mutations in the gene that codes for the tissue
nonspecific alkaline phosphatase.
• It is an autosomally inherited disorder with more than 300 different
gene defects reported so far.
• Although radiologic and bone histologic findings may resemble rickets and
osteomalacia, the condition is easily distinguished by the low serum alkaline
phosphatase levels (<40 IU/L).
129.
130. Concluding Remarks
• Rickets and osteomalacia are a group of disorders due to varied pathogenic
mechanisms, but they all respond to administration of vitamin D, calcium, or
phosphate supplements, removal of a tumor producing ectopic FGF23, or
administration of an antibody to FGF23.
• The resolution of clinical, biochemical, radiologic, and bone histologic
abnormalities is usually complete in most cases, but lifelong therapy is needed
in some forms of rickets and osteomalacia.
• In nutritional rickets and osteomalacia, 2°HPT may persist for months or
years despite clinical improvement and confers an increased fracture risk due
to irreversible cortical bone loss that has already occurred by the time of
diagnosis.
131. • In a few patients, particularly those with hypophosphatemic
rickets and osteomalacia, long-term oral phosphate therapy leads
to hypercalcemic 2°HPT (or tertiary hyperparathyroidism)
requiring parathyroidectomy.
• In most patients, the clinical response is excellent and gratifying,
both to the patients and caring physicians.
• However, one must not lose sight of the fact that genetic rickets
and osteomalacia, as well as TIOs, require lifelong follow-up for
the development of therapy related complications or malignant
transformation of the tumors causingTIO.
