Rickets Mankin1

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Review Article, Rickets, Osteomalacia, and Renal Osteodystrophy:

PART 1
HENRY J. MANKIN
J. Bone Joint Surg. Am. 56:101-128, 1974.
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Review Article
Rickets, Osteomalacia, and

Renal Osteody strophy
PART 1*
BY HENRY J. MANKIN, M.D.t, BOSTON, MASSACHUSETTS
Rickets and osteomalacia are syndromes of diverse etiology, characterized

pathophysiologically by a failure of normal mineralization of bone and epiphyseal cartilage
and clinically by skeletal deformity. Rickets, the more obvious of the two syndromes,
occurs in growing children and both bone and epiphyseal cartilage are affected. Regardless
of specific etiology, the rachitic syndromes present a highdegree of stereotypy and, when
florid, result in striking dwarfism and characteristic osseous deformities. Osteomalacia
occurs in individuals in whom growth in height has ceased, so that the manifestations are
often far less marked and the diagnosis is more difficult than with rickets,
Rickets and osteomalacia have many extraordinary and fascinating features.
Historically, they were among the earliest clinical syndromes to be defined, and the saga of
the search for vitamin D is one ofthe most exciting stories in medicine. Rickets is of interest
to ecologists, since it is probably the first disease which could be classified as resulting from
air pollution and to anthropologists, who have postulated that the effect of ultraviolet
light on vitamin D metabolism in the skin was an important factor in the development of
races with pigmented and non-pigmented skin and in their geographical distribution
The diseases are of interest to physiologists, since they are examples of a deficiency of a
single element, and to biochemists, because recent data on vitamin D metabolism not only
explain the rachitic syndromes, but may uncover many of the mysteries of the calcium
regulatory mechanisms. It is, however, for the pediatricians, internists, and orthopaedists
that rickets and osteomalacia hold the greatest interest. The differential etiological
diagnosis is perhaps one of the most complicated puzzles in medicine, requiring, for
solution, clinical acumen and special roentgenographic, biochemical, and metabolic
techniques. Once solved, however, the puzzle holds as its reward the fact that many of the
patients may be cured or materially aided by proper treatment.
History
In 1645, Daniel Whistler 227 wrote a treatise in Latin in which he described the
‘ ‘English disease, commonly known as rickets. ‘ ‘ The word rickets is believed to be a
corruption of any one of the following terms: wrick (Old English for twist); wiggates
(crooked gait); riquets (Norman for hunchback); or rachitis (deformity of the spine) 70#{149}
According to Bick, the disease was described by Soranus of Ephesus 202 the first century
in
AD. and by Girolamo Fabrizio d’Aquapendente #{176} in the sixteenth century, but neither of
these authors separated it from other types of skeletal deformities. In 1650, Francis
Glisson 83, Professor of Physic at the University of London and President of the Royal
College ofPhysicians, wrote the classic text on the subject, and his book is still unsurpassed
as a clinical description ofthe disease.
The first description ofthe histological changes in rickets and osteomalacia, published
by Pommer in 1885, fully defined the changes in the epiphyseal plate and cortical and
* Reprinted in part from the Cyclopedia of Medicine, Surgery, Specialties. Philadelphia, F. A. Davis Co.,
1973. (Permission obtained from the author, editor, and publisher for reproduction of portions of the text and
illustrations.)
t Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02 1 14.
VOL. 56-A, NO. I, JANUARY 1974 101

102 H. J. MANKIN
medullary bone. At the turn of the century, a number of investigators called attention to the
prevalence of rickets in children who lived in the crowded, dimly lit alleys of the cities of
Northern Europe 66, and in 1908 Findlay 67 was able to reproduce the disease in puppies
raised in a confined, darkened space. Several years later, Hutchison and Shah “ noted the
increased prevalence of the disorder in India in castes which practiced purdah, and in 1909
Schmorl 187 established the striking seasonal variation of the disease by autopsy findings.
Over 80 per cent of children dying of other causes during the winter had evidence of active
rickets, while less than 50 per cent of those who died during the summer showed these
findings. In 1919, Huldschinsky “ reversed the clinical changes in four children with
rickets by treatment with artificial ultraviolet irradiation from a mercury quartz vapor lamp,
and the role of sunlight in the prevention ofrickets was firmly established.
As the sunlight theory developed, other investigators became interested in dietary and
nutritional factors. In 1917, Hess and Unger 101 described the prevention of rickets in
children in New York City by administration of cod liver oil or by ultraviolet irradiation of
food. These findings stimulated Mellanby a British chemist, to search for the so-called
anti-rachitogenic factor. He established the fact that it was a fat-soluble sterol, but thought
at first that it was vitamin A. Around 1922, McCollum and co-workers 142.143 and
Shipley and associates 190 isolated the first ofthe vitamin D’s, and subsequently a number of
investigators established the various members of the vitamin D family and the relationship
of 7-dehydrocholesterol to calciferol 206.230, By the end of the 1920’s rickets and os-
teomalacia were considered to be deficiency diseases, and at least in theory were entirely
curable and preventable by the addition of vitamin D to the diet 100,172
It soon became apparent, however, that there were rachitic and osteomalacic patients
in whom the disease was resistant even to massive doses ofthe specific sterol. Albright and
co-workers 2 described three such patients in 1937, thus establishing a clinical entity which
they named “rickets resistant to vitamin D,’ and postulated that the resistance
‘ was due to a
chemical lesion in the renal tubule. Soon thereafter, Fanconi , Debr#{233}
and associates j”,
De Toni Lightwood and Wood 135, and Butler and co-workers D reported other types of
renal tubular syndromes which presented as hypophosphatemic rickets; these entities were
further characterized and classified by Dent Dent and Harris 52, and others 74.76,114.
183,199 In 1958, Winters and co-workers 231 clearly defined one form of hypophosphatemic
vitamin D-resistant rickets as a sex-linked dominant genetic error, establishing the heredi-
tary nature of the disorder.
Histological, metabolic, and biochemical studies of the affected skeletal system,
performed by Park 172,174 Dodds and Cameron 5558, Follis 68, Follis and Jackson 69, and
others 1,82,88,89 defined the pathogenesis of the deformities. The clinical and laboratory
investigations of Dent 50,51, Dent and Harris 52, Harrison and Harrison Howland
and Kramer Albright
‘ ‘#{176}, and co-workers 2,4,5 Stanbury and Lumb 205, Lightwood and
co-authors 134,136 and many others provided biochemical and metabolic data which
delineated the mechanism of development of the abnormalities of calcium and phosphorus
metabolism which characterize the disease.
The research of the last decade was dominated by two discoveries: the action of
vitamin D as a moderator of ribonucleic acid metabolism for the synthesis of a calcium-
binding protein 79.150.213.214, and the role of the liver and kidney in the activation of
exogenous and endogenous vitamin D to form metabolites of vitamin D and other active
sterols with enormous anti-rachitogenic properties ‘ 7,46,47#{149}
Calcium and Phosphorus Metabolism and Vitamin D

The metabolism of calcium and phosphate and the relationship of these materials to
normal skeletal mineralization are complex, and it is beyond the scope of this review to
discuss them in detail. The interested reader is referred to several excellent recently
published review articles ‘ 7,28.47,70,93.95.103.1 17,153,155.167,181 ,2o7.228 For this discussion,
THE JOURNAL OF BONE AND JOINT SURGERY

RICKETS, OSTEOMALACIA, AND RENAL OSTEODYSTROPHY 103
however, it is essential to establish several important points regarding the metabolism of

calcium and phosphate, particularly as related to the action of vitamin D.
The total calcium content in the body is estimated to be slightly more than one
kilogram 71.155 Ofthis, about one gram is in the plasma and extracellular fluid, while most
of the remainder is in the skeleton 228 The plasma contains approximately 0.3 gram of
calcium, and of this fraction about 65 per cent is ionized the remainder being mostly
complexed to protein (albumin) The total content of phosphate in the body is about 500
to 600 grams, and compared to calcium a larger fraction of this ubiquitous material is in the
soft tissues at the pH of body fluids 71.155, The ionized fraction in the blood stream is in the
form of HPO4 and H2PO4 (3.55 to 1) and constitutes an important buffer system for
acid-base regulation ‘#{176}“.
The metabolism of these two elements is dependent on two important factors, one
chemical and one physiological. Calcium phosphate is relatively insoluble at the pH of body
fluids, and must either be present in a concentration below that of the critical solubility
product of CaHPO4 or be held in solution in a supersaturated state by inhibitory materials or
membrane binding. A second factor of equal importance is the exquisite sensitivity of
muscle and nerve irritability and conductivity to the concentration of ionic calcium in the
intracellular and extracellular fluids 28 Since the calcium and phosphate content of the diet
may vary considerably, and since accretion, resorption, and exchange of mineral from the
bone may show vast fluctuations under normal conditions and in disease, there is an
elaborate series of homeostatic mechanisms controlling intestinal absorption, membrane
transfer, and renal excretion of these critical elements. These mechanisms carefully
guard the concentration of calcium and phosphate in plasma and extracellular fluid, and are
critical to the health of the individual and the integrity of the skeletal system.
The plasma levels of calcium are maintained at concentrations of 8.8 to 10.8 mil-
ligrams per 100 milliliters (4.4 to 5.4 milliequivalents per liter) and those of inorganic
phosphate range from 3.0 to 4.5 milligrams per 100 milliliters (1 .7 to 2.6 miiliequivaients
per liter) in adults, with somewhat higher values recorded for children 64,86,117,125.228 A
large fraction of the calcium, as already noted, is complexed to protein or is
non-ionized 117,124 Walser 221 demonstrated that the concentration of calcium which is
diffusible across the glomerular membrane is 1 .62 X i03M, and that of this, all but 7 per
cent is in the ionized form.
The absorption of calcium from the gut is not a passive process and, as will be
discussed subsequently, is dependent on vitamin D, parathormone, and, to a lesser extent,
calcitonin. Dietary intake varies considerably, but most individuals with a balanced diet
ingest between 0.6 and one gram ofcalcium per day 16,70,163 Absorption occurs best in the
proximal portion of the gastrointestinal tract, principally the lower duodenum and upper
jejunum, but may occur, to a limited extent, below this level 16,154,225 The net absorption
in the average adult who ingests one gram ofcalcium per day is about 200 to 250 milligrams,
with the remainder lost in the feces 16,155 A number of factors may modify the absorption of
calcium from the gastrointestinal tract 154,201 , An acid pH will favor absorption by
increasing the solubility of calcium salts, and, conversely, an alkaline pH diminishes the
absorptive capacity ‘#{176}. Calcium may be complexed, chelated, or precipitated by a variety
ofmaterials in the diet, rendering it unavailable forabsorption 16,201#{149}These include phytate,
oxalate, citrate, and excessive amounts of phosphate 7,16,31,148,155,229 The presence of bile
salts enhances calcium absorption by emulsifying ingested fat, thus decreasing the loss of
the fat-soluble vitamin D and diminishing the formation of insoluble calcium-fatty acid
soaps which render the calcium non-absorbable 15,218 Rapid motility or shortening of
the length of the small bowel may diminish absorption, and diseases of the intestinal
wall, such as sprue, tuberculosis, ileitis, and so forth, may cause major interference with
absorptive processes 149,165
The daily intake ofphosphate is on the order oftwo grams, and about two-thirds of this
VOL. 56-A, NO. 1, JANUARY 1974

104 H. J. MANKIN
is absorbed, usually from the lower portion of the small intestine 70,154,155.163, High
concentrations in the diet of calcium 12, aluminum 70,155, or beryllium salts 116,154,193,200
diminish absorption of this element by formation of insoluble salts.

Excretion of calcium and phosphate is principally mediated through the kidney. A
small portion of the absorbed calcium is excreted by the colon 154 and it has been shown
that during starvation or vitamin D deficiency the fecal excretion of calcium may exceed the
dietary intake. Excretion in the feces is not considered to be an important mechanism in
homeostasis except in conditions of severe renal disease 128,205 Renal excretion of calcium
under normal conditions varies considerably with the individual, the diet, and a variety of
factors related to bone metabolism 130 The level ofexcretion under ordinary circumstances
is less than 400 milligrams per day in adults and generally 4 to 6 milligrams per kilogram of
body weight in children 64,70,155 Values outside these ranges are indicative of abnormalities
in calcium balance, but are less significant ifdietary intake is not carefully controlled over
several days prior to the determinations. Urinary excretion of phosphate may also vary
considerably. The normal range for adults is 340 to 1 ,000 milligrams per day, while that for
children is 530 to 840 milligrams . These values reflect dietary intake even more than
those for calcium, and for proper evaluation metabolic studies of intake, output, serum
levels, and renal reabsorptive rates are required.
The renal mechanism for handling calcium closely parallels, and is in some way linked
to, that for handling sodium 222, The diffusible (ionized and non-ionized) calcium goes
through the glomerulus and is then reabsorbed in both the proximal and distal tubules with
high efficiency 130, The reabsorptive rate for calcium in the tubule recently has been shown
to be dependent on the action of vitamin D and parathormone 84 Although it has been
suggested that there is tubular secretion and a maximum reabsorptive rate for calcium, there
is little evidence that these factors are active under physiological conditions, since normally
over 95 per cent of the filtered calcium is reabsorbed 130 High concentrations of sodium in
the urine diminish calcium reabsorption 222, as do several of the tubular poisons. Parathor-
mone and certain diuretics increase the reabsorptive rate 70.84,
The renal mechanisms for the regulation of phosphate are considerably more compli-
cated than those for calcium 6,70,157,217 Since all ofthe inorganic phosphate is in the ionized
state, the concentration in the glomerular filtrate is equivalent to that of the serum, but over
90 per cent of the phosphate is reabsorbed in the proximal tubule. The rate of tubular
reabsorption is considerably influenced by parathormone 22,95,157.181.217 vitamin D, and
calcitonin 95,153,181 , There is an upper limit to the amount of phosphate that the tubules can
reabsorb (TmP); this has been estimated to be 2 to 6 milligrams per minute Secretion
6.53#{149} of
phosphate by the tubules has been postulated, but if there is such secretory activity, it is
probably not operative at normal serum levels 223, The reabsorptive capacity of the kidney
for phosphate, unlike that for calcium, is very sensitive to endogenous and exogenous
factors. Reabsorption may be significantly diminished by parathormone, 1 1-oxysteroids,
estrogens, deficiency or massive excess of vitamin D, a rise in plasma bicarbonate,
acidosis, and a variety of medications 10,11,70,93,95.154,157,162,167.207,214
The internal metabolism of calcium and phosphate is controlled by parathormone,

calcitonin, and vitamin D, all of which act to maintain concentrations of ionized calcium
and phosphate at levels that are consistent with normal muscle and nerve function and that
do not exceed the solubility product of 11347181 , Parathormone induces a
phosphate diuresis by decreasing the reabsorption ofphosphate, and mobilizes calcium and
phosphate directly from bone 3,27,70,95,181,221 As will be discussed, this hormone also plays
a role in the transport of calcium across the gut wall, in the exchange of mineral between the
bone crystal and the extracellular fluid, and in the reabsorption of calcium by the renal
tubules. Calcitonin, on the other hand, inhibits bone resorption and possibly favors bone
formation, thus lowering serum levels of calcium and phosphate 153,181, The rate of
elaboration of both of these hormones appears to be responsive to the level of ionized
THE JOURNAL OF BONE AND JOINT SURGERY.

calcium in the serum and to be regulated by negative feedback systems. Hypocalcemia

results in elaboration of parathyroid hormone, which in turn increases the serum calcium
level by mobilizing bone calcium, increasing absorption of calcium in the gut, and
increasing reabsorption by the renal tubules. In addition, the hormone acts to diminish
serum inorganic phosphate levels by altering tubular reabsorption of phosphate 1,11,181
Hypercalcemia, on the other hand, causes elaboration of calcitonin, which lowers calcium
by diminishing bone resorption 11,49.181 and possibly by decreasing absorption ofcaicium in
the gut 16,
The two principal vitamin D’s are calciferol (D2) and cholecalciferol (D3). (Vitamin
D1, the original material prepared by Askew and Windaus in 1932, was later found to be a
mixture of sterols and the name was dropped 70,) Both calciferol and cholecalciferol are
fat-soluble sterols similar in structure to cholesterol, and both have high anti-rachitogenic
potency 17,47.71.104 Vitamin D2, the major dietary source of vitamin D, is produced by
ultraviolet irradiation of ergosterol. Vitamin D3, which is formed in the body, is produced
by the action of ultraviolet light on 7-dehydrocholesterol, a substance synthesized by the
body and deposited in the skin in concentrations of approximately 3 2 micrograms per gram .
ofskin The precursors,
184, ergosterol and 7-dehydrocholesterol, have no anti-rachitogenic
properties, but radiant energy, in the wavelengths between 230 and 3 13 nanometers, slowly
breaks their ring structure and the bond between C9 and ClO atoms to convert the sterols to
their active forms (Fig. 1) 17.47,70,104
Cu3 3.cHcH_...c<CH3
CH3
iii’: Rcd/clien
ERGOSTEROL VITAMIN
(colclferol)
1/. V. Rod/ut/en
7- DEHYDROCHOLESTEROL VITAMIN D3
(choiscolclferol)
FIG. 1
The inactive sterols ergosterol and 7-dehydrocholesterol are converted to the active forms calciferol (vitamin
D2) and cholecalciferol (vitamin D3) by the action of ultraviolet light (230 to 313 nanometers). Radiant energy
opens the ring structure between C9 and ClO. (Reprinted by permission from Cyclopedia of Medicine, Surgery,
Specialities. Philadelphia, F. A. Davis Co. , 1973.)
Ingested vitamin D is absorbed in the upper two-thirds of the intestine and thence goes
into the lymphatics. This process is materially aided by the presence of bile salts 115,219,
Hence, patients with biliary, pancreatic, and cardiac disease often have a greatly diminished
absorption of the sterol. Once activated, both the ingested and the endogenous sterols are
bound in the plasma to a specific globulin fraction oflow molecular weight 17,115,175 In this
bound form they undergo two important metabolic conversions: one in the liver, the other in
the kidneys.
Recognition of the first conversion began in 1966, when Lund and DeLuca “
demonstrated the presence of a highly active polar metabolite of vitamin D3, which was
subsequently isolated and identified as 25-hydroxycholecaiciferol and then was
extensively studied 19,2426, The conversion of vitamin D3 to this more active substance is
VOL. 56-A, NO. I, JANUARY 1974

106 H. J. MANKIN
known to occur in the liver and to require reduced pyridine nucleotide and molecular
oxygen. After conversion, the resulting 25-hydroxycholecalciferol is bound to a globulin
indistinguishable from that to which vitamin D3 is bound.
Another polar metabolite, 25-hydroxyergocalciferol, described by Suda and
co-workers 212 in 1969, was subsequently shown to be the biologically active form of
vitamin D2, also formed by conversion in the liver (Fig. 2). For ease ofexpression, it has
been recommended 178 that 25 hydroxycholecalciferol and 25 hydroxyergocalciferol be
referred to as the 25-hydroxy vitamin D’s, and that in the description of all subsequent
metabolic conversions only the term “vitamin D” be used. This recommendation will be
followed in the rest of this review.
Both 25-hydroxy vitamin D’s are several times more active than vitamin D3 and
vitamin D2 in their effect on calcium absorption from the gut. However, as shown by later
studies, these materials are not the final biologically active substance, since a second
conversion occurs in the kidneys 72.168,179 as follows: The 25-hydroxy vitamin D’s are
further hydroxylated in the kidney eitherto a highly active form, 1 ,25-dihydroxy vitamin D,
or to an inactive form, 24,25-dihydroxy vitamin D, by a mitochondrial system similar to the
one present in the liver. This process is under the differential influence of parathor-
mone 48,73,156,182,188 and calcitonin 80,156 and is also sensitive to the level ofcalcium ion in
the serum 29.188 (Fig. 2). The prevailing concept ofthis control mechanism is that lowering
of the serum calcium and the resultant elaboration of parathormone favor the production of
the active 1 ,25-dihydroxy vitamin D 29,48,73,168 while an elevated calcium ion
concentration and the resultant release of calcitonin suppress this reaction and cause the
formation of the inactive form, 24,25-dihydroxy vitamin D 29,80 The metabolic fate of
these two substances is as yet unknown 77.107.108 It is, however, reasonably clear that the
active form is responsible for the absorption of calcium by the gut cells #{176},for the transfer of
calcium by bone cells from the crystal lattice to the extracellular fluid 105,179, and probably
for the reabsorption of calcium by the renal tubules after glomerular filtration 168
Currently under investigation are the actions and control mechanisms of other
metabolites, including 24,25-dihydroxy vitamin D; 21 ,25-dihydroxy vitamin D;
25,26-dihydroxy vitamin D; and 5,6-trans-25-hydroxy vitamin D 29,106,108
Ergosterol
1\
.. .
CV
.., Calciferol
(p2)
Liver 25(OH)vIt D
Cholesterol .- 7-Dehydrocholesterol . \, .\ .ChoIecalcIfero1

(03) i’
PT;/\\T
l,25(OH)2V1t.D 24,25(OH)2Vlt.O
Gut
fl\ Bone Kidney
CalcIum Transport
FIG. 2
Diagram depicting current knowledge of the metabolism and action of vitamin D. Ergosterol, derived from
exogenous sources, and 7-dehydrocholesterol, synthesized endogenously from cholesterol, are stored in the skin.
These inactive sterols are converted to calciferol and cholecalciferol by ultraviolet light and then undergo a
metabolic conversion in the liver to 25-hydroxy vitamin D, a more active form. A second conversion of this
material to two other forms then occurs in the kidney. In the presence of parathormone (which is elaborated in
response to hvpocalcemia), the 25-hydroxy vitamin D is converted to 1 ,25-dihydroxy vitamin D, which is highly
active in increasing the absorption ofcalcium across the gut wall, the mobilization ofcalcium from bone, and the
reabsorption of calcium by the renal tubule. Under the influence of calcitonin (which is elaborated in response to
hypercalcemia), on the other hand, 24,25-dihydroxy vitamin D, a far less active metabolite, is produced, the
formation of the more active form being suppressed.

Until recently, the action ofvitamin D at the molecular level was poorly understood ‘.
Early experiments demonstrated that the sterols are necessary for the transport of calcium
across the gut wall and that the materials exert some direct resorptive effect on
bone 13,45,96,112 Their action on the kidney, however, was less obvious, and it was
postulated that, at least in normal doses, the renal effects are secondary. Several studies,
chiefly those by Wasserman and associates 213,214 and by DeLuca 46 have now defined a
probable role for 1 ,25-dihydroxy vitamin D as a hormone and, indeed, the principal
hormone acting in the gut and possibly the bone cells. This sterol appears to serve as a
regulator of messenger ribonucleic acid synthesis for the passage of genetic information to
the ribosomes of the gut and bone cells 97,188,211,233 At the ribosomes, the message causes
the cells to assemble a calcium-binding protein 59,79,145,213 which, when activated in
some unknown manner by parathormone 9,17,48 is capable of carrying the calcium across
the cell membrane to the extracellular fluid 28,90,167 The vitamin, acting again in
conjunction with parathormone, also depletes mitochondrial stores ofcalcium in the same
cells 9,90,167 and stimulates the production of a brush-border alkaline phosphatase and a
calcium-dependent phosphatase 17,168, These actions apparently are part of the work
required to transport calcium ion against an electropotential gradient. Thus, I ,25-dihydroxy
vitamin D is responsible for directing and regulating the rate at which calcium traverses the
gut and bone cells
#{176} 13,47,181 and probably the renal tubular cells as well.
It is evident from the foregoing discussion that the mysteries surrounding the calcium
and phosphate homeostatic mechanisms have in large measure been unlocked by the
investigations ofthe last few years. The level ofcalcium in the serum is carefully controlled
by a complicated series of feedback mechanisms involving parathormone and calcitonin,
but principally by the production ofa highly potent sterol hormone, 1 ,25-dihydroxy vitamin
D, which, by its action in controlling synthesis of calcium-binding protein, mediates the
transport ofcalcium ion into and out ofthe extracellular and plasma spaces. The serum level
ofphosphate in part is controlled indirectly by the action ofparathormone and vitamin D on
bone, but in large measure by the exquisite sensitivity to parathormone of the renal tubular
mechanism for the resorption of phosphate. The three hormones, 25-dihydroxy vitamin D,
parathormone, and calcitonin, therefore act together to maintain the levels of calcium and
phosphate within the narrow range required for normal function of the neuromuscular
system and at concentrations below the critical solubility product of CaHPO4.
TABLE I
MINIMUM DAILY REQUIREMENTS FOR CALCIUM, PHOSPHATE, AND VITAMIN D
Adults Children
Calcium 400-500 mg 400 to 700 mg

Phosphate 1000-1500 mg 1000-4500 mg
Vitamin D 1.5-10 !.Lg 10 /-Lg
(100-400 I.U.) (400 lU.)
In addition to the endogenous hormones described above, it is apparent that there are
three exogenous contributions to the system: calcium, phosphate, and vitamin D. The
normal daily requirements for each of these materials are given in Table I 22,70,104,163 It
should be noted, however, that there is not universal agreement on any of these
requirements, particularly in the case of vitamin D, where figures previously published
were considered by some to be in the toxic range for infants.
VOL. 56-A, NO. 1 , JANUARY 1974

108 H. J. MANKIN
Pathophysiolojr of Rickets and Osteomalacia

Regardless ofthe specific etiology, the basic pathophysiological abnormality in all the
rachitic and osteomalacic syndromes is a diminution of the level of calcium, phosphate, or
both, in the plasma and extracellular fluid,
The Metabolic Abnormality (Hypovitaminosis D - The Prototype)
Vitamin D deficiency produces the simplest and most specific form of rickets and
osteomalacia, and in this lesion the metabolic abnormality is most clearly defined. In the
absence of an adequate intake of vitamin D or failure of sunlight to convert the
7-dehydrocholesterol in the skin to calciferol, insufficient 1 ,25-dihydroxy vitamin D is
produced 155,170 with the result that there is diminished absorption of calcium across the
intestinal barrier and decreased transport ofcalcium in (and out) ofthe bone. Ofthe ingested
calcium, only a small amount is absorbed and the rest is excreted in the feces. The body pool
ofcalcium contracts 98185, and the patient becomes hypocalcemic and hypocalciuric.
When hypocalcemia reaches a significant level, a negative feedback response causes
hyperplasia ofthe parathyroid glands 21,88 and elaboration ofparathormone in excess 1.8.14,
This hormone increases the serum levels of calcium by direct and indirect mobilization of
calcium (and phosphate) from the bone 10, by increasing the absorption of calcium in the
gut, and by increasing the reabsorption of calcium in the renal tubules. In addition,
parathormone acts on the renal tubules to reduce reabsorption of phosphate, thus causing a
phosphaturia 8,10.75 which, if sustained, results in hypophosphatemia. Bone resorption is
excessive 12, but bone formation is also increased 12 in an abortive attempt at compensation.
The pattern seen in the bone therefore is one of markedly increased resorption and
formation, but over-all there is a state of negative balance, with insufficient calcium and
phosphate available for the mineralization of the newly formed bone 78,91.98,185
Epiphyseal Plate Abnormalities
Immature individuals who become rachitic have characteristic histological,

biochemical, and metabolic changes in the epiphyseal cartilage. The histological lesions
were defined by the investigations of Pommer Von Recklinghausen 220 Park 172,174
and Dodds and Cameron 5558 and are virtually pathognomonic.
The normal epiphyseal plate has five zones 146, The resting zone, adjacent to the
epiphyseal nucleus, is composed ofcartilage in which the cells are sparse, small, rounded,
and randomly dispersed. On the metaphyseal side of this zone is the proliferative zone,
where the cells are regular, flattened, and arranged in columns. This zone is the site of
mitotic activity and length growth of the epiphyseal plate. Below this level lies the region
called the maturation zone, where the cells, still in columns, become increasingly large and
more rounded. These cells stain less densely and contain large amounts ofglycogen. At the
lowest part of this zone, often called the zone ofhypertrophy, the cell lacunae become very
large, but the cell nuclei are shrunken and appear faded when stained with hematoxylin and
eosin. In this region, vascular buds grow in from the metaphysis, appearing to enter the
empty lacunae at the base of the columns, while the bars of cartilage matrix between the
columns become heavily calcified. This entire region is called the zone of provisional
calcification. Lower in the metaphysis, the calcified cartilage bars become surrounded by
osteoblasts, which produce a seam of calcified osteoid around the still present calcified
cartilage bars. This region is called thezone ofprimary spongiosa (Fig. 3-A).
The alterations in this pattern in rickets are highly characteristic. The resting and
proliferative zones have essentially normal histological features and are indistinguishable
from those in the non-rachitic plate 55,56, The columns of cells in the zone of maturation,
however, are greatly elongated, increasing the axial height of the cartilaginous
plate 55,56,174 The cells are closely packed and irregularly distributed, so that the normal
columnar pattern is often unrecognizable. At the base ofthis zone, the hypertrophic cells are
ThE JOURNAL OF BONE AND JOINT SURGERY

FIG. 3-A FIG. 3-B FIG. 3-C
5. 1’
. .
.
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.s-. ‘S
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FIG. 3-D
Figs. 3-A through 3-D: Photomicrographs depicting changes in the epiphyseal plate in rickets. (Reprinted by
permission from Cyclopedia of Medicine, Surgery, Specialties. Philadelphia, F. A. Davis Co. , 1973).
Fig. 3-A: Normal epiphyseal plate of an immature rat (x 400).
Fig. 3-B: After six weeks on a diet deficient in phosphate and vitamin D. Note enormous increase in the axial
height of the cartilage mass, due primarily to an increased number of cells in the maturation zone. The normal
orderly columns are replaced by a disordered profusion of cells in irregular rows ( X 400).
Fig. 3-C: Under high power, the cells ofthe maturation zone in the rachitic rat are seen to resemble the cells of
the normal maturation zone ( X 900).
Fig. 3-D: Proximal epiphyseal plate of the humerus of an infant who died with florid rickets. Note marked
increase in the axial height of the plate, poorly developed zone of provisional calcification, and long tongues of
cartilage projecting into the metaphyseal bone (x 40).
VOL. 56-A, NO. I, JANUARY 1974

110 H. J. MANKIN
sparse in number and irregular in distribution, and the intervening matrix bars cannot be
identified. The zone of vascular invasion and provisional calcification is grossly disordered
and highly irregular. In many cases, this elongated maturation zone extends as irregular
tongues of cartilage far into the metaphysis (Figs. 3-B, 3-C, and 3-D). The enormous
profusion ofcartilage cells in the rachitic maturation zone not only increases the axial height
of the plate but also appears to extend beyond the normal width of the bone, producing an
irregular increase in transverse diameter This increased width of the plate produces
the palpable enlargement of the bone or rib ends characteristic of rickets and referred to as
“cupping” or ‘flaring”
‘ ofthe epiphyseal-metaphyseal area.
The causes of the changes in the epiphyseal plate are difficult to understand. The
etiology ofthe increase in the length ofthe maturation zone and the ‘ ‘cupping’ ‘ is especially
obscure. There are, however, logical mechanical explanations for these two phenomena
which, although not corroborated biochemically, may well be valid. In the normal
epiphyseal plate, vascular buds from the metaphysis grow into rigid tunnels of calcified
cartilage matrix surrounding the empty lacunae ofthe lower-most cells ofthe columns. The
metaphyseal face of the epiphyseal plate, viewed on end, therefore has a honey-comb
pattern (Fig. 4). The orderly ingrowth ofvessels appears to destroy the basilar cartilage cells
and intervening cartilage plates, thus serving as the normal mechanism which limits the
length of the cartilage columns. In rickets, the walls of the tunnels do not develop, since
calcium is not available for mineralization. Therefore, the delicate vascular buds are not
directed into the tunnels, and the normal mechanism limiting the length of the column is
lost. Proliferation continues essentially at the same rate as in normal plates, but degradation
is markedly diminished because ofthe inability ofthe vascular buds to invade (Fig. 4).
): . #{149}
FIG. 4
Diagram ofpostulated mechanism causing increased length ofthe columns ofcartilage in rickets. In the normal
epiphyseal plate (A), the calcified zone (shaded area) provides tunnels for the ingrowth ofdelicate vascular buds
which continue to destroy the last cells of the hypertrophic zone, thereby limiting the growth in length of the
column. In the rachitic epiphyseal plate (B), the calcium-deficient calcified zone does not provide tunnels, and the
normal vascular mechanism limiting the growth in length ofthe columns is lost (see text).
The second obscure characteristic of the epiphyseal area in rickets is cupping. In the
normal epiphyseal-metaphyseal junction, proliferation and growth of the cells of the
epiphyseal plate produce a force against the metaphysis analogous to that between a rigid
piston (the epiphysis) and a rigid cylinder (the metaphysis). The “piston’ is forced ‘ out of
the ‘ ‘cylinder’ rather like the piston of a steam engine,
‘ and growth in length occurs.
This model seems reasonable, since in the normal epiphyseal-metaphyseal region the

RICKETS, OSTEOMALACIA, AND RENAL OSTEODYSTROPHY ill
“piston” (cartilage) and the “cylinder” (the primary spongiosa) are rigid due to the
calcium salts deposited in the intercellular matrix. As long as the two structures remain rigid
while growth occurs, the “piston” is forced out of the “cylinder” and the epiphyseal
nucleus is pushed farther and farther away from the metaphysis along the long axis of the
bone, against the resistance of forces exerted by muscle pull, body weight, and so forth. In
the rachitic epiphyseal region, on the other hand, the piston and cylinder are softened to
varying degrees, so that they deform and collapse under the applied external forces and the
intrinsic growth force. As a result, the plate located between the large mass of softened
cartilage and the yielding metaphyseal bone becomes cupped (Fig. 5).
FIG. 5
Diagram showing a possible mechanism causing metaphyseal cupping. In the normal epiphyseal plate, growth
in length is produced by the force ofepiphyseal proliferation acting through the rigid zone ofcalcified cartilage and
the rigid ossified metaphysis (A). The arrangement is rather like a rigid piston and cylinder (B) (see text). In the
rachitic plate, the softened cartilage, metaphysis, and calcified zone collapse and spread as the result of distorted
growth pressure and external forces (Cand D).
In recent years, studies of the biochemistry and metabolism of the rachitic epiphyseal
plate have demonstrated significant abnormalities compared with the normal plate. Most of
these studies were performed on animals, but it is likely that similar abnormalities occur in
humans. The changes observed can be explained in part by the variations in calcium or
phosphate metabolism, but the genesis of some of the changes is obscure. Because of its
zonal structure, the metabolic activities in the normal epiphyseal plate are difficult to study
by standard chemical and metabolic techniques. Investigators have been forced to accept
over-all measurements as representative of all of the zones, or to attempt to utilize
complicated micro techniques. In studying the rachitic growth plate the problem posed by
the zones becomes even more complex, due to the profound alteration in the distribution of
cells and matrix in the rachitic plate which makes comparison of the data from the rachitic
plates with normal controls hazardous.
Despite these problems, investigators have managed to demonstrate a moderate
increase in the water content ‘#{176} and diminished concentrations of both protein and
proteoglycan 38,109 in the rachitic epiphyseal plate. The glycogen content, particularly in the

112 H. J. MANKIN
hypertrophic zone, has been shown to be reduced by both qualitative 68 and quantitative
methods 109 Synthesis of ribonucleic acid, protein, and polysaccharide, as determined by
autoradiographic studies using labeled precursors, is markedly diminished, particularly in
the cells of the maturation zone 60,146,191193 These changes suggest that the synthetic
apparatus in the maturation cells is badly impaired, possibly as a result ofsome alteration in
the quantity of enzymes synthesized or in the amount of energy produced. The rate of
deoxyribonucleic acid synthesis, on the other hand, has been shown to be almost
normal t46,191 in the rachitic epiphyseal plate, confirming earlier histological studies
The morphology of the proliferative zone, the site of deoxyribonucleic acid synthesis, is
altered minimally in rickets, suggesting that the metabolic aberration may spare the portion
of the plate which is responsible for length growth 60,
A number of studies ofthe enzymes in the rachitic plate have suggested that glycolysis
shifts from the aerobic to the anaerobic and hexose monophosphate shunt pathways 18.131,
The concentration of adenosine triphosphate is reduced 131, Ultrastructural studies of the

maturation cells show an “arrest” in the normal process ofmaturation, and the appearance
of large intracellular vacuoles and numerous mitochondria suggests that the cells are unable
to transport nutrients and products of synthesis effectively o The number of lysosomal
bodies is normal and a qualitative assessment of the lysosomal enzymes by histochemical
techniques shows little or no difference in these enzymes compared with those in normal
tissue 110,
These data suggest that the principle aberration in the rachitic epiphyseal plate is a
failure ofrespiratory processes, due primarily to a decrease in the production ofhigh energy
phosphate. Ribonucleic acid and protein synthesis are heavily dependent on high energy
bonds, both for energy to support cellular synthetic activities and for the formation of
precursors of polysaccharides, such as uridine diphosphate-glucuronic acid and uridine
diphosphate-galactosamine. The maturation cell, which appears to be affected by the
rachitic process selectively, suffers a virtual metabolic paralysis. The intriguing feature of
this abnormality is that it appears to attack the cells ofthe maturation zone selectively and to
spare those ofthe proliferative zone.
Bone Abnormalities
The gross, microscopic, and biochemical changes which occur in the bones of patients
with rickets or osteomalacia can be related more directly to the altered physiology. Grossly
the bones are smaller and lighter in weight than normal bone, and are deformed. When
analyzed, they are found to contain considerably less calcium and phosphate than normal.
Although recent evidence has suggested an abnormality in collagen cross-linking 19 it is
postulated that collagen is synthesized at a normal rate but that diminished levels of calcium
or phosphate, or both, decrease apatite crystal deposition in and on the collagen fibrils, so
that the volume of mineralized bone is decreased without significant decline in
osteoid 41,78,91
Other changes which occur are related to alterations in vitamin D and parathormone
metabolism 41 The diminished level of 1 ,25-dihydroxy vitamin D probably decreases the
exchange of calcium between bone and extracellular fluid, an effect which in theory would
favor retention of mineral within the skeleton 168 The chronic hypocalcemia, however,
causes an increase in circulating parathormone, parathyroid hyperplasia, and secondary
hyperparathyroidism, which increase bone destruction and decrease renal tubular
reabsorption of phosphate. Thus, findings of a mild to moderate osteitis fibrosa may be
superimposed on the histological changes of osteomalacia in long-standing rachitic or
osteomalacic syndromes.
These chemical abnormalities are clearly reflected by the histological picture.
Microscopic examination shows that both the cortical and the medullary bone are affected
by the osteomalacic process. The cortex shows increased porosity and diminished density as

FIG. 6-A FIG. 6-B

Figs. 6-A through 6-H: Roentgenographic changes in rachitic and osteomalacic syndromes. The osseous altera-
lions are decreased density, irregular cortical margins, coarse and fuzzy trabeculation, and pseudofractures. The
changes in the epiphyseal line include increased axial height of the cartilaginous portion of the plate, cupping or
flaring, and a poorly defined calcified zone. The roentgenographic alterations are similar regardless ofthe etiology
ofthe rachitic process, as shown by Figures 6-A through 6-G.
Fig. 6-A: Vitamin D-deficient rickets.
Fig. 6-B: Renal osteodystrophy. (Reprinted by permission from Cyclopedia of Medicine, Surgery, Specialties.
Philadelphia, F. A. Davis Co. , 1973.)
FIG. 6-C FIG. 6-D

Fig. 6-C: Vitamin D-resistant rickets.
Fig. 6-D: Rickets with neurofibromatosis.
shown by microradiography 12,78,87,91 and this pattern is reflected histologically by thinned

cortices containing large channels and irregular Haversian systems 58,78,U8, Trabecular
bone is also thinned and appears more porous than normal, while the total number of
trabeculae is diminished. The trabeculae show a characteristic (but not pathognomonic)
feature, the presence of osteoid seams 12,78,118.1 19 (Fig. 7-A). These trabeculae are

114 H. J. MANKIN
__ I
FIG. 6-E FIG. 6-F
Fig. 6-E: Vitamin D-resistant rickets with glycosuria.
Fig. 6-F: Proximal Fanconi syndrome.
FIG. 6-G FIG. 6-H
Fig. 6-G: Cystine storage disease.

Fig. 6-H: Typical Looser’s lines (Milkman’s pseudofractures) in the rib cage of a patient with Debr#{233}-
Dc Toni-Fanconi rickets. (Figure provided by Dr. H. L. Jaffe.)
composed ofthin strips ofmineralized bone surrounded by a layerofunmineralized osteoid,

presumably synthesized by the cells in preparation for nucleation and mineralization.
However, because of the deficit of calcium and phosphate, mineralization of the osteoid
does not occur. Osteoid seams are a cardinal feature of the bone changes in osteomalacia
and are important both in the diagnosis and in the evaluation of treatment. The width and
number (total count) of the osteoid seams provide a good index of the severity of the
process 12,78,91,119,180 In addition to the osteoid seams, the bones of patients with
long-standing rachitic or osteomalacic syndromes, as already noted, show histological
evidence of secondary hyperparathyroidism. Osteoclastic resorption, formation of new
bone, marrow fibrosis, and occasionally small “brown tumors’ may be observed ‘78.M,l55,

RICKETS, OSTEOMA LACIA, AND RENAL OSTEODYSTROPHY 115
Osteoid seams are generally found in relation to a single trabecula of bone, but
occasionally in one or more bones there is a large segment of the cortex or medullary bone
which consists almost entirely of osteoid, with very little mineralization present 118,155
When this region is large enough, it produces a characteristic ribbon-like linear radiolu-
cency visible on the roentgenograms. Such lesions, called Looser’s lines, umbauzonen, or
Milkman’s pseudofractures, are virtually diagnostic of the osteomalacic syndrome 70,
118,140.151.152,210
FIG. 7-A
FIG. 7-B
Figs. 7-A and 7-B: Bone changes in adult osteomalacia. Histologically the trabeculae show poor mineralization,
wide osteoid seams, and increased numbers ofresorption cavities(Fig. 7-A). Roentgenographically these findings
are manifested by diffusely diminished density, coarse trabeculae, and thinned and irregular cortices. The pelvis
has become so ‘ ‘softened’ ‘ in this sixty-year-old woman with chronic gastrointestinal osteomalacia that there is a
mild protrusio acetabulae (Fig. 7-B).

116 H. J. MANKIN
Parathyroid Gland
As previously indicated, the chronic diminution in serum calcium in patients with

long-standing rickets and osteomalacia causes secondary changes in the function and often
in the structure of the parathyroid glands. In 1914, Erdheim 61 demonstrated parathyroid
hyperplasia in patients with osteomalacia, and there is now a well established, although not
fully understood, relationship between chronic rickets of almost any cause and hyperplasia
of the clear cells of one, several, or all of the parathyroid glands 1.14.21.88.89.155.170,196
(Figs. 8-A and 8-B). This finding is most marked in renal osteodystrophy 3,23,35,171,198,205
but may occur in absorptive, renal tubular, or vitamin D-deficient rickets and osteomalacia
as well 8,I4,21,32,62,88,118,155,196
[I a’ ‘.#{149} #{149}T’
I., l#{149} #{149}4
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FIG. 8-A FIG. 8-B

Figs. 8-A, 8-B, and 8-C: Secondary hyperparathyroidism in renal osteodystrophy. With long standing renal
failure, the chronic hypocalcemic state results in clear-cell hyperplasia of the parathyroid gland. (Figures 8-A and
8-B generously donated by Dr. H. Dorfman, and reproduced by permission from Cyclopedia of Medicine,
Surgery, Specialties. Philadelphia, F. A. Davis Co. , 1973.)
Fig. 8-A: Marked hypertrophy of all four glands in a patient who died of severe renal failure.
Fig. 8-B: Hyperplasia principally affecting the clear cells (x 430).
Other Systems in Rickets and Osteomalacia
Although rickets and osteomalacia primarily affect those organs which are most
responsive to alterations in the body pools of calcium or phosphate, they are systemic
diseases, and occasionally their pathological changes are diffuse and widespread. Muscular
hypotonia ‘9 and abdominal and renal disturbances 158,159 as well as pulmonary and
cardiac disease 155, may occur in long-standing, severe rickets and osteomalacia.
In regard to systemic disorders associated with rickets, there is an unusual feature
commonly known as the paradox ofrickets 173 As the rickets becomes more severe, with
the result that the child becomes sicker systemically and his or her blood chemistries show
greater aberration, the changes in the epiphyseal plate become milder and may actually
disappear if the patient lives long enough. This paradoxical behavior is due to the fact that
rickets, by definition, is a disease of growth. If the patient becomes chronically ill with
respiratory, cardiac, or renal disease, growth is inhibited on a hypoproteinemic or
nutritional basis, and the epiphysealmanifestations of rickets (which are directly related to
the rapidity of growth) fade or even disappear.
Clinical Manifestations of Rickets and Osteomalacia

Rickets
The clinical pictures caused by rickets vary considerably depending on the age of the
child, the severity of the disease, and to some extent the underlying cause of the deficient

state. In general, however, the clinical findings in the syndromes are stereotyped and one
can rarely distinguish one form of rickets from another by physical examination alone
12,70,74,99,100.155,164,196
FIG. 8-C
Roentgenographic changes of secondary hyperparathyroidism in a patient with chronic renal disease. Note the
brown tumors in the proximal portion of the femur and ischial ramus on the right.
In infants and young children with florid rickets the pattern is particularly
characteristic, and is usually fully manifest by the age of six months or less. The child is
listless, apathetic, and irritable, and shows fairly profound hypotonia and muscle
weakness Occasionally this is so severe that a child one or two years old is unable to
walk, stand, or even sit without support 196,198 When compared with other children of the
same age, the child with rickets is shorter and, less commonly, has a lower body
weight. 70,170, The skin is pallid, or pasty, and with florid disease there may be a fairly
profound anemia 155.169, Ligamentous laxity is commonly associated with rickets, resulting
in a generally loose-jointed structure. Excessive sweating, particularly ofthe head and face,
is commonly noted. Tetany, laryngeal stridor, and convulsions may occur if the calcium
level drops significantly or there is alkalosis 70,155,198 Fortunately this complication is not
common, even in patients with severe disease. In the forms of rickets resulting from poor
nutrition, altered absorption, or chronic renal disease, other nutritional disorders may be
present and the child may exhibit signs of multiple vitamin deficiencies (especially scurvy)
and hypoproteinemia.
Examination of the skull of a child with rickets will often disclose asymmetrical
contours, usually with marked flattening ofone orthe other parietal bone 118, Frequently the
child is noted to have generalized softening of the calvarius (craniotabes), widening of the
sutures, and persistence of the anterior and posterior fontanels. Prominence of the frontal
bones (frontal bossing) is a common sign. The widened sutures and craniotabetic thickening
of the bones adjacent to the sutures create a bossed, cruciate pattern in the calvarium called
caput quadratum or ‘hot-cross-bun ‘ skull”.
Dental development in a child with rickets is often slow, so that eruption of teeth may
be considerably delayed. Teeth are generally poorly mineralized and demonstrate irregular
pits and grooves. Enamel hypoplasia and caries are frequent and severe in rachitic
children 118
The thorax in a child with florid rickets shows striking abnormalities. The cartilaginous
portions of costochondral junctions, as the result of changes similar to those seen in
epiphyseal cartilage of the long bones, become enlarged and cupped, producing a row of
firm, smooth, nodular masses on either side of the sternum: the so-called rachitic
rosary 118,196, There is often asymmetrical flattening ofone or the other hemithorax, and the

118 H. J. MANKIN
sternum may protrude or be acutely angulated. Pectus carinatum (or occasionally

excavatum) may be present. The softened lower ribs at the site of attachment of the
diaphragm may be indented, forming Harrison’s groove, a frequent finding in severely
affected children. Chronic cough, respiratory infection, and frequent episodes of
pneumomtis attest to the generalized debility and muscle weakness of patients with severe
rickets.
The abdomen of a child with rickets, due to hypotonia of the muscles, is frequently
markedly protuberant (rachitic pot belly). Diarrhea or constipation may be present. A
thoracic kyphosis is common(rachitic catback), and, ifthe child is able to walk, a waddling
gait and marked accentuation of the lumbar lordosis is frequently noted. Scoliosis is
uncommon, but occasionally may be severe and progressive.
The most striking findings are in the extremities. Profound hypotonia ofthe muscles of
the trunk and proximal segments of the limbs makes normal stance, gait, or even sitting
erect difficult and clumsy 198, The limbs may become deformed, and bowing of the tibiae,
femora, radii and ulnae is common. Rachitic saber shins and coxa vara may occur in
long-standing disease. Almost invariably, in even moderately severe cases, there is
palpable and visible enlargement of the ends of the long bones and the circumference of the
elbow, wrist, knee, and ankle joints is increased. Sausage-like enlargements of the ends of
the phalanges and metacarpals, with regular constrictions corresponding to the joints
(string-of-pearls deformity), may also occur. Children with florid rickets may suffer
pathological fractures ofthe long bones (especially the ulna, fibula, tibia, and femur) as the
result of minor trauma.
Osteomalacia
The clinical diagnosis of osteomalacia in an adult is often subtle and is considerably
more difficult to establish than that ofrickets in a child 36.100.102.189.232 Part ofthis difficulty
lies in the relatively mild changes in this syndrome, but the diagnosis is also obscured by the
historical confusion surrounding the nature of the osteomalacic process 189 Since the first
reports by early Arabian physicians 189, the entity has been described as a lesion of obscure
etiology, variously named mollities ossium 20,120 malacosteon 195, or hunger or war
osteopathy ‘ In the early 1 8th century the syndrome was recognized by obstetricians 126,
since most ofthe cases occurred during pregnancy, and severe narrowing ofthe pelvic outlet
was defined as a characteristic deformity (Kilian’s pelvis 126) In 1772, Levacher de Ia
Feutrie 133 suggested that the syndrome represented the adult counterpart ofrickets, but this
suggestion was ignored for over a century until Pommer in 1885 176 concluded that the
histological patterns of rickets and osteomalacia were identical. Clinicians continued to
disagree, however, and at various times the thyroid, adrenals, thymus, parathyroids,
pituitary, and ovaries were implicated as a cause of osteomalacia 144,161.189, In 1905,
Goldthwait and co-workers 85 clarified the situation by calcium balance studies, and by the
time vitamin D became available most clinicians correctly linked osteomalacia with rickets
and identified the cause as a deficiency ofcalcium 81,137
The clinical findings in osteomalacia are often subtle, and the patient with mild or
moderate disease may be totally asymptomatic for years 19,155 With moderately severe or
advanced disease, poorly localized bone pain and tenderness are common and occur in
multiple sites, most often the spine, pelvis, and proximal parts of the extremities 119.189,
Muscle weakness and hypotonia may be present and result in mild to moderate decrease in
functional capacity, a waddling gait, or, in severe cases, inability to walk 119.177.198.216,
Patients with osteomalacia may suffer from Milkman’s syndrome, a roentgenographic
entity in which the patient shows multiple spontaneous ribbon-like pseudofractures of the
long and flat bones without displacement or callus formation 118.140,151,152.186,210 A
Milkman’s pseudofracture (Looser’s line orumbauzone) occasionally becomes the site of a
true fracture, presumably as a result oftorsional, tensile, or shearing stress on the weakened
area in the bone. Occasionally an acute fracture is the initial complaint leading to the

diagnosis of the primary disease 102, The most common fractures are in the neck of the
femur, pubic ramus, spine, or ribs, and may produce severe debility. Considerable
shortening ofthe trunk may occur when the spine is extensively involved 118,119.189,
Roentgenographic Features of Rickets and Osteomalacia
The roentgenographic changes associated with rickets and osteomalacia clearly reflect
the physiological and pathological changes, particularly those in the shafts ofthe long bones
and epiphyseal plates. The lack ofcalcium, phosphate, or both available for mineralization
of the skeleton, and the specific alterations in the bones and epiphyseal plates, presumably
in response to the deficiency of these elements, are readily translated into the characteristic
and almost pathognomonic roentgenographic appearance.
The Bones
Roentgenograms of the long and flat bones show a generalized decrease in density
affecting both the cortical and medullary areas. The cortices appear thinned and the
trabeculae are indistinct and reduced in number 34,70,186,208 Areas ofrapid bone growth tend
to be more severely affected and the characteristic changes are often best seen in the
metaphyseal areas of the long bones the ribs, the pelvis 34,119, and the scapula 119,224
The small bones are generally less severely affected and may appear relatively normal s”.
The vertebrae are often markedly osteopenic in adults with osteomalacia 36,118 but usually
are less affected in rachitic children. Conversely, the caivarium is frequently severely
involved in children with rickets, but shows almost no change in adults with
osteomalacia 34,36,208 (Figs. 6-A through 7-B).
In addition to the reduction in the amount of bone, there is often a distinct difference in
its quality, which may be of importance in distinguishing rickets and osteomalacia from
other forms ofosteopenia, such as osteoporosis. The cortices are not only thinned, but their
outline is fuzzy and indistinct, and the endosteal margin tends to merge with the medullary
bone 65,119 The trabeculae in the medulla are reduced in amount, lacking the pencil-line
sharpness characteristic of normal or osteoporotic bone, and appear fuzzy, coarse, and
irregular in outline 65 Occasionally patients with long-standing osteomalacia show findings
of secondary hyperparathyroidism, characterized by erosions ofthe phalangeal cortices and
tufts and of the distal ends of the clavicles 118,215 (Figs. 6-A through 7-B).
As already described, one of the unusual and pathognomonic features of the
osteomalacic syndromes is the presence of Milkman’s pseudofractures (umbauzonen or
Looser’s lines) 118,186,208,210 The characteristic locations of these symmetrical, transverse,
ribbon-like zones of decreased density are: the concave side of the long bones, the medial
side ofthe neck ofthe femur, the pubic rami, the ribs, clavicles, and axillary borders of the
scapulae (Fig. 6-H). Although the pathogenesis of these defects is unknown, their
proximity to the sites of vessels in the bones has suggested that they are vascular in origin,
possibly the result of pressure on the softened bone or of the increased local blood
supply 132.155,210 Another theory, which is probably more valid, is that they occur at sites of
altered stresses on the softened bone, presumably related to muscle pull. These lines, when
present, are important in diagnosis, since only a few disease states may produce this pattern.
Occasionally one may see radiolucencies suggestive of pseudofractures in hyper-
parathyroidism, fibrous dysplasia, Paget’s disease, or neurofibromatosis, but they are more
likely to be true stress fractures, which may progress in a relatively short time to fracture
with displacement 127 or show evidence of healing and callus formation 118, The
pseudofractures of rickets or osteomalacia occasionally become complete fractures with
displacement, particularly when the part is subjected to significant trauma, but this
occurrence is unusual and one rarely sees roentgenographic evidence of callus
formation 102.155
The long bones of patients with rickets may show considerable deformity. Bowing of
the tibia or femur is common, but genu valgum may also occur. The forearms may show a
VOL. 56-A, NO. I , JANUARY 1974

120 H. J. MANKIN
curvature, usually producing prominence of the ulnar border. In adults with long-standing
osteomalacia, multiple pathological and often “silent” fractures can result in significant
deformities and disability I 19,208,209, Compression fractures of the vertebral segments may
alter the normal spinal curves or cause gibbus formation. Coxa vara may result from fracture
in the neck ofproximal part ofthe shaft ofthe femur 118.119,155,323 Pelvic fractures may so
distort the shape and symmetry of the innominate bones that the obstetrical dimensions are
grossly disturbed 126,189, Occasionally areas of increased bone density are seen in patients
with classic osteomalacia 208,209 The cause ofthis finding is unknown, but possible theories
are discussed in a subsequent section on renal osteodystrophy.
The Epiphyseal Plate
The roentgenographic changes in the bones of patients with rickets and osteomalacia
may be confused with those of other osteopenic states such as hyperparathyroidism or
osteoporosis, but the alterations in the epiphyseal regions of the growing child with rickets
are highly characteristic and should cause little difficulty in diagnosis 34,70,74,118,232
The axial height of the epiphyseal lines is markedly increased, reflecting the accumulation
ofcartilage cells in the rachitic maturation zone. The radiolucent area which represents the
growth plate may appear ten times or more wider than normal. The normal zone of
provisional calcification, as seen on roentgenograms, is a sharply defined, irregular or
serrated, dense white line on the metaphyseal side of the epiphyseal plate; in rickets this
zone appears fuzzy, indistinct, and far less dense than normal. The epiphyseal plate may
also show an increase in transverse width producing ‘cupping’ ‘ ‘ and flaring of the
metaphyseal bone adjacent to it (Figs. 6-A through 6-H).
The changes described vary considerably in degree, depending on the severity of the
disease, the site examined, and the age of the patient. In very florid rickets in younger
children, the axial width of the distal epiphyseal plate of the femur may be as much as two
centimeters, while in mild or partially treated resistant rickets in older children the plate may
be almost normal in appearance. The distal femoral, proximal tibial, and distal radial
epiphyseal plates usually show the most marked pathological changes, while the proximal
and distal humeral, proximal femoral, distal tibial, metacarpal, metatarsal, and phalangeal
epiphyseal regions are less altered. In very young children, in whom growth is occurring at a
rapid rate, the roentgenographic changes are usually marked. With advancing age or illness,
however, growth slows and the changes become less prominent. With epiphyseal closure,
the child, by definition, no longer has rickets, but has ‘ ‘graduated’ ‘ to osteomalacia.
Laboratory Diagnosis of Rickets and Osteomalacia

The diagnosis of a rachitic and osteomalacic syndrome may be suspected on the basis
of history and physical examination and may be made tentatively by evaluation of suitable
roentgenograms. Proof of the diagnosis and, perhaps more important, determination of the
specific cause ofthe syndrome must depend on the laboratory evaluation. The aberrations of
the calcium and phosphate content in blood, urine, and feces are diagnostic for the disease
process , and such tests should be performed for every patient suspected of having one of the
rachitic or osteomalacic syndromes. Other tests, as will be discussed, may provide more
information regarding the specific cause ofthe disease.
Calcium
The calcium content of the serum in patients with rickets or osteomalacia is generally
normal or slightly to moderately decreased 12.70.74.84.110,118.199, The serum calcium rarely
falls below 7.5 to 8 milligrams per 100 milliliters and may be as high as 10 milligrams per
100 milliliters. Despite the fact that in most patients rickets or osteomalacia is caused by a
decrease in the body’s pool of calcium, the serum calcium is maintained at a relatively high
level, presumably on the basis of increased activity of the parathyroid gland in response to

the chronic calcium deficit Urinary calcium is almost invariably diminished in rickets
and osteomalacia, a finding that is highly significant 12,70,74,84,199 The urinary output of
calcium in a child with rickets may fall considerably below the normal of 5 milligrams per
kilogram of body weight per twenty-four hours. In children on a standard diet, values of 3
milligrams or less per kilogram of body weight per twenty-four hours are considered
pathological and indicative of one of the hypocalcemic syndromes 117, In adults with
osteomalacia there may be considerable variation in the urinary excretion of calcium, and
the dietary intake should be carefully regulated prior to study. The usual finding in these
patients is a fairly marked decrease in the twenty-four-hour output of calcium, with values
ranging between 80 and 150 milligrams per twenty-four hours. On a dietary intake of750 to
1 ,000 milligrams of calcium per day, urinary excretion of under 200 milligrams of calcium
per twenty-four hours should excite concern 84.117 Fecal calcium is usually increased in
rickets and osteomalacia, but the level depends considerably on the dietary intake. It is not
unusual in patients receiving one gram of calcium per day in their diet to excrete almost all
of it in the feces, or, at times, even slightly more than the amount ingested. This finding is
particularly common in patients with renal osteodystrophy 205,
Inorganic Phosphate
The serum values for inorganic phosphate are almost always considerably diminished
in most forms ofrickets and osteomalacia. The exception is renal osteodystrophy, in which
filtration ofphosphate through the glomerulus is inadequate and as a result the serum values
rise considerably above normal 155.171.203.204, In most other variants of the disease, the
serum phosphate values range from 1 to 3.5 milligrams per 100 milliliters, even in children,
whose normal values are somewhat higher than those of adults 64,84,86,110.117 In general,
patients with rickets or osteomalacia on the basis of a renal tubular reabsorptive defect for
phosphate have a lower concentration of phosphate in the serum 86
The diminished reabsorption of phosphate by the renal tubules, or, expressed in

another way, the increased clearance ofphosphate, is an integral part ofthe pathogenesis of
the rachitic and osteomalacic syndromes. Some patients with relatively high serum
phosphate levels excrete large amounts of this material in the urine, far exceeding the
expected normal values of 500 to 800 milligrams per day in children and 300 to 1,000
milligrams per day in adults 64,117, The value obtained, however, may be difficult to assess
because of the variable dietary intake of phosphate. The kidneys of patients who are
markedly hypophosphatemic have less phosphate to deal with and hence, despite decreased
tubular reabsorption, these patients have normal or even low values for the
twenty-four-hour urinary excretion of phosphate 70,84,155,171) Of much more significance
than these values is the percentage of tubular reabsorption of phosphate. This simple
chemical determination eliminates the effect of dietary intake on the serum levels and
provides a percentage value for the efficiency of the tubular reabsorptive
mechanisms 84,119,155,171) Values below 85 per cent are considered significant, and certainly
values of 60 per cent or less are grossly abnormal. It should be pointed out, however, that
the reabsorptive rate for phosphate is subject to considerable variation and can be markedly
influenced bythe time of day, level of growth hormone, and a variety of other
factors 84,155,170 Furthermore, the diminished reabsorptive rate of phosphate may be
indicative of hyperparathyroidism, and the finding must be evaluated in the light of other
clinical and chemical evidence 70,166,
Other tests to assay the kidney’s ability to handle phosphate include determinations of
phosphate clearance, phosphate-creatinine clearance ratio, maximum tubular reabsorption
ofphosphate, and the efficiency ofthe kidneys in handling exogenous phosphate loads with
or without administered parathormone 37,53,84.166, These tests are of greater significance in
the diagnosis of hyperparathyroidism than in that of rickets or osteomalacia, and for most
situations calculation of the per cent tubular reabsorption of phosphate is sufficient 70,84,

122 H. J. MANKIN
Serum Alkaline Phosphatase
In rickets, and to a lesser extent in osteomalacia, the serum alkaline phosphatase is

significantly elevated 27,40,74,84,118,199 Values of 50 Bodansky units or more are not
uncommon in patients with active rickets, and although considerable variation may be
present it is rare that the values approach normal unless treatment is adequate 74.84,118.199
Other Serum and Urine Studies
Patients with rickets may have slight to moderate anemia 169 without other
hematological abnormalities. The erythrocyte sedimentation rate is usually normal. There
may be a moderate acidosis, occasionally as the result ofa renal tubular lesion 160 but also as
the result of elevation of the plasma citrate Urinary excretion of citrate is increased and
increased quantities of amino acids may be found in the urine, even in the absence of a
specific genetic reabsorptive lesion in the tubules 75,121123.160, Excessive hydroxyproline in
the urine is frequently noted in patients with rickets 42.129,104.197, Calcium balance studies
show a decreased pool of calcium and diminished rate of bone accretion 98,I8,185,
Bone Biopsy
A slightly low or normal serum calcium, low serum phosphate, elevated serum
alkaline phosphatase, diminished urinary excretion ofcalcium, and decreased percentage of
tubular reabsorption ofphosphate are highly suggestive ofthe rachitic or osteomalacic state.
The study which provides the most direct diagnostic evidence, however, is a bone biopsy of
the iliac crest 78,119,155,196 a simple procedure which can be performed under local
anesthesia using a small coring instrument. The finding ofwide osteoid seams surrounding
the trabeculae is virtually pathognomonic for the disease. Biopsy also permits
morphometric analysis using microradiography and tetracycline labeling, which provide a
means of quantitating the rates of bone formation and absorption and of assessing the
long-term effects oftreatment 78,91.196
TABLE II
PRINCIPAL CHEMICAL ABERRATIONS IN RICKETS AND OSTEOMALACIA
Values Seen in
Normal Values Rickets and Osteomalacia
Serum calcium (total) 8.8-10.8 mg/100 ml 7.5-10 mg/100 ml

Serum calcium (ionized)* 4.2-5.2 mg/100 ml 3.5-4.8 mg/100 ml
Serum inorganic phosphatet
Adult 2.5-4.5 mg/100 ml
Child 4.5-5.5 mg/100 ml 1-3.5 mg/100 ml
Infant 5.5-7 mg/l0O ml
Serum alkaline phosphatase
Adult 1.5-4 B.U4
Child 5-14 B.U. 15->50 B.U.
Infant 10-25 B.U.
Urinary calciumJ
Adult 150-250 mg/24 hrs. < 150 mg/24 hrs.
Child 4.5-7 mg/kg/24 hrs. <3 mg/kg/24 hrs.
Urinary phosphate
Adult 0.3-1.3 g/24 hrs. Variable
Child 0.53-0.84 g/24 hrs.
Per cent tubular reabsorption
of phosphate (% TRP)t 85-90 <80%
S Normal values may vary somewhat in different laboratories.
t Samples should be obtained in the morning under fasting conditions.

B.U. = Bodansky units.
#{182}
Study should be performed while the patient is maintained on a standard dietary intake.

The principal chemical aberrations in rickets and osteomalacia are summarized in

Table II. Other specific tests for the various renal tubular syndromes and special forms of
rickets will be discussed in Part II ofthis review, which will appear in the March 1974 issue
of The Journal.
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Rickets Mankin1

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This is an enhanced PDF from The Journal of Bone and Joint Surgery

Review Article, Rickets, Osteomalacia, and Renal Osteodystrophy:

This information is current as of October 17, 2006

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Rickets, Osteomalacia, and

BY HENRY J. MANKIN, M.D.t, BOSTON, MASSACHUSETTS

Rickets and osteomalacia are syndromes of diverse etiology, characterized

VOL. 56-A, NO. I, JANUARY 1974 101

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Calcium and Phosphorus Metabolism and Vitamin D

THE JOURNAL OF BONE AND JOINT SURGERY

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however, it is essential to establish several important points regarding the metabolism of

VOL. 56-A, NO. 1, JANUARY 1974

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diminish absorption of this element by formation of insoluble salts.

The internal metabolism of calcium and phosphate is controlled by parathormone,

THE JOURNAL OF BONE AND JOINT SURGERY.

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calcium in the serum and to be regulated by negative feedback systems. Hypocalcemia

VOL. 56-A, NO. I, JANUARY 1974

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Cholesterol .- 7-Dehydrocholesterol . \, .\ .ChoIecalcIfero1

THE JOURNAL OF BONE AND JOINT SURGERY

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MINIMUM DAILY REQUIREMENTS FOR CALCIUM, PHOSPHATE, AND VITAMIN D

Calcium 400-500 mg 400 to 700 mg

VOL. 56-A, NO. 1 , JANUARY 1974

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Pathophysiolojr of Rickets and Osteomalacia

The Metabolic Abnormality (Hypovitaminosis D - The Prototype)

Epiphyseal Plate Abnormalities

Immature individuals who become rachitic have characteristic histological,

ThE JOURNAL OF BONE AND JOINT SURGERY

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FIG. 3-A FIG. 3-B FIG. 3-C

VOL. 56-A, NO. I, JANUARY 1974

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THE JOURNAL OF BONE AND JOINT SURGERY

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VOL. 56-A, NO. 1, JANUARY 1974

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The concentration of adenosine triphosphate is reduced 131, Ultrastructural studies of the

THE JOURNAL OF BONE AND JOINT SURGERY

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FIG. 6-A FIG. 6-B

FIG. 6-C FIG. 6-D

shown by microradiography 12,78,87,91 and this pattern is reflected histologically by thinned

VOL. 56-A, NO. 1, JANUARY 1974

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FIG. 6-G FIG. 6-H

Fig. 6-G: Cystine storage disease.

composed ofthin strips ofmineralized bone surrounded by a layerofunmineralized osteoid,

THE JOURNAL OF BONE AND JOINT SURGERY

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VOL. 56-A, NO. 1, JANUARY 1974

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As previously indicated, the chronic diminution in serum calcium in patients with

FIG. 8-A FIG. 8-B

Other Systems in Rickets and Osteomalacia

Clinical Manifestations of Rickets and Osteomalacia

THE JOURNAL OF BONE AND JOINT SURGERY

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