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Clinical manifestations, diagnosis, and treatment of osteomalacia

Authors: Adi Cohen, MD, MHS, Matthew T Drake, MD, PhD


Section Editor: Peter J Snyder, MD
Deputy Editor: Jean E Mulder, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2018. | This topic last updated: Aug 03, 2017.

INTRODUCTION — Osteomalacia is a disorder of bone, characterized by decreased mineralization of newly


formed osteoid at sites of bone turnover. Several different disorders cause osteomalacia via mechanisms that
result in hypocalcemia, hypophosphatemia, or direct inhibition of the mineralization process. (See "Epidemiology
and etiology of osteomalacia".)

This topic review will present an overview of the clinical manifestations, diagnosis, and treatment of adults with
osteomalacia. The treatment of nutritional, hereditary vitamin D resistant, and pseudovitamin D-deficient rickets
in children is discussed separately. (See "Etiology and treatment of calcipenic rickets in children" and "Hereditary
hypophosphatemic rickets and tumor-induced osteomalacia".)

CLINICAL FEATURES

Clinical manifestations — Osteomalacia may be asymptomatic and present radiologically as osteopenia. It can


also produce characteristic symptoms, independently of the underlying cause, including diffuse bone and joint
pain, muscle weakness, and difficulty walking [1-3]. In a report of 17 patients with osteomalacia on bone biopsy,
the following findings were observed [4]:

● Bone pain and muscle weakness in 16 (94 percent)

● Bone tenderness in 15 (88 percent)

● Fracture in 13 (76 percent)

● Difficulty walking and waddling gait in four (24 percent)

● Muscle spasms, cramps, a positive Chvostek's sign, tingling/numbness, and inability to ambulate in one to
two (6 to 12 percent)

These symptoms may be insidious in onset. Bone pain is usually most pronounced in the lower spine, pelvis, and
lower extremities, where fractures have taken place, and may be associated with tenderness to palpation. The
pain is characterized as dull and aching and is aggravated by activity and weight bearing. Fractures may occur
with little or no trauma, typically involving the ribs, vertebrae, and long bones. Abnormal spinal curvature or
deformity of the thorax or pelvis appears only in severe osteomalacia of long duration [1].

The muscle weakness characteristically is proximal and may be associated with muscle wasting, hypotonia, and
discomfort with movement [1]. There may also be a waddling gait. It is likely that high levels of parathyroid
hormone (PTH) and low levels of phosphate and calcitriol all contribute to the myopathy since similar findings
occur in severe primary hyperparathyroidism.

Osteomalacia secondary to hypophosphatasia is associated with poorly healing metatarsal or other fractures,
chondrocalcinosis, and premature loss of teeth during childhood.

Laboratory findings — Laboratory abnormalities in osteomalacia are largely dependent upon the cause of the
osteomalacia (table 1). (See "Epidemiology and etiology of osteomalacia", section on 'Etiologic diagnosis'.)

In retrospective reviews of patients with biopsy-proven nutritional osteomalacia, the following laboratory
abnormalities were observed [4,5]:

● Alkaline phosphatase elevated in 95 to 100 percent

● Serum calcium and phosphorus reduced in 27 to 38 percent

● Urinary calcium low in 87 percent

● 25-hydroxyvitamin D (25[OH]D, calcidiol) <15 ng/mL in 100 percent

● PTH elevated in 100 percent

The majority of patients (40 of 43) in this review had nutritional osteomalacia from either a gastrointestinal
disorder or suboptimal nutrition and inadequate sun exposure. In these cases, 25(OH)D levels were very low (<10
ng/mL [25 nmol/L]), which differentiates vitamin D deficiency from the other causes of osteomalacia, such as
the renal phosphate wasting syndromes.

Radiographic findings — The radiological abnormalities in adults who develop osteomalacia are less striking
than those seen in children with rickets (see "Overview of rickets in children"). Reduced bone mineral density
(BMD) with thinning of the cortex is the most common finding, but it is very nonspecific. More specific are
changes in vertebral bodies and Looser zones. Infrequently, radiologic evidence of secondary
hyperparathyroidism can be seen.

Changes in vertebral bodies — Inadequate mineralization of osteoid and loss of secondary trabeculae lead to
a loss of radiologic distinctness of vertebral body trabeculae, making the radiograph appear of poor quality
(image 1 and image 2). With more advanced disease, softening leads to a concavity of the vertebral bodies
called codfish vertebrae. The vertebral disks appear large and biconvex. There may be spinal compression
fractures, but these are more common in osteoporosis.

Looser zones — Looser pseudofractures, fissures, or narrow radiolucent lines, 2 to 5 mm in width with


sclerotic borders, are a characteristic radiologic finding in osteomalacia (image 3) [6]. They often are bilateral,
symmetric, and lie perpendicular to the cortical margins of bones. They are most commonly found at the femoral
neck, on the medial part of the femoral shaft, immediately under the lesser trochanter or a few centimeters
beneath, and in the pubic and ischial rami. They may also occur at the ulna, scapula, clavicle, rib, and metatarsal
bones. Pseudofractures can also be seen with bone scans where they appear as hot spots [7]. The term
"Milkman syndrome" refers to the combination of multiple bilateral and symmetric pseudofractures in a patient
with osteomalacia [8].

Looser zones have been postulated to represent either [9,10]:

● Stress fractures that have been repaired by the laying down of inadequately mineralized osteoid, or

● Erosion of bone by arterial pulsations, since they often lie in apposition to arteries
Secondary hyperparathyroidism — Skeletal changes induced by longstanding secondary hyperparathyroidism
are less frequent than the above abnormalities. When they do occur, they include subperiosteal resorption of the
phalanges, bone cysts, and resorption of the distal ends of long bones such as the clavicle and humerus. (See
"Primary hyperparathyroidism: Clinical manifestations", section on 'Skeletal'.)

Other radiograph findings — More severe osteomalacia can lead to shortening and bowing of the tibia,
pathologic fractures, coxa profunda hip deformity (image 4A-B), and cephalopelvic disproportion (image 5).

Bone mineral density — Several studies have demonstrated markedly reduced spine, hip, and forearm BMD (as
measured by dual-energy x-ray absorptiometry [DXA]) in patients with osteomalacia related to vitamin D
deficiency [4,5]. However, BMD is not required for the diagnosis of osteomalacia, and BMD (DXA) findings are
unable to differentiate osteomalacia and osteoporosis.

In contrast, BMD tends to be normal or increased (especially at the lumbar spine) in adults with X-linked
hypophosphatemic rickets (XLH), axial osteomalacia, fibrogenesis imperfecta, and skeletal fluorosis [11-13]. This
discrepancy may be related in part to differences in PTH values in the two groups (high in vitamin D deficiency
and normal in the others). (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section
on 'X-linked hypophosphatemia' and "Epidemiology and etiology of osteomalacia", section on 'Defective bone
matrix'.)

DIAGNOSIS AND EVALUATION — Osteomalacia should be suspected in cases of bone pain associated with
malabsorption, gastric bypass surgery, celiac sprue, chronic hepatic disease, or chronic kidney disease. The
diagnosis is based on a combination of clinical features (which may include bone pain and tenderness, fractures,
and/or muscle weakness), laboratory results, radiologic findings, and, rarely, transiliac bone histomorphometry.
The majority of patients have nutritional osteomalacia and will have a very low serum 25-hydroxyvitramin D
(25[OH]D) (<10 ng/mL [25 nmol/L]), low to low-normal serum calcium and phosphate, and high parathyroid
hormone (PTH) and alkaline phosphatase (both total and bone-specific) levels.

Clinical evaluation, including history of gastrointestinal diseases or procedures, sun exposure, dietary habits, and
onset (insidious or acute) and duration of symptoms, may help determine the etiology of osteomalacia.
Laboratory abnormalities in osteomalacia are largely dependent on its cause (table 1), and therefore, laboratory
findings are used to diagnose and determine the etiology of osteomalacia. The initial laboratory evaluation
should include measurement of serum concentrations of:

● Calcium

● Phosphate

● Alkaline phosphatase

● 25(OH)D

● PTH

● Electrolytes, blood urea nitrogen (BUN), and creatinine

Radiographs may be helpful in certain settings (eg, severe bone pain), to distinguish osteomalacia from multiple
myeloma or Paget disease of bone. Bone biopsy and histomorphometry should be performed only when the
diagnosis of osteomalacia is in doubt or the cause of osteomalacia is not determined by noninvasive testing (eg,
to assess for one of the rare disorders of defective bone matrix, such as axial osteomalacia or fibrogenesis
imperfecta). (See "Epidemiology and etiology of osteomalacia", section on 'Defective bone matrix'.)
A delay in diagnosis of osteomalacia is commonly reported [4,14,15]. In one study of 33 women with
osteomalacia, the mean duration of symptoms before diagnosis was 2.5 years [14]. Diagnoses considered prior
to confirmation of osteomalacia included osteoporosis, Paget disease, malignancy, pseudohypoparathyroidism,
osteoarthritis, malabsorption, irritable bowel syndrome with depression, fibromyalgia, and somatization
disorders.

Interpretation of laboratory abnormalities — The goal of the laboratory evaluation is to distinguish vitamin D


deficiency or resistance from the phosphate wasting syndromes and other less common causes of osteomalacia
(table 1):

● In nutritional osteomalacia, 25(OH)D (calcidiol) is typically very low (<10 ng/mL [25 nmol/L]), calcium and
phosphate low to low-normal, and PTH and alkaline phosphatase high [1]. The serum concentration of 1,25-
dihydroxyvitamin D may be normal, low, or high, depending upon the severity and duration of vitamin D
deficiency, and is therefore not helpful in making the diagnosis [16].

● In primary renal phosphate wasting, serum phosphate is low and phosphate clearance is elevated. Serum
1,25-dihydroxyvitamin D levels are frequently inappropriately normal for the degree of hypophosphatemia
(1,25-dihydroxyvitamin D should increase in response to severe hypophosphatemia). Serum calcium and
25(OH)D levels are normal, and PTH and alkaline phosphatase levels are normal or mildly elevated. Patients
may also have other tubular defects (hypouricemia, aminoaciduria, and glucosuria) if the phosphate wasting
is part of a generalized Fanconi syndrome. Heavy metals in the urine may be increased if they are the cause
of the Fanconi syndrome. In patients with tumor-induced osteomalacia and hereditary hypophosphatemic
rickets, serum fibroblast growth factor (FGF) 23 levels may be elevated [17]. (See "Causes of
hypophosphatemia" and "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia".)

● In type 2 (proximal) renal tubular acidosis, there is a hyperchloremic metabolic acidosis and
hypophosphatemia. The latter reflects both proximal renal tubule phosphate wasting and secondary
hyperparathyroidism due to acidosis-induced hypercalciuria. (See "Etiology and diagnosis of distal (type 1)
and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA'.)

● In hypophosphatasia, the alkaline phosphatase level is low while the serum calcium and phosphate
concentrations are normal. Reduced activity of the alkaline phosphatase enzyme results in accumulation of
substrates, including phosphoethanolamine, inorganic pyrophosphate, and pyridoxal 5'-phosphate (PLP), in
blood and urine. In patients not taking a vitamin B6 (pyridoxine) supplement, elevated plasma PLP is a
marker of hypophosphatasia. Mutational analysis of the tissue-nonspecific isoenzyme of alkaline
phosphatase is available commercially, but mutations may not always correlate with disease severity
[18,19]. (See "Epidemiology and etiology of osteomalacia", section on 'Hypophosphatasia'.)

● In fibrogenesis imperfecta and axial osteomalacia, alkaline phosphatase, calcium, phosphate, and vitamin D
are usually normal. (See "Epidemiology and etiology of osteomalacia", section on 'Defective bone matrix'.)

● In skeletal fluorosis, serum calcium and phosphate are usually normal and alkaline phosphate is elevated.
Serum, urine, and bone fluoride content is increased [13].

Bone biopsy — Bone biopsy with double tetracycline labeling is the most accurate way to diagnose
osteomalacia. However, it is infrequently performed clinically because it is invasive and because the diagnosis
can usually be made from a combination of clinical and laboratory findings. The histomorphometric
characteristics of osteomalacia include (picture 1) [20]:

● Prolonged mineralization lag time

● Widened osteoid seams


● Increased osteoid volume

All of these features are necessary for the diagnosis because other disorders may show one of these findings.
Wide osteoid seams reflecting high turnover, for example, can be seen with hyperthyroidism, Paget disease, and
hyperparathyroidism. However, the mineral apposition rate is elevated in these disorders in contrast to the low
values in osteomalacia. (See "Epidemiology and etiology of osteomalacia", section on 'Pathogenesis'.)

DIFFERENTIAL DIAGNOSIS — Other causes of bone fractures, bone pain, and reduced bone mineral density
(BMD) include osteoporosis, malignancy, Paget disease, and hyperparathyroidism. Most of these diagnoses can
be distinguished from osteomalacia by the clinical history, physical examination, and a combination of laboratory
and radiologic studies. Bone biopsy using double tetracycline labeling (assuming that the patient is not allergic
to tetracycline) is performed rarely and is reserved for cases that are difficult to diagnose using noninvasive
methods [21].

● Osteoporosis occurs in different settings from osteomalacia, particularly postmenopausal women, older
adult subjects, and patients treated with chronic corticosteroid therapy. (See "Osteoporotic fracture risk
assessment" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal
women".)

Osteoporosis is characterized by normal serum levels of calcium, phosphate, and alkaline phosphatase. This
is in contrast to the frequent findings of one or more of the following in the different causes of
osteomalacia: hypophosphatemia, hypocalcemia, low levels of 25-hydroxyvitamin D (25[OH]D) (<10 ng/mL
[25 nmol/L]), and increased parathyroid hormone (PTH) and alkaline phosphatase levels (table 1) [22].
Although 25(OH)D levels may be low in patients with osteoporosis and a subset of these patients may also
have secondary elevations of PTH, 25(OH)D levels rarely are below 10 ng/mL (25 nmol/L). (See 'Laboratory
findings' above.)

Reduced BMD does not distinguish osteoporosis from osteomalacia. Patients with osteomalacia due to
vitamin D deficiency may have markedly reduced spine, hip, and forearm BMD. In such patients, treatment
with bisphosphonates, teriparatide, or other osteoporosis medications is not appropriate and may
exacerbate hypocalcemia. Osteomalacia related to vitamin D deficiency should be treated with vitamin D
and calcium, which often results in marked improvement in BMD. (See 'Vitamin D deficiency' below.)

● In patients with Paget disease of bone, alkaline phosphatase is elevated, but bone scan and radiographic
findings are unique. Plain radiographs of involved areas reveal cortical thickening, expansion, coarsening of
trabecular markings and mixed areas of lucency and sclerosis. (See "Clinical manifestations and diagnosis
of Paget disease of bone".)

● In patients with multiple myeloma, weakness, fatigue, and bone pain are common. Conventional radiographs
often reveal lytic lesions, as well as diffuse osteopenia and vertebral fractures. Many patients have anemia
and abnormal renal function at diagnosis, whereas patients with osteomalacia generally have normal renal
function. Alkaline phosphatase is usually not elevated in multiple myeloma, and hypercalcemia may be
present in some patients. Multiple myeloma is a common cause of type 2 renal tubular acidosis in adults
[23]. (See "Clinical features, laboratory manifestations, and diagnosis of multiple myeloma".)

● In patients with hyperparathyroidism, both PTH and calcium are elevated, whereas calcium levels are either
low or normal in osteomalacia. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and
evaluation".)

TREATMENT — The treatment of osteomalacia should be directed at reversal of the underlying disorder, if


possible, and correction of hypophosphatemia, hypocalcemia, and vitamin D deficiency.
Vitamin D deficiency — Vitamin D supplementation in patients who are deficient in this hormone leads to a
dramatic improvement in muscle strength and bone tenderness within weeks. Effects are typically most dramatic
when adequate calcium intake occurs simultaneously. Bone mineral density (BMD) may improve within three to
six months [5]. Multiple preparations of vitamin D and its metabolites are available. Vitamin D, rather than its
metabolites, is used when possible since the cost is modest. Vitamin D metabolites are required when there is
abnormal vitamin D metabolism (significant liver or renal disease). The recommended preparation and dose vary
with the clinical condition, as described below.

With each regimen, the serum calcium concentration and urinary calcium excretion are monitored, initially after
one month and three months, and then less frequently (every 6 to 12 months), until 24-hour urinary calcium
excretion is normal. The serum calcium concentration is monitored to permit early detection of hypercalcemia
from excessive dosing. Serum 25-hydroxyvitamin D (25[OH]D) should be measured approximately three to four
months after initiating therapy. The dose should be adjusted to prevent hypercalciuria or hypercalcemia. In most
cases, serum calcium and phosphate are normal after a few weeks of treatment, but alkaline phosphatase
remains elevated for several months. Healing of osteomalacia is considered to have occurred when there are
increases in urinary calcium excretion and BMD. Healing of the osteomalacia may take many months to a year or
more and varies with the degree and duration of the deficiency [24].

In addition to vitamin D supplementation, all patients should maintain a calcium intake of at least 1000 mg per
day since inadequate intake of calcium may contribute to the development of osteomalacia [25,26]. The
combination of calcium and vitamin D is more likely to produce radiographic evidence of nearly complete healing
of rickets (58 versus 19 percent in Nigerian children with nutritional rickets) [25]. A higher calcium dose (up to 4
g/day) may be necessary in patients with malabsorption (such as occurs following gastric bypass).

The treatment of vitamin D deficiency is reviewed in detail separately and briefly summarized here. (See "Vitamin
D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Vitamin D repletion'.)

● For patients with severe vitamin D deficiency (25[OH]D <10 ng/mL [25 nmol/L]), one common approach is to
treat with 50,000 international units of vitamin D2 or D3 orally once per week for six to eight weeks, and then
800 international units of vitamin D3 daily thereafter. However, the efficacy of this practice compared with
daily, weekly, or monthly dosing has not been rigorously established.

● In malabsorptive states, oral dosing and duration of treatment depend upon the vitamin D absorptive
capacity of the individual patient. Doses of vitamin D of 10,000 to 50,000 international units daily may be
necessary to replete patients with gastric bypass or malabsorption. Patients who remain deficient or
insufficient on such doses will need to be treated with hydroxylated vitamin D metabolites (calcidiol or
calcitriol), which are more readily absorbed, or with sun or sunlamp exposure.

● In liver disease, the vitamin D metabolite calcidiol (25[OH]D) should be used because it does not require
hepatic 25-hydroxylation. The onset of action is more rapid and the half-life of two to three weeks is shorter
than that of vitamin D3 and similar to that of vitamin D2. The dose in this situation is 50 to 200
micrograms/day [4].

Calcidiol is not readily available in the United States, so calcitriol may be used in patients with severe liver
disease who remain deficient after treatment with vitamin D2 or vitamin D3.

● Calcitriol (1,25-dihydroxyvitamin D) is a vitamin D metabolite available in capsules of 0.25 and 0.5


micrograms. It has a rapid onset of action and the half-life is only six hours. It is associated with a fairly high
incidence of hypercalcemia, and patients should be followed carefully. It is most useful in those with
decreased synthesis of calcitriol, as occurs in chronic renal failure or in type 1 vitamin D-dependent rickets
(due to an inactivating mutation in the 1-hydroxylase gene). (See "Etiology and treatment of calcipenic
rickets in children", section on '1-alpha-hydroxylase deficiency'.)

● Dihydrotachysterol (DHT) is available as tablets of 0.125, 0.2, and 0.5 mg. It is functionally equivalent to
1alpha-hydroxyvitamin D. It requires hepatic 25-hydroxylation prior to becoming therapeutically active. DHT
can be used in the disorders for which calcitriol is used. It has a rapid onset of action and a relatively short
duration of action.

Other causes — The treatment of hereditary and acquired renal phosphate wasting syndromes, renal
osteodystrophy, and renal tubular acidosis are discussed in greater detail elsewhere:

● Hereditary hypophosphatemic rickets is treated with a combination of phosphate supplementation and


calcitriol. Tumor-induced osteomalacia is treated similarly until the causative tumor can be removed, or
indefinitely if tumor removal is not possible. (See "Hereditary hypophosphatemic rickets and tumor-induced
osteomalacia".)

● In renal insufficiency, both oral and intravenous calcitriol can be used. (See "Management of secondary
hyperparathyroidism in dialysis patients" and "Management of secondary hyperparathyroidism in adult
nondialysis patients with chronic kidney disease".)

● Osteomalacia of renal tubular acidosis is treated initially with 5000 to 10,000 international units per day of
vitamin D. The acidosis is corrected with sodium and/or potassium citrate. Once the bone heals,
supraphysiologic doses of vitamin D (above 800 international units/day) should not be necessary. (See
"Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis".)

● For hypophosphatasia, there have been few treatment options. However, enzyme replacement therapy
(asfotase alfa) for perinatal, infantile, and juvenile-onset hypophosphatasia became available in October
2015 [27]. In a preliminary report, infusion of recombinant human tissue-nonspecific isoenzyme of alkaline
phosphatase was associated with improvement in skeletal radiographs and in pulmonary and physical
function in infants and young children [28]. In subsequent open-label, prospective studies including a total of
99 patients with perinatal, infantile, or juvenile-onset hypophosphatasia, enzyme replacement therapy was
associated with improved overall survival, ventilator-free survival, growth, and bone mineralization compared
with a historic cohort [27]. Studies in adult hypophosphatasia are underway [29]. (See "Epidemiology and
etiology of osteomalacia", section on 'Hypophosphatasia' and "Periodontal disease in children: Associated
systemic conditions", section on 'Hypophosphatasia'.)

● For patients with the rare skeletal disorder of defective bone matrix (axial osteomalacia and fibrogenesis
imperfecta), there are no established therapies, although a report of two brothers with fibrogenesis
imperfecta reported clinical, radiographic, and histologic improvement following treatment with recombinant
human growth hormone [30]. Patients with axial osteomalacia do not appear to deteriorate over time. In
contrast, patients with fibrogenesis imperfecta develop severe skeletal pain, debilitating fractures, and
progressive immobility [12]. (See "Epidemiology and etiology of osteomalacia", section on 'Defective bone
matrix'.)

PREGNANCY — Severe vitamin D deficiency resulting in osteomalacia has been described in dark-skinned


pregnant women who have emigrated from warm to cold climates in North America and Europe [31-33]. Other
risk factors for osteomalacia during pregnancy include limited sun exposure due to protective clothing,
malabsorption (eg, celiac disease, dietary intake of phytates that prevent calcium absorption), and malnutrition.
Pregnant women with osteomalacia have similar symptoms as nonpregnant adults (see 'Clinical manifestations'
above). They may present with persistent and nonspecific musculoskeletal pain and inability to bear weight.
Evaluation reveals similar biochemical findings as in nonpregnant adults. In some case reports, multiple
fractures were present [33,34]. Severe osteomalacia can be associated with cephalopelvic disproportion (image
5), necessitating cesarean delivery [34].

In case reports, pregnant women with severe osteomalacia (diagnosed at the time of delivery) were successfully
treated with high-dose vitamin D (600,000 international units intramuscularly as a single dose, after delivery) and
calcium supplementation (up to 1.5 g daily) [33,34]. The administration during pregnancy of such a high dose of
vitamin D has not been adequately studied. In case series from the 1960s, pregnant women with osteomalacia
were safely treated with calcium and 3000 to 6000 international units of vitamin D daily [35]. There are modern
day trials evaluating vitamin D dosing in pregnant women with vitamin D deficiency, some of whom had
secondary elevations in serum parathyroid hormone (PTH), but none of whom had vitamin D deficiency of
sufficient severity and duration to cause osteomalacia [36,37]. In these trials, vitamin D supplementation at 12 to
27 weeks gestation with 400, 800, 2000, or 4000 international units D3 daily or 200,000 international units as a
single oral dose was safe and successfully increased serum vitamin D concentrations. These trials are reviewed
in detail separately. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment",
section on 'Pregnancy'.)

Women who are diagnosed with osteomalacia during pregnancy should receive adequate calcium
(approximately 1000 to 1500 mg daily) and vitamin D. We typically start with 2000 to 4000 international units
daily and measure the serum 25-hydroxyvitamin D (25[OH]D) and calcium and urinary calcium excretion after one
month and three months, then less frequently (every 6 to 12 months), until 24-hour urinary calcium excretion is
normal. If the initial dose does not improve serum 25(OH)D after three to four months, the dose of vitamin D can
be increased by 1000 to 2000 international units/day, with continued monitoring of serum vitamin D and calcium
and urinary calcium. The serum calcium concentration is monitored to permit early detection of hypercalcemia
from excessive dosing. The dose of vitamin D should be decreased, as needed, to prevent hypercalciuria or
hypercalcemia.

SUMMARY AND RECOMMENDATIONS

● The clinical manifestations of osteomalacia may include bone pain and tenderness, muscle weakness,
difficulty walking, and a waddling gait. Laboratory findings depend upon the underlying cause of
osteomalacia (table 1). Typical laboratory features of nutritional osteomalacia include elevations in alkaline
phosphatase and parathyroid hormone (PTH) and decreases in calcium, phosphate, and 25-hydroxyvitamin
D (25[OH]D) concentrations. (See 'Clinical features' above and 'Laboratory findings' above.)

● The characteristic radiologic findings are Looser pseudofractures, fissures, or narrow radiolucent lines. In
addition, inadequate mineralization of osteoid and loss of secondary trabeculae lead to a loss of radiologic
distinctness of the vertebral body trabeculae and concavity of the vertebral bodies (codfish vertebrae). Bone
mineral density (BMD) is not required for the diagnosis of osteomalacia, and reduced BMD does not
distinguish osteoporosis from osteomalacia. However, several studies have demonstrated markedly reduced
spine, hip, and forearm BMD (as measured by dual-energy x-ray absorptiometry [DXA]) in patients with
osteomalacia related to vitamin D deficiency. (See 'Radiographic findings' above.)

● Osteomalacia should be suspected in cases of bone pain associated with malabsorption, gastric bypass
surgery, celiac sprue, chronic hepatic disease, or chronic kidney disease. The diagnosis is based upon a
combination of clinical features (bone pain, tenderness, and fractures; muscle weakness), laboratory results
(table 1), radiologic findings, and, rarely, bone histomorphometry. (See 'Diagnosis and evaluation' above.)

● Laboratory abnormalities in osteomalacia are largely dependent on its cause (table 1), and therefore,
laboratory findings are used to diagnose and determine the etiology of osteomalacia. Laboratory evaluation
should include measurement of serum concentrations of calcium, phosphate, alkaline phosphatase,
25(OH)D, PTH, electrolytes, blood urea nitrogen (BUN), and creatinine. Radiographs may be helpful in certain
settings (severe bone pain), to distinguish osteomalacia from multiple myeloma or Paget disease of bone.
Bone biopsy and histomorphometry should be performed only when the diagnosis of osteomalacia is in
doubt or the cause of osteomalacia is not determined with noninvasive testing, eg, to assess for one of the
rare disorders of defective bone matrix. (See 'Diagnosis and evaluation' above.)

● Treatment of osteomalacia depends upon the underlying etiology. For patients with osteomalacia secondary
to severe vitamin D deficiency, vitamin D repletion leads to a dramatic improvement in muscle strength and
bone tenderness within weeks. Many clinicians treat nutritional deficiency (25[OH]D <10 ng/mL [25 nmol/L])
with 50,000 international units of vitamin D2 or D3 orally once per week for six to eight weeks, followed by a
maintenance dose (eg, 800 international units of vitamin D3 daily) thereafter. (See 'Vitamin D deficiency'
above and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on
'Dosing'.)

● After initiation of vitamin D treatment, the serum calcium concentration and urinary calcium excretion are
monitored, first after one month and three months, and then less frequently (every 6 to 12 months). The
serum calcium concentration is monitored to permit early detection of hypercalcemia from excessive
dosing. Serum 25(OH)D should be measured approximately three to four months after initiating therapy. The
dose should be adjusted to prevent adverse effects of hypercalciuria or hypercalcemia. Biological and
radiological abnormalities may take up to one year or more to disappear. (See 'Vitamin D deficiency' above.)

● Hereditary hypophosphatemic rickets is treated with a combination of phosphate supplementation and


calcitriol. Tumor-induced osteomalacia is treated similarly until the causative tumor can be removed, or
indefinitely if tumor removal is not possible. (See "Hereditary hypophosphatemic rickets and tumor-induced
osteomalacia".)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge the late Charles J Menkes, MD,
who contributed to earlier versions of this topic review.

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Topic 2040 Version 19.0


GRAPHICS

Laboratory findings in the different causes of osteomalacia and osteoporosis

Serum 25- 1,25-


Serum Serum Parathyroid
Disorder alkaline hydroxyvitamin dihydroxyvitamin
phosphate calcium hormone
phosphatase D D

Vitamin D deficiency ↓ or N ↓ or N ↑ ↑ ↓↓ N or ↑ or ↓

Conditions associated ↓↓ N N or ↑ N N N
with urinary phosphate
wasting

Proximal renal tubular ↓ N N N N N


acidosis

Hypophosphatasia N N ↓ N N N

Osteogenesis N N N or ↑ N N N
imperfecta and axial
osteomalacia

Osteoporosis N N N N N or ↓ N

N: normal; ↓: reduced; ↓↓: very reduced; ↑: elevated.

Graphic 65400 Version 3.0


Hypophosphatemic osteomalacia: Radiographic findings

Spine films in a 37-year-old man with osteomalacia. The main findings are decreased bone
density, with blurring and deformity of the spine. The blurring makes the films appear of low
quality.

Courtesy of CJ Menkes, MD.

Graphic 56149 Version 3.0


Osteomalacia of the lumbar spine: Computed tomography

A 53-year-old man with osteomalacia. A CT examination revealed ill-defined trabeculae with


ground glass appearance consistent with osteomalacia.

CT: computed tomography.

Courtesy of Joseph Farnam, MD.

Graphic 87021 Version 2.0


Pseudofractures in osteomalacia

(A and B) Plain film images of Looser-Milkman pseudofractures of the pelvis and the left
femoral neck (arrows) in a patient with osteomalacia.
(C) CT of the pubic symphysis from a patient with osteomalacia. There is a pseudofracture
(white arrow) in the superior pubic ramus on the right.

CT: computed tomography.

A and B courtesy of CJ Menkes, MD.

Graphic 52768 Version 5.0


Tibial bowing in osteomalacia: Radiographic findings

Tibial shortening and bowing in a man with vitamin D-resistant rickets. A surgical osteotomy
was performed to correct the tibial bending (arrow).

Courtesy of CJ Menkes, MD.

Graphic 79529 Version 4.0


Coxa profunda abnormality in osteomalacia: Radiographic findings

Bone film in a patient with vitamin D-resistant rickets showing hip deformity with coxa
profunda (in which the femoral head comes deeply into the pelvis), coxa vara (in which the
angle between the femoral neck and the femoral shaft is diminished) (arrow), and rods
representing surgical treatment of pathologic fractures.

Courtesy of CJ Menkes, MD.

Graphic 57357 Version 4.0


Cephalopelvic disproportion in osteomalacia: Radiographic findings

Historical radiograph of a pregnant patient with osteomalacia secondary to lack of exposure


to sunlight and dietary causes resulting in cephalopelvic disproportion. Examination of the
pelvis shows distortion of the iliopubic regions (arrows) with narrowing of the pelvic outlet.
The fetal head (arrowhead) is deep in the pelvis and appears too large for the pelvic outlet.
The fetal spine is seen to the patient's right (dashed arrow).

Graphic 87020 Version 2.0


Micrograph showing low-turnover osteomalacia

Bone biopsy showing low-turnover osteomalacia associated with aluminum accumulation in


end-stage renal failure.
(Left panel) Goldner Masson trichrome stain shows thin mineralized bone in blue
surrounded by wide unmineralized osteoid with no cellular activity in orange-brown. There
are no osteoblasts or erosive surfaces present.
(Right panel) Villanueva stain following tetracycline labeling and viewed under fluorescent
light reveals a marked increase in width of the osteoid seams (orange) with no evidence of
mineralization of new bone (which would result in tetracycline deposition, as manifested by
a yellow line appearing beneath the osteoid seams).

Courtesy of L Darryl Quarles, MD.

Graphic 61773 Version 5.0

Micrograph showing normal bone histology

Histologic appearance of normal bone.


(Left panel) Goldner Masson trichrome stain shows mineralized lamellar bone in blue
and adjacent nonmineralized osteoid in red-brown. Osteoid usually comprises less than
25% of bone surfaces. The cellular area between the osseous structures is the marrow
space.
(Right panel) Villanueva-stained section viewed under polarized light following time-
spaced tetracycline labeling. Osteoid appears orange, mineralized bone is green, and
tetracycline markers appear as luminescent yellow-green bands within bone and
beneath osteoid (arrow). The distinct dual bands represent active mineralized bone
formation.

Courtesy of L Darryl Quarles, MD.

Graphic 66330 Version 6.0


Contributor Disclosures
Adi Cohen, MD, MHS Grant/Research/Clinical Trial Support: Amgen [Osteoporosis (Denosumab)]; Eli Lilly
[Osteoporosis (Teriparatide)]. Consultant/Advisory Boards (Spouse): Annapurna Pharmaceuticals [Cardiology
(No relevant product)]. Matthew T Drake, MD, PhD Nothing to disclose Peter J Snyder,
MD Grant/Research/Clinical Trial Support: AbbVie [Hypogonadism (Testosterone gel)]; Novo Nordisk [Growth
hormone (Somatropin)]; Novartis [Cushing's (LCI699)]; Cortendo [Cushing's]. Consultant/Advisory Boards: AbbVie
[Hypogonadism (Testosterone gel)]; Novartis [Cushing's (LCI699)]; Pfizer [Acromegaly (Pegvisomant)]; Watson
[Testosterone (Testosterone gel)]. Jean E Mulder, MD Nothing to disclose

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