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Tumor-induced osteomalaciaLessons learned.

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ARTHRITIS & RHEUMATISM
Vol. 58, No. 3, March 2008, pp 773–777
DOI 10.1002/art.23278
© 2008, American College of Rheumatology
Tumor-Induced Osteomalacia
Lessons Learned
E. Michael Lewiecki,1 Edward J. Urig, Jr.,2 and Ralph C. Williams, Jr.3
Tumor-induced osteomalacia is a rare acquired
metabolic disorder characterized by hypophosphatemia
and inappropriately low serum levels of 1,25dihydroxyvitamin D. Symptoms include chronic muscle
and bone pain, weakness, and fatigue in association with
a high risk of fragility fractures due to osteomalacia.
The diagnosis is commonly delayed for years due to the
nonspecific nature of the presenting symptoms, failure
to include determination of serum phosphorus levels in
blood chemistry testing, and difficulty in identifying the
responsible tumor. The pathogenesis of tumor-induced
osteomalacia involves tumor expression of fibroblast
growth factor 23, a hormone that inhibits proximal
renal tubular reabsorption of phosphate and downregulates renal conversion of 25-hydroxyvitamin D to its
active form, 1,25-dihydroxyvitamin D. The metabolic
abnormalities may be partially or completely corrected
with phosphate supplementation and calcitriol. A definitive diagnosis and treatment require excision of the
responsible tumor.
mis syndrome, seronegative polyarthritis, severe osteoporosis, and polyostotic Paget’s disease of bone. Following a hip fracture, further studies suggested the presence
of tumor-induced osteomalacia, also called oncogenic
osteomalacia. This is a rare paraneoplastic disorder
characterized by renal phosphate wasting associated
with hypophosphatemia and inappropriately low blood
levels of 1,25-dihydroxyvitamin D (1,25-[OH]2D), resulting in a condition similar to hypophosphatemic rickets.
The diagnosis of tumor-induced osteomalacia was confirmed by the dramatic improvement of symptoms and
correction of metabolic abnormalities following excision
of the responsible tumor.
This case illustrates the importance of including
metabolic bone disease in the differential diagnosis of
patients with persistent rheumatic symptoms of unknown origin and the perils of relying on standard
laboratory panels that do not provide important diagnostic information.
In this report, we describe an unusual case in
which the patient presented with bone and muscle pain,
progressive muscle weakness, and fragility fractures due
to an unrecognized metabolic bone disease. Despite
evaluation with numerous laboratory tests and imaging
studies by many specialists over a period of almost 2
years, the origin of his symptoms remained obscure. At
various times he was treated, unsuccessfully, for pirifor-
CASE REPORT
The patient, a 46-year-old Hispanic male cigarette smoker, considered himself healthy and vigorous
until April 2005, when he noted the onset of progressively severe pain in his buttocks, low back, arms, and
legs. He was initially evaluated by his primary care
physician and later by specialists that included an oncologist, an orthopedic surgeon, a physiatrist, and several
rheumatologists. An injection of botulinum toxin type A
in the right buttock for suspected piriformis syndrome
provided no relief. A glucocorticoid injection in the left
sacroiliac joint for apparent sacroiliitis did not help.
Nonsteroidal drugs, including diflunisal, celecoxib, oxycodone, and pregabalin, did not relieve the pain.
In April 2006, a physical examination showed that
the patient had great difficulty sitting or arising from a
seated position. Getting up on the examination table
1
E. Michael Lewiecki, MD: New Mexico Clinical Research
and Osteoporosis Center, Albuquerque; 2Edward J. Urig, Jr., DMD,
MS: St. Vincent Medical Center, Santa Fe, New Mexico; 3Ralph C.
Williams, Jr., MD: University of New Mexico School of Medicine,
Albuquerque.
Address correspondence and reprint requests to E. Michael
Lewiecki, MD, New Mexico Clinical Research and Osteoporosis
Center, 300 Oak Street NE, Albuquerque, NM 87106. E-mail:
lewiecki@aol.com.
Submitted for publication August 29, 2007; accepted in
revised form December 7, 2007.
773
774
caused much pain in his lower back, buttocks, and thighs,
and moderate pressure produced pain over the ribs of
the anterior chest and the left pectoral region. The
patient had tenderness in both forearms and upper arms
as well as in both quadriceps areas. His knees were
painful on flexion and extension, with no sign of synovitis
or fluid in any peripheral joint.
Laboratory tests showed that the white blood cell
count and differential, red blood cell count, platelet
count, and erythrocyte sedimentation rate (11 mm/hour)
were normal. The comprehensive metabolic panel, a
standardized set of blood chemistries performed at
laboratories throughout the US, showed normal results
for glucose, blood urea nitrogen, creatinine, sodium,
chloride, CO2, the anion gap, total protein, albumin,
globulin, the albumin:globulin ratio, calcium, aspartate
aminotransferase, alanine aminotransferase, and total
bilirubin, with an elevated level of total alkaline phosphatase of 205 IU/liter (reference range at outpatient
laboratory 41–130). The level of bone-specific alkaline
phosphatase was high at 164 IU/liter (normal 12–84).
Other laboratory tests that had normal or negative
results included tests for rheumatoid factor and antinuclear antibody, prostate-specific antigen level and
C-reactive protein level, serum protein electrophoresis,
and urinalysis. The clinical impression at that time was
widespread metastatic disease because of the rib tenderness, findings of increased uptake of radioactive-labeled
technetium in several ribs on a previous nuclear bone
scan, and past elevation of the serum alkaline phosphatase level.
In May 2006, an attempted transiliac bone biopsy
(without double tetracycline labeling) produced multiple
tissue fragments that showed no evidence of malignancy
in the marrow cells, and results of flow cytometry were
normal. Unfortunately, the specimens were uninterpretable for evaluation of metabolic bone disease, due to
fragmentation and lack of tetracycline labeling. A
1-week course of sulfasalazine and then a 2-week course
of prednisone in dosages as high as 60 mg/day provided
no relief of the patient’s unrelenting symptoms. Over the
following months, efforts to relieve pain with nonsteroidal drugs (including narcotic analgesics) continued, and
additional studies were done. A total body nuclear bone
scan with radiolabeled technetium, performed in August
2006, showed discrete foci of intense uptake in the right
anterior third and seventh ribs, with increased uptake in
both sacral alae, intense increased uptake on both sides
of the knee joints (particularly on the right side), increased uptake at both ankle joints, and discrete focal
increased uptake in the right mandible anteriorly.
LEWIECKI ET AL
In September 2006, evaluation by rheumatologists at a tertiary care medical center resulted in a
diagnosis of Paget’s disease. The patient was treated
with oral alendronate at a dosage of 40 mg/day and then
with 2 intravenous infusions of zoledronic acid (5 mg),
first in November 2006 and again in December 2006.
None of the treatments for Paget’s disease resulted in an
improvement in symptoms. In October 2006, a magnetic
resonance imaging study of the right knee revealed
multiple incomplete fracture planes paralleling the fused
epiphysial plates in both distal femurs and proximal
tibias medialis, corresponding to the areas of abnormal
increased uptake on prior nuclear bone scans. The
results of bone density testing by dual x-ray absorptiometry were interpreted as osteoporosis, based on a
lumbar spine (L2–L4) T score of ⫺3.0, using a female
reference database. Later the same month, a computed
tomography (CT) scan of the abdomen was read as
normal, with no evidence of metastatic disease in the
liver and no evidence of enlarged retroperitoneal lymph
nodes. CT examination of the pelvis showed undisplaced
fractures through both sacral alae and through the
anteromedial aspects of the iliac bones, extending into
the sacroiliac joints bilaterally, corresponding with areas
of increased uptake on the previous nuclear bone scan.
In November 2006, the serum 25-hydroxyvitamin
D (25[OH]D) level was 18 ng/ml (desirable level ⬎30),
and the serum C-telopeptide of type I collagen level was
254 pg/ml (reference range 60–700). The patient’s pain
and muscle weakness were now so severe that he used a
wheelchair most of the time.
On February 1, 2007, the patient fell at home,
sustaining an intertrochanteric fracture of the left hip.
He was admitted to the hospital for surgical repair. Bone
fragments obtained at the time of surgery were sent to
the laboratory for analysis. There was no histologic
evidence of malignancy or Paget’s disease, although
evaluation for metabolic bone disease was limited by the
absence of tetracycline labeling. Upon admission to the
hospital, the level of serum phosphorus, which was
measured for the first time in the course of his protracted illness, was low at 1.5 mg/dl (normal 2.4–5.0),
with values as low as 0.5 mg/dl prior to sufficient
phosphorus replacement. Selected baseline hospital laboratory values are shown in Table 1. The renal tubular
reabsorption of phosphate was low at 40% (normal
83–95%). The renal threshold phosphate concentration,
calculated from the nomogram described by Walton and
Bijvoet (1), was 0.6 mg/dl (normal 2.5–4.2). The serum
FGF-23 level was markedly elevated at 262 RU/ml
TUMOR-INDUCED OSTEOMALACIA
775
Table 1. Results of selected hospital laboratory tests prior to tumor
excision*
Test
Baseline
value
Reference
value
Serum calcium, mg/dl
Serum ionized calcium, mg/dl
Serum phosphorus, mg/dl
Serum alkaline phosphatase, units/liter
Serum 25-hydroxyvitamin D, ng/ml
Serum 1,25-dihydroxyvitamin D, pg/ml
Serum intact parathyroid hormone, pg/ml
24-hour urinary phosphorus, gm
24-hour urinary calcium, mg
7.4
4.6
1.5
177
18
6
129.3
2.05
22.5
8.1–10.2
4.6–5.4
2.4–5.0
20–150
30–60
15–60
14–72
0.9–1.3
50–300
(reference range ⬍180; Mayo Clinic Reference Laboratory, Rochester, MN).
A presumptive diagnosis of tumor-induced osteomalacia was made on the basis of clinical and laboratory
findings consistent with osteomalacia, hypophosphatemia, and elevated serum levels of FGF-23. A
radiolabeled total body octreotide scan showed an intense focus of uptake in the shaft of the right mandible
(Figure 1); this was the same region that showed increased uptake on a previous technetium bone scan.
Several days later, the right mandible lesion was excised
by an oral surgeon (EJU). The pathology report showed
a benign collection of fibrils and mesenchymal tissue
intertwined with apparent osteoid, with no histologic
features of malignancy (Figure 2). Postoperatively, the
patient was treated with calcitriol, large doses of oral
phosphorus, and calcium supplementation. He began
Figure 2. Microscopic appearance of fibrous tumor removed from the
patient’s mandible, showing numerous fibroblasts and spindle cells
surrounding areas of osteoid deposits (original magnification ⫻ 125).
rehabilitation and gradual ambulation in the hospital
and was discharged to home care. On a repeat assay
performed 10 days after surgery, serum FGF-23 was
undetectable. Four weeks after hospital discharge, the
patient was walking with a walker, with great improvement in the chronic bone and muscle pain. A repeat
radiograph of the left hip showed good position of the
intrafemoral rod and radiographic signs of bone healing.
Five months later, he continued to improve and was able
to ambulate with the aid of a cane and work at his
regular job.
DISCUSSION
Figure 1. Radiolabeled octreotide scan showing intense uptake in the
patient’s right mandible (arrow).
The diagnosis of tumor-induced osteomalacia is a
challenge under the best of circumstances. Symptoms of
osteomalacia are nonspecific and may be incorrectly
attributed to fibromyalgia, inflammatory arthritis, or a
functional disorder. Tumor-induced osteomalacia
should be included in the differential diagnosis in patients with progressive weakness, bone and muscle pain,
and fractures. Proximal myopathy, which is commonly
reported in patients with osteomalacia, may cause a
waddling gait and difficulty with ambulation. Proximal
myopathy was particularly disabling in this patient, eventually resulting in the need for a wheelchair. The typical
time from the onset of symptoms to a presumptive
diagnosis of tumor-induced osteomalacia is often longer
than 2.5 years (2), and the average time from then until
the responsible tumor is identified is ⬃5 years (3). The
search for these tumors is confounded by their usual
776
small size, slow growth, and difficulties with visualization
on standard imaging studies.
Although in this patient the period of time from
the onset of symptoms to diagnosis may have been
shorter than average, he suffered for almost 2 years with
his disease and its complications. His presentation and
subsequent course provide an interesting learning experience that may lead to a faster diagnosis for other
patients with tumor-induced osteomalacia. First, if serum phosphorus had been included in the original blood
chemistry panels to evaluate his symptoms, the finding
of a low level would likely have led to an evaluation of
the causes of hypophosphatemia and phosphate-wasting
syndromes. It is especially important to measure serum
phosphorus levels in patients with elevated alkaline
phosphatase levels and to obtain the blood specimen
when the patient is in a fasting state. Unlike the tight
control of serum calcium, phosphorus levels may fluctuate according to variables that include time of day and
dietary intake. Serum phosphorus levels are maintained
in the normal range due to complex interactions among
intestinal absorption, exchange with intracellular and
bone storage pools, and renal tubular reabsorption, with
the kidney being the principal organ responsible for
phosphorus homeostasis (4).
The differential diagnosis of hypophosphatemia
includes autosomal-dominant hypophosphatemic rickets
(ADHR), X-linked hypophosphatemic rickets (XLHR),
and tissue-induced osteomalacia. Although ADHR and
XLHR are biochemically indistinguishable from tissueinduced osteomalacia, the former two disorders typically
present in childhood and are associated with lowerextremity deformities and short stature. A definitive
diagnosis can be made by commercially available genetic
testing of the FGF-23 and PHEX genes, which are
defective in ADHR and XLHR, respectively, but not
tissue-induced osteomalacia (4). Second, the numerous
abnormalities found on imaging studies of the ribs,
femurs, spine, and pelvis, in association with the absence
of malignancy on bone marrow examination, should
have suggested the possibility of osteomalacia or other
types of intrinsic bone disease. Finally, although the
performance of a bone biopsy was appropriate in the
evaluation of this patient, its value was greatly diminished by the absence of double tetracycline labeling,
inappropriate technique in obtaining the specimen, and
failure to send the specimen to a center with experience
in diagnosing metabolic bone disease.
The complex clinical presentation was punctuated by the patient’s hip fracture, leading to hospitalization with appropriate metabolic evaluation. Because
LEWIECKI ET AL
mesenchymal tumors that may cause tumor-induced
osteomalacia commonly express somatostatin receptors
(5), an octreotide scan using a radiolabeled somatostatin
analog was performed. This clearly identified the small
mandible tumor responsible for the elevated level of
FGF-23. Interestingly, the mandibular abnormality was
also seen, but not recognized as being clinically significant, on the previous technetium bone scan, which is
considered to be an insensitive diagnostic tool for identifying these tumors (2).
Tumor-induced osteomalacia is typically caused
by benign mesenchymal tumors but has also been associated with various carcinomas, sarcomas, neurofibromatosis, linear nevus syndrome, and fibrous dysplasia of
bone. The tumors may occur in either bone or soft tissue
and seem to favor the extremities and craniofacial
region. The pathophysiology of tumor-induced osteomalacia is 2-fold: hypophosphatemia secondary to impaired
proximal renal tubular reabsorption of phosphate, and
inhibition of renal 25(OH)D–1-␣-hydroxylase activity,
which blunts the compensatory rise in serum 1,25(OH)2-D in response to hypophosphatemia.
Since the earliest descriptions of tumor-induced
osteomalacia (6,7), continuing efforts have been made to
identify humoral factors, or phosphatonins, responsible
for the profound metabolic abnormalities. Although a
variety of phosphatonin candidates are expressed by
tumors associated with tumor-induced osteomalacia (8–
10), accumulating evidence suggests that FGF-23 plays a
key role in the pathogenesis of tumor-induced osteomalacia (8) and other disorders of renal phosphate wasting,
such as ADHR (11) and XLHR (12). This is supported
by an analysis of 32 cases of mesenchymal tumors
associated with documented or suspected tumorinduced osteomalacia, in which FGF-23 was expressed in
17 of 21 cases that were evaluated by immunohistochemistry with polyclonal antibody and in 2 of 2 cases
evaluated by reverse transcriptase–polymerase chain reaction (13). FGF-23 expression appeared to be localized
to highly vascularized spindle cells that were characteristic of these tumors and likely responsible for tumorinduced osteomalacia.
In the patient described here, a high blood level
of FGF-23 was detected before the mandible tumor was
removed, and 10 days after the tumor was removed,
FGF-23 was undetectable. In some patients with a
presumptive diagnosis of tumor-induced osteomalacia,
the responsible tumor is never found, and ongoing
treatment with phosphorus supplements and calcitriol is
required. The definitive treatment of tumor-induced
osteomalacia is resection of the responsible tumor.
TUMOR-INDUCED OSTEOMALACIA
ACKNOWLEDGMENT
The image in Figure 1 was photographed by Mike
Adam.
AUTHOR CONTRIBUTIONS
Dr. Lewiecki had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of the
data analysis.
Study design. Lewiecki, Williams.
Acquisition of data. Lewiecki, Williams.
Analysis and interpretation of data. Lewiecki, Williams.
Manuscript preparation. Lewiecki, Urig, Williams.
Oral and maxillofacial surgery. Urig.
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