Cinacalcet in the Management of Tumor-Induced Osteomalacia
Jordan L Geller,1,2Azarmindokht Khosravi,2,3Marilyn H Kelly,3Mara Riminucci,4,5John S Adams,1and
Michael T Collins3
ABSTRACT: Both FGF-23 and PTH inhibit renal phosphate reabsorption. We treated two patients with TIO
and FGF-23–mediated hypophosphatemia with cinacalcet to test the hypothesis that medicinally induced
hypoparathyroidism would decrease renal phosphate wasting. Cinacalcet treatment resulted in increased
renal phosphate reabsorption, allowed for a decrease in phosphate supplementation, and showed evidence of
bone healing in one of the two patients.
Introduction: Tumor-induced osteomalacia (TIO) is a rare, acquired disease of renal phosphate wasting,
which results in hypophosphatemia and osteomalacia. It is caused by mesenchymal tumors that produce the
phosphate and vitamin D–regulating hormone, fibroblast growth factor (FGF)-23. Removal of the tumor is
curative, but the tumors are often difficult to locate. Medical treatment involves high doses of oral phosphate
and calcitriol, but the phosphate is often poorly tolerated and leads to diarrhea. Because PTH also promotes
phosphaturia, and patients with hypoparathyroidism are hyperphosphatemic in the setting of elevated serum
FGF-23, we postulated that the calcium-sensing receptor agonist, cinacalcet, which can induce hypoparathy-
roidism, would be an effective adjuvant in the treatment of TIO.
Materials and Methods: Two subjects with presumed TIO in whom the tumor was not located after extensive
testing and who did not tolerate medical therapy with phosphorus and calcitriol were treated with cinacalcet.
Results: Neither treatment with phosphorus nor combined treatment with phosphorus and calcitriol had an
effect on serum FGF-23 levels. Treatment with cinacalcet resulted in increased renal phosphate reabsorption
and serum phosphorus and allowed for a decrease in phosphate supplementation to a dose that was tolerated.
On this regimen, one patient showed significant bone healing as shown by resolution of activity on bone scan
and lack of osteomalacia as assessed by histomorphometry.
Conclusions: These data show that medically induced hypoparathyroidism with cinacalcet is a therapeutic
option for disorders of FGF-23–mediated hypophosphatemia and that, in the absence of PTH, the phospha-
turic effect of FGF-23 is decreased.
J Bone Miner Res 2007;22:931–937. Published online on March 12, 2007; doi: 10.1359/JBMR.070304
Key words: hypophosphatemia, fibroblast growth factor-23, phosphatonin, hypoparathyroidism, phosphate,
tamin D homeostasis.(1)Synthesized by osteogenic
cells,(2–4)FGF-23 acts in the proximal renal tubule to de-
crease renal phosphate reabsorption by inhibition of the
expression of the type 2 sodium-phosphate co-transporter
(NaPi2) and inhibition of the expression of the mitochon-
drial CYP 27B1-hydroxylase, which is responsible for con-
IBROBLAST GROWTH FACTOR-23 (FGF-23) is a peptide
hormone with an important role in phosphate and vi-
version of 25-hydroxyvitamin D3to its active metabolite,
Tumor-induced osteomalacia (TIO) is a paraneoplastic
syndrome caused by high serum levels of FGF-23 secreted
by benign mesenchymal neoplasms.(7,8)TIO typically
presents in adulthood with proximal muscle weakness, bone
pain, and pathological fractures. Biochemical findings
typically include hyperphosphaturia, hypophosphatemia,
inappropriately normal (or frankly low) serum 1,25-
dihydroxyvitamin D3, and markedly elevated serum FGF-
23.(9)Although the definitive treatment of TIO is removal
of the causative neoplasm, such tumors are notorious for
evading the most rigorous anatomic and functional investi-
The authors state that they have no conflicts of interest.
1Clinical Research Institute, Cedars-Sinai Medical Center and the David Geffen School of Medicine at UCLA, Los Angeles, California,
USA;2These authors contributed equally to this paper;3Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch,
National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services,
Bethesda, Maryland, USA;4Dipartimento di Medicina Sperimentale e Patologia, Universita “La Sapienza,” Rome, Italy;5Division of
Pathology, Department of Experimental Medicine, University of L’Aquila, L’Aquila, Italy.
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 22, Number 6, 2007
Published online on March 12, 2007; doi: 10.1359/JBMR.070304
© 2007 American Society for Bone and Mineral Research
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Address reprint requests to:
Michael T Collins, MD
Craniofacial and Skeletal Diseases Branch
National Institute of Dental and Craniofacial Research
National Institutes of Health
Department of Health and Human Services
Building 30, Room 228, MSC 4320
Bethesda, MD 20892-4320, USA
Received in original form September 6, 2006; revised form Febru-
ary 3, 2007; accepted March 5, 2007.
CINACALCET IN THE MANAGEMENT OF TUMOR-INDUCED OSTEOMALACIA937