To the Editor: Seufert et al. (Dec. 27 issue)1 describe a manwith tumor-induced (oncogenic) osteomalacia, in which the subcutaneousadministration of octreotide abolished renal tubular phosphatewasting. The authors suggest that in patients who cannot undergosurgery, phosphate wasting may be relieved by treatment withsomatostatin analogues, provided that the tumor expresses somatostatinreceptors. We believe that this statement is a misleading generalization.We observed a case of oncogenic osteomalacia in which total-bodyoctreotide scintigraphy detected the tumor. We therefore intravenouslyadministered octreotide at a dose of 600 µg per day forsix days — a dose in the same order of magnitude as thedose administered subcutaneously by Seufert et al. We did notobserve any effect on the biochemical variables (Figure 1).
Figure 1. Serum Phosphorus Level and Threshold for Renal Tubular Reabsorption of Phosphate during Intravenous Octreotide Therapy in a Patient with Tumor-Induced Osteomalacia.
The normal range for the serum phosphorus level is 0.8 to 1.4 mmol per liter; the normal range for the threshold for renal tubular reabsorption of phosphate is 0.8 to 1.6 mmol per liter.
The lack of response in our patient could be attributed eitherto the heterogeneous distribution of somatostatin receptorsamong tumor cells2,3 or to the prevalence of cells lacking somatostatinreceptors, as has been documented in some neuroendocrine tumors.3In the latter case, it is possible that treatment with the analoguesof somatostatin affects only some areas of the tumor. In fact,octreotide binds with high affinity to somatostatin receptorsubtypes 2 and 5 and with moderate affinity to subtype 3 butdoes not bind to subtypes 1 and 4. Finally, it is unclear whetherthe secretion of phosphaturic factors by the tumor cells ismodulated by somatostatin receptors. In any case, we do notsupport the widespread use of somatostatin analogues, especiallyconsidering their cost.
Federica Paglia, M.D. Simona Dionisi, M.D. Salvatore Minisola, M.D. Università degli Studi di Roma La Sapienza 00193 Rome, Italy salvatore.minisola{at}uniroma1.it
References
Seufert J, Ebert K, Müller J, et al. Octreotide therapy for tumor-induced osteomalacia. N Engl J Med 2001;345:1883-1888. [Free Full Text]
Wynick D, Anderson JV, Williams SJ, Bloom SR. Resistance to metastatic pancreatic endocrine tumours after long-term treatment with the somatostatin analogue octreotide (SMS 201-995). Clin Endocrinol (Oxf) 1989;30:385-388. [Medline]
Lamberts SWJ, van der Lely A-J, de Herrder WW, Hofland LJ. Octreotide. N Engl J Med 1996;334:246-254. [Free Full Text]
The authors reply:
To the Editor: Paglia et al. point out that octreotide therapydoes not affect phosphate wasting in all patients with tumor-inducedosteomalacia. We have become aware of similar cases characterizedby the obvious contradiction of positive results on octreotidescintigraphy and little therapeutic effect of the compound.By reporting our single case, we certainly did not mean to implythat the findings could be generalized to all tumors. The twofindings we wanted to stress are that tumors can be diagnosedwith the use of octreotide scans if conventional localizationprocedures fail and that a therapeutic trial of octreotide maybe worthwhile in individual patients. Furthermore, this casemight be considered as a paradigm for the novel concept of secretorycontrol of phosphaturic substances in humans. We notice differencesbetween the two patients such as the route of octreotide administrationand the basal phosphate reabsorption threshold — differencesthat can be evaluated only if one has the opportunity to analyzemore patients. However, fibroblast growth factor 23 was recentlyreported to suppress 25-hydroxyvitamin D3 1-hydroxylase activityin the kidney,1 which may, in part, explain the low levels of1,25-dihydroxyvitamin D3 in patients with tumor-induced osteomalacia.2This finding could contribute to the low renal tubular thresholdof phosphate reabsorption. Concomitant 1,25-dihydroxyvitaminD3 treatment in our patient may have had a permissive effecton normalization of phosphaturia. The relative heterogeneityof underlying histologic entities3,4 may serve as an alternativeexplanation for the lack of an effect of octreotide in octreotide-positivetumors. Although tumor-induced osteomalacia is a rare disorder,we propose that systematic analysis of somatostatin-receptorexpression has relevance to tumor-derived phosphatonin secretion.
In Table 1 of our article, the threshold for renal tubular reabsorptionof phosphate before octreotide therapy should have been 0.2mmol per liter, not 0.6 mmol per liter.
Jochen Seufert, M.D. Franz Jakob, M.D. University of Würzburg 97070 Würzburg, Germany j.seufert{at}mail.uni-wuerzburg.de
References
Shimada T, Mizutani S, Muto T, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A 2001;98:6500-6505. [Free Full Text]
Strewler GJ. FGF23, hypophosphatemia, and rickets: has phosphatonin been found? Proc Natl Acad Sci U S A 2001;98:5945-5946. [Free Full Text]
Crouzet J, Mimoune H, Beraneck L, Juan LH. Hypophosphatemic osteomalacia with plantar neurilemoma: a review of the literature (100 cases). Rev Rhum Engl Ed 1995;62:463-466. [Medline]
Park YK, Unni KK, Beabout JW, Hodgson SF. Oncogenic osteomalacia: a clinicopathologic study of 17 bone lesions. J Korean Med Sci 1994;9:289-298. [Medline]
Correction
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Seufert et al., 
-hydroxylase activity in the kidney,1 which may, in part, explain the low levels of 1,25-dihydroxyvitamin D3 in patients with tumor-induced osteomalacia.2 This finding could contribute to the low renal tubular threshold of phosphate reabsorption. Concomitant 1,25-dihydroxyvitamin D3 treatment in our patient may have had a permissive effect on normalization of phosphaturia. The relative heterogeneity of underlying histologic entities3,4 may serve as an alternative explanation for the lack of an effect of octreotide in octreotide-positive tumors. Although tumor-induced osteomalacia is a rare disorder, we propose that systematic analysis of somatostatin-receptor expression has relevance to tumor-derived phosphatonin secretion. 
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