Correspondence
Imatinib and Altered Bone and Mineral Metabolism
N Engl J Med 2006; 355:627-629August 10, 2006
- Article
To the Editor:
Berman and colleagues (May 11 issue)1 report their findings regarding the development of hypophosphatemia and associated changes in bone and mineral metabolism in patients with either chronic myelogenous leukemia or gastrointestinal stromal tumors who are taking imatinib. We have reviewed the global database of clinical trials sponsored by Novartis, as well as spontaneous post-marketing reports that cover approximately 200,000 patient-years of treatment with imatinib (unpublished data). There was a low incidence of reported hypophosphatemia or potential related events, although we recognize that the observations may be underreported.
Serum phosphate levels were routinely measured in two clinical trials — in the phase 1 trial 03001 involving a total of 143 patients, including 59 patients with chronic myeloid leukemia, and in the phase 2 trial 0102 involving 260 patients with chronic myeloid leukemia in blast crisis. Hypophosphatemia of Common Toxicity Criteria grade 2 or above was observed in 50 percent of the 403 patients (33 percent had grade 2, 15 percent grade 3, and 1.5 percent grade 4). However, in these two studies, hypophosphatemia was reported as an adverse event in only 3 percent of the patients. Hypophosphatemia is listed as a possible adverse event (<1 percent) in the product labeling on the basis of adverse events reported in the overall clinical-trials program in chronic myeloid leukemia.
Novartis supports the need for further studies to elucidate the effect of imatinib on phosphate levels or bone and mineral metabolism and to determine whether clinical monitoring or any specific therapy is required. Meanwhile, it would be prudent for physicians to monitor phosphate levels in their patients who are taking imatinib. Concerned patients should talk with their health care providers to evaluate their individual treatment needs.
1 ReferencesSamantha Owen, Ph.D.
Alan Hatfield, M.D.
Laurie Letvak, M.D.
Novartis Pharmaceuticals, East Hanover, NJ 07936-1080
samantha_jane.owen@novartis. com 1
Berman E ,Nicolaides M ,Maki RG , et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med 2006;354:2006-2013
Full Text | Web of Science | Medline
To the Editor:
Berman et al. suggest that in a subgroup of patients treated with imatinib mesylate, hypophosphatemia developed as a result of the suppression of bone turnover and renal phosphate wasting. However, several aspects of the report merit comment. First, phosphate levels were measured in only four patients before treatment, rendering it uncertain that hypophosphatemia is treatment-mediated. Second, calcium levels were not corrected for albumin levels, although levels of ionized calcium seem to be similar in the two study groups. Third, 50 percent of the patients had untreated low levels of 25-hydroxyvitamin D before evaluation. Fourth, blood sampling was not standardized with respect to time and fasting status — preanalysis variables that could significantly affect measurements of bone markers.1 Finally, the correlation analysis indicated an unexpected positive association between 1,25-dihydroxyvitamin D and phosphate levels, whereas no association between parathyroid hormone (PTH) levels and phosphate excretion was reported. Thus, before one suggests that inhibition of the platelet-derived growth factor receptor by imatinib results in hypophosphatemia, other mechanisms should be investigated, such as those implicated in patients with tumor-induced osteomalacia,2 although increased levels of fibroblast growth factor 23 are reported only in patients with chronic lymphocytic leukemia and plasma-cell dyscrasias.3
3 ReferencesSymeon Tournis, M.D.
George P. Lyritis, M.D., Ph.D.
Laboratory for Research of Musculoskeletal, System “Th. Garofalidis”, 14561 Athens, Greece
stournis@med.uoa. gr 1
Hannon R ,Eastell R . Preanalytical variability of biochemical markers of bone turnover. Osteoporos Int 2000;11:Suppl 6:S30-S44
CrossRef | Web of Science | Medline2
Kumar R . Tumor-induced osteomalacia and the regulation of phosphate homeostasis. Bone 2000;27:333-338
CrossRef | Web of Science | Medline3
Stewart I ,Roddie C ,Gill A , et al. Elevated serum FGF23 concentrations in plasma cell dyscrasias. Bone 2006;39:369-376
CrossRef | Web of Science | Medline
To the Editor:
Berman et al. diagnosed hypophosphatemia in 16 patients who were given imatinib for either leukemia or advanced gastrointestinal stromal tumors, yet the duration, reversibility, and clinical significance of imatinib-related hypophosphatemia remain unknown. Hypophosphatemia is occasionally associated with overt cancer.1-3
We have conducted a longitudinal follow-up of plasma phosphate and calcium levels in 11 patients who received 400 mg of imatinib daily as adjuvant treatment of gastrointestinal stromal tumors for a period of 3 to 24 months. Of these 11 patients, 9 (82 percent) had plasma phosphate levels below the normal range on at least one occasion during treatment, and most of the patients had lower mean plasma phosphate levels during treatment than at baseline (Table 1Table 1
Effect of Adjuvant Treatment with Imatinib on Plasma Phosphate Levels in Patients with Gastrointestinal Stromal Tumors.). The plasma phosphate levels had returned to the normal range in a sample obtained two to four months after the discontinuation of therapy in all but one of six patients in whom hypophosphatemia developed during treatment. None of the 11 patients had a bone fracture. These data might suggest that although hypophosphatemia is not infrequent during adjuvant treatment with imatinib, it appears to be reversible on discontinuation of the drug.Heikki Joensuu, M.D.
Helsinki University Central Hospital, FIN-00029 Helsinki, Finland
heikki.joensuu@hus. fi Peter Reichardt, M.D.
Charité Campus Virchow-Klinikum, 13125 Berlin, GermanyDrs. Joensuu and Reichardt report having received lecture fees and fees for service on the advisory board from Novartis, and Dr. Reichardt reports having received honoraria and research grants from Novartis.
3 References1
Jonsson KB ,Zahradnik R ,Larsson T , et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 2003;348:1656-1663
Full Text | Web of Science | Medline2
Carpenter TO . Oncogenic osteomalacia -- a complex dance of factors. N Engl J Med 2003;348:1705-1708
Full Text | Web of Science | Medline3
Ra'anani P ,Lahav M ,Prokocimer R ,Poles L ,Theodor E . Life threatening hypophosphatemia in a patient with Philadelphia chromosome-positive chronic myelogenous leukaemia in acute blastic crisis. Postgrad Med J 1992;68:283-286
CrossRef | Web of Science | Medline
Author/Editor Response
We agree with the recommendation of Owen and colleagues that physicians monitor phosphate levels in patients receiving imatinib, but we would like to emphasize that high levels of urinary phosphate excretion and abnormal markers of bone formation and resorption were noted in patients with normal serum phosphate levels. Thus, serum phosphate is not a sensitive marker for detecting abnormalities of bone metabolism. Whether hypophosphatemia will ultimately develop in patients who have normal phosphate levels but urinary phosphate wasting and whether any or all such patients are at risk for osteopenia remain to be determined. We are pleased that Novartis supports the need for further research in this very important area.
Tournis and Lyritis pose several important questions related to specific metabolic measurements. We studied relatively small numbers of patients with low serum phosphate levels (low-phosphate group) or normal serum phosphate levels (normal-phosphate group), and although blood and urine samples were not obtained during a fasting state, for reasons discussed in the article, sampling was clustered around 10 a.m. The PTH levels were high in the low-phosphate group during the time of the presumed PTH nadir, which suggests that the parathyroid function was, in fact, abnormal in this group. Moreover, 4 of 12 patients in the low-phosphate group had no measurable amount of osteocalcin (documented in the Supplementary Appendix of the article); values this low would not be expected during a nadir period. It is unlikely that tumor-induced osteomalacia could account for all these metabolic changes, since similar observations were made in patients with chronic myelogenous leukemia, gastrointestinal stromal tumors, and other forms of sarcoma and would probably also be made in patients with renal-cell cancer who were taking sunitinib or sorafenib,1 groups in which hypophosphatemia has been noted as well.
Last, a direct relationship between imatinib and hypophosphatemia was illustrated in one patient (Table 1Table 1
Effect of Stopping and Resuming Imatinib Therapy in Patient 5.), who had a normal pretreatment serum phosphate level; hypophosphatemia with an elevated parathyroid hormone value developed while this patient was taking imatinib, and when imatinib was temporarily discontinued, the serum phosphate level increased and the PTH level decreased.Joensuu and Reichardt present data on 11 patients with gastrointestinal stromal tumors, in 9 of whom hypophosphatemia developed that resolved on discontinuation of imatinib. These data appear to confirm our findings and are consistent with the data in Table 1.
1 ReferencesEllin Berman, M.D.
Martin Fleisher, Ph.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021
bermane@mskcc.org Nicholas P. Sauter, M.D.
Novartis Pharmaceuticals, East Hanover, NJ 07936- Citing Articles (10)
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E Jabbour, M Deininger, A Hochhaus. (2011) Management of adverse events associated with tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia 25:2, 201-210
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Valentina Baldazzi, Renato Tassi, Alberto Lapini, Alice Lunghi, Eleonora Garofoli, Salvatore Caruso, Marco Carini, Roberto Mazzanti. (2011) Sunitinib-induced hyperparathyroidism. Cancern/a-n/a
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Kate Vandyke, Andrea L Dewar, Peter Diamond, Stephen Fitter, Christopher G Schultz, Natalie A Sims, Andrew CW Zannettino. (2010) The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo. Journal of Bone and Mineral Research 25:8, 1759-1770
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G. Liamis, H. J. Milionis, M. Elisaf. (2010) Medication-induced hypophosphatemia: a review. QJM 103:7, 449-459
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Philipp Ivanyi, Thomas Winkler, Anika Großhennig, Christoph Reuter, Axel S. Merseburger, Arnold Ganser, Viktor Grünwald. (2010) Treatment with tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma is associated with drug-induced hyperparathyroidism: a single center experience in 59 patients. World Journal of Urology 28:3, 311-317
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K. Vandyke, S. Fitter, A. L. Dewar, T. P. Hughes, A. C. W. Zannettino. (2010) Dysregulation of bone remodeling by imatinib mesylate. Blood 115:4, 766-774
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R. A. de Oliveira, I. D. B. Marques, A. C. Seguro, L. Andrade. (2008) Electrolyte disturbances and acute kidney injury induced by imatinib therapy. NDT Plus 2:1, 27-29
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Helene François, Paul Coppo, Jean-Philippe Hayman, Bruno Fouqueray, Béatrice Mougenot, Pierre Ronco. (2008) Partial Fanconi Syndrome Induced by Imatinib Therapy: A Novel Cause of Urinary Phosphate Loss. American Journal of Kidney Diseases 51:2, 298-301
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(2007) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 16:2, i-xii
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