Correspondence

Imatinib Mesylate, Increased Bone Formation, and Secondary Hyperparathyroidism

N Engl J Med 2006; 355:2494-2495December 7, 2006

Article

To the Editor:

In a recent cross-sectional study, Berman et al. found that some patients who were treated with imatinib mesylate had hypophosphatemia, with low-normal serum calcium levels, elevated levels of parathyroid hormone, and low-normal bone turnover.1 It is not clear what mechanism (or mechanisms) underlie these biochemical abnormalities. We have prospectively studied biochemical indexes of calcium metabolism in blood and urine samples obtained after an overnight fast from nine patients (six men and three women, with a mean [±SD] age of 46±10 years) who had the BCR-ABL mutation and were starting imatinib therapy (at a dose of 400 mg daily) for chronic myeloid leukemia. None of the patients had metabolic bone disease, and none were receiving medications known to influence the metabolism of calcium. The study was approved by the Auckland Ethics Committee, and all patients gave written informed consent.

After therapy was begun, levels of the specific markers of bone formation (osteocalcin and procollagen type I N-terminal propeptide [PINP]) increased significantly from baseline, whereas levels of a bone-resorption marker (β-isomer of the C-terminal telopeptide of type I collagen [β-CTX]) were stable (Table 1Table 1Biochemical Indexes of Bone and Calcium Metabolism in Patients with Chronic Myeloid Leukemia Who Received Imatinib Therapy.). These changes in bone turnover were accompanied by a reduced serum calcium level, secondary hyperparathyroidism, phosphaturia, and a reduced serum phosphate level. The changes in levels of parathyroid hormone, serum phosphate, and renal tubular phosphate reabsorption did not progress between 3 and 6 months of therapy.

On the basis of these prospectively collected data, altered bone remodeling and secondary hyperparathyroidism appear to occur in the early stages of imatinib therapy. The most parsimonious explanation for these findings is that imatinib directly stimulates bone formation while restraining resorption,2 resulting in a net flux of calcium from extracellular fluid into bone, a decreased serum calcium level, and a compensatory rise in the level of parathyroid hormone, which causes phosphaturia and modest hypophosphatemia. An alternative explanation is that imatinib both inhibits the intestinal absorption of calcium (which induces secondary hyperparathyroidism) and inhibits bone resorption (which abrogates the expected increase in this measure induced by parathyroid hormone). Both of these potential mechanisms involve direct skeletal effects of imatinib, suggesting a role for imatinib-sensitive kinases in skeletal homeostasis in vivo. The observed biochemical changes are not consistent with a purely antiresorptive action of imatinib, since bone resorption did not decline, and increased bone formation does not occur in response to antiresorptive agents, such as bisphosphonates or estrogen, even though these agents cause transient secondary hyperparathyroidism.3 We suggest that the hypophosphatemia associated with the use of imatinib results from secondary hyperparathyroidism. Long-term studies of the effects of imatinib on bone metabolism and bone density are warranted.

Andrew Grey, M.D., F.R.A.C.P.
Susannah O'Sullivan, M.B., Ch.B., F.R.A.C.P.
Ian R. Reid, M.D., F.R.A.C.P.
Peter Browett, M.B., Ch.B., F.R.A.C.P.
University of Auckland, Auckland 1001, New Zealand
a.grey@auckland.ac.nz

Drs. Reid and Browett report receiving research funding and consulting fees from Novartis.

3 References

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