PLO is therefore associated with significant morbidity, a high prevalence of recognized risk factors for osteoporosis and a risk of recurrence in subsequent pregnancies. Bisphosphonate therapy administered soon after presentation substantially increases spinal bone density in patients with PLO.

Several lines of evidence suggest that imatinib may affect skeletal tissue. We show that inhibition by imatinib of PDGFR signaling in osteoblasts activates osteoblast differentiation and inhibits osteoblast proliferation and that imatinib inhibits osteoclastogenesis by both stromal cell-dependent and direct effects on osteoclast precursors. Introduction: Imatinib mesylate, an orally active inhibitor of the c-abl, c-kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, is in clinical use for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal cell tumors. Interruption of both c-kit and c-abl signaling in mice induces osteopenia, suggesting that imatinib might have adverse effects on the skeleton. However, biochemical markers of bone formation increase in patients with CML starting imatinib therapy, whereas bone resorption is unchanged, despite secondary hyperparathyroidism. We assessed the actions of imatinib on bone cells in vitro to study the cellular and molecular mechanism(s) underlying the skeletal effects we observed in imatinib-treated patients. Materials and Methods: Osteoblast differentiation was assessed using a mineralization assay, proliferation by [

T h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med 355;23 www.nejm.org december 7, 2006 * Plus-minus values are means ±SD. Statistical analyses were performed with the use of a mixed-models approach to repeated measures (PROC Mixed software, SAS, version 9.1). Significant time effects were investigated post hoc with the use of the Tukey method to preserve an overall level of significance of 0.05. All tests were two-tailed. Reference ranges for osteocalcin, PINP, and β-CTX are for men and premenopausal women. GFR denotes glomerular filtration rate, and ND not done. † P<0.01 for the comparison with the baseline value. ‡ P<0.05 for the comparison with the baseline value. § Testosterone was measured in men only. The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF SUSSEX on August 11, 2015. For personal use only. No other uses without permission.

Long-term treatment with imatinib leads to persistent mild secondary hyperparathyroidism. Despite this, bone turnover is decreased, and bone density is stable or increased. Evaluation of the skeletal actions and safety of imatinib during longer-term therapy is warranted.

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