Altered Bone and Mineral Metabolism in Patients Treated with Imatinb.
Authors: Berman Ellin , Nicolaides Maria , Sauter Nicolas , Chanel Suzanne , Wilson Brianne , Fleisher Martin 
Published: April 2020

Imatinib is a tyrosine kinase that effectively inhibits the bcr-abl fusion protein in Philadelphia (Ph) chromosome positive CML and c-kit, which is overexpressed in gastrointestinal stomal tumors (GIST). We identified a group of patients treated with Imatinib at Memorial Hospital who developed low phosphate (PO4) levels and studied metabolic bone and mineral parameters associated with this finding. A total of 61 patients who received a prescription for Imatinib from the hospital pharmacy were screened to determine whether a PO4 level had ever been drawn. Of these, 26 had at least one PO4 level, and 10 of these (38%) had a low value (&lt;2.5 mg/dL).Patients samples were then studied for calcium (Ca++), parathyroid horme (PTH), 25-(OH)-vitamin D and 1,25-(OH)2-vitamin D, as well as serum markers of bone formation (bone alkaline phosphatase and osteocalcin) and resorption (N-telopeptide). Urinary calcium and PO4 were measured and fractional excretion of PO4 (FEPO4) was calculated as well. A total of 10 patients (8 men, 2 women) median age 47 (range 32–60) with CML (n=8) or GIST (n=2) were studied. The median time interval between diagnosis and starting Imatinib was 3.8 mos (range 0.4–161) and the median interval between starting Imatinib and first low PO4 was 3.9 mos (range 0.3–23).

Results of Bone Metabolism

UPIN PO4 Calcium PTH FePO4 N-Telopep Osteocalcin Bone Alk phos ND: Not done: NMA: No measurable amount; 25-(OH)-vitD levels were low to mid-normal, and 1,25-(OH)2 vit D levels were typically borderline high or elevated (data not shown) 2.5–4.2mg/dL 8.5–10.5mg/dL 10–65pg/mL &lt; 5% 5.5–19.5nM 3.1–12.7ng/ml 15–441U/L 1 2.0 8.7 84 25 ND ND ND 2 1.7 8.6 97 24 ND ND ND 3 2.3 9.4 68 44 ND ND ND 4 1.9 9.5 84 25 7.1 3.7 18 5 1.8 8.9 85 17 6.2 NMA 15 6 2.1 9.3 83 23 ND ND ND 7 1.7 8.7 57 16 5.6 NMA 17 8 1.3 8.1 136 38 10.1 NMA 53 9 2.3 9.2 81 10 13.4 NMA 17 10 2.1 8.9 41 17 5.8 2.6 15

Two patients who temporarily stopped Imatinib had normalization of their PO4, which again decreased upon resumption of the drug. In summary, patients who develop hypophosphatemia while on Imatinib have low-normal to mildly low serum Ca++ but elevated PTH, elevated FEPO4, low-normal levels of N-telopeptide, very low levels of osteocalcin, and low levels of bone alkaline phosphatase. These values distinctly differ from patients with either inherited or tumor induced forms of hypophosphatemia with renal phosphate wasting (X-linked hypophosphatemic rickets, adult dominant hypophosphatemic rickets, and tumor-induced osteomalacia). Our preliminary data suggest that in some patients, Imatinib results in profound suppression of bone formation and mild suppression of bone resorption, leading to a state of hypodynamic bone remodeling. Further investigation is planned comparing patients on Imatinib who become hypophosphatemic and those who do not. Better characterization of bone and mineral metabolism in this setting is important for several reasons: (1) myalgias from Imatinb, a common side effect, may be related to hyphophosphatemia and correctible with appropriate replacement; (2) while these data are premature, it is conceivable that Imatinib might be useful in situations where suppression of bone formation and turnover is desirable, such as in osteoblastic bone metastases, osteopetrosis, and other diseases of abnormally increased bone formation.