Rebecca Frazier1, Alexander Hodakowski2, Xuan Cai2, Jungwha Lee3, Anaadriana Zakarija4, Brady Stein4, Valentin David5, Myles Wolf6, Tamara Isakova5, Rupal Mehta7. 1. Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Jesse Brown Veterans Administration Medical Center, Chicago, IL 60612, USA. Electronic address: Rebecca.frazier@northwestern.edu. 2. Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. 3. Division of Biostatistics, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. 4. Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. 5. Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. 6. Division of Nephrology, Department of Medicine, Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC 27701, USA. 7. Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Jesse Brown Veterans Administration Medical Center, Chicago, IL 60612, USA.
Abstract
BACKGROUND: Two weekly infusions of ferric carboxymaltose (FCM) are commonly prescribed for treatment of iron-deficiency anemia. However, administration of FCM increases intact levels of fibroblast growth factor 23 (FGF23), which causes hypophosphatemia due to renal phosphate wasting, calcitriol deficiency and secondary hyperparathyroidism. The adverse effects of FCM on mineral metabolism and bone health emerged from case reports and secondary analyses of trials. Data on these safety signals with FCM in clinical practice are limited because markers of mineral and bone metabolism are not routinely checked. METHODS: To obtain real-world experience with effects of FCM on mineral and bone metabolism, we conducted a prospective observational study of 16 women who were managed at a single-center hematology clinic for iron-deficiency anemia. From October 2016 to February 2018, all participants received two weekly infusions of FCM at a hematology infusion clinic. We hypothesized that FCM would decrease phosphate, increase intact FGF23 (iFGF23), and decrease c-terminal FGF23 (cFGF23). Secondary outcomes were changes in hemoglobin, iron indices, urine fractional excretion of phosphate (FePi), parathyroid hormone (PTH), calcitriol, calcium, osteocalcin, and bone-specific alkaline phosphatase (BAP). FCM was administered at weeks zero and one, and we measured laboratory values at weeks zero, one, two, and five of the study. We used linear mixed models to analyze the significance of the changes in laboratory values over time. RESULTS: After two FCM infusions, nearly all (14 of 16) participants developed hypophosphatemia. iFGF23 increased, cFGF23 decreased, and phosphate decreased significantly from week zero to week two (iFGF23 increased by +134.0% [40.6, 305.8], p < 0.001; cFGF23 decreased by -516.3% [-1332.7, -142.7], p = 0.002; phosphate decreased by -49.8 ± 15.4%, p < 0.001). There was also a significant increase in FePi, PTH, and BAP and a significant decrease in calcitriol and calcium from week zero to week two. There was no significant change in osteocalcin during this time period. iFGF23, but not PTH, was independently associated with decreased phosphate. iFGF23 was also significantly associated with decrease in calcitriol from week zero to week two. Elevation in BAP suggests disordered bone mineralization in response to FCM therapy. CONCLUSION: In this prospective observational study of women with iron deficiency anemia, two FCM infusions significantly altered markers of bone mineralization and mineral metabolism. The results suggest that FCM should be used cautiously in the treatment of iron-deficiency anemia. Published by Elsevier Inc.
BACKGROUND: Two weekly infusions of ferric carboxymaltose (FCM) are commonly prescribed for treatment of iron-deficiency anemia. However, administration of FCM increases intact levels of fibroblast growth factor 23 (FGF23), which causes hypophosphatemia due to renal phosphate wasting, calcitrioldeficiency and secondary hyperparathyroidism. The adverse effects of FCM on mineral metabolism and bone health emerged from case reports and secondary analyses of trials. Data on these safety signals with FCM in clinical practice are limited because markers of mineral and bone metabolism are not routinely checked. METHODS: To obtain real-world experience with effects of FCM on mineral and bone metabolism, we conducted a prospective observational study of 16 women who were managed at a single-center hematology clinic for iron-deficiency anemia. From October 2016 to February 2018, all participants received two weekly infusions of FCM at a hematology infusion clinic. We hypothesized that FCM would decrease phosphate, increase intact FGF23 (iFGF23), and decrease c-terminal FGF23 (cFGF23). Secondary outcomes were changes in hemoglobin, iron indices, urine fractional excretion of phosphate (FePi), parathyroid hormone (PTH), calcitriol, calcium, osteocalcin, and bone-specific alkaline phosphatase (BAP). FCM was administered at weeks zero and one, and we measured laboratory values at weeks zero, one, two, and five of the study. We used linear mixed models to analyze the significance of the changes in laboratory values over time. RESULTS: After two FCM infusions, nearly all (14 of 16) participants developed hypophosphatemia. iFGF23 increased, cFGF23 decreased, and phosphate decreased significantly from week zero to week two (iFGF23 increased by +134.0% [40.6, 305.8], p < 0.001; cFGF23 decreased by -516.3% [-1332.7, -142.7], p = 0.002; phosphate decreased by -49.8 ± 15.4%, p < 0.001). There was also a significant increase in FePi, PTH, and BAP and a significant decrease in calcitriol and calcium from week zero to week two. There was no significant change in osteocalcin during this time period. iFGF23, but not PTH, was independently associated with decreased phosphate. iFGF23 was also significantly associated with decrease in calcitriol from week zero to week two. Elevation in BAP suggests disordered bone mineralization in response to FCM therapy. CONCLUSION: In this prospective observational study of women with iron deficiency anemia, two FCM infusions significantly altered markers of bone mineralization and mineral metabolism. The results suggest that FCM should be used cautiously in the treatment of iron-deficiency anemia. Published by Elsevier Inc.