Bone Reports 13 (2020) 100712 Contents lists available at ScienceDirect Bone Reports journal homepage: www.elsevier.com/locate/bonr Case Report Severe osteomalacia with multiple insufficiency fractures secondary to T intravenous iron therapy in a patient with Rendu-Osler-Weber syndrome Eduardo Luis Callejas-Moragaa, , Enrique Casadob, Marta Gomez-Nuñezc, ⁎ Ana Paula Caresia-Arozteguid a Department of Internal Medicine, University Hospital Parc Taulí, Universitat Autònoma de Barcelona (UAB), Sabadell, Barcelona, Spain b Department of Rheumatology, University Hospital Parc Taulí, Universitat Autònoma de Barcelona (UAB), Sabadell, Barcelona, Spain c Department of Hematology, University Hospital Parc Taulí, Universitat Autònoma de Barcelona (UAB), Sabadell, Barcelona, Spain d Department of Nuclear Medicine, University Hospital Parc Taulí, Universitat Autònoma de Barcelona (UAB), Sabadell, Barcelona, Spain ARTICLE INFO ABSTRACT Keywords: Summary: This case report describes a 65-year-old man with a Rendu-Osler-Weber syndrome with secondary Osteomalacia chronic anaemia, who received multiple intravenous (IV) iron infusions and sustained diffuse bone pain sec- Fibroblast growth factor 23 ondary to multiple insufficiency fractures. Laboratory study confirmed fibroblast growth factor 23 (FGF-23)- Hypophosphatemia mediated hypophosphatemia as the main cause of a severe osteomalacia induced by ferric carboxymaltose Intravenous iron therapy (FCM). After 3 months or oral phosphate replacement and switching to iron sucrose, serum phosphate levels were normalized and patient improved clinically. Introduction: Some drugs can induce asymptomatic hypophosphatemia, which if sustained, can lead to a severe osteomalacia with multiple skeletal fractures. This complication has also been described with IV iron therapy. Methods: This case report describes a patient with Rendu-Osler-Weber syndrome with chronic iron deficiency anaemia, recurrently treated with FCM, who developed a severe osteomalacia with multiple skeletal fractures. Results: Laboratory study showed hypophosphatemia, with high ALP and high FGF-23. Images studies confirmed bone mass loss and multiple insufficiency fractures. A Fluorodeoxyglucose Positron Emission Tomography/ Computed Tomography (18F-FDG PET/CT) did not show hidden tumor, so a diagnosis of FCM-induced hypo- phosphatemic osteomalacia was performed. Phosphate replacement improved clinical symptoms of the patient. Conclusion: Intravenous iron therapy, mainly FCM form, can cause hypophosphatemia, and in some cases induce a severe osteomalacia with multiple fractures, so it seems advisable to monitor serum phosphate levels in high risk patients, as those who receive repeated dose. 1. Introduction Tumor-induced osteomalacia (TIO), also known oncogenic osteo- malacia, is a rare paraneoplastic syndrome associated with low phos- Osteomalacia is a metabolic bone disease defined by an impairment phate and caused by small endocrine tumors that secrete the phos- of bone mineralization. Skeletal fractures and bone or polyarticular phaturic hormone, fibroblast growth factor 23 (FGF23) (Agarwal et al., pain are the most frequent symptoms, being present in almost 90% of 2019; Ryan and Reiss, 1984). cases, with predominant location in lower extremities, pelvic ring and Some drugs can induce a decrease in serum phosphate levels spine (Gifre et al., 2011). Although the main cause of osteomalacia is through different mechanisms. Chronic treatment with nonabsorbable vitamin D deficiency, there are other less frequent causes as impaired antacids can decrease intestinal phosphate absorption (Lotz et al., vitamin D metabolism, vitamin D resistance or hypophosphatemia 1968). Insulin treatment of diabetic ketoacidosis, is effective to recover (Bhan et al., 2018). metabolic acidosis, but the intracellular phosphate shift decreases Among the causes of hypophosphatemia, are decrease in phosphate phosphate serum levels (Kebler et al., 1985). Some diuretics, tyrosine intestinal absorption, increase in phosphate urinary excretion or phos- kinase inhibitors (e.g. imatinib), or antiviral drugs (e.g. tenofovir), can phate redistribution (Gaasbeek and Meinders, 2005). induce a renal loss of phosphate (Manghat et al., 2014). ⁎ Corresponding author at: Department of Internal Medicine, Hospital Universitari Parc Taulí, Parc Taulí 1, 08208 Sabadell, Barcelona, Spain. E-mail address: elcallejas@tauli.cat (E.L. Callejas-Moraga). https://doi.org/10.1016/j.bonr.2020.100712 Received 22 June 2020; Received in revised form 8 August 2020; Accepted 19 August 2020 Available online 22 August 2020 2352-1872/ © 2020 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). E.L. Callejas-Moraga, et al. Bone Reports 13 (2020) 100712 Ferric carboxymaltose (FCM) is an iron formulation increasingly Table 1 prescribed due to its effectiveness and fast infusion time. FCM can cause Baseline laboratory data. hypophosphatemia secondary to fibroblast growth factor 23 (FGF23) Variable Patient Reference range dysregulation (Glaspy et al., 2020). In patients with chronic anaemia requiring long-term iron admin- Hemoglobin, g/L 8.4 130–175 Calcium, mg/dL 9.2 8.8–10.2 istration, a long-lasting hypophosphatemia can lead to osteomalacia Phosphate, mg/L 1.2 2.7–4.5 with associated bone pain and skeletal fractures. Gamma-glutamyl transferase, U/L 10 8–61 Hypophosphatemia is a widely known complication of FCM treat- Alkaline phosphatase, U/L 356 40–129 ment. However, to our knowledge only few cases of FCM induced os- 25-Hydroxyvitamin D, ng/mL 21.8 > 30 teomalacia were reported (Anand and Schmid, 2017; Klein et al., 2018; Parathyroid hormone, pg/mL 82 10–65 Creatinine, mg/dL 0.93 0.7–1.2 Schouten et al., 2009; Tozzi and Tozzi, 2019), being this the first case in Glomerular filtration rate CKD-EPI mL/min/1.73 m2 87.5 > 60 a patient with hereditary hemorrhagic telangiectasia (HHT) or Rendu- Thyrotropin, μU/mL 2.15 0.4–4.0 Osler-Weber syndrome. Cortisol, μg/dL 17.9 6.02–18.4 Total testosterone, ng/mL 7.18 1.93–7.40 Tryptase, μg/L 5.3 0–11 2. Case report 24-Hour urine calcium, mg/d 46.8 100–300 24-Hour urine phosphate, g/d 0.44 0.4–1.3 A 65-year-old man was evaluated in the Internal Medicine out- Fractional excretion of phosphate, % 5.9 <5 patient clinic because of widespread pain. Serum C-terminal FGF-23, RU/mL > 419 < 145 For the last 6 months prior to admission, the patient had been suf- Prostate specific antigen, ng/mL 0.9 0–4 IgG lambda, g/L 1.21 fering from increasing bone pain in both shoulders, pelvic girdle and IgM lambda, g/L 1.48 four limbs, which worsened with movements. Pain did not produce sleep disturbance but was intensively progressing, requiring crutch and FGF-23: fibroblast growth factor 23; CKD-EPI: Chronic Kidney Disease wheelchair to move. Patient didn't refer to weakness, asthenia, fever or Epidemiology Collaboration. constitutional symptoms such as weight loss. Personal history of interest included sensorineural deafness, type 2 Oral phosphate replacement with 3.56 g of sodium phosphate three diabetes treated with insulin and sitagliptin; and HHT with iron defi- times a day initially, and adjusting doses in the follow-up kept serum ciency chronic anaemia due to intestinal blood loss and epistaxis. phosphate levels within the normal range (2.8 mg/dL and 2.7 mg dL at Patient had been treated with oral ferrous sulphate for fifteen years, but the third and tenth weeks after starting the replacement, respectively he required monthly intravenous (IV) iron treatment with FCM in the –reference values [2.7–4.5 mg/dL] with a time interval between oral last two years. phosphate intake and blood extraction of 14 h). Patient also received A previous fibrogastroscopy showed gastric and duodenal angio- calcium and vitamin D, risedronate was discontinued and FCM was dysplasia, which was treated by ligation with elastic bands. switched to iron sucrose. During follow-up, patient's pain and mobility Three years before, the patient was diagnosed of osteoporosis, with gradually improved. low bone mineral density (BMD) (T-score −2.0 at lumbar spine and −2.2 at femoral neck) at dual-energy X-ray absorptiometry (DXA) and a mild vertebral fracture. Serum calcium and phosphate levels were 3. Discussion within the normal range. He had been treated with risedronate, calcium (500 mg/day) and vitamin D (400 IU of cholecalciferol) since then with FCM-induced hypophosphatemia is highly underdiagnosed and may good adherence. lead to a skeletal impairment with severe consequences in comorbidity Currently retired, he worked as a jeweller. He never smoked or and quality of life of patients. drank alcohol and had a normal body mass index. Although FCM-induced hypophosphatemia can be asymptomatic, On physical examination the patient was afebrile, pale, but showed when it remains in time, as occurs in chronic conditions may result in good general condition. He had several facial and oral angiodysplasias. severe osteomalacia, as in our patient. He had neither swelling nor limited joints, but showed tenderness on Our patient was previously diagnosed of osteoporosis with a mild both shoulders, knees and femurs. vertebral fracture, but with his BMD in the range of osteopenia. He had Laboratory analysis revealed calcium 9.2 mg/dL [8.8–10.2], phos- a normal serum calcium and phosphate and was treated with oral bi- phate 1.2 mg/L [2.7–4.5], alkaline phosphatase (ALP) 356 U/L sphosphonates, calcium and vitamin D for the last 3 years. [40–129], 25-hydroxyvitamin D 21.8 ng/mL [optimal levels > 30], Although he didn't suffer any new vertebral or non-vertebral frac- parathyroid hormone (PTH) 82 pg/mL [10–65], creatinine 0.93 mg/dL ture, a progressive impairment of bone mineralization was the cause of [0.7–1.2], 24-hour urine calcium 46.8 mg, phosphate 0.44 g, and a widespread bone pain as first symptom of osteomalacia. Bone scan fractional excretion of phosphate (FEPO4) was 5.9%; serum C-terminal showed multiple insufficiency fractures. FGF-23 > 419 RU/mL [reference values up to 145 RU/mL]); other Osteomalacia has been reported with non-nitrogen containing bi- laboratory test results are shown in Table 1. sphosphonates but not with third generation bisphosphonates, like ri- 99m Tc-MDP bone scan showed multiple hot spots located in several sedronate. ribs, left scapula, bilateral sacral ala, ischiopubic and iliopubic bran- The presence of hypophosphatemia, 24-hour urine phosphate > ches, right femoral head, left tibia internal plateau and both tarsi. All 100 mg and FEPO4 > 5% and high FGF-23, indicated renal phosphate the findings were suspicious of insufficiency fractures or Looser's zones wasting, hence considering the history of recurrent previous infusions (Fig. 1). Whole-body computed tomography and whole-body magnetic of FCM made us suspect this complication. resonance imaging excluded metastasis and confirmed multiple in- Several diseases can cause chronic blood loss requiring IV iron sufficiency fractures. therapy, mainly erosive gastritis, peptic ulcer, diverticulitis, benign A DXA scan showed a significant loss of BMD (T-score −3.14 at tumors, inflammatory bowel disease, angiodysplasia, haemorrhoids and lumbar spine and −3.86 at femoral neck). chronic haemolysis (Camaschella, 2015). With the diagnosis of FGF-23-mediated hypophosphatemic osteo- Our patient had a HHT, an autosomal dominant inherited disease in malacia probably induced by FCM, a tumoral origin (TIO) was likewise which patients commonly had anaemia due to chronic digestive losses excluded with an 18 Fluorodeoxyglucose Positron Emission as hematemesis or melena in 33% (Kjeldsen and Kjeldsen, 2000). As far Tomography/Computed Tomography (18F-FDG PET/CT) (Fig. 2). as we are concerned, this is the first case in the literature of FCM- 2 E.L. Callejas-Moraga, et al. Bone Reports 13 (2020) 100712 Fig. 1. Bone scintigraphy with revealed a characteristic metabolic pattern with a generalized increased uptake in axial skeleton. Multiple hypercaptive foci consistent with insufficiency fractures or Looser's zones were observed in multiple bilateral rib, left scapula, bilateral sacral ala, ischiopubic and iliopubic branches, right femoral head, left tibia internal plateau and both tarsi. induced hypophosphatemic osteomalacia in a patient with HHT. associated with this complication. In a recent systematic literature re- Severe hypophosphatemia is an IV iron treatment side effect firstly view hypophosphatemia associated to IV iron therapies was reported in described by Okada M et al. in 1983 (Okada et al., 1983). Despite the 19 randomized control trials (Glaspy et al., 2020). This complication heterogeneous methodology of the studies and the different definition has been observed in 0.0–92.1% patients treated with FCM (18 studies), of hypophosphatemia, FCM is the form of IV iron most frequently 0.0–40.0% treated with iron sucrose (5 studies), 0.4% treated with 3 E.L. Callejas-Moraga, et al. Bone Reports 13 (2020) 100712 Fig. 2. Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT). A hidden tumor was ruled out, but multiple skeletal fractures were highlighted (arrows). a Whole body maximum intensity projection. b Fused coronal view. c Fused axial slices. ferumoxytol (1 study), and 0.0% treated with low-molecular-weight vitamin D levels can contribute to osteomalacia. Although our patient iron dextran (1 study). was receiving vitamin D supplementation (400 IU/day of cholecalci- FCM is a IV effective and safe iron formulation taken up by the ferol) he had vitamin D insufficiency (21 ng/mL) at presentation. reticuloendothelial cells and released gradually to the serum, with little Maybe the dose of cholecalciferol was insufficient to keep higher 25- risk of release of cytotoxic free iron into the circulating blood (Ikuta hydroxyvitamin D levels. et al., 2019). 25-Hydroxyvitamin D and phosphate serum levels were normalized Despite the mechanism by which FCM raises FGF-23 remains un- after vitamin D and sodium phosphate replacement in addition to known it has been proposed that certain carbohydrate moieties present switching to another iron therapy. Serum phosphate levels often fluc- in FCM can inhibit the degradation of FGF-23 (Wolf et al., 2013), re- tuate in patients with oral phosphate supplementation and it depends sulting in proximal tubular reabsorption of phosphate reduction and on the time since the last dose. However, in our patient serum phos- active form of vitamin D decrease (Holick, 2007; Wolf et al., 2020). phate levels were within the normal range in several blood tests with a Secondary hyperparathyroidism, as we saw in our patient, due to hy- regular time interval between oral intake and blood extraction. Patient pocalcemia caused by decreased 1,25-dihydroxyvitamin D also can also received calcium and vitamin D, risedronate was discontinued and make a part in increased phosphate clearance. However, high PTH FCM was switched to iron sucrose. During follow-up, patient's pain and actually leads to normal calcium levels and hypophosphatemia. In ad- mobility gradually improved. dition animal models have shown that FGF-23 reduces 1,25-dihydrox- This case highlights that although a single or few infusions of IV iron yvitamin D by reducing its production and increasing its degradation therapy is usually safe, in cases requiring multiple doses it could be (Shimada et al., 2004). advisable to monitor closely phosphate serum levels and normalize 25- FCM-induced hypophosphatemia has been reported to be transient hydroxyvitamin D deficiency. and asymptomatic in most cases, so serum phosphate levels of patients treated with FCM do not need to be checked or monitored in most cases Informed consent (Ikuta et al., 2019). Nevertheless, in patients with existing risk factors, such as severe malnutrition, vitamin D deficiency or after prolonged Informed consent was obtained from the participant included in this exposure to high dose IV iron, as in the case of our patient, hypopho- study. sphatemia may require medical attention. 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