Saccharated ferric oxide (SFO)-induced osteomalacia: in vitro inhibition by SFO of bone formation and 1,25-dihydroxy-vitamin D production in renal tubules.
A 60-year-old man with portal hypertensive gastropathy due to type C liver cirrhosis developed severe bone pains, marked hypophosphatemia with inappropriately increased urinary excretion of phosphate (%TRP; 9.6%), and hyperalkaline phosphatasia, after intravenous administration of saccharated ferric oxide (SFO) at a dose of 80-240 mg/week over a period of more than 5 years. The total iron infused was estimated to be more than 25 g. On a diagnosis of SFO-induced osteomalacia, the infusion of iron was immediately discontinued, and phosphate and vitamin D2 (1000 IU/day) were administered. Serum levels of 25-OHD2 increased after 1 week, whereas levels of 1,25-(OH)2D2 did not increase until 3 months later, accompanied by improvement of renal tubular reabsorption of phosphate and gradual improvement of the bone pains. The patient has been doing well for the last 2 years, with normal serum levels of phosphate, calcium, and alkaline phosphatase, without any supplementation of phosphate, vitamin D, or iron-containing agents. In primary culture of neonatal mouse renal tubules, in which 1,25-(OH)2D3 was produced from 25-OHD3 in response to PTH, SFO significantly inhibited PTH-induced production of 1,25-(OH)2D3 at 30 mumol/L, which is attainable in the urine of patients receiving a therapeutic intravenous dose of SFO. Furthermore, SFO decreased the calcium content and inhibited 45Ca incorporation in cultured fetal mouse parietal bones at 3 mumol/L. Such SFO concentration may be transiently observed in the plasma of patients receiving excessive intravenous doses of SFO for a prolonged period. These in vitro findings together with the clinical observations suggest that SFO, after filtration through the glomerulus and reabsorption in the proximal renal tubules, impaired proximal renal tubular function, such as tubular reabsorption of phosphate and 1 alpha-hydroxylase activity, leading to hypophosphatemic osteomalacia. Furthermore, it is highly likely that SFO in the peripheral blood, when transferrin is saturated with iron, may impair bone formation and aggravate osteomalacia. Although SFO-induced osteomalacia is reversible simply by discontinuation of the agent, excessive and prolonged administration of SFO should be avoided.
Sato
K
K
Department of Medicine, Tokyo Women's Medical College, Japan.
Nohtomi
K
K
Demura
H
H
Takeuchi
A
A
Kobayashi
T
T
Kazama
J
J
Ozawa
H
H
D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D002117:Calcitriol / Q000378:metabolism; D002118:Calcium / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004872:Ergocalciferols / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology / Q000627:therapeutic use; D005290:Ferric Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry; D006471:Gastrointestinal Hemorrhage / Q000188:drug therapy / Q000209:etiology; D006801:Humans; D006975:Hypertension, Portal / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D017674:Hypophosphatemia / Q000139:chemically induced / Q000473:pathology; D007275:Injections, Intravenous; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000150:complications / Q000503:physiopathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D010018:Osteomalacia / Q000139:chemically induced* / Q000175:diagnosis / Q000188:drug therapy; D010146:Pain / Q000188:drug therapy; D010281:Parathyroid Hormone / Q000494:pharmacology; D010294:Parietal Bone / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D010710:Phosphates / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use / Q000652:urine
D004872:Ergocalciferols; D005290:Ferric Compounds; D010281:Parathyroid Hormone; D010710:Phosphates; C000499:ferric oxide; C003564:1,25-dihydroxyergocalciferol; D000469:Alkaline Phosphatase; D002117:Calcitriol; D002118:Calcium