title: Extravasation of hydroxymethylene diphosphonate-induced subcutaneous inflammation, histologically demonstrated in BALB/c mice.
abstract: We encountered local reactions at injection sites in 7 patients after an intravenous injection of (99m)Tc-hydroxymethylene diphosphonate ((99m)Tc-HDP). Archived bone scans showed radiopharmaceutical extravasation at injection sites in all patients. To identify the mechanism underlying these local reactions, we challenged BALB/c mice with an (99m)Tc-HDP injection and investigated the mechanism involved.
  
  
  METHODS
  Seven solutions were prepared: 0.1 M acetic acid, 0.1 M NaOH, 2.1 mM (99m)Tc-HDP, 4.7 mM (99m)Tc-methylene diphosphonate ((99m)Tc-MDP), 1.05 mM (99m)Tc-HDP diluted with normal saline, 37 MBq of (99m)Tc-pertechnetate, and normal saline. Six female BALB/c mice were subcutaneously injected in their backs with 0.04 mL of each solution. Backs were observed, and skin and subcutaneous tissues were acquired on days 5, 7, and 19 after injection. Two pathologists interpreted the histologic specimens.
  
  
  RESULTS
  The pH values of the 0.1 M acetic acid, 0.1 M NaOH, 2.1 mM (99m)Tc-HDP, 4.7 mM (99m)Tc-MDP, 1.05 mM (99m)Tc-HDP diluted with normal saline, 37 MBq (99m)Tc-pertechnetate, and normal saline were 3.28, 14.3, 4.79, 6.45, 6.16, 6.85, and 6.53, respectively. A slight redness was observed at (99m)Tc-HDP injection sites on day 5 after injection, and many inflammatory cells, such as neutrophils, were found to infiltrate subcutaneous tissues by light microscopy, suggesting active inflammation. However, no abnormality was found at (99m)Tc-MDP injection sites. On day 19, (99m)Tc-HDP injection sites appeared to have recovered and showed healed scars and almost-normal microscopic features.
  
  
  CONCLUSIONS
  Our results indicate that the local reaction induced by extravasation of (99m)Tc-HDP is probably caused by high acidity, and (99m)Tc-HDP should be administered carefully to avoid adverse reactions.
authors.affiliation: Department of Nuclear Medicine, Korea Cancer Center Hospital, Seoul, Korea.
authors.forename: Ilhan
authors.initials: I
authors.lastname: Lim
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
authors.forename: Jae Kyung
authors.initials: JK
authors.lastname: Myung
authors.forename: Kyeong Cheon
authors.initials: KC
authors.lastname: Jung
authors.forename: Yong Hyun
authors.initials: YH
authors.lastname: Jeon
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Kang
authors.forename: Young Hwa
authors.initials: YH
authors.lastname: Kim
authors.forename: June-Key
authors.initials: JK
authors.lastname: Chung
authors.forename: Dong Soo
authors.initials: DS
authors.lastname: Lee
mesh_terms: D000818:Animals; D004164:Diphosphonates / Q000009:adverse effects*; D003875:Drug Eruptions / Q000209:etiology* / Q000473:pathology*; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000209:etiology* / Q000473:pathology*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D015609:Organotechnetium Compounds / Q000009:adverse effects*
chemical_list: D004164:Diphosphonates; D015609:Organotechnetium Compounds; C060491:technetium Tc 99m hydroxydiphosphonate