Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1995 Sep;39(9):2013–2018. doi: 10.1128/aac.39.9.2013

Magnesium deficiency induces joint cartilage lesions in juvenile rats which are identical to quinolone-induced arthropathy.

R Stahlmann 1, C Förster 1, M Shakibaei 1, J Vormann 1, T Günther 1, H J Merker 1
PMCID: PMC162873  PMID: 8540708

Abstract

Quinolones accumulate in cartilage, and because they form chelate complexes with divalent cations, they possess the potential to induce a deficiency of functionally available magnesium. To test the hypothesis that quinolone-induced arthropathy is caused (or aggravated) by magnesium deficiency in cartilage, we induced magnesium deficiency by feeding juvenile rats a magnesium-deficient diet for 9 days and treated the rats with single oral doses of ofloxacin (0, 100, 300, 600, or 1,200 mg/kg of body weight) during this period. Additional groups of juvenile rats on a normal diet were treated with ofloxacin correspondingly. Typical cartilage lesions (e.g., swollen matrix, cleft formation) were found in knee joints of all magnesium-deficient rats, including those without ofloxacin treatment. Lesions in these groups were not distinguishable from lesions induced by a single dose of 600 mg of ofloxacin per kg of body weight or higher in rats on a normal diet. Ofloxacin levels in plasma after 600 mg/kg of body weight were approximately 10-fold higher than those in humans during therapy with this quinolone. Lesions in rats treated with ofloxacin plus magnesium deficiency were more pronounced than those in rats with normal magnesium concentrations. After intake of a magnesium-deficient diet for 9 days, the magnesium concentration in serum (mean +/- standard deviation) was 0.18 +/- 0.05 mmol/liter (control on normal diet, 0.82 +/- 0.10 mmol/liter). Magnesium concentrations in bone (femur) and cartilage (processus xiphoideus) samples were 64.7 +/- 10.5 and 14.3 +/- 3.9 mmol/kg of dry weight, respectively, which corresponded to approximately 50% of the concentrations measured in controls on a normal diet. It was concluded that quinolone-induced arthropathy is probably caused by a deficit of available magnesium in joint cartilage due to the formation of quinolone-magnesium chelate complexes. If juvenile patients must be treated with quinolones for serious infections, it seems prudent to ensure that these patients do not have a disturbed magnesium balance.

Full Text

The Full Text of this article is available as a PDF (1.7 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bendele A. M., Hulman J. F., Harvey A. K., Hrubey P. S., Chandrasekhar S. Passive role of articular chondrocytes in quinolone-induced arthropathy in guinea pigs. Toxicol Pathol. 1990;18(2):304–312. doi: 10.1177/019262339001800209. [DOI] [PubMed] [Google Scholar]
  2. Burkhardt J. E., Hill M. A., Carlton W. W. Morphologic and biochemical changes in articular cartilages of immature beagle dogs dosed with difloxacin. Toxicol Pathol. 1992;20(2):246–252. doi: 10.1177/019262339202000211. [DOI] [PubMed] [Google Scholar]
  3. Burkhardt J. E., Hill M. A., Lamar C. H., Smith G. N., Jr, Carlton W. W. Effects of difloxacin on the metabolism of glycosaminoglycans and collagen in organ cultures of articular cartilage. Fundam Appl Toxicol. 1993 Feb;20(2):257–263. doi: 10.1006/faat.1993.1034. [DOI] [PubMed] [Google Scholar]
  4. Chevalier X., Albengres E., Voisin M. C., Tillement J. P., Larget-Piet B. A case of destructive polyarthropathy in a 17-year-old youth following pefloxacin treatment. Drug Saf. 1992 Jul-Aug;7(4):310–314. doi: 10.2165/00002018-199207040-00007. [DOI] [PubMed] [Google Scholar]
  5. Chyský V., Kapila K., Hullmann R., Arcieri G., Schacht P., Echols R. Safety of ciprofloxacin in children: worldwide clinical experience based on compassionate use. Emphasis on joint evaluation. Infection. 1991 Jul-Aug;19(4):289–296. doi: 10.1007/BF01644970. [DOI] [PubMed] [Google Scholar]
  6. Deppermann K. M., Lode H. Fluoroquinolones: interaction profile during enteral absorption. Drugs. 1993;45 (Suppl 3):65–72. doi: 10.2165/00003495-199300453-00013. [DOI] [PubMed] [Google Scholar]
  7. Enomoto M., Leboy P. S., Menko A. S., Boettiger D. Beta 1 integrins mediate chondrocyte interaction with type I collagen, type II collagen, and fibronectin. Exp Cell Res. 1993 Apr;205(2):276–285. doi: 10.1006/excr.1993.1087. [DOI] [PubMed] [Google Scholar]
  8. Gough A. W., Kasali O. B., Sigler R. E., Baragi V. Quinolone arthropathy--acute toxicity to immature articular cartilage. Toxicol Pathol. 1992;20(3 Pt 1):436–450. doi: 10.1177/019262339202000313. [DOI] [PubMed] [Google Scholar]
  9. Höffken G., Borner K., Glatzel P. D., Koeppe P., Lode H. Reduced enteral absorption of ciprofloxacin in the presence of antacids. Eur J Clin Microbiol. 1985 Jun;4(3):345–345. doi: 10.1007/BF02013667. [DOI] [PubMed] [Google Scholar]
  10. Kato M., Onodera T. Effect of ofloxacin on the uptake of [3H]thymidine by articular cartilage cells in the rat. Toxicol Lett. 1988 Nov;44(1-2):131–142. doi: 10.1016/0378-4274(88)90139-7. [DOI] [PubMed] [Google Scholar]
  11. Kato M., Onodera T. Morphological investigation of cavity formation in articular cartilage induced by ofloxacin in rats. Fundam Appl Toxicol. 1988 Jul;11(1):110–119. doi: 10.1016/0272-0590(88)90275-8. [DOI] [PubMed] [Google Scholar]
  12. Kirchhofer D., Grzesiak J., Pierschbacher M. D. Calcium as a potential physiological regulator of integrin-mediated cell adhesion. J Biol Chem. 1991 Mar 5;266(7):4471–4477. [PubMed] [Google Scholar]
  13. Lode H., Höffken G., Olschewski P., Sievers B., Kirch A., Borner K., Koeppe P. Pharmacokinetics of ofloxacin after parenteral and oral administration. Antimicrob Agents Chemother. 1987 Sep;31(9):1338–1342. doi: 10.1128/aac.31.9.1338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Loeser R. F. Integrin-mediated attachment of articular chondrocytes to extracellular matrix proteins. Arthritis Rheum. 1993 Aug;36(8):1103–1110. doi: 10.1002/art.1780360811. [DOI] [PubMed] [Google Scholar]
  15. Lomaestro B. M., Bailie G. R. Quinolone-cation interactions: a review. DICP. 1991 Nov;25(11):1249–1258. doi: 10.1177/106002809102501115. [DOI] [PubMed] [Google Scholar]
  16. Neu H. C. Quinolone antimicrobial agents. Annu Rev Med. 1992;43:465–486. doi: 10.1146/annurev.me.43.020192.002341. [DOI] [PubMed] [Google Scholar]
  17. Palù G., Valisena S., Ciarrocchi G., Gatto B., Palumbo M. Quinolone binding to DNA is mediated by magnesium ions. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9671–9675. doi: 10.1073/pnas.89.20.9671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pertuiset E., Lenoir G., Jehanne M., Douchain F., Guillot M., Menkès C. J. Tolérance articulaire de la péfloxacine et de l'ofloxacine chez les enfants et adolescents atteints de mucoviscidose. Rev Rhum Mal Osteoartic. 1989 Nov;56(11):735–740. [PubMed] [Google Scholar]
  19. Samuelson W. M., Pleasants R. A., Whitaker M. S. Arthropathy secondary to ciprofloxacin in an adult cystic fibrosis patient. Ann Pharmacother. 1993 Mar;27(3):302–303. doi: 10.1177/106002809302700308. [DOI] [PubMed] [Google Scholar]
  20. Schaad U. B. Role of the new quinolones in pediatric practice. Pediatr Infect Dis J. 1992 Dec;11(12):1043–1046. doi: 10.1097/00006454-199211120-00010. [DOI] [PubMed] [Google Scholar]
  21. Schaad U. B., Wedgwood J. Lack of quinolone-induced arthropathy in children. J Antimicrob Chemother. 1992 Oct;30(4):414–416. doi: 10.1093/jac/30.4.414. [DOI] [PubMed] [Google Scholar]
  22. Stahlmann R., Förster C., Van Sickle D. Quinolones in children. Are concerns over arthropathy justified? Drug Saf. 1993 Dec;9(6):397–403. doi: 10.2165/00002018-199309060-00002. [DOI] [PubMed] [Google Scholar]
  23. Stahlmann R., Merker H. J., Hinz N., Chahoud I., Webb J., Heger W., Neubert D. Ofloxacin in juvenile non-human primates and rats. Arthropathia and drug plasma concentrations. Arch Toxicol. 1990;64(3):193–204. doi: 10.1007/BF02010725. [DOI] [PubMed] [Google Scholar]
  24. Takada S., Kato M., Takayama S. Comparison of lesions induced by intra-articular injections of quinolones and compounds damaging cartilage components in rat femoral condyles. J Toxicol Environ Health. 1994 May;42(1):73–88. doi: 10.1080/15287399409531864. [DOI] [PubMed] [Google Scholar]
  25. Tatsumi H., Senda H., Yatera S., Takemoto Y., Yamayoshi M., Ohnishi K. Toxicological studies on pipemidic acid. V. Effect on diarthrodial joints of experimental animals. J Toxicol Sci. 1978 Nov;3(4):357–367. doi: 10.2131/jts.3.357. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES