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

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.Quinolone-induced arthropathy is an unusual toxic effect observed with all known quinolones. Cartilage lesions are inducible in juvenile animals of multiple species, such as dogs (3,4,31), rats (14, 29), nonhuman primates (29), and others (9). The chondrotoxic potential of quinolones in humans under therapeutic conditions is low. Most juvenile patients have shown no signs of arthropathy after treatment with these drugs (1, 26). On the other hand, symptoms of arthropathy in juvenile and even adult patients have been described in a considerable number of case reports (e.g., references 5 and 24). Since most of these patients had cystic fibrosis-a disease which itself can be associated with arthropathy-the causal relationship in these observations and the indications for quinolone therapy in pediatrics remain matters for discussion (6,25,28).Recently, we hypothesized that quinolones might affect magnesium-dependent integrins of the ␤ 1 subfamily in articular cartilage as the primary event of...

Ciprofloxacin Induced Chondrotoxicity and Tendinopathy

“…Ciprofloxacin induced chrondrotoxicity was also explain on the basis that Ciprofloxacin chelates magnesium ions or divalent ions resulting in change function of chondrocytes surface integrin receptors (Stahlmann et al, 1995;Shakibaei et al, 2000;Lozo et al, 2004). This report is supported by the ability of magnesium to reverse or inhibit Ciprofloxacin induced chrondrotoxicity (Stahlmann et al, 1999;Stahlmann, 2002).…”

Toxic Effects of Quinolone Antibacterial Agents on the Musculoskeletal System in Juvenile Rats

“…The lesion seen in the present study was the same as those previously reported. Although its mechanisms are not completely understood, some suggested hypotheses include the involvement of mitochondrial dysfunction (2), interference of the drug with DNA metabolism (30), or interference with the extracellular matrix of joint cartilage by formation of quinolone-magnesium chelate complexes (5,27 Quinolones have been widely used. However, because of their toxic potential to the immature articular cartilage, which has been demonstrated in many animal species (2,6,7,14,16,26) …”

Immunohistochemistry of Articular Cartilage from Immature Beagle Dogs Dosed with Difloxacin

“…Quinolones are potent chelating agents (16,17,20) and there is emerging evidence that they damage juvenile joint cartilage of animals due to their chelating properties, in particular by forming stable chelate complexes with magnesium (24,27). In this respect, it is of interest that lameness and gait alterations closely resembling quinolone-induced arthropathy were described in magnesiumdeficient dogs almost 4 decades ago (26).…”