Fluoride Action Network

Exacerbation of rheumatoid arthritis by sodium fluoride treatment of osteoporosis.

May 12th, 2012

The following is an excerpt from:

Duell PB, Chesnut CH. (1991). Exacerbation of rheumatoid arthritis by sodium fluoride treatment of osteoporosis. Archives of Internal Medicine 151:783-4.

“Recent studies have suggested that sodium fluoride therapy may be an effective treatment for vertebral osteoporosis. Unfortunately, the high frequency of side effects may limit the use of this treatment modality. This report documents the repeated exacerbation of rheumatoid arthritis on three occasions after the initiation of sodium fluoride therapy. This apparent complication of sodium fluoride treatment may be mediated by stimulation of leukocyte production of reactive oxygen species and other mediators of the acute inflammatory response. We suggest that sodium fluoride should be used cautiously in patients with rheumatoid arthritis.

Several days after starting sodium fluoride therapy (22 mg F/day), she developed rapidly increasing upper- and lower- extremity joint inflammation with moderate to marked redness, swelling, synovial thickening, and increased warmth and pain in several areas previously affected by rheumatoid arthritis (shoulders, elbows, wrists, hands, ankles, and feet). Her wrists, hands, ankles, and feet were most severely affected. The arthritic flare was accompanied by an increase in morning stiffness lasting from 1 to 4 hours, increased fatigability, and a subjective decrease in grip strength. The joint inflammation, morning stiffness, fatigability, and reduced grip strength improved significantly after the sodium fluoride therapy was discontinued for 1 week, but worsened again several days after a brief rechallenge with sodium fluoride. Both flares of arthritis resolved 5 to 8 days after sodium fluoride therapy was discontinued, without the need for other changes in the patient’s medication regimen. After 10 weeks of stable rheumatoid arthritis, a third and final trial of sodium fluoride was initiated, again resulting in an acute exacerbation of joint inflammation and pain, increasing morning stiffness, increased fatigability, and reduced grip strength.

This case documents the repeated aggravation of rheumatoid arthritis following sodium fluoride treatment. Although these data do not conclusively prove that sodium fluoride caused the worsening of our patient’s rheumatoid arthritis, the reproducibility of this effect on three occasions suggests that there is a high probability that sodium fluoride has a causative role in this previously unreported complication. Moreover, there are experimental data that suggest that one might expect sodium fluoride to increase the activity of rheumatoid arthritis.

Activation of T lymphocytes and polymorponuclear leukocytes in the synovial fluid is believed to play an important role in the etiology of joint inflammation and destruction associated with rheumatoid arthritis. In particular, the production of reactive oxygen species and other inflammatory mediators by polymorphonuclear leukocytes is thought to help mediate acute inflammatory processes in the synovial fluid. (7)

Recent studies in a cell-free system have indicated that fluoride ion stimulates the activity of neutrophil-derived reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-dependent superoxide-generating oxidase and increases the production of superoxide. (8) Other investigators have shown that superoxide production by blood monocytes is stimulated ex vivo by fluoride ion. (9) Preliminary results (unpublished) in our laboratory have demonstrated dose-dependent stimulation of superoxide production by 10- to 100- umol/L fluoride ion in cultured human monocyte-derived macrophages, as measured per the method of Heinecke et al. (10) The therapeutic plasma concentration of fluoride is believed to be approximately 10 to 20 umol/L, although the associated concentration in synovial fluid is unknown. Hence, it is conceivable that fluoride ion may stimulate superoxide production in vivo in patients receiving sodium fluoride therapy, thereby increasing the activity of rheumatoid arthritis.

Fluoride ion may also contribute to leukocyte activation and inflammation via an unrelated mechanism. Mo1 is a plasma membrane glycoprotein found on human myeloid cells that functions as an adhesion-promoting molecule and as the C3bi receptor. Factors that increase expression of Mo1 would be expected to enhance cell activation and the attendant inflammatory responses. Stimulation of human neutrophils with fluoride ion ex vivo has been shown to increase expression of Mo1. (11) Thus, fluorie ion might stimulate the inflammatory response in vivo and cause worsening of rheumatoid arthritis by two or more potential mechanisms.”


(7) Lipsky PE. Rheumatoid arthritis. In: Braunwald E, Isselbacher KJ, Petersdorf RG, Wilson JD, Martin JB, Franci AS, eds. Harrison’s Principles of Internal Medicine 11th ed. New York, NY: McGraw-Hill International Book Co; 1987:1423-1428.

(8) Gabig TG, English D, Akard LP, Schell MJ. Regulation of neutrophil NADPH oxidase activation in a cell-free system by guanine nucleotides and fluoride. Evidence for participation of a pertussis and cholera toxin-insensitive G protein. J Biol Chem. 1987;262:1685-90.

(9) Bell AL, Hurst NP, Nuki G. Effect of corticosteroid therapy on blood monocyte superoxide generation in rheumatoid arthritis: studies in vitro and ex vivo. Br J Rheumatol. 1986;25:366-71.

(10) Heinecke JW, Baker L, Rosen H, Chait A. Superoxide-mediated modification of low density lipoprotein by arterial smooth muscle cells. J Clin Invest. 1986;77:757-61.

(11) Petrequin PR, Todd RF 3rd, Devall LJ, Boxer LA, Curnutte JT III. Association between gelatinase release and increased plasma membrane expression of the Mo1 glycoprotein. Blood. 1987;69:605-10.