In the 1960s and 1970s, doctors discovered that patients receiving kidney dialysis were accumulating very high levels of fluoride in their bones and blood, and that this exposure was associated with severe forms of osteomalacia, a bone-softening disease that leads to weak bones and often excruciating bone pain. Based on this discovery, dialysis units were ultimately modified to filter out fluoridated water from the dialysate. Dialysis patients still remain at risk of fluoride toxicity, however, due to their greatly diminished ability to excrete fluoride through their urine.

Fluoridation, Dialysis, & Osteomalacia (1960s-1970s)

“Five of the six patients exposed to fluoridated dialysate for an average of 23 months suffered bone pain and fractures, and three of these patients had incapacitating symptoms. Bone biopsy specimens from five patients exposed to fluoridated dialysate for more than 1 year were compared with those from six patients of approximately the same age, duration of azotemia, and duration of dialysis who were dialyzed using fluoride-free dialysate. The blood concentrations and ratios of bone fluoride to calcium were significantly higher in patients exposed to fluoridated dialysate. Although the severity of osteitis fibrosis was similar in the two groups, as reflected by the percentage of bone surface undergoing osteoclastic resorption, osteomalacia was significantly more severe in the fluoridated group.”
SOURCE: Johnson W, et al. (1979). Fluoridation and bone disease in renal patients. In: E Johansen, DR Taves, TO Olsen, Eds. Continuing Evaluation of the Use of Fluorides. AAAS Selected Symposium. Westview Press, Boulder, Colorado. pp. 275-293.

“Electron microscopical examination of iliac crest bone biopsy specimens from four patients suggests that fluoride induces the synthesis of disarrayed collagen by the activated osteoblasts… In the fluoridated group, osteoid seams were more abundant and wider than in the non-fluoridated group… This study has shown that hemodialysis with fluoridated water in chronic renal failure induces the activated osteoblasts to produce excessive osteoid in which the collagen fibrils are disarrayed. The risk of severe osteomalacia is reduced with the use of fluoride-free dialysate.”
SOURCE: Lough J, et al. (1975). Effects of fluoride on bone in chronic renal failure. Archives of Pathology 99: 484-487.

“The markedly increased incidence of osteomalacia in the fluoridated group supports previous reports that fluoride is an important factor… Since our patients in the fluoridated group were living in widely separate areas with different water supplies it seems unlikely that there was another common factor other than fluoride responsible for the higher incidence of osteomalacia. It is possible that the presence of other substances in untreated water is necessary before the toxic effects of fluoride become manifest… Forty-one patients on our chronic hemodialysis program were assessed for the degree of progression of bone disease over a period of 46 months. Four of 7 patients using fluoridated water developed florid osteomalacia, as opposed to none of the 34 patients in the non-fluoridated group… We conclude that the presence of fluoride in the dialysate, perhaps in conjunction with other substances, is associated with an increased incidence of osteomalacia. It therefore seems prudent to use non-fluoridated water in long-term hemodialysis.”
SOURCE: Cordy PE, et al. (1974). Bone disease in hemodialysis patients with particular reference to the effect of fluoride. Transactions of the American Society of Artifical Internal Organs 20: 197-202.

“within a year after starting dialysis the patient complained of chest pain and pain in the feet, and the skeletal radiologic survey showed generalized demineralization and fractures of the fifth through the eigth ribs posteriorly… In spite of a good appetite and a good intake of food, his body weight decreased by 11 kg. Because we had not seen such severe bone disease in a patient while on relatively high concentrations of dialysate calcium when fluoride-free water had been employed, we recommended in October, 1968, that a commercial mixed-bed deionizer be installed to remove the fluoride.. Bone resorption decreased and osteomalacia improved, coincident wtih the lowering of dialysate, serum and bone concentrations of fluoride… The excessive amounts of osteoid seen in the bone biopsy specimen and the decrease in osteomalacia subsequent to correcting the deionizer operation are consistent with a fluoride effect.”
SOURCE: Johnson WJ, Taves DR. (1974). Exposure to excessive fluoride during hemodialysis. Kidney International 5: 451-454.

“Hemodialysis with fluoridated water was associated with an elevation in serum alkaline phosphatase and an increase in renal osteodystrophy over a 2 year period, but without a control group of patients dialyzed wtih a fluoride free dialysate, it cannot be concluded that fluoride is responsible for these findings.”
SOURCE: Nielson E, et al. (1973). Fluoride metabolism in uremia. Transactions of the American Society of Artifical Internal Organs 19: 450-455.

“All 4 patients exposed to high-fluoride dialysate showed excessive osteoid formation… Osteoid formation was 9 times greater in those exposed to high-fluoride dialysate (1 ppm) than in those exposed to lower concentrations (0.095 ppm)… The presence of increased amounts of osteoid tissue in patients exposed to high-F dialysate is consistent with the observations of DeVeber and associates… Increased osteoid is typically found in fluorosis, hence, ascribing our findings to an F effect seems reasonable. There are several possible reasons for F causing increased osteoid. In vivo, excessive F can result in increased bone production and failure of mineralization… It may be noteworthy that 4 of the 5 patients with the most disabling symptoms of bone pain, muscle weakness, wasting and multiple spontaneous fractures were exposed to high-F dialysate. This would suggest that prolonged exposure to F can contribute to the bone disease seen in long-term hemodialysis… The use of F-free dialysate decreases the risk of severe morphologic osteomalacia.”
SOURCE: Jowsey J, et al. (1972). Effects of dialysate calcium and fluoride on bone disease during regular hemodialysis. Journal of Laboratory and Clinical Medicine 79: 204-214.

“At the Ottawa General Hospital, osteomalacia unresponsive to recommended therapy was the predominant bone lesion in our patients prior to deionization. Subsequent to deionization, no patient has developed clinical renal osteodystrophy of any type, and in particular no osteomalacia. Patients who began the program with secondary hyperparathyroidism improved with standard dialysis treatment. A patient with non-responsive osteomalacia prior to deionization responded normally following deionization by healing her fractures and calcifying her osteoid. Hence we found that we could not only prevent symptomatic osteomalacia by deionization, but could also reverse its course. This suggests that there was a factor in our tap water which prevented normal calcification of osteoid and that this is removed by deionization. We have previously reported high uptake of fluoride with an increase in the serum and bone levels of fluoride in our patients dialyzed with ordinary tap water. DeVeber and Jowsey have observed an increase in osteoid similar to ours in their dialysis patients treated with high fluoride dialysate. High fluoride concentrations have also been shown experimentally to lead to a defect in osteoid calcification. These observations suggest a role for fluoride in the osteomalacic disease in dialysis patients. Against fluoride being the only factor are reports from other centers denying the presence of osteomalacia in their patients on fluoridated dialysate. We conclude that the osteomalacia that occurs in dialysis patients is due to multiple factors that are removed by deionization. Fluoride may be one of the contributing factors.”
SOURCE: Posen GA, et al. (1972). Comparison of renal osteodystrophy in patients dialyzed with deionized and non-deionized water. Transactions of the American Society for Artificial Internal Organs 18: 405-411.

“In our hemodialysis center, opened in April 1964, fluoridated dialysis began with the fluoridation of the city water supply in November 1965. Our subsequent therapeutic failure was completely unexpected and a possible explanation was suggested by the observation of Taves et al. that the serum fluoride levels in patients chronically hemodialyzed with fluoridated water are comparable to those that cause fluorotic bone disease. Thus, the study of fluoride levels in our patients became of particular interest because several of them had been on fluoridated dialysate for much longer periods than those patients reported by Taves et al… Clinically, radiologically, and histologically, the disease seen in these patients was indistinguishable from uremic osteodystrophy, although the manifestations of bone disease tended to appear sooner and in more severe form in our patients maintained on fluoridated dialysate… Histologically and radiographically, these patients showed features of uremic osteodystrophy instead of the fluorosis characterized by exostoses and osteosclerosis. Nervertheless, the observed changes (osteomalacia, osteitis fibrosa and osteoporosis) were similar to those induced by high doses of fluoride in humans and experimental animals, in which widened osteoid seams have been observed, and where increased areas of resorption due to secondary hyperparathyroidism may be seen. Therefore, it seems likely that fluoride was aggravating the underlying renal osteodystrophy in our patients, and that this effect was enhanced by concomitant administration of high doses of vitamin D.”
SOURCE: Posen GA, et al. (1971). Renal osteodystrophy in patients on long-term hemodialysis with fluoridated water. Fluoride 4: 114-128.

“The concept that osteomalacia becomes progressively worse on chronic dialysis was reinforced by the findings in the repeat bone biopsies in that 6 of the 8 patients showed a significant increase in their osteoid index… Thus, the progression of osteomalacia appears to be the main reason for the increasing incidence of bone pain and pseudofractures which we and others have observed in patients on chronic dialysis for periods longer than 6 months. Jowsey, et al, has reported similar findings. When the patients reported by Kim, et al. are classified in the same manner as ours were, a similar higher incidence of osteomalacia and absence of severe osteitis fibrosa was observed in patients on chronic dialysis for more than 6 months… The reason(s) for the progression of osteomalacia, which we observed in our chronic dialysis patients, remain(s) unclear. Factors which could result in impaired mineralization which must be considered include fluoride, hypermagnesemia, and phosphate depletion.”
SOURCE: deVeber GA, et al. (1970). Changing patterns of renal osteodystrophy with chronic hemodialysis. Transactions of the American Society for Artificial Internal Organs 16: 479-486.

“These data suggest that the serum fluoride values seen in these patients are likely to result in altered bone formation. Further studies will be needed to rule out the possibility that more generalized effects are occurring, particularly in the 2 patients with the highest fluoride concentrations.”
SOURCE: Taves DR, et al. (1968). Hemodialysis with fluoridated dialysate. Transactions of the American Society for Artificial Internal Organs 14: 412-414.

Fluoridation, Dialysis, & Bone Damage (1990s-Present):

“Fluoride interfered with bone mineralization and increased osteoid content, which was most evident in osteomalacia and the mixed bone disorder. In addition, fluoride may interact with aluminum to worsen the osteomalacic lesion.”
SOURCE: Ng AHM, et al. (2004). Association between fluoride, magnesium, aluminum and bone quality in renal osteodystrophy. Bone 34: 216-224.

“[B]one fluoride content was significantly higher in the entire dialysis population than in controls (0.33 + 0.04% vs 0.13 + 0.018%, P=0.04). Bone fluoride levels were increased in osteomalacic patients (0.57 + 0.1%) compared with normal controls (0.13 + 0.01%, P 0.5% in 7/11 patients. These data show that mineralisation defects observed in hemodialyzed patients are frequently associated with high bone fluoride content. Fluoride may be considered as a potential etiological factor of osteomalacic osteodystrophy.”
SOURCE: Cohen-Solal ME, et al. (1996). Osteomalacia is associated with high bone fluoride content in dialysis patients. Bone 19: 135S.

“In the current study, concentrations of fluoride in the serum of patients with hemodialysis, for both male and female patients, were remarkably higher than those in healthy subjects… From the results obtained, it is suggested that the characteristic change of BMD in patients with hemodialysis, such as increase in BMD of the lumbar spine in spite of the decrease in that of the radius may be contributed to continuance of high concentration of fluoride in the serum. To control serum fluoride at an adequate level constantly, intake of fluoride should be controlled and also fluoride level maintenance system of the hemodialysis is desirable. Furthermore, frequent and long term monitoring of serum fluoride and BMD with hemodialysis patients are highly necessary.”
SOURCE: Takahashi Y. (1995). Effects of fluoride on bone metabolism in patients with hemodialysis. Bulletin of the Osaka Medical College 41: 27-35.

“From these results, it was suggested that absorbed F strongly affected the metabolism of bone, especially cancellous bone in the patients with long-term hemodialysis.”
SOURCE: Tanimura Y. (1994). Studies on serum fluoride and bone metabolism in patients with long term hemodialysis. Bulletin of the Osaka Medical College 40: 65-72.