[SEE PHOTOCOPY OF STUDY]

American Association for the Advancement of Science (AAAS)

Evaluation of the Use of Fluorides. AAAS Selected Symposium (1979)
Edited by E Johansen; DR Taves, & TO Olsen.

Fluoridation and bone disease in renal patients.

By William J. Johnson, Donald R. Taves and Jenifer Jowsey

About the Authors:

William J Johnson, director of the Mayo Artificial Kidney Center and professor of medicine with the Division of Nephrology at the Mayo Clinic, has been involved in the study of calcium and phosphorus metabolism and renal osteodystrophy, potassium metabolism, and uremic neuropathy. He is past chairman of the Minnesota State Medical Association's Committee on Dialysis and Transplantation and served on the editorial board of Nephron. He has published over 70 papers in his field.

Jenifer Jowsey, director of orthopaedic research at the Mayo Clinic and Mayo Foundation, has worked extensively on metabolic bone disease, particularly the prevention and treatment of osteoporosis. She received the Kappa Delta Award from the American Academy of Orthopaedic Surgeons in 1975. She is the author of some 230 publications including Metabolic Diseases of Bone (Saunders, 1977).

Donald R. Taves is associate professor of pharmacology and toxicology and of radiation biology and biophysics at the University of Rochester School of Medicine and Dentistry. He was a member of a subcommittee of the National Academy of Sciences Safe Drinking Water Study which examined the use of fluoride in drinking water and his principal area of specialization is the toxicology and pharmacology of fluoride.

\The Department of Nephrology at the Mayo Clinic examines approximately 100 new patients with end-stage renal disease each year. Some of these patients reside in areas where the naturally occurring fluoride concentration in tap water exceeds 1 ppm. During the course of several years, six patients have been seen in whom fluoride may have been the cause of detectable clinical and roentgenographic effects. Two of these cases have been reported previously from our institution (Juncos and Donadio, 1972). One patient had chronic glomerulonephritis, and the others had congenital renal disease of more than 15 years' duration before skeletal symptoms developed (Table 2). Most of the patients had high urine volumes (>3 L per day), the fluid intake being replaced by copious intake of water or in one instance, tea.

The most distinctive features suggesting fluorosis were the roentgenographic appearance of the skeleton and the severity of dental mottling (Table 3). The most characteristic roentgenographic finding was a diffuse increase in bone density which, in younger patients, assumed a ground-glass appearance; whereas in older patients, it showed a coarse trabecular pattern that became more obvious as the skeleton became more demineralized over the years and with progression of renal failure. In addition to the increase in bone density and the alteration of trabecular pattern, there was a prominent new subperiosteal bone formation, especially in the long bones in the upper and lower extremities, and calcification of the interosseous ligaments between tibia and fibula and between radius and ulna, as well as of the sacrotuberous ligaments of the pelvis and the longitudinal ligaments of the spinal column in some of the patients. In addition, three patients had pseudofractures, a common feature of osteomalacia.

Despite having severe symptomatic bone disease, none of the patients showed striking features of hyperparathyroidism, such as subperiosteal resorption or bone cysts, which, in the United States, are the more common manifestations of renal osteodystrophy. Plasma parathyroid hormone concentrations, although elevated in all of the patients, were relatively low considering the severity of the bone disease.

In addition, these patients developed severe skeletal changes or bone pain early in the course of renal failure when creatinine values were approximately 3 mg/dL. Symptoms referable to the skeleton varied. Two of the six patients were asymptomatic; four complained of arthralgia, especially of the knees, and of bone pain on weight-bearing involving the lower extremities; three of the patients had spontaneous fractures of metatarsals, ribs, and hip.

Bone biopsy specimens available from four patients showed a marked increase in the ratio of fluoride to calcium (Table 4). Biopsy specimens studied by quantitative microradiographic techniques showed a large percentage of bone surface covered by osteoid as well as thick osteoid seams with variable degrees of bone resorption and large areas of new bone formation.

Therapeutic measures included the elimination of fluoride from the drinking water, normalization of plasma calcium and phosphate concentrations, and the use of vitamin D analogs. Symptoms were lessened with these measures, but several patients continued to have fractures. Four patients have been free of symptoms or fractures since entering the dialysis program using fluoride-free dialysate and continuing efforts to maintain normal calcium and phosphate levels.

Case of Severest Disease. A 69-year-old man experienced excessive frequent urge to urinate associated with pyuria in 1958. Signs of infection cleared after sulfonamide therapy, but urinary frequency, nocturia, and polyuria persisted. The urine was of fixed specific gravity and showed a trace of protein. Mild azotemia appeared in 1960, followed by bone pain, arthralgia of the knees and feet, and spontaneous "march fractures" of both feet - a total of 13 by 1963.

Examination of the urine revealed no infection, but a 24-hour specimen showed an increased content of glucose and amino acid nitrogen. The urine was alkaline, while the blood showed some evidence of systemic acidosis. Blood sugar levels were normal, azotemia was mild, and alkaline phosphatase activity was elevated, but values for serum calcium, phosphate, and total protein were normal. An excretory urogram showed small kidneys. Skeletal roentgenograms showed healing fractures of the metatarsals and phalangeal bones of both feet, areas of increased bone density with a coarse trabecular pattern involving predominantly the axial skeleton and the calcification of interosseous ligaments, and new subperiosteal bone formation.

Bone biopsy of the iliac crest showed an increase of uncalcified osteoid tissue on bone surfaces, decreased mineral density around osteocytes, low mineralization of cement lines, and much interstitium with an irregular patttern.

After treatment with oral calcium supplements and vitamn D, bone pain decreased but the patient experienced additional fractures. Osteosclerosis increased, but serum alkaline phosphatase values decreased to normal. A bone biopsy specimen taken in 1968 showed healing of osteomalacia. Chemical values showed a high concentration of fluoride in serum (14 uM) and bone (4.7 to 6.5 moles of fluoride per 100 moles of calcium) and in drinking water (2 ppm or 106 uM) relative to the concentration of fluoride in the urine (78 uM).

At this point, the patient was advised to stop drinking tap water and to use only fluoride-free spring water or distilled water for both drinking and cooking. Serum fluoride concentrations decreased (to 8 uM), and for a period of approximately 8 years, the patient was relatively free of bone pain and did not experience further fractures.

In 1971, renal function temporarily deteriorated further. After peritoneal dialysis, renal function spontaneously improved. In 1974, the patient fell, sustaining a hip fracture that required internal fixation. Osteomalacia has persisted despite vitamin D therapy and reasonable control of systemic acidosis and secondary hyperparathyroidism. These findings were interpreted as representing adult Fanconi's syndrome wihth osteomalacia and superimposed fluorosis.

Concluding Remarks

The available evidence suggests that some patients wtih long-term renal failure are being affected by drinking water with as little as 2 ppm fluoride. All of the patients showed increased bone density, and two showed calcification of interosseous ligaments which is thought to be diagnostic of skeletal fluorosis. The average concentration of fluoride in bone of 4.4 moles of fluoride per 100 moles of calcium is equivalent to 9,000 ppm of fluoride on an ash weight basis and is in the middle range of the values that have been reported for advanced fluorosis. The excessive osteoid formation seen in these patients is probably accentuated by fluoride.

... The meaning of these findings for community fluoridation will depend on whether or not further work will clearly show adverse effects in patients with renal failure drinking water with a concentration of 1 ppm of fluoride and whether these effects can be easily avoided. The finding of adverse effects in patients drinking water with 2 ppm of fluoride suggests that a few similar cases may be found in patients imbibing 1 ppm, especially if large volumes are consumed, or in heavy tea drinkers and if fluoride is indeed the cause.

It would seem prudent, therefore, to monitor the fluoride intake of patients with renal failure living in high fluoride areas. The serum concentration may indicate whether the patient should be advised to drink low fluoride water and will provide a check regarding compliance. Tentatively, a shift to low fluoride water should be made before the serum fluoride concentration reaches 5 uM, since evidence of fluorosis has been reported when the average serum concentrations of fluoride are 8 uM.