Abstract
Summary
Fluoride has fallen into discredit due to the absence of an anti-fracture effect. However, in this meta-analysis, a fracture reducing potential was seen at low fluoride doses [≤20 mg fluoride equivalents (152 mg monofluorophosphate/44 mg sodium fluoride)]: OR = 0.3, 95% CI: 0.1–0.9 for vertebral and OR = 0.5, 95% CI: 0.3–0.8 for non-vertebral fractures.
Introduction
Fluoride is incorporated into bone mineral and has an anabolic effect. However, the biomechanical competence of the newly formed bone may be reduced.
Methods
A systematic search of PubMed, Embase, and ISI web of science yielded 2,028 references.
Results
Twenty-five eligible studies were identified. Spine BMD increased 7.9%, 95% CI: 5.4–10.5%, and hip BMD 2.1%, 95% CI: 0.9–3.4%. A meta-regression showed increasing spine BMD with increasing treatment duration (5.04 ± 2.16%/year of treatment). Overall there was no significant effect on the risk of vertebral (OR = 0.8, 95% CI: 0.5–1.5) or non-vertebral fracture (OR = 0.8, 95% CI: 0.5–1.4). With a daily dose of ≤20 mg fluoride equivalents (152 mg monofluorophosphate/44 mg sodium fluoride), there was a statistically significant reduction in vertebral (OR = 0.3, 95% CI: 0.1–0.9) and non-vertebral (OR = 0.5, 95% CI: 0.3–0.8) fracture risk. With a daily dose >20 mg fluoride equivalents, there was no significant reduction in vertebral (OR = 1.3, 95% CI: 0.8–2.0) and non-vertebral (OR = 1.5, 95% CI: 0.8–2.8) fracture risk.
Conclusions
Fluoride treatment increases spine and hip BMD, depending on treatment duration. Overall there was no effect on hip or spine fracture risk. However, in subgroup analyses a low fluoride dose (≤20 mg/day of fluoride equivalents) was associated with a significant reduction in fracture risk.
This is a preview of subscription content, access via your institution.


References
Haguenauer D, Welch V, Shea B et al (2000) Fluoride for the treatment of postmenopausal osteoporotic fractures: a meta-analysis. Osteoporos Int 11:727–738
Meunier PJ, Roux C, Seeman E et al (2004) The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 350:459–468
Posner AS (1996) The effect of fluoride on bone mineralisation. In: Fejerskov O, Ekstrand J, Burt BA (eds) Fluoride in dentistry, 1st edn. Munksgaard, Copenhagen, pp 88–96
Qu H, Wie M (2006) The effect of fluoride contents in fluoridated hydroxyapatite on osteoblast behavior. Acta Biomater 2:113–119
Kassem M, Mosekilde L, Eriksen EF (1994) Effects of fluoride on human bone cells in vitro: differences in responsiveness between stromal osteoblast precursors and mature osteoblasts. Eur J Endocrinol 130:381–386
Khokher MA, Dandona P (1990) Fluoride stimulates 2H-thymidine incorporation and alkaline phosphatase production by human osteoblasts. Metabolism 39:1118–1121
Eriksen EF, Mosekilde L, Melsen F (1985) Effect of sodium fluoride, calcium, phosphate and vitamin D2 on trabecular bone balance and remodeling in osteoporotics. Bone 6:381–389
Charles P, Mosekilde L, Jensen FT (1985) The effects of sodium fluoride, calcium phosphate, and vitamin D2 for one to two years on calcium and phosphorus metabolism in postmenopausal women with spinal crush fracture osteoporosis. Bone 6:201–206
Briancon D, Meunier PJ (1981) Treatment of osteoporosis with fluoride, calcium, and vitamin D. Orthop Clin North Am 12:629–648
Vesterby A, Gundersen HJG, Melsen F, Mosekilde L (1991) Marrow space star volume in iliac crest decreases in osteoporotic patients after continuous treatment with fluoride, calcium and vitamin. Bone 12:33–37
Melsen F, Eriksen EF, Mosekilde L (1996) Clinical aspects of fluoride in bone. In: Fejerskov O, Ekstrand J, Burt BA (eds) Fluoride in dentristy, 1st edn. Munksgaard,Copenhagen, pp 96–111
Sogaard CH, Mosekilde L, Richards A, Mosekilde L (1994) Marked decrease in trabecular bone quality after five years of sodium fluoride therapy - assessed by biomechanical testing of iliac crest bone biopsies in osteoporotic patients. Bone 15:393–399
Schnitzler CM, Solomon L (1985) Trabecular stress fractures during fluoride therapy for osteoporosis. Skeletal Radiol 14:276–279
Haguenauer D, Welch V, Shea B, Tugwell P, Wells G (2000) Fluoride for treating postmenopausal osteoporosis. Cochrane Database Syst Rev CD002825
Riggs BL, Seeman E, Hodgson SF, Taves DR, O’Fallon WM (1982) Effect of the fluoride/calcium regimen on vertebral fracture occurrence in postmenopausal osteoporosis. Comparison with conventional therapy. N Engl J Med 306:446–450
Grove O, Halver B (1981) Relief of osteoporotic backache with fluoride, calcium, and calciferol. Acta Med Scand 209:469–471
Christiansen C, Christensen MS, McNair P et al (1980) Prevention of early bone postmenopausal loss: controlled 2-year study in 315 normal females. European J Clin Invest 10:273–279
Böhning D (2000) Computer-assisted analysis of mixtures and applications: meta-analysis, disease mapping and others, 1st edn. Chapman&Hall/CRC, Boca Raton
Griffith LE, Walter SD (1997) The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol 50:683–691
Knapp G, Hartung J (2003) Improved tests for a random effects meta-regression with a single covariate. Stat Med 22:2693–2710
Siddiqi A, Burrin JM, Noonan K et al (1997) A longitudinal study of markers of bone turnover in Graves’ disease and their value in predicting bone mineral density. J Clin Endocrinol Metab 82:753–759
Jowsey J, Riggs BL, Kelly PJ, Hoffman DL (1972) Effect of combined therapy with sodium fluoride, vitamin D and calcium in osteoporosis. Am J Med 53:43–49
Riggs BL, Hodgson SF, O’Fallon WM et al (1990) Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 322:802–809
Orcel P, De Vernejoul MC, Prier A et al (1990) Stress fractures of lower limbs in osteoporotic patients treated with fluoride. J Bone Miner Res 5:S91–S94
Vestergaard P, Jorgensen NR, Mosekilde L, Schwarz P (2007) Effects of parathyroid hormone alone or in combination with antiresorptive therapy on bone mineral density and fracture risk - a meta-analysis. Osteoporos Int 18:45—57
O’Donnell S, Cranney A, Wells GA, Adachi JD, Reginster JY (2006) Strontium ranelate for preventing and treating postmenopausal osteoporosis. Cochrane Database Syst Rev CD005326
Abitbol V, Mary JY, Roux C et al (2002) Osteoporosis in inflammatory bowel disease: effect of calcium and vitamin D with or without fluoride. Aliment Pharmacol Ther 16:919—927
Adachi JD, Bell MJ, Bensen WG et al (1997) Fluoride therapy in prevention of rheumatoid arthritis induced bone loss. J Rheumatol 24:2308—2313
Adachi JD, Bell MJ, Bensen WG, et al (1996) A randomized, double-blind, placebo-controlled trial of the effects of fluoride on lumbar spine bone mineral density in patients with rheumatoid arthritis. Arthritis Rheum 39:661
Alexandersen P, Riis BJ, Christiansen C (1999) Monofluorophosphate combined with hormone replacement therapy induces a synergistic effect on bone mass by dissociating bone formation and resorption in postmenopausal women: a randomized study. J Clin Endocrinol Metab 84:3013–3020
Gambacciani M, Spinetti A, Taponeco F et al (1995) Treatment of postmenopausal vertebral osteopenia with monofluorophospate: a long-term calcium-controlled study. Osteoporos Int 5:467–471
Guanabens N, Pares A, Monegal A et al (1997) Etidronate versus fluoride for treatment of osteopenia in primary biliary cirrhosis: preliminary results after 2 years. Gastroenterology 113:219–224
Guanabens N, Farrerons J, Perez-Edo L et al (2000) Cyclical etidronate versus sodium fluoride in established postmenopausal osteoporosis: a randomized 3 year trial. Bone 27:123–128
Guaydier-Souquieres G, Kotzki PO, Sabatier JP, Basse-Cathalinat B, Loeb G (1996) In corticosteroid-treated respiratory diseases, monofluorophosphate increases lumbar bone density: a double-masked randomized study. Osteoporos Int 6:171–177
Gutteridge DH, Stewart GO, Prince RL et al (2002) A randomized trial of sodium fluoride (60 mg) +/- estrogen in postmenopausal osteoporotic vertebral fractures: increased vertebral fractures and peripheral bone loss with sodium fluoride; concurrent estrogen prevents peripheral loss, but not vertebral fractures. Osteoporos Int 13:158–170
Hansson T, Roos B (1987) The effect of fluoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study. Calcif Tissue Int 40:315–317
Kleerekoper M, Peterson EL, Nelson DA et al (1991) A randomized trial of sodium fluoride as a treatment for postmenopausal osteoporosis. Osteoporos Int 1:155–161
Lems WF, Jacobs JW, Bijlsma JW et al (1997) Is addition of sodium fluoride to cyclical etidronate beneficial in the treatment of corticosteroid induced osteoporosis? Ann Rheum Dis 56:357–363
Lems WF, Jacobs WG, Bijlsma JW et al (1997) Effect of sodium fluoride on the prevention of corticosteroid-induced osteoporosis. Osteoporos Int 7:575–582
Lippuner K, Haller B, Casez JP, Montandon A, Jaeger P (1996) Effect of disodium monofluorophosphate, calcium and vitamin D supplementation on bone mineral density in patients chronically treated with glucocorticosteroids: a prospective, randomized, double-blind study. Miner Electrolyte Metab 22:207–213
Mamelle N, Dusan R, Martin JL et al (1988) Risk-benefit ratio of sodium fluoride treatment in primary vertebral osteoporosis. Lancet 2:361–365
Meunier PJ, Sebert JL, Reginster JY et al (1998) Fluoride salts are no better at preventing new vertebral fractures than calcium-vitamin D in postmenopausal osteoporosis: the FAVOStudy. Osteoporos Int 8:4–12
Pak CY, Sakhaee K, Adams-Huet B et al (1995) Treatment of postmenopausal osteoporosis with slow-release sodium fluoride. Final report of a randomized controlled trial. Ann Intern Med 123:401–408
Reginster JY, Meurmans L, Zegels B et al (1998) The effect of sodium monofluorophosphate plus calcium on vertebral fracture rate in postmenopausal women with moderate osteoporosis. A randomized, controlled trial. Ann Intern Med 129:1–8
Ringe JD, Dorst A, Kipshoven C, Rovati LC, Setnikar I (1998) Avoidance of vertebral fractures in men with idiopathic osteoporosis by a three year therapy with calcium and low-dose intermittent monofluorophosphate. Osteoporos Int 8:47–52
Ringe JD, Kipshoven C, Coster A, Umbach R (1999) Therapy of established postmenopausal osteoporosis with monofluorophosphate plus calcium: dose-related effects on bone density and fracture rate. Osteoporos Int 9:171–178
Ringe JD, Dorst A, Faber H et al (2005) Efficacy of etidronate and sequential monofluorophosphate in severe postmenopausal osteoporosis: a pilot study. Rheumatol Int 25:296–300
Sebert JL, Richard P, Mennecier I, Bisset JP, Loeb G (1995) Monofluorophosphate increases lumbar bone density in osteopenic patients: a double-masked randomized study. Osteoporos Int 5:108–114
Von Tirpitz C, Klaus J, Bruckel J et al (2000) Increase of bone mineral density with sodium fluoride in patients with Crohn’s disease. Eur J Gastroenterol Hepatol 12:19–24
Von Tirpitz C, Klaus J, Steinkamp M et al (2003) Therapy of osteoporosis in patients with Crohn’s disease: a randomized study comparing sodium fluoride and ibandronate. Aliment Pharmacol Ther 17:807–816
Jadad AR, Moore RA, Carroll D et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12
Acknowledgements
Research librarian Ms. Edith Clausen is acknowledged for skilful help with the references.
Financial support
Laura og Jens Veng Christensens Foundation, and Bagermester August H. Jensen og Hustrus Legat provided financial support.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Vestergaard, P., Jorgensen, N.R., Schwarz, P. et al. Effects of treatment with fluoride on bone mineral density and fracture risk - a meta-analysis. Osteoporos Int 19, 257–268 (2008). https://doi.org/10.1007/s00198-007-0437-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-007-0437-6