Key Findings: Mechanisms by which fluoride may reduce bone strength

1) There are several plausible mechanisms by which fluoride can reduce bone strength.

2) In all likelihood, the mechanisms by which fluoride reduces bone strength vary depending on the degree of fluoride exposure and/or the presence of overt skeletal fluorosis.

3) Fluoride has been found to reduce bone strength before skeletal fluorosis is detectable. Thus, several of the mechanisms discussed below likely occur before fluorosis is present.

Excerpts from the Scientific Literature:

1) Reduced Cortical Bone Density
2) Damage to Mineral-Collagen interface
3) Damage to Collagen
4) Hypo-mineralization
5) Hyper-mineralization
6) Non-Uniformity of Mineralization
7) Osteocyte Damage

Mechanisms: Reduced Cortical Density: (back to top)

It is now well acknowledged in the scientific literature that fluoride has a contradictory effect on bone density. While fluoride often increases bone density in trabecular bone (the primary bone of the axial skeleton), it often decreases bone density in cortical bone (the primary bone of the appendicular skeleton). Fluoride's ability to reduce cortical bone has been documented most extensively in human clinical trials, and in studies of humans with skeletal fluorosis. However, it has also been documented in humans living in communities in the United States with 3.8 to 4 ppm fluoride in water (Phipps 1990; Sowers 1991). Reduced cortical bone density is a particularly important risk factor for hip fracture, as one of the primary sites of hip fracture (the femoral neck) gains up to 95% of its strength from the intregity of cortical bone.

Reduced cortical bone density is also important for most forms of "non-vertebral" fractures, particularly wrist fracture. It is interesting, therefore, to note that the two main forms of bone fracture associated with water fluoridation (at 1 ppm) are hip and wrist fracture - as these two bone sites are primarily dependent on the quality of cortical bone.

"The strength of the femoral neck is due mainly to its shell of cortical bone. Computer analyses indicate 90%-95% of the strength of this region is from cortical rather than trabecular bone."
SOURCE: Gordon SL, Corbin SB. (1992). Summary of workshop on drinking water fluoride influence on hip fracture on bone health. (National Institutes of Health, 10 April, 1991). Osteoporosis International 2:109-17.

"The dramatic increase in the predominantly trabecular bone of the axial skeleton during fluoride therapy is not accompanied by a corresponding increase in the predominantly cortical bone of the appendicular skeleton...Indeed, several investigators have reported that cortical bone decreases significantly during treatment...These reports raise the possibility that fluoride therapy may protect against fractures of the vertebral bodies (which consist of predominantly trabecular bone) but may not protect the proximal femur, and could even increase the risk for fractures of this bone, which is predominantly cortical...Since hip fracture is more catastrophic than is vertebral fracture, it will be important for future studies to evaluate the effect of sodium fluoride therapy on mineral content of the proximal femur."
SOURCE: Riggs BL. (1983). Treatment of osteoporosis with sodium fluoride: an appraisal. Bone and Mineral Research. 2: 366-393.

"The site of predilection for stress fractures, namely the metaphysis, with its thin cortex, may be determined by the decrease in cortical bone mass observed in fluoride therapy."
SOURCE: Schnitzler CM, Solomon L. (1985). Trabecular stress fractures during fluoride therapy for osteoporosis. Skeletal Radioliology 14:276-9.

"Because of the association between hip fracture and low femoral cortical thickness, and because of the reported decrease in cortical forearm density using Ca and NaF, it seems unwise to use NaF treatment in patients with hip fracture following minor trauma."
SOURCE: Gutteridge DH, et al. (1990). Spontaneous hip fractures in fluoride-treated patients: potential causative factors. Journal of Bone and Mineral Research 5(Suppl 1):S205-15.

"significant bone loss occurred by 27 months at all nonspinal sites examined. The greatest loss occurred in the lower tibia/fibula, where the loss at the shaft site was 7.3%. The lower tibia/fibula is a common site of fluoride-related stress fractures and these BMD results help to explain the mechanism of this common complication of treatment with NaF."
SOURCE: Gutteridge DH, 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. Osteoporosis International 13:158-70.

"In four of the six hip fractures in this study, the history strongly suggested that the fracture occurred before the patient fell. The spontaneous character of the fracture in our patients, and in other reports, suggest that fluoride treatment probably increases the risk of stress fractures. This may be the result of the formation of qualitatively abnormal bone and/or the redistribution of calcium from the appendicular cortical bone to the axial skeleton."
SOURCE: Hedlund LR, Gallagher JC. (1989). Increased incidence of hip fracture in osteoporotic women treated with sodium fluoride. Journal of Bone and Mineral Research 4:223-5.

"We have documented a clinically relevant increase in vertebral BMD, although there was a significant reduction in cortical BMD at the radial site... In the absence of a control group it is not possible to conclude from our data whether a significant response to fluoride in trabecular or axial skeletal sites necessarily translates into higher than expected losses from cortical bone. This is of some concern, because fluoride therapy has been implicated as a cause of increased frequency of femoral neck fractures, as occurred in 2 of our patients... Although data on femoral neck BMD were not available in this study, clearly such measurements would have been of great importance."
SOURCE: Hodsman AB, Drost DJ. (1989). The response of vertebral bone mineral density during the treatment of osteoporosis with sodium fluoride. Journal of Clinical Endocrinology and Metabolism 69(5):932-8.

Mechanisms: Damage to Mineral-Collagen interface: (back to top)

The quality and strength of bone is dependent to a large degree on the quality of bonding between its organic component (collagen) and its inorganic content (bone mineral). When this bonding is impaired, the strength of the bone is reduced, particularly the tensile strength. Several studies have found that fluoride impairs this "interfacial bonding". More importantly, studies have found that fluoride can damage this bonding in the absence of demonstrable skeletal fluorosis (Fratzl 1996; Turner 1993).

"In this study, despite the observed increased in hardness of both cancellous and cortical bone, the fracture stress and elastic modulus of vertebrae tested in compression and femora tested in three-point bending were decreased by fluoride treatment. The fact that the hardness (which is dependent largely on the mineral content) increases even though the modulus (which depends on both the mineral content and the collagen) decreases suggests that there is a change in the relationship between the bone mineral and the collagen. The mechanical strength of bone is thought to derive mainly from the interface between the collagen and the mineral, so if fluoride administration alters bone mineral, it may affect this interface and therefore result in modified mechanical properties."
SOURCE: Chachra D, et al. (1999). The effect of fluoride treatment on bone mineral in rabbits. Calcified Tissue International 64:345-351.

"A slight increase in the average thickness of the mineral crystals as well as changes in the structure of the mineral/collagen composite were found in the case of fluoride-treated animals... These findings suggest that small changes in the structure of the mineral/collagen composite in bone may considerably affect its biomechanical properties."
SOURCE: Fratzl P, et al. (1996). Effects of sodium fluoride and alendronate on the bone mineral in minipigs: a small-angle x-ray scattering and backscattered electron imaging study. Journal of Bone and Mineral Research 11: 248-253.

"The severe deterioration of the collagen/mineral compound and the nearly complete lack of normal 'old' bone suggest biomechanical incompetence and explain the pathological fractures."
SOURCE: Roschger P, et al. (1995). Bone mineral structure after six years fluoride treatment investigated by backscattered electron imaging (BSEI) and small angle x-ray scattering (SAXS): a case report. Bone 16:407.

"The bone strength deficit caused by fluoride accumulation in bone is not always associated with gross bone pathology (i.e. woven bone formation), but may be caused by decreased bone lipid content and calcification defects induced by decreased bonding strength at the crystal-matrix interface."
SOURCE: Turner CH, et al. (1993). A mathematical model for fluoride uptake by the skeleton. Calcified Tissue International 52: 130-138.

"Interfacial bonding interactions between the mineral and organic constituents of bone play an important role in the mechanical properties of cortical bone... Under a uniaxial tensile force, modification of interfacial bonding by phosphate and fluoride ions results in a reduction in the ultimate and yield stress and elastic modulus. In tension, phosphate ions effect is reversible upon removal of phosphate ions, while the fluoride ion effect is irreversible. Interestingly, when tested in compression, phosphate ion treatment results in a stiffening effect, while fluoride ions continue to lower the ultimate stress and elastic modulus."
SOURCE: Walsh WR, Guzelsu N. (1993). The role of ions and mineral-organic interfacial bonding on the compressive properties of cortical bone. Bio-medical materials and engineering 3: 75-84.

"The decreased bone-breaking strength caused by fluoride ingestion may result from a decreased bonding strength between the crystal material and collagen matrix of the bone. Fluoride might induce a decrease in bone lipids acting as a chemical link between the organic and inorganic phases of the bone. This would in turn produce decreased elasticity and increased brittleness."
SOURCE: Bird DM, Carriere D, Lacombe D. (1992). The effect of dietary sodium fluoride on internal organs, breast muscle, and bones in captive American kestrels (Falco sparverius). Archives of Environmental Contamination and Toxicology 22:242-6.

"The mechanical properties of composite material (such as bone) rely on the properties of its constituents as well as the interfacial bonding between them... This study demonstrates the importance of interfacial bonding between the mineral and organic constituents of bone through fluoride ion treatments. Fluoride ions alter interfacial bonding between the mineral and organic components of bone by exchanging with OH ions of bone mineral and creating an unfavourable electrostatic condition by a rise in pH. The reduction in interfacial bonding due to fluoride action lowers the mechanical properties of bone tissue."
SOURCE: Walsh WR, Guzelsu N. (1991). Fluoride ion effect on interfacial bonding and mechanical properties of bone. Journal of Biomechanics 24: 237.

"The mechanical properties of bone are influenced, principally, by the behaviour of two phase materials of the bone: the mineral substance which contributes to the compressive strength and the collagen matrix which plays a major role in tensile strength. Therefore, any alterations of physico-chemical composition or the structural changes in these materials bring about some eventual modifications on the physical properties of the bone."
SOURCE: Bang S. (1978). Biophysical study of compact bone tissue in demic fluorosis. In: B Courvoisier B, et al. (1978). Fluoride and Bone; Proceedings of the Second Symposium CEMO, Nyon, Switzerland, Oct. 9-12, 1977. Hans Huber Publishers, Bern. pp. 77-81.

"As suggested by Currey, bone may be looked upon as a two-phase material (hydroxyapatite crystals embedded in a collagen matrix) which can function efficiently only if there is a very firm bonding between the fibers and the matrix. The decrease in the modulus of elasticity observed by us, together with the lower limit of elasticity and increased ductility, may result from a decreased bonding strength at the crystal-matrix surface. In this context the decreased lipid content of bone of fluoride-treated animals is of interest. Perhaps, as suggested in the literature, the lipids could act as a chemical link between the mineral and the organic phases of calcified tissues."
SOURCE: Wolinksy I, et al. (1972). Effects of fluoride on metabolism and mechanical properties of rat bone. American Journal of Physiology 223: 46-50.

Mechanisms: Damage to Collagen: (back to top)

Along with potentially altering/damaging the interface between the bone mineral and collagen matrix, fluoride may also directly damage the quantity/quality of the collagen itself. Since the collagen component of bone plays a vital role in maintaining the tensile strength (versus compressive strength) of bone, any damage to the collagen would make the bone more prone to fracture.

"Collagen synthesized and laid down during fluoride exposure is under hydroxylated and inadequately crosslinked. As a consequence, this collagen is rapidly catabolized and collagen content of the bone is decreased."
SOURCE: Bird DM, Carriere D, Lacombe D. (1992). The effect of dietary sodium fluoride on internal organs, breast muscle, and bones in captive American kestrels (Falco sparverius). Archives of Environmental Contamination and Toxicology 22:242-6.

"A permanently reduced bone strength might be expected if fluoride affects the bone matrix by inhibition of collagen cross-linking, changes the glycosaminoglycans, or forms fluorapatite crystals of minor biomechanical competence."
SOURCE: Mosekilde L, et al. (1987). Compressive strength, ash weight, and volume of vertebral trabecular bone in experimental fluorosis in pigs. Calcified Tissue Research 40: 318-322.

"As a tissue, bone is rich in collagen. When fluoride enters bone structure in toxic amounts, it modifies not only the mineral metabolism but also the collagen component of bone matrix."
SOURCE: Krishnamachari KA. (1986). Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease. Progress in Food and Nutrition Sciences 10(3-4):279-314.

"In the fluoride-treated group, collagen synthesis was found to be defective, while it was normal in the controls."
SOURCE: Uslu B. (1983). Effect of fluoride on collagen synthesis in the rat. Research and Experimental Medicine 182:7-12.

"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."
SOURCE: Lough J, et al. (1975). Effects of fluoride on bone in chronic renal failure. Archives of Pathology 99: 484-487.

"We evaluated one aspect of bone quality, collagen birefringence, which is primarily determined by collagen bundle orientation... The diminished collagen birefringence observed in the present study and previously found in endemic fluorosis has also been observed in patients with renal osteodystrophy..."
SOURCE: Baylink D, et al. (1970). Effects of fluoride on bone formation, mineralization, and resorption in the rat. In: TL Vischer, ed. (1970). Fluoride in Medicine. Hans Huber, Bern. pp. 37-69.

"As previously suggested by Johnson decreased or abnormal collagen seemed to be present in these fluoridated zones of the bone on the basis of polarized light study of decalcified unstained sections."
SOURCE: Cass RM, et al. (1966). New bone formation in osteoporosis following treatment with sodium fluoride. Archives of Internal Medicine 118: 111-116.

"The collagen in a fluoride-laden skeleton also is probably abnormal; in vitro studies have shown that fluorine inhibits collagen synthesis in bone."
SOURCE: Adams PH, Jowsey J. (1965). Sodium fluoride in the treatment of osteoporosis and other bone diseases. Annals of Internal Medicine 63: 1151-1155.

"With well-developed mottling, portions of the osteones failed to calcify (X-ray microscopy), the calcified portions revealed an abnormal pattern of calcification, and the organic collagen matrix of the entire osteone was abnormal."
SOURCE: Johnson LC. (1965). Histogenesis and mechanisms in the development of osteofluorosis. In: H.C.Hodge and F.A.Smith, eds : Fluorine chemistry, Vol. 4. New York, N.Y., Academic press (1965) 424-441.

Mechanisms: Hypo-mineralization: (back to top)

Fluoride is well known to be able to cause a mineralization defect in bone known as "hypomineralization." Hypomineralization refers to an increase in the amount of "osteoid" tissue present in bone. Osteoid is bone tissue that is not yet mineralized. Thus, if osteoid is present in excess amounts, a bone will be more prone to fracture - as is the case with the bone disease osteomalacia (a condition of excess osteoid). While fluoride's ability to increase osteoid tissue has been most extensively documented in human clinical trials and high-dose animal experiments, it has also been observed in humans (with healthy kidney function) drinking with as little as 1.5 ppm fluoride, and in humans (with impaired kidney function) drinking water with as little as 1 ppm (Ng 2004). Thus, this form of mineralization defect may be a relevant mechanism by which fluoride could increase bone fractures in fluoridated communities, and it is certainly a relevant mechanism for higher-dose exposures.

"In contrast to calcium phosphate deficiency, high fluoride intake had no effect on trabecular bone volume, but instead increased the amount of unmineralized osteoid, particularly in older rats. This impairment of mineralization by fluoride appeared to be the primary cause of the diminshed vertebral strength."
SOURCE: Turner CH, et al. (2001). Combined effects of diets with reduced calcium and phosphate and increased fluoride intake on vertebral bone strength and histology in rats. Calcified Tissue International 69: 51-57.

"The main histolological change induced by fluoride is the increase of osteoid volume... This increase in osteoid parameters was observed in our study already at fluoride concentrations above 1.5 ppm."
SOURCE: Arnala I, et al. (1985). Effects of fluoride on bone in Finland. Histomorphometry of cadaver bone from low and high fluoride areas. Acta Orthopaedica Scandinavica 56:161-6.

"The osteomalacic condition (of fluorosis) to some extent varies with the species and age of the animal. Certain features are common, however... Common features are the reduced strength of the bones, the tendency to form exostoses, bone atrophy, and a deficient calcification."
SOURCE: Roholm K. (1937). Fluoride intoxication: a clinical-hygienic study with a review of the literature and some experimental investigations. H.K. Lewis Ltd, London.

Mechanisms: Hyper-mineralization: (back to top)

In contrast to its ability to cause hypo-mineralization (UNDER-mineralized bone), fluoride can also cause hyper-mineralization (OVER-mineralized bone). As with hypo-mineralized bone, hyper-mineralized bone can also weaken the integrity of bone, primarily by altering the bonding between the bone mineral and the collagen matrix.

"Fluoride also affects bone strength of well-mineralized bone, possibly by altering mineral crystal size and packing. Fluoride tends to increase mineral crystal width, and may alter the electrostatic bonding between mineral crystals and the collagen matrix. Both effects may diminish the mechanical properties of the bone."
SOURCE: Turner CH, et al. (1997). Fluoride treatment increased serum IGF-1, bone turnover, and bone mass, but not bone strength, in rabbts. Calcified Tissue International 61: 77-83.

"In both cases, in which the coating was supposed to be either hypo- or hypermineralized, a loss of mechanical properties was found."
SOURCE: Fratzl P, et al. (1994). Abnormal bone mineralization after fluoride treatment in osteoporosis: a small-angle x-ray-scattering study. Journal of Bone and Mineral Research 9:1541-9.

"Hypermineralized fluorotic tissue has a greater true density than normal mineralized tissue. The physicochemical abnormalities of this tissue, however, again raise questions regarding a possible decrease in mechanical strength."
SOURCE: Carter DR, Beaupre GS. (1990). Effects of fluoride treatment on bone strength. Journal of Bone and Mineral Research 5(Suppl 1):S177-S184.

"This increased hardness is most likely due to an increased concentration of mineral or an increased mineral-to-matrix ratio... An increased number of microfractures was found frequently in fluorotic bone. They were generally located in old bone with a high mineral-to-matrix concentration ratio... More frequent and abrupt variations in this ratio were found in fluorotic bone, and this probably increased the susceptibility of areas with a high ratio to microfractures."
SOURCE: Baylink DJ, Bernstein DS. (1967). The effects of fluoride therapy on metabolic bone disease. Clinical Orthopaedics and Related Research 55: 51-85..

Mechanisms: Non-Uniformity of Mineralization: (back to top)

Fluoride can cause both hypo-mineralization and hyper-mineralization of bone tissue. However, the entire bone is usually not impacted. Instead, there are "pockets" of mineralization disorders, in which the hypo- or hyper-mineralized bone is surrounded by normally mineralized bone. The resulting lack of homogenity in the bone tissue can decrease the strength, leaving it more prone to fracture.

"One histological characteristic of fluoride-treated bone, however, tends to be the nonuniformity of the mineralized tissue. There can be regions of relatively normal bone that are adjacent to either hypo- or hypermineralized tissue. This nonuniformity can lead to even greater losses in cancellous bone strength than would be caused by homogenous changes."
SOURCE: Carter DR, Beaupre GS. (1990). Effects of fluoride treatment on bone strength. Journal of Bone and Mineral Research 5(Suppl 1):S177-S184.

Fluoride-induced "reduction in bone quality" has been attributed to: "nonuniformity of bone mineralization, to decreased bending strength at the crystal-matrix interface, or to inadequate crosslinks in the organic matrix.."
SOURCE: Lafage MH, et al. (1995). Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs: a one year study. Journal of Clinical Investigations 95: 2127-2133.

Mechanisms: Osteocyte Damage: (back to top)

The osteocyte is a type of bone cell which is increasingly believed to play an important role in repairing defects that arise in bone, thereby maintaining its structural integrity. Being that osteocytes are engulfed in bone mineral, and take part in the bone resorption process, they are known to be impacted by high levels of fluoride accumulation in bone. For, when the osteocytes resorb bone with a high-fluoride content, the fluoride is liberated from the bone structure, leading to elevated and potentially toxic concentrations to the osteocytes. This, in turn, can cause osteocyte cell damage or death. Thus, to the extent that fluoride bone accumulation can damage the osteocytes, it can in turn damage the integrity of the bone. Fluoride-induced damage to osteocytes may be a particularly important factor in the pathogenesis of fluoride-induced microfractures, as microfractures are often found in areas of bone with dead or damaged osteocytes.

"The co-localization of microfractures and osteocytes fits with the hypothesis that in vivo fatigue damage could be repaired by remodeling processes triggered by osteocytes."
SOURCE: Muglia MA, Marotti G. (1996). Osteocyte and microfracture location in human lamellar bone. Bone 19: 155S.

"The results support the sensory role of the osteocyte network as the decline in osteocyte lacunar density in human cortical bone is associated with the accumulation of microcracks and increase in porosity with age."
SOURCE: Vashishth D, et al. (2000). Decline in osteocyte lacunar density in human cortical bone is associated with accumulation of microcracks with age. Bone 26:375-80.

"The impact of losing osteocytes in bone may be great. In human bone, osteocyte cell death can occur in association with age and both osteoporosis and osteoarthritis, leading to increased fragility. Such fragility may be due to increased brittleness via micropetrosis and/or loss of the ability to sense fatigue microfracture and signal to other cell types for repair."
SOURCE: Noble BS, et al. (1997). Identification of apoptotic changes in osteocytes in normal and pathological human bone. Bone 20:273-82.

"An increased number of microfractures was frequently found in fluorotic bone. In nonfluorotic and fluorotic bone, microfractures were usually located in highly mineralized areas of old bone with an increased number of dead osteocytes... [D]ead and degenerating osteocytes were found frequently in the region of microfractures, and viable osteocytes appear to be necessary for the optimum mechanical function of bone. It is possible that osteocytes are involved in the maintenance of structural integrity at an ultra-microscopic level and that impaired osteocyte function increases the tendency for small defects to become microfractures."
SOURCE: Baylink DJ, Bernstein DS. (1967). The effects of fluoride therapy on metabolic bone disease. Clinical Orthopaedics and Related Research 55: 51-85.