Fluoride Action Network

Fluoride’s Differential Effect on Bone Density: Trabecular vs. Cortical Bone

Fluoride Action Network | April 2012 | By Michael Connett

Based on fluoride’s ability to increase bone mass, doctors in the 1960s began using fluoride as an experimental drug in human clinical trials as a treatment for osteoporosis. The hope was that fluoride would increase the bone density of the patients and thereby help to prevent fractures. Since fluoride was found to increase, rather than decrease, fracture rates, fluoride therapy for osteoporosis has never been approved by the FDA for anything other than experimental use.

Although the clinical studies of fluoride treatment have repeatedly confirmed that fluoride can increase bone density, they have also confirmed that fluoride reduces bone density as well. At first glance, such results may appear contradictory, but they are actually consistent with the fact that fluoride’s effect on bone density depends on the type of bone is being studied. While fluoride tends to increase the density of trabecular bone (aka cancellous bone), it tends to decrease the density of cortical bone.

Fluoride’s differential effects on trabecular and cortical bone helps to explain why it affects different areas of the skeleton differently. This is because trabecular bone is the primary bone type in the “axial skeleton” (spine, pelvis, & ribs), whereas cortical bone is the primary bone type in the “appendicular skeleton” (arms, legs, femoral neck). As displayed in the following table, therefore, clinical trials found that fluoride tended to increase the density in the axial skeleton, while tending to decrease it in the appendicular skeleton.

Fluoride & Bone Density:
Effects Depend on Type of Bone & (Ergo) Area of Skeleton
Axial Skeleton Appendicular Skeleton
Bones Involved:  Spine, Pelvis, Ribs, Skull Legs, arms, femoral neck (hip)
Type of Bone: Primarily Trabecular Primarily Cortical
Fluoride’s General Effect: No effect or Increased Density No effect or Reduced Density

Fluoride’s differential effect on trabecular and cortical has been documented in other contexts besides clinical trials. As demonstrated below, the differential effect has reported in studies of patients with skeletal fluorosis as well as studies comparing the bone density of humans living in high-fluoride versus low-fluoride areas.

Fluoride-induced reductions in cortical bone density would be expected to reduce bone strength. By contrast, fluoride-induced increases in bone density are generally not accompanied by increases in the bone’s strength due to the defective quality of the new bone. Nevertheless, the increased mass of the bone can help to compensate for the reductions in bone quality and thus mitigate the fracture risk.

Fluoride’s differential effect on bone density thus helps to explain why fluoride has been linked (in both clinical and epidemiological studies) to increased rates of non-vertebral fractures, such as the hip and femoral neck, while having little effect on vertebral fracture rates.

1) Human Clinical Trials

“The BMD changes in the present study are suggestive of an anabolic action of fluoride at trabecular sites (the spine) and a catabolic action at cortical sites (the femoral neck).”
SOURCE: Morabito N, et al. (2003). Three-year effectiveness of intravenous pamidronate versus pamidronate plus slow-release sodium fluoride for postmenopausal osteoporosis. Osteoporosis International 14: 500-6.

“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(2):158-70.

“Forearm bone density was actually lower in the fluoride groups at both 2 and 4 years. Since the forearm has a different composition of trabecular and cortical tissue, this differential effect might be expected.”
SOURCE: Haguenauer D, et al. (2000). Fluoride for the treatment of postmenopausal osteoporotic fractures: a meta-analysis. Osteoporosis International 11:727-38.

“It is a consistent finding that fluoride treatment in osteoporosis results in greater amounts of trabecular bone and a decrease in cortical bone.”
SOURCE: Krook L, Minor RR. (1998). Fluoride and alkaline phosphatase. Fluoride 31: 177-182.

“It is important to note that Femoral Neck BMD in some individuals decreased markedly (by as much as 19%) for a minimal increment in Lumbar Spine. This does suggest that fluoride therapy can decrease Femoral Neck BMD (and possibly increase fracture risk) without any potential benefit at the lumbar spine… [A]ll patients treated with fluoride need to have BMD measurements at the Lumbar Spine and Femoral Neck to allow discontinuation of fluoride if this disparity in BMD changes is observed.”
SOURCE: Patel S, et al. (1996). Fluoride pharmacokinetics and changes in lumbar spine and hip bone mineral density. Bone 19:651-5.

“Fluoride has been shown to increase bone formation to a larger extent in trabecular bone than cortical bone and, therefore, to exert a greater response in the axial than the appendicular skeleton.”
SOURCE: Sogaard CH, et al. (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: 393-99.

“The osteogenic effect has consistently been documented in trabecular bone of the axial skeleton. The effect of fluoride on the peripheral skeleton is less clear and experience has been primarily limited to the radius, where bone density was either reduced or unchanged during fluoride therapy.”
SOURCE: Dure-Smith BA, et al. (1991). Fluoride therapy for osteoporosis: A review of dose response, duration of treatment, and skeletal sites of action. Calcified Tissue International 49(Suppl): S64-S67.

“While only two pretreatment biopsies are available and showed minimal tunneling, we have never seen this degree of cortical porosity and resorption in biopsies in numerous similar untreated patients. We believe these latter important structural changes to be fluoride related.”
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.

“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.

“In the lumbar spine, a site containing a predominance of cancellous bone, the bone mineral density increased linearly at a rate of about 10 percent per year. In contrast, there was a substantial loss of bone from the shaft of the radius, a site with a predominance of cortical bone. Decreases in bone mineral content in the radial shaft have been found previously during fluoride treatment. Ruegsegger used computed tomography to assess the changes in the two types of bone and found a gain in cancellous bone but a loss in cortical bone. These results suggest that fluoride therapy causes a redistribution of bone from the cortical to the cancellous department.”
SOURCE: Riggs BL, et al. (1990). Effect of fluoride treatment on the fracture rates in postmenopausal women with osteoporosis. New England Journal of Medicine 322:802-809.

“It has been shown that fluoride therapy can actually increase lumbar spine density and increase trabecular bone volume on iliac crest biopsies. The effect of therapeutic doses of fluoride on cortical bone, however, is not as clear. Bone mass measured at sites of predominantly cortical bone showed either no change or small decreases after fluoride therapy. These findings led Eastell and Riggs (1987) to state that ‘Some evidence suggests that trabecular bone may increase at the expense of cortical bone during fluoride therapy.'”
SOURCE: Phipps KR, Burt BA. (1990). Water-borne fluoride and cortical bone mass: a comparison of two communities. Journal of Dental Research 69: 1256-1260.

“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 69:932-8.

“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(4):276-9.

“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.

“In this series, we found increased vertebral trabeculation in one third of the patients, but this was associated with, if anything, decreased density of the distal radius, a site containing predominantly cortical bone. The possibility that trabecular (lamellar) bone is increased at the expense of cortical (osteonal) bone cannot be excluded at the present time.”
SOURCE: Riggs BL, et al. (1980). Treatment of primary osteoporosis with fluoride and calcium: Clinical tolerance and fracture occurrence. Journal of the American Medical Association 243: 446-44.

2) Studies of Patients with Skeletal Fluorosis

“Fluorosis is known to be more prominent in the axial skeleton than the peripheral.”
SOURCE: Kumar S, et al. (2011). Skeletal fluorosis mimicking seronegative spondyloarthropathy: a deceptive presentation. Tropical Doctor 41:247-48.

“By stimulating osteoblasts, fluoride promotes bone formation in cortical and trabecular bone, but its effect on trabecular bone is greater, occurs earlier, and leads to a more pronounced increase in spine density on x-ray films. Indeed, in our patients, BMD measured at the spine (>66% trabecular bone) was significantly higher than that measured at the hip (25% trabecular bone).”
SOURCE: Hallanger Johnson JE, et al. (2007). Fluoride-related bone disease associated with habitual tea consumption. Mayo Clinic Proceedings 82(6):719-24.

“Radiographs from 1993 and 1998 documented the appearance of marked osteosclerosis and cortical thickening throughout the entire spine (especially the lumbar region) and pelvis during this 5-year period. The ribs were similarly affected. Radiographs of the calvarium, hands, proximal femora, and knees were unremarkable. . . . Dual-energy X-ray absorptiometry documented markedly elevated bone mineral density in the lumbar spine but normal density in the hip.”
SOURCE: Whyte MP, et al. (2005). Skeletal fluorosis and instant tea. American Journal of Medicine 118:78-82.

“In skeletal fluorosis, involvement of the axial skeleton is characteristic, and changes are most marked in the spine, pelvis, and forearm.”
SOURCE: Savas S, et al. (2001). Endemic fluorosis in Turkish patients: relationship with knee osteoarthritis. Rheumatology International 21: 30-5.

“It is very interesting to observe that in the majority of our cases, osteosclerosis in the spine and pelvis was always combined with osteoporosis of the long bones. It might be an indication that the axial skeleton undergoes a quite different pathological process from the appendicular skeleton…”
SOURCE: Lian ZC, Wu EH. (1986). Osteoporosis–an early radiographic sign of endemic fluorosis. Skeletal Radiology 15:350-3.

“Osteosclerosis was particularly prominent in axial bones of the spine, pelvis, and ribs… The peculiarity of peripheral osteomalacia was its frequent association with axial osteosclerosis… Some cases showed axial osteosclerosis exclusively, others axial osteosclerosis in association with peripheral osteoporosis or osteomalacia.”
SOURCE: Daijei H. (1984). Further observations on radiological changes of endemic foodborne skeletal fluorosis. Fluoride 17: 9-14.

“the intensity of changes is most marked in the axial skeleton and becomes less toward the periphery.”
SOURCE: Morris JW. (1965). Skeletal fluorosis among Indians of the American Southwest. American Journal of Roentgenology, Radium Therapy & Nuclear Medicine 94: 608-615.

3) Studies on Individuals Consuming Elevated Levels of Fluoride in Water

“Depending upon which fluoride exposure method is used, two different sets of conclusions can be drawn from this study. If the ecologic measure (city of residence) is used, then exposure to higher levels of fluoride in community water systems increases lumbar spine and proximal femur BMD. If the individual level measure (daily fluoride intake) is used, then exposure to higher levels of fluoride in community water systems decreases forearm BMD… The anatomical site differences noted in both the ecologic and individual level analyses may be partially explained by differences in the proportions of cortical vs trabecular bone at each site. Cortical bone accounts for 50 to 95% of the forearm, depending upon the region of interest, while only 10 to 33% of the vertebrae is cortical bone… The differential impact of fluoride on cortical and trabecular bone has been demonstrated in a recent clinical trial where fluoride was used as a therapy for osteoporosis.”
SOURCE: Phipps KR, et al. (1998). The association between water-borne fluoride and bone mineral density in older adults. Journal of Dental Research 77:1739-1748.

“young women in the higher-fluoride community had significantly lower mean bone mass than did women in the control and higher-calcium communities. Furthermore, the mean loss of radial bone (primarily cortical), expressed as absolute difference or percentage of loss, was greater in women of the higher-fluoride community than in women of the control and higher-calcium communities… We could determine no reason, apart from the higher fluoride exposure, why women in the higher-fluoride community should have greater loss of bone mass than women in the other two communities.”
SOURCE: Sowers MR, et al. (1991). A prospective study of bone mineral content and fracture in communities with differential fluoride exposure. American Journal of Epidemiology 133: 649-660.

“living in a community with high levels of water-borne fluoride was associated with decreased bone mass*… a Lordsburg woman (high-fluoride community, 3.5 ppm) had approximately 7% less bone mass than a Deming (low fluoride community) peer of similar weight and years since menopause… The negative association we found between fluoride exposure and bone mass was not an anticipated result, since this study was stimulated by the hypothesis that fluoride may actually prevent overall skeletal osteopenia by increasing cortical bone mass. However, we cannot attribute this result to bias or random error, since the other significant findings were consistent with theoretical considerations and prior research.” (*”For this study, bone mass of the distal radius (75% cortical bone) was utilized as the measure of cortical bone osteopenia.”)
SOURCE: Phipps KR, Burt BA. (1990). Water-borne fluoride and cortical bone mass: a comparison of two communities. Journal of Dental Research 69: 1256-1260.

“If therapeutic doses of fluoride do have a differential effect on cortical and trabecular bone mass (in clinical trials), a differential effect may also be noted at lower doses.”
SOURCE: Phipps KR, Burt BA. (1990). Water-borne fluoride and cortical bone mass: a comparison of two communities. Journal of Dental Research 69: 1256-1260.