Spinal fractures during fluoride therapy for osteoporosis: Relationship to spinal bone density

Farley, S. M.; Wergedal, Jon E.; Farley, John R.; G, Javier; Schulz, Eloy; Talbot, J. R.; Libanati, Cesar; Lindegren, L.; Bock, Merlo; Goette, Marie-Christine; Mohan, Subburaman; Kimball-Johnson, P.; Perkel, Victor S.; Cruise, Robert J.; Baylink, David J.

doi:10.1007/bf01624143

Cited by 46 publications

(9 citation statements)

References 16 publications

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“…NaF is so far the most potent stimulator of bone formation that has been used clinically (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)45). In spite of clearcut increases in bone mass, the effect of fluoride treatment on osteoporotic fractures is equivocal.…”

Section: Discussionmentioning

confidence: 99%

“…There are conflicting reports on the effect of NaF treatment on fracture rates in osteoporotic patients (recently reviewed in references 6 and 7): some studies found no reduction or even an increase ( 8-1I1 ), whereas others showed a significant reduction in fracture rate (12)(13)(14)(15)(16). These differences have been attributed to the NaF dose (17), which was higher in studies in which treatment did not reduce the incidence of fractures (18).…”

Section: Introductionmentioning

confidence: 99%

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Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. A one-year study.

Lafage

Balena²,

Battle³

et al. 1995

J. Clin. Invest.

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Fluoride stimulates trabecular bone formation, whereas bisphosphonates reduce bone resorption and turnover. Fracture prevention has not been convincingly demonstrated for either treatment so far. We compared the effects of 1-yr treatment of 9-mo-old minipigs with sodium fluoride (NaF, 2 mg/kg/d p.o.) or alendronate (ALN, 4 amino-l-hydroxy-on the biomechanical and histomorphometric properties of pig bones. As expected, NaF increased and ALN decreased bone turnover, but in these normal animals neither changed mean bone volume. NaF reduced the strength of cancerous bone from the LA vertebra, relative to control animals, and the stiffness (resistance to deformation) of the femora, relative to the ALN group. In the ALN-treated animals, there was a strong positive correlation between bone strength and L5 cancerous bone volume, but no such correlation was observed in the NaF group. Furthermore, the modulus (resistance to deformation of the tissue) was inversely related to NaF content and there was a relative decrease in bone strength above 0.25 mg NaF/g bone. Moreover, within the range of changes measured in this study, there was an inverse correlation between bone turnover, estimated as the percentage of osteoid surface, and modulus. These findings have relevant implications regarding the use of these agents for osteoporosis therapy. (J. Clin. Invest. 1995. 95:2127-2133

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. A one-year study.

Lafage

Balena²,

Battle³

et al. 1995

J. Clin. Invest.

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“…Nevertheless, this consistent anabolic effect on bone mass has not invariably been found to be associated with an increase in bone strength. Indeed, the fracture rate has been found to be either decreased or uninfluenced or still increased by fluoride treatment [52,[55][56][57][58][59][60][61]. Several possible explanations have been proposed for the discrepancy, among them the severity of osteoporosis at the beginning of treatment, the absolute daily doses, the dosing schedule, and the duration of treatment [62].…”

Section: Predictive Value Of Preclinical Studiesmentioning

confidence: 95%

Importance of Preclinical Studies in the Development of Drugs for Treatment of Osteoporosis: A Review Related to the 1998 WHO Guidelines

Bonjour

Ammann

Rizzoli

1999

Osteoporosis International

100

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Osteoporosis, which is defined as a disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk, is a major health issue worldwide. Among the various strategies to prevent and cure this devastating ailment, an important objective is the development of new efficacious and safe drugs. This situation prompted the World Health Organization (WHO) to provide a comprehensive statement of guiding principles for the design, implementation and interpretation of both preclinical testing and clinical trials in osteoporosis. These guidelines, which are now available, underline the crucial importance of the preclinical evaluation, particularly for assessing the effect of an intervention on bone strength. This concept is heightened by the lack of a validated technique for noninvasively evaluating bone strength in humans and the multiple difficulties and heavy burden inherent in the evaluation of fracture rate in clinical trials. The WHO guidelines emphasize that a comprehensive and adequate preclinical program is expected to provide key information on the relationship between bone mass and strength and thus attenuate the burden of clinical studies. The present report provides a review of experimental evidence in support of the preclinical program as proposed in the WHO guidelines. This program is based on the recent development and refinement of animal models of osteoporosis that mimic the human condition according to the conceptual definition of the disease. Many preclinical studies carried out in appropriate animal models with agents that exert either antiresorbing or anabolic effects on bone indicate that they have been highly predictive of the drug action in humans in terms of both bone mass and remodeling, as well as of bone strength whenever fracture rate has been documented in clinical trials. Based on this evidence the WHO guidelines propose strategies according to which the results of preclinical evaluation will determine the end-points required in the different phases of the clinical development of the drug. Such a distribution of task assignment between preclinical and clinical programs should optimize the progress of research available to patients already suffering from or at risk of osteoporosis.

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“…Despite the current controversy regarding fluoride and fracture prevention, clinical data indicate that fluoride is the single most effective agent currently available for increasing bone volume in the osteoporotic skeleton [1][2][3][4][5][6][7][8][9][10]. Histomorphometric analyses have shown that fluoride increases bone Offprint requests to: J. R. Farley volume by increasing the bone-forming surface [10][11][12][13], and in vitro data have further suggested that this increase in osteoblast number may be mediated by direct effects of fluoride on osteoblast-like cells [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Fluoride increases net45Ca uptake by SaOS-2 cells: The effect is phosphate dependent

et al. 1993

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Previous in vitro studies have shown that the effect of fluoride to increase avian osteoblast-like cell proliferation was dependent on the phosphate concentration. In vitro studies have further revealed that fluoride could also have direct effects on osteoblast-like cells to increase phosphate uptake and transiently increase cytosolic calcium. The current studies were intended to determine whether fluoride could increase net 45Ca uptake by human osteosarcoma (SaOS-2) cells and, if so, whether those effects would also be phosphate dependent. The results of these studies indicate that fluoride increased net 45Ca uptake by SaOS-2 cells, with biphasic dose and time dependencies. After 30 minutes of exposure, net 45Ca uptake was increased to a greater extent by 50 microM fluoride (217 +/- 16% of control, P < 0.001) than by 200 microM fluoride; and the stimulatory effect of 100 microM fluoride on net 45Ca uptake was greater after 20 minutes (187 +/- 22% of control, P < 0.001) than after 60 minutes (122 +/- 7% of control, P < 0.05). These effects of fluoride to increase net 45Ca uptake were dependent on the phosphate concentration in the medium. Fluoride had no effect on net 45Ca uptake in medium containing 0.4 mM phosphate, but increased net 45Ca uptake in medium containing 1.2 or 2.0 mM phosphate (P < 0.005). As the phosphate concentration was increased, the biphasic fluoride dose-response curve was shifted to a lower range of fluoride concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

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Spinal fractures during fluoride therapy for osteoporosis: Relationship to spinal bone density

Cited by 46 publications

References 16 publications

Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. A one-year study.

Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. A one-year study.

Importance of Preclinical Studies in the Development of Drugs for Treatment of Osteoporosis: A Review Related to the 1998 WHO Guidelines

Fluoride increases net45Ca uptake by SaOS-2 cells: The effect is phosphate dependent

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