Although fluoride increases bone mass, the newly formed bone may have reduced strength. To assess the effect of fluoride treatment on the fracture rate in osteoporosis, we conducted a four-year prospective clinical trial in 202 postmenopausal women with osteoporosis and vertebral fractures who were randomly assigned to receive sodium fluoride (75 mg per day) or placebo. All received a calcium supplement (1500 mg per day). Sixty-six women in the fluoride group and 69 women in the placebo group completed the trial. As compared with the placebo group, the treatment group had increases in median bone mineral density of 35 percent (P less than 0.0001) in the lumbar spine (predominantly cancellous bone), 12 percent (P less than 0.0001) in the femoral neck, and 10 percent (P less than 0.0001) in the femoral trochanter (sites of mixed cortical and cancellous bone), but the bone mineral density decreased by 4 percent (P less than 0.02) in the shaft of the radius (predominantly cortical bone). The number of new vertebral fractures was similar in the treatment and placebo groups (163 and 136, respectively; P not significant), but the number of nonvertebral fractures was higher in the treatment group (72 vs. 24; P less than 0.01). Fifty-four women in the fluoride group and 24 in the placebo group had side effects sufficiently severe to warrant dose reduction; the major side effects were gastrointestinal symptoms and lower-extremity pain. We conclude that fluoride therapy increases cancellous but decreases cortical bone mineral density and increases skeletal fragility. Thus, under the conditions of this study, the fluoride-calcium regimen was not effective treatment for postmenopausal osteoporosis.

https://www.nejm.org/doi/pdf/10.1056/NEJM199003223221203

Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis.

Increased bone turnover has been suggested as a potential risk factor for osteoporotic fractures. We investigated this hypothesis in a prospective cohort study performed on 7598 healthy women more than 75 years of age. One hundred and twenty-six women (mean years 82.5) who sustained a hip fracture during a mean 22-month follow-up were age-matched with three controls who did not fracture. Baseline samples were collected prior to fracture for the measurement of two markers of bone formation and three urinary markers of bone resorption: type I collagen cross-linked N- (NTX) or C-telopeptide (CTX) and free deoxypyridinoline (free D-Pyr). Elderly women had increased bone formation and resorption compared with healthy premenopausal women. Urinary excretion of CTX and free D-Pyr, but not other markers, was higher in patients with hip fracture than in age-matched controls (p = 0.02 and 0.005, respectively). CTX and free D-Pyr excretion above the upper limit of the premenopausal range was associated with an increased hip fracture risk with an odds ratio (95% confidence interval) of 2.2 (1.3-3.6) and 1.9 (1.1-3.2), respectively, while markers of formation were not. Increased bone resorption predicted hip fracture independently of bone mass, i.e., after adjustment for femoral neck bone mineral density (BMD) and independently of mobility status assessed by the gait speed. Women with both a femoral BMD value of 2.5 SD or more below the mean of young adults and either high CTX or high free D-Pyr levels were at greater risk of hip fracture, with an odds ratio of 4.8 and 4.1, respectively, than those with only low BMD or high bone resorption. Elderly women are characterized by increased bone turnover, and some markers of bone resorption predict the subsequent risk of hip fracture independently of hip BMD. Combining the measurement of BMD and bone resorption may be useful to improve the assessment of the risk of hip fracture in elderly women.

Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study.

Changes of bone turnover with aging are responsible for bone loss and play a major role in osteoporosis Although an increase of bone turnover has been documented at the time of menopause, the subsequent abnormalities of bone resorption and formation and their potential role in determining bone mass in the elderly have not been investigated To address this issue, we have measured a battery of new sensitive and specific markers of bone turnover in a population-based study of 653 healthy women analyzed cross-sectionally, including 432 women postmenopausal from 1 to 40 years, and the data were correlated with bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) at different skeletal sites Bone formation was assessed by serum osteocalcin (OC), serum bone-specific alkaline phosphatase (B-ALP), serum C-propeptide of type I collagen (PICP), and bone resorption by the urinary excretion of two pyridinoline cross-linked peptides (NTX and CTX) Bone turnover increased in perimenopausal women with both irregular menses and elevated serum follicle stimulating hormone (FSH) Menopause induced a 37-52% and 79-97% increase in the bone formation and bone resorption marker levels, respectively (p < 00001 except for PICP) In postmenopausal women, bone formation markers did not decrease with age When resorption markers were corrected by whole body bone mineral content (BMC), the fraction of bone resorbed per day was not correlated with age in postmenopausal women and remained elevated for up to 40 years after menopause In premenopausal women, the bone turnover rate accounted for only 0-10% of the variation in whole body BMC, total hip, distal radius, and lumbar spine BMD With increasing time after menopause, the importance of the bone turnover rate as a determinant of bone mass increased at all sites and accounted for up to 52% of the BMD variance in elderly women Thus, in women 20 years or more postmenopause, bone turnover was higher in those in the lowest quartile than in those in the highest quartile of BMD In elderly women, 20 years since menopause and over, but not in younger ones, serum PTH was negatively correlated with serum 25-hydroxyvitamin D (r = -022, p < 005) and explained only 5-8% of the bone turnover variance (p < 001-0001) These data indicate that the overall rates of both bone formation and bone resorption remain high in elderly women The rate of bone turnover appears to play an increasing role as a determinant of bone mass with increasing time since menopause with a high bone turnover rate being associated with a low bone mass Thus assessing bone marker levels may be useful in the evaluation of osteoporosis risk In elderly women, secondary hyperparathyroidism caused in part by reduced serum 25-hydroxyvitamin D appears to be a marginal determinant of an increased bone turnover rate

Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis

▪Objective:To evaluate the tolerance and effectiveness of transdermal estrogen for women with established postmenopausal osteoporosis and vertebral fractures. ▪Design:Double-blind, randomi...

Treatment of Postmenopausal Osteoporosis with Transdermal Estrogen

OSTEOPOROSIS is one of the most important disorders associated with aging.1 , 2 More than 1.5 million Americans have fractures related to osteoporosis each year, with attendant pain, deformity, and loss of independence. The annual cost to the U.S. health care system is at least $10 billion.1 , 2 Because of the aging of the population and increases over time in the incidence of fractures, these already huge costs will more than double over the next 30 years3 unless a comprehensive program of prevention and treatment is initiated soon. The most important preventable cause of fractures is low bone mass. During the course of . . .

The Prevention and Treatment of Osteoporosis

We measured the serum concentrations of 2 biochemical markers of bone formation, bone Gla-protein (BGP) and bone alkaline phosphatase (BAP), in 164 normal subjects and 164 patients with metabolic bone disorders. The data were reported as Z scores (deviation in SDs from the sex-specific age regression in normal subjects). Both serum BGP and BAP distinguished abnormalities well (mean Z scores for BGP and BAP, respectively) and gave concordant results in patients with hypoparathyroidism (−1.7, −1.4), hyperthyroidism (+1.1, +1.8), primary hyperparathyroidism (+3.6, +2.5), acromegaly (+1.2, +2.8), and postmenopausal osteoporosis (+0.4, +1.9). The 2 markers gave discordant results, however, in patients with glucocorticoid excess (−2.4, +0.9), Paget’s disease (+1.8, +41.8), chronic renal failure (+16.3, +0.4), and osteolytic metastases (−1.4, +5.9). These discrepancies may have occurred because srum BGP and BAP concentrations reflect different aspects of osteoblast function or because there are differences in th...

Concurrent assays of circulating bone Gla-protein and bone alkaline phosphatase: effects of sex, age, and metabolic bone disease.

The cause of bone loss in postmenopausal osteoporosis--decreased bone formation or increased bone resorption--is controversial. Synthesis of bone--Gla protein (BGP), a specific osteoblast product, is stimulated by 1,25-dihydroxyvitamin D3 [1,25(OH)2D] in vitro. Thus, increases in serum BGP levels during 1,25(OH)2D administration might provide a useful dynamic index of osteoblast function. We compared 14 postmenopausal osteoporotic women with 12 age-matched postmenopausal normal women before and during 6 d of 1,25(OH)2D administration (2.0 micrograms/d). Serum BGP levels were similar at baseline and increased during treatment in both groups (P less than 0.001). However, trend analysis showed a greater (P less than 0.01) increase in the osteoporotic women. These data do not support the hypothesis that defective osteoblast function is the major cause of bone loss in postmenopausal osteoporosis.

/pdf/1-25-dihydroxyvitamin-d-stimulation-test-for-osteoblast-3jrla4teoy.pdf

R J Duda

Papers

Concurrent assays of circulating bone Gla-protein and bone alkaline phosphatase: effects of sex, age, and metabolic bone disease.

1,25-Dihydroxyvitamin D stimulation test for osteoblast function in normal and osteoporotic postmenopausal women.