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We previously showed that circulating undercarboxylated osteocalcin (ucOC) is elevated in elderly women and is a powerful marker of the subsequent risk of hip fracture in elderly institutionalized women (J Clin Invest 1993; 91:1769). To investigate the relationship between bone mass and ucOC, we measured bone mineral density (BMD) of the hip with dual‐energy x‐ray absorptiometry in 98 elderly institutionalized women, 81.4 + 6.0 years old. ucOC was negatively correlated with BMD at all sites (r= –0.26 to –0.38, p< 0.001 to p< 0.0001), even after exclusion of the effect of age by partial correlation (for the femoral neck, r= –0.26, p< 0.01) and after controlling for serum parathyroid hormone. BMD was significantly lower at all sites of measurement in women with elevated ucOC (> 1.65 ng/ml, upper limit of the normal range in young women) than in those with normal ucOC (for the neck, 0.58 + 0.13 versus 0.43 + 0.13 g/cm2, p< 0.001). Similar results were obtained for ucOC expressed as the fraction of total OC (ucOC %). Multiple regression showed that ucOC has the highest predictive value for BMD when including age and body weight in the equation. In summary, our data indicate that serum ucOC is an independent determinant of BMD of the hip in elderly women. The mechanism by which serum ucOC is related to bone mass is unclear and should be addressed in further studies. However, our data suggest that ucOC level may be an interesting marker in the investigation of bone status in the elderly.

The anabolic effects of sodium fluoride (NaF) on trabecular bone mass in osteoporosis is now well established. In vivo histologic studies performed in humans and other animals have shown that fluoride induces an increase in osteoblast number at the tissue level. To determine the mechanisms of action of fluoride on osteoblasts, we studied the effects of NaF on short‐ and long‐term cultures of human osteoblastic cells derived from bone explants obtained from 21 donors. In short‐term experiments, bone‐derived cells were exposed to NaF for 4 days. At doses ranging from 10−11to 10−5M, NaF did not modify the alkaline phosphatase (AP) activity or osteocalcin secretion. In long‐term experiments, half the bone samples from 15 donors were cultured for 4 months in the presence of 10−5M NaF and the other half were maintained in NaF‐free medium. Observations by light and electron microscopy disclosed no morphologic modification in bone ex‐plants after 4 months of exposure to NaF, despite an increase in the bone fluoride content. After the first month of culture, slight but not significant increases were noted in 6 of 10 cases for AP activity, 4 of 10 for osteocalcin secretion, and 5 of 7 for [3H]thymidine incorporation. After 4 months of culture in the presence of NaF, no change in AP activity or cell proliferation was noted. In contrast, the osteocalcin secretion significantly decreased (p< 0.05). These data suggest that, in vitro, under the conditions of this study, there is no direct effect of fluoride on the proliferation or activity (AP activity and osteocalcin secretion) of human osteoblastic cells and that this effect is very likely mediated by a cofactor.

The major part of fluoride ingested is fixed on calcified tissues, mainly in bone tissue, and then is progressively but slowly recycled during bone remodeling. Thus, the measurement of bone fluoride content allows the determination of the extent of bone fluoride retention, and this parameter constitutes a useful complement to bone histology for the diagnosis of skeletal fluorosis and could also be used for the management of fluoride treatment of osteoporosis. A simple method is described to measure the fluoride content in calcined human iliac bone samples. Bone ashes were diluted in perchloric acid, and the measurement of the bone fluoride content was performed using a specific ion electrode combined with a reference electrode. Reference values are given for bone tissue from 76 control subjects (0.08 ± 0.05% of bone ash), from two groups of 117 and 102 untreated osteoporotic patients (0.05 ± 0.03% and 0.08 ± 0.05%, respectively), from 166 sodium fluoride‐treated osteoporotic patients (mean bone fluoride content varying from 0.24 to 0.67%, depending on the duration of therapy), and from 96 patients showing typical skeletal fluorosis (mean bone fluoride content varying from 0.56 to 1.33%, depending on the etiology of fluorosis and the relationship with the amount of fluoride ingested as well as with the duration of fluoride exposure). During a prolonged exposure of adult bone tissue to fluoride, the early bone fluoride uptake is variable and depends on the remodeling activity; then it increases rapidly before becoming more or less stable at a maximum level.

1. The histological effects of deferoxamine therapy were assessed on transiliac bone biopsies taken after double tetracycline labelling from 16 uraemic patients undergoing chronic haemodialysis, all having aluminium deposits in bone. Eight patients had osteomalacia, five had an ‘aplastic’ bone lesion and three a high bone turnover with a marked increase in osteoid volume. 2. Deferoxamine was administered intravenously once a week at doses ranging from 1 to 6 g for a mean duration of 7.6 ± 3.3 (sd) months. 3. Deferoxamine therapy was associated with significant reductions in stainable aluminium deposits, osteoid volume, osteoid surfaces and thickness index of osteoid seams. The osteoblastic osteoid surfaces as well as the bone formation rates also increased significantly. 4. A rise in resorption parameters and in serum parathyroid hormone levels was observed in patients with osteomalacia. The percentage reductions in stainable aluminium and in osteoid volume were correlated with the degree of hyperparathyroidism. 5. These data show that deferoxamine therapy reduces stainable bone aluminium and improves bone mineralization in low turnover osteomalacia and that the presence of hyperparathyroidism is associated with an increased response to deferoxamine therapy.

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< 0.0001 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= −0.22,p< 0.05) and explained only 5–8% of the bone turnover variance (p< 0.01‐0.001). 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.

Histomorphometric analysis of undecalcified sections was performed in transiliac biopsy cores taken from 29 patients (16 men, 13 women, aged 51 ± 17 years) suffering from skeletal fluorosis due to chronic exposure to fluoride. The origin of the exposure, known in 20 patients, was either hydric (endemic or sporadic), or industrial, or in a few cases iatrogenic. Measured on calcined bone using a specific ion electrode, bone fluoride content was significantly high in each specimen (mean ± SD: 0.79 ± 0.36% of bone ash) as compared to control values (< 0.10%). The radiologically evident osteosclerosis observed in each patient was confirmed by the significant increase of cancellous bone volume (40.1 ± 11.2 vs. 19.0 ± 2.8% in controls, p< 0.0001). There were significant increases in cortical width (1292 ± 395 vs. 934 ± 173 μm, p< 0.0001) and porosity (14.4 ± 6.4 vs. 6.5 ± 1.7%, p< 0.002), but without reduction of cortical bone mass. Osteoid parameters were significantly increased in fluorotic patients. The increase in cancellous osteoid perimeter was almost threefold greater than that noted in cancellous eroded perimeter. The fluorotic group had a greater number of osteoblasts than controls, with a very high proportion of flat osteoblasts. In 15 patients doubly labeled with tetracycline, the mineral apposition rate was significantly decreased, while mineralization lag time significantly increased. Bone formation rate and adjusted apposition rate were significantly decreased in skeletal fluorosis. Cancellous wall width was normal in fluorosis but the formation period and active formation period were significantly increased. Skeletal fluorosis is thus characterized by an unbalanced coupling in favor of bone formation, and also by a great number of osteoblasts with a high proportion of flat osteoblasts. These osteoblasts have a very increased formation period mainly due to a prolonged inactive formation period. Our results support the view that fluoride may have a dual effect on osteoblasts: an increased birthrate at the tissue level, and a toxic effect at the individual cell level. The addition of these two effects represents, however, a marked increase of bone formation at the organ level.