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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 by water (endemic or sporadic), or industrial, or in a few cases iatrogenic. Measured on calcified 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 (less than 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 less than 0.0001). There were significant increases in cortical width (1292 +/- 395 vs. 934 +/- 173 microns, p less than 0.0001) and porosity (14.4 +/- 6.4 vs. 6.5 +/- 1.7%, p less than 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Eighty one women with vertebral osteoporosis were treated for up to 2 years with fluoride administered either as monofluorophosphate (MFP, 200 mg/day, i.e., 26.4 mg fluoride-ion) or sodium fluoride (NaF, 50 mg/day, i.e., 22.6 mg fluoride-ion). All patients received calcium supplementation (1 g of Ca2+/day) taken apart from NaF and in the same tablet for MFP. Despite almost similar fluoride dosage of both regimens, the early increase in the bone mineral density (BMD) of the lumbar spine was higher with MFP than with NaF, reaching 11% and 4%, respectively, at 1 year (p = 0.007), and 21% and 6%, respectively, at 18 months (p less than 0.001). The incidence of lower extremity pain syndrome related to benign stress microfractures was also higher with MFP than with NaF (35% and 15%, respectively, p less than 0.01). Urinary fluoride levels were higher in the MFP than in the NaF group (9.6 +/- 3.5 vs. 6.8 +/- 3.4 at one year, p = 0.003), suggesting that this difference in efficacy and tolerance is related to a better bioavailability of fluoride provided by MFP than by NaF. The occurrence of a stress microfracture could not be predicted by any clinical, biochemical, or densitometric parameter before treatment, but patients presenting with a stress microfracture during the course of the treatment had a higher gain in bone mass than those without stress fractures (at 1 yr+11 vs. +5%, p = 0.03 and at 18 months +18 vs. +6.9%, p less than 0.02). In conclusion, there is a clear correlation between the efficacy and the occurrence of side effects of fluoride therapy in osteoporosis.(ABSTRACT TRUNCATED AT 250 WORDS)

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, p0.001 to p0.0001), even after exclusion of the effect of age by partial correlation (for the femoral neck, r = -0.26, p0.01) 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, p0.001). 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.

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.

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.

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.

A link between bone mineral density and skin color has been reported recently, and pigmentation has been shown to affect cutaneous vitamin D production. In the present study, we investigated the relationship between phototype, global self-assessed sun exposure, geographical location and vitamin D serum levels in 1191 French adults. When the factors were analyzed separately, individuals with lower phototypes as well as those with lower sun exposure showed significantly lower levels of vitamin D than those with darker phototypes or those with higher sun exposure. However, when factors were analyzed as a whole, the vitamin D status was no longer linked with the phototype, but with sun exposure and geographical location. Since phototypes and global self-assessments of sun exposure were positively linked, our data suggest that lower vitamin D levels in fair-skinned individuals are due to their sun exposure behavior.

Resume Propos Le but de cette etude etait de determiner les facteurs associes a la valeur de la densite minerale osseuse (DMO) mesuree au niveau du col du femur dans un groupe de femmes d'âge moyen considerees a risque d'osteoporose (statut precaire en vitamine D [25(OH)D3 36 pg/mL]). Methodes Cette etude a ete conduite en deux temps chez 122 femmes de la cohorte SUVIMAX (supplementation en vitamines et mineraux antioxydants). L'impact de differentes variables, dont l'âge, l'indice de masse corporelle (IMC), le statut en vitamine D, la consommation d'alcool, l'intensite d'exposition au soleil et le phototype sur la DMO a ete teste a l'aide de modeles de regression. Resultats Aucun lien significatif n'a ete retrouve entre la DMO et les variables documentant le statut en vitamine D et le taux de parathormone, ni le phototype. Cependant, les phototypes les plus clairs ont tendance a etre associes avec les valeurs les plus basses de DMO. En revanche, la valeur moyenne de la DMO diminue significativement avec l'âge et augmente avec l'indice de masse corporelle et le niveau d'activite physique. Conclusion Quel que soit leur phototype, les femmes a statut precaire en vitamine D devraient adopter une supplementation en vitamine D associee a un apport adapte en calcium tout au long de l'annee, sans negliger l'adoption de mesures de protection solaire et le maintien d'un niveau satisfaisant d'activite physique, pour ameliorer leur densite osseuse et prevenir le risque fracturaire.

Objective: To assess the cost implications for a preventive treatment strategy for institutionalised elderly women with a combined 1200 mg/day calcium and 800 IU/day vitamin D3 supplementation in seven European countries. Design: Retrospective cost effectiveness analysis based on a prospective placebo-controlled randomised clinical trial. Data sources: Recently published cost studies in seven European countries. Clinical results from Decalyos, a 3-year placebo-controlled study in elderly institutionalised women. Trials: Decalyos study, with 36 months follow-up of 3270 mobile elderly women living in 180 nursing homes, allocated to two groups. One group received 1200 mg/day elemental calcium in the form of tricalcium phosphate together with 800 IU/day (20 μg) of cholecalciferol (vitamin D3), the other placebo. Results: In the 36 months analysis of the Decalyos study, 138 hip fractures occurred in the group of 1176 women, receiving supplementation and 184 hip fractures in the placebo group of 1127 women. The mean duration of treatment was 625.4 days. Adjusted to 1000 women, 46 hip fractures were avoided by the calcium and vitamin D3 supplementation. For all countries, the total costs in the placebo group were higher than in the group receiving supplementation, resulting in a net benefit of €79 000–711 000 per 1000 women. Conclusion: This analysis suggests that the supplementation strategy is cost saving. The results may underestimate the net benefits, as this treatment has also shown to be effective in decreasing the incidence of other non-vertebral fractures in elderly institutionalised women.

The vitamin D status of a general adult urban population was estimated between November and April in 1569 subjects selected from 20 French cities grouped in nine geographical regions (between latitude 43 degrees and 51 degrees N). Major differences in 25-hydroxyvitamin D (25(OH)D) concentration were found between regions, the lowest values being seen in the North and the greatest in the South, with a significant 'sun' effect (r = 0.72; p = 0.03) and latitude effect (r = -0.79; p = 0.01). In this healthy adult population, 14% of subjects exhibited 25(OH)D valuesor = 30 nmol/l (12 ng/ml), which represents the lower limit (2 SD) for a normal adult population measured in winter with the same method (RIA Incstar). A significant negative correlation was found between serum intact parathyroid hormone (iPTH) and serum 25(OH)D values (p0.01). Serum iPTH held a stable plateau level at 36 pg/ml as long as serum 25(OH)D values were higher than 78 nmol/l (31 ng/ml), but increased when the serum 25(OH)D value fell below this. When the 25(OH)D concentration became equal to or lower than 11.3 nmol/l (4.6 ng/ml), the PTH values reached the upper limit of normal values (55 pg/ml) found in vitamin D replete subjects. These results showed that in French normal adults living in an urban environment with a lack of direct exposure to sunshine, diet failed to provide an adequate amount of vitamin D. It is important to pay attention to this rather high prevalence of vitamin D insufficiency in the general adult population and to discuss the clinical utility of winter supplementation with low doses of vitamin D.

It was recently demonstrated that calcium and vitamin D supplements were capable of decreasing the incidence of hip fractures in institutionalized elderly subjects through a reduction of senile secondary hyperparathyroidism. As there are no appropriate data to recommend such a supplement to the elderly living at home, the aim of this study was to determine the incidence of senile secondary hyperparathyroidism in old French women from the general community, its relation to vitamin D status, and its contribution to bone turnover. Four hundred and forty women, aged 75-90 yr, were randomly selected from the general community by mailing from electoral listing in 5 French cities whose latitude varies from 49 degrees 9N to 43 degrees 6N. At the end of the winter, with previous hip fractures or those who were institutionalized were excluded. The results obtained in these women were compared to those obtained in 59 institutionalized old women and 54 younger healthy women. In the five cities for the women living at home, we found a mean PTH value greater than that obtained in young women (63 +/- 28 vs. 43 +/- 15 pg/ml; P = 0.001), but lower that that found in institutionalized women (76 +/- 49 pg/mL; P = 0.05). The mean 25-hydroxyvitamin D (25OHD) level was not different in subjects from the 5 cities, but in all of them it was significantly greater than that found in 59 institutionalized women (42.5 +/- 25.0 vs. 15.5 +/- 6.5 nmol/L; P = 0.0001) but lower than that in young adults (P < 0.001). The main determinants of PTH were in equal ratio, i.e. age (r = 0.19; P < 0.001), 25OHD, and, to a lesser degree, creatinine clearance (r = 0.10; P = 0.03). For 25OHD, the main determinant was the personal outdoor score and, to a lesser extent, the amount of daily sunlight in the city. The mean values of biochemical markers of bone turnover, bone alkaline phosphatase, osteocalcin, and Crosslaps, were significantly increased compared with the results obtained in young women, and significant negative correlations were found between these markers and hip bone mineral density. These results show that vitamin D status of a French aged population in good health and living at home depends mainly on lifestyle. Like institutionalized women, old women living at home exhibit clear evidence of senile hyperparathyroidism in the winter, secondary in part to a reduced 25OHD level and associated with biological signs of increased bone turnover. The maintenance of PTH within the normal range for healthy adults by vitamin D and calcium treatment might constitute an approach for the prevention of bone loss in the entire aged population.

Fluoride treatment is used to increase bone formation and cancellous bone mass in patients suffering from postmenopausal osteoporosis with vertebral fractures. Patients submitted to similar therapeutic protocols have shown various histological responses to the treatment, some developing calcification defects and others not. In fact, the bone histological response to fluoride salts depends on the cumulative uptake of fluoride by bone. To clarify the relationship between the presence of calcification defects (identified by the presence of mottled bone and linear formation defects) and the bone fluoride content, a retrospective study was performed on 29 women with type 1 osteoporosis and treated for several months (11-24) with sodium fluoride (50 mg/day), calcium and vitamin D. Bone fluoride content always significantly increased after treatment, but it was significantly higher in patients showing calcification defects than in those having no defects. These differences between the two groups of patients were not due to differences in clinical details (no significant differences concerning age, duration of treatment, total amount of fluoride ingested, renal function) or in their bone remodelling activity. Thus, it may be hypothesized that the high bone fluoride uptake is due to different individual responses from one patient to another concerning the bioavailability of the same dose of fluoride. This is difficult to predict, except by testing the individual bioavailability of the compound to be used in each patient before starting long-term treatment.

It has been previously shown that the level of circulating undercarboxylated osteocalcin (ucOC) is elevated in elderly women in comparison with young, healthy, premenopausal ones. To understand the mechanism of the increase in the ucOC in the elderly and to assess its potential consequences on bone fragility, we have measured ucOC in the sera of 195 elderly institutionalized women 70-101 yr of age. In 45 women (23%) serum ucOC was above the upper limit of the normal range for young women. The level of ucOC was negatively correlated with 25OHD (r = -0.32, P < 0.001) even after excluding the effect of age, parathyroid hormone (PTH), and creatinine by partial correlation (r = -0.24, P < 0.002). During an 18-mo follow-up, 15 women sustained a hip fracture and their baseline ucOC level was higher (P < 0.01) in women who subsequently sustained hip fracture than in the nonfracture group contrasting with no significant differences for serum calcium, phosphate, alkaline phosphatase, creatinine, PTH, 250HD, and total and carboxylated OC. The risk of hip fracture was increased in women with elevated ucOC (relative ratio 5.9, 99.9% Cl 1.5-22.7, P < 0.001). During 1 yr of calcium/vitamin D2 treatment, ucOC decreased (P < 0.05), especially in those with the initially increased values (from 2.22 +/- 0.35 to 1.41 +/- 0.29 ng/ml, P

The mechanisms underlying glucocorticoid-induced osteoporosis in humans are a defect in bone formation associated with increased bone resorption. The latter may be due to elevated parathyroid hormone (PTH) levels induced by the impairment of intestinal calcium absorption caused by corticosteroids. In this study we analysed the effects of corticosteroids in old ewes, a potential model for the study of human bone turnover. Two groups of seven 9-year-old female sheep were selected. The first group was injected intramuscularly with a daily dose of 30 mg methylprednisone (MP) during the first 2 months and 15 mg during the last month. After 2 and 3 months of treatment, blood samples were taken. At the end of the experiment the animals were slaughtered and the iliac crest kept for bone histomorphometry. Serum osteocalcin (sOC) rapidly and markedly decreased in the MP-treated group compared with controls (−77%;p

The synthesis of osteocalcin or bone gla protein by osteoblasts is markedly stimulated by 1,25-(OH)2D, a key hormone in the regulation of bone mineralization. The circulating levels of osteocalcin have been shown to reflect both the osteoid matrix production and the formation rate of mineralized bone in several metabolic bone diseases (osteoporosis, thyrotoxicosis, primary hyperparathyroidism) in which both mechanisms are tightly coupled because of the absence of mineralization defect. In this study, we measured in 12 patients (7 women, 5 men, 56 +/- 15 yr old) with untreated osteomalacia serum osteocalcin and vitamin D metabolites (25OHD and 1,25-(OH)2D). The results were correlated with biochemical and histomorphometric assessment of bone remodeling. Osteomalacia was due to vitamin D deficiency (5 cases), to vitamin D malabsorption (6 cases), and to hypophosphataemia in 1 case. When compared to control values, serum osteocalcin was increased in patients with osteomalacia (7.4 +/- 4 vs. 3.7 +/- 1.3 ng/mL; P less than 0.001) and was positively correlated with serum alkaline phosphatase (r = 0.65; P = 0.03) and negatively with 25 OHD (r = -0.61; P = 0.04). Serum osteocalcin was not correlated with 1,25-(OH)2D [r = -0.45; not significant (NS)] even after exclusion of the patient with hypophosphataemia. Serum osteocalcin was positively correlated with the osteoid volume and osteoid perimeter (r = 0.71 and 0.69 respectively; P less than 0.01) but not with any of the tetracycline-based parameter of bone mineralization at the tissue level (r ranging from -0.41 to +0.42, NS). Serum 25 OHD, but not 1,25-(OH)2D, was positively correlated with the mineralization rate (r = 0.59; P less than 0.05 and r = 0.54; NS). We conclude that in patients with osteomalacia, a condition which is characterized by an increased osteoid accumulation due to a decreased mineralization rate, the increased level of serum osteocalcin reflects the increased osteoid synthesis but not the mineralization defect. In this disease, serum osteocalcin is inversely correlated to the severity of vitamin D deficiency reflected by serum 25 OHD, but not to the serum levels of 1,25-(OH)2D.

Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DEXA) in 133 normal females on five regions of the femoral site: neck, trochanteric, intertrochanteric, Ward's triangle, and total area of the proximal femur. One hundred and twenty-five women (56 older than 65, range 65-97, and 69 with an age range of 21-65) were also examined for spinal bone mineral density. The mean in vivo precision (CV%) of the measurements with repositioning assessed on five young and eight elderly patients was ranged from 0.7% to 1.7% but lower for Ward's triangle (CV = 2.95% and 3.87%). Between 30 and 90 years, a linear age-related bone mineral decrease was found at all sites with a similar magnitude of bone loss for the femoral neck, total or intertrochanteric regions (-33% to -39%). A greater decrease was found for the Ward's triangle region (-61%). In the subgroup of elderly women (65-97 years old), the lumbar BMD measured with an anteroposterior incidence did not decrease significantly with age, contrasting with an average 27% decrease of the BMD of the hip between 65 and 90 years of age. In addition, 31 patients suffering either from a cervical (n = 12) or pertrochanteric (n = 19) fracture were measured on their contralateral femur 15 to 30 days after the fracture event. The mean calculated BMD values were, depending on the measured area, from 14% to 21% lower than those reported for age-matched controls (z-score from -1.11 to -0.65). A fracture threshold was determined for each site from this population and the elderly controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Ossein-hydroxyapatite compound (OHC) is a protein-mineral complex derived from bovine bone. Its effects on bone remodeling were studied in old ewes which have seasonal variations in bone remodeling. Seven animals received 200 mg OHC/kg b.w./day for 90 days from July to September. The control group consisted of 7 untreated animals followed for the same period of time. OHC was administered through a fistula into the fourth stomach. A significant decrease of bone histomorphometric parameter values was noted in controls at the end of the experiment, due to seasonal variations: the cancellous eroded perimeter decreased by 45%, the osteoblastic perimeter by 60% and the bone formation rate at the cell level by 20%. In contrast, in the treated-group, these parameters tended to increase or did not change. In conclusion, counteracting the significant seasonal reduction of bone remodeling in ewes, OHC seems able to stimulate directly or indirectly bone metabolism, especially when osteoblast activity is reduced and may partly prevent the seasonal reduction of bone turnover.

The evolution of bone changes induced by fluoride after the end of exposure was investigated in lambs. Sodium fluoride (NaF) was given orally at a dose of 3.5 mg/kg per day to 14 animals for 120 days. A group of 7 control and 7 treated lambs was slaughtered at the end of NaF administration (T120) and another group 120 days after the end of NaF exposure (T240). At T120, the bone fluoride content (BFC) was very significantly increased in treated animals. The histomorphometric analysis confirmed that fluoride induces an increase in bone formation (the osteoid perimeter and area were 3-fold and 4.5-fold higher respectively in treated than in control animals). The number of osteoblasts was significantly augmented. Serum osteocalcin level was twice as high in treated animals compared with controls. The bone formation rate at the tissue level (BFR) doubled after treatment, but the apposition rate (Aj.AR) was half that in the control group. The mineralization lag time (Mlt) was 120 days in treated animals compared with 42 days in controls. At T240, BFC had decreased by 50% compared with the level at T120, but it was still significantly higher than in controls. The osteoid and osteoblastic parameters were 2 and 1.3 times higher than in control animals. BFR remained significantly increased in treated animals, but Aj.AR and Mlt were similar in control and treated animals. In conclusion, after 4 months of NaF exposure fluoride induced an increase in osteoblast natality and bone formation at the tissue level, associated with a toxic effect at the individual cell level. Four months after the end of NaF exposure, positive effects on bone formation were still present but the evidence of cellular toxicity had disappeared.

The early effects of two doses of sodium fluoride (NaF) on bone remodeling was studied in 14 ewes divided into two groups. Group I received orally 1 mg NaF/kg/day and group II received a five-fold greater dose. No calcium supplement was given. Transiliac bone biopsies and blood samples were taken before treatment (T0) and after 45 (T45) days of treatment. Bone fluoride content significantly increased in group II. In both groups, a significant decrease of serum calcium and phosphorus, and a slight but nonsignificant augmentation in serum parathyroid hormone were noted. Osteoid perimeter and area were significantly increased. The osteoid width significantly increased in both groups, but was twice higher in group II than I. At T45, the osteoblast perimeter increased in both groups. Osteoid perimeter was significantly correlated with serum osteocalcin values (r = 0.74; p less than 0.001) and bone fluoride content (r = 0.64; p less than 0.01). The bone formation rate at tissue level tended to increase in both groups. Concerning the apposition rate, a decrease was noted which was 1.5-fold higher in group II than in I. The increased formation period resulted from a prolonged inactive period in group II. These results point out a stimulatory effect of fluoride on the birth rate of osteoblasts. However, fluoride prolonged the lifespan of osteoblasts that had reduced activity.

We investigated the role of vitamin D and of parathyroid hormone (PTH) in the regulation of bone mineral density (BMD), tone dimensions and seasonal variation of bone turnover in 881 men aged 19-85 years. Bone mineral content (BMC) and BMD of the lumbar spine, hip and whole body were measured with HOLOGIC 1000W and those of distal forearm with an OSTEOMETER DTX 100 device. Bone formation was evaluated using osteocalcin, bone alkaline phosphatase and N-terminal extension propeptide of type I collagen (PINP). Bone resorption was evaluated by 24-hour excretion of deoxypyridinoline and of C-terminal telopeptide of collagen type I. In young men (55 yrs) PTH level decreased with age (r = -0.18, P0.005) whereas 25-hydroxyvitamin D (25OHD) concentration was stable. In older men (55 years) 25OHD decreased whereas PTH increased with age (r = -0.27 and r = 0.21, P = 0.0001). In young men, 25OHD level varied with season but not PTH, biochemical markers of bone turnover nor BMD. In young men, 25OHD, but not PTH, was a significant determinant of BMC, cortical thickness and of biomechanical properties of the femoral neck. Biochemical bone markers and BMD were not correlated with PTH nor with 25OHD. In elderly men, winter levels of 25OHD were lowest whereas those of PTH, bone resorption markers and PINP were highest. After adjustment for age, body weight and season, biochemical markers of bone turnover were correlated with PTH. In elderly men, 25OHD and PTH were significant determinants of BMC, cortical thickness and of biomechanical parameters of the femoral neck. Men with vertebral deformities had lower concentrations of 25OHD, higher PTH levels and slightly elevated urinary excretion of biochemical markers of bone resorption compared with men without vertebral deformities. In conclusion, in young men, 25OHD discloses a seasonal variability in contrast to PTH and biochemical bone markers. In this group, 25OHD is a significant determinant of BMC and BMD but not of bone size. In elderly men, seasonal variation of 25OHD and PTH concentrations result in seasonal variation of bone resorption. In this group, both 25OHD and PTH are determinants of BMC and cortical thickness of the femoral neck and, consequently, of its mechanical parameters.

Vitamin D insufficiency has been shown to be very common in the elderly population. In addition, serum 25 hydroxyvitamin D (25 OHD) concentrations in the lower half of the normal range appeared to be present in 70 to 100% of institutionalized elderly subjects (1) and in 40% of French ambulatory older women living at home (2). The concept of vitamin D insufficiency, which has a biological effect on calcium homeostasis and skeletal metabolism, needs to be distinguished from the concepts of both vitamin D deficiency, which leads to osteomalacia, and from vitamin D sufficiency, which has no effect on calcium homeostasis. The threshold of the serum 25 OHD concentration that separates vitamin D sufficiency from insufficiency can be defined from biological effects, in particular the increase in serum parathyroid hormone (PTH) secretion and the conversion of 1.25(OH)2 D from 25 OHD. The increased secretion of PTH in vitamin D insufficiency is well documented (3–5) and contributes to bone fragility and probably to bone fractures in the elderly through increased bone turnover (6–9).

The two main determinants of hip fractures are falls and bone loss leading to an intrinsic femoral fragility. Substantial femoral bone loss continues throughout old age, with a continuous and exponential increase in the risk of hip fracture; thus any reduction or arrest of this loss will induce an important reduction in the incidence of hip fracture. Preventive measures may be achieved during childhood by increasing peak bone mass with calcium and exercise, by using long-term estrogen replacement therapy after menopause, but also by using vitamin D and calcium supplements for late prevention in the elderly. Vitamin D insufficiency and a deficit in calcium intake are very common in the elderly living either in institutions or at home and the cumulative response to these deficits is a negative calcium balance which stimulates parathyroid hormone secretion. This senile secondary hyperparathyroidism is one of the determinants of femoral bone loss and can be reversed by calcium and vitamin D supplements. We have shown in a 3-year controlled prospective study that the daily use of supplements (1.2 g calcium and 800 IU vitamin D3) given in a large population of 3270 elderly ambulatory women living in nursing homes reduced the number of hip fractures by 23% (intention-to-treat analysis). In parallel, serum parathyroid hormone concentrations were reduced by 28% and low baseline serum 25-hydroxy vitamin D concentration returned to normal values. After 18 months of treatment the bone density of the total proximal femoral region had increased by 2.7% in the vitamin D3-calcium group and decreased by 4.6% in the placebo group (p

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 10−11 to 10−5 M, 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 10−5 M 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.

Hypovitaminosis D and a low calcium intake contribute to increased parathyroid function in elderly persons. Calcium and vitamin D supplements reduce this secondary hyperparathyroidism, but whether such supplements reduce the risk of hip fractures among elderly people is not known.We studied the effects of supplementation with vitamin D3 (cholecalciferol) and calcium on the frequency of hip fractures and other nonvertebral fractures, identified radiologically, in 3270 healthy ambulatory women (mean [+/- SD] age, 84 +/- 6 years). Each day for 18 months, 1634 women received tricalcium phosphate (containing 1.2 g of elemental calcium) and 20 micrograms (800 IU) of vitamin D3, and 1636 women received a double placebo. We measured serial serum parathyroid hormone and 25-hydroxyvitamin D (25(OH)D) concentrations in 142 women and determined the femoral bone mineral density at base line and after 18 months in 56 women.Among the women who completed the 18-month study, the number of hip fractures was 43 percent lower (P = 0.043) and the total number of nonvertebral fractures was 32 percent lower (P = 0.015) among the women treated with vitamin D3 and calcium than among those who received placebo. The results of analyses according to active treatment and according to intention to treat were similar. In the vitamin D3-calcium group, the mean serum parathyroid hormone concentration had decreased by 44 percent from the base-line value at 18 months (P0.001) and the serum 25(OH)D concentration had increased by 162 percent over the base-line value (P0.001). The bone density of the proximal femur increased 2.7 percent in the vitamin D3-calcium group and decreased 4.6 percent in the placebo group (P0.001).Supplementation with vitamin D3 and calcium reduces the risk of hip fractures and other nonvertebral fractures among elderly women.

To assess whether an interval of a few hours would be advisable between an intake of sodium fluoride (NaF) and that of calcium salts when treating osteoporotic patients with vertebral collapse, we carried out three pharmacokinetic studies in 12 healthy fasting volunteer subjects to compare the fluoride bioavailability provided by NaF alone and NaF combined with two calcium salts. The results were as follows: (1) When NaF is accompanied by calcium, the fluoride peak level is lower and delayed. (2) Fluoride absorption varied greatly among individuals in both experiments, but none of the 6 subjects proved to be nonabsorbers. (3) The areas under the curves obtained with each of the three preparations were not significantly different, but 24-h urinary fluoride was significantly lower in volunteers receiving simultaneously NaF and calcium salts than in volunteers receiving only NaF.

The pyridinium derivatives hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) are intermolecular crosslinking compounds of collagen which are only present in its mature form. Contrasting to the wide distribution of type I and II collagens, HP and LP are absent from skin, ligament and fascia, and their major sources are bone and cartilage. Using a specific HPLC assay, we have determined the 24-h excretion of HP and LP crosslinks in normal adults of both sexes, in patients with primary hyperparathyroidism and in patients with Paget's disease of bone before and after intravenous treatment with amino-propylidene bisphosphonate (APB). Mean adult normal values were 33 +/- 13 pmol/mumol creatinine for HP and 6.3 +/- 3.4 pmol/mumol creatinine for LP. In women, menopause induced a 2-3-fold increase of HP and LP reflecting the well documented postmenopausal increase of bone turnover. In the urine of patients with primary hyperparathyroidism and of patients with active Paget's disease of bone, urinary crosslinks were significantly higher than in age-matched controls, with a mean 3- and 12-fold increase, respectively. Urinary excretion of hydroxyproline is a well recognized but poorly sensitive marker of bone turnover, reflecting resorption. In the same patients, the effect of menopause and disease state on hydroxyproline excretion was much less dramatic than on HP and LP. During intravenous APB treatment of pagetic patients, there was an early decrease of HP and LP, which was significant after 24 h and reached 62% at 4 days, contrasting with a late and milder decrease of urinary hydroxyproline. Because APB is a potent inhibitor of resorption which does not have a direct short-term effect on bone formation, these data also indicate that urinary excretion of HP and LP reflect only collagen degradation occurring during osteoclastic resorption and not the degradation of newly synthesized collagen. We conclude that urinary HP and LP excretion represents the first sensitive and specific marker of bone resorption. Its use should be valuable in the clinical investigation of metabolic bone diseases, especially osteoporosis.

We have previously shown that elderly women with an increased serum undercarboxylated osteocalcin (ucOC) level have an increased risk of sustaining a hip fracture as compared to those with normal serum ucOC. We reassessed our findings on a larger number of hip fractures that occurred over 3 years in 183 institutionalized women (aged 70-97 years) belonging to a large prospective clinical trial. Total OC, carboxylated OC, ucOC, and alkaline phosphatase were significantly higher at baseline in those who sustained a hip fracture during the follow-up. The age-adjusted odds ratio for hip fracture was three times higher in women with increased ucOC at baseline (odds ratio = 3.1, 99.9% C.I. = 1.7-6.0, p < 0.001). In the logistic regression, ucOC was still predictive of the hip fracture when age and parathyroid hormone concentration were included into the model (odds ratio = 2.6, 95% C.I. = 1.05-6.4). These data confirm that ucOC is a marker of the increased risk of hip fracture in elderly institutionalized women. Serum ucOC may reflect some nutritional deficiency associated with increased bone fragility.

We recently showed that daily supplementation with 1.2 g calcium and 800 IU cholecalciferol over 18 months substantially decreased the risk of hip fractures and other non-vertebral fractures in elderly women living in nursing homes.1 We report the results of a further 18 months of treatment. A total of 3270 mobile elderly women (mean age 84 (SD 6) years) living in 180 nursing homes were enrolled in the study. Half the women received 1.2 g calcium daily in the form of tricalcium phosphate, together with 800 IU (20 μg) cholecalciferol; the other half received a double placebo. All subjects were followed up every six months; biochemical variables were measured at baseline and every year in a subgroup of 52 women. Hip fractures and all non-vertebral fractures were separately analysed using a log …

Background. Hypovitaminosis D and a low calcium intake contribute to increased parathyroid function in elderly persons. Calcium and vitamin D supplements reduce this secondary hyperparathyroidism, but whether such supplements reduce the risk of hip fractures among elderly people is not known. Methods. We studied the effects of supplementation with vitamin D3 (cholecalciferol) and calcium on the frequency of hip fractures and other nonvertebral fractures, identified radiologically, in 3270 healthy ambulatory women (mean [±SD] age, 84±6 years). Each day for 18 months, 1634 women received tricalcium phosphate (containing 1.2 g of elemental calcium) and 20 μg (800 IU) of vitamin D3, and 1636 women received a double placebo. We measured serial serum parathyroid hormone and 25-hydroxyvitamin D (25(OH)D) concentrations in 142 women and determined the femoral bone mineral density at base line and after 18 months in 56 women. Results. Among the women who completed the 18-month study, the number of hip fra...

A hemodialyzed patient showing x-ray and biochemical evidence of apparently pure severe hyperparathyroidism underwent a tetracycline-labeled transiliac bone biopsy. The bone biopsy not only confirmed the hyperparathyroid bone lesions but also revealed an impairment of bone mineralization induced by aluminum. This was demonstrated by a reduction of double-labeled osteoid surfaces, a significant increase in the osteoid seam thickness, and the presence of extensive aluminum deposits in bone. The planned parathyroidectomy was postponed, and deferoxamine (DFO) therapy, 2 g once a week, was initiated. A second bone biopsy, taken 6 months later, showed recovery of normal bone mineralization but the persistence of hyperparathyroid bone lesions. This was associated with a considerable reduction in the extent of aluminum deposits on trabecular bone surfaces. This observation shows that severe and apparently pure hyperparathyroidism can be associated with an impairment of bone mineralization induced by aluminum. This suggests that bone mineralization and aluminum overload should be evaluated in dialyzed patients who are being considered for parathyroidectomy.

Calcium and vitamin D status were studied in 193 healthy elderly French people. Calcium intake was less than 500 mg/d in 62% of the patients and the vitamin D intake was less than 5 micrograms/d in all patients. They also exhibited reduced levels of serum calcium (SCa) and 25-hydroxyvitamin D (25-OHD) and high levels of parathyroid hormone (PTH) and alkaline phosphatase (SAP). The response to calcium (1000 mg/d) and ergocalciferol (20 micrograms/d) supplementation given for 6 mo was evaluated in 65 patients with 69 subjects taken as controls. The treatment induced a significant increase in SCa and in 25-OHD levels, and a subsequent decrease in PTH levels without modification of the mean calcitriol levels. The biochemical changes were more marked in long-stay hospital patients than in outpatients. All these changes were significantly different from those observed in the control group. Increasing the calcium and vitamin D intake reduces the biochemical signs of secondary hyperparathyroidism in elderly people.

Transiliac undecalcified bone biopsy specimens were taken after tetracycline double labeling from 14 patients with radiologic evidence of osteosclerotic metastases from prostatic carcinoma. The histomorphometric analysis showed an increased trabecular bone volume in all patients, and in seven morphologic and dynamic evidence of osteomalacia (Group 1). The seven other patients demonstrated an extension of apposition surfaces without evidence of osteomalacia (Group 2). Group 1 was different from Group 2 in terms of a greater increase in serum alkaline phosphatase and a lower urinary calcium. In four Group 1 patients, a second bone sample taken after two to six months of treatment with vitamin D and calcium provided evidence of improving osteomalacia. The high incidence of osteomalacia in osteosclerotic metastases of prostatic origin appears to be the result of the increase in bone formation induced by prostatic cells, and the unability to satisfy the high calcium demand for new bone.

The aim of this study was to determine the ability of disodium dichloromethylene diphosphonate (Cl2MDP) to reduce the hypercalcemia secondary to skeletal metastases and induced by stimulation of bone resorption by malignant cells. Five patients with hypercalcemia due to bone metastases of breast or renal cancer were treated orally for 4 wk with 3,200 mg of Cl2MDP and 4 wk with a placebo in a double blind, crossover study. During the Cl2MDP period of administration four patients experienced a rapid and significant decrease in serum calcium and urinary calcium excretion together with an increase in alkaline phosphatase. In the remaining patient who developed a sudden paraplegia at the onset of the therapy followed by a marked increase in serum calcium levels and urinary calcium excretion, Cl2MDP was able to reverse this worsening of hypercalcemia or to reduce serum and urinary calcium to normal values. For all patients, urinary hydroxyproline excretion was unchanged during the Cl2MDP period when compared with the prestudy or placebo periods. From these results, and because of the rapid relapse of hypercalcemia during the placebo period or after withdrawal of the treatment, we can conclude that Cl2MDP is capable of reducing excessive mobilization of calcium resulting from bone metastases.

Clinical and biochemical resistance to sodium etidronate therapy is not rare in patients with severe Paget's disease of bone, especially after several courses of treatment. Sixteen patients with Paget's disease of bone and well-documented resistance to sodium etidronate were treated with a new diphosphonate, aminohexane diphosphonate, given orally for three months at a daily dose of 400 mg. These patients comprised a selected population of patients with very active disease, as shown by a mean 20-fold increase of serum alkaline phosphatase levels before aminohexane diphosphonate therapy. Aminohexane diphosphonate induced a striking reduction of serum alkaline phosphatase and urinary hydroxyproline levels sustained for up to 18 months after withdrawal of treatment. Two patients had a relapse 14 to 16 months after treatment, and received a second course of aminohexane diphosphonate with the same efficacy. This was accompanied by marked clinical improvement, a reduction of the radioisotope uptake by pagetic bones, and radiologic healing of osteolytic lesions in some cases. Iliac crest biopsy specimens taken after tetracycline double-labeling showed no impairment of bone mineralization. No clinical or biochemical adverse effects have been observed.

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.

Serum parathyroid hormone and 25 hydroxyvitamin D were measured in 124 normal subjects aged from 20 to 90 years. There was a significant progressive increase in serum parathyroid levels with age associated with a progressive decrease in total serum calcium. After the sixth decade there was a significant reduction of 25 hydroxyvitamin D serum levels. In each age group, there were no significant differences between men and women in all parameters measured. In normal elderly subjects there is an age-related decline of calcium absorption associated with reduced calcium intake and sun exposure leading to secondary hyperparathyroidism. These results emphasize the importance of calcium and vitamin D supplementation in elderly European population, not only in long-stay patients but in ambulatory normal people after 60 years.

Nineteen patients with Paget's disease and four patients with hypercalcemia of malignancy underwent hypocalcemic therapy with etidronate disodium (etidronate) administered intravenously. The dosage for patients with Paget's disease was 4.3 mg/kg/day, infused on each of seven consecutive days. Nine of the 19 patients also received oral etidronate 5 mg/kg/day for three months after administration of intravenous therapy. Etidronate administered orally sustained the decreases in urinary hydroxyproline produced by the infusions, whereas levels returned to pretreatment values in most patients receiving only the intravenously administered drug. Serum alkaline phosphatase levels were not reduced in the 10 patients receiving only intravenously administered etidronate, but they declined by approximately 50 percent in the nine patients who received the additional orally administered etidronate. Transiliac-crest bone biopsy specimens obtained three months after intravenous therapy revealed a regular lamellar structure, compared with the characteristic woven pattern of pagetic bone. In all four patients with hypercalcemia of malignancy, normocalcemia was achieved by the 10th day of treatment using a dosage of 4.3 mg/kg/day. Oral etidronate therapy was beneficial in maintaining normocalcemia.

A protein responsible for the biochemical syndrome similar to primary hyperparathyroidism associated with certain tumors has been recently characterized and its effects at the level of bone and kidney reported. However, the relative role of tubular reabsorption of calcium (Ca) and bone resorption in the pathogenesis of hypercalcemia induced by this factor is still debated. We investigated the effects of a synthetic amino-terminal fragment of parathyroid hormone-related protein [PTHrP-(1-34)] administered chronically by intraperitoneal osmotic minipumps in thyroparathyroidectomized (TPTX) rats. Clearance studies performed on day 6 of treatment after a 24 h fast revealed an increase in renal tubular reabsorption of Ca and a decrease in renal tubular reabsorption of phosphate (Pi), accompanied by an increase in cAMP excretion. PTHrP-(1-34) (90 pmol/h) stimulated bone resorption as evaluated by an increment in fasting urinary Ca excretion. Although the bone resorption inhibitor aminopropylidene diphosphonate fully corrected urinary Ca excretion and reduced plasma Ca from 3.04 +/- 0.07 to 2.44 +/- 0.21 mM (p less than 0.05), this latter value remained considerably higher than in TPTX control rats (1.54 +/- 0.12 mM, p less than 0.01). In contrast, when the agent WR-2721, which is known to decrease the renal tubular reabsorption of Ca by a PTH-independent mechanism, was given, a further drop in plasma Ca and an increase in urinary Ca excretion were observed. These findings are similar to those found in animals implanted with the hypercalcemic Leydig cell tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

Mean (+/- SD) serum bone Gla-protein (BGP or osteocalcin) was normal (7.0 +/- 3.3 ng/ml) in 26 patients with untreated postmenopausal osteoporosis ( PMO ). But 9 patients had values either above (4) or below (5) the normal values obtained in 35 age-matched control women (6.9 +/- 1.25 ng/ml). Serum BGP correlated positively with relative osteoid volume, relative osteoid surfaces, tetracycline labelled surfaces, and bone formation rate but not with resorption surfaces. Based on normal values for osteoid volume, patients were classified as having high (HF, 9 patients), normal (NF, 12 patients) and low osteoid formation (LF, 5 patients). Serum BGP (+/- SEM) was significantly lower in LF group (2.7 +/- 0.9 ng/ml) and significantly higher in HF group (9.7 +/- 0.8 ng/ml) than in the NF group (7.0 +/- 0.6 ng/ml). Serum alkaline phosphatase and urinary hydroxyproline did not discriminate between these three groups and did not correlate significantly with any of the measured histomorphometric indices in biopsy specimens in these patients. Serum BGP appears to be a specific marker for bone formation and can predict the histological profile in PMO . Serum BGP might be useful in investigating patients with PMO and should be valuable in assessing the effects of treatments that increase bone formation.

Bone fluoride content (BFC) was measured and histomorphometric analysis of undecalcified sections was performed in transiliac biopsy cores 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, BFC was significantly high in each specimen (mean +/- SD; 0.79 +/- 0.36% on bone ash). The radiologically evident osteosclerosis observed in each patient was confirmed by a significant increase in cancellous bone volume (40.1 +/- 11.2% vs. 19.0 +/- 2.8% in controls, p less than 0.0001). There were significant increases in cortical width (1292 +/- 395 mcm vs. 934 +/- 173 mcm, p less than 0.0001) and porosity (14.4 +/- 6.4% vs. 6.5 +/- 1.7%, p less than 0.002), but without reduction of cortical bone mass. Cancellous osteoid volume and perimeter, as well as width of osteoid seams, were significantly increased in fluorotic patients. The increase in cancellous osteoid perimeter was almost three-fold greater than that noted in cancellous eroded perimeter. In 15 patients doubly labeled with tetracycline, the mineral apposition rate was significantly decreased, mineralization lag time was significantly increased. The fluorotic group had a greater number of osteoblasts than controls with a very high proportion of flat osteoblasts. The ultrastructural characteristics reflecting the activity of the bone cells were clearly visible on electron microscopy. Bone formation rate and adjusted apposition rate were significantly decreased in skeletal fluorosis. On stained sections and microradiographs, bone tissue showed typical modifications for skeletal fluorosis (linear formation defects, mottled bone). The volume of cancellous interstitial mineralization defects and the proportion of mottled periosteocytic lacunae were markedly increased in skeletal fluorosis. These two parameters were significantly correlated together but neither of these was significantly correlated with BFC. Renal function did not significantly influence the changes in BFC and histomorphometry of fluorotic patients. Skeletal fluorosis is thus characterized by an unbalanced coupling in favor of bone formation, and a great number of osteoblasts with a high proportion of flat osteoblasts.(ABSTRACT TRUNCATED AT 400 WORDS)

As first shown by Russell et al1,2, disodium ethane-1-hydroxy-1, 1 diphosphonate (E.H.D.P.) has a powerful depressive effect on the increased bone turnover which characterizes Paget’s disease of bone. When ingested in doses of greater than 5 mg per kg per day, however, it causes a mineralization defect in addition to having a marked antiosteoclastic effect1–6. Accordingly, a diphosphonate free of such a side-effect would be preferable for the treatment of not only Paget’s disease, but of any other condition of hyperosteoclastosis, whatever the mechanisms of osteoclastic differenciation. To date, two compounds have been suggested in this connection: 3 amino-1-hydroxy-propane-1, 1 diphosphonate (A.H.P.D.P.) investigated by Bijvoet and al.7, and disodium dichloromethylene diphosphonate (Cl2M.D.P.), a drug similar in structure to E.H.D.P.

To evaluate the potential role of aluminum (Al) in a subset of dialysis patients with aplastic bone disease, we have studied tetracycline-labeled bone biopsies of 32 patients (22 males and 10 females, 45–73 years) on maintenance hemodialysis. Selection criteria included normal resorption surfaces (RS) and osteoid thickness. Eleven patients (Group I) had no stainable bone Al (Al -; 61.7 ± 7.2 years) and 21 (Group II) had stainable bone Al (Al +; 57.7 ± 6.8 years). Serum Al was normal to slightly elevated in Group I, but significantly higher in Group II (p < 0.01). Al surfaces (AlS), undetectable in Group I, were 67.8 ± 17.9% in Group II. Bone Al content (BAC) was much lower in Group I than in Group II (14.8 ± 3.7 vs. 113.8 ± 100.2 μg/g, p < 0.01), but higher in Group I than in controls (p < 0.05). Extensive thin osteoid seams were present in Group II. AlS was correlated with OS (r = 0.56, p < 0.001) and OV (r = 0.48, p < 0.01). Labeled surfaces were decreased in both groups. Labeled osteoid surfaces (TLS/OS) were below 2 SD of the mean control values in 96% of patients and calcification rate (CR) was depressed below 0.20 μm/day in 44% of patients. Bone formation rate (BFR) was strikingly depressed, values being below one SD of the mean control value in 92–100% of patients at both levels and below 2 SD of the mean in 82% of patients at BMU levels. Mineralization lag time (OMP) was markedly prolonged above 2 SD of controls in 89% of patients. A major observation was in the extent of osteoblast osteoid surfaces (OblS/OS) which was found significantly different in Group I (34.2%) than in Group II (15%) (p < 0.001); these differences were consistently found in osteoid surfaces covered by different morphological types of osteoblasts (plump, intermediate, and flat). Negative correlations were found between AlS and OblS/OS (r = −0.57, p < 0.001), intermediate OblS/OS (r = −0.38, p < 0.05) and flat OblS/OS (r = −0.56, p < 0.01). These findings indicate an impairment of osteoblastic function, with depression of bone formation at all levels, and strongly suggest a toxic effect of Al on osteoblasts.

Bone gla-protein (BGP), also called osteocalcin1,2, is the most abundant non-collagenous bone protein. BGP is synthesized by the osteoblasts, is concentrated in the bone matrix and also found circulating in the blood. The measurement of BGP in serum by radioimmunoassay3 has proved to be a useful tool for assessing bone turnover in a variety of metabolic or endocrine bone diseascs4–6 and more specifically bone formation in osteoporosis7.

19 patients with Paget's disease were treated orally for 6 months with disodium dichloromethylene diphosphonate. 1600 mg/day (10 patients) significantly reduced urine hydroxyproline, serum alkaline phosphatase, urine calcium, and the number of pagetic bone osteoclasts. Tetracycline double labelling revealed undisturbed bone mineralisation. There was improvement on quantitative bone-scans and bone pain diminished. There was a transient increase in parathyroid hormone level in 13 of the 19 patients during treatment, which was associated with a high serum 1,25 (OH) 2 D 3 . No adverse clinical side-effects have been observed and biochemical remission has persisted for 9 months.

Serum bone Gla-protein (S-BGP) and other serum biochemical parameters, including alkaline phosphatase (S-AP) and immunoreactive PTH (S-iPTH), were measured in 42 patients undergoing chronic hemodialysis. Each patient also had a tetracycline-labeled transiliac bone biopsy, allowing correlations between the biochemical and trabecular bone histomorphometric parameters, S-BGP was markedly increased [64.0 +/- 74.8 (+/- SD) vs. 6.2 +/- 2.2 ng/ml in normal subjects] significantly correlated with S-AP (r = 0.53) and S-iPTH (r = 0.55) levels. S-BGP was significantly higher in the 14 patients with high turnover renal osteodystrophy (HT-ROD; S-BGP, 138.5 +/- 90.8 ng/ml) than in the 28 patients with low turnover (LT-ROD; S-BGP, 26.8 +/- 14.8 ng/ml). S-BGP was significantly correlated with the cellular parameters of bone resorption and formation (r = 0.57-0.69) and with the dynamic parameters of bone formation (r = 0.62-0.82). The extent of stainable bone aluminum was significantly negatively correlated with S-BGP (r = -0.51) and serum iPTH (r = -0.33), but not with S-AP. S-BGP measurement allowed better discrimination between LT-ROD and HT-ROD groups than did S-AP measurement. However, in the patients with LT-ROD, S-BGP did not discriminate between patients with or without osteomalacia. We conclude that S-BGP is a valuable marker for evaluating bone remodeling and, more specifically, the bone formation rate at the tissue level in hemodialyzed patients.

Serum bone Gla-protein (sBGP) was measured in 32 patients with untreated Paget's disease of bone. Despite clinical and biological symptoms of active disease in all patients, sBGP was normal in 13/32 patients (41%). There was a striking discrepancy between the moderate increase of sBGP above normal values (11.4 +/- 4.5 vs 6.0 +/- 2.1 ng/ml) and the marked increase of both serum alkaline phosphatase (sAP) and urinary hydroxyproline (uOHP). sBGP was weakly correlated with sAP (r = 0.50, p less than 0.01), uOHP (r = 0.48, p less than 0.01) and with the extension of the disease (r = 0.48, p less than 0.01). We conclude that sBGP is not a sensitive marker of bone turnover in patients with Paget's disease of bone, and should be interpreted with caution in this condition.