: The aims of this study were to identify risk factors for hip fracture in men aged 50 years or more. We identified 730 men with hip fracture from 14 centers from Portugal, Spain, France, Italy, Greece and Turkey during the course of a prospective study of hip fracture incidence and 1132 age-stratified controls selected from the neighborhood or population registers. The questionnaire examined aspects of work, physical activity past and present, diseases and drugs, height, weight, indices of co-morbidity and consumption of tobacco, alcohol, calcium, coffee and tea. Significant risk factors identified by univariate analysis included low body mass index (BMI), low sunlight exposure, a low degree of recreational physical activity, low consumption of milk and cheese, and a poor mental score. Co-morbidity including sleep disturbances, loss of weight, impaired mental status and poor appetite were also significant risk factors. Previous stroke with hemiplegia, prior fragility fractures, senile dementia, alcoholism and gastrectomy were associated with significant risk, whereas osteoarthrosis, nephrolithiasis and myocardial infarction were associated with lower risks. Taking medications was not associated with a difference in risk apart from a protective effect with the use of analgesics independent of co-existing osteoarthrosis and an increased risk with the use of anti-epileptic agents. Of the potentially ‘reversible’ risk factors, BMI, leisure exercise, exposure to sunlight and consumption of tea and alcohol and tobacco remained independent risk factors after multivariate analysis, accounting for 54% of hip fractures. Excluding BMI, 46% of fractures could be explained on the basis of the risk factors sought. Of the remaining factors low exposure to sunlight and decreased physical activity accounted for the highest attributable risks (14% and 9% respectively). The use of risk factors to predict hip fractures had relatively low sensitivity and specificity (59.6% and 61.0% respectively). We conclude that lifestyle factors are associated with significant differences in the risk of hip fracture. Potentially remediable factors including a low degree of physical exercise and a low BMI account for a large component of the total risk.

The aims of this study were to determine common international risk factors for hip fracture in women aged 50 years or more. We studied women aged 50 years or more who sustained a hip fracture in 14 centers from Portugal, Spain, France, Italy, Greece, and Turkey over a 1-year period. Women aged 50 years or more selected from the neighborhood or population registers served as controls. Cases and controls were interviewed using a structured questionnaire on work, physical activity, exposure to sunlight, reproductive, history and gynecologic status, height, weight, mental score, and consumption of tobacco, alcohol, calcium, coffee, and tea. Significant risk factors identified by univariate analysis included low body mass index (BMI), short fertile period, low physical activity. lack of sunlight exposure, low milk consumption, no consumption of tea, and a poor mental score. No significant adverse effects of coffee or smoking were observed. Moderate intake of spirits was a protective factor in young adulthood, but otherwise no significant effect of alcohol intake was observed. For some risks, a threshold effect was observed. A low BMI and milk consumption were significant risks only in the lowest 50% and 10% of the population, respectively. A late menarche, poor mental score, low BMI and physical activity, low exposure to sunlight, and a low consumption of calcium and tea remained independent risk factors after multivariate analysis, accounting for 70% of hip fractures. Excluding mental score and age at menarche (not potentially reversible), the attributable risk was 56%. Thus, about half of the hip fractures could be explained on the basis of the potentially reversible risk factors sought. In contrast, the use of risk factors to "predict" hip fractures had moderate sensitivity and specificity. We conclude that variations in lifestyle factors are associated with significant differences in the risk of hip fracture, account for a large component of the total risk, and may be of some value in selecting individuals at high risk.

We assessed the incidence of hip fracture and ecological correlates in residents of 14 communities in six countries of Southern Europe. Hip fracture cases were recorded prospectively in defined catchment areas over a 1-year interval. A retrospective questionnaire was used to assess ecological differences between communities. During a 1-year period of observation a total of 3629 men and women over the age of 50 years were identified with hip fracture from a catchment of 3 million. In all communities the fracture rate increased exponentially with age. There were large and significant differences between centres in the doubling time for hip fracture risk with age and in crude and age-standardized rates. Greater than 4-fold and 13-fold differences in age-standardized risk were found amongst men and women respectively. The lowest rates were observed from Turkey and the highest from Seville, Crete and Porto. Fractures were significantly more frequent among women than men with the exception of three rural Turkish centres. Indeed, in rural Turkey the normal female/male ratio was reserved. Variations in incidence between regions were greater than the differences within centres between sexes, and there was a close and significant correlation between incidence rates for men and those for women in the regions studied. Excess female morbidity increased progressively from the age of 50 years but attained a plateau after the age of 80 years, suggesting a finite duration of the effect of the menopause. The retrospective questionnaire completed by 80% of cases suggested that differences in incidence between the communities studied could not be explained by differences in gonadal status in women. In both men and women cross-cultural associations were found with factors related to age or socioeconomic prosperity, the majority of which disappeared after adjustment for age. We conclude that there are marked and sizeable differences in the incidence rates of hip fracture throughout Southern Europe. The reasons for these differences are not known but affect both men and women, and are likely to be related to lifestyle or genetic factors rather than to differences in endocrine status.

Les auteurs, après avoir décrit le protocole de l'exploration fonctionnelle en cause, en précisent les possibilités et les indications en matière de diagnostic des maladies osseuses.

The risk of hip fracture is higher among persons living in long-term care than among persons living at home. The aim of this study was to explain the difference in risk between the two types of residence by identifying differences in the respective risk factor profiles. Information from the Mediterranean osteoporosis (MEDOS) study questionnaire was used for statistical analyses of 107 non-demented female cases and 225 neighbourhood controls matched for age, sex, and residential area. The statistical analyses incorporated adjustments of the risk estimates by unconditional multivariate logistic regression. Urban background, activity, and morbidity were found to differ between the two types of residence. The detected differences in risk factor profiles were, however, not considered to be sufficient as an explanation for the difference in risk of fracture.

We have evaluated the in vivo and in vitro changes in osteoblast characteristics induced by estrogen deficiency and 17 beta-estradiol (E2) treatment in ovariectomized (OVX) rats. Estrogen deficiency induced osteopenia and increased bone turnover, as evidenced by bone histomorphometry at 1, 3, and 6 mo postovariectomy. Bone surface osteoblastic cells (OB) isolated from tibias of OVX rats, OVX rats treated with E2 (10 micrograms/kg body wt), and sham rats showed no difference in alkaline phosphatase activity and osteocalcin production in vitro. In contrast the proliferation rate of OB cells was higher in OVX rats compared with sham rats at all time points post-surgery, as shown by [3H]thymidine incorporation and cell number. The proliferation rate of alkaline phosphatase-positive marrow cells was also higher in OVX rats compared with sham rats. E2 treatment of OVX rats corrected histologic indexes of bone resorption and formation and normalized OB cell proliferation. induced by estrogen deficiency in OVX rats is related to an increased proliferation of osteoblast precursor cells present in the marrow stroma and along the endosteal bone surface.

Osteocalcin is the most abundant non-collagenous protein produced in the process of bone formation. A specific radioimmunoassay has been developed using a rabbit antiserum raised against osteocalcin extracted from rat bone. The sensitivity of the assay was tested in male and female rats under different experimental conditions: ovariectomy led to a mild increase in circulating osteocalcin (70.6 +/- 6.9 vs 51.6 +/- 6.3 ng/ml; p < 0.05) and deprivation of dietary calcium elevated plasma levels further (119 +/- 6.3 ng/ml; p < 0.01). As expected, pharmacological enhancement of bone turnover with calcitriol produced a significant increase in plasma osteocalcin (296 +/- 24.1 vs 89.5 +/- 5.1 ng/ml; p < 0.01), whereas prednisolone, a steroidal compound known to inhibit osteoid mineralization, significantly reduced circulating concentrations of this protein (70 +/- 7.4 vs 100 +/- 6.3 ng/ml; p < 0.05). Plasma kinetics recorded in female rats between birth and the 100th week revealed a highly significant (p < 0.001) elevation peaking at the third week (231 +/- 70.6 ng/ml) and slowly declining to reach values measured at birth (41.3 +/- 9.2 ng/ml) at the 16th week (47 +/- 4.6 ng/ml). Subsequently, a small but significant (p < 0.05) decline towards senescence was recorded. The osteocalcin surge preceded the period of rapid growth (weeks 3 to 11) estimated by vertebral length progression, showing a tendency to stabilize as growth spurt slowed down. A moderate but significant (p < 0.01) increment was observed after mating (87.8 +/- 5.1 vs 69.5 +/- 4.0 ng/ml). Although plasma osteocalcin remained stable during lactation, average levels were elevated in comparison with age-matched non-pregnant controls.(ABSTRACT TRUNCATED AT 250 WORDS)

To evaluate whether treatment with a mitogenic agent may increase bone formation and bone mass in osteopenia induced by estrogen deficiency, we determined the effect of oral fluoride treatment on bone and bone cells in ovariectomized rats. Sodium fluoride (NaF) was administered to 3-month-old ovariectomized rats 1 day after ovariectomy (OVX) for 1, 3, and 6 months. NaF was given in drinking water at the dose of 1 mg/kg body weight per day. Fluoride administration led to a partial prevention of the bone loss induced by OVX as shown by histologic analysis of tibial metaphysis and by evaluation of femoral calcium content. These beneficial effects of fluoride were more striking at early time points (1 and 3 months postovariectomy) than after 6 months of treatment. The increase in trabecular bone volume in OVX rats treated with fluoride was associated with a rise in the osteoblast surface, which was increased by 60, 72, and 235% at 1, 3, and 6 months postovariectomy compared to untreated OVX rats. In OVX rats and in sham-operated rats plasma osteocalcin was increased in correlation with the osteoblast surface. However, these two parameters were not correlated in OVX rats treated with fluoride. The heat-labile bone-specific alkaline phosphatase in plasma was decreased in OVX rats treated with fluoride compared to OVX rats, suggesting that both the number and the activity of osteoblasts were affected by NaF treatment. To examine the effect of fluoride on the osteocalcin production and the proliferative capacity of bone cells, osteoblastic cells were isolated by collagenase digestion from the bone surface of tibia in treated and untreated OVX rats.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE:To examine the effects of taking drugs affecting bone metabolism on the risk of hip fracture in women aged over 50 years.DESIGN:Retrospective, population based, case-control study by questionnaire.SETTING:14 centres in six countries in southern Europe.SUBJECTS:2086 women with hip fracture and 3532 control women matched for age.MAIN OUTCOME MEASURES:Number of drugs affecting bone metabolism taken and length taken for.RESULTS:Women taking drugs affecting bone metabolism had a significantly decreased risk of hip fracture. After adjustment for differences in other risk factors, the relative risk of hip fractures was 0.55 (95% confidence interval 0.31 to 0.85) in women taking oestrogens, 0.75 (0.60 to 0.94) in those taking calcium, and 0.69 (0.51 to 0.92) in those taking calcitonin. The fall in risk was not significant for anabolic steroids (0.6 (0.29 to 1.22)). Neither vitamin D nor fluorides were associated with a significant decrease in the risk of hip fracture. The effect on hip fracture risk increased significantly with increasing duration of exposure (risk ratio 0.8 (0.61 to 1.05) for less than median exposure v 0.66 (0.5 to 0.88) for greater than median exposure). Drugs were equally effective in older and younger women, with the exception of oestrogen.CONCLUSIONS:Oestrogen, calcium, and calcitonins significantly decrease the risk of hip fracture. Short term intervention late in the natural course of osteoporosis may have significant effects on the incidence of hip fracture.

MC-903 is a novel vitamin D analogue which has been shown to promote epidermal cell differentiation but is 100 times less active than 1,25 dihydroxyvitamin D3 (1,25(OH)2D) in causing hypercalcemia. In order to determine the activity of this compound on bone cells, we have compared the effects of MC-903 and 1,25 dihydroxyvitamin D3 (1,25(OH)2D) on parameters of cell proliferation and differentiation in cultured normal human osteoblastic cells derived by migration from trabecular bone fragments. Dose response curves showed that MC-903 was 10 to 100 times less effective than 1,25(OH)2D in stimulating the synthesis of the osteoblast specific protein osteocalcin by human bone cells depending on the basal osteocalcin production. In cells showing high basal osteocalcin synthesis, 1,25(OH)2D (10−8 M) was 2- to 3-fold more potent than MC-903 (10 −8 M) in inducing osteocalcin from 48 to 96 h of treatment. The greater activity of 1,25(OH)2D over MC-903 was observed in human bone cell cultures with elevated basal osteocalcin levels, indicating that the response to 1,25(OH)2D but not to MC-903 was amplified in cells with the higher osteoblastic characteristics. The effects of MC-903 and 1,25(OH)2D on alkaline phosphatase activity were not markedly different. Transforming Growth Factor-β (TGFβ) (0.5 ng/mL, 48 h) was found to completely suppress the osteocalcin synthesis induced by 1,25(OH)2D (10−8 and 10−9 M), whereas the MC-903-induced osteocalcin synthesis was not affected, suggesting a negative interaction between TGFβ and 1,25(OH)2D but not MC-903 on osteocalcin synthesis. In contrast, the stimulatory effect of TGFβ (0.5 ng/mL, 48 h) on alkaline phosphatase activity in quiescent human osteoblastic cells was suppressed by both MC-903 and 1,25(OH)2D. The two vitamin D derivatives induced similar effects on DNA synthesis in human bone cells and did not affect the stimulation of [3H] thymidine incorporation into DNA induced by TGFβ (0.5 ng/mL). The results show that 1,25(OH)2D and MC-903 exert equipotent effects on DNA synthesis and alkaline phosphatase activity but distinct effects on the synthesis of the bone specific protein osteocalcin. The finding that MC-903 has less potent effects than 1,25(OH)2D on a specific osteoblastic function further indicates that this compound may be useful in the treatment of psoriatic lesions.

Ten-week-old pigs were treated with 4 different treatment schedules of porcine calcitonin for 2 months. Groups C1 and C4 received continuous treatment: C1 had daily IM injections (4 IU/kg/BW (body weight) each injection), and C4 was infused with a minipump implanted subcutaneously delivering 4 IU/kg/BW/day. Groups C2 and C3 received intermittent calcitonin treatment (each injection 4 IU/kg/BW): C2 was given 1 out of every four days, C3 was injected 5 consecutive days out of 20 days. The total dosage received in C1 versus C4 and C2 versus C3 were the same. Results were evaluated by histomorphometry after double tetracycline labeling on iliac trabecular bone. Resorption surfaces were decreased in groups C2, C3 and C4, but bone volume, osteoclast surfaces, and interstitial bone thickness were not modified in any group receiving calcitonin. Osteoblast and mineralizing surfaces were increased in group C2, C3 and C4. Plasma 1,25-dihydroxyvitamin D concentration and bone formation rate were increased in groups C2 and C4. Plasma immunoreactive parathyroid hormone levels and parathyroid weights were not increased in any treated groups. In conclusion, 2-month calcitonin treatment did not decrease the amount of bone resorbed in growing pigs. Continuous calcitonin infusion and intermittent calcitonin administration induced an increase in the extent of active bone formation which might be in part dependent on an increased production of 1,25 dihydroxyvitamin D.

We investigated a possible "in vivo" effect of cyclosporin A, an immunosuppressive agent, on normal rat bone remodeling. At an oral daily dose of 7 mg/kg for 14 days, the blood level of cyclosporin A was in the usual effective range and no change in renal function or magnesium metabolism was observed. Treated rats had decreased bone resorption: urinary hydroxyproline, plasma acid phosphatase, and the number of osteoclasts in caudal vertebrae were significantly reduced. By contrast, bone formation assessed by dynamic histomorphometry after double tetracycline labeling was increased. No modification of calciotropic hormones (vitamin D metabolites and parathyroid hormone as assessed by urinary cyclic AMP) was observed at the end of the treatment. These results suggest that in vivo cyclosporin A treatment induces bone remodeling modifications related to either a direct or a lymphokine-mediated effect on bone cells.

In order to find out whether the response of osteoporosis to sodium fluoride treatment or complications arising from this treatment are related to the retention of fluoride in bones, we measured bone fluoride concentrations in 30 patients with primary osteoporosis who had been treated with sodium fluoride for 1 to 8 years. We found a significant correlation (r = 0.74, P less than 0.001) between bone fluoride concentration and total amount of fluoride ingested. However, with any given amount of sodium fluoride, the bone fluoride concentration could vary by up to three times from a patient to another. There was a significant correlation between bone fluoride concentration and trabecular bone volume on the hand (r = 0.54, P less than 0.001) and thickness of osteoid borders measured on the same biopsy specimen on the other hand (r = 0.45, P less than 0.001). Five patients developed lower limb bone fissures after 11 to 18 months of sodium fluoride treatment, but their bone fluoride concentration was not significantly different from that of the 25 patients who had no fracture. These data suggest a relationship between the degree of stimulation of bone formation by fluoride and the bone concentration of that substance; however, peripheral fractures are not dependent on bone fluoride concentration.

In order to study trabecular bone remodeling in postmenopausal osteoporosis we compared bone biopsies of 44 osteoporotic women aged 50–70 to those of 23 nonosteoporotic women, matched for age, who had a bone biopsy during anesthesia for knee arthritis. Trabecular bone volume, mean wall thickness, osteoblastic surfaces, labeled surfaces, and bone formation rate were decreased in osteoporotic women compared with control women. The osteoclast number and the osteoclastic surfaces were the same in the two groups. The normal distribution of the histomorphometric static parameters in osteoporotic patients did not allow the separation of subgroups. These data indicate that decreased bone formations is a major contributing factor leading to trabecular bone loss in postmenopausal osteoporosis.

18 patients with Paget's disease resistant to calcitonin and/or to EHDP (ethane-hydroxy bisphosphonate) were treated with APD (disodium amino-hydroxypropylidene-bisphosphonate). The efficacy of the product was judged by the decrease in serum alkaline phosphatases and of hydroxyproline in the 24-hour urine specimen. The treatment lasted for a maximum of 6 months. Administration of APD was stopped before six months if he hydroxyproline content in the urine returned to normal (except in the case of four patients where the early interruption of treatment was due to lack of supplies). Of the 14 patients who followed the regular course of treatment, the urine hydroxyproline became normal between the first and the sixth month of treatment in 11 patients: at the start, all had a 24-hour urine hydroxyproline content equal to or less than 2.1 mmol/l 24 h (275 mg/24 h). The baseline 24-hour urine hydroxyproline in the remaining three patients was higher (3.55; 2.30; 3.28 mmol/24 h), but the level was reduced by 50% after 6 months of treatment. Alkaline phosphatases were reduced in the same proportions but the decrease occurred at a slightly later date. The residual activity was evaluated in 9 subjects who had not received any treatment for one year: in 8 out of the 9 patients the parameters used for measuring bone activity had not appreciably altered. Treatment with APD was restarted in 4 patients after a period of 12 to 36 months without therapy, and its efficacy was found to be comparable to that of the drug's first use. In all, APD demonstrated remarkable efficacy in pagetic patients resistant to both calcitonin and/or EHDP.

We report the clinical and biological picture of 34 primary hyperparathyroidism (PHT) cases, diagnosed in rheumatology. It concerned 25 women and 9 men, aged 61 + 11 years. The PHT was often asymptomatic (47 p. cent of cases) at the time of diagnosis. The clinical manifestations were dominated by asthenia (50 p. cent) and renal lithiasis (47 p. cent). We found a chondrocalcinosis in 29 p. cent of patients. No patient presented any bony manifestations of cystic osteitis; 7 out of 34 patients (including 6 women between 57 and 74 years) presented vertebral compression. The mean calcemia was 117 +/- 9 mg/l. There were no hypercalcemic attack. The dosage of PTH and cyclic AMP were elevated in 29 out of 32 and 28 out of 31 patients respectively. In all patients, the level of either of these two tests was increased. The chloremia/phosphoremia ratio was also extremely predictive of HBP, since it was increased, exceeding 3.3 in 33 out of 34 patients. The 25-hydroxyvitamin D levels (25 (OH) D) were normal. The levels of 1,25 (OH) 2D were markedly spread (37 +/- 16 pg/ml) and not significantly different from the reference group. Patients with lithiasis did not present a higher level of 1,25 (OH) 2D. A bone histomorphometry carried out in 15 patients showed a bone trabecular volume similar to that of the reference with the same age. The osteoclastic resorption was increased in all cases and was not correlated with the PTH level, but was significantly correlated with the level of 1,25 (OH) 2D (r = 0.79 p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The prevalence of pathological calcifications in the menisci and articular cartilage of both knees was investigated macroscopically and radiologically in 130 consecutive autopsies. The mean age of the subjects was 72 +/- 13 years. Only 8 subjects were less than 50 years old. All had been admitted to hospital and no patient had a history of joint disorders. Half of the patients were male. Calcifications were found in 27 (20.7%) cases, all over 60 years of age. There were 15.4% males and 26.1% females affected. The incidence of intraarticular calcifications in females increased from 11.1-37.5% and in males from 20-29.4% for the 60-69 year age group and the over 80-year age group, respectively. One third of affected cases had only meniscal and 2/3 had both meniscal and chondral calcifications. Isolated meniscal calcifications were found more often in 1 and mixed meniscal and chondral calcifications were found in both knees. Severe destructive articular cartilage lesions were observed significantly more often in joints with intraarticular calcifications than in joints of age matched subjects without calcifications. Joints with calcifications showed little evidence of synovial inflammation. Similarly, no specific relationship was found between the presence of crystal and amyloid deposits in the knees examined.