A phase IV, two-armed, randomized, cross-over study comparing compliance with once-a-month administration of vitamin D3 to compliance with daily administration of a fixed-dose combination of vitamin D3 and calcium during two 6-month periods.

UNLABELLED: In a randomized, cross-over study, once monthly administration of vitamin D3 was preferred over a once daily administration of a fixed-dose combination of vitamin D3 and calcium, with a better compliance but without any significant difference in the increase in vitamin D levels. INTRODUCTION: The aim of the present study was to compare a once-monthly administration of vitamin D3 to a daily administration of a fixed-dose combination of vitamin D3 and calcium during two treatment periods of 6 months. METHODS: One hundred volunteers aged 50 years old or older were randomized to receive either one drinkable ampoule containing 25,000 IU vitamin D3 (D-Cure®, SMB) once monthly (group VD) or one chewable tablet containing 1000 mg calcium carbonate + 800 IU vitamin D3 (Steovit Forte®, Takeda) once daily (group VDCa) during 6 months. After the first 6 months of treatment, the groups were reversed according to the randomized cross-over design. Treatment compliance (i.e. the primary outcome), preference, acceptability and vitamin D levels and adverse events were all collected. RESULTS: For the two periods, the patients had a significantly higher compliance in the VD group than in the VDCa group (p < 0.0001). During the study, 50 (56.8 %) patients preferred the VD treatment, 16 (18.2 %) patients preferred the VDCa, and for 22 (25.0 %) patients, neither treatment was preferred. At the end of the first 6 months of treatment, the mean (SD) increase of 25(OH)D was 6.57 ng/mL (8.19) in the VD group and 3.88 ng/mL (10.0) in the VDCa group (p = 0.16 between groups). CONCLUSION: In this study, a once-monthly administration of vitamin D3 was preferred over a once-daily administration of a fixed-dose combination of vitamin D3 and calcium, with a better compliance but without any significant difference in the increase in vitamin D levels.

Total joint replacement after glucosamine sulphate treatment in knee osteoarthritis: results of a mean 8-year observation of patients from two previous 3-year, randomised, placebo-controlled trials.

OBJECTIVE: To assess the incidence of Total Joint Replacement (TJR) during the long-term follow-up of patients with knee osteoarthritis (OA) formerly receiving treatment with glucosamine sulphate or placebo. METHODS: Knee OA patients participating in two previous randomised, placebo-controlled, double-blind, 3-year trials of glucosamine sulphate and receiving treatment for at least 12 months, were systematically contacted to participate in a long-term follow-up retrospective assessment of the incidence of total knee replacement. RESULTS: Out of 340 patients with at least 12 months of treatment, 275 (i.e., 81%) could be retrieved and interviewed for the present evaluation: 131 formerly on placebo and 144 on glucosamine sulphate. There were no differences in baseline disease characteristics between groups or with the patients lost to follow-up. The mean duration of follow-up was approximately 5 years after trial termination and treatment discontinuation, making up a total of 2178 patient-years of observation (including treatment and follow-up). Total knee replacement had occurred in over twice as many patients from the placebo group, 19/131 (14.5%), than in those formerly receiving glucosamine sulphate, 9/144 (6.3%) (P=0.024, chi-square test), with a Relative Risk that was therefore 0.43 (95% confidence interval (CI): 0.20-0.92), i.e., a 57% decrease compared with placebo. The Kaplan Meier/Log-Rank test survival analysis confirmed a significantly decreased (P=0.026) cumulative incidence of total knee replacements in patients who had received glucosamine sulphate. A pharmacoeconomic analysis in a subgroup of subjects suggested that patients formerly on glucosamine sulphate had recurred to less symptomatic medications and use of other health resources than those from the placebo group during the last year of follow-up. CONCLUSIONS: Treatment of knee OA with glucosamine sulphate for at least 12 months and up to 3 years may prevent TJR in an average follow-up of 5 years after drug discontinuation.

Osteoarthritic patients with high cartilage turnover show increased responsiveness to the cartilage protecting effects of glucosamine sulphate.

OBJECTIVE: Glucosamine sulphate has been shown in a large double-blind, placebo-controlled clinical trial to prevent structural damage and improve clinical symptoms of osteoarthritis (OA). We investigated whether early response in a newly developed biochemical marker of collagen type II degradation (CTX-II, CartiLaps ELISA) could reflect the long-term preservation of hyaline cartilage. METHODS: Study subjects comprised 212 knee OA patients participating in a clinical trial of the effects of glucosamine sulphate. Disease symptoms were assessed quarterly by WOMAC scoring and X-ray analysis was performed at baseline and after 3 years. Urine samples were obtained at baseline and after 1, 2 and 3 years for measurement in the CartiLaps assay. The measurements were corrected for creatinine. RESULTS: At baseline the patients had an average concentration of urinary CTX-II of 222.4 +/- 159.5 ng/mmol creatinine. This was significantly above the CTX-II levels measured in urine samples from 415 healthy controls (169.1 +/- 92.3 ng/mmol, p < 0.0001). There was no significant difference in the CTX-II response in the placebo group and the glucosamine treated group. However, those with high cartilage turnover presented a significant decrease in CTX-II after 12-month glucosamine treatment. Thus, three group with CTX II concentrations above normal average + 1SD decreased 15.5% after 12-month therapy. The 12 months change in CTX-II in OA patients with elevated CTX-II at baseline correlated with the change in average joint space width observed after 36 months (R = 0.43, p < 0.05). Increased baseline levels of CTX-II were associated with a worsening of the WOMAC index (p < 0.01). CONCLUSION: The data indicate that measurement of urinary collagen type II C-telopeptide fragments enables the identification of OA patients with high cartilage turnover who at the same time are most responsive to therapy with structure modifying drugs.

Strontium ranelate: a new paradigm in the treatment of osteoporosis.

Not one of the currently available medications has, so far, unequivocally demonstrated its ability to fully prevent the occurrence of new vertebral or peripheral osteoporotic fractures once osteoporosis is established. Therefore, several new therapies are currently under development to optimize the risk/benefit ratio of osteoporosis treatment. Strontium ranelate is composed of an organic moiety (ranelic acid) and of two atoms of stable nonradioactive strontium. In vitro, strontium ranelate increases collagen and noncollagenic proteins synthesis by mature osteoblast enriched cells. The effects of strontium ranelate on bone formation were confirmed as strontium ranelate enhanced pre-osteoblastic cell replication. The stimulation by strontium ranelate of the replication of osteoprogenitor cell and collagen, as well as noncollagenic protein synthesis in osteoblasts, provides substantial evidence to categorize strontium ranelate as a bone-forming agent. In the isolated rat osteoclast assay, a pre-incubation of bone slices with strontium ranelate induced a dose- dependent inhibition of the bone resorbing activity of treated rat osteoclast. Strontium ranelate also dose-dependently inhibited, in a chicken bone marrow culture, the expression of both carbonic anhydrase II and the alpha-subunit of the vitronectin receptor. These effects showing that strontium ranelate significantly affects bone resorption due to a direct and/or matrix-mediated inhibition of osteoclast activity and also inhibits osteoclasts differentiation, are compatible with the profile of an anti-resorptive drug. In normal rats, administration of strontium ranelate induces an improvement in the mechanical properties of the humerus and/or the lumbar vertebra associated with a commensurate increase in bone dimension, shaft and volume. Strontium ranelate was administered in 160 early postmenopausal women, in a 24-month, double-blind, placebo-controlled, prospective randomized study. Daily oral dose of 125 mg, 500 mg and 1 g of strontium ranelate were compared with a placebo. At the conclusion of the study, the percent variation of lumbar-adjusted bone mineral density from baseline was significantly different in the group receiving 1 g/day of strontium ranelate compared with placebo (+1.41% vs. -0.98%, respectively). Increase in total hip and neck bone mineral density averages, respectively, 3.2% and 2.5%. Strontium ranelate does not induce any significant adverse reaction compared with those observed in women receiving a placebo for the same duration. In a phase II study, the effect of strontium ranelate in postmenopausal women with vertebral osteoporotic fractures was assessed during a double-blind, placebo-controlled trial. Doses of 500 mg, 1 g and 2 g daily of strontium ranelate or placebo were given to 353 Caucasian women with prevalent osteoporosis. At the conclusion of this 2-year study, the annual increase in lumbar-adjusted bone mineral density of the group receiving 2 g of strontium ranelate was + 2.97%. This result was significantly different compared with placebo. A significant increase in bone alkaline phosphatase and, over a 6-month period, a significant decrease in urinary-pyridium crosslinks (NTX) were evidenced. During the second year of treatment, the dose of 2 g was associated with a 44% reduction in the number of patients experiencing a new vertebral deformity. Bone histomorphometry showed no mineralization defects. The same percentage of withdrawals following an adverse effect was observed for patients receiving placebo and for those receiving 2 g of strontium ranelate. The compound was further investigated in a large phase III program that included two extensive trials for the treatment of severe osteoporosis, one assessing the effects of strontium ranelate on the risk of vertebral fractures (SOTI) and one evaluating its effects on peripheral (nonspinal) fractures (TROPOS). The primary analysis of the SOTI study, evaluating the effect of 2 g of strontium ranelate on vertebral fracture rates, revealed a 41% reduction in the relative risk of expein the relative risk of experiencing a first new vertebral fracture with strontium ranelate, throughout the 3-year study, compared with placebo. The TROPOS study, showed a significant (p = 0.05) reduction in the relative risk of experiencing a first non-vertebral fracture in the group treated with strontium ranelate throughout the 3-year study compared with placebo in the intention-to-treat population. A 41% reduction in the relative risk of experiencing a hip fracture was demonstrated in the per protocol population. All these results imply that strontium ranelate is a new, effective and safe treatment for vertebral and nonvertebral osteoporosis, with a unique mode of action.

Prevention of early postmenopausal bone loss by strontium ranelate: the randomized, two-year, double-masked, dose-ranging, placebo-controlled PREVOS trial.

Early postmenopausal women ( n = 160) were randomised to receive placebo or strontium ranelate (SR) 125 mg/day, 500 mg/day or 1 g/day for 2 years (40 participants per group). All participants received calcium 500 mg/day. The primary efficacy parameter was the percent variation in lumbar bone mineral density (BMD), measured using dual-energy X-ray absorptiometry. Secondary efficacy criteria included hip BMD and biochemical markers of bone turnover. At month 24, SR 1 g/day significantly increased lumbar BMD compared with placebo [mean (SD) +5.53% (5.12); p<0.001] for measured values and [mean (SD) +1.41% (5.33%); p<0.05] for values adjusted for bone strontium content. The annual increase for adjusted values was +0.66% compared with -0.5% with placebo, with an overall beneficial effect after 2 years of about 2.4% with SR 1 g/day relative to placebo. There were no other significant between-group differences in adjusted lumbar BMD. Femoral neck and total hip BMD were also significantly increased at month 24 with SR 1 g/day compared with placebo [mean (SD): +2.46% (4.78) and +3.21% (4.68), respectively; both p<0.001)]. SR 1 g/day significantly increased bone alkaline phosphatase at all time points ( p<0.05) compared with baseline and between-group analysis showed a significant increase, compared with placebo, at month 18 ( p = 0.048). No effect on markers of bone resorption was observed. SR was as well tolerated as placebo. The minimum does at which SR is effective in preventing bone loss in early postmenopausal non-osteoporotic women is therefore 1 g/day.

Administration of a supplement containing both calcium and vitamin D is more effective than calcium alone to reduce secondary hyperparathyroidism in postmenopausal women with low 25(OH)vitamin D circulating levels.

BACKGROUND AND AIMS: Supplementation of postmenopausal women with calcium alone or calcium-vitamin D association was suggested to have positive effects on bone turnover and bone density, as well as to lower fracture incidence. The beneficial effect appears to be mediated by a reduction in parathyroid hormone secretion. Our aim was to compare the respective efficacy of calcium and calcium-vitamin D supplements in reducing serum parathyroid hormone levels in postmenopausal women with prevalent low 25(OH)vitamin D levels. METHODS: One hundred consecutive ambulatory postmenopausal women with serum 25(OH)vitamin D levels below 18 ng/mL were included in a randomized, prospective, open label study. For a duration of 90 days, the women were randomly assigned to a daily supplementation of either one tablet of calcium gluconolactate and carbonate (500 mg calcium), or one powder-pack of an association of calcium carbonate (500 mg calcium), citric acid (2.175 gr) and cholecalciferol (200 IU). Changes observed during the 90 days of the study in circulating PTH levels were the primary endpoint, while changes in serum 25(OH)D levels were assessed as secondary endpoint. RESULTS: A significant difference was observed between the calcium-vitamin D (CaD) and the calcium (Ca) only groups for changes occurring during the 90 days of the study in PTH (-14.5+/-40% and +2.5+/-46%) (p=0.009) and 25(OH)D (+67+/-77% and +18+/-55%) (p<0.001) circulating levels. PTH changes between baseline and day 90 were significant in the CaD group, but not in the Ca group. The odds ratio for a patient in group Ca to experience an absolute (<12 ng/mL) deficiency in circulating 25(OH)vitamin D levels, compared to a group CaD patient was statistically increased (OR: 3.22, 95% CI: 1.33-7.80). CONCLUSIONS: Our results support the recommendation of supplementing postmenopausal women with low circulating levels of 25(OH)vitamin D with a combination of calcium and vitamin D, rather than with calcium alone.

Evaluation of the simple calculated osteoporosis risk estimation (SCORE) in a sample of white women from Belgium.

Identifying patients at risk of developing an osteoporosis-related fracture will continue to be a challenge. The "gold standard" for osteoporosis diagnosis is bone densitometry. However, economic issues or availability of the technology may prevent its use under a mass screening scenario. A risk assessment instrument, the "simple calculated osteoporosis risk estimation" (SCORE), has been reported to appropriately identify women likely to have low (t score < or = -2 SD) bone mineral density (BMD) and who should be referred for bone densitometry. The aim of our study is to evaluate the discriminatory performance of SCORE in a random sample of postmenopausal white women from Belgium. For this purpose, we gathered medical data on 4035 consecutive patients aged > or = 45 years, either consulting spontaneously or referred for a BMD measurement to an outpatient osteoporosis center located at the University of Liège, Belgium. BMD measurements, using dual-energy X-ray absorptiometry (DXA) technology, were taken at the hip (total and neck) and lumbar spine (L2-4). At the recommended cutoff point of 6, SCORE had a sensitivity of 91.5% to detect low BMD at any of the measured sites, a specificity of 26.5%, a positive predictive value of 52.8%, and a negative predictive value of 77.7%. According to SCORE, 18% of the patients would not be recommended for densitometry. Among these, 10.9% were misclassified as they had osteoporosis (t score < or = -2.5 SD) at one or more of the sites investigated. The negative predictive errors of SCORE, when failing to detect osteoporosis, were only 1% for the total hip, 3.2% for the femoral neck, and 8.8% for the lumbar spine. We conclude that, notwithstanding the high values of sensitivity, SCORE specificity is too low to be useful as a diagnostic tool for screening patients at high risk to later develop osteoporosis. Nevertheless, from a resource allocation perspective, this instrument can be used with relative confidence to exclude patients who do not need a BMD measurement, and would therefore provide an opportunity to realize substantial cost savings in comparison to a mass screening strategy.

Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial.

BACKGROUND: Treatment of osteoarthritis is usually limited to short-term symptom control. We assessed the effects of the specific drug glucosamine sulphate on the long-term progression of osteoarthritis joint structure changes and symptoms. METHODS: We did a randomised, double-blind placebo controlled trial, in which 212 patients with knee osteoarthritis were randomly assigned 1500 mg sulphate oral glucosamine or placebo once daily for 3 years. Weightbearing, anteroposterior radiographs of each knee in full extension were taken at enrolment and after 1 and 3 years. Mean joint-space width of the medial compartment of the tibiofemoral joint was assessed by digital image analysis, whereas minimum joint-space width--ie, at the narrowest point--was measured by visual inspection with a magnifying lens. Symptoms were scored by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index. FINDINGS: The 106 patients on placebo had a progressive joint-space narrowing, with a mean joint-space loss after 3 years of -0.31 mm (95% CI -0.48 to -0.13). There was no significant joint-space loss in the 106 patients on glucosamine sulphate: -0.06 mm (-0.22 to 0.09). Similar results were reported with minimum joint-space narrowing. As assessed by WOMAC scores, symptoms worsened slightly in patients on placebo compared with the improvement observed after treatment with glucosamine sulphate. There were no differences in safety or reasons for early withdrawal between the treatment and placebo groups. INTERPRETATION: The long-term combined structure-modifying and symptom-modifying effects of gluosamine sulphate suggest that it could be a disease modifying agent in osteoarthritis.

Depressive vulnerability is not an independent risk factor for osteoporosis in postmenopausal women.

Major depression has been repeatedly but not consistently reported to be associated with low bone mineral density (BMD) and to an increased risk for fracture in women. We have investigated, in healthy postmenopausal women, whether depressive symptomatology, assessed by the General Health Questionnaire (GHQ), was associated to a significant decrease in BMD, hence supporting the hypothesis of an independent pathogenetic link between the two disorders. We investigated 121 postmenopausal women, aged 48-77 years, spontaneously attending a screening visit for osteoporosis in an outpatient facility. BMD of the spine and the non-dominant hip (total and neck areas) were measured by Dual Energy X-Ray absorptiometry. All subjects completed to the 'General Health Questionnaire' translated and validated in French. No significant correlations were observed between the GHQ score and BMD of the spine (P = 0.54), the total hip area (P = 0.65), or the femoral neck area (P = 0.65). No differences in terms of spinal or femoral BMD were observed between women with GHQ score < 5 or > or = 5. When comparing values of BMD between women within the upper and the lower quartiles for GHQ score, no difference was observed for spine (P = 0.69), total hip (P = 0.80), or femoral neck (P = 0.93). Similarly, GHQ scores were not significantly different when comparing women in the upper and lower quartiles of BMD distribution at the spine or the hip. In conclusion, notwithstanding the clinical pattern of postmenopausal osteoporosis can lead to depression and, on the other hand, hormonal and behavioral disturbances reported in depression might be enhancing factors for accelerated bone loss, our present results do not support the hypothesis that otherwise healthy postmenopausal women with increased depressive complaints are also more prone to exhibit osteoporotic fractures.

High prevalence of low femoral bone mineral density in elderly women living in nursing homes or community-dwelling: a plausible role of increased parathyroid hormone secretion.

The present study was designed to visit elderly women living in nursing homes and to compare their femoral neck bone mineral density (BMD) and circulating levels of parathyroid hormone (PTH) and 25-OH vitamin D (25-OHD) with those of subjects living at home, in the immediate vicinity of the nursing homes. Of 1483 women, aged 70 years and older, who were selected, 993 agreed to participate in this trial. Their femoral neck BMD (n = 993) was measured by dual-energy X-ray absorptiometry, with a specific device installed in a mobile truck. The circulating levels of 25-OHD and PTH were assessed after an overnight fast (n = 748). After stratification for age, there were no significant differences in mean femoral neck BMD values, prevalence of femoral neck osteoporosis, mean serum 25-OHD and prevalence of absolute or relative 25-OHD deficiency between the two groups. Serum levels of PTH were significantly higher in women over 80 years old living in nursing homes, compared with the community-dwelling women. After adjustment for age, a significant relation was found between femoral neck BMD and PTH levels in the whole population (p = 0.004) and in community-dwelling subjects (p = 0.039). When stratifying our population by quartiles of serum PTH values, the odds ratios for femoral neck osteoporosis were significantly increased for the top two quartiles compared with the lowest one both before (p = 0.00146) and after (p = 0.0013) adjustment for age and type of housing. From this study we conclude that femoral osteoporosis is largely underestimated in European women. Living in a nursing home is not, per se, a risk factor for decreased femoral BMD, and circulating PTH levels are a key determinant of low femoral bone density and osteoporosis.

Plasma estradiol concentrations and pharmacokinetics following transdermal application of Menorest 50 or Systen (Evorel) 50.

OBJECTIVES: In order to compare the pharmacokinetics of two transdermal estrogen replacement therapy (ERT) systems designed to release 50 micrograms 17 beta-estradiol/day, two studies were performed in healthy postmenopausal volunteers. METHODS: Both studies had a cross-over design and incorporated a 1-week wash-out period between treatments. In the first study, Menorest 50 and Systen 50 (Evorel 50) were compared over four days of application in 30 women. In the second, 13 women wore each of the two systems for a total of 12 days each (three patches each for 4 days), and comparison was made during the third patch period (steady state, between days 8 and 12). Plasma 17 beta-estradiol levels were assayed using specific direct radioimmunoassays, and pharmacokinetic parameters were calculated by standard methods. All the samples of the first study were re-analysed using a different radioimmunoassay and the results of both assays were compared. RESULTS: In both studies, plasma 17 beta-estradiol levels rose at a comparable rate and reached similar peak levels with each of the two formulations. Levels then remained relatively constant throughout both evaluation periods with Menorest 50, but began to decline after 12 hours in the first study and after 30 h under steady state conditions in the second study with Systen 50. The difference between the two products was statistically significant in both studies. Analysis of pharmacokinetic parameters confirmed the greater bioavailability of Menorest 50. In addition, 17 beta-estradiol levels remained within the suggested therapeutic ranges for relief of acute symptoms and protection against osteoporosis for longer periods of time with Menorest 50 than with Systen 50. CONCLUSION: Since the acute efficacy, long-term protective effects, side effects and risks associated with ERT may depend on critical threshold plasma levels, much attention should be paid to the pharmacokinetic profiles of different formulations. The comparison of these two different radioimmunoassays demonstrates the comparability of their results.

Acute changes in serum calcium and parathyroid hormone circulating levels induced by the oral intake of five currently available calcium salts in healthy male volunteers.

Several calcium supplements are currently available and many of them are marketed without proper comparison of the bioavailability of the actual preparations. The aim of the present trial was to evaluate and compare the acute changes in serum calcium (Ca) and parathyroid hormone (PTH) levels following the oral administration of a vehicle and of five calcium salts currently prescribed in Western Europe. No significant changes in serum Ca or PTH levels were observed after administration of the vehicle. All calcium salts induced significant increases in serum Ca and decreases in serum PTH compared to baseline values. Comparison of the six response curves revealed a significantly greater increase in serum Ca and a greater decrease in serum PTH after each of the calcium salts than observed after the vehicle. However, no statistically significant differences were observed between the different calcium salts for serum Ca increments. The decrease in serum PTH observed after administration of an ossein-hydroxyapatite complex was significantly less important than after the four other calcium salts, even if statistically different than after vehicle. When assessing the area under the curve (AUC) of PTH values, we observed that calcium carbonate and citrate induce a significantly greater decrease in serum PTH than the other calcium salts which are, however, statistically more active than the vehicle. Serum PTH is decreased under the lower limit of the normal range (10 pg/ml), between t60 and t120 for calcium carbonate and citrate and between t60 and t90 for calcium gluconolactate while the mean PTH values remain within the normal range throughout the study with calcium pidolate, the ossein-hydroxyapatite complex and the vehicle. In conclusion, all calcium preparations significantly increase serum calcium and decrease serum parathormone, compared to what is observed after oral intake of a vehicle. However, significant differences in suppression of parathormone are observed between the different calcium preparations and might be of importance for their clinical use.

Prediction of bone loss rate in healthy postmenopausal women.

Prevention of fractures is the only way to drastically reduce osteoporosis-related health expenditures. In order to optimize the cost/benefit ratio of a strategy of prevention, it is essential to identify, as early as possible, women who will develop fractures later in their life. Therefore, and since postmenopausal bone loss is an asymptomatic process, screening procedures should detect, at the time of the menopause, women whose postmenopausal bone loss is higher than the mean, and will, a couple of years later, exhibit a low mineral content and a subsequent high risk for fractures. For 3 years we have followed a cohort of 92 healthy women who had undergone menopause less than 36 months previously. By a multivariate discriminant analysis based on the differences in lumbar bone density, assessed by dual photon absorptiometry, and in a few routine biochemical parameters (serum phosphorus, estrone, androstenedione, and urine calcium) observed during the first 6 months of the study, we have been able to correctly predict the rate of spinal bone loss, observed at the end of the 3 years, in 76% of the subjects. All of the women who presented a bone loss higher than 10% over the 3 years were correctly isolated by our discriminant functions after 6 months of follow-up. We conclude that a measurement of lumbar bone mineral density coupled with a few routine biochemical determinations, repeated twice at a 6-month interval in healthy postmenopausal women, can isolate 100% of postmenopausal "fast bone losers" with an overall specificity of 76%.

Plasma concentration of estradiol following transdermal administration of Systen 50 or Menorest 50.

Circulating levels of 17 beta estradiol (E2) following the administration of fixed doses of E2, show a great variability in kinetics depending upon the product administrated, the routes of administration, and the interindividual variations in absorption and metabolism. This might have important implications both in terms of tolerance and effectiveness. Two new forms of transdermal E2 (SYSTEN Cilag and MENOREST Rhone-Poulenc Rorer) have been recently accepted in Europe for the treatment of climacteric symptoms. The present study was undertaken to compare the pharmacokinetic characteristics of plasma E2 profile under these two drugs. It was carried out in 30 healthy postmenopausal volunteers according to good clinical practice after informed consent, as a single blind, randomised, cross-over study during the classical wearing period of 4 days. Plasma E2 concentration was determined 24 hours before, 1/2 hour before and then 2, 4, 8, 12, 24, 48, 72, 84, 96 hours after the first patch administration. E2 measurement was performed using a specific direct radioimmunoassay developed in the FRH laboratories. The main criteria for this method were an intraassay coefficient of variation (CV) less than 6%, an interassay CV less than 8% in a concentration range of 15-140 pg/ml and a quantitative detection limit (LOQ) of 2.7 pg/ml with a 20% CV. The following kinetic parameters were analysed: C(max), C(mean), C96 and MRT. The bioequivalence was assessed by analysis of variance of C(max), C(mean), C96 and AuC after logarithmic transformation, complemented by Westlake test (95%). Data show that these two products are identical in terms of C(max) but C(mean), C96 and AuC are statistically greater when MENOREST 50(R) is administered; furthermore, E2 levels decrease more rapidly and more deeply with SYSTEN 50 than MENOREST 50. The differences of pharmacokinetic profiles after administration of two different forms of the same dose of 50 micrograms transdermal 17 beta estradiol might have important medical consequences.

Prevention of postmenopausal bone loss by rectal calcitonin.

A group (150) of healthy women, who had been menopausal for less than 5 years and who had never received any form of treatment to prevent bone loss were entered into a randomized, controlled study comprising three arms. They were randomly allocated to the double-blind administration of five suppositories per week containing either 100 IU of salmon calcitonin or a placebo, or to a group receiving a suppository containing 200 IU of salmon calcitonin three times per week. All women received 500 mg/day of calcium supplementation. After 12 months, bone mineral density (BMD) of the spine, measured by dual energy X-ray absorptiometry, decreased significantly (P < 0.01) in the placebo group by 3.1% (SD: 3.6%) but did not change in the two calcitonin groups [+1.3% (3.5%) with 100 IU/day and +2.3% (4.0%) with 200 IU 3/week]. The differences in response between the placebo group and the two calcitonin groups were significant (P < 0.05), but the difference between the two regimens of calcitonin administration was not. No differences appeared among the three groups for the response at the level of the hip. Evolution of biochemical markers reflecting bone turnover did not differ significantly among groups. Nearly 40% of the women withdrew prematurely because of local (rectal or intestinal) intolerance to repetitive suppositories, with a nonsignificantly different frequency in the placebo or calcitonin groups. We conclude that rectal calcitonin might be an interesting preventive approach against trabecular postmenopausal bone loss but that long-term acceptability of suppositories should be evaluated in view of each patient's sensibility or cultural background.

A double-blind, placebo-controlled, dose-finding trial of intermittent nasal salmon calcitonin for prevention of postmenopausal lumbar spine bone loss.

PURPOSE: Nasal administration of salmon calcitonin (SCT) has been suggested for preventing trabecular bone loss during the first years following the menopause, but no conclusive evidence has appeared about the minimal effective dose. Since nasal calcitonin is highly expensive, it makes sense to define this dose. PATIENTS AND METHODS: We performed a double-blind, placebo-controlled, randomized, single-center study with a 3-arm parallel-group design. The subjects were 251 healthy women who had experienced natural menopause within the past 6 to 72 months and were not affected by any diseases or treatments that interfere with calcium metabolism. They were randomly allocated in groups of 6 to receive intranasal SCT 50 IU (n = 84), SCT 200 IU (n = 84), or placebo (n = 83). All treatments were given on 5 consecutive days per week. Statistical analysis was based on two populations: intention-to-treat (IT) and valid completers (VC). The main assessments performed were bone mineral density of the lumbar spine (LSBMD) and biochemical parameters reflecting bone turnover (serum alkaline phosphatase, urinary calcium/creatinine, and hydroxyproline/creatinine ratios). RESULTS: Changes over the treatment period were comparable in the IT and VC populations. In the group receiving the placebo, LSBMD decreased from baseline to end point by a mean of 6.28% (95% confidence interval [CI] -7.69 to -4.89) in the IT population and 6.98% (95% CI -8.86 to -5.11) in the VC population (P = 0.0001, end LSBMD versus baseline LSBMD). LSBMD increased slightly with the 50-IU/d dose of SCT, by 0.82% (95% CI -0.26 to 1.89) in the IT population, and 0.51% (95% CI -0.69 to 1.72) in the VC (P = NS, versus baseline). Subjects who received SCT 200 IU/d experienced significant increases of 2.03% (95% CI 0.92 to 3.15) in the IT population and 2.26% (95% CI 1.01 to 3.51) in the VC (both P = 0.001). The difference between the evolution of the combined groups receiving nasal SCT and the group treated with the placebo was highly significant (P = 0.0001). No significant changes were recorded in biochemical parameters reflecting bone turnover. CONCLUSIONS: SCT 50 IU/d administered nasally and intermittently appears to prevent lumbar bone loss in nonobese early postmenopausal women.

Long-term performance in vitro and in vivo of dual-energy X-ray absorptiometry.

Dual-energy X-ray absorptiometry (DXA) is actually considered as one of the most appropriate techniques for measuring bone mineral content (BMC) and bone mineral density (BMD). An anthropomorphic phantom and a 25-year-old girl were repeatedly measured, 160 times and 50 times respectively, over an 18-month period to investigate performance in vitro and in vivo of a commercial DXA equipment (HOLOGIC QDR 1000). DXA is a highly accurate technique, the BMC and BMD determinations only overestimated the exact value of the phantom by 0.20% and 0.51% respectively. In vivo long-term (18 months) reproducibility of BMD of the spine is characterized by an interassay coefficient of variation (CVt) of 0.8% while, for the different regions of interest of the hip, BMD CVt varies from 1.1% (total zone) to 5.3% (Ward's triangle). In the subject tested, BMD sensitivity for changes of 2.2% at the lumbar spine and 3% at the hip were recorded.

Bone mineral density of the spine and the hip measured with dual energy X-ray absorptiometry: normal range and fracture threshold for western European (Belgian) postmenopausal females.

Bone mineral density (BMD) of the spine and the different regions of interest (ROI) of the hip were measured by dual energy X-ray absorptiometry in 278 healthy Belgian postmenopausal women and 93 postmenopausal type I osteoporotic females in order to: a) determine the normal range for lumbar and hip BMD values; b) define an "hypothetical" fracture threshold in this population; c) determine the preferential region to be considered for clinical use in type I osteoporosis. In the normal subjects, there is a negative relationship (< 0.001) between age or time elapsed since menopause (Tm) and BMD measured at the level of the spine or at the ROI of the hip. For the spine, evidence of a curvilinear relationship was assessed. Regressions of BMD at the hip as a function of age or time elapsed since menopause, were best fitted by a linear relationship. In the population of postmenopausal women who have experienced a vertebral crush fracture, no relationships were observed between spine BMD and age or Tm but the osteoporotic women had a spine BMD significantly lower compared to age-matched normal controls: Z-score = -1.2 +/- 0.6 (mean +/- SD) (p < 0.0001). Fracture threshold calculated as the 90th percentile of spine BMD measured in osteoporotic patients was 0.840 g/cm2, corresponding to the mean value -1 SD for a population of women aged 51 years.