Equivalence of a single dose (1200 mg) compared to a three-time a day dose (400 mg) of chondroitin 4&6 sulfate in patients with knee osteoarthritis. Results of a randomized double blind placebo controlled study.

OBJECTIVE: Evaluation of the efficacy and safety of a single oral dose of a 1200 mg sachet of chondroitin 4&6 sulfate (CS 1200) vs three daily capsules of chondroitin 4&6 sulfate 400 mg (CS 3*400) (equivalence study) and vs placebo (superiority study) during 3 months, in patients with knee osteoarthritis (OA). DESIGN: Comparative, double-blind, randomized, multicenter study, including 353 patients of both genders over 45 years with knee OA. Minimum inclusion criteria were a Lequesne index (LI) ≥ 7 and pain ≥ 40 mm on a visual analogue scale (VAS). LI and VAS were assessed at baseline and after 1-3 months. Equivalence between CS was tested using the per-protocol procedure and superiority of CS vs placebo was tested using an intent-to-treat procedure. RESULTS: After 3 months of follow-up, no significant difference was demonstrated between the oral daily single dose of CS 1200 formulation and the three daily capsules of CS 400. Patients treated with CS 1200 or CS 3*400 were significantly improved compared to placebo after 3 months of follow-up in terms of LI (<0.001) and VAS (P < 0.01). No significant difference in terms of security and tolerability was observed between the three groups. CONCLUSION: This study suggests that a daily administration of an oral sachet of 1200 mg of chondroitin 4&6 sulfate allows a significant clinical improvement compared to a placebo, and a similar improvement when compared to a regimen of three daily capsules of 400 mg of the same active ingredient.

Comparison of the proportion of patients potentially treated with an anti-osteoporotic drug using the current criteria of the Belgian national social security and the new suggested FRAX criteria.

To assess the number of anti-osteoporosis treatments that would be reimbursed by the Belgian social security if either FRAX or the current criteria were used to determine access to reimbursement. This is a retrospective study based on data from 1,000 women randomly selected from an outpatient hospital specialized in bone metabolism in Belgium. Proportions of potentially refunded treatments between FRAX and current criteria were compared. Out of the 1,000 women files, 890 have sufficient information to assess FRAX. In Belgium, current criteria include a bone mineral density (BMD) T score below -2.5 at the lumbar spine, the femoral neck or the total hip and/or at least a prevalent vertebral fracture. Using these criteria, 167 women (18.8 %) would have access to reimbursement. Using the criteria based on the validated Belgian FRAX tool, only 116 women (13.0 %) would have access to reimbursement, meaning that access to reimbursement based on FRAX criteria would reduce by 30 % the anti-osteoporosis drug expenses covered by the national social security. Interestingly, only 65 women out of the 116 (56.0 %) selected with the FRAX criteria were also selected with the current criteria of the national social security. A substantial proportion of individuals that would potentially receive a reimbursement for their treatment using the FRAX criteria do not have access to any refund for their treatment with the current criteria. Since patients identified with the FRAX tool are those with the highest risk profile for future fractures, reappraisals of treatment reimbursement guidelines are expected in Belgium.

Perception, knowledge, and use by general practitioners of Belgium of a new WHO tool (FRAX) to assess the 10-year probability of fracture.

The FRAX tool that calculates the 10-year probability of having a fracture has recently been validated for Belgium. Little is known about the perception and knowledge that GPs have about this tool in their daily practice. A survey has been conducted as part of a screening campaign for various diseases. The primary objective of the present study was to assess the perception and the knowledge of the FRAX tool by GPs. The secondary objective was to assess the impact of an information brochure about the FRAX tool on these outcomes. The survey was sent to a sample of 700 GPs after only half of them had received the information brochure. The survey results show that, out of the 193 doctors who responded to the survey, one-third know the FRAX tool but less than 20 % use it in their daily clinical practice. Among those who use it, the FRAX tool is largely seen as a complementary but not as an essential tool in the diagnosis or in the management of osteoporosis. It appears that the brochure could improve the knowledge of the FRAX tool but it would not be more efficient on its use in daily practice than the other sources of information. At present, the use of the FRAX tool in Belgium is limited but an information brochure could have a positive impact on the knowledge of the FRAX tool.

Health-related quality of life after total knee or hip replacement for osteoarthritis: a 7-year prospective study.

OBJECTIVE: To assess health-related quality of life (HRQOL) in a prospective study with 7 years of follow-up in 49 consecutive patients who underwent a total joint replacement because of osteoarthritis. METHODS: Generic HRQOL was assessed with the short-form 36 (SF-36) and specific HRQOL with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: Out of the 39 subjects who have completed the 7 years of follow-up of this study, 22 (56.4 %) underwent a hip replacement surgery and the other 17 (43.6 %) a knee replacement. Six months after surgery, a significant improvement, compared to preoperative scores, was observed in two of the eight dimensions of the SF-36 (i.e. physical function and pain). The same dimensions, pain and physical function, at the same time, 6 months after surgery, measured by the WOMAC, showed a significant improvement as well, but there was no significant change in the stiffness score. From 6 months to the end of follow-up, changes in SF-36 scores showed a significant improvement in physical function (p = 0.008), role-physical (p = 0.004) and role-emotional (p = 0.01) while all scores of the WOMAC improved (p < 0.001 for pain, p < 0.001 for stiffness and p < 0.01 for physical function). CONCLUSION: The improvements observed in HRQOL at short term after surgery, are at least maintained over a 7-year follow-up period.

Comprehensive therapy in osteoporosis using a single drug: from ADFR to strontium ranelate.

In vitro, strontium ranelate increases collagen and non-collagenic proteins synthesis by mature osteoblast enriched cells. The effects of strontium ranelate on bone formation were confirmed as the drug enhanced preosteoblastic cell replication. In the isolated rat osteoclast, a preincubation of bone slices with strontium ranelate induced a dose-dependent inhibition of the bone resorbing activity of treated rat osteoclast. Strontium ranelate dose-dependently inhibited preosteoclast differentiation. In a phase II dose ranging trial Strontium ranelate (500 mg, 1000 mg, 2000 mg/day) or placebo were given to 353 postmenopausal women with prevalent vertebral osteoporosis. At the conclusion of this 2-year study, the annual increase in lumbar BMD of the group receiving 2000 mg of strontium ranelate was + 7.3%, a significant increase in bone alkaline phosphatase, over a 6-month period and a significant decrease in N-telopeptide crosslinks throughout the 2-year period were seen. During the second year of treatment, the dose of 2000 mg was associated with a 44% reduction in the number of patients experiencing a new vertebral deformity. The primary analysis of the SOTI study, evaluating the effect of strontium ranelate 2000 mg on vertebral fracture rates, revealed a 41% reduction in the relative risk of patient experiencing a first new vertebral fracture with strontium ranelate throughout the 3-year study. The TROPOS study showed a significant reduction in the risk of experiencing a first non-vertebral fracture by 16% in the group treated with strontium ranelate throughout the 3-year study. A reduction in the risk of experiencing a hip fracture by 36% was also demonstrated in the patients at high risk of hip fracture (age > or =74 years and Femoral Neck T score < or = -2.4 according to NHANES normative value). All these results suggest that strontium ranelate is a new, effective and safe treatment of vertebral and non-vertebral osteoporosis, with a unique mode of action.

Long-term (3 years) prevention of trabecular postmenopausal bone loss with low-dose intermittent nasal salmon calcitonin.

The long-term effect of intermittent low-dose nasal salmon calcitonin on trabecular early postmenopausal bone loss was assessed as follow-up to a previously published study. Randomized controlled group comparison was made of 287 healthy women with 6-36 months of natural menopause and no treatment interfering with calcium metabolism at an outpatient clinic for research in bone and cartilage metabolism. The 287 women were randomly allocated to 3 years of treatment with either 500 mg/day, 5 days/week of calcium or the same amount of calcium plus 50 IU/day, 5 days per week of nasal salmon calcitonin. A total of 186 women complied with the study protocol throughout. The main outcome measures were bone mineral density of the lumbar spine (DPA) and biochemical parameters reflecting bone turnover (serum alkaline phosphatases, urinary calcium/creatinine, and hydroxyproline/creatinine ratio). The average changes in bone mineral density after 36 months showed a positive (p < 0.05) outcome (1.8 +/- 5.7%; mean +/- SD) in the group treated with salmon calcitonin and calcium and a significant (p < 0.01) loss (-5.8 +/- 4.8%) in patients receiving calcium alone. The difference between the evolution of the two groups was significantly (p < 0.01) different after 6 months of treatment and remained so until the end of the study. No significant changes were recorded in biochemical parameters reflecting bone turnover. As previously shown during a 1 year follow-up, nasal salmon calcitonin given at low dose and intermittently, in association with calcium, can counteract trabecular postmenopausal bone loss.

Reduction in PINP, a marker of bone metabolism, with raloxifene treatment and its relationship with vertebral fracture risk.

In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis, defined by low bone mineral density and/or prevalent vertebral fractures (VF), were randomized to placebo or raloxifene (60 or 120 mg/day). All women received daily calcium (500 mg) and vitamin D (400-600 IU) supplements. Our previous analyses found that changes in BMD and biochemical markers of bone turnover are poorly predictive of the reduction in VF risk observed with raloxifene. This present study evaluated the effects of raloxifene on type I procollagen N-terminal propeptide (PINP), a new marker of bone turnover. Logistic regression analysis models evaluated the relationships between the changes at 1 year in PINP, serum osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), and urinary excretion of type I collagen C-telopeptide fragments normalized to creatinine (CTx/Cr), and the risk of new VF at 3 years for placebo and pooled raloxifene. A subset of 967 women (mean age = 68 years) from the MORE cohort had PINP, OC, BSAP, and CTx evaluated at baseline. Both doses of raloxifene significantly decreased (P < 0.001) all biochemical markers of bone turnover from baseline. Compared to baseline, PINP levels were decreased by medians of 11.0% and 40.8% in the placebo and pooled raloxifene groups, respectively. In addition, the placebo and pooled raloxifene groups decreased serum OC by 8.5% and 31.8%, BSAP by 15.8% and 34.6%, and urinary CTx/Cr excretion by 5.6% and 46.5%, respectively, from baseline. In the pooled raloxifene group, the logistic regression relationship between 3-year VF risk and 1-year percentage change for each biochemical marker was statistically significant with PINP (slope estimate = 0.0085, P = 0.009), OC (slope estimate = 0.0068, P = 0.035), and BSAP (slope estimate = 0.0056, P = 0.039), but not with CTx/Cr (slope estimate = 0.0027, P = 0.192). Furthermore, the percent decrease in PINP at 1 year could account for 28% of the total reduction in vertebral fracture risk. In conclusion, a 1-year decrease in PINP, BSAP, or OC, but not CTx/Cr, may be predictive of the 3-year VF risk reduction with raloxifene therapy in this subset of postmenopausal women with osteoporosis.

Effect of high doses of oral risedronate (20 mg/day) on serum parathyroid hormone levels and urinary collagen cross-link excretion in postmenopausal women with spinal osteoporosis.

The present study describes the biological effects of risedronate, a pyridinyl bisphosphonate, on bone and assesses the safety and tolerability of risedronate when given at high doses, with or without calcium, to postmenopausal women with spinal osteoporosis. This single-center descriptive, double-blind, placebo-controlled, randomized, parallel group study included 32 postmenopausal white women with at least one radiographically confirmed vertebral compression fracture. Patients were randomized to one of four different dose regimen groups: (i) R-P, risedronate 20 mg/day for 14 days, followed by placebo for 42 days; (ii) R-CP-P, risedronate 20 mg/day for 14 days, followed by elemental calcium 1000 mg/day and placebo for 14 days, then by placebo for 28 days; (iii) R-CP-R-CP, risedronate 20 mg/day for 7 days, followed by elemental calcium 1000 mg/day and placebo for 21 days, then risedronate 20 mg/day for 7 days, and finally elemental calcium 1000 mg/day and placebo for 21 days; and (iv) P, placebo for 56 days. The biological response was investigated by measuring serum calcium, parathyroid hormone (PTH), and 2 h urinary pyridinoline/creatinine (Pyr/Cr) and deoxypyridinoline/creatinine (DPyr/Cr) ratios at baseline and at days 3, 7, 14, 21, 28, 35, 42, 49, 56, and 84. Overall, there were no consistent trends observed between the active group and placebo for serum calcium. In groups R-P, R-CP-P, and R-CP-R-CP, mean serum PTH levels were elevated above baseline values for the entire 56 day treatment period and remained elevated, although to a lesser extent, at the day 84 follow-up visit. The effect of calcium supplementation on PTH was variable. Urinary Pyr/Cr and DPyr/Cr ratios were decreased from baseline over the entire study period in all groups receiving risedronate. The maximum observed percent decreases from baseline for Pyr/Cr and DPyr/Cr were -46.9% and -58.8%, respectively, at day 49 in the R-CP-R-CP group. In conclusion, risedronate given orally at a dose of 20 mg/day, continuously for 7 or 14 days, resulted in the expected biological response in osteoporotic women. The time course of changes in PTH levels following cessation of dosing was unaffected by calcium supplementation. There was no evidence of a PTH-mediated rebound in bone resorption following cessation of therapy. Furthermore, based on collagen cross-link data, patients did not show an excessive reduction in bone turnover.

Subchondral tibial bone mineral density predicts future joint space narrowing at the medial femoro-tibial compartment in patients with knee osteoarthritis.

Preliminary studies have shown that dual-energy X-ray absorptiometry (DXA) produces images of sufficient quality for a precise and accurate measurement at density of the subchondral bone. The objective of this study was to investigate the relationship between baseline subchondral tibial bone mineral density (BMD) and joint space narrowing observed after 1 year at the medial femoro-tibial compartment of the knee joint. Fifty-six consecutive patients, from both genders, with knee osteoarthritis diagnosed according to the American College of Rheumatology criteria, were included in the study. Radiographic posteroanterior views were taken, at baseline and after 1 year of follow-up. Minimum joint space width (JSW) measurement, at the medial femoro-tibial joint, was performed with a 0.1-mm graduated magnifying lens. Baseline BMD of the subchondral tibial bone was assessed by DXA. The mean +/- SD age of the patients was 65.3 +/- 8.7 years, with a body mass index of 28.0 +/- 4.9 kg/m(2). The minimum JSW was 3.5 +/- 1.5 mm and the mean BMD of the subchondral bone was 0.848 +/- 0.173 g/cm(2). There was a significant negative correlation between subchondral BMD and 1-year changes in minimum JSW (r = -0.43, p = 0.02). When performing a multiple regression analysis with age, sex, body mass index, and minimum JSW at baseline as concomitant variables, BMD of the subchondral bone as well as JSW at baseline were independent predictors of 1-year changes in JSW (p = 0.02 and p = 0.005, respectively). Patients in the lowest quartile of baseline BMD (<0.73 g/cm(2)) experienced less joint space narrowing than those in the highest BMD quartile (>0.96 g/cm(2)) (+0.61 +/- 0.69 mm versus -0.13 +/- 0.27 mm; p = 0.03). Assessment of BMD of the subchondral tibial bone is significantly correlated with future joint space narrowing and could be used as a predictor of knee osteoarthritis progression.

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.

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.

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.

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.

Effect of collagen hydrolysate in articular pain: a 6-month randomized, double-blind, placebo controlled study.

OBJECTIVE: Evaluation of the efficacy and safety of a food supplement made of collagen hydrolysate 1200 mg/day versus placebo during 6 months, in subjects with joint pain at the lower or upper limbs or at the lumbar spine. DESIGN: Comparative double-blind randomized multicenter study in parallel groups. SETTING: 200 patients of both genders of at least 50 years old with joint pain assessed as ≥30 mm on a visual analogical scale (VAS). INTERVENTION: Collagen hydrolysate 1200 mg/day or placebo during 6 months. MAIN OUTCOME MEASURE: Comparison of the percentage of clinical responder between the active collagen hydrolysate group and the placebo group after 6 months of study. A responder subject was defined as a subject experiencing a clinically significant improvement (i.e. by 20% or more) in the most painful joint using the VAS score. All analyses were performed using an intent-to-treat procedure. RESULTS: At 6 months, the proportion of clinical responders to the treatment, according to VAS scores, was significantly higher in the collagen hydrolysate (CH) group 51.6%, compared to the placebo group 36.5% (p<0.05). However, there was no significant difference between groups at 3 months (44.1% vs. 39.6%, p=0.53). No significant difference in terms of security and tolerability was observed between the two groups. CONCLUSIONS: This study suggests that collagen hydrolysate 1200 mg/day could increase the number of clinical responders (i.e. improvement of at least 20% on the VAS) compared to placebo. More studies are needed to confirm the clinical interest of this food supplement.

Prevention of osteoporosis with nasal salmon calcitonin: effect of anti-salmon calcitonin antibody formation.

The amino acid sequence of salmon calcitonin (SCT) differs considerably from that of the human hormone and specific antibodies (Ab) develop in a significant proportion of patients after parenteral or nasal administration of SCT. Controversy remains regarding the functional importance of these Ab. We report on the development of specific anti-SCT Ab in a population of postmenopausal women receiving nasal SCT for prevention of postmenopausal bone loss, and compare the effects of nasal SCT in women with or without Ab. Thirty-nine per cent of women developed Ab after 6 months of treatment with SCT, 52% after 12 months, and 61% after 18 and 24 months. After 24 months the AB titre was 3.47-17.7 x 10(-9) M/l (mean +/- SD: 13.3 +/- 3.1 x 10(-9) M/l). No significant differences appeared between the changes in lumbar bone mineral density (BMD) measured in the whole population (n = 44) (mean +/- SD: +1.06 +/- 3.9%), the patients without Ab (n = 17) (+0.05 +/- 3.7%) or in those with Ab (n = 27) (+1.7 +/- 4.6%). During the same period, a control population randomly assigned to a 500 mg/day calcium intake showed a significant loss of lumbar BMD (-4.57 +/- 4.9%) (p < 0.01). In conclusion, in healthy postmenopausal women nasal SCT seems to maintain the same preventive effect against bone loss whether or not Ab are present.

Acute biochemical variations induced by four different calcium salts in healthy male volunteers.

Calcium (Ca) supplements have positive effects in growing children, reduce bone loss in late-postmenopausal women with a low calcium diet and, in association with vitamin D3 supplements, may reduce non-vertebral fracture rates in elderly women. However, for many formulated pharmaceutical products their relative beneficial effects have not been conclusively established. We have compared the acute (6 h) metabolic responses following oral administration of two preparations of calcium gluconolactate and carbonate (CG and CG'), tricalcium phosphate (TCP) and calcium citrate (CC), given on separate occasions in each of 10 healthy young male volunteers. The subjects fasted overnight for 12 h and continued to fast during the experimental procedure. A 1000 mg dose of each Ca salt was ingested at weekly intervals. Blood was drawn after 30, 60, 90, 120, 180, 240, 300 and 360 min for measurement of serum Ca, phosphorus (P), parathyroid hormone (PTH) and whole plasma calcitonin (iCT). All Ca supplements induced significant (+6.4% to +8.1%; p < 0.01) increases in Ca and significant suppression of PTH (-37.4% to -57.4%; p < 0.01). Comparison of response curves revealed significantly (p < 0.01) more marked Ca increase and PTH suppression with CC than with the other three Ca salts. CG' and CC induced marginal decreases in serum P and the overall curve of P variations was different for TCP compared with CG, CG' and CC. No significant variation of iCT was recorded during the test.(ABSTRACT TRUNCATED AT 250 WORDS)

Paget's disease of bone treated with a five day course of oral tiludronate.

Chloro-4-phenyl thiomethylene bisphosphonate (tiludronate) is a new drug which can be used as an inhibitor of bone resorption. As it remains in bone for a long time, and as mineralisation defects have only been seen at doses much higher than those required to decrease osteoclastic activity, it could be given at high doses over a short period of time. Eighteen patients with Paget's disease of bone were randomly allocated to three therapeutic groups receiving respectively 600, 800, and 1200 mg/day tiludronate for five days. Serum alkaline phosphatase activity and the urinary hydroxyproline/creatinine ratio were quickly and drastically reduced in all three groups. A significant reduction of serum alkaline phosphatases and the hydroxyproline/creatinine ratio was still present six months after the five day therapeutic course, reflecting a sustained activity of tiludronate even after stopping treatment. Dose dependent short and long term reductions of bone turnover rate were observed. Biochemical assessment of haematological, renal, or hepatic tolerance did not show any toxicity of tiludronate. Fifty per cent of patients treated by a dose of 1200 mg/day reported gastrointestinal disturbances, however, making this dosage unsuitable for clinical practice.

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%.

A 2-year phase II study with 1-year of follow-up of risedronate (NE-58095) in postmenopausal osteoporosis.

This paper presents the results of a two-center, double-masked, placebo-controlled, randomized, oral-dose study of risedronate treatment in postmenopausal osteoporosis. Patients had at least one, but no more than four prevalent vertebral fractures at baseline. They received either 2.5 mg continuous risedronate, 2.5 mg cyclic risedronate, or placebo for 2 years. Both risedronate and placebo were formulated as hard gelatin capsules. All women furthermore received a daily calcium supplement of 1 g which was taken separately from the study drug. During the 1-year of follow-up, all women received only a daily calcium supplement of 1 g. A total of 132 patients were enrolled (44 in each treatment group), of which 73% completed the 2-year treatment period and 70% all 3 years. Generally the outcome of the study was negative. Lumbar spine bone mineral density (BMD) increased 1.2% (NS) and 0.8% (NS) and after 2 and 3 years in the group treated with continuous risedronate, 1.7% (NS) and 2.3% (p < 0.05) in the group treated with cyclic risedronate, and 0.6% (NS) and 1.7% (NS) in the placebo group. BMD in the femoral neck increased 2.9% (p < 0.05) and 0.9% (NS) after 2 and 3 years in the group treated with continuous risedronate, 1.3% (NS) and 2.4% (p < 0.01) in the group treated with cyclic risedronate, and 1.3% (NS) and 2.6% (p < 0.01) in the placebo group. The differences between all three groups in spinal and femoral BMD after 2 years were not statistically significant, but reached statistical significance after 3 years (p < 0.01) in the femoral neck. Only minor changes were observed in the measured markers of bone turnover. Both the incidence and rate of new vertebral fractures showed no overall differences between the groups. The distribution of adverse events was similar across treatment groups. None of the serious adverse events were considered causally related to risedronate. The lack of effect shown in the present study may be explained by insufficient dose regimen and/or impaired absorption from the intestinal tract. Further investigations (ongoing phase III trials) are needed to define future dose regimens in order to validate the effect on bone mass, fracture rate and biochemical markers. In these studies another formulation of the drug and other dosing instructions are used.