Brigitte Zegels

Development and assessment of the Osteoporosis Index of Risk (OSIRIS) to facilitate selection of women for bone densitometry.

A simple questionnaire would be useful to identify individuals most in need of bone mineral density (BMD) testing. We designed a new predictive model and risk assessment instrument based on an extensive review of the literature evaluating risk factors for osteoporosis, and tested its performance in a large cohort of postmenopausal women in whom BMD was measured by dual x-ray absorptiometry. In total, 1303 postmenopausal women from an outpatient osteoporosis clinic participated in this study. The Osteoporosis Index of Risk (OSIRIS) is based on four variables: age, body weight, current hormone replacement therapy use and history of previous low impact fracture. The sensitivity and specificity for an OSIRIS value of +1 were respectively 78.5% and 51.4%. The AUC under the ROC curve of OSIRIS was 0.71. Three categories were arbitrarily created using OSIRIS, with cutoff of +1 and -3. The low risk category (OSIRIS > +1) represented 41% of all women; only 7% of the women in this category had osteoporosis. The prevalence of osteoporosis was very high (66%) among the group at high risk (OSIRIS < -3 representing 15% of all women). The prevalence of osteoporosis was 39% in the intermediate risk group (-3 < OSIRIS < +1, 44% of all women). In conclusion, OSIRIS is a simple index based on four easy-to-collect variables from postmenopausal women, it shows a high degree of accuracy, and performed well for classifying the degree of risk of osteoporosis in western European women of Caucasian lineage. Based on this instrument it is possible to propose a strategy that would initiate treatment in women with very high risk, postpone BMD measurement in women with low risk and limit BMD measurement to women with intermediate risk of osteoporosis, this would spare more than 55% of the densitometry bill compared with a mass screening scenario.

The Effect of Sodium Monofluorophosphate Plus Calcium on Vertebral Fracture Rate in Postmenopausal Women with Moderate Osteoporosis. A Randomized, Controlled Trial

During the past 30 years, fluoride salts have been studied as agents for the treatment of osteoporosis in postmenopausal women with the expectation that stimulation of osteoblastic proliferation and activity and the subsequent increase in bone formation would be followed by a significant decrease in fracture rates [1-3]. It is widely accepted that fluoride is effective in increasing trabecular bone mass in the spine [4]. However, discrepant results have been obtained from studies evaluating the effects of fluoride salts on cortical bone mass and, more important, on the quality of the newly synthesized bone and on vertebral and nonvertebral fracture rates [5-9]. These differences are probably related to differences in fluoride dose, formulation, and regimen; duration of therapy; and treated populations. Because bone-forming agents such as fluoride are expected to work mainly by increasing bone mineral content without restoring disrupted bone tissue integrity, they may be particularly useful in patients with mild to moderate osteoporosis in whom the microarchitecture of the skeleton is not excessively damaged. To test this hypothesis, we studied the effect of low-dose fluoride (sodium monofluorophosphate [MFP]) plus calcium in a 4-year, randomized, double-blind, controlled clinical trial in postmenopausal women with moderately low bone mineral density (BMD) of the spine. Methods Patients Our study included white postmenopausal women with lumbar (L2 to L4) BMD of the spine below the 90th percentile of the distribution of BMD of the spine seen in Belgian women with osteoporosis [10, 11]. This degree of bone loss corresponded to a T-score of 2.5,in accordance with the operational definition of osteoporosis recently proposed by a World Health Organization study group [12]. Patients were included in the study regardless of whether they had previously had vertebral or nonvertebral fractures; most of the patients were thought to be free of vertebral fractures at enrollment. Previous hip fracture was an exclusion criterion. All patients were free of other causes of osteoporosis, such as diseases or medications known to interfere with bone metabolism; none had been treated with any drug for postmenopausal osteoporosis; and no such treatment was allowed during the study. Hormone replacement therapy was continued, for ethical reasons, in women for whom it had been prescribed before enrollment for purposes other than bone therapy. Randomization was not stratified with respect to hormone replacement therapy. Patients with bone diseases other than osteoporosis, renal insufficiency, hypochlorhydria, or severe chronic disorders that could have interfered with the study were excluded. Study Design Patients were randomly assigned in a blinded manner to one of two therapeutic groups. Every day for 4 years, they received either two chewable tablets that each contained 76 mg of MFP (10 mg of equivalent fluoride [fluoride ion]) and 1250 mg of calcium carbonate (500 mg of equivalent calcium) or two chewable tablets that each contained 1250 mg of calcium carbonate alone and were similar in appearance to the MFP-plus-calcium tablets. Total daily dosages, therefore, were 20 mg of equivalent fluoride plus 1000 mg of calcium in the MFP-plus-calcium group and 1000 mg of calcium in the calcium-only group. The two tablets were taken at different meals. We determined compliance at each study visit by asking each patient for the number of days on which she had not taken the tablets and by counting the unused tablets. Compliance was expressed as the percentage of tablets taken (100% if the patient had taken all of the tablets). Patients received randomization numbers sequentially. Randomization was computer generated in blocks of four according to a strict standard operating procedure by persons who had no contact with the persons in the center who assigned patients to study groups. The randomization code was kept at the study sponsors facility under secure conditions that were detailed in writing. The clinical research center was given opaque, sealed envelopes, each of which contained the code for one patient. Treatment assignment and other relevant information were thus concealed and were to be revealed only in the case of a medical emergency. Blinding was achieved by using the following procedures. First, the persons who did the visual readings of the spine radiographs saw the codes only after the results were analyzed. Second, the data were analyzed under blinded conditions: that is, a first analysis was done with groups A and B; the analysts did not know which group had received which treatment. Efficacy Evaluation Criteria The primary end point was the number of patients with new vertebral fractures during the 4-year treatment period, in accordance with recently published guidelines for the evaluation of drugs to be registered in Europe for the prevention or treatment of osteoporosis [13]. Standardized lateral radiographs of the thoracic and lumbar spine were obtained at enrollment and at each year of follow-up, for up to 4 years, in a single radiology center. The radiographs were sent to an independent assessor. Films were digitized, and the anterior, middle, and posterior heights of each vertebral body from the fourth thoracic (T4) to the fifth lumbar (L5) were determined (accuracy of the digitizer, 0.025 mm) by a computer program. This was done by persons with no knowledge of treatment assignment or film sequence. A new vertebral fracture (incident fracture) was defined as a reduction of at least 20% and an absolute decrease of at least 4 mm in any height of at least one vertebral body between enrollment and the latest follow-up film. All fractures, including borderline cases, were confirmed by visual reading. This definition was applied to vertebrae that were not fractured at enrollment, whereas fractures present at enrollment were determined on the digitized enrollment radiographs by using the Melton-Riggs 25% unadjusted algorithm [14]. The possible progression of such baseline lesions was assessed with the Vertebral Deformity Index obtained for each vertebra (T5 through L5); these were then summed to obtain the Spine Deformity Index, a continuous measure of vertebral deformities [15]. The Spine Deformity Index was also used as a secondary variable in patients with incident or progressing vertebral deformities, in whom it was expressed as the mean change between the last observed value and baseline. Bone mineral density was measured by using dual-energy x-ray absorptiometry on the same densitometer (Hologic QDR 1000, Waltham, Massachusetts) at 6-month intervals at the lumbar spine (L2 to L4) and the nondominant hip (total hip) after previously described and validated procedures were performed [11, 16]. In our hands, the long-term coefficients of variation of dual-energy x-ray absorptiometry are 0.8% for BMD of the spine and 1.1% for BMD of the total hip [17]. Biochemical determinations of bone remodeling were made at 6-month intervals. Bone formation was assessed by radioimmunoassay of serum bone-specific alkaline phosphatase (Ostase, Hybritech, San Diego, California). For bone resorption, we measured the ratio of urinary hydroxyproline to creatinine on the second fasting urine spot (2-hour morning urine) (Hypronostikon kit, Organon Technika, Oss Boxtel, the Netherlands). All peripheral (nonvertebral) fractures that occurred during the study were recorded independently of the nature and severity of the trauma that may have determined them. Statistical Analysis All analyses were done according to the intention-to-treat approach: that is, all patients who had at least one valid measurement after randomization were considered in the analysis, whether they were still taking the study drug or not. In the case of drop-out and, thus, discontinuation of therapy with the study medication, the patient was invited to return to the clinic at annual intervals (for 4 years, if possible) so that the radiography necessary to record outcome could be done. An exact-significance chi-square test was done to compare the number of patients with new vertebral fractures in the two groups. We calculated 95% CIs for vertebral fracture rates in each study group and for the difference in rates between the two groups, along with the point estimates of these rates. These rates were also expressed in terms of the number needed to treat for 4 years to prevent one fracture, including values for the lower and upper bounds of the 95% CIs. Changes in the Spine Deformity Index in patients with incident or progressing vertebral deformities were compared by analysis of variance. Analysis of variance for repeated measurements was used to compare the absolute values for BMD of the spine over the course of the study in the two groups. Analysis of variance for repeated measurements was also done to compare BMD of the total hip and percentage changes in biochemical markers of bone remodeling throughout the study. All P values are two-tailed. All statistical analyses were done with the SPS/WIN 6.2 statistical package (SPS, Inc., Chicago, Illinois). Role of Study Sponsor The trial was approved by the Ethical Committee of Liege University (registration no. 90/43-1262 of 14 May 1990), and all patients gave full informed consent before inclusion. The Rotta Research Group, which markets MFP and calcium combinations in Germany, Italy, and other countries, provided the drugs and funding for the study. Scientists from the Rotta Research Group were directly involved in the design, monitoring, and data management of the study and agreed to be listed as authors. However, the Rotta Research Group as a corporate entity had no control over the decision to approve or submit the manuscript for publication. Results Two hundred patients were enrolled in the study. The characteristics of the entire patient sample (100 patients were assigned to each group) at enrollment are shown in Table 1. The

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.

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.

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

Abstract: 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, bur 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.

Role of biochemical markers of bone turnover as prognostic indicator of successful osteoporosis therapy

Most of the currently available anti-osteoporosis medications promptly and significantly influence the rate of bone turnover. Biochemical markers of bone turnover now provide a high sensitivity to change, allowing the detection of these bone turnover changes within a couple of weeks. Since the anti-fracture efficacy of inhibitors of bone resorption or stimulators of bone formation appears to be largely independent of baseline bone turnover, biochemical markers do not appear to play a significant role in the selection of one particular drug, for an individual patient. However, there are consistent data showing that short-term changes in biochemical markers of bone turnover may be significant predictors of future changes in bone mineral density or fracture reduction, hence suggesting that bone turnover markers play a significant role in the monitoring of anti-osteoporosis therapy.

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 3.47−17.7×10−9 M/l (mean ±SD: 13.3±3.1×10−9 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.

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

SummaryBone 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 spin 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.

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.

Influence of daily calcium and vitamin D supplementation on parathyroid hormone secretion

Calcium and vitamin D supplementation has been shown to reduce secondary hyperparathyroidism and play a role in the management of senile osteoporosis. In order to define the optimal regimen of calcium and vitamin D supplementation to produce the maximal inhibition of parathyroid hormone secretion, we have compared the administration of a similar amount of Ca and vitamin D, either as a single morning dose or split in two doses, taken 6 hours apart. Twelve healthy volunteers were assigned to three investigational procedures, at weekly intervals. After a blank control procedure, when they were not exposed to any drug intake, they received two calcium-vitamin D supplement regimens including either two doses of Orocal D3 (500 mg Ca and 400 IU vitamin D) 6 hours apart or one water-soluble effervescent powder pack of Cacit D3 in a single morning dose (1000 mg Ca and 880 IU vitamin D). During the three procedures (control and the two calcium-vitamin D supplementations), venous blood was drawn every 60 minutes for up to 9 hours, for serum Ca and serum PTH measurements. The order of administration of the two Ca and vitamin D supplementation sequences was allocated by randomization. No significant changes in serum Ca were observed during the study. During the 6 hours following Ca and vitamin D supplementation, a statistically significant decrease in serum PTH was observed with both regimens, compared with baseline and with the control procedure. Over this period of time, no differences were observed between the two treatment regimens. However, between the sixth and the ninth hour, serum PTH levels were still significantly decreased compared with baseline with split dose Orocal D3 administration, while they returned to baseline value with the Cacit D3 preparation. During this period, the percentage decrease in serum PTH compared with baseline was significantly more pronounced with Orocal D3 than with Cacit D3 (P = 0.0021). We therefore conclude that the administration of two doses of 500 mg of calcium and 400 IU of vitamin D3 6 hours apart provides a more prolonged decrease in serum PTH levels than the administration of the same total amount of Ca and vitamin D as a single morning dose in young healthy volunteers. This might have implications in terms of protection of the skeleton against secondary hyperparathyroidism and increased bone resorption and turnover in elderly subjects.