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Background: Strontium ranelate, a new oral drug shown to reduce vertebral fracture risk in postmenopausal women with osteoporosis, was studied in the Treatment of Peripheral Osteoporosis (TROPOS) study to assess its efficacy and safety in preventing nonvertebral fractures also., Methods: Strontium ranelate (2 g/d) or placebo were randomly allocated to 5091 postmenopausal women with osteoporosis in a double-blind placebo-controlled 5-yr study with a main statistical analysis over 3 yr of treatment., Findings: In the entire sample, relative risk (RR) was reduced by 16% for all nonvertebral fractures (P = 0.04), and by 19% for major fragility fractures (hip, wrist, pelvis and sacrum, ribs and sternum, clavicle, humerus) (P = 0.031) in strontium ranelate-treated patients in comparison with the placebo group. Among women at high risk of hip fracture (age > or = 74 yr and femoral neck bone mineral density T score < or = -3, corresponding to -2.4 according to NHANES reference) (n = 1977), the RR reduction for hip fracture was 36% (P = 0.046). RR of vertebral fractures was reduced by 39% (P < 0.001) in the 3640 patients with spinal x-rays and by 45% in the subgroup without prevalent vertebral fracture. Strontium ranelate increased bone mineral density throughout the study, reaching at 3 yr (P < 0.001): +8.2% (femoral neck) and +9.8% (total hip). Incidence of adverse events (AEs) was similar in both groups., Conclusion: This study shows that strontium ranelate significantly reduces the risk of all nonvertebral and in a high-risk subgroup, hip fractures over a 3-yr period, and is well tolerated. It confirms that strontium ranelate reduces vertebral fractures. Strontium ranelate offers a safe and effective means of reducing the risk of fracture associated with osteoporosis.

Objectives: To analyse the effect of a dose increase in patients with severe rheumatoid arthritis (RA) with insufficient clinical response to 3 mg/kg infliximab every 8 weeks., Methods: Patients suffering from active refractory RA despite methotrexate, were treated with i.v. infusions of infliximab (3 mg/kg) on week 0, 2, 6 and every 8 weeks thereafter. Based on the clinical judgement at week 22, patients received a dose increase of 100 mg from week 30 on. The American College of Rheumatology (ACR) core set for disease activity measures was regularly assessed., Results: Five hundred and eleven RA patients were included. At week 22, 61.4, 34 and 14.1% of all patients met ACR 20, ACR 50 and ACR 70 criteria, respectively, and 6.1% of patients were in remission. A low swollen joint count at baseline was correlated with improvement at week 22 for ACR 20 (P < 0.06), ACR 50 (P < 0.06) and ACR 70 (P < 0.005). The change in HAQ score between weeks 0 and 22 was predictive for response at week 54 (P < 0.01). The dose of infliximab was increased by 100 mg in 22% of the patients. Most baseline values of patients requiring dose increase were higher (P < or = 0.001) than the baseline values of the remaining patients. Increasing the dose of infliximab by one vial from week 30 on could circumvent the partial loss of response in these patients., Conclusion: Infliximab use in this large out-patient cohort resulted in a significant clinical improvement. A subgroup that partially lost response during the first 22 weeks could regain response by adding 100 mg of infliximab to the subsequent doses. Due to the current study design, however, a regression to the mean like effect could not be ruled out.

Unlabelled: In human cancellous bone, osteoclastic perforations resulting from normal remodeling were generally considered irreversible. In human vertebral samples, examined by backscatter electron microscopy, there was clear evidence of bridging of perforation defects by new bone formation. Hence trabecular perforations may not be irreversible., Introduction: Preservation of the trabecular bone microarchitecture is essential to maintain its load-bearing capacity and prevent fractures. However, during bone remodeling, the osteoclasts may perforate the platelike trabeculae and disconnect the structure. Large perforations (>100 microm) are generally considered irreversible because there is no surface on which new bone can be laid down. In this work, we investigated the outcome of these perforations on human vertebral cancellous bone., Materials and Methods: Using backscatter electron microscopy, we analyzed 264 vertebral bone samples from the thoracic and lumbar spine of nine subjects (44-88 years old). Nine fields (2 x 1.5 mm) were observed on each block. Several bone structural units (BSUs) were visible on a single trabecula, illustrating a dynamic, historical aspect of bone remodeling. A bridge was defined as a single and recent BSU connecting two segments of trabeculae previously separated by osteoclastic resorption. They were counted and measured (length and breadth, microm)., Results and Conclusion: We observed 396 bridges over 2376 images. By comparison, we found only 15 microcalluses on the same material. The median length of the bridge was 165 microm (range, 29-869 microm); 86% being longer than 100 microm and 35% longer than 200 microm. Their breadth was 56 microm (range, 6-255 microm), but the thinnest were still in construction. Bridges were found in all nine subjects included in the study, suggesting that it is a common feature of normal vertebral bone remodeling. These observations support the hypothesis that perforation could be repaired by new bone formation, and hence, might not be systematically irreversible.

Objective: We previously described a novel radiolabelled monoclonal antibody (1.2B6), which reacts with porcine E-selectin, for targeting activated endothelium as a means of imaging inflammatory disorders, and presented initial clinical work based on (111)In-labelled antibody. The aim of the present study was to evaluate a Fab fragment of 1.2B6 labelled with (99m)Tc in patients with rheumatoid arthritis (RA) by comparison with (i) (111)In-labelled 1.2B6 F(ab')(2) and (ii) conventional bone scanning., Methods: (99m)Tc-1.2B6-Fab ( approximately 440 MBq) and (111)In-1.2B6-F(ab')(2) ( approximately 27 MBq) were compared in 10 patients using a double-isotope protocol. Images were obtained 4 and 20-24 h after injection. Two normal volunteers were also imaged. In a separate group of 16 patients, (99m)Tc-1.2B6-Fab and (99m)Tc-oxidronate ((99m)Tc-HDP) ( approximately 740 MBq) were compared on the basis of visual and semi-quantitative analysis of joint uptake (joint/soft tissue ratios) 4 h after injection. The respective biodistributions and blood clearances of the two 1.2B6 fragments were also compared., Results: Image contrast was slightly better with (99m)Tc-Fab at 4 h but equal for the two tracers at 24 h. Diagnostic accuracy, taking joint tenderness or swelling as the clinical endpoint, was 76% for both fragments at 24 h. Plasma clearance of (99m)Tc-Fab was faster than that of (111)In-F(ab')(2) (t(1/2) 142 vs 421 min; P<0.0001). (99m)Tc-Fab appeared somewhat unstable in vivo, as shown by activity in the thyroid gland and bowel. The diagnostic accuracy of (99m)Tc-Fab was 88%, higher than that of (99m)Tc-HDP (57%) as a result of the low specificity of the latter in RA. Receiver operating characteristic (ROC) curve analysis using joint/soft tissue ratios as a variable cut-off showed that (99m)Tc-Fab discriminates better than (99m)Tc-HDP between actively inflamed and silent joints (Z=4.72; P<0.0001). No uptake of (99m)Tc-Fab was observed by inactive or normal joints, whereas (99m)Tc-HDP was taken up by all joints to a variable degree, making the decision as to whether a particular joint is actively involved or chronically damaged very difficult., Conclusion: (99m)Tc-anti-E-selectin-Fab scintigraphy can be used successfully to image synovitis with better specificity than (99m)Tc-HDP bone scanning. The advantages over (111)In-1.2B6-F(ab')(2) are easier availability of the radionuclide, improved physical properties and optimal imaging 4 h after injection.

The aim of this study was to compare the action of two regimens of intravenous (iv) pamidronate in the primary prevention of glucocorticoid-induced osteoporosis (GC-OP). The primary purpose of the study was to determine whether any differences in bone mineral density (BMD) appeared after 1 year. A secondary endpoint aimed at assessing the remodeling parameters in order to better understand the mechanisms of action of the various regimens. Thirty-two patients, who required first-time, long-term glucocorticoid therapy at a daily dose of at least 10 mg of prednisolone, were studied. Simultaneously with the initiation of their glucocorticoid treatment, patients also were randomly allocated to receive a single iv infusion of 90 mg of pamidronate at the start (group A); a first infusion of 90 mg of pamidronate followed, subsequently, by an iv infusion of 30 mg pamidronate every 3 months (group B); and a daily 800-mg elemental calcium supplement given as calcium carbonate (group C), which also was taken by patients in groups A and B. Patients were matched for starting glucocorticoid doses, sex, menopausal status, and hormonal replacement therapy. Lumbar spine and hip (total and subregions) BMDs were measured at the outset and repeated at 6-month intervals by dual-energy X-ray absorptiometry (DXA; Hologic QDR-2000). Bone turnover was assessed by measurement of total and bone-specific serum alkaline phosphatase activity (B-ALP), serum osteocalcin (OC), and serum C-telopeptide cross-links of type I collagen (CTX). After 1 year, the mean BMD changes for groups A, B, and C were, respectively, 1.7, 2.3, and -4.6% at the lumbar spine; 1.2, 1.2, and -3.1% at the femoral neck; 1.0, 2.6, and -2.2% for the total hip region. No difference was observed between pamidronate regimens but a highly significant difference was observed between both pamidronate regimens and the control group at the lumbar spine (p < 0.001), at the femoral neck (p < 0.01), and for the total hip (p < 0.05). A significant decrease of serum C-telopeptide was observed, after 3 months, in groups A and B (p = 0.029), but a sustained decrease of bone resorption over time was observed only in group B. As far as BMD evolution over 1 year was concerned, iv pamidronate, given either as a single infusion or once every 3 months, effectively achieved primary prevention of GC-OP.

Long-term use of high-dose corticosteroids often results in bone loss, which may lead to osteoporosis-related fractures. This was a multicenter, double-blind study in which 290 ambulatory men and women receiving high-dose oral corticosteroid therapy (prednisone > or = 7.5 mg/day or equivalent) for 6 or more months were randomized to receive placebo, risedronate 2.5 mg/day, or risedronate 5 mg/day for 12 months. All patients received calcium 1 g and vitamin D 400 IU daily. The primary endpoint was lumbar spine bone mineral density (BMD) at month 12. Additional measurements included BMD at the femoral neck and trochanter and the incidence of vertebral fractures. Overall, there were statistically significant treatment effects on BMD at 12 months at the lumbar spine (p < 0.001), femoral neck (p = 0.004), and trochanter (p = 0.010). Risedronate 5 mg increased BMD at 12 months by a mean (SEM) of 2.9% (0.49%) at the lumbar spine, 1.8% (0.46%) at the femoral neck, and 2.4% (0.54%) at the trochanter, whereas BMD was maintained only in the control group. Although not powered to show fracture efficacy, we observed a reduction in the incidence of vertebral fractures of 70% in the combined risedronate treatment groups, relative to placebo (p = 0.042). Risedronate was well tolerated, had a good safety profile, and was not associated with gastrointestinal adverse events. We conclude that risedronate increases BMD and potentially reduces the incidence of vertebral fractures in patients with corticosteroid-induced osteoporosis.

Objective: To evaluate whether bone loss occurs over time in pre-menopausal systemic lupus erythematosus (SLE) patients., Methods: We performed a longitudinal bone mineral density (BMD) analysis in a group of 35 pre-menopausal female SLE patients. Lumbar spine and hip (total and sub-regions) BMDs were measured twice 21 +/- 11 (mean +/- S.D.) months apart by dual-energy X-ray absorptiometry., Results: In the whole cohort of SLE patients, significant bone loss was observed at the lumbar spine (-1.22%/yr) but not at the total hip. Further analyses indicated that lumbar spine bone loss (-2.12%/yr) occurred exclusively in the subgroup of patients who had taken a mean prednisolone daily dose >7.5 mg between the two BMD measurements. Moreover, bone loss was more important in patients who had previously received a cumulative prednisolone dose 7.5 mg.

We determined prospectively the prevalence of avascular osteonecrosis (AON) by magnetic resonance imaging (MRI) of both lower limbs in a group of 40 systemic lupus erythematosus (SLE) patients, and correlated the results with their serum antiphospholipid antibody (APL Ab) status and their glucocorticoid (GC) intake. APL Ab were detected by anticardiolipin ELISA and by lupus anticoagulant assays. Cumulated prednisolone doses were computed by chart review. The prevalence of AON was 37.5%, with most patients being asymptomatic despite involvement of multiple sites. The number of epiphyseal, metaphyseal and diaphyseal AON sites per patient did not differ between APL Ab-positive and APL Ab-negative patients nor between patients with high and low APL Ab titres. By contrast, a striking correlation was found between the prevalence and severity of AON and GC therapy. In conclusion, this prospective MRI study indicates that the prevalence of AON in SLE patients correlates strongly with GC therapy, but not with APL Ab status.

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by polyclonal B cell activation and by the production of anti-double-stranded (ds) DNA antibodies. Given the inhibitory effects of IL-12 on humoral immune responses, we investigated whether IL-12 displayed such an activity on in vitro immunoglobulin production by SLE PBMC. Spontaneous IgG, IgG1, IgG2, IgG3 and IgM antibody production was dramatically reduced by addition of IL-12. These results were confirmed by Elispot assays detecting IgG- and anti-dsDNA-secreting cells. While IL-6 and TNF titres measured in PBMC supernatants were not modified by addition of IL-12, interferon-gamma (IFN-gamma) titres were up-regulated and IL-10 production down-regulated. Since addition of IFN-gamma did not down-regulate immunoglobulin production and since the inhibitory activity of IL-12 on immunoglobulin synthesis was not suppressed by anti-IFN-gamma antibody, we concluded that the effect of IL-12 on immunoglobulin production was not mediated through IFN-gamma. Our data also argue against the possibility that down-regulation of endogenous IL-10 production was responsible for the effect of IL-12. Thus, inhibition of IL-10 production by IFN-gamma was not accompanied by inhibition of immunoglobulin production, and conversely, restoration of IL-10 production by anti-IFN-gamma antibody did not suppress the inhibitory activity exerted by IL-12 on immunoglobulin production. Taken together, our data indicate that reduction of excessive immunoglobulin and anti-dsDNA antibody production by lupus PBMC can be achieved in vitro by IL-12, independently of IFN-gamma and IL-10 modulation.

We measured lumbar spine, hip (total and sub-regions) and total body bone mineral densities (BMDs) by dual-energy X-ray absorptiometry (DXA) in 47 premenopausal female patients suffering from systemic lupus erythematosus (SLE). As compared to health controls, SLE patients had lower BMDs at all trabecular and cortical sites. Comparison of BMDs between patients ever and never treated with glucocorticoids indicated that patients who had ever received glucocorticoids had a significantly lower lumbar spine BMD compared to those who never did. Moreover, bone loss in patients ever treated with glucocorticoids was commensurate with their cumulated oral glucocorticoid intake. Interestingly, patients never treated with glucocorticoids had a lower hip BMD compared to controls, thereby suggesting that the disease per se might induce some bone loss. Taken together, SLE patients suffer from a significant trabecular and cortical bone loss indicative of an increased risk of future fracture.

Osteoporosis constitutes a major financial burden for society, which will increase in the near future owing to the ageing of the population. Women are the most common victims of involutional osteoporosis because of post-menopausal bone loss induced by oestrogenic deficit. Men are nevertheless not completely untouched by osteoporosis, however, compared to women, they are under less threat. Every effort should be made to curtail the financial burden on society and to improve the quality of life of sufferers. The first steps should be to increase the calcium intake, the level of exercise and to decrease the risk of falls. A preventive therapy with oestroprogestogens should be instituted at the time of the menopause, provided there is no contraindication. In the absence of fracture data, the modalities of alternative therapies like calcitonin and bisphosphonates are still debated. For people already suffering from fractures, restorative therapy should be considered. Sodium fluoride therapy is able to provoke a decrease in vertebral fracture frequency without compromising cortical bone strength provided elementary rules for its use are respected. Whether bisphosphonates can protect against fractures is still unsettled. Vitamin D has a physiological role, particularly in institutionalized elderly patients deprived of any exposure to the sun. Anabolic steroids are not devoid of side effects, and furthermore, no fracture data are so far available.

The gastrointestinal absorption of enteric-coated (EC) tablets of sodium fluoride (NaF) with respect to different time schedules of administration of calcium supplements in solution was tested. It was found that the simultaneous administration of these two medications under these formulations did not interfere with fluoride absorption. The calcium was also well absorbed as shown by the rise in serum ionized calcium concentration. Other schedules were studied as well, such as EC NaF tablets taken 1 hour after or 3 hours before the administration of calcium supplements. No superiority was shown, on the contrary, compared with the simultaneous administration of both medications. It was concluded that EC tablets of NaF and calcium supplements in solution can be provided simultaneously to enhance compliance.

A cohort of 101 patients were treated with enteric-coated sodium fluoride tablets and calcium supplements. Vitamin D was also given in supra-physiologic doses in 70% of the cases. Lumbar bone mineral density (BMD), as measured by dual-photon absorptiometry, increased in a linear fashion up to four years, irrespective of the value of initial BMD and of the underlying condition, be it involutional osteoporosis (the vast majority), glucocorticoid osteoporosis, or even osteogenesis imperfecta. Estrogen replacement therapy (ERT) seemed to promote the fluoride-induced increase in lumbar BMD, as did the vitamin D supplements. Of these patients, 17% proved "resistant" to the therapy. There was no way of predicting who would be in this category. Compared with an age- and sex-matched control group, women showed significantly different behavior of their bone mass. In the control group, the losses were highly significant at the lumbar spine and at all three scanning sites of the forearm, as measured by single-photon absorptiometry. In contrast, the fluoride group had a significant gain of BMD at the lumbar spine and changes of BMC at the forearm were not significant. Fluoride thus preserved bone mass at the appendicular skeleton, while increasing it at the axial skeleton. When comparing the patients who received vitamin D supplements and those who did not, there was a significant difference in the appendicular skeleton. The distal forearm in the vitamin D-supplemented group tended to gain, whereas the midforearm lost significant bone mass. The trend was reversed in the group without vitamin D-supplementation, a more favorable pattern. Therefore, vitamin D supplements should not, as a rule, be provided to such patients. The biochemical hallmark of the fluoride-induced changes is a slight rise of the alkaline phosphatase within the normal range. Alkaline phosphatase levels that exceed the upper limit of normal signal a warning that too much fluoride and/or too little calcium supplements are being administered, or that a fluoride-related complication is impending or has occurred (e.g., a stress fracture). Osteosclerosis was achieved in 69% of the cases who had a radiological followup of at least four years (average period of appearance: 1.8 years). Stress fractures in the lower limbs occurred in 17 patients, almost exclusively in females, and appeared on average 2.2 years after initiation of therapy. In this group of stress fractures there was significant cortical bone loss at midforearm.(ABSTRACT TRUNCATED AT 400 WORDS)

Circulating levels of parathyroid hormone (PTH) in six patients with pseudohypoparathyroidism type I (PSPI) have been measured by two immunoassays and by cytochemical bioassay and compared with measurements in normal subjects and patients with clinically defined hyper- and hypoparathyroidism. In all PSPI patients, the levels of immunoreactive PTH were in the hyperparathyroid range, whereas the bioactive levels were either in the normal or close to the normal range. In one patient from whom the dihydrotachysterol therapy was withdrawn, both immunoreactive and bioactive PTH concentrations increased. The finding that the PTH measured by RIA in these PSPI patients may have reduced biological activity may explain some of the clinical findings of hypoparathyroidism in this syndrome.

Despite the high circulating levels of immunoreactive PTH in patients with pseudohypoparathyroidism type I (PSPI) the levels of bioactive PTH (bioPTH) have been found to be close to the normal range. To elucidate this dissociation, we have studied the recovery of the biological activity of bovine PTH added to the plasma of patients with either PSPI, or with hypoparathyroidism (PTX), primary hyperparathyroidism (HPT) or of normal subjects. In PSPI (n = 10) the recovery of biological activity was 5.6% +/- 3.6 (mean +/- SEM) whereas in PTX (n = 7), in HPT (n = 4) and in normal subjects (n = 8) it was 79% +/- 5, 75% +/- 9 and 68% +/- 4, respectively. In another PSPI patient, who had undergone total parathyroidectomy, bioPTH was undetectable but the recovery from the plasma of added PTH was 84%. Thus we have found inhibition of PTH bioactivity by plasma of PSPI patients which was absent after parathyroidectomy.