Upper gastrointestinal safety of oral bisphosphonate in hospitalized patients.

Oral bisphosphonates are effective medications for the prevention of fractures in people suffering from osteoporosis. They are associated with gastrointestinal adverse reactions the most severe being an esophageal ulcer. It is unclear if oral bisphosphonates have a similar gastrointestinal safety profile in the hospital setting as in the community setting because hospitalized patients are often bedridden which may hinder proper drug administration. INTRODUCTION: To evaluate the incidence of upper gastrointestinal symptoms in hospitalized patients taking oral bisphosphonate. METHODS: This single-center prospective cohort study included hospitalized adult patients actively taking risedronate or alendronate. Upper gastrointestinal symptoms were actively assessed at the baseline and 1 to 5 h following the administration of the oral bisphosphonate. RESULTS: A total of 298 patients were included in the study. The mean age was 64 ± 15 years. During the follow-up period, gastric and esophageal symptoms affected 32 patients (10.7%). Epigastric burning, dysphagia, and regurgitation were reported in 4.4% (n = 13), 3% (n = 9), 2.7 (n = 8), and 2.3% (n = 7) patients, respectively. Heartburn, retro-sternal pain, and odynophagia were observed in 1.7% (n = 5), 1.7% (n = 5), and 0.3% (n = 1) patients. CONCLUSION: The incidence of adverse reaction was similar to that reported in community trials. The administration of oral bisphosphonate in hospitalized patients does not represent an additional risk for upper gastrointestinal adverse events. Treatment should be optimized during the hospital stay to improve the pharmacological management of osteoporosis.

Performance of predictive tools to identify individuals at risk of non-traumatic fracture: a systematic review, meta-analysis, and meta-regression.

There is no consensus on which tool is the most accurate to assess fracture risk. The results of this systematic review suggest that QFracture, Fracture Risk Assessment Tool (FRAX) with BMD, and Garvan with BMD are the tools with the best discriminative ability. More studies assessing the comparative performance of current tools are needed. INTRODUCTION: Many tools exist to assess fracture risk. This review aims to determine which tools have the best predictive accuracy to identify individuals at high risk of non-traumatic fracture. METHODS: Studies assessing the accuracy of tools for prediction of fracture were searched in MEDLINE, EMBASE, Evidence-Based Medicine Reviews, and Global Health. Studies were eligible if discrimination was assessed in a population independent of the derivation cohort. Meta-analyses and meta-regressions were performed on areas under the ROC curve (AUCs). Gender, mean age, age range, and study quality were used as adjustment variables. RESULTS: We identified 53 validation studies assessing the discriminative ability of 14 tools. Given the small number of studies on some tools, only FRAX, Garvan, and QFracture were compared using meta-regression models. In the unadjusted analyses, QFracture had the best discriminative ability to predict hip fracture (AUC = 0.88). In the adjusted analysis, FRAX with BMD (AUC = 0.81) and Garvan with BMD (AUC = 0.79) had the highest AUCs. For prediction of major osteoporotic fracture, QFracture had the best discriminative ability (AUC = 0.77). For prediction of osteoporotic or any fracture, FRAX with BMD and Garvan with BMD had higher discriminative ability than their versions without BMD (FRAX: AUC = 0.72 vs 0.69, Garvan: AUC = 0.72 vs 0.65). A significant amount of heterogeneity was present in the analyses. CONCLUSIONS: QFracture, FRAX with BMD, and Garvan with BMD have the highest discriminative performance for predicting fracture. Additional studies in which the performance of current tools is assessed in the same individuals may be performed to confirm this conclusion.

Denosumab compared to other treatments to prevent or treat osteoporosis in individuals at risk of fracture: a systematic review and meta-analysis.

UNLABELLED: The aim of this review is to compare the efficacy and safety of denosumab over other treatments for osteoporosis. The results of this study suggest that the safety of denosumab and its efficacy in reducing fractures is not significantly different from bisphosphonates. Denosumab was, however, more effective in increasing bone mineral density. INTRODUCTION: This study was conducted to compare the efficacy and safety of denosumab over other pharmacological treatments for osteoporosis in individuals at risk of fracture. METHODS: Randomised controlled trials comparing denosumab with another pharmacological treatment for osteoporosis were searched in MEDLINE, EMBASE and CENTRAL. Identified articles were screened by two independent reviewers and assessed for inclusion. Data from included studies were extracted and meta-analyses were conducted using random effects models. RESULTS: Nine studies including a total of 4890 postmenopausal women were identified. The follow-up period varied from 12 to 24 months. In all studies except one, the comparator treatment was a bisphosphonate. There was no statistically significant difference between patients receiving denosumab and those receiving a bisphosphonate in terms of fracture risk (RR[95 % CI] = 1.15 [0.84-1.58]), adverse events (RR[95 % CI] = 0.99 [0.96-1.02]) or deaths (OR[95 % CI] = 0.58 [0.12-2.71]). Withdrawals due to adverse events were less frequent in denosumab than in other treatment groups but the difference did not reach statistical significance (OR[95 % CI] = 0.68 [0.45-1.04]). The percent change in bone mineral density at the total hip, lumbar spine, femoral neck and one-third radius was significantly higher in participants who received denosumab (e.g. mean difference [95 % CI] at the total hip: 1.06 [0.86-1.25]). CONCLUSIONS: These results suggest that, after 12 to 24 months, the safety and efficacy of denosumab for reducing fracture risk is not significantly different from bisphosphonates despite higher gains in bone mineral density. In a clinical setting, denosumab may demonstrate greater effectiveness.

Bone safety with risedronate: histomorphometric studies at different dose levels and exposure.

UNLABELLED: This report describes bone safety and histomorphometric data across different dose levels and dosing frequencies of risedronate. Normal bone structure and histomorphometric data were observed, with ongoing bone remodeling and mineralization regardless of dose. These data are reassuring and do not suggest compromised bone remodeling during treatment with established risedronate regimens. INTRODUCTION: The efficacy and bone safety of risedronate 5 mg daily were established in pivotal phase III randomized, placebo-controlled clinical studies. Histomorphometric analysis of paired biopsies demonstrated bone safety as reflected by presence of fluorescent tetracycline double-labels in all evaluable biopsies. This report describes bone safety and histomorphometric data across studies of various dose regimens of risedronate. METHODS: Bridging studies, with bone mineral density as the primary endpoint, demonstrated non-inferiority of risedronate 35 mg and 50 mg once a week, risedronate 150 mg once a month, and a risedronate 75-mg dose on two consecutive days a month versus risedronate 5 mg daily. The low oral bioavailability and known dosing limitations due to food interactions of bisphosphonates have led to development of an oral delayed-release dose form of risedronate 35 mg to be taken weekly, before or after breakfast. Bone biopsies were collected at 24 months in studies involving these risedronate dosing regimens; bone safety and histomorphometric data were evaluated. RESULTS: Qualitative bone histology showed normal mineralization of newly formed bone without evidence of pathological findings, such as osteomalacia, bone marrow dyscrasia, or bone marrow fibrosis. Importantly, ongoing bone remodeling, based on fluorochrome labeling, was observed in all patients regardless of dose and exposure. Key histomorphometric variables were comparable to those observed with the risedronate 5 mg daily dose and were within the range seen in healthy pre- and post-menopausal women. CONCLUSIONS: Overall, the results are reassuring with respect to bone safety and histomorphometric data, and do not suggest oversuppression of bone remodeling during treatment with these established risedronate regimens.

The impact of educational interventions on modifiable risk factors for osteoporosis after a fragility fracture.

The purpose of this study was to investigate the impact of two educational interventions on the intake of calcium and vitamin D supplements and modifiable risk factors for osteoporosis in women ≥50 years with a fragility fracture (FF). Within 6-8 months of fracture, women were randomized to one of three intervention groups: usual care (UC), written materials (WM), or videocassette and written materials (VC). The written materials for patients and their physician provided information on osteoporosis, FF, and available treatments; written materials for physician were provided through patients. The videocassette presented similar information as the written material, but in greater depth. Twelve months after randomization, the effectiveness of the interventions was assessed. The study cohort consisted of 1,175 women undiagnosed and untreated for osteoporosis. After 12 months, the mean intake of Ca supplements increased by 33, 93, and 91 mg/day for the UC, WM, and VC groups, respectively (p value, WM vs UC = 0.163; VC vs UC = 0.026); the corresponding mean increases for vitamin D were 58, 105, and 118 IU/day (p value, WM vs UC = 0.214; VC vs UC = 0.012). The proportion of women who increased their Ca and vitamin D intake by supplements was similar in all three groups. The intervention had a greater impact in those not taking supplements at randomization and had no impact on modifiable risk factors. In women without diagnosis and treatment for osteoporosis, the interventions seem effective at increasing the amounts of Ca and vitamin D supplements, but not effective at inciting more women to increase their consumption. Therefore, the clinical significance of the impact of the intervention is difficult to evaluate.

Direct medical costs attributable to peripheral fractures in Canadian post-menopausal women.

UNLABELLED: This study determined the cost of treating fractures at osteoporotic sites (except spine fractures) for the year following fracture. While the average cost of treating a hip fracture was the highest of all fractures ($46,664 CAD per fracture), treating other fractures also accounted for significant expenditures ($5,253 to $10,410 CAD per fracture). INTRODUCTION: This study aims to determine the mean direct medical cost of treating fractures at peripheral osteoporotic sites in the year post-fracture (through 2 years post-hip fracture). METHODS: Health administrative databases from the province of Quebec, Canada were used to estimate the cost of treating peripheral fractures at osteoporotic sites for the year following fracture (through 2 years for hip fractures). Included in costs analyses were physician claims, emergency and outpatient clinic costs, hospitalization costs, and subsequent costs for treatment of complications. RESULTS: A total of 15,827 patients (mean age 72 years) who suffered one fracture at an osteoporotic site had data for analyses. Hip/femur fractures had the highest rate of hospital stays related to fracture (91%) and the highest rate of hospital stays associated with a post-fracture complication (8%). In the year following fracture, the mean (SD) costs (2009 Canadian dollars) of treating acute fractures and post-fracture complications were: hip/femur fracture $46,664 ($43,198), wrist fracture $5,253 ($18,982), and fractures at other peripheral sites $10,410 ($27,641). The average (SD) cost of treating post-fracture complications at the hip/femur in the second year post-fracture was $1,698 ($12,462). Hospitalizations associated with the fracture accounted for 88% of the total cost of fracture treatment. CONCLUSIONS: The treatment of hip fractures accounts for a significant proportion of the costs associated with the treatment of peripheral osteoporotic fractures. Interventions to reduce the incidence of fractures, particularly hip fractures, would result in significant cost savings to the health care system and would preserve quality of life in many patients.

The impact of two educational interventions on osteoporosis diagnosis and treatment after fragility fracture: a population-based randomized controlled trial.

UNLABELLED: This study assessed whether osteoporosis diagnosis and treatment after an osteoporotic fracture can be increased by providing osteoporosis reading material to patients and family doctors or by watching a videocassette about osteoporosis. Educating patients about osteoporosis had little impact on whether a woman received an osteoporosis diagnosis or treatment. INTRODUCTION: The purpose of this study was to investigate the impact of two education-based interventions on osteoporosis diagnosis and treatment in women ≥ 50 years of age after fragility fracture. METHODS: Six to eight months after fracture, women were randomized into three groups: (1) control, (2) written materials, or (3) videocassette and written materials. Written materials for both the patient and physician detailed osteoporosis, fragility fracture, and available treatments; written materials for physicians were provided through patients. The educational videocassette presented similar information as the written material, but in greater depth. Rates of osteoporosis diagnosis and treatment following intervention were compared among groups using survival analysis methods. Statistical significance was set at p < 0.0167. RESULTS: At randomization, 1,174 women were without osteoporosis diagnosis and treatment, and after follow-up, 12% of the control group, 15% of the written materials group (p = 0.073), and 16% (p = 0.036) of the videocassette and written materials group were diagnosed with osteoporosis (statistical comparisons to control). Treatment rates were 8% for the control group, 12% for the written materials group (p = 0.052), and 11% for the videocassette and written materials group (p = 0.157). At randomization, 1,314 women were without treatment and after follow-up therapy was initiated in 10% of the control group, 13% of the written materials group (p = 0.107), and 13% of the videocassette and written materials group (p = 0.238). CONCLUSIONS: The educational interventions assessed in this trial were not satisfactory to increase osteoporosis diagnosis or treatment in recently fractured women to a clinically meaningful degree.

Factors influencing the treatment of osteoporosis following fragility fracture.

UNLABELLED: Treatment rates of osteoporosis after fracture are very low. Women who suffer a fragility fracture have a greater chance of receiving anti-fracture treatment if they had low bone mineral density (BMD), a fracture at the hip, femur or pelvis, administration of calcium and vitamin D supplements and/or an age > or =60 years. INTRODUCTION: This investigation identifies the predictors of osteoporosis treatment 6 to 8 months following fragility fracture in women >50 years of age. METHODS: In this prospective cohort study, women were recruited 0 to 16 weeks following fracture and classified as having experienced fragility or traumatic fractures (phase 1). Six to 8 months following fracture, women completed a questionnaire on demographic features, clinical characteristics and risk factors for osteoporosis (phase 2). Osteoporosis treatment was defined as initiating anti-fracture therapy (bisphosphonate, raloxifene, nasal calcitonin and teriparatide) after fracture in those previously untreated. RESULTS: Of the 1,273 women completing phase 1, 1,001 (79%) sustained a fragility fracture, and of these women, 738 were untreated for osteoporosis at phase 1 and completed the phase 2 questionnaire. Significant predictors of treatment included BMD result, fracture site, administration of calcium and vitamin D supplements at the time of fracture and age > or =60 years. All other risk factors for osteoporosis, such as fracture history after the age of 40 years, family history of osteoporosis and comorbidities did not significantly influence the treatment rate. CONCLUSIONS: Physicians largely based their decision to treat on BMD results and not on the clinical event-fragility fracture.

Risedronate dosing before breakfast compared with dosing later in the day in women with postmenopausal osteoporosis.

UNLABELLED: Two studies in postmenopausal women with osteoporosis provide information about the efficacy and safety of dosing oral risedronate 5 mg daily at a time other than before breakfast (i.e., 2 h before and 2 h after any food and drink other than plain water). A significant increase in lumbar spine BMD was observed for both treatment regimens in the two studies. However, smaller increases in lumbar spine BMD were observed with flexible dosing versus before-breakfast dosing. Geographic region, compliance, and consistency of dosing time appear to affect the amount of increase in BMD observed with flexible dosing. INTRODUCTION: Two studies in postmenopausal women with osteoporosis provide additional information about the efficacy and safety of dosing oral risedronate 5 mg daily at a time other than before breakfast (i.e., 2 h before and 2 h after any food and drink other than plain water). METHODS: One study, flexible dosing, was a 6-month North American study in 730 patients randomized to before-breakfast dosing or flexible dosing later in the day. A second study, IMPACT, was a large (N = 2382), 1-year multinational study in patients that chose their dosing regimen (before breakfast or later in the day). These studies were used to examine the bone mineral density (BMD) response with different dosing regimens. RESULTS: A significant increase in lumbar spine BMD was observed for both treatment regimens in the two studies. However, in both studies, the flexible dosing group had a smaller increase from baseline compared to the before-breakfast regimen (ratio of flexible dosing to before breakfast: flexible dosing study, 0.52; IMPACT study, 0.75). In addition, a relationship between geographic region and BMD response was observed with flexible dosing in both studies. Patients in the flexible dosing group who had greater dosing compliance (based on the number of times the bottle was opened) and consistency of dosing time (bottle opened within a 1.5-h window) had a greater increase in lumbar spine BMD. CONCLUSION: Results of these two studies demonstrate that overall flexible dosing of risedronate leads to smaller BMD gains compared to before-breakfast dosing. This result may be due to poorer adherence to the flexible dosing instructions that may be more pronounced in patients in certain geographic regions. If patients cannot abide by before-breakfast dosing and flexible dosing is an approved option, one can expect suboptimal BMD results with flexible dosing.

Comparison of direct health care costs related to the pharmacological treatment of osteoporosis and to the management of osteoporotic fractures among compliant and noncompliant users of alendronate and risedronate: a population-based study.

UNLABELLED: This population-based study aimed to compare direct health care costs related to the pharmacological treatment of osteoporosis and to the management of osteoporotic fractures among compliant and noncompliant users of alendronate and risedronate. During a 2-year follow-up period, compared to those with medication possession ratio (MPR) > or = 80%, women with MPR < 80% incurred significantly higher physician care costs and hospital care costs. INTRODUCTION: This study aimed to compare direct health care costs related to the treatment of osteoporosis and osteoporotic fractures among compliant and noncompliant users of alendronate and risedronate. METHODS: A cohort of 15,027 women having initiated alendronate or risedronate was identified. MPR and direct health care costs (physician care, hospital care, drugs) were assessed during a 2-year period. Regression models were used to estimate mean predicted cost for compliant (MPR > or = 80%) and noncompliant (MPR < 80%) women. RESULTS: Mean predicted physician care cost (in Canadian dollars) was $51 among women with MPR < 80% and $34 among those with MPR > or = 80%: mean difference $17, 95% confidence interval (CI) $2-22. Mean predicted hospital care cost was $568 among women with MPR < 80% and $379 among those with MPR > or = 80%: mean difference $189, 95% CI $56-320. Mean predicted drug cost was $439 among women with MPR < 80% and $1,068 among those with MPR > or = 80%: mean difference $-639, 95% CI $-649 to -629. CONCLUSION: Compared to compliant women, noncompliant women incurred significantly higher physician care and hospital care costs. Due to lower drug costs, total direct health care costs were lower among noncompliant women.

The role of mineralization and organic matrix in the microhardness of bone tissue from controls and osteoporotic patients.

Degree of mineralization of bone (DMB) is a major intrinsic determinant of bone strength at the tissue level but its contribution to the microhardness (Vickers indentation) at the intermediary level of organization of bone tissue, i.e., Bone Structural Units (BSUs), has never been assessed. The purpose of this study was to analyze the relationship between the microhardness, the DMB and the organic matrix, measured in BSUs from human iliac bone biopsies. Iliac bone samples from controls and osteoporotic patients (men and women), embedded in methyl methacrylate, were used. Using a Vickers indenter, microhardness (kg/mm2) was measured, either globally on surfaced blocks or focally on 100 microm-thick sections from bone samples (load of 25 g applied during 10 sec; CV=5%). The Vickers indenter was more suited than the Knoop indenter for a tissue like bone in which components are diversely oriented. Quantitative microradiography performed on 100 microm-thick sections, allowed measurement of parameters reflecting the DMB (g/cm3). Assessed on the whole bone sample, both microhardness and DMB were significantly lower (-10% and -7%, respectively) in osteoporotic patients versus controls (p<0.001). When measured separately at the BSU level, there were significant positive correlations between microhardness and DMB in controls (r2=0.36, p<0.0001) and osteoporotic patients (r2=0.43, p<0.0001). Mineralization is an important determinant of the microhardness, but did not explain all of its variance. To highlight the role of the organic matrix in bone quality, microhardness of both osteoid and adjacent calcified matrix were measured in iliac samples from subjects with osteomalacia. Microhardness of organic matrix is 3-fold lower than the microhardness of calcified tissue. In human calcanei, microhardness was significantly correlated with DMB (r2=0.33, p=0.02) and apparent Young's modulus (r2=0.26, p=0.03). In conclusion, bone microhardness measured by Vickers indentation is an interesting methodology for the evaluation of bone strength and its determinants at the BSU level. Bone microhardness is linked to Young's modulus of bone and is strongly correlated to mineralization, but the organic matrix accounts for about one third of its variance.

The care gap in diagnosis and treatment of women with a fragility fracture.

UNLABELLED: In women aged 50 years or more who experienced a fracture, 81% suffered a fragility fracture. Six to eight months after fragility fracture, 79% had either not been investigated for osteoporosis or prescribed anti-fracture therapy. Despite fragility fractures being common in this population osteoporosis is under-diagnosed and under-treated. INTRODUCTION: The objective of this study was to evaluate the diagnostic and treatment rates for osteoporosis six months following fragility fracture. METHODS: This prospective cohort study was set in the general community from the Province of Quebec, Canada. Women at least 50 years of age who suffered a fracture were recruited during their initial visit to the hospital and had their fracture type classified as either fragility or traumatic. Six-to-eight months after fragility fracture, women were again contacted to evaluate the diagnostic and treatment rates of osteoporosis. RESULTS: Of the 2,075 women recruited over a 25 month period 1,688 (81%) sustained a fragility fracture and 387 (19%) sustained a traumatic fracture. Nine hundred and three participants with a fragility fracture were again contacted six-to-eight months after fracture. For the 739 women not on treatment on the recruitment day, only 15.4% initiated pharmacological therapy in the six-to-eight-month period following fracture and 79.0% had either not been investigated for osteoporosis or prescribed anti-fracture treatment. CONCLUSIONS: The proportion of fragility fractures to total fractures is higher than previously reported. Despite the availability of diagnostic modalities, effective treatments, and adequate health care assessments, there is a substantial care gap in the management of osteoporosis.

Accuracy of height loss during prospective monitoring for detection of incident vertebral fractures.

Vertebral fractures are the most common type of osteoporotic fracture, but more than two-thirds remain undetected. We have examined the relationship between height loss and the development of new vertebral fractures to determine whether there is a height loss threshold that has useful clinical accuracy to detect new fractures. We studied 985 postmenopausal women with osteoporosis in the placebo arms of the Vertebral Efficacy with Risedronate Therapy studies. Height was measured annually for 3 years using a wall-mounted stadiometer. New fractures were determined using quantitative and semi-quantitative radiographic morphometry. The relationship between height loss over three years and the number of new vertebral fractures was: height loss (cm) = 0.95 x number of new vertebral fractures-0.4 cm (r = 0.33). The odds ratio for the development of a new fracture increased up to 20.6 (95% confidence interval, 9.3, 45.8) when height loss was greater than 4.0 cm. At a threshold of > 2.0 cm height loss over 3 years, sensitivity was 35.5% for detecting new vertebral fractures and specificity was 93.6%. These findings show that there is a strong relationship between the amount of height loss and the risk of a new vertebral fracture. While there is no cut-off that can reliably rule in a new fracture, height loss of < or = 2.0 cm over 1-3 years has acceptable accuracy for ruling out an incident fracture.

Five years of treatment with risedronate and its effects on bone safety in women with postmenopausal osteoporosis.

We have recently reported that risedronate preserves normal bone formation and decreases bone remodeling in women with postmenopausal osteoporosis after 3 years of treatment. We report now the results of a 2-year extension study. The primary objective of this study was to determine the effect of 5 years of risedronate treatment (5 mg daily) on bone quality and bone remodeling based on paired transiliac bone biopsies. There were additional measurements that included bone turnover markers and bone mineral density (BMD). Histologic evaluation of biopsy sections (placebo, n = 21; risedronate, n = 27) yielded no pathologic findings after 5 years in either treatment group. Histomorphometric assessment of paired biopsy specimens after 5 years (placebo, n =12; risedronate, n = 13) found no statistically significant differences between treatment groups in structural or resorption parameters. There was a significant reduction in osteoid (-27%) and mineralizing surfaces (-49%) from baseline values in the risedronate group that were also significantly different from placebo at 5 years. Similarly, activation frequency decreased significantly (-77%) in the risedronate group, although it was not significantly different from placebo at 5 years (0.09 vs. 0.21, respectively). Double tetracycline labels were identified in all biopsy specimens indicating continuous bone turnover. After 5 years of risedronate treatment, serum bone-specific alkaline phosphatase (bone ALP) and N-telopeptide (NTX) decreased significantly from baseline by 33.3% and 47.5%, respectively. In the placebo group, bone ALP decreased by 3.9% (P = NS), whereas NTX decreased by 27.0% (P < 0.005). Lumbar spine BMD increased significantly in the risedronate group (9.2%), whereas no significant change was seen in the placebo group (-0.26%). Risedronate was overall well tolerated; during the 2-year study extension nonvertebral fractures occurred in 7 patients in placebo and 2 patients in risedronate groups. The findings from this study are consistent with the antiremodeling effect of risedronate and support long-term bone safety and antifracture efficacy of risedronate treatment.

Ability of peripheral DXA measurement to diagnose osteoporosis as assessed by central DXA measurement.

In order to evaluate the utility of peripheral measurement of bone mineral density (BMD) in the diagnosis of osteoporosis, we measured BMD at the spine and femoral neck with central dual-energy X-ray absorptiometry (DXA), at phalanx with AccuDXA (Schick) as well as proximal and distal forearm with pDXA (Norland) in 835 women ranging in age from 20 to 85 yr. In receiver operating characteristic (ROC) curves, where a positive case was defined as a T-score < or = -2.5 either on spine or femoral neck, the areas under the curve were not significantly different between sites. At a T-score of -2.5 as determined by each peripheral apparatus, sensitivity and specificity were, respectively, 0.39 and 0.95 for phalanx and 0.75 and 0.85 for proximal forearm whereas they were 0.42 and 0.96 for distal forearm. Using optimal absolute BMD cutoff values improved the results. Sensitivity and specificity were, respectively, 0.79 and 0.83 for phalanx at an absolute BMD value of 0.436 and 0.84 and 0.79 for proximal forearm at a value of 0.703, whereas they were 0.90 and 0.75 for distal forearm at a value of 0.208. Combining the two forearm measurements improves the results slightly. At cutoff values of 0.641 and 0.252, respectively for proximal and distal forearms, sensitivity was 0.83 and specificity was 0.84. Therefore, a peripheral measurement of BMD together with a good clinical evaluation of the osteoporosis risk profile of the patient, can be an interesting tool for the diagnosis of osteoporosis in areas where central DXA is not available.

Risedronate rapidly reduces the risk for nonvertebral fractures in women with postmenopausal osteoporosis.

Prevention of nonvertebral fractures, which account for a substantial proportion of osteoporotic fractures, is an important goal of osteoporosis treatment. Risedronate, a pyridinyl bisphosphonate, significantly reduces clinical vertebral fracture incidence within 6 months. To determine the effect of risedronate on osteoporosis-related nonvertebral fractures, data from four large, randomized, double-blind, placebo-controlled, Phase III studies were pooled and analyzed. The population analyzed consisted of postmenopausal women, with and without vertebral fractures, who had low bone mineral density (lumbar spine T-score <-2.5). Patients received placebo (N = 608) or risedronate 5 mg daily (N = 564) for 1 to 3 years. At baseline, 58% had at least one prevalent vertebral fracture, and the mean lumbar spine T-score was -3.4. Among placebo-treated patients, the presence of prevalent vertebral fractures did not increase the risk of incident nonvertebral fractures overall, although fractures of the humerus and hip and pelvis were more common in patients who had prevalent vertebral fractures than in those who did not. Risedronate 5 mg significantly reduced the incidence of nonvertebral fractures within 6 months compared with control. After 1 year, nonvertebral fracture incidence was reduced by 74% compared with control ( P = 0.001), and after 3 years, the incidence was reduced by 59% ( P = 0.002). The results indicate that risedronate significantly reduces the incidence of osteoporosis-related nonvertebral fractures within 6 months.

Quantitative immunogold labeling of bone sialoprotein and osteopontin in methylmethacrylate-embedded rat bone.

Methylmethacrylate (MMA) embedding of undecalcified bone is routinely employed for histomorphometric analyses. Although MMA-embedded bone has been used for immunolabeling at the light microscopic level after removal of the resin, there are no such reports for electron microscopy. The aim of the present study was to determine whether MMA embedding can be used for ultrastructural immunolabeling and how it compares to LR White (LRW), an acrylic resin frequently used for immunocytochemistry of bone. Rat tibiae were fixed by vascular perfusion with aldehyde and embedded either in MMA or LRW resin. Thin sections were processed for postembedding protein A-gold immunolabeling with antibodies to rat bone sialoprotein (BSP) and osteopontin (OPN). The density of gold particles over bone was quantified. The density and distribution of immunolabeling for BSP and OPN respectively, were comparable between MMA and LRW. These results indicate that MMA performs as well as LRW for the ultrastructural immunolabeling of noncollagenous bone matrix proteins.

Positive effect of etidronate therapy is maintained after drug is terminated in patients using corticosteroids.

Following a 52-wk randomized controlled trial of intermittent cyclic etidronate therapy in patients using corticosteroids, we performed a 52-wk open-label trial of calcium alone in 114 corticosteroid-treated patients to determine whether the beneficial effect of etidronate is maintained after the drug is discontinued. All patients were given 500 mg/d of elemental calcium. Sixty-one and 53 patients made up the former placebo and etidronate groups, respectively. A total of 89 (98%) of patients in the former placebo and etidronate groups remained on corticosteroids throughout the second year. The mean (SE) percentage change in bone mineral density of the lumbar spine, femoral neck, and trochanter were compared between groups. The difference between groups in mean percentage change from baseline (wk 0, initiation of etidronate or placebo therapy) in the bone density of the lumbar spine, femoral neck, and trochanter, following 104 wk, was 3.8 (0.9), 3.0 (1.1), and 4.3 (1.1), respectively (p < 0.05, all sites), in favor of the former etidronate group. While not significant, the former placebo group demonstrated a slightly larger rate of decline in bone density over the second year than the former etidronate group at all three sites. Following the discontinuation of etidronate therapy, there was no accelerated bone loss and there was evidence of a residual protective effect in both the lumbar spine and femoral neck for up to 1 yr posttreatment.

Immunohistochemical detection of inducible nitric oxide synthase, nitrotyrosine and manganese superoxide dismutase following hyperglycemic focal cerebral ischemia.

We have characterized the temporal changes in iNOS, MnSOD and nitrotyrosine immune reactivity in a rat model of permanent middle cerebral artery occlusion under acute hyperglycemic or normoglycemic conditions followed by either 3- or 24-h recovery. We found that the macroscopic labeling pattern for all three antibodies colocalized with the ischemic core and penumbra which was determined by cresyl violet histological evaluation in adjacent sections. Hyperglycemia induced prior to ischemia resulted in earlier infarction which correlated with increased immunoreactivity for iNOS, MnSOD and nitrotyrosine. In the penumbral region of the frontal cortex, labeling of specific cell structures was largely limited to cortical neurons near the corpus callosum and was apparent earlier in the hyperglycemic rats. Increased polymorphonuclear leukocyte adhesion in blood vessels was observed at 24 h in the hyperglycemic group. At both of the recovery times studied, we observed only minor vascular staining for nitrotyrosine and none for iNOS. Our results are consistent with hyperglycemia resulting in an early and concomitant increase in both superoxide and nitric oxide production which can lead to peroxynitrite formation that then nitrates tyrosine residues. It would appear that hyperglycemic ischemia contributes to the early induction of key enzymes involved in nitric oxide bioavailability.