Fracture rate associated with quality metric-based anti-osteoporosis treatment in glucocorticoid-induced osteoporosis.

UNLABELLED: Anti-osteoporosis medication (AOM) use in patients exposed to glucocorticoids is thought to reduce fractures. We found post-menopausal women using glucocorticoids for at least 90 days who also used an AOM within 90 days had 48 % fewer fractures by 1 year and 32 % fewer fractures by 3 years compared to non-AOM users. INTRODUCTION: The purpose of this study is to explore the effectiveness of adherence to quality measures by estimating the effect of anti-osteoporosis medication (AOM) initiation within 90 days after chronic (≥90 days) glucocorticoid (GC) therapy on osteoporotic fracture. METHODS: A new-user cohort was assembled using the MarketScan databases between 2000 and 2012. Included patients were female, age ≥50 at GC initiation, had a first GC fill daily dose ≥10 mg and persisted for at least 90 days. During a 365-day baseline period, patients were excluded for prior GC or AOM (bisphosphonate, denosumab, teriparatide) use, fracture, or cancer diagnosis. Initiators of an AOM in the 14 days pre- or 90 days post-GC fill were characterized as AOM users; those without, AOM non-users. Follow-up began 91 days after GC fill with patients followed until fracture, loss of continuous enrollment, initiation of AOM by AOM non-users, or end of study period. A propensity score was estimated for AOM receipt using all measured covariates and converted to a stabilized inverse probability of treatment weights (IPTW). Weighted hazard ratios (HR) and associated 95% confidence intervals (95% CI) were estimated using weighted Cox proportional hazard models. RESULTS: Of the 7885 women eligible for the study, 12.1% were AOM users. AOM use was associated with lower fracture incidence: weighted HR of 0.52 (95% CI 0.29, 0.94) at 1 year and weighted HR of 0.68 (95% CI 0.47, 0.99) at 3 years. CONCLUSIONS: AOM initiation within 90 days of chronic GC use was associated with a fracture reduction of 48% at 1 year and 32% at 3 years.

Cost-effectiveness of bone densitometry among Caucasian women and men without a prior fracture according to age and body weight.

UNLABELLED: We used a microsimulation model to estimate the threshold body weights at which screening bone densitometry is cost-effective. Among women aged 55-65 years and men aged 55-75 years without a prior fracture, body weight can be used to identify those for whom bone densitometry is cost-effective. INTRODUCTION: Bone densitometry may be more cost-effective for those with lower body weight since the prevalence of osteoporosis is higher for those with low body weight. Our purpose was to estimate weight thresholds below which bone densitometry is cost-effective for women and men without a prior clinical fracture at ages 55, 60, 65, 75, and 80 years. METHODS: We used a microsimulation model to estimate the costs and health benefits of bone densitometry and 5 years of fracture prevention therapy for those without prior fracture but with femoral neck osteoporosis (T-score ≤ -2.5) and a 10-year hip fracture risk of ≥3%. Threshold pre-test probabilities of low BMD warranting drug therapy at which bone densitometry is cost-effective were calculated. Corresponding body weight thresholds were estimated using data from the Study of Osteoporotic Fractures (SOF), the Osteoporotic Fractures in Men (MrOS) study, and the National Health and Nutrition Examination Survey (NHANES) for 2005-2006. RESULTS: Assuming a willingness to pay of $75,000 per quality adjusted life year (QALY) and drug cost of $500/year, body weight thresholds below which bone densitometry is cost-effective for those without a prior fracture were 74, 90, and 100 kg, respectively, for women aged 55, 65, and 80 years; and were 67, 101, and 108 kg, respectively, for men aged 55, 75, and 80 years. CONCLUSIONS: For women aged 55-65 years and men aged 55-75 years without a prior fracture, body weight can be used to select those for whom bone densitometry is cost-effective.

Follicle-stimulating hormone and bioavailable estradiol are less important than weight and race in determining bone density in younger postmenopausal women.

UNLABELLED: The association between follicle-stimulating hormone (FSH) and bone density was tested in 111 postmenopausal women aged 50-64 years. In the multivariable analysis, weight and race were important determinants of bone mineral density. FSH, bioavailable estradiol, and other hormonal variables did not show statistically significant associations with bone density at any site. INTRODUCTION: FSH has been associated with bone density loss in animal models and longitudinal studies of women. Most of these analyses have not considered the effect of weight or race. METHODS: We tested the association between FSH and bone density in younger postmenopausal women, adjusting for patient-related factors. In 111 postmenopausal women aged 50-64 years, areal bone mineral density (BMD) was measured at the lumbar spine, femoral neck, total hip, and distal radius using dual-energy X-ray absorptiometry, and volumetric BMD was measured at the distal radius using peripheral quantitative computed tomography (pQCT). Height, weight, osteoporosis risk factors, and serum hormonal factors were assessed. RESULTS: FSH inversely correlated with weight, bioavailable estradiol, areal BMD at the lumbar spine and hip, and volumetric BMD at the ultradistal radius. In the multivariable analysis, no hormonal variable showed a statistically significant association with areal BMD at any site. Weight was independently associated with BMD at all central sites (p < 0.001), but not with BMD or pQCT measures at the distal radius. Race was independently associated with areal BMD at all sites (p ≤ 0.008) and with cortical area at the 33% distal radius (p = 0.004). CONCLUSIONS: Correlations between FSH and bioavailable estradiol and BMD did not persist after adjustment for weight and race in younger postmenopausal women. Weight and race were more important determinants of bone density and should be included in analyses of hormonal influences on bone.

Clinical performance of osteoporosis risk assessment tools in women aged 67 years and older.

UNLABELLED: Clinical performance of osteoporosis risk assessment tools was studied in women aged 67 years and older. Weight was as accurate as two of the tools to detect low bone density. Discriminatory ability was slightly better for the OST risk tool, which is based only on age and weight. INTRODUCTION: Screening performance of osteoporosis risk assessment tools has not been tested in a large, population-based US cohort. METHODS: We conducted a diagnostic accuracy analysis of the Osteoporosis Self-assessment Tool (OST), Osteoporosis Risk Assessment Instrument (ORAI), Simple Calculated Osteoporosis Risk Estimation (SCORE), and individual risk factors (age, weight or prior fracture) to identify low central (hip and lumbar spine) bone mineral density (BMD) in 7779 US women aged 67 years and older participating in the Study of Osteoporotic Fractures. RESULTS: The OST had the greatest area under the receiver operating characteristic curve (AUC 0.76, 95% CI 0.74, 0.77). Weight had an AUC of 0.73 (95% CI 0.72, 0.75), which was >or=AUC values for the ORAI, SCORE, age or prior fracture. Using cut points from the development papers, the risk tools had sensitivities >or=85% and specificities

Vitamin D analogs versus native vitamin D in preventing bone loss and osteoporosis-related fractures: a comparative meta-analysis.

It has been suggested that early postmenopausal women and patients treated with steroids should receive preventive therapy (calcium, vitamin D, vitamin D analogs, estrogens, or bisphosphonates) to preserve their bone mineral density (BMD) and to avoid fragility fractures. We designed the present study to compare the effects of native vitamin D to its hydroxylated analogs alfacalcidol 1-alpha(OH)D and calcitriol 1,25(OH)(2)D. All randomized, controlled, double-blinded trials comparing oral native vitamin D and its analogs, alfacalcidol or calcitriol, to placebo or head-to-head trials in primary or corticosteroids-induced osteoporosis were included in the meta-analysis. Sources included the Cochrane Controlled Trials Register, EMBASE, MEDLINE, and a hand search of abstracts and references lists. The study period January 1985 to January 2003. Data were abstracted by two investigators, and methodological quality was assessed in a similar manner. Heterogeneity was extensively investigated. Results were expressed as effect-size (ES) for bone loss and as rate difference (RD) for fracture while allocated to active treatment or control. Publication bias was investigated. Fourteen studies of native vitamin D, nine of alfacalcidol, and ten of calcitriol fit the inclusion criteria. The two vitamin D analogs appeared to exert a higher preventive effect on bone loss and fracture rates in patients not exposed to glucocorticoids. With respect to BMD, vitamin D analogs versus placebo studies had an ES of 0.36 (P < 0.0001), whereas native vitamin D versus placebo had an ES of 0.17 (P = 0.0005), the interclass difference being highly significant (ANOVA-1, P < 0.05). When restricted to the lumbar spine, this intertreatment difference remained significant: ES = 0.43 (P = 0.0002) for vitamin D analogs and ES = 0.21 (P = 0.001) for native vitamin D (analysis of variance [ANOVA-1], P = 0.047). There were no significant differences regarding their efficacies on other measurement sites (ANOVA-1, P = 0.36). When comparing the adjusted global relative risks for fracture when allocated to vitamin D analogs or native vitamin D, alfacalcidol and calcitriol provided a more marked preventive efficacy against fractures: RD = 10% (95% Confidence interval [CI-2] to 17) compared to RD = 2% (95% CI, 1 to 2), respectively. The analysis of the spinal and nonspinal showed that fracture rates differed between the two classes, thereby confirming the benefits of vitamin D analogs, with significant 13.4% (95% CI 7.7 to 19.8) and. 6% (95% CI 1 to 12) lower fracture rates for vitamin D analogs, respectively. In patients receiving corticosteroid therapy, both treatments provided similar global ESs for BMD: ES = 0.38 for vitamin D analogs and ES = 0.41 for native vitamin D (ANOVA-1, P = 0.88). When restriced to spinal BMD, D analogs provided significant effects, whereas native vitamin D did not: ES = 0.43 (P < 0.0001) and ES = 0.33 (P = 0.21), respectively. The intertreatment difference was nonsignificant (ANOVA-1, P = 0.52). Neither D analogs for native vitamin D significantly prevented fractures in this subcategory of patients: RD = 2.6 (95%CI, -9.5 to 4.3) and RD = 6.4 (95%CI, -2.3 to 10), respectively. In head-to-head studies comparing D analogs and native vitamin D in patients receiving corticosteroids, significant effects favoring D analogs were found for femoral neck BMD: ES = 0.31 at P = 0.02 and spinal fractures: RD = 15% (95%CI, 6.5 to 25). Publication bias was not significant. Our analysis demonstrates a superiority of the D analogs atfacalcidol and calcitriol in preventing bone loss and spinal fractures in primary osteoporosis, including postmenopausal women. In corticosteroid-induced osteoporosis, the efficacy of D analogs differed depending on the comparative approach: indirect comparisons led to nonsignificant differences, whereas direct comparison did provide significant differences. In this setting, D analogs seem to prevent spinal fractures to a greater extent than do native vitamin D, but this assumption should be confirmed on a comprehensive basis in multiarm studies including an inactive comparator.

Validation and comparative evaluation of the osteoporosis self-assessment tool (OST) in a Caucasian population from Belgium.

BACKGROUND: Risk indices have been developed to identify women at risk of low bone mineral density (BMD) who should undergo BMD testing. AIM: To compare the performance of four risk indices in White ambulatory women in Belgium. DESIGN: Epidemiological cross-sectional study. METHODS: Records were analysed for 4035 postmenopausal White women without Paget's disease or advanced osteoarthritis, seen at an out-patient osteoporosis centre between January 1996 and September 1999. Osteoporosis risk index scores were compared to bone density T-scores. The ability of each risk index to identify women with low BMD (T-score < -2.0) or osteoporosis (T < -2.5) was evaluated. RESULTS: Using an Osteoporosis Self-Assessment Tool (OST) score <2 to recommend DXA referral, sensitivity ranged from 85% at the lumbar spine to 97% at the total hip to detect BMD T-scores of

Group A streptococcal sepsis and ovarian vein thrombosis after an uncomplicated vaginal delivery.

BACKGROUND: Group A streptococcal puerperal sepsis is an uncommon peripartum infection that can quickly progress to a fulminant, multisystemic infection and life-threatening toxin-mediated shock. This infection can be asymptomatic during a short hospital stay after a routine delivery. Early treatment with antibiotics might not alter the course of tissue destruction caused by the exotoxin A. METHODS: Literature searches were performed using the key words "puerperal infections," "streptococcal infections," "septic sacroiliitis," "postpartum septic arthritis," and "postpartum ovarian vein thrombosis." After patient consent was obtained, a report was prepared documenting the disease course, diagnosis, and treatment of a case of puerperal sepsis with multiple serious complications. RESULTS AND CONCLUSION: Puerperal sepsis occurs when streptococci colonizing the genital tract or acquired nosocomially invade the endometrium, adjacent structures, lymphatics, and bloodstream. A lack of symptoms early in the course of infection is common; later, minor somatic complaints can quickly progress to septic shock as effects of the exotoxin A are manifest. Women who complain of fever, pelvic pain, or unexplained systemic symptoms in the early postpartum period should have a detailed history and physical examination. All sites of suspected infection should be cultured. If sepsis is suspected, diagnostic imaging includes chest radiographs, contrast-enhanced computed tomographic scans, or magnetic resonance imaging to rule out ovarian vein thrombosis, pelvic abscess, or sacroiliac septic arthritis. Broad-spectrum antibiotic coverage must be initiated immediately after collection of cultures. Clindamycin plus a beta-lactam antibiotic is preferred for streptococcal toxic shock syndrome.

Confirmatory platelet-activating factor receptor antagonist trial in patients with severe gram-negative bacterial sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. BN 52021 Sepsis Investigator Group.

OBJECTIVE: To determine the efficacy and safety of using natural platelet-activating factor receptor antagonist (PAFra), BN 52021, to treat patients with severe Gram-negative bacterial sepsis. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial. SETTING: Fifty-nine academic medical center intensive care units in Europe. PATIENTS: Six hundred nine patients with severe sepsis, suspected to be related to Gram-negative bacterial infection, who received PAFra or placebo. INTERVENTIONS: Patients were randomized to receive either a dose of PAFra (120 mg iv) every 12 hrs over a 4-day period or placebo over a 4-day period. MEASUREMENTS AND MAIN RESULTS: The patients were well matched at study entry for severity of illness and for risk factors known to influence the outcome of sepsis. Among all randomized patients, the 28-day, all-cause mortality rate was 49% (152/308) in the placebo group, and 47% (140/300) in the PAFra group (p=.50). When analyzed on the basis of the previously defined target population, the 28-day, all-cause mortality rate was 50% (115/232) in the placebo group and 44% (94/212) in the PAFra group, yielding a 12% reduction in mortality rate (p=.29). In patients with documented infection involving other organisms, there was no difference between treated and placebo groups. When the outcomes of organ dysfunctions were examined in the overall population and in the documented Gram-negative bacterial infection population, the number of patients who resolved hepatic dysfunction tended to be higher in the treated group than in the placebo group (p=.06). The number of adverse events reported were not different between the two groups. CONCLUSIONS: A 4-day administration of the studied PAFra (BN 52021) failed to demonstrate a statistically significant reduction in the mortality rate of patients with severe sepsis suspected to be related to Gram-negative bacterial infection. If PAFra treatment has any therapeutic activity in severe Gram-negative bacterial sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial.

Analysis of human articular chondrocyte CD44 isoform expression and function in health and disease.

Interactions between articular chondrocytes and components of the extracellular matrix are of potential importance in the normal function of cartilage and in the pathophysiology of arthritis. Little is known of the basis of these interactions, but cell adhesive molecules such as CD44 are likely to be involved. Immunohistology using six well-characterized anti-CD44 monoclonal antibodies demonstrated standard CD44 isoform (CD44H) expression by all chondrocytes in normal and osteoarthrotic (OA) cartilage but absence of the CD44E variant. Polymerase chain reaction (PCR) of reverse transcribed mRNA from monolayer cultures of normal and OA chondrocytes using primer sequences which span the region containing variably spliced exons produced a predominant band representing the standard form of CD44, which lacks the variable exons 6-15 (v1-v10). No product was seen at the expected size of the epithelial variant of CD44 (CD44v8-10). Use of exon-specific primers, however, showed expression of variant exons resulting in multiple minor isoforms. Standard CD44 was also shown to be the predominantly expressed isoform identified by immunoprecipitation, but human articular chondrocytes did not adhere to hyaluronan in vitro. Chondrocyte CD44 may function as an adhesion receptor for other matrix molecules such as fibronectin or collagen.

Chondrocyte heterogeneity: immunohistologically defined variation of integrin expression at different sites in human fetal knees.

During development and at maturity different forms of cartilage vary in morphology and macromolecular content. This reflects heterogeneity of chondrocyte activity, in part involving differential interactions with the adjacent extracellular matrix via specialized cell surface receptors such as integrins. We undertook an immunohistological study on a series of human fetal knee joints to assess variation in the expression of integrins by chondrocytes and potential matrix ligands in articular, epiphyseal, growth plate, and meniscal cartilage. The results show that articular chondrocytes (beta 1+, beta 5 alpha V+, alpha 1+, alpha 2+/-, alpha 5+, weakly alpha 6+, alpha V+) differed from epiphyseal (beta 1+, beta 5 alpha V+, alpha 1+/-, alpha 2+/-, alpha 5+, alpha 6+, alpha V+) growth plate (beta 1+, beta 5 alpha V+, alpha 1-, alpha 2-, alpha 5+, alpha 6+, alpha V+), and meniscal cells (beta 1+, beta 5 alpha V+, alpha 1+, strongly alpha 2+, alpha 5+, alpha 6+, alpha V+ in expression of integrin subunits. There was no expression of beta 3, beta 4, beta 6, or alpha 3 by chondrocytes. These results differ from previous reports on the expression of integrins by adult articular cartilage, where alpha 2 and alpha 6 are not seen. Variation in distribution of matrix ligands was also seen. Fibronectin, laminin and Type VI collagen were expressed in all cartilages but there was restricted expression of tenascin, ED-A and ED-B fibronectin isoforms (articular cartilage and meniscus), and vitronectin (absent from growth plate cartilage). Regulated expression of integrins by chondrocytes, associated with changes in the pericellular matrix composition, is of potential importance in control of cartilage differentiation and function in health and disease.

Prostaglandin production and metabolism in self-differentiating human fetal lung organ culture.

PGE2 and PGF2 alpha are released into the media of human fetal lung organ cultures in decreasing amounts with time. This decline in PGs is not due to culture failure or loss of synthetic capacity, which can be stimulated by fetal bovine serum, nor is it due to increased catabolism of PGE2 to 13,14-dihydro-15-keto-PGE2 (PGEM) or of PGF2 alpha to 13,14-dihydro-15-keto-PGF2 alpha (PGFM). Immunohistochemically reactive PGs are not retained within lung cells. Antisera against methyl-moximated derivatives of PGEM or PGFM and preceded by derivatization on tissue sections of PGs by methyl-moximation not only demonstrate the localization of PGEM and PGFM in epithelial cells and blood vessels, but also show an overall decline in immunoreactivity with time. In addition electron microscopy of uncultured fetal lung removed directly after termination reveals various degrees of mitochondrial damage and in some cases plasma membrane blebs which resolve during the period in culture and as fetal lung self-differentiates. It is proposed that oxidative and mechanical stresses, occurring during termination of pregnancy or tissue preparation, result in cell damage and increased lung prostaglandin production, which, although decreasing during culture as cells recover, is sufficient to trigger terminal self-differentiation.

Prostaglandins PGE2 and PGF2 alpha in human fetal lung: immunohistochemistry and release from organ culture.

Immunohistochemical studies in human fetal lung have shown that epithelial and endothelial cells are both strongly and equally reactive for PGE2. In contrast, epithelial PGF2 alpha reactivity varied between fetuses, in some as intense as endothelial staining and in others very much less. As lung organ cultures differentiated, the intensity of PGE2 staining declined in airways and blood vessels, although it was still weakly positive at 10 days. In contrast, epithelial cells rapidly became negative for PGF2 alpha, whereas PGF2 alpha positivity was retained in blood vessels, albeit less obviously. PGF2 alpha and PGE2 were released into the media of organ cultures in decreasing amounts as cultures progressed. Amounts of released PGF2 alpha were greater by 2- to 10-fold than PGE2. Our findings suggest that the endogenous production of prostaglandins by human fetal lung in organ culture has a key role in the self-differentiation process that occurs in the absence of sera or added growth factors or hormones.

Self-differentiation of human fetal lung organ culture: the role of prostaglandins PGE2 and PGF2 alpha.

Addition of PGE2, but not PGF2 alpha, to fetal lung organ cultures accelerates the process of self-differentiation with increased dilatation of terminal airsacs and differentiation of the epithelial lining. Indomethacin reduces the endogenous production by organ cultures of PGE2, PGF2 alpha, 13,14-dihydro-15-keto-PGE2, and 13,14-dihydro-15-keto-PGF2 alpha and retards the process of self-differentiation. Prolonged exposure of cultures to indomethacin results in cell necrosis. Indomethacin inhibition of self-differentiation can be reversed and accelerated by the addition of PGE2. Addition of PGF2 alpha in the presence of indomethacin prevents indomethacin-associated cell necrosis but does not accelerate dilatation or differentiation beyond that of cultures in sera-free media without additions. We propose that the endogenous production of PGE2 is a key process in the mechanism of self-differentiation of human fetal lung in organ culture.

Application of fluoroimmunoassay to cerebrospinal fluid immunoglobulin G and albumin.

Special solid-phase fluoroimmunoasssay protocols were used to measure the amount of immunoglobulin G (IgG) and albumin in 1,511 samples of cerebrospinal fluid. The fluoroimmunoassay is an inhibition test conducted on the surface of a plastic probe, whose fluorescence is inversely related to the concentration of spinal fluid IgG or albumin. A microcomputer interfaced with the fluorometer calculates the sample IgG or albumin from a calibration curve based on standard cerebrospinal fluid values. The test and interpretation take less than 90 min. Correlation coefficients for over 100 cerebrospinal fluid samples tested by both fluoroimmunoassay and radial immunodiffusion were: IgG, 0.90 (slope, 1.04); albumin, 0.95 (slope, 0.99). The within-run precision (coefficient of variation) was: IgG, 4.4%; albumin, 6.3%. Run-to-run precision on a midrange sample was: IgG, 7.7%, albumin, 11.7%. These findings establish the simplicity, speed, and precision of the modified fluoroimmunoassay system for specific cerebrospinal fluid proteins.