The detection of estrogen receptor-α (ERα) in osteoblasts and osteoclasts over 20 years ago suggested that direct effects of estrogens on both of these cell types are responsible for their beneficial effects on the skeleton, but the role of ERα in osteoblast lineage cells has remained elusive. In addition, estrogen activation of ERα in osteoclasts can only account for the protective effect of estrogens on the cancellous, but not the cortical, bone compartment that represents 80% of the entire skeleton. Here, we deleted ERα at different stages of differentiation in murine osteoblast lineage cells. We found that ERα in osteoblast progenitors expressing Osterix1 (Osx1) potentiates Wnt/β-catenin signaling, thereby increasing proliferation and differentiation of periosteal cells. Further, this signaling pathway was required for optimal cortical bone accrual at the periosteum in mice. Notably, this function did not require estrogens. The osteoblast progenitor ERα mediated a protective effect of estrogens against endocortical, but not cancellous, bone resorption. ERα in mature osteoblasts or osteocytes did not influence cancellous or cortical bone mass. Hence, the ERα in both osteoblast progenitors and osteoclasts functions to optimize bone mass but at distinct bone compartments and in response to different cues.

Osteoclasts resorb the mineralized matrices formed by chondrocytes or osteoblasts. The cytokine receptor activator of NFκB ligand (RANKL) is essential for osteoclast formation and thought to be supplied by osteoblasts or their precursors. However, RANKL is expressed by a variety of cell types and it is unclear which of them are essential sources for osteoclast formation. Here we have used a conditional mouse RANKL allele and a series of Cre-deleter strains to demonstrate that hypertrophic chondrocytes and osteocytes, both of which are embedded in matrix, are essential sources of the RANKL that controls mineralized cartilage resorption and bone remodeling, respectively. Moreover, osteocyte RANKL is responsible for the bone loss associated with unloading. Contrary to the current paradigm, RANKL produced by osteoblasts or their progenitors does not contribute to bone remodeling. These results suggest that the rate-limiting step of matrix resorption is controlled by cells embedded within the matrix itself.

Programs to reduce central line–associated bloodstream infections (CLABSIs) have improved the safety of hospitalized patients. Efforts are underway to disseminate these successes broadly to reduce other types of hospital-acquired infectious and noninfectious preventable harms. Unfortunately, the ability to broadly measure and prevent other types of preventable harms, especially infectious harms, needs enhancement. Moreover, an overarching research framework for creating and integrating evidence will help expedite the development of national prevention programs. This article outlines a 5-phase translational (T) framework to develop robust research programs that reduce preventable harm, as follows: phase T0, discover opportunities and approaches to prevent adverse health care events; phase T1, use T0 discoveries to develop and test interventions on a small scale; phase T2, broaden and strengthen the evidence base for promising interventions to develop evidence-based guidelines; phase T3, translate guidelines into clinical practice; and phase T4, implement and evaluate T3 work on a national and international scale. Policy makers should use this framework to fill in the knowledge gaps, coordinate efforts among federal agencies, and prioritize research funding.

Sustained parathyroid hormone (PTH) elevation stimulates bone remodeling (ie, both resorption and formation). The former results from increased RANKL synthesis, but the cause of the latter has not been established. Current hypotheses include release of osteoblastogenic factors from osteoclasts or from the bone matrix during resorption, modulation of the production and activity of osteoblastogenic factors from cells of the osteoblast lineage, and increased angiogenesis. To dissect the contribution of these mechanisms, 6-month-old Swiss-Webster mice were infused for 5 days with 470 ng/h PTH(1-84) or 525 ng/h soluble RANKL (sRANKL). Both agents increased osteoclasts and osteoblasts in vertebral cancellous bone, but the ratio of osteoblasts to osteoclasts and the increase in bone formation was greater in PTH-treated mice. Cancellous bone mass was maintained in mice receiving PTH but lost in mice receiving sRANKL, indicating that maintenance of balanced remodeling requires osteoblastogenic effects beyond those mediated by osteoclasts. Consistent with this contention, PTH, but not sRANKL, decreased the level of the Wnt antagonist sclerostin and increased the expression of the Wnt target genes Nkd2, Wisp1, and Twist1. Furthermore, PTH, but not sRANKL, increased the number of blood vessels in the bone marrow. Weekly injections of the RANKL antagonist osteoprotegerin at 10 µg/g for 2 weeks prior to PTH infusion eliminated osteoclasts and osteoblasts and prevented the PTH-induced increase in osteoclasts, osteoblasts, and blood vessels. These results indicate that PTH stimulates osteoclast-dependent as well as osteoclast-independent (Wnt signaling) pro-osteoblastogenic pathways, both of which are required for balanced focal bone remodeling in cancellous bone. © 2010 American Society for Bone and Mineral Research.

Both aging and loss of sex steroids have adverse effects on skeletal homeostasis, but whether and how they may influence each others negative impact on bone remains unknown. We report herein that both female and male C57BL/6 mice progressively lost strength (as determined by load-to-failure measurements) and bone mineral density in the spine and femur between the ages of 4 and 31 months. These changes were temporally associated with decreased rate of remodeling as evidenced by decreased osteoblast and osteoclast numbers and decreased bone formation rate; as well as increased osteoblast and osteocyte apoptosis, increased reactive oxygen species levels, and decreased glutathione reductase activity and a corresponding increase in the phosphorylation of p53 and p66shc, two key components of a signaling cascade that are activated by reactive oxygen species and influences apoptosis and lifespan. Exactly the same changes in oxidative stress were acutely reproduced by gonadectomy in 5-month-old females or males and reversed by estrogens or androgens in vivo as well as in vitro.We conclude that the oxidative stress that underlies physiologic organismal aging in mice may be a pivotal pathogenetic mechanism of the age-related bone loss and strength. Loss of estrogens or androgens accelerates the effects of aging on bone by decreasing defense against oxidative stress.

Summary

Aging or glucocorticoid excess decrease bone strength more than bone mass in humans and mice, but an explanation for this mismatch remains elusive. We report that aging in C57BL/6 mice was associated with an increase in adrenal production of glucocorticoids as well as bone expression of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1, the enzyme that activates glucocorticoids. Aging also decreased the volume of the bone vasculature and solute transport from the peripheral circulation to the lacunar-canalicular system. The same changes were reproduced by pharmacologic hyperglucocorticoidism. Furthermore, mice in which osteoblasts and osteocytes were shielded from glucocorticoids via cell-specific transgenic expression of 11β-HSD type 2, the enzyme that inactivates glucocorticoids, were protected from the adverse effects of aging on osteoblast and osteocyte apoptosis, bone formation rate and microarchitecture, crystallinity, vasculature volume, interstitial fluid, and strength. In addition, glucocorticoids suppressed angiogenesis in fetal metatarsals and hypoxia inducible factor 1α transcription and VEGF production in osteoblasts and osteocytes. These results, together with the evidence that dehydration of bone decreases strength, revealed that endogenous glucocorticoids increase skeletal fragility in old age as a result of cell autonomous effects on osteoblasts and osteocytes leading to interconnected decrements in bone angiogenesis, vasculature volume, and osteocyte-lacunar-canalicular fluid.

Estrogens diminish oxidative stress in bone and bone marrow, attenuate the generation of osteoblasts, and decrease the prevalence of mature osteoblast apoptosis. We have searched for the molecular mechanism of these effects using as tools a mouse model bearing an estrogen receptor α (ERα) knock-in mutation that prevents binding to DNA (ERαNERKI/−) and several osteoblast progenitor cell models expressing the wild-type ERα or the ERαNERKI/−. We report that the ability of estrogens to diminish the generation of reactive oxygen species, stimulate the activity of glutathione reductase, and decrease the phosphorylation of p66shc, as well as osteoblastogenesis and osteoblast number and apoptosis, were fully preserved in ERαNERKI/− mice, indicating that the DNA-binding function of the ERα is dispensable for all these effects. Consistent with the attenuation of osteoblastogenesis in this animal model, 17β-estradiol attenuated bone morphogenetic protein 2 (BMP-2)–induced gene transcription and osteoblast commitment and differentiation in murine and human osteoblastic cell lines. Moreover, 17β-estradiol attenuated BMP-2-induced differentiation of primary cultures of calvaria- or bone marrow–derived osteoblastic cells from ERαNERKI/− mice as effectively as in cells from wild-type littermates. The inhibitory effect of the hormone on BMP-2 signaling resulted from an ERα-mediated activation of ERKs and the phosphorylation of Smad1 at the linker region of the protein, which leads to proteasomal degradation. These results illustrate that the effects of estrogens on oxidative stress and the birth and death of osteoblasts do not require the binding of ERα to DNA response elements, but instead they result from the activation of cytoplasmic kinases. © 2010 American Society for Bone and Mineral Research

Hypophosphatasia is an inborn error of metabolism characterized by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) and skeletal disease due to impaired mineralization of cartilage and bone matrix. We investigated two independently generated TNSALP gene knock-out mouse strains as potential models for hypophosphatasia. Homozygous mice (−/−) had < 1% of wild-type plasma TNSALP activity; heterozygotes had the predicted mean of ~50%. Phosphoethanolamine, inorganic pyrophosphate, and pyridoxal 5′-phosphate are putative natural substrates for TNSALP and all were increased endogenously in the knock-out mice. Skeletal disease first appeared radiographically at ~10 days of age and featured worsening rachitic changes, osteopenia, and fracture. Histologic studies revealed developmental arrest of chondrocyte differentiation in epiphyses and in growth plates with diminished or absent hypertrophic zones. Progressive osteoidosis from defective skeletal matrix mineralization was noted but not associated with features of secondary hyperparathyroidism. Plasma and urine calcium and phosphate levels were unremarkable. Our findings demonstrate that TNSALP knock-out mice are a good model for the infantile form of hypophosphatasia and provide compelling evidence for an important role for TNSALP in postnatal development and mineralization of the murine skeleton.

Glucocorticoid administration is required for many inflammatory and autoimmune diseases, but use of these drugs is associated with skeletal side effects including bone loss, fractures, and osteonecrosis. Fractures often occur without a reduction in bone mineral density, strongly suggesting that glucocorticoid excess adversely affects other aspects of bone strength. Although the primary effects of glucocorticoid excess on the skeleton are directly on bone cells, a vascular connection between these cells and the loss of bone strength appears likely. This review examines this connection and how it may explain the greater decline in bone strength than loss of bone mass that occurs with glucocorticoid excess.

Introduction

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are increasingly isolated, with USA300-0114 being the predominant clone in the USA. Comparative whole genome sequencing of USA300 isolates collected in 2002, 2003 and 2005 showed a limited number of single nucleotide polymorphisms and regions of difference. This suggests that USA300 has undergone rapid clonal expansion without great genomic diversification. However, whole genome comparison of CA-MRSA has been limited to isolates belonging to USA300. The aim of this study was to compare the genetic repertoire of different CA-MRSA clones with that of HA-MRSA from the USA and Europe through comparative genomic hybridization (CGH) to identify genetic clues that may explain the successful and rapid emergence of CA-MRSA.

Materials and Methods

Hierarchical clustering based on CGH of 48 MRSA isolates from the community and nosocomial infections from Europe and the USA revealed dispersed clustering of the 19 CA-MRSA isolates. This means that these 19 CA-MRSA isolates do not share a unique genetic make-up. Only the PVL genes were commonly present in all CA-MRSA isolates. However, 10 genes were variably present among 14 USA300 isolates. Most of these genes were present on mobile elements.

Conclusion

The genetic variation present among the 14 USA300 isolates is remarkable considering the fact that the isolates were recovered within one month and originated from a confined geographic area, suggesting continuous evolution of this clone.

Summary

Aging increases oxidative stress and osteoblast apoptosis and decreases bone mass, whereas forkhead box O (FoxO) transcription factors defend against oxidative stress by activating genes involved in free radical scavenging and apoptosis. Conditional deletion of FoxO1, 3 and 4 in three month-old mice resulted in an increase in oxidative stress in bone and osteoblast apoptosis and a decrease in the number of osteoblasts, the rate of bone formation, and bone mass at cancellous and cortical sites. The effect of the deletion on osteoblast apoptosis was cell autonomous and resulted from oxidative stress. Conversely, overexpression of a FoxO3 transgene in mature osteoblasts decreased oxidative stress and osteoblast apoptosis, and increased osteoblast number, bone formation rate and vertebral bone mass. We conclude that FoxO-dependent oxidative defense provides a mechanism to handle the oxygen free radicals constantly generated by the aerobic metabolism of osteoblasts and is thereby indispensable for bone mass homeostasis.

Objective

To formulate a model for translating manual infection control surveillance methods to automated, algorithmic approaches.

Design

We propose a model for creating electronic surveillance algorithms by translating existing manual surveillance practices into automated electronic methods. Our model suggests that three dimensions of expert knowledge be consulted: clinical, surveillance, and informatics. Once collected, knowledge should be applied through a process of conceptualization, synthesis, programming, and testing.

Results

We applied our framework to central vascular catheter associated bloodstream infection surveillance, a major healthcare performance outcome measure. We found that despite major barriers such as differences in availability of structured data, in types of databases used and in semantic representation of clinical terms, bloodstream infection detection algorithms could be deployed at four very diverse medical centers.

Conclusions

We present a framework that translates existing practice—manual infection detection—to an automated process for surveillance. Our experience details barriers and solutions discovered during development of electronic surveillance for central vascular catheter associated bloodstream infections at four hospitals in a variety of data environments. Moving electronic surveillance to the next level—availability at a majority of acute care hospitals nationwide—would be hastened by the incorporation of necessary data elements, vocabularies and standards into commercially available electronic health records.

Background

When Staphylococcus aureus is isolated in urine, it is thought to usually represent hematogenous spread. Because such spread might have special clinical significance, we evaluated predictors and outcomes of S. aureus bacteriuria among patients with S. aureus bacteremia.

Methods

A case-control study was performed at John H. Stroger Jr. Hospital of Cook County among adult inpatients during January 2002-December 2006. Cases and controls had positive and negative urine cultures, respectively, for S. aureus, within 72 hours of positive blood culture for S. aureus. Controls were sampled randomly in a 1:4 ratio. Univariate and multivariable logistic regression analyses were done.

Results

Overall, 59% of patients were African-American, 12% died, 56% of infections had community-onset infections, and 58% were infected with methicillin-susceptible S. aureus (MSSA). Among 61 cases and 247 controls, predictors of S. aureus bacteriuria on multivariate analysis were urological surgery (OR = 3.4, p = 0.06) and genitourinary infection (OR = 9.2, p = 0.002). Among patients who died, there were significantly more patients with bacteriuria than among patients who survived (39% vs. 17%; p = 0.002). In multiple Cox regression analysis, death risks in bacteremic patients were bacteriuria (hazard ratio 2.9, CI 1.4-5.9, p = 0.004), bladder catheter use (2.0, 1.0-4.0, p = 0.06), and Charlson score (1.1, 1.1-1.3, p = 0.02). Neither length of stay nor methicillin-resistant Staphylococcus aureus (MRSA) infection was a predictor of S. aureus bacteriuria or death.

Conclusions

Among patients with S. aureus bacteremia, those with S. aureus bacteriuria had 3-fold higher mortality than those without bacteriuria, even after adjustment for comorbidities. Bacteriuria may identify patients with more severe bacteremia, who are at risk of worse outcomes.

BACKGROUND

Bisphosphonates decrease bone resorption and are commonly used to treat or prevent osteoporosis. However, the effect of bisphosphonates on their target cells remains enigmatic, since in patients benefiting from therapy, little change, if any, has been observed in the number of osteoclasts, which are the cells responsible for bone resorption.

METHODS

We examined 51 bone-biopsy specimens obtained after a 3-year, double-blind, randomized, placebo-controlled, dose-ranging trial of oral alendronate to prevent bone resorption among healthy postmenopausal women 40 through 59 years of age. The patients were assigned to one of five groups: those receiving placebo for 3 years; alendronate at a dose of 1, 5, or 10 mg per day for 3 years; or alendronate at a dose of 20 mg per day for 2 years, followed by placebo for 1 year. Formalin-fixed, undecalcified planar sections were assessed by bone histomorphometric methods.

RESULTS

The number of osteoclasts was increased by a factor of 2.6 in patients receiving 10 mg of alendronate per day for 3 years as compared with the placebo group (P<0.01). Moreover, the number of osteoclasts increased as the cumulative dose of the drug increased (r = 0.50, P<0.001). Twenty-seven percent of these osteoclasts were giant cells with pyknotic nuclei that were adjacent to superficial resorption cavities. Furthermore, giant, hypernucleated, detached osteoclasts with 20 to 40 nuclei were found after alendronate treatment had been discontinued for 1 year. Of these large cells, 20 to 37% were apoptotic, according to both their morphologic features and positive findings from in situ end labeling.

CONCLUSIONS

Long-term alendronate treatment is associated with an increase in the number of osteoclasts, which include distinctive giant, hypernucleated, detached osteoclasts that are undergoing protracted apoptosis.

Background

A 55-year-old woman with a 5-year history of osteoporosis treated for 4 years with an oral aminobisphosphonate presented with a recent vertebral fracture. A bone biopsy specimen revealed giant osteoclasts with more than 40 nuclear profiles.

Investigations

Bone mineral density determinations, measurement of serum 25-hydroxyvitamin D, intact parathyroid hormone, calcium, inorganic phosphorus, alkaline phosphatase and creatinine levels, urinary excretion levels of the N-telopeptide of type 1 collagen, and bone biopsy. Examination of the patient and review of the bone specimen.

Diagnosis

Giant osteoclasts after long-term bisphosphonate use, without evidence of malignancy.

Management

Interpretation of the bone biopsy specimen listed several bone disorders. The bone specimen was reviewed and the histological differential diagnosis was carefully considered. The giant osteoclasts were detached from bone and frequently apoptotic in a normal marrow stroma, with low-to-normal amounts of osteoid and osteoblasts. These features are typical of giant osteoclast formation after long-term aminobisphosphonate therapy. The patient was reassured that the bone findings were unlikely to be detrimental. Aminobisphosphonate treatment was reinstituted, and 1 year later the patient was asymptomatic.

Intermittent administration of parathyroid hormone (PTH) stimulates bone formation on the surface of cancellous and periosteal bone by increasing the number of osteoblasts. Previous studies of ours in mice demonstrated that intermittent PTH increases cancellous osteoblast number at least in part by attenuating osteoblast apoptosis, but the mechanism responsible for the anabolic effect of the hormone on periosteal bone is unknown. We report that daily injections of 100 ng/g of PTH(1–34) to 4–6 month old mice increased the number of osteoblasts on the periosteum of lumbar vertebrae by 2–3 fold as early as after 2 days. However, the prevalence of apoptotic periosteal osteoblasts was only 0.2% in vehicle treated animals, which is ~20-fold lower than is the case for cancellous osteoblasts. Moreover, PTH did not have a discernable effect on periosteal osteoblast apoptosis. Administration of BrdU for 4 days failed to label periosteal osteoblasts under either basal conditions or following administration of PTH. Cancellous osteoblasts, on the other hand, were labeled under basal conditions, but PTH did not increase the percentage of BrdU-positive cells. Thus, intermittent PTH does not increase cancellous or periosteal osteoblast number by stimulating the proliferation of osteoblast progenitors. Consistent with high turnover of cancellous osteoblasts as compared to that of periosteal osteoblasts, ganciclovir-induced ablation of replicating osteoblast progenitors in mice expressing thymidine kinase under the control of the 3.6kb rat Col1A1 promoter resulted in disappearance of osteoblasts from cancellous bone over a 7–14 day period, whereas periosteal osteoblasts were unaffected. However, 14 days of pre-treatment with ganciclovir prevented PTH anabolism on periosteal bone. We conclude that in cancellous bone, attenuation of osteoblast apoptosis by PTH increases osteoblast number because their rate of apoptosis is high, making this effect of the hormone profound. However, in periosteal bone where the rate of osteoblast apoptosis is low, PTH must exert pro-differentiating and/or pro-survival effects on post-mitotic pre-osteoblasts. Targeting the latter cells is an effective mechanism for increasing osteoblast number in periosteal bone where the production of osteoblasts from replicating progenitors is slow.

Increasing bacterial antimicrobial resistance has prompted physicians to choose broad-spectrum antimicrobials in order to reduce the likelihood of inactive empirical therapy. However, for bacteremic patients already receiving supportive care, it is unclear whether delay of active antimicrobial therapy significantly impacts patient outcomes. We performed a retrospective cohort study of patients with monomicrobial bloodstream infections at a large urban hospital in the United States from 2001 to 2006. We assessed the impact of delay of active antimicrobial therapy on mortality by using multivariable logistic regression modeling with and without propensity score methodology. We evaluated 1,523 episodes of monomicrobial bacterial bloodstream infections at our institution. Nine hundred eighty-three bacteremic episodes (64.5%) were treated with an active antimicrobial agent within 24 h of the index blood culture; the remaining 540 episodes (35.5%) were considered to have delay of active antimicrobial therapy. In adjusted analysis, among patients in the non-intensive-care-unit setting with an absolute neutrophil count (ANC) of <100 cells/μl, delay was associated with increased mortality (odds ratio [OR], 18.0; 95% confidence interval [CI], 2.84 to 114.5; P < 0.01); among intensive-care-unit patients with an ANC of <100 cells/μl, the effect of delay on mortality was nearly significant (OR, 5.56; 95% CI, 0.85 to 36.3; P = 0.07). However, for patients who were nonneutropenic (ANC, >500 cells/μl) or had ANCs of 100 to 500 cells/μl, delay was not associated with increased mortality. While the delay of active antimicrobial therapy was not significantly associated with higher mortality for most patients in this cohort, patients with severe neutropenia appeared to be vulnerable.

Connexin (Cx)43 is required for inhibition of osteocyte and osteoblast apoptosis by bisphosphonates in vitro. Herein, we evaluated its requirement for the in vivo actions of bisphosphonates using mice in which Cx43 was deleted specifically from osteocytes and osteoblasts (Cx43ΔOb–Ot/− mice). Effective removal of Cx43 was confirmed by the presence of the deleted form of the gene and by reduced mRNA and protein expression in osteoblastic cells and bones obtained from Cx43ΔOb–Ot/− mice. The amino-bisphosphonate alendronate (2.3 μmol/kg/d) was injected daily into 5-mo-old female mice (n = 6–11) for 31 days, starting 3 days before implantation of pellets releasing the glucocorticoid prednisolone (2.1 mg/kg/d). Cx43ΔOb–Ot/− mice and their littermates (Cx43fl/−, Cx43ΔOb–Ot/+, and Cx43fl/+) gained bone with similar kinetics and exhibited identical bone mass from 2 to 4.5 mo of age, indicating that Cx43 deletion from osteocytes and mature osteoblasts does not impair bone acquisition. In addition, prednisolone induced a similar increase in osteocyte and osteoblast apoptosis in Cx43ΔOb–Ot/− or in control Cx43fl/− littermates. However, whereas alendronate prevented prednisolone-induced apoptosis in control Cx43fl/− mice, it was ineffective in Cx43ΔOb–Ot/− mice. In contrast, alendronate inhibited glucocorticoid-induced bone loss in both type of animals, suggesting that inhibition of resorption is the predominant effect of alendronate against the early phase of glucocorticoid-induced bone loss. Taken together with earlier in vitro evidence, these findings show that Cx43 is required for the anti-apoptotic effect of bisphosphonates on osteocytes and osteoblasts.

Osteocytes, former osteoblasts buried within bone, are thought to orchestrate skeletal adaptation to mechanical stimuli. However, it remains unknown whether hormones control skeletal homeostasis through actions on osteocytes. Parathyroid hormone (PTH) stimulates bone remodeling and may cause bone loss or bone gain depending on the balance between bone resorption and formation. Herein, we demonstrate that transgenic mice expressing a constitutively active PTH receptor exclusively in osteocytes exhibit increased bone mass and bone remodeling, as well as reduced expression of the osteocyte-derived Wnt antagonist sclerostin, increased Wnt signaling, increased osteoclast and osteoblast number, and decreased osteoblast apoptosis. Deletion of the Wnt co-receptor LDL related receptor 5 (LRP5) attenuates the high bone mass phenotype but not the increase in bone remodeling induced by the transgene. These findings demonstrate that PTH receptor signaling in osteocytes increases bone mass and the rate of bone remodeling through LRP5-dependent and -independent mechanisms, respectively.

Two mouse strains, AKR/J and SAMP6, were assessed longitudinally for bone mineral density of the spine. They displayed very different time courses of bone accrual, with the SAMP6 strain reaching a plateau for vertebral BMD at 3 months, whereas AKR/J mice continued to increase spine BMD for at least 8 months. Among 253 F2 progeny of an AKR/J x SAMP6 cross, at 4 months of age the BMD variance was 5-6% of the mean, versus 15% for weight. Variance increased with age for every parameter measured, and was generally higher among males. The ratio of 6-month/4-month spine BMDs, termed ΔsBMD, had a normal distribution with 5.7% variance, and was largely independent of spine BMD (R=-0.23) or body weight (R=-0.12) at maturity. Heritability of the Δs BMD trait was calculated at 0.59. Genetic mapping identified two significant loci, both distinct from those observed for BMD at maturity - implying that different genes regulate skeletal growth vs. remodeling. A locus on the X chromosome, replicated in two mouse F2 populations (P<10-4 for combined discovery and confirmation), affects age-dependent BMD change for both spine and the full skeleton. Its position agrees with a very narrow region identified by association mapping for effects on lumbar bone density in postmenopausal women (Parsons et al., Hum Mol Genet 2005). A second locus, on chromosome 7, was observed in only one cross. Single-nucleotide polymorphisms (SNPs) are highly clustered near these loci, distinguishing the parental strains over only limited spans.

Recent studies have suggested that community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections are encroaching upon nosocomial settings. We assessed the performance characteristics of a rule using the antimicrobial phenotype to predict genotype. This rule could be applied for epidemiologic purposes to describe the trend in CA-MRSA infections over time.

BACKGROUND

Chronic administration of glucocorticoids is associated with bone loss and increased fracture risk, particularly in the trabecular bone of the vertebrae.

OBJECTIVE

To assess the prevalence of asymptomatic vertebral fractures in postmenopausal women undergoing long-term glucocorticoid therapy.

DESIGN AND INTERVENTION

This was a multicenter, cross-sectional outpatient study of postmenopausal women. Inclusion criteria included age >45 years, glucocorticoid therapy for ≥6 months with a cumulative dose ≥1.35 g of a prednisone equivalent, and diagnosis of rheumatoid arthritis, systemic lupus erythematosus, polymyalgia rheumatica, other vasculitides or connective tissue diseases, asthma, or chronic obstructive pulmonary disease. Patients with back pain, previous vertebral fracture, Paget’s disease, or using antiosteoporotic medication were excluded; however, calcium and vitamin D supplements were permitted. Participants underwent a medical interview that assessed socio-demographic factors, details of glucocorticoid therapy, and risk factors for osteoporosis. Health-related quality of life was evaluated with the European Foundation for Osteoporosis questionnaire. A back-function questionnaire rated the participants’ ability to perform activities of daily living. Vertebral fractures were identified from lateral and antero-posterior thoracolumbar radiographs. Hip and lumbar spine BMD were assessed by dual energy X-ray absorptiometry and quantitative ultrasound.

OUTCOME MEASURE

The primary outcome measure was the prevalence of asymptomatic vertebral fractures.

RESULTS

The study enrolled a total of 551 women (median age 65.2 years). Rheumatoid arthritis was the most common reason for glucocorticoid therapy (53.2%). One or more asymptomatic vertebral fractures were present in 37.02% of participants, whereas 14.42% had two or more fractures. A bimodal distribution of these fractures was observed, with peaks at the T7 and T11 thoracic vertebrae. The prevalence of asymptomatic vertebral fractures increased with age; 47.98% of participants ≥70 years of age presented with at least one fracture (P = 0.006). There was a strong association between polymyalgia rheumatica and fracture prevalence; 51.09% of affected patients had one or more fracture (P=0.012). When the data were adjusted for age, cumulative glucocorticoid dose, therapy duration, and fracture history, however, this association became weaker (43.20%), and was similar to the fracture prevalence of 43.36% observed in patients with other vasculitides or connective-tissue diseases. There was no correlation between fracture prevalence and cumulative glucocorticoid dose or therapy duration. Additionally, lumbar spine and hip BMD, calcaneal bone stiffness, and health-related quality of life were not associated with the number or severity of vertebral fractures. Time since menopause and history of nonvertebral fractures both showed a significant association with asymptomatic vertebral fracture (P<0.001 and P = 0.002, respectively). Back function score showed a modest association with the number of asymptomatic vertebral fractures.

CONCLUSION

A high prevalence of asymptomatic vertebral fractures was observed in postmenopausal women undergoing long-term glucocorticoid therapy, which suggests a need for careful evaluation of this patient subgroup.