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Biomedical subjects

Solomon Epstein

Publications and source records attributed to Solomon Epstein.

14 recordsLinked to original sources
PubMed2006

Long-term proton pump inhibitor therapy and risk of hip fracture.

CONTEXT: Proton pump inhibitors (PPIs) may interfere with calcium absorption through induction of hypochlorhydria but they also may reduce bone resorption through inhibition of osteoclastic vacuolar proton pumps. OBJECTIVE: To determine the association between PPI therapy and risk of hip fracture. DESIGN, SETTING, AND PATIENTS: A nested case-control study was conducted using the General Practice Research Database (1987-2003), which contains information on patients in the United Kingdom. The study cohort consisted of users of PPI therapy and nonusers of acid suppression drugs who were older than 50 years. Cases included all patients with an incident hip fracture. Controls were selected using incidence density sampling, matched for sex, index date, year of birth, and both calendar period and duration of up-to-standard follow-up before the index date. For comparison purposes, a similar nested case-control analysis for histamine 2 receptor antagonists was performed. MAIN OUTCOME MEASURE: The risk of hip fractures associated with PPI use. RESULTS: There were 13,556 hip fracture cases and 135,386 controls. The adjusted odds ratio (AOR) for hip fracture associated with more than 1 year of PPI therapy was 1.44 (95% confidence interval [CI], 1.30-1.59). The risk of hip fracture was significantly increased among patients prescribed long-term high-dose PPIs (AOR, 2.65; 95% CI, 1.80-3.90; P<.001). The strength of the association increased with increasing duration of PPI therapy (AOR for 1 year, 1.22 [95% CI, 1.15-1.30]; 2 years, 1.41 [95% CI, 1.28-1.56]; 3 years, 1.54 [95% CI, 1.37-1.73]; and 4 years, 1.59 [95% CI, 1.39-1.80]; P<.001 for all comparisons). CONCLUSION: Long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture.

Aged↗
PubMed2006

Evidence that calcineurin is required for the genesis of bone-resorbing osteoclasts.

Here, we demonstrate that the Ca(2+)/calmodulin-sensitive phosphatase calcineurin is a necessary downstream mediator for osteoclast differentiation. Using quantitative PCR, we detected the calcineurin isoforms Aalpha, Abeta, Agamma (catalytic), and B1 (regulatory) in osteoclast precursor RAW-C3 cells. We found that, although the expression of these isoforms remained relatively unchanged during osteoclast differentiation, there was a profound increase in the expression of their primary substrate for calcineurin, nuclear factor of activated T cells (NFAT)c1. For gain-of-function studies, we incubated osteoclast precursors for 10 min with a calcineurin fusion protein (TAT-calcineurin Aalpha); this resulted in its receptorless influx into >90% of the precursor cells. A marked increase in the expression of the osteoclast differentiation markers tartrate-resistant acid phosphatase (TRAP) and integrin beta(3) followed. In addition, the expression of NFATc1, as well as the alternative substrate for calcineurin, IkappaBalpha, was significantly enhanced. Likewise, transfection with constitutively active NFAT resulted in an increased expression of both TRAP and integrin beta(3). In parallel loss-of-function studies, transfection with dominant-negative NFAT not only inhibited osteoclast formation but also reversed the induction of NFATc1, TRAP, and integrin beta(3) by TAT-calcineurin Aalpha. The expression of these markers was also inhibited by calcineurin Aalpha U1 small nuclear RNA, which significantly reduced calcineurin Aalpha mRNA and protein expression. Consistent with these observations, we observed a reduction in osteoclastogenesis in calcineurin Aalpha(-/-) cells and in osteoclast precursors treated with the calcineurin inhibitors cyclosporin A and FK506. Together, the gain- and loss-of-function experiments establish that calcineurin Aalpha is necessary for osteoclast formation from its precursor and that this occurs via an NFATc1-dependent mechanism.

Acid Phosphatase↗
PubMed2006

Ibandronate treatment for osteoporosis: rationale, preclinical, and clinical development of extended dosing regimens.

Ibandronate is a potent nitrogen-containing bisphosphonate available as a once-monthly oral formulation for the treatment and prevention of osteoporosis. Preclinical experiments with estrogen-depleted rats, dogs, and monkeys demonstrated the efficacy of daily and intermittent ibandronate dosing. Initial clinical trials explored the optimal dosing regimens for oral administration in humans. The Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE) and Monthly Oral Ibandronate in Ladies (MOBILE) trials demonstrated that long-term daily and intermittent administration of ibandronate was efficacious for increasing bone mineral density, reducing markers of bone turnover, and preventing fractures, while maintaining bone quality. These preclinical and clinical ibandronate trials provided progressive evidence that a simple, long interval dosing regimen could offer efficacy and safety comparable with currently available bisphosphonates. It is anticipated that once-monthly ibandronate may have a positive impact on patient adherence, and ultimately, on fracture protection in osteoporotic women.

Animals↗
PubMed2006

Update of current therapeutic options for the treatment of postmenopausal osteoporosis.

BACKGROUND: Osteoporosis is a common chronic condition in elderly women and is associated with decreased bone strength and an increased risk for fractures. As the incidence of osteoporotic fractures continues to rise, it is important to identify the most effective therapies for reducing patients' risk of fracture. OBJECTIVE: This article reviews the medication classes commonly used for treating osteoporosis and the efficacy, tolerability, and drug-interaction potential of specific medications. The evidence for the use of combination therapies is summarized, as are the agents under investigation. METHODS: Relevant articles were identified through a search of MEDLINE (August 1985-August 2005) using the terms osteoporosis, postmenopausal, fracture, and efficacy combined with drug therapy, calcium, vitamin D, estrogen, progesterone, selective estrogen modulators, calcitonin, strontium ranelate, bisphosphonates, alendronate, risedronate, ibandronate, pamidronate, parathyroid hormone, combination therapy, and zoledronic acid. The identified articles were reviewed for suitability, with priority given to meta-analyses. RESULTS: Among the therapeutic options for the treatment of osteoporosis, the bisphosphonates appear to provide the greatest antiresorptive efficacy, with some bisphosphonates providing 7% to 8% increases in bone mineral density and 60% to 70% decreases in markers of bone resorption. Bisphosphonates also may reduce the incidence of new vertebral fractures by 50% to 52%. CONCLUSIONS: Bisphosphonates are currently the first choice for the treatment of osteoporosis. Use of intermittent regimens of the newer bisphosphonates appears to be a promising alternative to administration of daily or weekly treatment.

Anabolic Agents↗
PubMed2006

Nonsteroid immune modulators and bone disease.

Glucocorticoids have been the main agents for preventing organ rejection,but unfortunately they possess serious side effects. Newer immunosuppressive agents have therefore been introduced to overcome these effects and have had a dramatic impact on reducing the incidence of organ rejection, enhancing donor organ acceptance, and hence patient survival posttransplantation. However, calcineurin inhibitors (CIs), such as cyclosporine and tacrolimus, also have serious effects causing rapid and severe bone loss in animal models and humans. The mechanism accounting for this action is unclear at present, but the role of T lymphocyte action via RANKL seems to be of essence in triggering bone loss. The mechanism is complex and in vitro studies often produce results that are opposite to those seen in vivo. In addition to acute, rapid, and severe bone loss (ARSBL), the clinical picture shows an extremely high incidence of fractures at all sites, and depends upon the organ transplanted, preexisting bone disease, interval before transplantation, and the dose and duration of multiple immunosuppressive drugs. Other immune-modifying drugs, such as azathioprine, mycophenolate mofetil, and sirolimus, which are used in conjunction with glucocorticoids and CIs have not been shown to promote bone loss experimentally or clinically. With the exception of glucocorticoids, all of the agents discussed here demand further investigation with regard to their effects on bone health in the clinical setting.

Bone Diseases↗
PubMed2006

Modeling of serum C-telopeptide levels with daily and monthly oral ibandronate in humans.

A previously validated kinetic-pharmacodynamic model was applied to changes in a marker of bone resorption (serum C-telopeptide cross-links of type I collagen [sCTX]) using data from a large-scale clinical trial of ibandronate (Monthly Oral iBandronate In LadiEs [MOBILE]). The model showed rapid and significant suppression of sCTX compared to baseline with daily and monthly ibandronate, and gradual recovery of sCTX levels between monthly doses. This modeled, post-dose oscillatory pattern of sCTX paralleled significant increases in BMD and was associated with an acceptable safety profile for patients in MOBILE, suggesting that the between-dose recovery of sCTX does not negatively affect the efficacy of once-monthly ibandronate.

Biomarkers↗
PubMed2005

Calcineurin regulates bone formation by the osteoblast.

Two of the most commonly used immunosuppressants, cyclosporine A and tacrolimus (FK506), inhibit the activity of a ubiquitously expressed Ca(2+)/calmodulin-sensitive phosphatase, calcineurin. Because both drugs also cause profound bone loss in humans and in animal models, we explored whether calcineurin played a role in regulating skeletal remodeling. We found that osteoblasts contained mRNA and protein for all isoforms of calcineurin A and B. TAT-assisted transduction of fusion protein TAT-calcineurin Aalpha into osteoblasts resulted in the enhanced expression of the osteoblast differentiation markers Runx-2, alkaline phosphatase, bone sialoprotein, and osteocalcin. This expression was associated with a dramatic enhancement of bone formation in intact calvarial cultures. Calcineurin Aalpha(-/-) mice displayed severe osteoporosis, markedly reduced mineral apposition rates, and attenuated colony formation in 10-day ex vivo stromal cell cultures. The latter was associated with significant reductions in Runx2, bone sialoprotein, and osteocalcin expression, paralleled by similar decreases in response to FK506. Together, the gain- and loss-of-function experiments indicate that calcineurin regulates bone formation through an effect on osteoblast differentiation.

Animals↗
PubMed2005

Bone metabolism in renal transplant patients treated with cyclosporine or sirolimus.

Sirolimus is a new immunosuppressive agent used as treatment to prevent acute renal allograft rejection. One of the complications of renal transplantation and subsequent long-term immunosuppression is bone loss associated with osteoporosis and consequent fracture. Two open-label, randomized, phase 2 studies comparing sirolimus versus cyclosporine (CsA) included indices of bone metabolism as secondary end-points. Markers of bone turnover, serum osteocalcin and urinary N-telopeptides, were measured over a 1-year period in 115 patients receiving either CsA or sirolimus as a primary therapy in combination with azathioprine and glucocorticoids (study A) or mycophenolate mofetil (MMF) and glucocorticoids (study B). Urinary excretion of N-telopeptides and the concentrations of serum osteocalcin were consistently higher in the CsA-treated patients and significantly different at week 24 for N-telopeptides and at weeks 12, 24, and 52 for osteocalcin. In conclusion, future trials are warranted to test whether a sirolimus-based regimen conserves bone mineral density compared with a CsA-based regimen.

Adult↗
PubMed2005

The roles of bone mineral density, bone turnover, and other properties in reducing fracture risk during antiresorptive therapy.

Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. Properties related to bone strength include rate of bone turnover, bone mineral density, geometry, microarchitecture, and mean degree of mineralization. These properties (with or without bone density) are sometimes collectively referred to as bone quality. Antiresorptive agents may reduce fracture risk by several separate but interrelated effects on these individual properties. For example, antiresorptive agents have been reported to reduce bone turnover, stabilize or increase bone density, preserve or improve microarchitecture, reduce the number or size of resorption sites, and improve mineralization. Although changes in bone architecture and mineralization are not currently measurable in clinical practice, bone turnover is assessed easily in vivo and affects the other bone properties. Moreover, antiresorptive therapies that produce larger decreases in bone turnover markers together with larger increases in bone mineral density are associated with greater reductions in fracture risk, especially at sites primarily composed of cortical bone such as the hip. Reductions in fracture risk are the most convincing evidence of good bone quality. Data from well-designed randomized clinical trials with up to 10 years of continuous antiresorptive therapy have shown that certain antiresorptive agents effectively reduce fracture risk and (together with extensive preclinical data) suggest no deleterious effects on bone quality.

Bone Density↗
PubMed2004

Ibandronate: a clinical pharmacological and pharmacokinetic update.

Ibandronate is a potent nitrogen-containing bisphosphonate. It has a strong affinity for bone mineral and potently inhibits osteoclast-mediated bone resorption. Ibandronate is effective for the treatment of hypercalcemia of malignancy, metastatic bone disease, postmenopausal osteoporosis, corticosteroid-induced osteoporosis, and Paget's disease. Oral ibandronate is rapidly absorbed (t(max) < 1 hour), with a low bioavailability (0.63%) that is further reduced (by up to 90%) in the presence of food. Ibandronate has a wide therapeutic index and is not metabolized and, therefore, has a low potential for drug interactions. Given its metabolic stability, ibandronate is eliminated from the blood by partitioning into bone (40%-50%) and through renal clearance (CL(R) approximately 60 mL/min). The CL(R) of ibandronate is linearly related to creatinine clearance. The sequestration of ibandronate in bone (V(D) > 90 L) results in a multiphasic elimination (t((1/2)) range approximately 10-60 hours), characterized by the slow release of ibandronate from the bone compartment. The potency of ibandronate and its sequestration into bone allow ibandronate to be developed as oral and intravenous injection formulations that can be administered with convenient extended between-dose intervals.

Biological Availability↗
PubMed2003

Disorders associated with acute rapid and severe bone loss.

We describe a constellation of bone diseases characterized by the common feature of acute, rapid, and severe bone loss accompanied by dramatic fracture rates. These disorders are poorly recognized, resulting mainly from systemic diseases, frailty, immobilization, and immunosuppressive drugs, such as glucocorticoids and the calcineurin inhibitors. The opportunity to prevent or treat fractures is commonly missed because they are often not detected. Ideally, patients need to be identified early and preventative therapy initiated promptly to avoid the rapid bone loss and fractures. The most effective therapy at present seems to be the bisphosphonates, particularly when bone resorption is predominant. However, more severe forms of bone loss that result from an osteoblastic defect and reduced bone formation may benefit potentially more from newer anabolic agents, such as recombinant human parathyroid hormone (rhPTH).

Bone Diseases, Metabolic↗
PubMed2002

Molecular cloning, expression, and function of osteoclastic calcineurin Aalpha.

This study explores the role of the calmodulin- and Ca(2+)-sensitive phosphatase calcineurin A in the control of bone resorption by mature osteoclasts. We first cloned full-length calcineurin Aalpha and Abeta cDNA from a rabbit osteoclast library. Sequence analysis revealed an approximately 95 and 86% homology between the amino acid and the nucleotide sequences, respectively, of the two isoforms. The two rabbit isoforms also showed significant homology with the mouse, rat, and human homologs. In situ RT-PCR showed evidence of high levels of expression of calcineurin Aalpha mRNA in freshly isolated rat osteoclasts. Semiquantitative analysis of staining intensity revealed no significant difference in calcineurin Aalpha expression in cells treated with vehicle vs. those treated with the calcineurin (activity) inhibitors cyclosporin A (8 x 10(-7) M) and FK506 (5 x 10(-9) and 5 x 10(-7) M). We then constructed a fusion protein comprising calcineurin Aalpha and TAT, a 12-amino acid-long arginine-rich sequence of the human immunodeficiency virus protein. Others have previously shown that the fusion of proteins to this sequence results in their receptor-less transduction into cells, including osteoclasts. Similarly, unfolding of the TAT-calcineurin Aalpha fusion protein by shocking with 8 M urea resulted in its rapid influx, within minutes, into as many as 90% of all freshly isolated rat osteoclasts, as was evident on double immunostaining with anti-calcineurin Aalpha and anti-TAT antibodies. Pit assays performed with TAT-calcineurin Aalpha-positive osteoclasts revealed a concentration-dependent (10-200 nM) attenuation of bone resorption in the absence of cell cytotoxicity or changes in cell number. TAT-hemaglutinin did not produce significant effects on bone resorption or cell number. The study suggests the following: 1) the 61-kDa protein phosphatase calcineurin Aalpha can be effectively tranduced into osteoclasts by using the TAT-based approach, and 2) the transduced protein retains its capacity to inhibit osteoclastic bone resorption.

Amino Acid Sequence↗
PubMed2002

A novel mechanism for coupling cellular intermediary metabolism to cytosolic Ca2+ signaling via CD38/ADP-ribosyl cyclase, a putative intracellular NAD+ sensor.

CD38 is an ectocyclase that converts NAD+ to the Ca2+-releasing second messenger cyclic ADP-ribose (cADPr). Here we report that in addition to CD38 ecto-catalysis, intracellularly expressed CD38 may catalyze NAD+-->cADPr conversion to cause cytosolic Ca2+ release. High levels of CD38 were found in the plasma membranes, endoplasmic reticulum, and nuclear membranes of osteoblastic MC3T3-E1 cells. More important, intracellular CD38 was colocalized with target ryanodine receptors. The cyclase also converted a NAD+ surrogate, NGD+, to its fluorescent product, cGDPr (Km approximately 5.13 microM). NAD+ also triggered a cytosolic Ca2+ signal. Similar results were obtained with NIH3T3 cells, which overexpressed a CD38-EGFP fusion protein. The Delta(-49)-CD38-EGFP mutant with a deleted amino-terminal tail and transmembrane domain appeared mainly in the mitochondria with an expected loss of its membrane localization, but the NAD+-induced cytosolic Ca2+ signal was preserved. Likewise, Ca2+ release persisted in cells transfected with the Myr-Delta(-49)-CD38-EGFP or Delta(-49)-CD38-EGFP-Fan mutants, both directed to the plasma membrane but in an opposite topology to the full-length CD38-EGFP. Finally, ryanodine inhibited Ca2+ signaling, indicating the downstream activation of ryanodine receptors by cADPr. We conclude that intracellularly expressed CD38 might link cellular NAD+ production to cytosolic Ca2+ signaling.

3T3 Cells↗