Treatment patterns in women with postmenopausal osteoporosis using abaloparatide: a real-world observational study.

Review of medical records from 173 women with osteoporosis who received abaloparatide treatment revealed that 96.0% had at least one visit for osteoporosis management and 55.5% had medication support group access. The most common reasons for discontinuing treatment were financial (31.2%) and tolerability (22.8%). Most patients (64.8%) completed treatment as prescribed. PURPOSE: Abaloparatide is approved for the treatment of women with postmenopausal osteoporosis at high risk for fracture. This study evaluated real-world treatment patterns for patients new to abaloparatide, regardless of osteoporosis treatment history. METHODS: Data for patients with ≥ 1 prescription for abaloparatide were collected retrospectively from six academic and clinical practice settings across the US. RESULTS: A total of 173 patients were enrolled (mean [SD] age, 69.8 [7.4] years). At the time of abaloparatide treatment initiation, 78.6% had received other osteoporosis medications. Mean (SD) time from discontinuation of osteoporosis medications prior to initiation of abaloparatide was 1.7 (3.2) years. Twenty-four months of follow-up data from the initiation date of abaloparatide was collected from 94.0% of patients and 6.0% of patients had 12-24 months of follow-up. During the follow-up period, 96.0% of patients had at least one visit for osteoporosis management and 55.5% had access to a medication support program. The median duration of therapy was 18.6 months and 105/162 (64.8%) completed abaloparatide treatment as prescribed. The most common reasons for treatment discontinuation were financial (31.2%) and tolerability (22.8%). Following completion of a course of treatment with abaloparatide, 82/162 (50.6%) patients transitioned to another osteoporosis medication. The median time between abaloparatide treatment course completion and the initiation of follow-on medication was 21 days. CONCLUSION: Most patients completed treatment with abaloparatide as prescribed, and over half continued with an antiresorptive agent. This favorable conduct may be the result of regular follow-up visits and accessibility to both medication and patient support services.

Comparison of the cost-effectiveness of sequential treatment with abaloparatide in US men and women at very high risk of fractures.

BACKGROUND: Osteoporotic-related fractures represent an increasing burden to patients, health care systems and society. AIMS: This study estimated cost-effectiveness of sequential treatment with abaloparatide (ABL) followed by alendronate (ALN) compared to relevant alternative strategies in US men and women aged 50 to 80 years at very high fracture risk (bone mineral density T-score ≤ - 2.5 and a recent fracture). METHODS: A lifetime Markov-based microsimulation model was used to estimate healthcare costs and quality-adjusted life years (QALYs). Comparators were sequential treatment with unbranded teriparatide (TPTD)/ALN, generic ALN monotherapy, and no treatment. Analyses were conducted based on initial fracture site (hip, vertebral, or any fracture) and treatment efficacy data (derived from clinical trials or a recent network meta-analysis). RESULTS: From all analyses completed, sequential ABL/ALN demonstrated more QALYs for lower healthcare costs versus unbranded TPTD/ALN. No treatment was dominated (higher costs for less QALYs) versus ALN monotherapy. Sequential ABL/ALN resulted in favorable cost-effectiveness (at US threshold of $150,000/QALY) versus generic ALN monotherapy in men aged ≥ 50 years with any fracture type, women aged ≥ 65 years with any fracture type, and women aged ≥ 55 years having a hip or vertebral fracture. DISCUSSION: Similar cost-effectiveness of sequential ABL/ALN versus unbranded TPTD/ALN, ALN monotherapy, and no treatment was observed in both US men and women at very high fracture risk, with a moderate improvement in cost-effectiveness in men versus women and in patients with a hip or vertebral fracture. CONCLUSIONS: Sequential therapy with ABL/ALN was cost-effective in US men and women at very high risk of fractures.

Development and biophysical characterization of a humanized FSH-blocking monoclonal antibody therapeutic formulated at an ultra-high concentration.

Highly concentrated antibody formulations are oftentimes required for subcutaneous, self-administered biologics. Here, we report the development of a unique formulation for our first-in-class FSH-blocking humanized antibody, MS-Hu6, which we propose to move to the clinic for osteoporosis, obesity, and Alzheimer's disease. The studies were carried out using our Good Laboratory Practice (GLP) platform, compliant with the Code of Federal Regulations (Title 21, Part 58). We first used protein thermal shift, size exclusion chromatography, and dynamic light scattering to examine MS-Hu6 concentrations between 1 and 100 mg/mL. We found that thermal, monomeric, and colloidal stability of formulated MS-Hu6 was maintained at a concentration of 100 mg/mL. The addition of the antioxidant L-methionine and chelating agent disodium EDTA improved the formulation's long-term colloidal and thermal stability. Thermal stability was further confirmed by Nano differential scanning calorimetry (DSC). Physiochemical properties of formulated MS-Hu6, including viscosity, turbidity, and clarity, confirmed with acceptable industry standards. That the structural integrity of MS-Hu6 in formulation was maintained was proven through Circular Dichroism (CD) and Fourier Transform Infrared (FTIR) Spectroscopy. Three rapid freeze-thaw cycles at -80 °C/25 °C or -80 °C/37 °C further revealed excellent thermal and colloidal stability. Furthermore, formulated MS-Hu6, particularly its Fab domain, displayed thermal and monomeric storage stability for more than 90 days at 4°C and 25°C. Finally, the unfolding temperature (Tm) for formulated MS-Hu6 increased by >4.80 °C upon binding to recombinant FSH, indicating highly specific ligand binding. Overall, we document the feasibility of developing a stable, manufacturable and transportable MS-Hu6 formulation at a ultra-high concentration at industry standards. The study should become a resource for developing biologic formulations in academic medical centers.

Development and Biophysical Characterization of a Humanized FSH-Blocking Monoclonal Antibody Therapeutic Formulated at an Ultra-High Concentration.

Highly concentrated antibody formulations are oftentimes required for subcutaneous, self-administered biologics. Here, we report the creation of a unique formulation for our first-in- class FSH-blocking humanized antibody, MS-Hu6, which we propose to move to the clinic for osteoporosis, obesity, and Alzheimer's disease. The studies were carried out using our Good Laboratory Practice (GLP) platform, compliant with the Code of Federal Regulations (Title 21, Part 58). We first used protein thermal shift, size exclusion chromatography, and dynamic light scattering to examine MS-Hu6 concentrations between 1 and 100 mg/mL. We found that thermal, monomeric, and colloidal stability of formulated MS-Hu6 was maintained at a concentration of 100 mg/mL. The addition of the antioxidant L-methionine and chelating agent disodium EDTA improved the formulation's long-term colloidal and thermal stability. Thermal stability was further confirmed by Nano differential scanning calorimetry (DSC). Physiochemical properties of formulated MS-Hu6, including viscosity, turbidity, and clarity, conformed with acceptable industry standards. That the structural integrity of MS-Hu6 in formulation was maintained was proven through Circular Dichroism (CD) and Fourier Transform Infrared (FTIR) spectroscopy. Three rapid freeze-thaw cycles at -80°C/25°C or -80°C/37°C further revealed excellent thermal and colloidal stability. Furthermore, formulated MS-Hu6, particularly its Fab domain, displayed thermal and monomeric storage stability for more than 90 days at 4°C and 25°C. Finally, the unfolding temperature (T m ) for formulated MS-Hu6 increased by >4.80°C upon binding to recombinant FSH, indicating highly specific ligand binding. Overall, we document the feasibility of developing a stable, manufacturable and transportable MS-Hu6 formulation at a ultra-high concentration at industry standards. The study should become a resource for developing biologic formulations in academic medical centers.

Cost-Effectiveness of Sequential Abaloparatide/Alendronate in Men at High Risk of Fractures in the United States.

BACKGROUND AND OBJECTIVES: Abaloparatide (ABL) significantly increases bone mineral density in men with osteoporosis similar to what was reported in postmenopausal women with osteoporosis. The cost effectiveness of sequential treatment with ABL followed by alendronate (ALN) in men at high fracture risk was compared to relevant alternative treatments. METHODS: A Markov-based microsimulation model based on a lifetime US healthcare decision maker perspective was developed to evaluate the cost (expressed in US$2021) per quality-adjusted life-years (QALYs) gained of sequential ABL/ALN. Comparators were sequential treatment unbranded teriparatide (TPTD)/ALN, generic ALN monotherapy, and no treatment. Discount rates of 3% were used. Consistent with practice guidelines, patients received 18 months of ABL or TPTD followed by ALN for 5 years, or 5 years of ALN monotherapy. Analyses were conducted in high-risk men aged over 50 years defined as having a bone mineral density T-score ≤-2.5 and a recent fracture. Time-specific risk of subsequent fracture after a recent fracture, incremental costs up to 5 years following fractures, real-world medication adherence, and mostly US men-specific data were included in the model. One-way and probabilistic sensitivity analyses were conducted to assess the robustness of results. RESULTS: Over the full age range, sequential ABL/ALN led to more QALYs for lower costs than sequential unbranded TPTD/ALN, while no treatment was dominated (more QALYs, lower costs) by ALN monotherapy. The costs per QALY gained of sequential ABL/ALN were lower than the US threshold of US$150,000 versus generic ALN monotherapy. The probabilities that sequential ABL/ALN was cost effective compared to ALN monotherapy were estimated at 51% in men aged 50 years and between 88 and 90% in those aged ≥ 60 years. CONCLUSIONS: Sequential therapy using ABL/ALN may be cost effective compared with generic ALN monotherapy in US men aged ≥ 50 years at high fracture risk, especially in those aged ≥ 60 years. Unbranded TPTD/ALN and no treatment were dominated interventions (less QALY, more costs) compared with ABL/ALN or ALN monotherapy.

Optimizing a therapeutic humanized follicle-stimulating hormone-blocking antibody formulation by protein thermal shift assay.

Biopharmaceutical products are formulated using several Food and Drug Administration (FDA) approved excipients within the inactive ingredient limit to maintain their storage stability and shelf life. Here, we have screened and optimized different sets of excipient combinations to yield a thermally stable formulation for the humanized follicle-stimulating hormone (FSH)-blocking antibody, MS-Hu6. We used a protein thermal shift assay in which rising temperatures resulted in the maximal unfolding of the protein at the melting temperature (Tm ). To determine the buffer and pH for a stable solution, four different buffers with a pH range from 3 to 8 were screened. This resulted in maximal Tm s at pH 5.62 for Fab in phosphate buffer and at pH 6.85 for Fc in histidine buffer. Upon testing a range of salt concentrations, MS-Hu6 was found to be more stable at lower concentrations, likely due to reduced hydrophobic effects. Molecular dynamics simulations revealed a higher root-mean-square deviation with 1 mM than with 100 mM salt, indicating enhanced stability, as noted experimentally. Among the stabilizers tested, Tween 20 was found to yield the highest Tm and reversed the salt effect. Among several polyols/sugars, trehalose and sucrose were found to produce higher thermal stabilities. Finally, binding of recombinant human FSH to MS-Hu6 in a final formulation (20 mM phosphate buffer, 1 mM NaCl, 0.001% w/v Tween 20, and 260 mM trehalose) resulted in a thermal shift (increase in Tm ) for the Fab, but expectedly not in the Fc domain. Given that we used a low dose of MS-Hu6 (1 µM), the next challenge would be to determine whether 100-fold higher, industry-standard concentrations are equally stable.

Bone circuitry and interorgan skeletal crosstalk.

The past decade has seen significant advances in our understanding of skeletal homeostasis and the mechanisms that mediate the loss of bone integrity in disease. Recent breakthroughs have arisen mainly from identifying disease-causing mutations and modeling human bone disease in rodents, in essence, highlighting the integrative nature of skeletal physiology. It has become increasingly clear that bone cells, osteoblasts, osteoclasts, and osteocytes, communicate and regulate the fate of each other through RANK/RANKL/OPG, liver X receptors (LXRs), EphirinB2-EphB4 signaling, sphingolipids, and other membrane-associated proteins, such as semaphorins. Mounting evidence also showed that critical developmental pathways, namely, bone morphogenetic protein (BMP), NOTCH, and WNT, interact each other and play an important role in postnatal bone remodeling. The skeleton communicates not only with closely situated organs, such as bone marrow, muscle, and fat, but also with remote vital organs, such as the kidney, liver, and brain. The metabolic effect of bone-derived osteocalcin highlights a possible role of skeleton in energy homeostasis. Furthermore, studies using genetically modified rodent models disrupting the reciprocal relationship with tropic pituitary hormone and effector hormone have unraveled an independent role of pituitary hormone in skeletal remodeling beyond the role of regulating target endocrine glands. The cytokine-mediated skeletal actions and the evidence of local production of certain pituitary hormones by bone marrow-derived cells displays a unique endocrine-immune-skeletal connection. Here, we discuss recently elucidated mechanisms controlling the remodeling of bone, communication of bone cells with cells of other lineages, crosstalk between bone and vital organs, as well as opportunities for treating diseases of the skeleton.

FSH-blocking therapeutic for osteoporosis.

Pharmacological and genetic studies over the past decade have established the follicle-stimulating hormone (FSH) as an actionable target for diseases affecting millions, namely osteoporosis, obesity, and Alzheimer's disease. Blocking FSH action prevents bone loss, fat gain, and neurodegeneration in mice. We recently developed a first-in-class, humanized, epitope-specific FSH-blocking antibody, MS-Hu6, with a KD of 7.52 nM. Using a Good Laboratory Practice (GLP)-compliant platform, we now report the efficacy of MS-Hu6 in preventing and treating osteoporosis in mice and parameters of acute safety in monkeys. Biodistribution studies using 89Zr-labeled, biotinylated or unconjugated MS-Hu6 in mice and monkeys showed localization to bone and bone marrow. The MS-Hu6 displayed a ß phase t½ of 7.5 days (180 hr) in humanized Tg32 mice. We tested 217 variations of excipients using the protein thermal shift assay to generate a final formulation that rendered MS-Hu6 stable in solution upon freeze-thaw and at different temperatures, with minimal aggregation, and without self-, cross-, or hydrophobic interactions or appreciable binding to relevant human antigens. The MS-Hu6 showed the same level of "humanness" as human IgG1 in silico and was non-immunogenic in ELISpot assays for IL-2 and IFN-γ in human peripheral blood mononuclear cell cultures. We conclude that MS-Hu6 is efficacious, durable, and manufacturable, and is therefore poised for future human testing.

Overview of Causality Assessment for Drug-Induced Liver Injury (DILI) in Clinical Trials.

Causality assessment for suspected drug-induced liver injury (DILI) during drug development and following approval is challenging. The IQ DILI Causality Working Group (CWG), in collaboration with academic and regulatory subject matter experts (SMEs), developed this manuscript with the following objectives: (1) understand and describe current practices; (2) evaluate the utility of new tools/methods/practice guidelines; (3) propose a minimal data set needed to assess causality; (4) define best practices; and (5) promote a more structured and universal approach to DILI causality assessment for clinical development. To better understand current practices, the CWG performed a literature review, took a survey of member companies, and collaborated with SMEs. Areas of focus included best practices for causality assessment during clinical development, utility of adjudication committees, and proposals for potential new avenues to improve causality assessment. The survey and literature review provided renewed understanding of the complexity and challenges of DILI causality assessment as well as the use of non-standardized approaches. Potential areas identified for consistency and standardization included role and membership of adjudication committees, standardized minimum dataset, updated assessment tools, and best practices for liver biopsy and rechallenge in the setting of DILI. Adjudication committees comprised of SMEs (i.e., utilizing expert opinion) remain the standard for DILI causality assessment. A variety of working groups continue to make progress in pursuing new tools to assist with DILI causality assessment. The minimum dataset deemed adequate for causality assessment provides a path forward for standardization of data collection in the setting of DILI. Continued progress is necessary to optimize and advance innovative tools necessary for the scientific, pharmaceutical, and regulatory community.

Romosozumab in Skeletally Mature Adults with a Fresh Unilateral Tibial Diaphyseal Fracture: A Randomized Phase-2 Study.

BACKGROUND: Romosozumab is an antibody that binds and inhibits sclerostin, thereby increasing bone formation and decreasing bone resorption. A double-blinded, randomized, phase-2, dose-finding trial was performed to evaluate the effect of romosozumab on the radiographic and clinical outcomes of surgical fixation of tibial diaphyseal fractures. METHODS: Patients (18 to 82 years old) were randomized 3:1:1:1:1:1:1:1:1:1 to a placebo or 1 of 9 romosozumab treatment groups. Patients received subcutaneous injections of romosozumab or the placebo postoperatively on day 1 and weeks 2, 6, and 12. The primary outcome was the time to radiographic evidence of healing ("radiographic healing") analyzed after the week-24 assessments had been completed for all patients. RESULTS: A total of 402 patients were randomized: 299 to the romosozumab group and 103 to the placebo group. The median time to radiographic healing (the primary outcome) ranged from 14.4 to 18.6 weeks in the romosozumab groups and was 16.4 weeks (95% confidence interval [CI]: 14.6 to 18.0 weeks) in the placebo group, which was not a significant difference. There was also no significant difference in the median time to clinical healing, no relationship between romosozumab dose/frequency and unplanned revision surgery, and no apparent treatment benefit in terms of physical function. The safety and tolerability profile of romosozumab was comparable with that of the placebo. CONCLUSIONS: Romosozumab did not accelerate tibial fracture-healing in this patient population. Additional studies of patients at higher risk for delayed healing are needed to explore the potential of romosozumab to accelerate tibial fracture-healing. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Teduglutide for the treatment of adults with intestinal failure associated with short bowel syndrome: pooled safety data from four clinical trials.

BACKGROUND: In multiple clinical studies, teduglutide reduced parenteral support (PS) with a consistent safety profile in adults with short bowel syndrome-associated intestinal failure (SBS-IF). The objective of this study was to assess adverse events (AEs) from a pooled data set. METHODS: Safety data from four prospective clinical trials of teduglutide in patients with SBS-IF were assimilated. AEs were evaluated in patient groups based on treatment received in each study and in populations stratified to create distinct subgroups based on aetiology, bowel anatomy and baseline PS volume requirements. RESULTS: Safety data are reported for up to 2.5 years, totalling 222 person-years exposure to teduglutide. In most patients, AEs were reported as mild or moderate in severity in all patient groups and occurred at comparable rates between patients who received teduglutide or placebo. Several common gastrointestinal AEs, including abdominal pain, nausea and abdominal distension, were reported more frequently earlier in the course of treatment, with their frequency declining over time. Fewer gastrointestinal AEs were reported in patients with vascular causes of SBS-IF and patients with most of their colon-in-continuity than in other patient subgroups. Across the patient stratification subgroups, the predominant treatment-emergent AEs for which patients receiving teduglutide had a significantly increased relative risk were abdominal distension and gastrointestinal stoma complication compared with patients receiving placebo. CONCLUSIONS: Teduglutide had a safety profile consistent with prior adult data and no new safety concerns were identified. The most frequently reported AEs were gastrointestinal in origin, consistent with the underlying disease condition and intestinotrophic actions of teduglutide. CLINICAL TRIAL REGISTRY INFORMATION: NCT00081458/EudraCT, 2004-000438-35; NCT00798967/EudraCT, 2008-006193-15; NCT00172185/EudraCT, 2004-000439-27; NCT00930644/EudraCT, 2009-011679-65.

A Randomized, Placebo-Controlled Study of Romosozumab for the Treatment of Hip Fractures.

BACKGROUND: Romosozumab is a bone-forming antibody that increases bone formation and decreases bone resorption. We conducted a double-blinded, randomized, phase-2, dose-finding trial to evaluate the effect of romosozumab on the clinical outcomes of open reduction and internal fixation of intertrochanteric or femoral neck hip fractures. METHODS: Patients (55 to 94 years old) were randomized 2:3:3:3 to receive 3 subcutaneous injections of romosozumab (70, 140, or 210 mg) or a placebo postoperatively on day 1 and weeks 2, 6, and 12. The primary end point was the difference in the mean timed "Up & Go" (TUG) score over weeks 6 to 20 for romosozumab versus placebo. Additional end points included the time to radiographic evidence of healing and the score on the Radiographic Union Scale for Hip (RUSH). RESULTS: A total of 332 patients were randomized: 243 to receive romosozumab (70 mg, n = 60; 140 mg, n = 93; and 210 mg, n = 90) and 89 to receive a placebo. Although TUG scores improved during the study, they did not differ significantly between the romosozumab and placebo groups over weeks 6 to 20 (p = 0.198). The median time to radiographic evidence of healing was 16.4 to 16.9 weeks across treatment groups. The RUSH scores improved over time across treatment groups but did not differ significantly between the romosozumab and placebo groups. The overall safety and tolerability profile of romosozumab was comparable with that of the placebo. CONCLUSIONS: Romosozumab did not improve the fracture-healing-related clinical and radiographic outcomes in the study population. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized, Double-Blind, Phase 2, Parallel Group Study.

Over 12 months, romosozumab increased bone formation and decreased bone resorption, resulting in increased bone mineral density (BMD) in postmenopausal women with low BMD (NCT00896532). Herein, we report the study extension evaluating 24 months of treatment with romosozumab, discontinuation of romosozumab, alendronate followed by romosozumab, and romosozumab followed by denosumab. Postmenopausal women aged 55 to 85 years with a lumbar spine (LS), total hip (TH), or femoral neck T-score ≤-2.0 and ≥-3.5 were enrolled and randomly assigned to placebo, one of five romosozumab regimens (70 mg, 140 mg, 210 mg monthly [QM]; 140 mg Q3M; 210 mg Q3M) for 24 months, or open-label alendronate for 12 months followed by romosozumab 140 mg QM for 12 months. Eligible participants were then rerandomized 1:1 within original treatment groups to placebo or denosumab 60 mg Q6M for an additional 12 months. Percentage change from baseline in BMD and bone turnover markers (BTMs) at months 24 and 36 and safety were evaluated. Of 364 participants initially randomized to romosozumab, placebo, or alendronate, 315 completed 24 months of treatment and 248 completed the extension. Romosozumab markedly increased LS and TH BMD through month 24, with largest gains observed with romosozumab 210 mg QM (LS = 15.1%; TH = 5.4%). Women receiving romosozumab who transitioned to denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels with placebo. With romosozumab 210 mg QM, bone formation marker P1NP initially increased after treatment initiation and gradually decreased to below baseline by month 12, remaining below baseline through month 24; bone resorption marker ß-CTX rapidly decreased after treatment, remaining below baseline through month 24. Transition to denosumab further decreased both BTMs, whereas after transition to placebo, P1NP returned to baseline and ß-CTX increased above baseline. Adverse events were balanced between treatment groups through month 36. These data suggest that treatment effects of romosozumab are reversible upon discontinuation and further augmented by denosumab. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

Pharmacokinetic equivalence, comparable safety, and immunogenicity of an adalimumab biosimilar product (M923) to Humira in healthy subjects.

The aims of this randomized, double-blind, three-arm, single-dose study were to demonstrate pharmacokinetic (PK) equivalence of the adalimumab biosimilar M923 (hereafter referred to as "M923") to each of 2 reference products, and to assess M923's safety and immunogenicity. Primary PK endpoints were maximum observed concentration (Cmax ), area under the curve (AUC) from time 0 extrapolated to infinity (AUC0-inf ), and AUC from time 0 to 336 hours (AUC0-336 ). Secondary endpoints included safety and immunogenicity assessments. Healthy subjects were randomized 1:1:1 to receive a 40-mg dose of M923 (n = 107); adalimumab US Humira (n = 105), hereafter referred to as "US Humira"; or adalimumab EU Humira (n = 103), hereafter referred to as "EU Humira." PK equivalence was demonstrated for all primary PK endpoints. Geometric least squares means ratios (GMRs) for Cmax , AUC0-inf , and AUC0-336 were 99.4, 100.9, and 100.5, respectively, between the M923 and EU Humira arms and 102.6, 104.2, and 102.9 between the M923 and US Humira arms. The 90% confidence intervals of the GMRs for all PK endpoints were within prespecified confidence bounds of 80%-125%. Adverse event rates were similar across the M923 (47.7%), US Humira (50.9%), and EU Humira (53.3%) arms and were generally mild (73.7%) or moderate (22.0%). The proportion of subjects with a confirmed antidrug antibody (ADA) response was similar across study arms. This study demonstrated bioequivalent PK among M923, US Humira, and EU Humira and demonstrated that the PK parameters were consistent with similar safety and tolerability profile and ADA response rates.

Balancing benefits and risks of glucocorticoids in rheumatic diseases and other inflammatory joint disorders: new insights from emerging data. An expert consensus paper from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).

PURPOSE: This consensus review article considers the question of whether glucocorticoid (GC) therapy is still relevant in the treatment of rheumatic diseases, with a particular focus on rheumatoid arthritis (RA), and whether its side effects can be adequately managed. Recent basic and clinical research on the molecular, cellular and clinical effects of GCs have considerably advanced our knowledge in this field. An overview of the subject seems appropriate. METHODS: This review is the result of a multidisciplinary expert working group, organised by European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. The recent literature was surveyed and the salient evidence synthetized. RESULTS: The pathophysiological basis of RA (and other inflammatory rheumatic diseases) now strongly implicates the adaptive immune system in addition to innate mechanisms. The molecular effect of GCs and differential GC sensitivity is better understood, although exploiting this knowledge is still in its infancy. The newer treatment strategies of early and aggressive control of RA have gr eatly improved clinical outcomes, but improvements are still possible. Newer targeted anti-inflammatory drugs have made an important impact, yet they too are associated with numerous side effects. DISCUSSION: Short durations of moderate doses of GCs are generally well tolerated and have a positive benefit/risk ratio. Patients should be assessed for fracture risk and bone preserving agents and be prescribed calcium and vitamin D supplementation. CONCLUSIONS: Within a strategy of a disease modifying approach to inflammatory disease, combination therapy including a GC is effective approach.

Sclerostin: how human mutations have helped reveal a new target for the treatment of osteoporosis.

In the 1990s there was a tremendous mood of optimism among pharmaceutical scientists that identification of disease-associated variations in the human genome would result in a surge of new drug targets (the 'gene-to-drug' mantra). To date the expected deluge of new drugs has not arrived. However, a small number of drugs arising directly from the study of rare human disorders showing Mendelian inheritance are now entering late stage clinical trials. Here we describe the advantages of this approach and discuss the background and early clinical trial findings with antibodies directed at a target identified in this way.

Safety and efficacy of WC2031 versus vibramycin for the treatment of uncomplicated urogenital Chlamydia trachomatis infection: a randomized, double-blind, double-dummy, active-controlled, multicenter trial.

BACKGROUND: Recent studies have raised concern about efficacy of azithromycin for Chlamydia trachomatis infection. Research investigating new antibiotic regimens for chlamydia has been sparse, especially regimens that may reduce adherence difficulties with the recommended twice-daily doxycycline regimen. METHODS: We conducted a randomized, double-blind, double-dummy, active-controlled, multicenter trial with the objective of evaluating the safety and efficacy of WC2031 (doxycycline hyclate delayed-release 200-mg tablet) orally once daily for 7 days versus Vibramycin (doxycycline hyclate capsule) 100 mg orally twice daily for 7 days for treatment of uncomplicated urogenital chlamydia. Men and nonpregnant women aged 19-45 years with a urogenital chlamydial diagnosis or a sexual partner with chlamydia were eligible. The primary outcome was microbial cure by nucleic acid amplification testing at day 28. Noninferiority of WC2031 was inferred if the lower limit of the 95% confidence interval (CI) of the difference in cure rates was >-10%. RESULTS: A total of 495 subjects were randomized. The modified intent-to-treat (mITT) population with evaluable efficacy consisted of 323 subjects. Baseline patient characteristics did not differ between the mITT groups. Microbial cure rates for WC2031 were 95.5% (95% CI, 92.3-98.8) versus 95.2% (95% CI, 92.0-98.4) for Vibramycin (95% CI for the difference in cure rates, -4.3% to 4.9%). Types of adverse events were comparable. Nausea and vomiting occurred less frequently with WC2031 than with Vibramycin (13% vs 21% and 8% vs 12%, respectively). CONCLUSIONS: WC2031 was noninferior to Vibramycin for uncomplicated urogenital chlamydia treatment, better tolerated, and demonstrated comparable safety. WC2031 could improve treatment adherence over twice-daily Vibramycin. CLINICAL TRIALS REGISTRATION: NCT01113931.

Pharmacokinetics, safety, and tolerability of teduglutide, a glucagon-like peptide-2 (GLP-2) analog, following multiple ascending subcutaneous administrations in healthy subjects.

Teduglutide, a glucagon-like peptide-2 (GLP-2) analog, is currently being evaluated for the treatment of short-bowel syndrome, Crohn's disease, and other gastrointestinal disorders. The pharmacokinetics, safety, and tolerability of teduglutide in healthy subjects (N = 64) were assessed following daily subcutaneous administrations for 8 days in a double-blinded, randomized, placebo-controlled, ascending-dose study. Teduglutide treatments were administered as a 50-mg/mL (10, 15, 20, 25, 30, 50, and 80 mg) or 20-mg/mL (20 mg) formulation. Blood samples were collected on days 1 and 8, and plasma concentrations of teduglutide were measured using a liquid chromatography/tandem mass spectrometry method. Mean systemic exposures to teduglutide were very similar on days 1 and 8, suggesting minimal, if any, accumulation following once-daily repeated administrations. The apparent clearance of teduglutide following administration of the 50-mg/mL formulation was constant over the dose range, with mean values in male and female subjects of 0.155 and 0.159 L/h/kg, respectively. Peak plasma concentrations and total exposure of teduglutide after subcutaneous injection of a 20-mg/mL formulation (1.0 mL) were approximately 15% and 78% higher than those observed with the 50-mg/mL formulation (0.4 mL), respectively. Teduglutide treatments were safe and well tolerated. All but 1 adverse event was assessed as mild or moderate in severity. No relationship between teduglutide treatments and frequency of adverse events was observed, with the exception of injection site pain, which increased as a function of dose and injected volume. Results from the current study will assist in the dose selection in future efficacy studies.

Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.

BACKGROUND: A single infusion of intravenous zoledronic acid decreases bone turnover and improves bone density at 12 months in postmenopausal women with osteoporosis. We assessed the effects of annual infusions of zoledronic acid on fracture risk during a 3-year period. METHODS: In this double-blind, placebo-controlled trial, 3889 patients (mean age, 73 years) were randomly assigned to receive a single 15-minute infusion of zoledronic acid (5 mg) and 3876 were assigned to receive placebo at baseline, at 12 months, and at 24 months; the patients were followed until 36 months. Primary end points were new vertebral fracture (in patients not taking concomitant osteoporosis medications) and hip fracture (in all patients). Secondary end points included bone mineral density, bone turnover markers, and safety outcomes. RESULTS: Treatment with zoledronic acid reduced the risk of morphometric vertebral fracture by 70% during a 3-year period, as compared with placebo (3.3% in the zoledronic-acid group vs. 10.9% in the placebo group; relative risk, 0.30; 95% confidence interval [CI], 0.24 to 0.38) and reduced the risk of hip fracture by 41% (1.4% in the zoledronic-acid group vs. 2.5% in the placebo group; hazard ratio, 0.59; 95% CI, 0.42 to 0.83). Nonvertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%, and 77%, respectively (P<0.001 for all comparisons). Zoledronic acid was also associated with a significant improvement in bone mineral density and bone metabolism markers. Adverse events, including change in renal function, were similar in the two study groups. However, serious atrial fibrillation occurred more frequently in the zoledronic acid group (in 50 vs. 20 patients, P<0.001). CONCLUSIONS: A once-yearly infusion of zoledronic acid during a 3-year period significantly reduced the risk of vertebral, hip, and other fractures. (ClinicalTrials.gov number, NCT00049829.)

Distribution and correlates of serum 25-hydroxyvitamin D levels in a sample of patients with hip fracture.

BACKGROUND: Vitamin D deficiency is common in older populations, particularly during the winter months due to low levels of ultraviolet light exposure, and in nursing home residents. OBJECTIVE: The main objective of the current study was to assess the distribution of serum 25-hydroxyvitamin D and its correlates in a sample of men and women with recent hip fractures who were part of a large clinical trial. METHODS: This was a cross-sectional exploratory study of screened and ultimately randomized patients with hip fractures. They were part of a multinational (115 clinical centers in 20 countries), randomized, placebo-controlled, double-blind study testing the efficacy of a yearly IV bisphosphonate (zoledronic acid) in the prevention of new clinical fractures in patients with recent hip fracture repair. Levels of 25-hydroxyvitamin D, calcium, alkaline phosphatase, creatinine clearance, and albumin were measured at a screening visit using blood serum. Demographic variables were assessed by patient self-report. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry of the nonfractured hip. RESULTS: This report included 1174 screened patients (526 with vitamin D measured) and 655 (385 with vitamin D measured) patients randomized before the protocol amendment. In screened patients, levels of 25-hydroxyvitamin D were low (median, 14.7 ng/mL; interquartilc range, 7.6, 21.65). Overall, 51% were at or below the clinically meaningful threshold of 15 ng/mL. Among those patients randomized, the level of 25-hydroxyvitamin D was significantly positively related to male sex (rho, 0.13; P < 0.05), serum calcium (rho, 0.16; P < 0.01), and BMD at the femoral neck (rho, 0.22; P < 0.01) in bivariate analyses. Low serum 25-hydroxyvitamin D (<15 ng/mL) was related only to low serum calcium (odds ratio, 0.16; 95% CI, 0.05-0.52) in multivariable logistic models controlling for sex, age, race, body mass index, living at home, alkaline phosphatase, and creatinine clearance. CONCLUSIONS: We concluded that vitamin D insufficiency was a common problem in this population of elderly patients who had recently suffered a hip fracture. This insufficiency was related only to serum calcium in multivariable controlled models but cannot be reliably identified or excluded by measuring serum calcium alone. Physicians should be encouraged to check and monitor patients' serum levels of 25-hydroxyvitamin D.