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1.  Quality of Life in Sarcopenia and Frailty 
Calcified tissue international  2013;93(2):101-120.
The reduced muscle mass and impaired muscle performance that defines sarcopenia in older individuals is associated with increased risk of physical limitation and a variety of chronic diseases. It may also contribute to clinical frailty.
A gradual erosion of quality of life (QoL) has been evidenced in these individuals, although much of this research has been done using generic QoL instruments, particularly the SF-36, which may not be ideal in older populations with significant comorbidities.
This review and report of an expert meeting, presents the current definitions of these geriatric syndromes (sarcopenia and frailty). It then briefly summarises QoL concepts and specificities in older populations, examines the relevant domains of QoL and what is known concerning QoL decline with these conditions. It calls for a clearer definition of the construct of disability and argues that a disease-specific QoL instrument for sarcopenia/frailty would be an asset for future research and discusses whether there are available and validated components that could be used to this end and whether the psychometric properties of these instruments are sufficiently tested. It calls also for an approach using utility weighting to provide some cost estimates and suggests that a time trade off study could be appropriate.
doi:10.1007/s00223-013-9758-y
PMCID: PMC3747610  PMID: 23828275
Age; aging; muscle weakness; quality of life; malnutrition
2.  How to define responders in osteoarthritis 
Background
Osteoarthritis is a clinical syndrome of failure of the joint accompanied by varying degrees of joint pain, functional limitation, and reduced quality of life due to deterioration of articular cartilage and involvement of other joint structures.
Scope
Regulatory agencies require relevant clinical benefit on symptoms and structure modification for registration of a new therapy as a disease-modifying osteoarthritis drug (DMOAD). An international Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and International Osteoporosis Foundation was convened to explore the current burden of osteoarthritis, review current regulatory guidelines for the conduct of clinical trials, and examine the concept of responder analyses for improving drug evaluation in osteoarthritis.
Findings
The ESCEO considers that the major challenges in DMOAD development are the absence of a precise definition of the disease, particularly in the early stages, and the lack of consensus on how to detect structural changes and link them to clinically meaningful endpoints. Responder criteria should help identify progression of disease and be clinically meaningful. The ideal criterion should be sensitive to change over time and should predict disease progression and outcomes such as joint replacement.
Conclusion
The ESCEO considers that, for knee osteoarthritis, clinical trial data indicate that radiographic joint space narrowing >0.5 mm over 2 or 3 years might be a reliable surrogate measure for total joint replacement. On-going research using techniques such as magnetic resonance imaging and biochemical markers may allow the identification of these patients earlier in the disease process.
doi:10.1185/03007995.2013.792793
PMCID: PMC3690437  PMID: 23557069
magnetic resonance imaging; osteoarthritis; X-ray; responder; structure-modifying drug; pain
3.  Selective Determinants of Low Bone Mineral Mass in Adult Women with Anorexia Nervosa 
We investigated the relative effect of amenorrhea and insulin-like growth factor-I (sIGF-I) levels on cancellous and cortical bone density and size. We investigated 66 adult women with anorexia nervosa. Lumbar spine and proximal femur bone mineral density was measured by DXA. We calculated bone mineral apparent density. Structural geometry of the spine and the hip was determined from DXA images. Weight and BMI, but not height, as well as bone mineral content and density, but not area and geometry parameters, were lower in patients with anorexia nervosa as compared with the control group. Amenorrhea, disease duration, and sIGF-I were significantly associated with lumbar spine and proximal femur BMD. In a multiple regression model, we found that sIGF-I was the only significant independent predictor of proximal femur BMD, while duration of amenorrhea was the only factor associated with lumbar spine BMD. Finally, femoral neck bone mineral apparent density, but not hip geometry variables, was correlated with sIGF-I. In anorexia nervosa, spine BMD was related to hypogonadism, whereas sIGF-I predicted proximal femur BMD. The site-specific effect of sIGF-I could be related to reduced volumetric BMD rather than to modified hip geometry.
doi:10.1155/2013/897193
PMCID: PMC3619547  PMID: 23634145
5.  A botulinum toxin–derived targeted secretion inhibitor downregulates the GH/IGF1 axis 
The Journal of Clinical Investigation  2012;122(9):3295-3306.
Botulinum neurotoxins (BoNTs) are zinc endopeptidases that block release of the neurotransmitter acetylcholine in neuromuscular synapses through cleavage of soluble N-ethylmaleimide-sensitive fusion (NSF) attachment protein receptor (SNARE) proteins, which promote fusion of synaptic vesicles to the plasma membrane. We designed and tested a BoNT-derived targeted secretion inhibitor (TSI) targeting pituitary somatotroph cells to suppress growth hormone (GH) secretion and treat acromegaly. This recombinant protein, called SXN101742, contains a modified GH-releasing hormone (GHRH) domain and the endopeptidase domain of botulinum toxin serotype D (GHRH-LHN/D, where HN/D indicates endopeptidase and translocation domain type D). In vitro, SXN101742 targeted the GHRH receptor and depleted a SNARE protein involved in GH exocytosis, vesicle-associated membrane protein 2 (VAMP2). In vivo, administering SXN101742 to growing rats produced a dose-dependent inhibition of GH synthesis, storage, and secretion. Consequently, hepatic IGF1 production and resultant circulating IGF1 levels were reduced. Accordingly, body weight, body length, organ weight, and bone mass acquisition were all decreased, reflecting the biological impact of SXN101742 on the GH/IGF1 axis. An inactivating 2–amino acid substitution within the zinc coordination site of the endopeptidase domain completely abolished SXN101742 inhibitory actions on GH and IGF1. Thus, genetically reengineered BoNTs can be targeted to nonneural cells to selectively inhibit hormone secretion, representing a new approach to treating hormonal excess.
doi:10.1172/JCI63232
PMCID: PMC3428092  PMID: 22850878
6.  Adverse Reactions and Drug–Drug Interactions in the Management of Women with Postmenopausal Osteoporosis 
Calcified Tissue International  2011;89(2):91-104.
The pharmacological management of disease should involve consideration of the balance between the beneficial effects of treatment on outcome and the probability of adverse effects. The aim of this review is to explore the risk of adverse drug reactions and drug–drug interactions with treatments for postmenopausal osteoporosis. We reviewed evidence for adverse reactions from regulatory documents, randomized controlled trials, pharmacovigilance surveys, and case series. Bisphosphonates are associated with gastrointestinal effects, musculoskeletal pain, and acute-phase reactions, as well as, very rarely, atrial fibrillation, atypical fracture, delayed fracture healing, osteonecrosis of the jaw, hypersensitivity reactions, and renal impairment. Cutaneous effects and osteonecrosis of the jaw are of concern for denosumab (both very rare), though there are no pharmacovigilance data for this agent yet. The selective estrogen receptor modulators are associated with hot flushes, leg cramps, and, very rarely, venous thromboembolism and stroke. Strontium ranelate has been linked to hypersensitivity reactions and venous thromboembolism (both very rare) and teriparatide with headache, nausea, dizziness, and limb pain. The solidity of the evidence base depends on the frequency of the reaction, and causality is not always easy to establish for the very rare adverse reactions. Drug–drug interactions are rare. Osteoporosis treatments are generally safe and well tolerated, though they are associated with a few very rare serious adverse reactions. While these are a cause for concern, the risk should be weighed against the benefits of treatment itself, i.e., the prevention of osteoporotic fracture.
doi:10.1007/s00223-011-9499-8
PMCID: PMC3135835  PMID: 21637997
Osteoporosis; Adverse drug reaction; Drug–drug interaction; Bisphosphonate; Denosumab; SERM; Strontium ranelate; Teriparatide
7.  Cutaneous Side Effects of Antiosteoporosis Treatments 
Cutaneous adverse reactions are reported for many therapeutic agents and, in general, are observed in between 0% and 8% of treated patients depending on the drug. Antiosteoporotic agents are considered to be safe in terms of cutaneous effects, however there have been a number of case reports of cutaneous adverse reactions which warrant consideration. This was the subject of a working group meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis in April 2009, which focused on the impact of cutaneous adverse reactions and drug-induced hypersensitivity in the management of postmenopausal osteoporosis. This position paper was drafted following these discussions and includes a flowchart for their recognition. Cutaneous adverse reactions observed with antiosteoporotic agents were reviewed and included information from case reports, regulatory documents and pharmacovigilance. These reactions ranged from benign effects including exanthematous or maculopapular eruption (drug rash), photosensitivity and urticaria, to the severe and potentially life-threatening reactions of angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), Stevens Johnson syndrome and toxic epidermal necrolysis. A review of the available evidence demonstrates that cutaneous adverse reactions occur with all commonly used antiosteoporotic treatments. Notably, there are reports of Stevens Johnson syndrome and toxic epidermal necrolysis for bisphosphonates, and of DRESS and toxic epidermal necrolysis for strontium ranelate. These severe reactions remain very rare (<1 in 10,000 cases). In general, with proper management and early recognition, including immediate and permanent withdrawal of the culprit agent, accompanied by hospitalization, rehydration and systemic corticosteroids if necessary, the prognosis is positive.
doi:10.1177/1759720X10387202
PMCID: PMC3383534  PMID: 22870464
antiosteoporosis treatments; cutaneous adverse reactions; hypersensitivity reactions; osteoporosis
8.  Strontium ranelate and alendronate have differing effects on distal tibia bone microstructure in women with osteoporosis 
Rheumatology International  2010;30(10):1341-1348.
The structural basis of the antifracture efficacy of strontium ranelate and alendronate is incompletely understood. We compared the effects of strontium ranelate and alendronate on distal tibia microstructure over 2 years using HR-pQCT. In this pre-planned, interim, intention-to-treat analysis at 12 months, 88 osteoporotic postmenopausal women (mean age 63.7 ± 7.4) were randomized to strontium ranelate 2 g/day or alendronate 70 mg/week in a double-placebo design. Primary endpoints were changes in microstructure. Secondary endpoints included lumbar and hip areal bone mineral density (aBMD), and bone turnover markers. This trial is registered with http://www.controlled-trials.com, number ISRCTN82719233. Baseline characteristics of the two groups were similar. Treatment with strontium ranelate was associated with increases in mean cortical thickness (CTh, 5.3%), cortical area (4.9%) and trabecular density (2.1%) (all P < 0.001, except cortical area P = 0.013). No significant changes were observed with alendronate. Between-group differences in favor of strontium ranelate were observed for CTh, cortical area, BV/TV and trabecular density (P = 0.045, 0.041, 0.048 and 0.035, respectively). aBMD increased to a similar extent with strontium ranelate and alendronate at the spine (5.7% versus 5.1%, respectively) and total hip (3.3% versus 2.2%, respectively). No significant changes were observed in remodeling markers with strontium ranelate, while suppression was observed with alendronate. Within the methodological constraints of HR-pQCT through its possible sensitivity to X-ray attenuation of different minerals, strontium ranelate had greater effects than alendronate on distal tibia cortical thickness and trabecular volumetric density.
doi:10.1007/s00296-010-1542-y
PMCID: PMC2908746  PMID: 20512336
Biochemical markers; Bone mineral density; Cortical bone; Microstructure; Trabecular bone
9.  Zoledronic Acid for the Treatment and Prevention of Primary and Secondary Osteoporosis 
There is increasing interest in therapies that can be administered less frequently and/or avoid gastrointestinal irritation. The efficacy of once-yearly zoledronic acid (5 mg) in the treatment and prevention of osteoporosis has been evaluated in different patient populations. In the 3-year HORIZON-Pivotal Fracture Trial in postmenopausal women with osteoporosis, zoledronic acid reduced the risk of vertebral and hip fracture by 70% and 41%, respectively, versus placebo. The efficacy of zoledronic acid in preventing subsequent fracture in patients with a hip fracture was evaluated in the HORIZON-Recurrent Fracture Trial. New vertebral and nonvertebral fractures were significantly reduced by treatment initiated within 90 days of incident hip fracture, without evidence of delayed fracture healing. Data from a 1-year study show that a single zoledronic acid 5-mg infusion is superior to oral risedronate 5 mg/day for treatment and prevention of glucocorticoid-induced osteoporosis. Increases in bone mineral density and decreases in bone turnover markers were significantly greater with zoledronic acid than with risedronate. Two different treatment regimens of zoledronic acid were found to be more effective than placebo for prevention of bone loss in postmenopausal women and reducing markers of bone turnover after 2 years.
In conclusion, zoledronic acid 5 mg once-yearly infusion has demonstrated marked efficacy in the treatment and prevention of primary and secondary osteoporosis, with a combination of fracture risk reduction and prevention of bone loss at key sites. It is the only agent shown to reduce the incidence of fracture and mortality in patients with a previous low-trauma hip fracture.
doi:10.1177/1759720X09352920
PMCID: PMC3383464  PMID: 22870433
bone mineral density; glucocorticoid-induced osteoporosis; hip fractures; osteopenia; osteoporosis; postmenopausal; zoledronic acid
10.  Effects of the SERM raloxifene on calcium and phosphate metabolism in healthy middle-aged men 
Background. Sex hormones are important regulators of calcium and phosphate homeostasis. Estradiol appears to be a major determinant of bone health in the male gender. However, physiological effects of estrogens on calcium and phosphate homeostatic fluxes in men are still poorly understood.
Objective. We investigated the influence of 6 weeks of the SERM raloxifene, an estrogen agonist in bone, but devoid of feminizing actions, on calcium and phosphate metabolism in healthy middle-aged men.
Design. In a double-blind, randomized, placebo-controled, cross-over study, we evaluated the influence of 120 mg/day of raloxifene on calciotropic hormones levels, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption, as assessed by the calciuric response to an oral calcium load.
Results. As compared to the placebo period, raloxifene treatment decreased the response to an oral calcium load, together with a decrease in 1,25(OH)2D3 and in IGF-I serum levels. Maximal renal tubular phosphate reabsorption was decreased in raloxifene-treated men following the calcium load. The renal handling of calcium was not changed.
Conclusion. These results are compatible with the hypothesis that raloxifene is associated with lower IGF-I and 1,25(OH)2D3 levels, with consequently reduced intestinal calcium absorption capacity.
PMCID: PMC2781229  PMID: 22461168
renal handling, intestinal calcium absorption, calciotropic hormones, males, bone.
11.  Evaluation of symptomatic slow-acting drugs in osteoarthritis using the GRADE system 
Background
Symptomatic slow-acting drugs (SYSADOA) have been largely studied over the last decade. The objective of this study is to prepare a document providing recommendations for the use of SYSADOA in osteoarthritis (OA).
Methods
The following interventions were taken into consideration: avocado/soybean unsaponifiables, chondroitin sulfate, diacereine, glucosamine sulfate, hyaluronic acid, oral calcitonin, risedronate, strontium ranelate. Recommendations were based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The GRADE system is based on a sequential assessment of the quality of evidence, followed by assessment of the balance between benefits versus downsides and subsequent judgment about the strength of recommendations.
Results
Chondroitin sulfate, diacereine, glucosamine sulfate, avocado/soybean unsaponifiables and hyaluronic acid have demonstrated pain reduction and physical function improvement with very low toxicity, with moderate to high quality evidence. Even if pre-clinical data and some preliminary in vivo studies have suggested that oral calcitonin and strontium ranelate could be of potential interest in OA, additional well-designed studies are needed.
Conclusion
In the benefit/risk ratio, the use of chondroitin sulfate, diacereine, glucosamine sulfate, avocado/soybean unsaponifiables and hyaluronic acid could be of potential interest for the symptomatic management of OA.
doi:10.1186/1471-2474-9-165
PMCID: PMC2627841  PMID: 19087296
12.  A randomized double-blind placebo-controlled trial to investigate the effects of nasal calcitonin on bone microarchitecture measured by high-resolution peripheral quantitative computerized tomography in postmenopausal women — Study protocol 
Trials  2008;9:19.
Background
Bone microarchitecture is a significant determinant of bone strength. So far, the assessment of bone microarchitecture has required bone biopsies, limiting its utilization in clinical practice to one single skeletal site. With the advance of high-resolution imaging techniques, non-invasive in vivo measurement of bone microarchitecture has recently become possible. This provides an opportunity to efficiently assess the effects of anti-osteoporotic therapies on bone microarchitecture. We therefore designed a protocol to investigate the effects of nasal salmon calcitonin, an inhibitor of osteoclast activity, on bone microarchitecture in postmenopausal women, comparing weight bearing and non-weight bearing skeletal sites.
Methods
One hundred postmenopausal women will be included in a randomized, placebo-controlled, double-blind trial comparing the effect of nasal salmon calcitonin (200 UI/day) to placebo over two years. Bone microarchitecture at the distal radius and distal tibia will be determined yearly by high-resolution peripheral quantitative computerized tomography (p-QCT) with a voxel size of 82 μm and an irradiation of less than 5 μSv. Serum markers of bone resorption and bone formation will be measured every 6 months. Safety and compliance will be assessed. Primary endpoint is the change in bone microarchitecture; secondary endpoint is the change in markers of bone turnover.
Hypothesis
The present study should provide new information on the mode of action of nasal calcitonin. We hypothezise that - compared to placebo - calcitonin impacts on microstructural parameters, with a possible difference between weight bearing and non-weight bearing bones.
Trial Registration
ClinicalTrials.gov NCT00372099
doi:10.1186/1745-6215-9-19
PMCID: PMC2373283  PMID: 18405390
13.  β-Arrestin2 Regulates the Differential Response of Cortical and Trabecular Bone to Intermittent PTH in Female Mice 
Cytoplasmic arrestins regulate PTH signaling in vitro. We show that female β-arrestin2-/- mice have decreased bone mass and altered bone architecture. The effects of intermittent PTH administration on bone microarchitecture differed in β-arrestin2-/- and wildtype mice. These data indicate that arrestin-mediated regulation of intracellular signaling contributes to the differential effects of PTH at endosteal and periosteal bone surfaces.
Introduction: The effects of PTH differ at endosteal and periosteal surfaces, suggesting that PTH activity in these compartments may depend on some yet unidentified mechanism(s) of regulation. The action of PTH in bone is mediated primarily by intracellular cAMP, and the cytoplasmic molecule β-arrestin2 plays a central role in this signaling regulation. Thus, we hypothesized that arrestins would modulate the effects of PTH on bone in vivo.
Materials and Methods: We used pDXA, μCT, histomorphometry, and serum markers of bone turnover to assess the skeletal response to intermittent PTH (0, 20, 40, or 80 μg/kg/day) in adult female mice null for β-arrestin2 (β-arr2-/-) and wildtype (WT) littermates (7-11/group).
Results and Conclusions: β-arr2-/- mice had significantly lower total body BMD, trabecular bone volume fraction (BV/TV), and femoral cross-sectional area compared with WT. In WT females, PTH increased total body BMD, trabecular bone parameters, and cortical thickness, with a trend toward decreased midfemoral medullary area. In β-arr2-/- mice, PTH not only improved total body BMD, trabecular bone architecture, and cortical thickness, but also dose-dependently increased femoral cross-sectional area and medullary area. Histomorphometry showed that PTH-stimulated periosteal bone formation was 2-fold higher in β-arr2-/- compared with WT. Osteocalcin levels were significantly lower in β-arr2-/- mice, but increased dose-dependently with PTH in both β-arr2-/- and WT. In contrast, whereas the resorption marker TRACP5B increased dose-dependently in WT, 20-80 μg/kg/day of PTH was equipotent with regard to stimulation of TRACP5B in β-arr2-/-. In summary, β-arrestin2 plays an important role in bone mass acquisition and remodeling. In estrogen-replete female mice, the ability of intermittent PTH to stimulate periosteal bone apposition and endosteal resorption is inhibited by arrestins. We therefore infer that arrestin-mediated regulation of intracellular signaling contributes to the differential effects of PTH on cancellous and cortical bone.
doi:10.1359/JBMR.041204
PMCID: PMC1586119  PMID: 15765183
β-arrestin; PTH; knockout; bone architecture; bone remodeling

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