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Effects of two administration schemes of intramuscular clodronic acid on bone mineral density: a randomized, open-label, parallel-group study
No full textBACKGROUND:
Clodronic acid is a bisphosphonate used in the prevention and treatment of postmenopausal bone loss. Previous evidence suggests a direct dose-response relationship for the densitometric effect of clodronic acid. Therefore, as it is widely accepted that a reduction in the dosing frequency of bisphosphonates may improve adherence and therefore therapeutic outcomes, an increase in the interval between consecutive administrations of clodronic acid might be associated with a concomitant increase in the overall bisphosphonate dose received. However, to our knowledge, a direct comparison of the effects of intramuscular clodronic acid 100 mg once weekly with a regimen consisting of a higher dose and a longer interval between two consecutive administrations is still lacking.
OBJECTIVE:
This study compared the increase in bone mineral density (BMD) achieved with two different administration schemes of intramuscular clodronic acid (100 mg once weekly and 200 mg every 2 weeks) in patients with postmenopausal osteoporosis.
STUDY DESIGN AND SETTING:
This randomized, open-label, parallel-group trial was conducted in the Osteoporosis and Instrumental Diagnosis Center 'OsteoArticolar' (University of Siena, Siena, Italy) between January 2007 and December 2009.
PATIENTS:
Consecutive women aged 50-80 years with postmenopausal osteoporosis, diagnosed ≥5 years prior to inclusion in the study, were eligible for participation in this study.
INTERVENTION:
Patients were randomized to receive either intramuscular clodronic acid (Clasteon®) 100 mg (group A) + lidocaine (lignocaine) once weekly or intramuscular clodronic acid 100 mg + lidocaine for two consecutive days every 2 weeks (group B), for 2 years.
RESULTS:
In total, 30 patients were randomized to group A and 30 patients to group B. Significant increases in mean ± SD BMD of the lumbar spine versus baseline values were observed in both groups at 1 and 2 year(s) from treatment initiation (group A - year 1: +2.8% ± 1.7%, p < 0.05; year 2: +3.5% ± 2.2%, p < 0.01; group B - year 1: +2.7% ± 2.1%, p < 0.05; year 2: +3.9% ± 2.2%, p < 0.01). Mean ± SD BMD at the femoral neck also significantly increased versus baseline in group A at both timepoints (year 1: +2.3% ± 1.9%, p < 0.05; year 2: +2.5% ± 1.9%, p < 0.05), while the increase reported in group B was significant only after 2 years of treatment (year 1: +1.9% ± 2.2%; year 2: +2.8% ± 1.8%; p < 0.05). Significant mean ± SD increases in total femur BMD were observed only in group A at 2 years (+2.4% ± 1.9, p < 0.05). No differences between study groups were reported. Two non-traumatic vertebral fractures were observed in group A (6.6%) and three in group B (10.0%). Treatment was well tolerated; mild pain at injection site was observed in three patients (one in group A, 3.3%; two in group B, 6.6%).
CONCLUSION:
This randomized study suggests, for the first time to the author's knowledge, a similar effect of intramuscular clodronic acid 100 mg once weekly and 200 mg every 2 weeks (two 100 mg administrations on two consecutive days) on BMD in women with postmenopausal osteoporosis. The administration of intramuscular clodronic acid 200 mg every 2 weeks may therefore represent a new therapeutic option in the treatment of postmenopausal osteoporosis
Clodronate: New directions of use
No full textClodronate is the father of bisphosphonates. For over three decades it has been subject of study in biological and clinical areas, proving to be an extremely interesting molecule from different points of view. It has been the first drug for osteoporosis that can be administered pulsatorily (once every 15 days or once a week). This, along with good tolerability, has been the first cause of its success, when there were no solid data in literature about its antifracture efficacy. There are three published studies that prove its antifracture effect: two by McCloskey published in 2004 and 2007 on BMR, and our study about fracture prevention in corticosteroids OP. In these studies a dose of 800 mg/day orally administered or 100 mg/week I.M. was used, and they are basically the same if you consider that clodronate absorption, orally administered, is on average 1.9%. However, a series of works where higher doses were used (1600 mg orally administered) with greater effectiveness on bone mass, especially in higher risk populations, lead us to consider the use of 200 mg i.m. formulation. First of all, we proved densitometric equivalence of 200 mg i.m./14 days and 100 mg i.m./week in a first study; then, in a second study, we proved a greater densitometric efficacy of 200 mg/week compared to 100 mg/week, clearer at femoral level, where the drug had not proven to prevent femoral fracture because of inadequate bone mass increase at that level. Moreover, as for ibandronate case, monthly dose was doubled compared to pivotal trial, in order to maximize the effects on femoral bone mass and therefore prevent femoral fractures. Consequently, on the basis of the risk envelope, whether it is identified according to BMD and the presence of one risk factor at least or more correctly identified through risk chart (FRAX or DeFRA), you can put forward a differential use of 100 mg i.m. and 200 mg i.m., weekly, "off-label" or every 14 days, adjusting doses in relation to fracture risk and painful symptoms gravity, as well as improving its ease of use and therefore assist compliance. Common experience and clinical and biological works have proved that clodronate has an analgesic effect that can be increased by doubling the doses. The analgesic effect is present not only with patients with fractures, but also with patients suffering from osteoarthritis or arthritis. Therefore, the drug would fit well in the therapeutic program of rheumatic patient, also because of its symptomatic effects. Clodronate at small doses (2 mg) could also have protective effects on cartilage (introduction of intra-articular formulation is expected) and at 10-100 fold higher doses it has certainly anti-inflammatory effects and more specifically antimacrophage and anticytokine effects (IL-1, IL-6, TNFalpha, PGE). These effects are amplified by putting clodronate in monolayer liposomes. This drug, therefore, has to be considered as adjuvant in arthritis therapy, whose origin can be linked to a strong osteoclastic activation caused by an increase of cytokines and the RANKL/OPG relationship. It is clear that clodronate can work on cytokine at first and on osteoclastic effector in the end. The drug has been used "off-label" for decades intravenously in complex regional pain syndrome (CRPS type 1) in relation to schemes that change according to different Authors and according to cumulative doses ranging from 3 to 5 g. The introduction on the market of the 200 mg i.m. formulation could allow to get more practical but equally effective schemes. For example, we used this scheme: 200 mg/day for 10 days and then 200 mg every other day for 20 days (cumulative dose of 4 g in a month). Said scheme can be repeated in the following months in particular cases. Results, as for efficacy and lack of relapses, show that clodronate is the leader drug for this syndrome. In recent years, relationship between costs and benefits has started to matter, especially after the creation of some algorithms, such as FRAX, that let us choose patients with a higher fracture risk in 10 years, and after pharmaceutic-economic models that let us calculate FRAX intervention threshold, on the basis of drug price and monitoring, antifracture efficacy, quality of life and how much a community can or wants to spend. In this respect, a sub-analysis of McCloskey's study on people over the age of 75, conducted on 3974 subjects, shows that clodronate is more efficient with patients with a higher fracture risk, calculated according to FRAX. Furthermore, another study by McCloskey revealed that, for a 100-pound/year drug (very similar to clodronate), 'cost effective' intervention threshold is about 7-10%. In conclusion, clodronate prevents fractures, decrease osteo-articular pain, is easy to handle, tolerable and had a great cost/benefit relationship
Effect of Clodronate Treatment on Risk of Fracture: A Systematic Review and Meta-analysis
No full textA systematic review and a meta-analysis of data of literature were performed to evaluate the efficacy of clodronate in the reduction of risk of fractures in patients with osteoporosis or tumour diseases. A systematic review was conducted to identify original articles, reviews, and any other literature report suitable for the purposes of the meta-analysis, limited to prospective randomized trials that included a placebo or an untreated control arm. The search has identified 18 trials, 13 of which in patients with cancer diseases (breast cancer and multiple myeloma were prevalent), 4 in patients with osteoporosis/low BMD, and 1 in elderly women living in community. A placebo control arm was used in 13 trials. Treatment and follow-up duration ranged from 3 months to 5 years. The meta-analysis showed that treatment with clodronate was associated with a reduction of the probability of new fractures compared with controls (OR = 0.572, 95 % CI 0.465–0.704 for new vertebral fractures; OR = 0.668, 95 % CI 0.494–0.905 for new non-vertebral fractures; and OR = 0.744, 95 % CI 0.635–0.873 for new overall fractures in those articles where vertebral and non-vertebral new fractures were not considered separately). Similar findings were observed in the separate analysis in patients with cancer forms or osteoporosis. The results of the meta-analysis have demonstrated that clodronate is effective in reducing the risk of vertebral, non-vertebral, and overall fractures in patients with skeletal fragility
Understanding bisphosphonates and osteonecrosis of the jaw: Uses and risks
No full textOBJECTIVE: Bisphosphonates are chemically stable analogs of pyrophosphate compounds, which have been used to treat multiple disorders of calcium metabolism. Although bisphosphonates have been employed for many years and have demonstrated an excellent safety profile, severe osteonecrosis of the jaw (ONJ) has been described in patients with bone metastases who have been treated with bisphosphonates. METHODS: In this review we describe the reasons for ONJ and discuss the varying effects of different bisphosphonates on the development of ONJ. Bisphosphonates tend to accumulate in bone, subject to remodeling (such as the jaw) and can affect osteoclast-mediated bone resorption and osteoclast formation, leading to the osteonecrosistic phenomenon. RESULTS: Risk factors for previously -treated patients include the type of bisphosphonates (amino or non-amino), length of treatment and route of administration, the presence of co-morbidities and/or treatment with immune-suppressing drugs, and the presence of other risk factors in addition to the type of intervention required. In oncological patients currently in treatment withreceiving intravenous bisphosphonates, greater consideration must be taken depending on the length of treatment already undertaken and concomitant therapies. In these patients, a preventive dental surgery visit and examination of the case would be advisable prior to beginning treatment with bisphosphonates. CONCLUSIONS: Practical approaches in the prevention of ONJ include thorough pre-treatment evaluation and performing any preventative procedures (treat periodontal conditions, extract loose teeth, provide protective and endodontic therapies); initiating amino-bisphosphonates only after any gum tissue damage has healed; establishing a regimented check-up schedule and hygieneic precautions the patient can take; and during bisphosphonate treatment conduct any dental procedures in the least invasive manner during bisphosphonate treatment
Could this be the pioneering case of short-blanket syndrome? Comment on: Development of ultrasound enthesitis score to identify patients with enthesitis having spondyloarthritis: prospective, double-blinded, controlled study. Milutinovic et al. Clin Exp
No full textClodronic acid formulations available in Europe and their use in osteoporosis: a review.
No full textClodronic acid (Cl(2)-MBP [dichloromethylene bisphosphonic acid], clodronate) is a halogenated non-nitrogen-containing bisphosphonate with antiresorptive efficacy in a variety of diseases associated with excessive bone resorption. The drug is believed to inhibit bone resorption through induction of osteoclast apoptosis, but appears also to possess anti-inflammatory and analgesic properties that contrast with the acute-phase and inflammatory effects seen with nitrogen-containing bisphosphonates. Clodronic acid has been shown to be effective in the maintenance or improvement of bone mineral density when given orally, intramuscularly or intravenously in patients with osteoporosis. Use of the drug is also associated with reductions in fracture risk. The intramuscular formulation, which is given at a dose of 100 mg weekly or biweekly, is at least as effective as daily oral therapy and appears more effective than intermittent intravenous treatment. Intramuscular clodronic acid in particular has also been associated with improvements in back pain. The drug is well tolerated, with no deleterious effects on bone mineralization, and use of parenteral therapy eliminates the risk of gastrointestinal adverse effects that may be seen in patients receiving bisphosphonate therapy
Osteoarthritis and osteoporosis: correlations between two clinical entities
Full text linkOsteoarthritis (OA) and osteoporosis (OP) are two common muscoloskeletal diseases, especially in the elderly, which have a significant socio-economic impact. Both conditions are multi-factorial. OP is a systemic disease of the skeleton characterized by reduced mass and qualitative alterations of the bone, leading to increased risk of fracture; OA is an imbalance in tissue homeostasis, which leads to cartilage deterioration, sclerosis of subchondral bone and osteophytosis..
A Comprehensive Overview of the Hereditary Periodic Fever Syndromes
No full textInnate immunity is a critical partner in the regulation of inflammation and some mutations in genes implied in innate immunity pathways can cause genetic disorders characterized by seemingly unprovoked self-limited inflammatory attacks. These rare conditions are collectively named “hereditary periodic fever syndromes” (HPFS), and protean pathogenetic mechanisms combined with several clinical phenotypes characterize at least four distinct conditions: (1) familial Mediterranean fever, which is the prototype and the most widely recognized among HPFS, inherited as an autosomal recessive disorder showing recurrent dysregulated inflammatory processes, caused by an abnormal interaction between cytoskeleton and inflammasome, a key-signaling platform that releases interleukin-1β (IL-1β); (2) the group of cryopyrin-associated periodic syndrome, which upsets directly the production of IL-1β, with a dominant pattern of inheritance; (3) tumor necrosis factor receptor-associated periodic syndrome, which is an autosomal dominant disorder subverting the functions and traffic of a cell membrane protein; and (4) mevalonate kinase deficiency, which is an autosomal recessive metabolic disorder halting the biosynthesis of cholesterol. MEFV, NLRP3, TNFRSF1A, and MVK are respectively the four causing genes of these conditions, all resulting in excessive IL-1β signaling, though the encoded proteins act at different levels in cytoskeletal filament organization, apoptosis, and activation of the IL-1β-structured inflammasome. The differential diagnosis of HPFS can be challenging, as there are no universally accepted diagnostic algorithms, and near half of patients may have a specific disease without any genetic pathogenetic variant identified. Herein, we outline the most relevant aspects of HPFS at the crossroads between clinical medicine and immunology and all the most recent advances in their treatment, as the increasing use of IL-1 antagonists has achieved unexpected clinical results in a large number of patients
High prevalence of ultrasound-defined enthesitis in patients with metabolic syndrome. Comment on: How normal is the enthesis by ultrasound in healthy subjects? Di Matteo et al
No full textRanking antireabsorptive agents to prevent vertebral fractures in postmenopausal osteoporosis by mixed treatment comparison meta-analysis
No full textINTRODUCTION: Bisphosphonates are considered as a first-line therapy for the prevention and treatment of osteoporosis, showing in double-blind, randomized, controlled trials a significant reduction of incidence of new vertebral fractures compared to placebo. Recently also, Denosumab has been shown to reduce the appearance of new vertebral fractures by blocking RANK. There are not head to head comparative studies between the above mentioned drugs. Mixed treatment comparison, an extension of traditional meta-analysis, is able to compare simultaneously several drugs across a range producing a synthetic evidence of efficacy and a range of probability as to the best treatment. OBJECTIVES: The aim of this study is to simultaneously compare alendronate, risedronate, ibandronate, zolendronate and denosumab in the prevention of OP vertebral fractures in a Bayesian meta-analysis for assessing indirect comparisons. MATERIALS AND METHODS: A search for randomized controlled trials involving alendronate, risedronate, ibandronate, zolendronate and denosumab was conducted using several databases. Randomized controlled trials (RCTs) with a double blind treatment period of at least 3 years were included. Men and Glucorticoid Induced osteoporosis, RCTs having as primary or secondary endpoints continuous values as body mineral density (BMD) and studies comparing different dosing regimens of the same agent, which are not used in clinical practice, were excluded. Only fully published reports were considered. RESULTS: A total of 9 RCTs were identified providing data on 31,393 participants. Zolendronate had the highest probability (52%) of being the most effective treatment towards placebo, followed by denosumab (46% probability), ibandronate and then alendronate and risedronate against placebo. CONCLUSIONS: Although the mixed treatment comparisons among alendronate, risedronate, ibandronate, zolendronate and denosumab did not show a statistically significant difference, this analysis suggests that zolendronate, compared to placebo, is expected to provide the highest rate of reduction in vertebral fractures affecting osteoporosis affected patients
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