Adherence to treatment of osteoporosis: a need for study.

UNLABELLED: Adherence to anti-osteoporosis medications is currently low and is associated with poor anti-fracture efficacy. This manuscript reviews the potential design of clinical studies that aim to demonstrate improved adherence, with new chemical entities to be used in the management of osteoporosis. INTRODUCTION: Several medications have been unequivocally shown to decrease fracture rates in clinical trials. However, in real life settings, long-term persistence and compliance to anti-osteoporosis medication is poor, hence decreasing the clinical benefits for patients. METHODS: An extensive search of Medline from 1985 to 2006 retrieved all trials including the keywords osteoporosis, compliance, persistence or adherence followed by a critical appraisal of the data obtained through a consensus expert meeting. RESULTS: The impact of non-adherence on the clinical development of interventions is reviewed, so that clinicians, regulatory agencies and reimbursement agencies might be better informed of the problem, in order to stimulate the necessary research to document adherence. CONCLUSION: Adherence to therapy is a major problem in the treatment of osteoporosis. Both patients and medication factors are involved. Adherence studies are an important aspect of outcomes studies, but study methodologies are not well developed at the moment and should be improved. Performing adherence studies will be stimulated when registration authorities accept the result of these studies and include the relevant information in Sect. 5.1 of the summary of product characteristics. Reimbursement authorities might also consider such studies as important information for decisions on reimbursement.

[Clinical trials for medicinal products. New European and national legal rules]. / Klinische Prüfung von Arzneimitteln. Neues europäisches und nationales rechtliches Regelwerk.

With the 12th Amendment of the German Drug Law, in addition to other changes, transformation requirements resulting from the Directive 2001/20/EU of the European Parliament and the Council on clinical trials for medicinal products for humans have been fulfilled. Resulting changes in this context for competent federal authorities and other institutions involved are briefly presented and their relevance discussed. These new legal regulations provide a number of opportunities to plan clinical trials more effectively and to perform them in a more structured and better harmonized way, thus leading to increased safety for patients and more reliable results.

Total joint replacement of hip or knee as an outcome measure for structure modifying trials in osteoarthritis.

OBJECTIVE: The Group for the Respect of Ethics and Excellence in Science (GREES) organized a working group to assess the value of time to joint surgery as a potential therapeutic failure outcome criterion for osteoarthritis (OA) of the hip or knee in the assessment of potential structure modifying agents. METHODS: PubMed was searched for manuscripts from 1976 to 2004. Relevant studies were discussed at a 1-day meeting. RESULTS: There are no accepted guidelines for 'time to' and 'indications for' joint replacement surgery. A limited number of trials have examined joint replacement surgery within the study population. Several parameters, particularly joint space narrowing (interbone distance), correlate with surgical intervention. However, at the level of the knee, none of the parameters have positive predictive value for joint replacement surgery better than 30%. In contrast, lack of significant joint space narrowing has a strong negative predictive value for joint replacement surgery (>90%), that remains after controlling for OA pain severity. CONCLUSION: At this time, GREES cannot recommend time to joint surgery as a primary endpoint of failure for structure modifying trials of hip or knee OA-as the parameter has sensitivity but lacks specificity. In contrast, in existing trials, a lack of progression of joint space narrowing has predictive value of >90% for not having surgery. GREES suggests utilizing joint space narrowing (e.g., >0.3-0.7 mm) combined with a lack of clinically relevant improvement in symptoms (e.g., >/=20-25%) for 'failure' of a secondary outcome in structure modifying trials of the hip and knee.

The use of placebo-controlled and non-inferiority trials for the evaluation of new drugs in the treatment of postmenopausal osteoporosis.

Registration of new agents for the treatment of postmenopausal osteoporosis has been based over the past few years on placebo-controlled phase III trials with the incidence of patients with new vertebral/nonvertebral fractures as the most usual primary endpoint. The use of a placebo in diseases where an active treatment is available has been a matter of debate following the update of the Declaration of Helsinki by the World Medical Association which questioned this trial design. Current regulatory recommendations within the European Union suggest that placebo-controlled trials are still the best option when assessing the efficacy and safety of new drugs intended for the treatment of postmenopausal osteoporosis. This suggestion seems to be in apparent contradiction with the current content of the Declaration of Helsinki. This paper addresses the ethics and feasibility of placebo-controlled trials in the treatment of postmenopausal osteoporosis, in the light of available therapeutic options, and discusses possible alternative approaches in those patients where placebo treatment could be deemed to be unethical. It is concluded that placebo-controlled trials remain the most efficient design to establish the efficacy and safety of a new agent for the treatment of postmenopausal osteoporosis. Such trials are feasible and ethically acceptable in patients with osteoporosis but without prevalent vertebral fractures. Conversely, in patients with prevalent vertebral fractures, placebo-controlled trials are ethically questionable and non-inferiority trials are more appropriate. A relative margin of non-inferiority of 20-30% is suggested, to be discussed on a case by case basis.

[Contribution of psychomotricity in respiratory rehabilitation programs]. / Apport de la psychomotricité au sein de la prise en charge des patients insuffisants respiratoires dans le cadre d'un programme de réhabilitation.

Pulmonary rehabilitation traditionally benefits COPD patients through physical training, optimization of medical treatment, education and nutritional advice. In this paper we introduce psychomotricity which provides these with a more global approach to pulmonary rehabilitation. This approach takles postural tone, mobility, anxiety and self-confidence in order to improuve control of breathing and perception of breathlessness. Consequently handicap is reduced and its adverse effects are curbed. Psychomotricity, through corporeal techniques and relaxation, complements the other components of pulmonary rehabilitation. We report on our experience with ninety patients. All the assessments were carried out before and after the program. This study showed significant improvement in many outcomes including psychomotricity assessments, quality-of-life questionnaire scores and visual analogue scales. Psychomotricity, when incorporated into a multi-disciplinary rehabilitation program, appears to help patients regain self-confidence and use their capacities in a better way. This technique gives patients better control over their handicap and allows them to face the future with more dignity.

Background for studies on the treatment of male osteoporosis: state of the art.

Male osteoporosis represents an important, although long underestimated, public health problem. Both in men and in women aging is accompanied by continuous bone loss and by an exponential increase in the incidence of osteoporotic fracture, with a female to male incidence ratio of about 2 to 3 to 1 in the elderly for hip and vertebral fractures. Morbidity after osteoporotic fractures appears to be more serious and mortality more common in men than in women. To date, no single treatment has been proved to be effective and safe in published prospective studies. The present report, based on a systematic search of the literature on male osteoporosis, summarises the state of the art on the clinical consequences of male osteoporosis and its risk factors, in relation to the present state of knowledge about female osteoporosis. This constitutes the background for the design of rational clinical development strategies for therapeutic interventions in male osteoporosis. From this review of the literature it is apparent that notwithstanding the existing sex differences in pathophysiology of osteoporosis and the difference in age-specific incidence of osteoporotic fractures, there are also important similarities between osteoporosis in women and men. The higher incidence of fracture in women than in men results from quantitative differences in risk factors rather than from different risk factors. Even though there are sex differences in bone geometry, incidence of fracture seems to be similar in men and women for a same absolute areal bone mineral density. However, the lack of data on the changes in fracture rates in men resulting from pharmacological intervention, leading to changes in bone mineral density or bone turnover, remains the main limitation for extrapolation of established treatment outcomes from women to men.

Breastfeeding pattern in a population with different levels of poverty in Southern Brazil.

A cross-sectional study was conducted on 477 poor children aged 12-59 months in order to investigate their breastfeeding pattern, taking into account the poverty level of their families. Although the population living in extreme poverty had the same pattern of breastfeeding as the rest of the poor population, the former group should still have priority in breastfeeding promotion programs, since they are the population who benefit most with breastfeeding.

Poverty levels and children's health status: study of risk factors in an urban population of low socioeconomic level.

To test the hypothesis that the low socioeconomic population living in shanty towns in Porto Alegre presents different levels of poverty which are reflected on its health status, a cross-sectional study was designed involving 477 families living in Vila Grande Cruzeiro, Porto Alegre, Brazil. The poverty level of the families was measured by using an instrument specifically designed for poor urban populations. Children from families living in extreme poverty (poorest quartile) were found to have higher infant mortality rate, lower birth weights, more hospitalizations, and higher malnutrition rates, in addition to belonging to more numerous families. Thus, the shanty town population of Porto Alegre is not homogeneous, and priority should be given to the more vulnerable subgroups.

[Documentation and assessment of adverse drug effects with ofloxacin as an example]. / Dokumentation und Bewertung von Arzneimittelnebenwirkungen am Beispiel des Ofloxacins.

A systematical and comprehensive evaluation of all reports on adverse drug reactions ascribed to ofloxacin since this antibiotic was launched (1985) until October 1988 shows that rare and severe adverse drug reactions are more often reported spontaneously than in the course of clinical trials. In particular, severe reductions of white blood cell counts, shock and shock fragments, and impairment of sensory organs and renal functions have for the first time been detected by spontaneous case reports. The results demonstrate exemplarily the potency of the spontaneous reporting system as superior to that of clinical trials in providing information on rare adverse drug reactions.

Effect of plasma exchange on the steady-state kinetics of digoxin and digitoxin.

The pharmacokinetic effect of extracorporeal elimination can be evaluated from the extracorporeal elimination rate constant, from the amount of drug removed, and from extracorporeal clearance. To compare the validity of these approaches in clinical practice, the effect of multiple plasma exchanges on the steady-state kinetics of digoxin (5 patients) and digitoxin (9) was investigated. For digoxin, an unchanged elimination half-life (28 hours) and only slight increase in the total body clearance was found (from 203 to 204 ml/min). There was a more pronounced effect on the kinetics of digitoxin, where the elimination half-life decreased from 4.3 to 3.6 days, and the total body clearance increased from 4.4 to 4.7 ml/min. For digoxin there was no statistically significant difference between observed and predicted steady-state trough plasma concentrations. For digitoxin, the observed trough plasma concentrations at steady-state correlated well (p less than 0.05) with the predicted concentrations calculated from the amount removed or from extracorporeal clearance. The magnitude of the kinetic effect of plasma exchange is overestimated using the extracorporeal elimination rate constant; but the effect of extracorporeal elimination can be adequately evaluated from the amount of drug removed and from extracorporeal clearance. These later approaches can be considered model-independent. Thus, the influence of multiple plasma exchanges on the steady-state kinetics of digoxin and digitoxin will be limited and dosage adjustment is not required, if these drugs are given after - not before - the procedure and hypoalbuminaemia is corrected.

[Trial for digitalis withdrawal in hemodialysis patients]. / Digitalis-Auslassversuch bein Hämodialyse-Patienten.

The indication for digitalis treatment was investigated in a controlled and prospective study lasting 12 months in 110 patients on long-term haemodialysis. In ten patients, digitalis was needed because of tachyarrhythmia due to atrial fibrillation and in five because of recurrent pulmonary edema. In 57 patients receiving digitoxin, therapy was discontinued for 4 to 6 weeks, whereas 13 patients not yet treated with digitalis, received digitoxin for 4 weeks. Without digitoxin, trial fibrillation occurred in 4 patients, while no patient experienced atrial fibrillation with digitoxin (P = 0.002). In 13 patients, radiological findings (heart enlargement, pulmonary congestion) were better with digitoxin than without. Thus digitoxin appeared to be clearly indicated in 29% of the haemodialysed patients. Additionally, digitalis was indicated in 31 patients because of heart enlargement, pulmonary congestion and (or) previous pulmonary edema. Initially, 76% of the patients were receiving digitoxin, whereas, after the investigation, the rate was only 57% (P less than 0.001). The prospective frequency of clinically apparent digitoxin intoxication was low (3%) and so were the overall toxic plasma digitoxin levels (5%). Digitalis should be given deliberately but not restrictively to haemodialysis patients, since atrial fibrillation (13%) and heart failure (50%) are frequent and often concealed.

Effect of repeated plasma exchange on steady state kinetics of digoxin and digitoxin.

The effect of repeated plasma exchanges on the steady state kinetics of digoxin (3 patients) and digitoxin (4 patients) was investigated in 7 patients. Plasma exchange was performed 3 times a week for 4 weeks up to 12 exchanges using a hollow fiber membrane. In each exchange, 4000 ml plasma were filtered within 1 to 2 h and replaced by an albumin containing (20 g/l) physiological electrolyte solution. Digoxin and digitoxin concentrations in blood and filtered plasma were measured by radioimmunoassay. The effects due to the amount eliminated by plasma exchange were distinguished from the effects due to hypoalbuminemia. The eliminative effect was confined to the plasma compartment. It resulted in a marginal decrease in the elimination half-life from 1.6 to 1.59 days for digoxin and 4.3 to 4.2 days for digitoxin. Theoretically, it can be calculated that the hypoalbuminemia caused an increase in the volume of distribution from 451 to 497 l (digoxin) and 35 to 50 l (digitoxin) and a further decrease in the elimination half-life from 4.2 to 4.1 days in the case of digitoxin (not digoxin). If given within 2 h prior to plasma exchange, 13 to 50% of the digitoxin dose (not digoxin) was eliminated. Alteration of digoxin and digitoxin dosage during repeated plasma exchanges is not recommended, but drugs should be given after, not before plasma exchange.

Quantitative thin-layer chromatographic determination of dihydroergot alkaloids.

Direct, quantitative, thin-layer chromatographic methods for the determination of dihydroergot alkaloids are described, in particular the determination of dihydroergotamine with dihydroergokryptine as internal standard. The internal standard was added to plasma, which was extracted twice in dichloromethane; the organic phase was removed under nitrogen, the residue resolved in ethanol and applied on a silica gel G-60 plate. Dihydroergotamine and the internal standard can be measured directly by fluorescence, with excitation at 264 nm and with use of a Zeiss remission filter FL 39. The percentage recovery from this method is 49.17 +/- 6.71% (plasma). These methods enable the determination of 10 pmol dihydroergotamine per ml of plasma (ca. 6.8 ng/ml) with a coefficient of variation of 10.3%. They have proved useful in biochemical and pharmaceutical applications.

Ultrastructural studies of the contorted and contralateral testicle in unilateral testicular torsion.

In 7 patients with acute unilateral testicular torsion, bilateral orchiopexy was performed and biopsies were made at the same time for the purpose of light microscopic (semi-thin section method) and electron microscopic examination. All tissue specimens from the twisted and non-twisted gonads showed changes in the form of tubular atrophy, atrophy of the Leydig cells and malformation at the spermatid level. The results indicate primary tissue damage of the testicles, which was already present before torsion occurred. Nevertheless, it is not possible, on the basis of the these findings, to determine definitely whether the disorders of spermiogenesis frequently found in unilateral testicular torsion are the result of possible congenital dysplasia or damage to the germinal epithelium caused by recurrent subtorsion.