G. Bouvenot

Adherence to treatment of osteoporosis: a need for study

SummaryAdherence 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.IntroductionSeveral 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.MethodsAn 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.ResultsThe 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.ConclusionAdherence 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.

Recommendations for the registration of new chemical entities used in the prevention and treatment of osteoporosis

Osteoporotic fractures are now widely recognized as a major health problem in elderly populations, causing significant morbidity and mortality and imposing a considerable financial burden on the health services [1]. Recent advances in the clinical management of osteoporosis, in particular the development of accurate and precise techniques to measure bone mass and the identification of agents that prevent or reverse bone loss, have resulted in increased therapeutic intervention in this disease. However, requirements for registration of an agent for prevention or treatment of osteoporosis are not uniform, leading to wide geographical variations in prescribing patterns. Within Europe, for example, several drugs are licensed for these indications in certain countries, but not in others. The need to standardize registration requirements of drugs for osteoporosis prompted the development of a European Working Group, composed of clinicians working in the field of bone disease and representatives of drug regulation authorities. The aim of this group was to generate guidelines for the development of new agents for prevention and treatment of osteoporosis, particularly postmenopausal osteoporosis. This paper reports recommendations for the preclinical and clinical studies that are considered by the group to be necessary prerequisites for drug registration in the future. The recommendations are based on currently available knowledge and technology and should be relevant to all European countries.

Do estrogens effectively prevent osteoporosis-related fractures?

Since Albright, [1] some 60 years ago, reported the benefi-cial effects of estrogens for decreasing urinary calcium ex-cretion and suggested that these harmones might be usefulin preventing postmenopausal osteoporosis, estrogen re-placement therapy (ERT) has been consistently regarded asthe first choice for prevention of trabecular and corticalbone loss in postmenopausal women [2–5]. However, seri-ous controversies remain over the cost/effectiveness oftreating every woman at the time of menopause [6], theoptimal timing for starting ERT [5], the minimal effectivedose of ERT acting on bone [7], and the duration of ERTneeded to prevent osteoporotic fractures [8]. The effective-ness of ERT for preventing osteoporosis-related fractures isundisputed and requirements for marketing authorizationfor ERT products have lightened compared with currentrequests for other therapeutic medications developed in thisfield [9, 10]. However, although the skeletal benefits ofERT for preventing trabecular or cortical bone loss canhardly be challenged, one might be wary of published evi-dence that prolonged ERT use unequivocally reduces therisk of hip fracture. Controlled clinical trials and systematicreviews were located using Medline 1970–1999 andEMBASE 1980–1999. Since 1985 we have searched scien-tific journals on bone and bibliographies of review articles.All prospective controlled trials were included for evalua-tion of the effects of hormone replacement therapy (HRT)on bone loss. A total of 57 prospective controlled trials wereidentified, 46 of which were randomized clinical trials(RCTs) and 15 were double blinded. All clinical trials as-sessing the effects of HRT on fracture rates were consid-ered. Two RCTs and one systematic review were identified[11].In the 46 randomized controlled trials comparing estro-gen (with or without progestins) (HRT) with placebo orcalcium on bone loss prevention, the study population var-ied from 14 to 875 women and the duration was from .5 to10 years. In general, they drew similar conclusions, i.e, thatestrogen intervention reduces the rate of postmenopausalbone loss at trabecular and cortical sites. An early double-blind trial [12] reported the preventive effects of HRT oncortical (metacarpal) bone loss for up to 10 years. Morerecent double-blind, placebo-controlled, randomized clini-cal trials confirmed these findings for oral [13], percutane-ous [14, 15], or transdermal [16] estrogens at the spine [13,14, 16], the forearm [16], and/or the hip [13, 16] for up to3 years. Two prospective open studies [17, 18] showedsimilar results for estrogen implants after 1 year. Whenstandardized for technique used for bone mineral density(BMD) assessment, the magnitude of the point estimatedifferences between the HRT and the control group variedgreatly from one study to another, depending upon the doseof HRT used (dose-related effect on bone mass in most

Recommendations for the registration of agents used in the prevention and treatment of glucocorticoid-induced osteoporosis

Glucocorticoid-induced osteoporosis is an important clinical problem, but there is little consensus about its management and in many countries no drug is licensed specifically for its prevention or treatment. In contrast, a number of agents are licensed for postmenopausal osteoporosis; however, extrapolation of data obtained in preclinical and clinical studies of postmenopausal osteoporosis to glucocorticoid-induced osteoporosis is problematic because of fundamental differences in the pathogenesis and pathophysiology of the two conditions. Prompted by the lack of standardization for registration requirements of agents for osteoporosis, and consequent wide geographical variations in prescribing patterns, we reported recommendations for the registration of new chemical entities in the prevention and treatment of postmenopausal osteoporosis [1]. Because of the particular problems associated with the evaluation of agents for glucocorticoidinduced osteoporosis, it was felt that specific recommendations for the registration of agents for use in the prevention and treatment of this condition were appropriate. This article reports the recommendations of our group for preclinical and clinical studies for registration of drugs for the prevention and treatment of glucocorticoid-induced osteoporosis. As in the case of our previously reported recommedations [1], these are based on currently available knowledge and technology and should be relevant to all European countries.

Assessing chronic pain in general practice: Are guidelines relevant? A cluster randomized controlled trial

Objectives: To evaluate the impact of using pain assessment scales on the management of musculoskeletal chronic pain. Methods: Cluster-randomized controlled multicentre trial in French general practice settings. Practices were randomized by region before patient recruitment. The inclusion concerned patients suffering from musculoskeletal chronic pain. General practitioners assigned to the scale group used two validated assessment instruments; those assigned to the control group cared for their patients according to their usual practice. The primary end-point was the level of relief obtained and the secondary changes in prescription of painkilling modalities. Results: A total of 155 general practitioners included 772 successive patients suffering from musculoskeletal chronic pain. The control group reported a mean level of relief of 50.7% compared with one of 41.1% in the scale group (p<0.0001). In the intervention group, physicians decreased significantly their prescription of level two painkillers. Conclusions. In general practice, the use of pain assessment scales is not associated with greater pain relief. The lesser level of pain relief obtained in the scale group does provide evidence that using pain assessment scales does not enhance the relief of chronic pain in patients in primary care. Guidelines which recommend the systematic use of scales for the assessment and monitoring of chronic pain are not tailored to either the context or the patients encountered in the primary care setting.