Summary 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.

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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.

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.

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.