An operational definition of musculoskeletal decline in older people is needed to allow development of interventions for prevention or treatment, as was developed for the treatment of osteoporosis. Frailty and sarcopenia are linked, but distinct, correlates of musculoskeletal aging that have many causes, including age-related changes in body composition, inflammation, and hormonal imbalance. With the emergence of a number of exciting candidate therapies to retard the loss of muscle mass with aging, the derivation of a consensual definition of sarcopenia and physical frailty becomes an urgent priority. Although several consensual definitions have been proposed, these require clinical validation. An operational definition, which might provide a threshold for treatment/trial inclusion, should incorporate a loss of muscle mass as well as evidence of a decrease in muscle strength and/or physical activity. Evidence is required for a link between improvements in the measures of muscle strength and/or physical activity and clinical outcomes to allow development of interventions to improve clinical outcomes in frail older patients.

This review provides a framework for the development of an operational definition of sarcopenia and of the potential end points that might be adopted in clinical trials among older adults. While the clinical relevance of sarcopenia is widely recognized, there is currently no universally accepted definition of the disorder. The development of interventions to alter the natural history of sarcopenia also requires consensus on the most appropriate end points for determining outcomes of clinical importance which might be utilized in intervention studies. We review current approaches to the definition of sarcopenia and the methods used for the assessment of various aspects of physical function in older people. The potential end points of muscle mass, muscle strength, muscle power, and muscle fatigue, as well as the relationships between them, are explored with reference to the availability and practicality of the available methods for measuring these end points in clinical trials. Based on current evidence, none of the four potential outcomes in question is sufficiently comprehensive to recommend as a uniform single outcome in randomized clinical trials. We propose that sarcopenia may be optimally defined (for the purposes of clinical trial inclusion criteria as well as epidemiological studies) using a combination of measures of muscle mass and physical performance. The choice of outcome measures for clinical trials in sarcopenia is more difficult; co-primary outcomes, tailored to the specific intervention in question, may be the best way forward in this difficult but clinically important area.

Estimates of lifetime risk of osteoporotic fracture have assumed that mortality rates do not change. Since mortality in the elderly is decreasing in all regions of the world we assessed the effect of this on lifetime risks for hip fracture using Sweden as a reference country. Lifetime risks of hip fracture at the age of 50 years were 4.6% and 13.9% in men and women respectively, assuming all survive to current average life expectancy. Estimates increased to 8.1% and 19.5% when based on present mortality and to 11.1% and 22.7% respectively based on predicted mortality. We conclude that lifetime risks of hip fracture have been considerably underestimated.

There are quite a few disorders for which regulatory agencies have required a treatment to demonstrate a statistically significant effect on multiple endpoints, each at the one-sided 2.5% level, before accepting the treatment's efficacy for the disorders. Depending on the correlation among the endpoints, this requirement could lead to a substantial reduction in the study's power to conclude the efficacy of a treatment. To investigate the prevalence of this requirement and propose possible solutions, a multiple-disciplinary Multiple Endpoints Expert Team sponsored by Pharmaceutical Research and Manufacturers of America was formed in November 2003. The team recognized early that many researchers were not fully aware of the implications of requiring multiple co-primary endpoints. The team proposes possible solutions from both the medical and the statistical perspectives. The optimal solution is to reduce the number of multiple co-primary endpoints. If after careful considerations, multiple co-primary endpoints remain a scientific requirement, the team proposes statistical solutions and encourages that regulatory agencies be receptive to approaches that adopt modest upward adjustments of the nominal significance levels for testing individual endpoints. Finally, the team hopes that this report will draw more attention to the problem of multiple co-primary endpoints and stimulate further research.

Clinical features of adrenal steroid deficiency occur in patients with the acquired immunodeficiency syndrome (AIDS). To determine the frequency of aberrations in peripheral steroid levels in patients with AIDS and AIDS-related complex (ARC) we measured morning recumbent plasma cortisol, deoxycorticosterone, 18-hydroxydeoxycorticosterone (18-OHDOC), corticosterone, aldosterone, and 18-hydroxycorticosterone concentrations before and after administration of 0.25 mg ACTH (Cosyntropin) in 74 randomly selected hospitalized patients with AIDS and 19 patients with ARC. Basal (0800 h) cortisol levels in the AIDS patients were significantly higher (P less than 0.01) than those in normal subjects, while other ACTH-dependent steroids of the 17-deoxypathway, deoxycorticosterone, corticosterone, and 18-OHDOC, were normal. These latter steroids increased subnormally in response to ACTH in patients with either AIDS (P less than 0.001) or ARC (P less than 0.005), but in ARC patients plasma 18-OHDOC levels were significantly higher than in those with AIDS (P less than 0.001). Supraphysiological doses of ACTH were then administered for 3 consecutive days to 14 patients with AIDS and 9 with ARC, which confirmed and amplified the subnormal responses of these steroids in AIDS. The mean plasma cortisol response was reduced on the third day only in AIDS patients, whereas in the ARC patients the steroid responses were normal. Angiotensin III infusion and postural stimulation increased plasma aldosterone and 18-hydroxycorticosterone levels in AIDS and ARC patients. Defective stimulation of 18-OHDOC alone or in combination with defective stimulation of other 17-deoxysteroids can be a harbinger of subsequent impaired adrenal capacity in AIDS.