GREES has outlined a set of guidelines for the development of a DMOAD for OA. Although these guidelines are subject to change as new information becomes available, the information above is based on the present knowledge in the field with the addition of expert opinion.

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.

We confirmed in a large group of patients the beneficial effects of rhGH therapy on body composition, metabolic parameters and general well-being and found a consistent drop in number of sick days and hospitalization rate. These effects were maintained during two years of therapy, except for an attenuation in body composition changes after 24 months. The high incidence of fluid-related adverse events suggests that it may be better to start with lower doses of rhGH and to increase the dose more slowly over a number of weeks. The finding of suboptimal high or low IGF-1 levels in many patients reinforces guidelines not to give rhGH in a weight-dependent dose but to titrate it individually for each patient.

The existence of circadian variations in serum TSH levels was investigated in 8 normal subjects. The analysis of the data indicated the presence of 2 different reproducible phenomena, a circadian rhythm characterized by an important acrophase and lower amplitude higher frequency variations, with period between 1 and 3 hours. It is suggested that neural mechanisms are at the origin of both the high., frequency variations and the circadian phenomenon, this latter being related to the sleep-wake cycle. A significant difference, between nocturnal and diurnal mean TSH levels was observed in women, but not in men.The existence of circadian rhythmic variations in the secretion pattern of different human pituitary hormones (ACTH and consequently cortisol (1,2), GH (3), FSH (4))has been demonstrated. Until now such a rhythmic pattern could not be demonstrated for TSH secretion (5,6,7,8). However, Nicoloff et al. (9) have suggested the existence of circadian variations of serum TSH levels with a maximum between midnight and 4 a.m., and a minimum around 6 p.m.; these data supported a negative regulation of TSH levels by hydrocortisone.The present study reports more extensive observations of the circadian variations of serum TSH levels in normal man.PATIENTS AND METHODS.. Eight human volunteers (5 males and 3 females), aged 22 to 65 years, clinically and biologically euthyroid, were submitted to blood sampling, every 30 min during 24 hr, through a plastic indwelling needle frequently rinsed with saline. Three of the 5 male volunteers, hospitalized patients for benign non-endocrine diseases, were confined in bed during the observation period, while the other subjects kept their usual life schedule. Their night sleep was rarely interrupted. Three of them were submitted to a second experiment 3 weeks later.Serum TSH was measured by a slightly modified double antibody radioimmunoassay (10,11) and the results were expressed in yU per ml in terms of the international reference standard A preparation (N.M.R.C., Mill-Hill, England); 200 yl TSH-free human serum were added in each tube of the standard curve. In order to avoid the interassay error, all the samples for a given subject were measured in the same assay. Under these conditions the coefficient of variation for several determinations of the same sample fell generally below 2.5 %. Serum total proteins were estimated by the Biuret technique adapted to the Technicon autoanalyser.Statistical analysis of the data included the detection of the possible periodicities by the periodogram method (12,13). RESULTS.Important changes in serum TSH levels were observed during the 24-hours span. Analysis of the data showed two kinds of variations. First, a circadian rhythm characterized by the presence of a peak (acrophase) of TSH levels between 4 a.m. and 6 a.m.; this pediodicity was confirmed by the periodogram analysis and was detected in all subjects except one. Secondly, significant high frequency variations,