{'fraction_non_alphanumeric': 0.028548612497504493, 'fraction_numerical': 0.010980235575963266, 'mean_word_length': 4.738831615120275, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Relationship between IGF-I and skeletal aging.

With advancing age, bone mass steadily declines. Between early adulthood and old age, women lose about 50% of their cancellous bone and 30% of their cortical bone, and men lose about 30% and 20% respectively. At the same time, there is a progressive decline in the circulating and skeletal concentrations of insulin-like growth factor-I (IGF-I). Expectations are high that the continuous decline in IGF-I activity with age may be a major, and potentially preventable, cause of skeletal aging. Indeed, there is convincing evidence for a role for IGFI as an osteotropic agent: it is present in large amounts in human skeletal tissue. Numerous in vitro and animal studies have demonstrated anabolic effects of IGF-I on bone cell metabolism (1). Positive associations between circulating IGF-I or related parameters and bone mineral density (BMD) have been reported for both normal individuals and patients with osteoporosis (2). Additional support for an anabolic skeletal function of IGF-I comes from patients with a deficiency or excess of growth hormone (GH). Bone mass and circulating IGF-I concentrations are both lower than normal in GH deficiency of childhood and young adult onset and can be, at least in part, restored by GH replacement. Correspondingly, patients with GH excess tend to have a higher than normal bone density (3). In view of these data, the results of the study by Janssen et al. (4) in this issue of the European Journal of Endocrinology must be disappointing. Analyzing circulating free and total IGF-I concentrations in a large population-based sample of 55–80-year-old men and women, these authors barely observed a positive relationship between circulating IGF-I and BMD in men, and no relationship at all in women. However, sobering as these data are, they are fully in line with the weak or missing associations between circulating IGF components and BMD in the few other populationbased studies that have been reported so far (5–7). Population-based studies are the best option to guard against confounding bias, such as nutrition or physical fitness. This may be one of the reasons why the relationship between IGF-I and BMD is much weaker than that reported in several studies with more selected patients. There are various explanations for the weak performance of circulating IGF-I as a determinant of human bone mass in old age. First, the impact of IGF-I on adult bone may indeed be modest. BMD in adults who have acquired GH deficiency after full skeletal maturation is only 0.5-1 standard deviations below that of agematched controls, and there is no evidence for a progressive bone loss with time (3). One reason for the seemingly larger impact of IGF-I during childhood and adolescence may be a gradual blunting of the anabolic effect of IGF-I on bone with age. IGF-I stimulates both bone formation and bone resorption, and the proportion between the two might change as a function of age. In vitro studies have suggested that human osteoblasts are less responsive to IGF-I in old age (8). It is as yet unclear whether this is balanced by a similar decline in the responsiveness of osteoclastic cells. Even the weak association between circulating IGF-I and bone mass in the elderly may be reminiscent of the beneficial effects of IGF-I on peak bone mass, as individual differences in IGF-I activity may persist throughout life. Compatible with such an hypothesis of a waning anabolic effect of IGF-I on bone, circulating IGF parameters in the 50– 80-year-old men and women from the Heidelberg cohort of the European Vertebral Osteoporosis Study study were weakly positively correlated with baseline BMD values (5), but not with longitudinal changes in BMD over a 2–3 year observation period (11). However, there are many pitfalls that may result in an underestimation of the true impact of IGF-I on skeletal aging. One of the most critical issues is whether circulating IGF-I concentrations are representative of skeletal IGF-I concentrations. It is conceivable that skeletal IGF-I activity differs greatly from that of circulating IGF-I because of the complex IGF regulatory system in bone tissue. In fact, data from our laboratory suggest that, despite age-associated decreases in both human cancellous bone matrix and serum, IGF-I concentrations between the two compartments hardly correlate with each other at all (11). Of possibly even greater significance, only bone matrix IGF-I was significantly associated with trabecular bone volume in these samples, indicating that measuring circulating IGF-I levels may underestimate the impact of IGF-I on bone metabolism. It is also important to distinguish between the role of IGF-I in the decline of bone mass with age per se and its role as a determinant of the variability in this decline, because these may be two different issues. The relative decrease in IGF-I activity in old age, particularly in European Journal of Endocrinology (1998) 138 617–618 ISSN 0804-4643