Medical and pediatric oncology最新文献

Glucocorticoid therapy is the most common cause of secondary iatrogenic osteoporosis. The bone loss occurs predominantly due to a decrease in bone formation, although increased bone resorption also occurs. Glucocorticoids induce osteoblast apoptosis and increase osteoclast survival and activity. Most of these effects are mediated through the RANKL-OPG system but perturbations in gonadal hormone activity and calcium balance may also contribute significantly to bone loss. Future therapies in the treatment and prevention of glucocorticoid-induced osteoporosis may be targeted at restoring the hormonal and cytokine balance to nullify the apoptotic effect of glucocorticoids on bone forming cells.

Since both estrogen and androgen are present in each sex, it has been difficult to discern the exact role that each sex steroid plays in skeletal physiology. However, studying clinical syndromes in which there is either only estrogen or androgen action has allowed us to gain insight into the unique role that each sex steroid plays in the growing skeleton. In complete androgen insensitivity syndrome (AIS) the only functional sex steroid receptor is that for estrogen. Effected XY females have a pubertal growth spurt that is typical of normal females, both in magnitude and timing. Individuals with AIS have a mild reduction in bone density but it is difficult to distinguish whether this is the result of androgen resistance or estrogen deficiency. These observations suggest that estrogen action only is sufficient to induce a normal pubertal growth spurt, epiphyseal maturation, and near normal bone mineral accretion in women. Until recently, the skeletal effects of estrogen were not thought to be of importance in the male. Conventional wisdom dictated that, in the male, testosterone mediated these skeletal changes. The notion that estrogen is of little importance in the male has been challenged by the recent discovery of two human syndromes in which estrogen action is lacking. In males with either estrogen resistance (inability to respond to circulating estrogen) or aromatase deficiency (inability to synthesize estradiol), as a result of the lack of estrogen action, a pubertal growth spurt does not appear to occur. Furthermore, complete epiphyseal maturation does not take place allowing for continued growth in adulthood and resultant tall stature. Finally normal bone mineral accretion does not take place resulting in severe osteoporosis. These findings indicate that estrogen plays a critical role in skeletal physiology of males as well as females.

The management of oestrogen deficiency bone loss needs to include general measures to protect against osteoporosis, the identification and treatment of other reversible causes of bone loss, and the use of proven agents for the treatment of osteoporosis. The general measures include improved physical activity, adequate diet (paying particular attention to calcium and vitamin D), and avoidance of behaviours that promote bone loss, such as smoking and alcohol abuse. The diseases that should be identified, other than estrogen-deficiency, include primary hyperparathyroidism, thyrotoxicosis and celiac disease. The treatments that are proven to prevent fractures in women with estrogen deficiency, include hormone replacement therapy, raloxifene, nasal calcitonin, bisphosphonates, (alendronate and risedronate) and parathyroid hormone. The most appropriate therapy in the younger woman is HRT, although the trial-based evidence that HRT prevents fractures is not strong. There is a wide choice of preparations and the use of continuous combined preparations avoids regular menstrual periods, one of the limitations to the use of HRT. Raloxifene has less effect on bone mineral density than HRT, but a similar effect on vertebral fractures and does not result in menstrual bleeding or increased risk of breast cancer. There is recent evidence suggesting that the beneficial effects on lipids translate into reduced risk of cardiovascular disease. Bisphosphonates are the standard treatment for the older woman with osteoporosis. Alendronate has been found to reduce the risk of spine, hip, and wrist fractures and has approval for a once weekly regimen, an approach that appears to prevent GI side effects. Risedronate reduces the risk of spine and non-vertebral fractures within the first year of treatment and has been shown to reduce the risk of hip fracture. It has not been associated with an excess of GI side effects. Parathyroid hormone therapy results in increases in BMD that are even greater than estrogen and the bisphosphonates and to an even greater reduction in the risk of fractures, particularly non-vertebral fractures. It works by stimulation of bone formation rather than by inhibition of bone resorption. However, it has to be given by daily injection. Thus, we have a wide choice of therapies for the woman with osteoporosis due to ovarian failure.