Complications of Androgen Deprivation Therapy: Prevention and Treatment

The myriad effects of androgen deprivation therapy (ADT) in men were really not appreciated until those without metastatic prostate cancer received such treatment. For example, fatigue-now recognized as a common toxicity of ADT- was once more likely attributed to metastatic disease. Today, however, patients who are otherwise fully functional, healthy, and asymptomatic are being treated for a rising prostate-specific antigen level after primary therapy. In these men, the side effects of ADT can be very dramatic and are more clearly related to the initiation of therapy. Clarification Needed
The article by Holzbeierlein et al provides a thoughtful review of some of the complications associated with ADT and treatment options. The subtitle of the article also refers to the prevention of complications, but this topic is addressed mainly in the section entitled "Prevention of Osteoporosis." However, the concept of "prevention of osteoporosis" should be clarified, as discussed below. Bone Mineral Density and Bisphosphonates
The authors correctly emphasize that the loss of bone mineral density due to ADT can become significant and that, when osteoporotic fractures occur in men, they result in greater morbidity and mortality than is seen in women with fractures. Although men who are treated with ADT do have a significant loss of bone mineral density, this does not always lead to the development of osteoporosis or even osteopenia. At present, no prospective data are available on the incidence of osteoporosis in men treated with ADT or the resulting fracture rate. It is likely that such data will never be available because of the widespread use of bisphosphonates in this disease. What urologists, medical oncologists, and others treating such patients should understand is that a loss of bone mineral density does not necessarily lead to osteoporosis, that all patients with osteoporosis do not sustain fractures, and that some men without osteoporosis are prone to fracture as well. Therefore, while it behooves the physician to monitor for osteoporosis and treat it if it occurs (as one would do with a female patient), there is no established role for preventing loss of bone mineral density by administering a bisphosphonate concurrently with ADT in men with normal bone mineral density. Nonetheless, many physicians are initiating such therapy despite the absence of data on its potential long-term toxicities under these circumstances. 'Prophylactic' Therapy
The "prophylactic" use of bisphosphonates in this setting has been driven, in part, by a misunderstanding of the reports by Smith et al on the effects of pamidronate(Drug information on pamidronate) or zoledronic acid on bone mineral density in patients without bone metastases before and after 1 year of ADT.[1,2] These randomized prospective studies both showed that ADT alone caused significant loss of bone mineral density, whereas ADT plus a bisphosphonate could prevent loss of bone mineral density (pamidronate) or actually increase this parameter (zoledronic acid). These investigators did not recommend that bisphosphonate therapy be administered to all patients who are starting ADT, although many have interpreted their data in this manner. Certainly men with osteoporosis at baseline before the initiation of ADT should be treated with bisphosphonates, but others should merely be monitored periodically with dualenergy x-ray absorptiometry (DXA) or quantitative computed tomography (Q-CT). Hence, a better subhead for this section of the article by Holzbeierlein et al would have been "Monitoring and Treating Patients for Osteoporosis." While this is the current state of the art, the inhibition of bone turnover may one day be shown to prevent or delay the onset of bone metastases. Padalecki et al have demonstrated that zoledronic acid(Drug information on zoledronic acid) prevents bone metastases in a metastatic prostate cancer model.[3] At present, there are no human data showing that bone metastases can be prevented with bisphosphonate therapy, although studies to assess this possibility are under development in the cooperative group setting. If bisphosphonate therapy is shown to prevent or delay bone metastases, its use as "prophylaxis" when starting ADT would be justified. Exercise Benefit
Holzbeierlein et al do mention exercise as a lifestyle modification that can be recommended to patients on ADT, but it should be emphasized that exercise has great potential to prevent or minimize many of the complications of such therapy. A single recent prospective randomized study in prostate cancer patients treated with ADT showed that a program of supervised resistance exercises (vs no exercise) increased upper and lower body strength, improved quality of life, and decreased fatigue after only 12 weeks.[4] Although resistance exercise had been shown to elevate mood, build muscle, and reduce body fat in healthy older men,[5-11] there is a paucity of data on the benefits of exercise in prostate cancer patients per se. Nevertheless, exercise has been studied in the context of many of the complications referred to in the article in other settings. For example, resistance exercise has been shown to increase bone mineral density.[12] Muscle strength and mass are also enhanced with resistance training.[12] Presumably, basal metabolism increases with resistance exercising,[13] and this, in turn, results in loss of body fat mass and an increase in lean body mass.[14] Resistance training has been shown to improve glycemic control in diabetics.[ 14] This is important because ADT has been shown to increase insulin levels, with glucose intolerance developing after only 3 months of therapy.[15] Androgen deprivation therapy has also been shown to alter lipid profiles,[16] and resistance exercise improves high-density lipoprotein levels.[17] In addition, resistance exercise improves aerobic capacity and endurance.[ 18] Aerobic exercise, which has been studied mainly in breast cancer patients, improves many measures of "biopsychosocial" functioning including cardiovascular fitness, body composition, self-esteem, mood states, and fatigue.[19-23] To my knowledge, aerobic exercise interventions have not been studied in prostate cancer patients. Conclusions
Holzbeierlein et al conclude that patients should be informed of the potential effects of ADT and that lifestyle modifications such as exercise, diet, and vitamin supplementation should be recommended. Although this is good advice in theory, most physicians do not really know what to tell their patients about exercise, diet, or vitamin supplementation. A nutritionist will estimate a patient's daily dietary intake of calcium and vitamin D and make specific recommendations for supplementation. Healthy dietary habits and recommendations for weight loss can also be made, if necessary. With respect to exercise, a balanced program of aerobic and resistance exercises should be recommended. A physical therapist or licensed personal trainer-ideally one with a fitnessrelated academic degree and experience- should be consulted to instruct the patient in such a program. Unfortunately, reimbursement for such services is lacking. This deserves further attention, as exercise has farreaching potential benefits (beyond alleviating the side effects of ADT) and could actually extend overall survival. More research is clearly needed to better understand and counteract the adverse effects of ADT. However, recognizing that these adverse affects could actually decrease survival in men who would otherwise live for many years underscores the need to distinguish those without metastases who will benefit from ADT from those in whom therapy can be delayed.