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Prostate cancer (PCa) is extremely common in the male population. It is estimated that 238,590 men will be diagnosed and 29,720 will die from the disease in 2013.1
Of the roughly 2.5 million men in the U.S. living with PCa,2 one-third or more are treated with androgen deprivation therapy (ADT).3 ADT is now routinely used in patients in combination with radiation for intermediate- and high-risk disease, in men with a rising PSA after primary therapy, and in men with metastatic disease.
Furthermore, ADT is often given continuously or intermittently for the lifetime of the patient once it is initiated. Although ADT has been shown to improve outcomes in men with advanced PCa, its use does not come without significant adverse effects (AEs) including sexual, loss of cognitive function, depression, fatigue, hot flashes, increased body fat, and decreased muscle mass. ADT is also well known to accelerate bone loss and to increase the risk of fractures.4
Furthermore, men with PCa often have preexisting conditions that put them at increased fracture risk, such as advanced age, increased risk of falling, and preexisting osteopenia or osteoporosis.5,6
Men with metastatic PCa are also at risk for developing AEs on bone health (skeletal-related events [SREs]). In this article, we review some of the key aspects of bone health that urologists should take into consideration when managing PCa patients.
For a more detailed review, we would suggest a review article by Saylor P.J., et al.7 Another useful reference that addresses ADT-induced osteoporosis and prevention of SREs is the 2013 National Comprehensive Cancer Network (NCCN) Guidelines for PCa available here.
Bone health and ADT
In longitudinal studies of men, aging is associated with a rate of bone loss of up to 0.5% to 1% per year starting from middle age.8 Several factors accelerate bone loss in the aging male, including physical inactivity, insufficient dietary calcium intake, reduced intestinal calcium absorption, vitamin D deficiency, and a gradual decline in gonadal androgen production.9
Osteoporosis is a common consequence of ADT due to accelerated bone loss from treatment-induced reduction in androgen and estrogen levels impacting on osteoclast and osteoblast function. The key pathophysiologic event leading to ADT-induced accelerated bone loss is increased osteoclast activity, as evidenced by elevated urinary markers of bone turnover.10
Numerous cross-sectional and longitudinal studies of men with PCa treated with ADT demonstrate a progressive decline in bone mineral density (BMD),11,12 and bone loss occurs most rapidly during the first year of therapy.13 This early and acute loss of BMD underlies the need for monitoring and possibly early preventive therapy in men at risk for fractures treated with ADT.
Likewise, urologists should consider BMD studies in PCa patients undergoing radiotherapy who receive ADT.
While bone loss and reduction in BMD are well known consequences of ADT, the main concern is increased risk of osteoporotic fractures. Whereas urologists typically do not report numerous examples of ADT-induced osteoporotic fractures in their clinical practice, the data from observational studies suggests a markedly increased risk of clinical fractures with increased duration of ADT.14
Perhaps the best evidence comes from the placebo arms of large prospective, double-blind, randomized trials in men receiving ADT for nonmetastatic PCa. In a trial of denosumab to assess its effects on BMD and fracture risk, the placebo group had a 3.9% cumulative incidence of a new vertebral fracture at 36 months and a 7.2% incidence of fracture at any site.15
Another study evaluating toremifene for preventing new fractures in men with PCa on ADT found a two-year incidence of new vertebral fracture of 4.9% in the placebo group.16 In a large population-based review from the Surveillance, Epidemiology and End Results (SEER) database, 19.4% of men surviving five years after a diagnosis of PCa who were receiving ADT suffered from a fracture compared with 12.6% of men not receiving ADT. Furthermore, the relative risk of fracture increased steadily with increasing duration of ADT.14 Fractures are well known to have significant consequences, with up to 31% of elderly men dying within one year of suffering a hip fracture.17