Androgen Deprivation Therapy-induced Fractures in Men With Nonmetastatic Prostate Cancer: What Do We Really Know?

Summary and Introduction

Summary

Androgen deprivation therapy (ADT) alone or in combination with radiation therapy or other drugs is increasingly used for the treatment of localized, high-risk, or biochemical relapse of prostate cancer (PC). Bone mineral density (BMD) loss is rapid during the first year of ADT; up to 4.6% of total hip, femoral neck, and lumbar spine BMD loss has been reported in PC patients without bone metastases (nonmetastatic PC). In prospective studies, concurrent administration of a bisphosphonate or selective estrogen receptor modulator stabilized or increased BMD. Results of retrospective studies of ADT-treated patients who did not receive antiresorptive therapy have demonstrated a 21–37% increase in fracture risk. Because of the documented bone loss and increased fracture risk, patients should receive adequate counseling, monitoring, and therapy aimed at preventing or treating ADT-induced bone loss. Future studies should address the long-term impact of antiresorptive therapy on actual fracture rate and the impact on quality of life and healthcare costs.

Introduction

In 2007 nearly 220,000 men are expected to be diagnosed with prostate cancer.^[1] Many of these men will eventually receive androgen deprivation therapy (ADT), such as orchiectomy or gonadotropin- releasing hormone (GnRH) agonist therapy (with or without antiandrogen therapy), for treatment of locally advanced or metastatic disease.^[2,3] ADT has been shown to improve survival times when given in combination with radiation therapy in men with localized prostate cancer and when given after radical prostatectomy in men with node-positive disease.^[4–7] Although ADT is also commonly used in men with biochemical relapse, to date there are no prospective trials showing that ADT confers a survival benefit for all patients with this stage of disease. Because ADT suppresses testosterone levels, numerous adverse effects, such as sexual dysfunction, cognitive and mood changes, hot flashes, metabolic changes and skeletal complications, can occur.^[3,8–27] Clinicians must have a thorough understanding of these adverse effects and how they should be managed.

Skeletal complications, such as bone loss and fractures, have emerged as important adverse effects associated with ADT in men with prostate cancer. Bone loss results from ADT-induced testosterone and estrogen deficiencies.^[2] During ADT, testosterone and estrogen levels fall to <95% and <80%, respectively, of normal levels and usually rise gradually after therapy is discontinued.^[2,28] Return of normal testosterone levels is variable, and in some cases, the original testosterone level never recovers.^[28,29] The time to recovery of initial testosterone levels after discontinuation of ADT is generally longer in men with lower baseline testosterone levels (i.e. <212 ng/ml), men over 65 years of age, and men receiving ADT for more than 24–30 months.^[29–31]

Testosterone exerts its effects on the bone remodeling process by stimulating proliferation of osteoblasts (bone-formation cells) and inhibiting apoptosis of osteoblasts and osteoclasts (bone-resorption cells).^[32] Testosterone might also indirectly affect bone remodeling via aromatization of testosterone to estrogen.^[32] Estrogen is the dominant steroid regulating bone resorption. A deficiency of estrogen shifts the balance of bone remodeling towards increased bone resorption by activating osteoclasts, decreasing osteoclast apoptosis, and possibly by decreasing osteoblast formation, proliferation, and function and increasing osteoblast apoptosis.^[32] This process results in the formation of resorption cavities that are usually beyond the capacity of osteoblastic repair, resulting in net bone loss.^[32] The results of prospective studies show that men with nonmetastatic prostate cancer experience annual reductions in the bone mineral density (BMD) of the femoral neck, lumbar spine, and total hip bone of up to 4.6%, a rate that equals or exceeds bone loss in other populations at risk of declining BMD (Figure 1).^{[2,17–26,33–35]} BMD loss and microarchitectural deterioration of bone can decrease bone strength and increase the risk of bone fractures.^[36–39] Fractures have been associated with significant morbidity, reduced quality of life (QOL), and increased mortality, although the impact of fractures per se has not been evaluated in men with nonmetastatic prostate cancer.^[40,41]

Figure 1. (click image to zoom) A comparison of cancer-therapy-induced bone loss versus normal bone loss in men and women. aHormonal therapy consisted of the aromatase inhibitor anastrazole.[2,17–26,33–35] Abbreviations: ADT, androgen deprivation therapy; BCa, breast cancer; BMD, bone mineral density; GnRH, gonadotropinreleasing hormone; PC, prostate cancer.

This article reviews what is known and what is implied from other high-risk populations about the prevalence, risk factors, consequences, prevention strategies, and monitoring recommendations for bone loss and fractures in men with nonmetastatic prostate cancer receiving ADT.