Doyle-Lindrudan and DiPaola: Progress in prostate cancer research in New Jersey ablation therapy, without metastasis, has also been documented. Increased skeletal fractures have been associated with the use of androgen ablation therapy and decreased bone mineral density (BMD) (Melton et al, 2003; Diamond et al, 2004; Krupski et al, 2004). Shahinian, et al reviewed the records of 50,613 men who were linked in the database of the Surveillance, Epidemiology, and End Results program and Medicare as having received a diagnosis of prostate cancer between 1992 through 1997 and being at least 66 years of age. Comparisons were limited to men who received at least one dose of a gonadotropin-releasing hormone agonist or underwent an orchiectomy within 6 months after receiving the diagnosis with those with prostate cancer who received neither type of treatment at any time after diagnosis. The primary outcomes were the occurrence of any fracture and the occurrence of a fracture resulting in hospitalization. The review demonstrated that 19.4 percent of those who received androgen deprivation therapy (ADT) had a fracture, as compared with 12.6 percent of those not receiving ADT (P<0.001) (Shahinian et al, 2005). Multiple studies have now demonstrated improved bone mineral density with bisphosphonate therapy. For example, a study by Diamond et al. (1998) looked at markers of bone turnover and bone mineral density in men with disseminated prostate cancer treated with combined androgen blockade prior to and after 6 months of intermittent cyclic etidronate and calcium supplementation. The results of this study show that after treatment with etidronate, a significant increase in BMD was observed in the femoral neck and lumbar spine, concluding that adjuvant therapy with intermittent cyclic etidronate may prevent the high bone turnover and decrease the risk of spinal fractures. A second study involving patients with locally advanced, lymph node positive or recurrent prostate cancer and no bone metastases were randomly assigned to treatment with either a 22.5mg IM depot leuprolide injection and 60mg i.v. pamidronate every 12 weeks versus 22.5mg IM depot leuprolide injection alone (Smith et al, 2001). The results revealed that the men receiving the depot leuprolide injection alone had a decrease in bone mineral density in the lumbar spine and hip. In contrast, the bone mineral density did not change significantly in the men treated with depot leuprolide and i.v. pamidronate. A recent study looked at a third generation bisphosphonate, zoledronic acid in the prostate cancer population (Smith et al, 2003). This study involved a randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation for nonmetastatic prostate cancer. Zoledronic acid at a dose of 4mg i.v. was given every 3 months for one year. Results demonstrated that men receiving zoledronic acid had an increase in mean bone mineral density in the lumbar spine by 5.6% as compared to a decrease by 2.2% in those given placebo. Mean bone mineral density of the femoral neck, trochanter and total hip also increased in the zoledronic acid group and decreased in the placebo group. In summary, these data suggest that bisphosphonates may reduce the bone loss associated with ADT in men without metastasis, but the effect of bisphosphonates to decrease
rates of fracture is unclear and needs further study.
III. Clinical studies of bisphosphonates in metastatic prostate cancer Clinical studies have also assessed the role of bisphosphonates in men with metastatic prostate cancer to bone; randomized phase III studies have included the assessment of clodronate, pamidronate and zoledronic acid. For example, a double blind, placebo controlled, randomized trial was completed (Dearnaley et al, 2003) to determine whether the first generation bisphosphonate sodium clodronate improved bone progression-free survival times among men with bone metastases from prostate cancer. Between 1994 and 1998, 311 men who were started or responding to first line hormone therapy for bone metastases were randomly assigned to receive oral sodium clodronate or placebo for a maximum of three years. The primary endpoint was symptomatic bone progression free survival (BPFS). Secondary endpoints included overall survival, treatment toxicity and change in World Health Organization (WHO) performance status. After a median follow up of 59 months, the sodium clodronate group was reported to have a better symptomatic BPFS, but this was not statistically significant (hazard ratio (HR) =0.79, 95% confidence interval (CI)=0.61 to 1.02; P=.066). Patients in the clodronate group were less likely to have worsened WHO performance status (HR+ 0.71, 96% CI= 0.56 to 0.92; P=.008). The clodronate group did experience more gastrointestinal problems and increased LDH levels and required more frequent modification of the trial drug dose. Results of subgroup analyses suggested that clodronate might be more effective if started earlier after diagnosis of metastatic bone disease. These results suggest that further studies are needed to determine a benefit of bisphosphonates on BPFS in men with metastatic prostate cancer that are responding to ADT. In contrast to studies on this group of patients with metastasis responding to ADT, studies of patients with metastatic disease and progression on ADT have more definitive conclusions. For example, a study randomly assigned patients with HRPC and metastasis to treatment with i.v. zoledronic acid at 4mg, zoledronic acid at 8mg (subsequently reduced to 4mg) or placebo every 3 weeks for 15 months. Skeletal related events, time to first SRE, skeletal morbidity rate, pain and analgesic scores, disease progression and safety were assessed. SRE was defined as pathologic bone fracture (vertebral or nonvertebral), spinal cord compression, surgery to bone, radiation to bone (including radioisotopes) or a change of antineoplastic therapy to treat bone. The study demonstrated that a greater proportion of patients who received placebo had an SRE than those who received zoledronic acid at 4mg (44.2 % versus 33.2%) (Saad, 2002; Saad et al, 2002). These data, therefore, demonstrated a benefit to zoledronic acid in patients with metastatic prostate cancer, with hormone refractory disease. This study however does not assess the bone density status of the men and therefore does not clearly differentiate between malignant or osteoporotic 402