Progress in prostate cancer research: a focus on bone health

Cancer Therapy Vol 3, page 401 Cancer Therapy Vol 3, 401-406, 2005 Progress in prostate cancer research: a focus on bone health Review Article Susan Doyle-Lindrud 1, * and Robert S. DiPaola 1,2 1 Department of Medicine, University of Medicine and Dentistry- Robert Wood Johnson Medical School, New Brunswick New Jersey, USA. 2 The Dean and Betty Gallo Prostate Cancer Center at The Cancer Institute of New Jersey, New Brunswick New Jersey, USA *Correspondence: Susan Doyle-Lindrud, MS, NPC, The Dean and Betty Gallo Prostate Cancer Center, The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey 08901; Phone: (732) 235-6988; Fax: (732) 235-8095; E-mail: Lindrusm@umdnj.edu Key words: prostate cancer, Clinical studies of bisphosphonates, Potential recommendations, Abbreviations: androgen deprivation therapy, (ADT); bone mineral density, (BMD); bone progression free survival, (BPFS); confidence interval, (CI); dual energy x-ray absorptiometry, (DEXA); hazard ratio, (HR); hormone refractory prostate cancer, (HRPC); quantitative computed tomography, (QCT); World Health Organization, (WHO) Received: 15 March 2005; Revised: 24 June 2005 Accepted: 27 June 2005; electronically published: July 2005 Summary One in six men will be diagnosed with prostate cancer in their lifetime; in this year, approximately 200,000 will be diagnosed with, and 30,000 will die of prostate cancer (Hemminki et al; Jemal et al, 2004). Recent advances reported this past year in the therapy of prostate cancer include data demonstrating the survival benefit of chemotherapy in metastatic hormone refractory prostate cancer (HRPC) (Gulley and Dahut, 2004). Despite these successes, many questions about the management of prostate cancer need to be answered. For example, further studies are needed to determine the value of chemotherapy earlier in the progression of disease, the value of chemopreventive approaches, and efforts to decrease morbidity of the disease and current therapies. This review will focus on recent and ongoing studies with bisphosphonates in prostate cancer. I. Introduction Recent data supports a potential role of bisphosphonates to decrease bone complications of androgen ablation therapy in patients with non-metastatic prostate cancer and to decrease skeletal problems in patients with metastatic prostate cancer. The primary treatment for metastatic prostate cancer and locally advanced non-metastatic prostate cancer is androgen deprivation therapy (ADT). This is usually obtained through an orchiectomy or by treatment with a gonadotropin-releasing hormone agonist. Studies reveal that adjuvant androgen deprivation therapy improves survival for men with locally advanced prostate cancer treated with radiation therapy and for men with lymph node positive prostate cancer treated with radical prostatectomy and pelvic lymphadenectomy (Bolla et al, 2002; Messing et al, 2002). An unfortunate complication of such therapy is a decrease in bone mineral density. A recent study by Shahinian, et al in The NEJM demonstrated that androgen-deprivation therapy for prostate cancer may increase the risk of fracture (Shahinian et al, 2005). Recent data also demonstrates that treatment with bisphosphonates may improve bone density in men without metastatic disease and decrease skeletal related events in men with hormone refractory bone metastasis (Saad, 2002; Smith et al, 2003). Despite possible benefits of bisphosphonates, specific guidelines on the use of bisphosphonates in patients with nonmetastatic disease, to decrease bone loss, or metastatic disease, to decrease skeletal events are unclear. II. Clinical studies of bisphosphonates in non-metastatic prostate cancer Multiple studies have demonstrated that androgen ablation therapy represents an important risk factor for osteoporosis in men (Barrass et al, 2004). This effect to decrease bone density in men on androgen ablation therapy has occurred within 6 months (Daniell et al, 2000). The significance of bone loss in patients on androgen 401

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

Cancer Therapy Vol 3, page 403 fractures. This leaves the question as to whether the decreased risk of fracture was related to osteoporosis or metastatic disease. IV. Bisphosphonates and pain palliation In addition to the important benefit of bisphosphonates on SRE in the prostate cancer population, is the potential benefit of pain palliation from the osseous metastatic disease. Studies thus far have been both positive and negative and further studies will be needed to understand the role of bisphosphonates for pain palliation. Eastham. et al (2005) looked at the effect of zoledronic acid on bone pain and skeletal morbidity in patients with advanced prostate cancer. 422 patients were enrolled. Zoledronic acid 4mg or placebo was given intravenously every three weeks. Bone pain was assessed using the Brief Pain Inventory (BPI) at 6 week intervals. Of the 371 evaluable patients, 73% reported a baseline BPI score of 2.8 (range 0-10) in both groups. Among the patients receiving zoledronic acid, mean baseline pain scores of -10%, -4% and 1% at months 3, 6 and 9 respectively were reported compared with increases of 6%, 9% and 13% from baseline in the placebo group (P=.021 at month 3). After month 12, both groups had increases in pain scores, although the zoledronic acid treated patients had smaller increases (range of 1% to 6%) compared to placebo (15% to 25%) (Eastham et al, 2005). Studies not revealing benefit include an analysis of two multicenter, double-blind, randomized, placebocontrolled trials involving patients with bone pain due to metastatic prostate cancer, with disease progression after first-line hormonal therapy. Intravenous pamidronate disodium (90 mg) or placebo was administered every 3 weeks for 27 weeks. Efficacy was measured via selfreported pain score (Brief Pain Inventory), and analgesic use. The results of the two trials were pooled. There were no sustained significant differences between the pamidronate and placebo groups in self-reported pain measurements and analgesic use. The conclusion of this analysis, with inherent limitations of a pooled analysis, was that Pamidronate disodium failed to demonstrate a significant overall treatment benefit compared with placebo in palliation of bone pain (Wong, 2004). An open-label study conducted in community centers assessed the safety of zoledronic acid 4 mg intravenously over 15 minutes every 3 4 weeks for a planned six infusions as treatment of bone metastases in patients with multiple myeloma, breast cancer, or prostate cancer with and without previous bisphosphonate exposure. Adverse events (AEs), pain, and quality-of-life (QOL) scores were recorded. Of 638 patients, 415 patients (65%) had received prior bisphosphonate therapy. 102 prostate cancer patients were enrolled. The change from baseline pain score was analyzed using paired t-tests. Kaplan-Meier estimates were used to assess time to development of pain for patients who reported no pain upon study entry. Pain assessments were conducted at baseline, before each infusion, and at the final study visit using a 100-mm visual analog scale(vas). Patients with prostate cancer experienced a reduction in pain scores from baseline at visit 2 only, although there was never any increase in pain noted on the pain score assessment (Vogel et al, 2004) V. Antitumor effects Recent clinical studies have looked at whether bisphosphonates interfere with the growth and survival of metastatic cancer cells in the bone. A study by Lee, et al (2001) looked at the effect of pamidronate and zoledronic acid on the growth and survival of prostate cancer cell lines in vitro. Treatment of PC3, DU145 and LNCaP cells with pamidronate or zoledronic acid significantly reduced the growth of all three cell lines. Pamidronate was shown to induce cell death in all three lines studied (Lee et al, 2001). A second study by Dumon et al looked at the biological effects of bisphosphonates on cell survival. The study compared four bisphosphonates; clodronate, pamidronate, ibandronate and zoledronic acid. Cell cycle phases were analyzed and apoptotic effects were assessed. The results revealed that the clodronate exhibited only a slight inhibitory effect on cell growth. In contrast, the aminobisphosphonates decreased cell growth in a time and dose dependent manner (Dumon et al, 2004). A clinical phase III, double blind study assessing the development of bone metastases from prostate cancer (Mason, ASCO 2004) looked at patients with stage T2-T4 prostate cancer with no evidence of metastatic bone disease. The primary endpoint was time to the development of symptomatic bone metastases or death from prostate cancer. 508 patients were randomized and followed over 3.5 years. Patients were either given oral clodronate or placebo. Results revealed no difference in time to symptomatic bone metastases, death from prostate cancer or overall survival (Mason, 2004). In summary, the findings on antitumor effect have been evaluated in vitro and will need to be confirmed in clinical trials. This is an area that needs further study and may translate into additional therapeutic regimens in the future. VI. Ongoing studies Although there is not enough information at the present time to give definitive guidelines for the use of bisphosphonates in all of the stages of prostate cancer, there are ongoing clinical trials. One ongoing study is a CALGB protocol 90202 for metastatic prostate cancer patients, initiating androgen ablation within 3 months of study. It is a randomized, double blind phase III study comparing zoledronic acid 4 mg i.v. every 4 weeks, versus placebo i.v. every 4 weeks. The objectives of this study are to determine whether treatment with zoledronic acid, at the time of initiating androgen ablation therapy for metastatic prostate cancer will delay time to first skeletal related event, and to determine whether treatment with zoledronic acid will decrease the proportion of men with one or more vertebral fractures at two years compared to placebo in 403

Doyle-Lindrudan and DiPaola: Progress in prostate cancer research in New Jersey men receiving androgen ablation therapy for metastatic prostate cancer. A second study, involving the same population, metastatic prostate cancer to bone, commencing androgen ablation is being conducted by the Hoosier Oncology Group. It is a Phase III, Randomized, Double Blind, Placebo Controlled Trial evaluating the ability of risedronate to prevent skeletal related events. Patients were randomized to either daily oral risedronate combined with androgen deprivation or daily oral placebo combined with androgen deprivation. The primary objective of this study was to evaluate a daily oral dose of 30mg risedronate as compared to placebo to prevent skeletal complications in patients undergoing androgen deprivation for metastatic prostate cancer by measuring the time to a skeletal related event. The MRC trial entitled, Systemic Therapy in Advancing or Metastatic Prostate Cancer Evaluation of Drug Efficacy (STAMPEDE) trial is a multicentre international, randomized study, that will assess the safety and efficacy of three drugs, Zoledronic Acid, docetaxel and a cox 2 inhibitor in combination and alone along with ADT and a control arm of ADT. Further studies will also be needed to better define toxicities associated with short or long term use of therapy. For example, a poorly understood complication which may be associated with the use of the intravenously administered bisphosphonates pamidronate and zoledronate is osteonecrosis of the jaw (Greenberg, 2004). In 2003, Marx described 36 cases of necrotic jaw bone seen in patients receiving intravenous bisphosphonates as part of their cancer therapy. 78% of the cases occurred after dental extractions and 22% were spontaneous. These patients were also receiving chemotherapy drugs and corticosteroids which put into question whether these factors were the cause of the osteonecrosis (Marx, 2003). In June 2004, Ruggiero, et al performed a retrospective chart review of patients who presented for Oral Surgery service between February 2001 and November 2003 with the diagnosis of refractory osteomyelitis and a history of chronic bisphosphonate therapy. This review revealed 63 cases of osteonecrosis of the jaw; 56% had received an intravenous bisphosphonate for at least 6 months as part of cancer therapy and six were receiving long term oral bisphosphonate therapy for osteoporosis. Most occurred after dental extractions, but some were spontaneous (Ruggiero et al, 2004). Clearly, these retrospective associations need further study. VII. Conclusions Skeletal complications in men with prostate cancer are an under-recognized problem. Men undergoing treatment with androgen ablation for their prostate cancer, even without metastasis, are at increased risk of bone loss, and men with bone metastasis are at risk for adverse skeletal related events. Recent studies have demonstrated a benefit of bisphosphonates to improve bone density in men without bone metastasis receiving ADT, and to decrease skeletal related events in men with hormone refractory metastatic prostate cancer. The benefit of bisphosphonates in other stages of progression of prostate cancer are less clear at this point and further studies are needed. Likewise, further studies are needed to better understand other potential short term or long term toxicities. Accrual to clinical trials will be critical, and should be encouraged, to better define the use of bisphosphonate therapy in prostate cancer. References Barrass BJ, Thurairaja R and Persad RA (2004) More should be done to prevent the harmful effects of long-term androgen ablation therapy in prostate cancer. BJU Int 93, 1175-1176. Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Mattelaer J, Lopez Torecilla J, Pfeffer JR, Lino Cutajar C, Zurlo A and Pierart M (2002) Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 360, 103-106. Daniell HW, Dunn SR, Ferguson DW, Lomas G, Niazi Z and Stratte PT (2000) Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 163, 181-186. Dearnaley DP, Sydes MR, Mason MD, Stott M, Powell CS, Robinson AC, Thompson PM, Moffat LE, Naylor SL and Parmar MK (2003) A double-blind placebo-controlled randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 95, 1300-1311. Diamond TH, Campbell J, Bryant C and Lynch W (1998) The effect of combined androgen blockade on bone turnover and bone mineral densities in men treated for prostate carcinoma, longitudinal evaluation and response to intermittent cyclic etidronate therapy. Cancer 83, 1561-1566. Diamond TH, Bucci J, Kersley JH, Aslan P, Lynch WB and Bryant C (2004a) Osteoporosis and spinal fractures in men with prostate cancer, risk factors and effects of androgen deprivation therapy. J Urol 172, 529-532. Dumon, JC, Journe, F, Kheddoumi, N, Lagneaux, L, Body, JJ (2004) Cytostatic and apoptotic effects of bisphosphonates on prostate cancer cells. Eur Urol 45, 521-528; discussion 528-529. Eastham J, McKiernan J, Gleason D, Zheng M, Saad F (2005) Effect of zoledronic acid on bone pain and skeletal morbidity in patients with advanced prostate cancer; analysis by baseline pain. ASCO Abstract No. 4561, Greenberg MS (2004) Intravenous bisphosphonates and osteonecrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 98, 259-260. Gulley J and Dahut WL (2004) Chemotherapy for prostate cancer, finally an advance! Am J Ther 11, 288-294. Hemminki K, Rawal R and Bermejo JL (2004) Prostate cancer screening changing age-specific incidence trends and implications on familial risk. Int J Cancer 113, 312-5. Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ and Thun MJ (2004) Cancer statistics 2004. CA Cancer J Clin 54, 8-29. Krupski TL, Smith MR, Chan Lee W, Pashos CL, Brandman J, Wang Q, Botteman M and Litwin MS (2004) Natural history of bone complications in men with prostate carcinoma initiating androgen deprivation therapy. Cancer 101, 541-549. Lee, MV, Fong, EM, Singer, FR, Guenette, RS (2001) Bisphosphonate treatment inhibits the growth of prostate cancer cells. Cancer Res 61, 2602-2608. Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws, a growing epidemic. J Oral Maxillofac Surg 61, 1115-1117. 404

Cancer Therapy Vol 3, page 405 Mason, MD (2004) Development of bone metastases from prostate cancer: first results of the MRC PR04 randomised controlled trial (ISCRTN61384873). J Clin Oncol 22, 384 Melton LJ, 3rd Alothman KI, Khosla S, Achenbach SJ, Oberg AL and Zincke H (2003) Fracture risk following bilateral orchiectomy. J Urol 169, 1747-1750. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED and Trump D (1999) Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 341, 1781-1788. Ruggiero SL, Mehrotra B, Rosenberg TJ and Engroff SL (2004) Osteonecrosis of the jaws associated with the use of bisphosphonates, a review of 63 cases. J Oral Maxillofac Surg 62, 527-534. Saad F (2002) Zoledronic acid significantly reduces pathologic fractures in patients with advanced-stage prostate cancer metastatic to bone. Clin Prostate Cancer 1, 145-152. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA and Chen B (2002) A randomized placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94, 1458-1468. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS (2005) Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352, 154-164. Smith MR, Eastham J, Gleason DM, Shasha D, Tchekmedyian S and Zinner N (2003) Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 169, 2008-2012. Smith MR, McGovern FJ, Zietman AL, Fallon MA, Hayden DL, Schoenfeld DA, Kantoff PW and Finkelstein JS (2001) Pamidronate to prevent bone loss during androgendeprivation therapy for prostate cancer. N Engl J Med 345, 948-955. Vogel CL, Yanagihara RH, Wood AJ, Schnell FM, Henderson C, Kaplan BH, Purdy MH, Orlowski R, Decker JL, Lacerna L, Hohneker JA ( 2004) Safety and pain palliation of zoledronic acid in patients with breast cancer, prostate cancer, or multiple myeloma who previously received bisphosphonate therapy. Oncologist 9, 687-695. Wong R (2004) No difference between pamidronate disodium and placebo in relieving bone pain in men with advanced prostate cancer. Cancer Treat Rev 30, 395-400. 405

Doyle-Lindrudan and DiPaola: Progress in prostate cancer research in New Jersey 406