The Use of Bisphosphonates in the Management of ... - Springer Link

The Use of Bisphosphonates in the Management of Bone Metastatic Prostate Cancer Sebastiano Mercadante, MD

Address Anestesia and Intensive Care Unit & Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Via S. Lorenzo 312, Palermo, 90146, Italy. E-mail: [email protected] Current Urology Reports 2002, 3:244–249 Current Science Inc. ISSN 1527-2737 Copyright © 2002 by Current Science Inc.

Improved understanding of the pathophysiology of prostate cancer–induced metabolic bone disease implies that bisphosphonates may have a role in the treatment of this disorder. Although prostate cancer cells stimulate osteoblasts, resulting in a marked increase in bone volume and the classic radiologic aspect of sclerotic metastases, accelerated bone resorption has been reported by histomorphometric and biochemical studies. The significant relationship between the biochemical parameters of bone resorption and formation suggests a coupling between these two processes in metastatic prostate cancer. Several studies have demonstrated that administration of bisphosphonates is one of the most cost-effective palliative treatments for patients with prostate carcinoma and bone metastases, both as first-line and long-term therapy. With appropriate doses, a large proportion of patients can be maintained free of bone pain until death. Studies of the efficacy of lower doses to prevent skeletal morbidity in patients without metastases or with asymptomatic bone lesions are warranted.

Introduction Prostate cancer is the most common malignancy in elderly men and is often associated with bone metastases. In spite of new developments in hormonal therapies, the overall survival rate for this malignancy remains unchanged. Because effective second-line treatments are not yet available, disease management becomes difficult in cases of hormonal escape. Androgen ablation is the treatment of choice, but the majority of patients relapse within 2 to 3 years of initiation of therapy. Ninety percent to 95% of patients with hormone refractory prostate cancer present with bone metastases. The development of skeletal metastases is associated with a significant increase in morbidity because of severe bone pain that eventually

becomes refractory to conventional analgesia. Eighty percent to 90% of men with terminal metastatic prostate cancer suffer from pathologic fractures, spinal cord compression, weight loss, anemia, and thrombocytopenia [1••]. The bone resorption index in patients with bone metastatic prostate cancer correlates with bone pain and is an independent predictor of adverse skeletal events. Present therapeutic strategies focus on the palliation of symptoms and improvement in quality of life. Therefore, an effective decrease in bone pain appears to be of relevant importance in the economy of palliative treatment.

Prostate Cancer–induced Changes in Bone Metabolism and Bisphosphonates All bisphosphonates are characterized by a phosphoruscarbon-phosphorus–containing central structure that promotes their binding to the mineralized bone matrix. In addition, they also have a variable R chain that determines their relative potency, adverse effects, and precise mechanism of action. Following administration, bisphosphonates avidly bind to exposed bone mineral around resorbing osteoclasts, leading to very high local concentrations of bisphosphonate in the resorption lacunae. Rapid and exciting progress has been made since the first successful use of bisphosphonates for the treatment of cancer hypercalcemia. Improved understanding of the pathophysiology of prostate cancer–induced metastatic bone disease implies that bisphosphonates may have a role in the treatment of this disorder. The clinical use of these agents is not immediately obvious, given the predominantly osteoblastic nature of the metastatic process. Prostate cancer cells stimulate osteoblasts (due to specific mitogenic factors in a paracrine fashion) and result in a marked increase in bone volume. This can be documented in patients as the classic radiologic aspect of sclerotic metastases. The paradox of increased bone volume with accelerated bone resorption has been explained by histomorphometric and biochemical studies, which demonstrate that bone resorption is associated with the replacement of normal lamellar skeletal architecture by abnormal woven bone generated by osteoblastic hyperstimulation. This process results in osteosclerosis,

The Use of Bisphosphonates in the Management of Bone Metastatic Prostate Cancer • Mercadante

increased bone volume, and destruction of normal bone. In addition to producing osteoblastic metastases, prostate cancer cells are also responsible for major osteoclastic bone destruction because of paracrine stimuli by osteoclast-secreted epidermal growth factor [2•]. These histomorphometric changes are paralleled by disturbances in calcium metabolism. Calcium uptake is increased in the metastatic skeleton as a consequence of osteoblastic hyperactivity, while there is a mobilization of calcium from nonlesioned areas of the skeleton to compensate for the metastatic calcium sink effect and to maintain normal serum calcium. Another compensatory mechanism is increased intestinal calcium absorption. Increase in osteoblastic activity seems to be mediated by parathyroid hormone and vitamin D. Significant increases of osteocalcin and alkaline phosphatase, as well as elevated urinary excretion of hydroxyproline and pyridinium, have been reported to reflect an increase in bone turnover [3]. The significant relationship between the biochemical parameters of bone resorption and formation suggests a coupling between these two processes in metastatic prostate cancer.

Effects of Bisphosphonates on Bone Metastases In preliminary studies, men with hormone refractory prostate cancer received pamidronate or no treatment at all. Assessment of bisphosphonate effect was accomplished by iliac crest biopsies and monitoring of hydroxyproline excretion. The significant decrease in the indices of bone breakdown (such as lowering of hydroxyproline excretion) and the preservation of tumor-free bone volume after orchiectomy sustained the bisphosphonate therapeutic effect [4,5]. In a comparison study of 48 patients, all bone markers, including osteocalcin, total and specific alkaline phosphatase, serum type I collagen C-terminal propeptide (all for bone formation), and urinary excretion and serum concentration of type I collagen (for bone resorption), were significantly higher in patients with bone metastases from prostate cancer compared with healthy age-matched controls, patients with localized prostate cancer, or those with benign prostatic hyperplasia. The effect of 120 mg of pamidronate was assessed in a subset of 14 patients with endocrine-resistant bone metastases 14 days after a single intravenous (IV) injection of the bisphosphonate. All patients demonstrated a mean 60% to 70% decrease in resorption markers; bone formation markers remained stable with this therapy. Although bone-specific alkaline phosphatase and type I collagen propeptide immunoassays are currently the most sensitive markers to assess bone formation in prostate cancer, with their levels correlating with the extent of the bone involvement, their sensitivity remains limited, suggesting that the currently available biochemical markers cannot be used as a surrogate for diagnostic bone scan in

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the assessment of metastatic disease. Therefore, bone markers are most commonly used to monitor the effects of bisphosphonate treatment for metastatic bone disease, with a drop in marker levels indicating a corresponding reduction of bone pain [6]. We are only just beginning to understand the mechanisms through which bisphosphonates exert their activity. Metastatic prostate cancer interferes with physiologic remodeling by abnormal release of hormones and paracrine factors physiologically involved in the modulation of osteoblastic and osteoclastic activity. Increasing evidence indicates that despite the osteoclastic nature of metastatic prostate cancer bone lesions, osteolysis is a regular feature of advancing disease and may cause skeletal morbidity. Although bone metastases are osteosclerotic, histologic and biochemical studies indicate an increase of both formation and bone resorption, because abnormal osteoblastic bone formation within metastases is preceded by osteoclastic activation [7]. This observation provides the rationale for the use of bisphosphonates for managing bone metastatic prostate cancer. Bisphosphonates are potent inhibitors of normal and pathologic bone resorption. Preferentially localizing to sites of active bone resorption and formation, they directly exert an inhibitory effect on mature osteoclasts. Moreover, increased bone resorption may also be a generalized phenomenon most likely due to iatrogenic osteoporosis, or related to a hyperparathyroid response to increased calcium demand. Because patients with advanced prostate cancer are androgen-deprived and at risk for bone demineralization, the bone strengthening effects of bisphosphonate therapy may have a second benefit. Androgen-deprivation therapy with a gonadotropinreleasing hormone agonist, frequently used in the treatment of metastatic and nonmetastatic prostate cancer [8], commonly decreases bone mineral density and increases a patients’ risk of fracture. Bisphosphonates have been used for the treatment of osteoporosis to improve bone mineral density and reduce the incidence of bone fractures [9], and evidence suggests that patients with metastatic prostate cancer may also benefit from this treatment modality. Intravenous pamidronate administered to men undergoing treatment with a gonadotropin-releasing hormone agonist for prostate cancer prevented bone loss in the hip and spine. Patterns of bone absorption marker excretion, including plasmatic alkaline phosphatase, osteocalcin, urinary deoxypyridinoline, and N-telopeptide, were characterized by a sharp and transient decrease with treatment, followed by a return to baseline concentrations before the next treatment [10••]. Because low bone mineral density is an important determinant for the risk of fracture, these findings are relevant for prevention of bone fractures in patients undergoing hormone therapy for treatment of metastatic prostate cancer.

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Other Possible Effects of Bisphosphonates in Prostate Cancer It is an intriguing possibility that the observed clinical utility of bisphosphonates in managing skeletal metastases may, in part, derive from direct inhibition of prostate cancer cell growth in the bone microenvironment. Using flow cytometry, pamidronate treatment induced significant amounts of cell death in different prostate tumor cell lines. In contrast, zoledronate did not induce cell death, but instead exerted dramatic effects on cell proliferation. Although both drugs reduced prostate cancer cell growth in the presence of serum, zoledronate was more potent under these conditions [11]. In an experimental simulation of the putative route by which prostate tumor cells spread to the vertebral column, bisphosphonate treatment delayed the onset of skeletal metastases. In this scenario, where synergeneic, metastatic prostate tumor cells were induced to metastasize to bone, bisphosphonate treatment was initiated 1 day prior to injection and continued for 5 additional days. Results were assessed by monitoring the rate of onset of skeletal metastasis–induced paralysis [12].

Clinical Studies in Patients with Bone Metastases from Prostate Cancer Although skeletal metastases frequently develop in patients with advanced hormone refractory prostate cancer, there are sparse systematic data on the clinical efficacy of bisphosphonates for the treatment of symptomatic skeletal metastases due to prostate cancer. In addition, only a few controlled studies have sufficient patient numbers available (Table 1). Different bisphosphonates have been used in patients with prostate cancer. Although a significant palliative response has been described with etidronate [13], a bisphosphonate with a low antiresorbing potency compared with clodronate and pamidronate, this agent did not show any benefit in a controlled study comparing etidronate with a placebo [14]. Etidronate is the least potent inhibitor of bone resorption and has the most marked effect on bone mineralization, leading to osteomalacia. In an early open study, a small number of patients with prostate cancer metastatic to bone were treated with 300 mg of IV clodronate for 2 weeks and then 3200 mg orally or 100 mg intramuscularly. These patients reported a significant improvement in pain and Karnofsky index scores [15]. These results were confirmed in subsequent studies with larger patient samples. In one multicenter trial, 80 of 92 patients experienced a dramatic improvement of bone pain after treatment with 300 mg IV clodronate infused daily for 10 days [16]. In this study, a small number of patients received 2 weeks' treatment with IV infusion of either 300 mg clodronate or saline. The differences in both pain score and analgesic consumption were so striking that the trial was not extended for ethical

reasons, and all patients on placebo were given IV clodronate. Oral administration of 1200 mg clodronate for 2 weeks was completely ineffective in 11 patients. Twelve patients treated with intramuscular administration of 100 mg clodronate for 2 weeks reported a significant decrease in analgesic consumption, but not in pain score. Bone pain relapsed fairly soon in most of the 13 patients given IV clodronate for 2 weeks. However, in 18 patients a maintenance therapy with clodronate 1200 mg/d for at least 6 weeks after a 2-week IV treatment course did prevent the relapse of bone pain. No hematologic toxicity was ever observed [16]. However, patients reported only transient pain relief in a controlled study of oral clodronate [17]. This result was attributed to the occurrence of osteomalacia, a condition also observed in the control group. Of 57 patients with advanced prostate cancer and a failure of prior hormonal treatment, 39 concluded a double-blind placebo-controlled trial in which they were randomly allocated to receive either clodronate 300 mg or placebo daily for 5 consecutive days. Participating patients were thereafter maintained on 1600 mg of clodronate administered orally or placebo daily for 3 months [18]. Bone resorption was noted to markedly increase, especially in biopsies taken from tumor-involved bone. Both treatments induced a significant decrease in bone resorption, but were associated with the development of hypocalcemia, secondary hypoparathyroidism, hypophosphatemia, and severe impairment of mineralization of newly formed bone (osteomalacia). Therefore, the transitory nature of metastatic bone pain relief achieved with antiresorptive agents may be due to the development of osteomalacia in response to these agents [18]. Another open-label study administered IV clodronate 300 mg/d for 8 days, followed by an oral dose of 1600 mg of clodronate. Seventy-one percent of 41 patients reported a significant decrease in pain for a mean duration of 7 weeks, covering about 60% of total patient survival time. Pain relapse was controlled by another cycle of IV clodronate [19]. The percentage of patients reporting significant pain relief was somewhat lower in subsequent studies (37% and 56%, respectively) [20,21]. These studies administered the same dose of IV clodronate (300 mg), but for different treatment duration periods (10 and 6 days, respectively) [20,21]. Bone histomorphometry was studied in patients receiving complete androgenic blockade clodronate. Clodronate induced an antiresorptive effect expressed as the eroded/bone surface and as the osteoclast number/ bone surface. Bone volume and osteoid formation also decreased after 6 months of treatment, probably because of the drug’s effect on osteoblasts [22]. A larger number of patients (85 total) with painful bone metastases due to hormone refractory prostate cancer were treated with IV clodronate for 8 days. In this open prospective nonrandomized trial [23], each patient received clodronate 300 mg/d followed by an oral


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Table 1. Randomized trials examining the clinical benefits of bisphosphonates for the treatment of bone metastases due to prostate cancer Study

Patients, n

Agents tested

Adami and Mian [16]

13

Clodronate 200 mg IV for 2 wks and saline

Smith [14] Elooma et al. [17]

57 75

Taube et al. [18]

39

Smith et al. [10••]

47

Etidronate ~ 300 mg PO and placebo Clodronate 3.2 g PO then 1.6 g PO and placebo Clodronate 300 mg IV, then 1600 mg PO and placebo Pamidronate 60 mg q12 wks + leuprolide and leuprolide

Comments Better pain relief and less analgesic consumption; trial interrupted for striking differences No benefit Transient better pain relief and less analgesic consumption Transient pain relief, ostemalacia due to hypocalcemia-hypophosphatemia Significant differences in bone loss in men receiving pamidronate

IV—intravenously; PO—by mouth.

maintenance phase of 1600 mg/d. Patients received analgesic medication during an initial adjustment and stabilization period. Seventy-five percent of patients reported a palliative response, with a significant decrease in mean pain scores from 7.9 to 2.5. The first analgesic effect was observed after an average of 4 days of parenteral therapy. At this time, 22% of patients were completely pain-free without further need of analgesics, and the others had significantly decreased their daily consumption of analgesics. The mean survival was 12 weeks, with a duration of palliative effect of about 9 weeks. All patients received 300 mg of IV clodronate at 14-day intervals. Improvement in bone pain was paralleled by an improvement in the mean Karnofsky index, a change attributed mainly to better mobility. Twenty-five percent of patients studied, specifically those with extraosseous metastases and advanced disease, failed to respond to this regimen. The predominant adverse effect reported by patients was gastrointestinal discomfort associated with the oral administration of clodronate, necessitating discontinuation of therapy in 6% of patients [23]. In a 48-week, open label study, patients were randomly treated with hormone therapy or a combination of gonadotropin-releasing hormone agonist and pamidronate (60 mg every 12 weeks) [10••]. Treatment also included bicalutamide, calcium, and vitamin D. The two groups exhibited significant differences in the mean changes in bone mineral density and serum concentrations of specific alkaline phosphatase, osteocalcin, urinary deoxypyridinoline, and N-telopeptide. Because low bone mineral density is an important determinant of the risk of fracture, pamidronate may reduce this risk in men receiving hormone therapy. A similar effect has been observed in women treated with pamidronate for postmenopausal osteoporosis. Changes in biochemical markers of bone turnover observed in the course of this study were complex: after a sharp post-treatment decrease, these values returned to near baseline concentrations before the next treatment. One explanation for this result could be the long intervals between administra-

tion of pamidronate doses for metastatic prostate cancer, compared with protocols used in the treatment of breast cancer [10••]. Olpadronate is a new agent that is more potent than the other commonly used bisphosphonates (etidronate, clodronate, and pamidronate). Clinical and biochemical responses after IV administration of olpadronate (4 mg/d for 5 days) have been studied in patients with prostate cancer and bone metastases [24]. This clinical response was paralleled by rapid and significant suppression of bone resorption and was characterized by a concurrent decrease in bone pain and analgesic use. Patients were maintained on continuous oral therapy with olpadronate 20 mg/d daily in order to sustain this positive response. The transient pain relief in patients treated with IV olpadronate paralleled documented transient changes in urinary calcium and hydroxyproline excretion. Suppression of bone resorption was short-lived in patients who did not receive additional oral therapy, and within 6 weeks after treatment hydroxyproline excretion returned to pretreatment levels. Sustained pain relief in patients treated with oral olpadronate was associated with a sustained decrease in urinary excretion of bone resorption indices. Olpadronate significantly improved bone resorption without having a significant effect on serum alkaline phosphatase activity [24]. Ibandronate is a highly potent bisphosphonate, 50 and 500 times more potent than pamidronate and clodronate, respectively. Reflecting the typical absorption of bisphosphonates, the IV route of administration of this agent is 100 times more effective than oral administration. In a dose-finding study, 110 patients with radiologically confirmed bone metastases, including 16 patients with prostate cancer, were recruited over a 12-month period to participate in a double-blind placebo-controlled evaluation of four oral dose levels of ibandronate (5, 10, 20, and 50 mg). Four weeks after starting treatment a dosedependent reduction was observed in urinary calcium excretion, collagen crosslink excretion, pyridinoline, and

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deoxpyridinoline. This represented a clear dose-response relationship, with the greatest changes observed at the 20 mg and 50 mg dose levels. However, 8% of patients equally distributed across the five groups discontinued treatment within the first month because of gastrointestinal intolerability. No significant effects of treatment were demonstrated on bone pain and analgesic intake over time or between the treatment groups. Pain relief in individual patients was not related to the dose of ibandronate or the changes observed in bone resorption markers. However, these data cannot be transferred to patients with prostate cancer because of the low number of patients with this disease in this group, who were not considered separately [25•].

Comments on Bisphosphonate Treatment Bisphosphonates are commonly well tolerated by patients. Adverse effects include fewer gastrointestinal disturbances by oral administration, mild and transient hyperalgesic effect, and hypocalcemia and hypophosphatemia; as a consequence, these agents have a potential for nephrotoxicity. In some patients receiving bisphosphonates there is indirect biochemical and histologic evidence of osteomalacia. With bisphosphonate therapy there is a transient striking prevalence of osteoblastic activity over bone resorption, occasionally causing the appearance of symptomatic hypocalcemia. In order to potentially improve the final outcome of this therapy, the use of large oral supplements of calcium is recommended, particularly at start of therapy [7]. In order to obtain optimal therapeutic results in patients with metastatic prostate carcinoma, initial bisphosphonate administration should be followed by maintenance treatment at doses sufficient to keep bone resorption suppressed. Oral bioavailability is poor (1%–2%), although administration efficiency increases with increasing doses. However, it should be noted that the efficacy of oral bisphosphonates diminishes when the drug is given with food. One way of bypassing this limitation could be with repeated bisphosphonate infusions, the dose and frequency of which would need to be determined. Most bisphosphonate studies in patients with prostate cancer have been performed with clodronate, where parenteral administration of clodronate is a major prerequisite to bone saturation and consequent rapid onset of pain control. Subsequent oral administration in doses of more than 1600 mg may allow persistent pain relief. However, due to the low oral bioavailability and occurrence of intolerable gastrointestinal adverse effects, repeated cycles of IV clodronate may be helpful after oral maintenance therapy fails [23]. A combination of mitoxantrone and prednisone are currently the standard palliative treatment for symptomatic prostate cancer. Bisphosphonate treatment of painful bone metastases appears equal or better to mitoxantrone

and prednisone therapy in terms of percentage of patients obtaining pain relief or reduction of analgesic consumption. Moreover, adverse effects of the combination therapy seem more serious than gastrointestinal adverse effects commonly reported with bisphosphonate use. However, a direct comparative study between these treatments has never been performed [23].

Bisphosphonate Therapy: Economic Analysis This class of drugs, especially the newer, more potent ones, is quite expensive. Although bisphosphonates have been proven to have some analgesic effect in bone metastases of differential origin, few studies are available evaluating the cost-effectiveness of treating malignant disease and pain with these agents. In addition, healtheconomic investigations directed at finding optimal strategies for patient management with bisphosphonates are also lacking. In one study with a follow-up of 6 months, treatment with pamidronate reduced pain and did not add noticeably to the cost of treatment [26]. A cost-utility analysis suggested that bisphosphonates, namely pamidronate, provided patients with a substantial quality-adjusted survival benefit at a reasonable cost over a 12-month period [27]. Shorter infusion time associated with the administration of zoledronate compared with pamidronate yields substantial time saving for patients, as well as treatment opportunity benefits for outpatient oncology facilities [28]. Unfortunately, these studies have been performed in patients with different primary tumors, and not patients with prostate cancer, who have distinct physiopathologic aspects compared with other cancers.

Conclusions Bone metastases in advanced hormone refractory prostate cancer are a major clinical problem resulting in significant morbidity and decreased quality of life. The effect of prostate cancer skeletal metastases may be modulated by bisphosphonates, resulting in improved pain, mobility, and decreased osteolysis. Similar results have been reported for bisphosphonate treatment for advanced breast cancer. The clinical use of bisphosphonates rests on a number of basic and clinical observations that provide ample evidence that, in prostate cancer, the metastatic process is associated with increased bone resorption. Bisphosphonates have not been shown to prolong survival. Evidence regarding the beneficial effects of bisphosphonates in reducing morbidity from metastatic prostate cancer is reasonably solid. Administration of bisphosphonates could be a cost-effective palliative treatment for patients with prostate carcinoma–derived bone metastases, both as a first-line and long-term therapy, as demonstrated in breast cancer. With appropriate doses, a large proportion of patients can be maintained free of


bone pain until death. However, the choice of optimal bisphosphonate agent, mode of administration, dosage, and duration of treatment must be determined in large, controlled studies before their widespread use can be advocated. Studies of the ability of lower doses to prevent skeletal morbidity in patients without metastases or with asymptotic bone lesions are warranted.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.•• Smith JA, Soloway MS, Young MJ: Complications of advanced prostate cancer. Urology 1999, 54(Suppl 6A):8–14. Authoritative review of complications associated with advanced prostate cancer. 2.• Berruti A, Dogliotti L, Tucci M, et al.: Metabolic bone disease induced by prostate cancer: rationale for the use of bisphosphonates. J Urol 2001, 66:2023–2031. Comprehensive review of the metabolic changes in metastatic bone cancer and rationale for using bisphosphonates as treatment. 3. Bichler KH, Petri E, Hub A, et al.: Investigations on bone metabolism of urological tumors forming metastases. Urol Int 1996, 56:61–68. 4. Clarke NW, McClure J, George NJ: Disodium pamidronate identifies differential osteoclastic bone resorption in metastatic prostate cancer. Br J Urol 1992, 69:64–70. 5. Clarke NW, McClure J, George NJ: The effects of orchidectomy on skeletal metabolism in metastatic prostate cancer. Scand J Urol Nephrol 1993, 27:475–483. 6. Garnero P: Markers of bone turnover in prostate cancer. Cancer Treat Rev 2001, 27:187–192. 7. Adami S: Bisphosphonates in prostate carcinoma. Cancer 1997, 80(Suppl 8):1674–1679. 8. The Medical Research Council Prostate Cancer Working Party Investigators Group: Immediate versus deferred treatment for advanced prostatic cancer: initial results of the medical Research Council Trial. Br J Urol 1997, 79:235–246. 9. Orwoll E, Ettinger M, Weiss S, et al.: Alendronate for the treatment of osteoporosis in men. N Engl J Med 2000, 343:604–610. 10.•• Smith M, McGovern FJ, Zietman AL, et al.: Pamidronate to prevent bone loss during androgen deprivation therapy for prostate cancer. New Engl J Med 2001, 345:948–955. Long-term randomized, controlled, open-label study assessing bone mineral density. This study demonstrated that pamidronate, given 60 mg every 12 weeks, is able to prevent bone loss in men receiving gonadropin-releasing hormone agonist. 11. Lee MV, Fong EM, Singer FR, Genette RS: Bisphosphonate treatment inhibits the growth of prostate cancer cells. Cancer Res 2001, 5:2602–2608. 12. Sun YC, Geldof AA, Newling DW, Rao BR: Progression delay of prostate tumor skeletal metastasis effects by bisphosphonates. J Urol 1992, 148:1270–1273.

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Carey PO, Lippert MC: Treatment of painful prostatic bone metastases with oral etidronate disodium. Urology 1988, 32:403–407. 14. Smith JA: Palliation of painful bone metastases from prostate cancer using sodium etidronate: result of randomised, prospective, double–blind placebo controlled study. J Urol 1989, 141:85–87. 15. Adami S, Salvano G, Guarrera G, et al.: Dichloromethylenedisphosphonate in patients with prostate carcinoma metastatic to skeleton. J Urol 1985, 134:1152–1154. 16. Adami S, Mian M: Clodronate therapy of metastatic bone disease in patients with prostatic carcinoma. Rec Results Cancer Res 1989, 116:67–72. 17. Elooma I, Kylmala T, Tammela T: Effect of oral clodronate: a controlled study in patients with metastatic prostate cancer. Int Urol Nephrol 1992, 24:159–166. 18. Taube T, Kylmala T, Lamberg-Allardt, et al.: The effect of clodronate on bone in metastatic prostate cancer. Histomorphometric report of a double-blind randomised placebocontrolled study. Eur J Cancer 1994, 30A:751–758. 19. Vorreuther R: Bisphosphonates as an adjunct to palliative therapy of bone metastases from prostatic carcinoma: a pilot study on clodronate. Br J Urol 1993, 72:792–795. 20. Cresswell SM, English PJ, Hall RR, et al.: Pain relief and quality of life assessment following intravenous and oral clodronate in hormone-escaped metastatic prostate cancer. Br J Urol 1995, 76:360–365. 21. Kyimala T, Tammela TL, Lindholm TS, et al.: The effect of combined intravenous and oral clodronate treatment on bone pain in patients with metastatic prostate cancer. Ann Chir Gynaecol 1994, 83:316–319. 22. Fernandez-Conde M, Alcover J, Aaron JE, et al.: Skeletal response to clodronate in prostate cancer with bone metastases. Am J Clin Oncol 1997, 20:471–476. 23. Heidenreich A, Hofmann R, Engelmann UH: The use of bisphosphonate for the palliative treatment of painful bone metastasis due to hormone refractory prostate cancer. J Urol 2001, 65:136–140. 24. Pelger RC, Hamdy NA, Zwinderman AH, et al.: Effects of the bisphosphonate olpadronate in patients with carcinoma of the prostate metastatic to the skeleton. Bone 1998, 22:403–408. 25.• Coleman RE, Purohit OP, Black C, et al.: Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease. Ann Oncol 1999, 10:311–316. Randomized, controlled, dose-finding study of a new potent agent for the treatment of metastatic bone disease from different primary tumors, including a small number of patients with prostate cancer. 26. Gessner U, Koeberle D, Thuerlimann B, et al.: Economic analysis of terminal care for patients with malignant osteolytic bone disease and pain treated with pamidronate. Support Care Cancer 2000, 8:115–122. 27. Dranitsaris G, Hsu T: Cost utility analysis of prophylactic pamidronte for the prevention of skeletal related events in patients with advanced breast cancer. Support Care Cancer 1999, 7:271–279. 28. DesHarnais Castel L, Bajwa K, Markie JP, et al.: A microcosting analysis of zoledronic acid and pamidronate therapy in patients with metastatic bone disease. Support Care Cancer 2001, 9:545–551.