Aetiology and impact of prostate cancer-related bone metastases

Prostate cancer is the most commonly diagnosed malignancy in males in the UK, with nearly 25 000 cases being reported in 1999 (www.cancerresearchuk.org/statistics). Prostate cancer-related morbidity and mortality are closely associated with the formation of metastases. Bone is the preferred site for these metastases, and estimates indicate that bone metastases are present in more than 80% of men with advanced prostate cancer.^1,2 A UK study has shown that bone metastases are present in up to 50% of men at the time of first presentation.³

Considerable morbidity arises from various complications from bone metastases, and it is estimated that the average frequency of a 'skeletal-related event' in patients with bone metastases is 3–4 months, with these events invariably leading to a reduced quality of life.⁴ Common presentations include pain, spinal cord compression, pathological fracture, and abnormalities in serum calcium levels.⁵ Patients with hormone-refractory metastatic prostate cancer are particularly prone to incapacitating progressive bone disease.⁶

The normal resculpturing of bone is governed by the coupled processes of bone resorption and formation. Modelling occurs in localised areas of cortical and trabecular bone known as bone metabolic units. Osteoclast-mediated resorption usually takes about 7–10 days, while the subsequent formation phase, governed by osteoblasts, lasts approximately 3 months (Figure 1). Local 'coupling' factors produced in the bone marrow regulate the remodelled bone.⁷

Figure 1.

Normal bone remodelling. (i) Resorption: stimulated osteoblast precursors release factors that induce osteoclast differentiation and activity. Osteoclasts remove bone mineral and matrix, creating an erosion cavity. (ii) Reversal: mononuclear cells prepare bone surface for new osteoblasts to begin forming bone. (iii) Formation: successive waves of osteoblasts synthesize an organic matrix to replace resorbed bone and fill the cavity with new bone. (iv) Resting: bone surface is covered with flattened lining cells. A prolonged resting period follows with little cellular activity until a new remodelling cycle begins. 'Published with kind permission of Novert's Pharmaceuticals'.

Full figure and legend (214K)

The rich milieu of growth factors in the bone environment provides an attractive 'soil' for the seeding of certain tumour cells. In the presence of such cells, factors from tumour-induced breakdown of bone stimulate growth of further cancer cells, which in turn leads to further increases in bone resorption (Figure 2). This has been described as the vicious cycle.⁷ As an example, tumour cells have been shown to release PTHrP, which stimulates osteoclastic resorption, via messaging from the osteoblast.⁸ The resultant osteolysis releases several bone-derived growth factors, such as TGF. Normally, TGF serves to limit bone resorption via a negative feedback mechanism, but in the bone metastasis, TGF stimulates invading tumour cells, partly accounting for this vicious cycle.⁹

Figure 2.

Pathogenesis of bone metastases. Factors are released by tumour cells that stimulate both osteoclast (1) and osteoblast (2) activity. Excessive new bone formation (3) occurs around tumour cell deposits, resulting in low bone strength and potential vertebral collapse. Osteoclastic (4) and osteoblastic (5) activity releases growth factors that stimulate tumour cell growth, perpetuating the cycle of bone resorption and abnormal bone growth. 'Published with kind permission of Novert's Pharmaceuticals'.

Full figure and legend (201K)

Prostate cancer bone metastases usually appear on radiographs as areas of increased bone density, being principally sclerotic in nature. This suggests the occurrence of osteoblast-mediated excessive bone formation, in response to the presence of tumour cells. However, biochemical and histomorphometric studies indicate that osteolysis (excessive bone destruction) is also concurrently increased, and probably represents a vital initial step in the establishment of the metastases.^5,6,7,10,11. For example, recent studies using biochemical indices of bone turnover in patients with prostate cancer have found that although the disease is characterised by osteoblastic metastases, there is also a direct correlation between skeletal metastases and bone resorption markers.^12,13 Indeed, the excretion of these indices was better correlated than plasma alkaline phosphatase, which is an accepted index of bone formation. It is now largely accepted that osteolysis is an important component of the influence of malignancy on bone, even when profound increases in new bone formation are also observed.¹⁴ The classic sclerotic bone lesions seen in prostate cancer represent an uncoupling of normal bone resorption and deposition shifting the balance towards new matrix formation and mineralisation. Thus, it follows that interfering with the process of osteolysis could have an important influence on the development of prostate cancer metastases.

Current treatment options for bone metastases

Given the nature of the vicious cycle described above, options that can be considered for the treatment of metastatic bone disease are: (i) directly reducing tumour cell proliferation, for example, by direct inhibition of growth factors and cytokines, (ii) antagonising the effect of tumour cells on the host, or (iii) a combination of these. Direct antitumour treatment options include: chemotherapy, surgery, endocrine therapy, or radiotherapy. In practice, chemotherapy has for many years had no established role in prostate cancer, but encouraging results are now indicating some benefit in the most advanced cases, with agents such as mitoxantrone,^15,16 docetaxel,^17,18,19 estramustine,^20,21 and thalidomide.²² Surgical tumour removal is not appropriate in the metastatic setting. For many years, endocrine therapy has represented the mainstay of treatment for patients with advanced prostate cancer. When the hormone-refractory state has been reached though, a palliative approach is often sought. Radiotherapy can provide local control of symptoms. Calcitonin or gallium nitrate, as indirect antitumour treatments, are occasionally used in a palliative setting for medical control of hypercalcaemia, although this condition is rare in prostate cancer.⁴ Otherwise, there have been very few options that have proved beneficial in this setting. There is therefore a great deal of interest in seeking out alternative therapies for the large number of men suffering from metastatic prostate cancer.

Bisphosphonates: evolution of a therapeutic theory

Bisphosphonates are a well-established class of drugs that have been known for many years to inhibit bone turnover, and have become established therapeutic options in the treatment of diseases such as Paget's disease, osteoporosis, and general tumour-associated bone disease (such as hypercalcaemia).

The. structure of these drugs is characterised by a central P–C–P bond, which promotes their binding to the mineralised bone matrix, and a variable R' chain, which determines the relative potency, side effects, and the precise mechanism of action (Figure 3). Following administration, bisphosphonates bind strongly to exposed bone mineral around resorbing osteoclasts, leading to very high local concentrations (possibly up to 1000 M) in the resorption lacunae.²³

Figure 3.

Schematic molecular structure of bisphosphonates.

Full figure and legend (9K)

Bisphosphonates have been shown to reduce bone turnover by primarily inhibiting osteoclast function. It has been proposed that these drugs can be thought of as working at three levels.²⁴ At the tissue level, they decrease bone turnover via initial inhibition of bone resorption, with suppressed bone formation following as a consequence of this. At the cellular level, bisphosphonates exert their activity principally via actions on osteoclasts, inhibiting their formation, migration, and osteolytic activity, as well as directly inducing apoptosis. It has been shown that bisphosphonates also act partly via modulation of signalling from osteoblasts to osteoclasts (Figure 4).²⁵ At the molecular level, the mode of action of bisphosphonates depends on their structure. Non-nitrogen-containing bisphosphonates (in which the R' chain contains no N atom) are metabolised to nonhydrolysable ATP analogues, that become toxic as they accumulate.²⁶ The more recently developed and more potent nitrogen-containing bisphosphonates act via inhibition of the mevalonate pathway.^27,28 This pathway usually provides the cell with lipids that are required for the normal post-translational modification of GTP-binding proteins, the functions of which are essential for many normal cellular processes.

Figure 4.

Mechanisms of action of bisphosphonates. 'Published with kind permission of Novert's Pharmaceuticals'.

Full figure and legend (155K)

The action of bisphosphonates on osteoclasts alone represented an initial rationale for investigating their potential use in prostate cancer-associated bone disease, as a reduction in osteoclast activity would reduce the release of growth factors in the bone environment and make it a less fertile soil for the seeding of tumour cells, as indicated above.²⁹

Early animal work in the 1980s demonstrated that the bisphosphonates clodronate and etidronate inhibited tumour-mediated osteolysis induced by implanted prostate cancer cells.^30,31,32 A later exciting development came when in vitro work established that bisphosphonates also act directly on tumour cells themselves. They have been shown to inhibit cell proliferation and viability, and induce apoptosis in a number of cancer cell lines, including prostate cancer.^{33,34,35,36,37} Work in our centre with breast cancer cells provided early evidence that inhibition of the mevalonate pathway was again central to the observed apoptotic effects.³⁸ We recently published similar results for various prostate cancer cell lines,³⁵ and provided evidence that the resultant apoptosis was dependent on the activation of caspases. Unpublished work in our laboratory has confirmed an apoptotic effect on prostate cancer cells at concentrations that are likely to be physiologically relevant. Other work has shown bisphosphonates to inhibit the adhesion of cancer cells to bone slices,^39,40 and to inhibit their invasion through extracellular matrices.^41,42

In addition to the work outlined above, a number of clinical studies have investigated the usefulness of bisphosphonates in various settings. The results of several small pilot studies encouraged breast cancer investigators to evaluate early-generation bisphosphonates, using either regular intravenous infusions of pamidronate, enteric-coated oral pamidronate, or either oral or parenteral clodronate. A reduction in skeletal morbidity was usually reported. There were initially rather fewer studies in the prostate cancer setting, although some early work showed reductions in bone pain with clodronate,^43,44 although this was not later borne out in randomised studies with this drug.^45,46 Early small-scale studies with pamidronate provided encouraging signs of its potential benefit,^47,48 but it was several years before a well-designed randomised study was published on the use of later-generation bisphosphonates in prostate cancer.

Development of more modern bisphosphonates

Pharmacological advances have led to several newer bisphosphonates being developed in recent years. The question of whether bisphosphonate potency is directly associated with therapeutic efficacy was investigated in the work by van der Pluijm et al.⁴⁰ They demonstrated that the relative order of potency of six bisphosphonates (etidronate, clodronate, pamidronate, olpadronate, alendronate, and ibandronate) in inhibiting the adhesion of cancer cells to cortical and trabecular bone corresponded to their relative antiresorptive potencies in vivo as well as their ranking in in vitro bone resorption assays, with predictive value for their clinical efficacy.

It is therefore reasonable to suggest that using more potent bisphosphonates could simplify treatment and possibly improve the therapeutic effectiveness of bisphosphonate therapy. Potencies of various bisphosphonates discovered to date are shown in Table 1.⁴⁹

Table 1 - Relative potencies of bisphosphonates, measured on a molar basis in an in vivo assay, namely the inhibitory activity on bone resorption induced by 1,25 dihydroxyvitamin D3 in the thyroparathyroidectomised rat⁴⁹.

Full table

The most recent group of bisphosphonates to be developed is the so-called third generation, the most potent of which is zoledronic acid (Zometa^®, Novartis). Recent large targeted studies indicate that this agent could help clinicians to manage effectively bone metastases in prostate cancer patients.

The most noteworthy trial, whose first results were published by Saad et al⁵⁰ in 2002, investigated 643 patients with hormone-refractory prostate cancer and a history of bone metastases. These subjects were randomised to receive a double-blind treatment regimen of intravenous zoledronic acid at either 8 mg (n=221) or 4 mg (n=214), or placebo (n=208), every 3 weeks for 15 months. Infusions were given over 15 min. During the trial, renal safety concerns merited the reduction of the 8-mg dose to doses of 4 mg.⁵¹

Primary efficacy measures included: proportion of patients with skeletal-related events, time to first event, skeletal morbidity rate, pain and analgesic scores, and disease progression. Safety analyses were also performed.

Results have recently been presented with follow-up extended to 24 months.⁵¹ The study showed that patients receiving 4 mg zoledronic acid experienced 22% fewer skeletal-related events than the placebo cohort (38 vs 49%; P=0.028). The median time to the first skeletal event was 488 days with placebo, and 321 days for patients receiving zoledronic acid 4 mg (P=0.009). This represents a difference of more than 5 months. The placebo group also witnessed higher increases in pain and analgesic scores. The median survival was extended by 77 days in patients treated with 4 mg zoledronic acid compared with placebo, a nonsignificant difference.

Zoledronic acid was well tolerated, and although renal function deterioration was seen in approximately 20% of patients in the 8-mg cohort, compared with placebo, the 4-mg group showed a relative risk ratio of only 1.07 (P=0.882).

The authors concluded that in patients with metastatic prostate cancer, treatment with 4 mg zoledronic acid every 3 weeks reduces skeletal-related events, when compared to placebo. Further, they confirmed that at this recommended dose and regimen, the benefit-to-risk ratio is acceptable for patients with hormone-refractory prostate cancer metastatic to bone. They proposed that further work is warranted to investigate earlier intervention with zoledronic acid, such as in patients with advanced prostate cancer and rising PSA on endocrine therapy, who have not yet developed metastases. It should be noted though that one such study (Novartis Protocol 704) had to be prematurely ended when an unexpected low frequency of events was observed. Other trials are proposed or underway, under the auspices of the EORTC, EAU, and MRC. These look at the potential benefit of zoledronic acid in hormone-naïve patients who have not developed metastases but who are at a high risk of doing so. The MRC trial ('STAMPEDE', looking in addition at celecoxib and docetaxel) is also recruiting those who have had adjuvant or neoadjuvant hormonal therapy, and those with metastases.

That reducing SREs in prostate cancer patients with bone metastases may well also be economically beneficial is suggested by work that has shown that, in the Netherlands at least, around 50% of the total cost of care for such patients is directly attributable to the treatment of SREs.⁵²

The results of the study by Saad et al compare favourably to those recently published from the MRC Pr05 trial.⁵³ This looked at the use of oral clodronate, a first-generation bisphosphonate, in patients with bone metastases who had just started or were responding to first-line therapy. While a tendency towards increased bone progression-free survival was seen with 2080 mg/day clodronate, this difference was not statistically significant. The clodronate group reported significantly more gastrointestinal problems and increased lactate dehydrogenase levels, prompting a significant number of dose adjustments in this group.

A further potential benefit of bisphosphonate treatment is related to the bone loss that is known to occur in prostate cancer patients. It has been shown that many patients with advanced prostate cancer have a lower bone mineral density at diagnosis, even before commencing androgen deprivation therapy.^54,55 This is of course compounded by the known osteoporotic effects of LHRH analogues, to which many patients are now being exposed for longer durations. Recently published results showed that, in patients without bone metastases receiving androgen deprivation therapy, 4 mg zoledronic acid significantly increased the bone mineral density, while a decrease was seen in the placebo group (P<0.001).⁵⁶. A previous study using the second-generation bisphosphonate pamidronate failed to show an increase in bone mineral density,⁵⁷ although it did prevent bone loss when compared to placebo.

Zoledronic acid is the only bisphosphonate with these clinically proven indications for use in prostate cancer. Its ease of administration, as a short 15-min intravenous infusion, is especially important considering that previous-generation bisphosphonates, such as pamidronate, have a standard infusion time of 2–4 h. Such longer infusion times would clearly incur costs in terms of clinical staff time and healthcare resources. The simpler mode of administration with zoledronic acid means that clinicians may shortly be able to offer community-based bisphosphonate treatment, which should benefit healthcare budgets and patients alike. However, further research is required until this can become the standard of care.

Conclusions

• Bone is the most important metastatic site in prostate cancer.
• Skeletal complications, including fractures, are relatively common in prostate cancer.
• Accelerated bone resorption is an important component of the pathophysiology of bone metastases.
• Bisphosphonates are potent, safe, and well tolerated inhibitors of bone resorption.
• Skeletal morbidity is significantly reduced by administration of bisphosphonates.
• Studies suggest that zoledronic acid, a potent, third-generation bisphosphonate, could play a vital role in the management of bone metastases from prostate cancer.

References

1. Carlin BI, Andriole GL. The natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma. Cancer 2000; 88: 2989–2994. | Article | PubMed | ChemPort |
2. Pentyala SN et al. Prostate cancer: a comprehensive review. Med Oncol 2000; 17: 85–105. | PubMed |
3. George NJ. Natural history of localised prostatic cancer managed by conservative therapy alone. Lancet 1988; 1: 494–497. | Article | PubMed | ISI | ChemPort |
4. Coleman RE. Uses and abuses of bisphosphonates. Ann Oncol 2000; 11 (Suppl 3): 179–184. | Article | PubMed |
5. Scher HI, Chung LW. Bone metastases: improving the therapeutic index. Semin Oncol 1994; 21: 630–656. | PubMed | ISI | ChemPort |
6. Berruti A et al. Incidence of skeletal complications in patients with bone metastatic prostate cancer and hormone refractory disease: predictive role of bone resorption and formation markers evaluated at baseline. J Urol 2000; 164: 1248–1253. | Article | PubMed | ChemPort |
7. Mundy GR. Bone resorption and turnover in health and disease. Bone 1987; 8 (Suppl 1): S9–16. | PubMed |
8. Thomas RJ et al. Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology 1999; 140: 4451–4458. | Article | PubMed | ISI | ChemPort |
9. Guise TA, Mundy GR. Cancer and bone. Endocr Rev 1998; 19: 18–54. | Article | PubMed | ISI | ChemPort |
10. Clarke NW, McClure J, George NJ. Morphometric evidence for bone resorption and replacement in prostate cancer. Br J Urol 1991; 68: 74–80. | PubMed | ChemPort |
11. Garnero P et al. Markers of bone turnover for the management of patients with bone metastases from prostate cancer. Br J Cancer 2000; 82: 858–864. | Article | PubMed | ISI | ChemPort |
12. Ikeda I, Miura T, Kondo I. Pyridinium cross-links as urinary markers of bone metastases in patients with prostate cancer. Br J Urol 1996; 77: 102–106. | Article | PubMed |
13. Takeuchi S et al. Urinary pyridinoline and deoxypyridinoline as potential markers of bone metastasis in patients with prostate cancer. J Urol 1996; 156: 1691–1695. | Article | PubMed | ISI | ChemPort |
14. Goltzman D. Mechanisms of the development of osteoblastic metastases. Cancer 1997; 80: 1581–1587. | Article | PubMed | ChemPort |
15. Kantoff PW et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol 1999; 17: 2506–2513. | PubMed | ISI | ChemPort |
16. Tannock IF et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996; 14: 1756–1764. | PubMed | ISI | ChemPort |
17. Beer TM, Pierce WC, Lowe BA, Henner WD. Phase II study of weekly docetaxel in symptomatic androgen-independent prostate cancer. Ann Oncol 2001; 12: 1273–1279. | Article | PubMed | ISI | ChemPort |
18. Berry W, Dakhil S, Gregurich MA, Asmar L. Phase II trial of single-agent weekly docetaxel in hormone-refractory, symptomatic, metastatic carcinoma of the prostate. Semin Oncol 2001; 28: 8–15. | Article | PubMed | ISI | ChemPort |
19. Picus J, Schultz M. Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results. Semin Oncol 1999; 26: 14–18. | PubMed | ISI | ChemPort |
20. Savarese DM et al. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and Leukemia Group B. J Clin Oncol 2001; 19: 2509–2516. | PubMed | ISI | ChemPort |
21. Smith PH et al. A comparison of the effect of diethylstilbestrol with low dose estramustine phosphate in the treatment of advanced prostatic cancer: final analysis of a phase III trial of the European Organization for Research on Treatment of Cancer. J Urol 1986; 136: 619–623. | PubMed |
22. Figg WD et al. A randomized phase II trial of docetaxel (taxotere) plus thalidomide in androgen-independent prostate cancer. Semin Oncol 2001; 28: 62–66. | Article | PubMed |
23. Sato M et al. Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest 1991; 88: 2095–2105. | PubMed | ISI | ChemPort |
24. Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev 1998; 19: 80–100. | Article | PubMed | ChemPort |
25. Vitte C, Fleisch H, Guenther HL. Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated resorption. Endocrinology 1996; 137: 2324–2333. | Article | PubMed | ISI | ChemPort |
26. Frith JC et al. Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5'-(beta, gamma-dichloromethylene) triphosphate, by mammalian cells in vitro. J Bone Miner Res 1997; 12: 1358–1367. | PubMed | ISI | ChemPort |
27. Amin D et al. Bisphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis. J Lipid Res 1992; 33: 1657–1663. | PubMed | ISI | ChemPort |
28. Luckman SP et al. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Min Res 1998; 13: 581–589.
29. Green JR, Clezardin P. Mechanisms of bisphosphonate effects on osteoclasts, tumor cell growth, and metastasis. Am J Clin Oncol 2002; 25: S3–S9. | Article | PubMed |
30. Nemoto R, Kanoh S, Koiso K, Harada M. Establishment of a model to evaluate inhibition of bone resorption induced by human prostate cancer cells in nude mice. J Urol 1988; 140: 875–879. | PubMed |
31. Pollard M, Luckert PH. Effects of dichloromethylene diphosphonate on the osteolytic and osteoblastic effects of rat prostate adenocarcinoma cells. J Natl Cancer Inst 1985; 75: 949–954. | PubMed |
32. Pollard M, Luckert PH. The beneficial effects of diphosphonate and piroxicam on the osteolytic and metastatic spread of rat prostate carcinoma cells. Prostate 1986; 8: 81–86. | PubMed |
33. Aparicio A et al. In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia 1998; 12: 220–229. | Article | PubMed | ISI | ChemPort |
34. Lee MV, Fong EM, Singer FR, Guenette RS. Bisphosphonate treatment inhibits the growth of prostate cancer cells. Cancer Res 2001; 61: 2602–2608. | PubMed | ISI | ChemPort |
35. Oades GM et al. Nitrogen containing bisphosphonates induce apoptosis and inhibit the mevalonate pathway, impairing Ras membrane localization in prostate cancer cells. J Urol 2003; 170: 246–252. | PubMed | ISI | ChemPort |
36. Senaratne SG et al. Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer 2000; 82: 1459–1468. | Article | PubMed | ISI | ChemPort |
37. Shipman CM et al. Bisphosphonates induce apoptosis in human myeloma cell lines: a novel anti-tumour activity. Br J Haematol 1997; 98: 665–672. | Article | PubMed | ISI | ChemPort |
38. Senaratne SG, Mansi JL, Colston KW. The bisphosphonate zoledronic acid impairs Ras membrane [correction of impairs membrane] localisation and induces cytochrome c release in breast cancer cells. Br J Cancer 2002; 86: 1479–1486. | Article | PubMed | ChemPort |
39. Boissier S et al. Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to unmineralized and mineralized bone extracellular matrices. Cancer Res 1997; 57: 3890–3894. | PubMed | ISI | ChemPort |
40. van der Pluijm G et al. Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. J Clin Invest 1996; 98: 698–705. | PubMed | ChemPort |
41. Boissier S et al. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 2000; 60: 2949–2954. | PubMed | ISI | ChemPort |
42. Denoyelle C et al. New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects. Br J Cancer 2003; 88: 1631–1640. | Article | PubMed |
43. Adami S et al. Dichloromethylene-diphosphonate in patients with prostatic carcinoma metastatic to the skeleton. J Urol 1985; 134: 1152–1154. | PubMed |
44. Cresswell SM 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. | PubMed |
45. Elomaa I et al. Effect of oral clodronate on bone pain. A controlled study in patients with metastatic prostatic cancer. Int Urol Nephrol 1992; 24: 159–166. | PubMed |
46. Kylmala T et al. Concomitant i.v. and oral clodronate in the relief of bone pain–a double-blind placebo-controlled study in patients with prostate cancer. Br J Cancer 1997; 76: 939–942. | PubMed |
47. Clarke NW, Holbrook IB, McClure J, George NJ. Osteoclast inhibition by pamidronate in metastatic prostate cancer: a preliminary study. Br J Cancer 1991; 63: 420–423. | PubMed |
48. Pelger RC, Nijeholt AA, Papapoulos SE. Short-term metabolic effects of pamidronate in patients with prostatic carcinoma and bone metastases. Lancet 1989; 2: 865. | Article | PubMed |
49. Green JR, Muller K, Jaeggi KA. Preclinical pharmacology of CGP 42'446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res 1994; 9: 745–751. | PubMed | ISI | ChemPort |
50. Saad F et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94: 1458–1468. | Article | PubMed | ChemPort |
51. Saad F et al. Zoledronic acid is well tolerated for up to 24 months and significantly reduces skeletal complications in patients with advanced prostate cancer metastatic to the bone. Presented at: American Urological Association Annual Meeting 2003; Abstract 1472.
52. Groot MT, Boeken Kruger CG, Pelger RC, Uyl-de Groot CA. Costs of prostate cancer, metastatic to the bone, in the Netherlands. Eur Urol 2003; 43: 226–232. | Article | PubMed | ChemPort |
53. Dearnaley DP et al. A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 2003; 95: 1300–1311. | Article | PubMed | ChemPort |
54. Smith MR et al. Low bone mineral density in hormone-naive men with prostate carcinoma. Cancer 2001; 91: 2238–2245. | Article | PubMed |
55. Hussain SA et al. Immediate dual energy X-ray absorptiometry reveals a high incidence of osteoporosis in patients with advanced prostate cancer before hormonal manipulation. BJU Int 2003; 92: 690–694. | Article | PubMed |
56. Smith MR et al. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 2003; 169: 2008–2012. | Article | PubMed | ISI | ChemPort |
57. Smith MR et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001; 345: 948–955. | Article | PubMed | ISI | ChemPort |