What is the evidence for the use of bisphosphonates in the prevention of skeletal related events?

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What is the evidence for the use of bisphosphonates in the prevention of skeletal related events?

There are three double-blind multi-centred RCTs examining whether bisphosphonates prevent SREs such as pathological fractures and treatments for bone pain in men with prostate cancer. The trials differ in the type of bisphosphonate, disease stages of the patients, and definition of a skeletal-related event. Two were high-quality long-term (more than one year of treatment) trials. The third was of lower quality and of shorter duration (27 weeks).

Hormone-naïve metastatic bone disease

Dearnaley et al 2003[1] found in a trial with 311 men that those treated with sodium clodronate (an oral bisphosphonate) for a maximum of three years had a longer median symptomatic bone progression free survival (23.6 months) when compared with men treated with placebo (19.3 months). However, the difference in two-year bone progression-free survival rates for the clodronate arm (49%) and the placebo arm (41%) of 8% (95% CI= -1 to 18) and the hazard ratio with a median of 59 months follow up of 0.79 (95% CI=0.61 to 1.02), did not achieve statistical significance (p=0.07). The study was designed with 80% power to detect an 11% improvement in symptomatic bone progression-free survival at two years at the =0.05 level. The authors suggested that the inability to achieve statistical significance may have been related to the small number of subjects and the use of oral rather than intravenous drug administration, given the known relatively poor absorption of bisphosphonates from the gut.

Hormone refractory/castrate resistant disease either asymptomatic or with minimal symptoms from metastatic bone disease

Saad et al[2]compared a highly potent zoledronic acid (intra –venous (iv) versus placebo in a doubleblind trial: Two hundred and fourteen men were randomised to receive 4mg of zoledronic acid, 221 men to receive 8mg of zoledronic acid, and 208 men to receive placebo, every three weeks for 15 months. However, because of deteriorating renal function the dose in the 8mg group was reduced to 4mg and this group was identified as 8/4mg. After 15 months of treatment, SREs, which included treatments to prevent as well as treat symptomatic bone disease, occurred in 33.2% of men receiving 4mg of zoledronic acid compared with 44.2% in the placebo group; a statistically significant difference (p=0.02) of 11.1% (95% CI=-20.3 to -1.8) (NNT = 9). The results were similar in the 8/4mg group but not statistically significantly different to placebo (p=0.22), with 38.5% of men developing a SRE. Over 15 months, 22.1% of men in the placebo group developed a pathological fracture, whereas for those treated with 4mg of zoledronic acid, the incidence of fractures was 13%, a statistically significant reduction of 9% (p=0.02). For those in the 4/8mg group the reduction in incidence was 7.2 % , (p=0.05). The need for radiotherapy and the incidence of spinal cord compression were lower but not significantly so in the treated groups (23% versus 29%, p=0.14 for the need for radiotherapy and 4.2% versus 6.7%, p=0.26 for spinal cord compression). At 24 months follow up30, SREs (ie composite of bone related endpoints) had occurred in 38% of the 4mg treated group compared with 49% in the placebo group, a statistically significant (p=0.03) difference of 11%, (95% CI=-20.2 to -1.3).

Hormone refractory/castrate resistant disease with painful bone metastases

In a RCT (n=378) of pamidronate disodium (iv), Small et al 2003[3] did not find a significant overall reduction in the number of SREs in the pamidronate arm (23%) compared with the placebo arm (24%) after 27 weeks of treatment (p=1.00).

Four low-quality, underpowered RCTs examined the effects on response and progression of bisphosphonates as an adjunct to chemotherapy. In an open phase 2 trial with 72 men, Figg et al 2005[4]compared alendronate plus ketoconazole with ketoconazole alone in hormone-independent prostate cancer and found no difference in response rate ( p=1.00) or progression-free survival (p = 0.27). Eloma et al 1992[5] and Kylmala et al 1997[6] found that for those with six month (n=54) and 12 month (n=15) follow-up assessments, the addition of clodronate to estramustine did not significantly reduce the incidence of progression. Similarly, Ernst et al 2003[7], in a trial with 209 men, did not find that clodronate given in addition to mitoxantrone and prednisone significantly improved symptomatic progression-free survival. There was no specific reference made to SREs, however.

Prevention of bone metastases for patients with clinically organ-confined/non-metastatic prostate cancer

A recent paper by Mason et al 2007[8] reports that in a randomised placebo-controlled trial with a median follow up of ten years, men with locally advanced disease (most of whom received hormone therapy or radiotherapy as primary treatment), did not receive any benefit in terms of decreased incidence of symptomatic bone metastases or prostate cancer death when given sodium clodronate orally at a dose of 2080mg per day for a maximum of five years (hazard ratio=1.31, 95% CI=0.84 to 2.05).

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Evidence summary and recommendations

Evidence summary Level References
Oral sodium clodronate resulted in a modest but not statistically significant decrease in symptomatic skeletal-related events in hormone-naïve metastatic bone prostate cancer. II [1]
Zoledronic acid (iv) 4mg three-weekly for 15 months significantly reduced skeletal-related events in men with asymptomatic or mildly symptomatic hormone refractory prostate cancer. II [2], [9]
Pamidronate disodium (iv) 90mg three-weekly for 27 weeks did not reduce skeletal-related events in men with symptomatic hormone refractory prostate cancer. II [3]
Evidence-based recommendationQuestion mark transparent.png Grade
Zoledronic acid should be considered for the prevention of skeletal related events in men with asymptomatic or mildly symptomatic hormone resistant/castrate resistant metastatic prostate cancer.

Men as part of the informed consent process should be made aware that nine men will need to be treated for one to achieve a benefit and that there is a 5% risk of osteonecrosis of the jaw occurring during treatment.

Renal function needs to be monitored during treatment. Ideally treatment should be confined to men whose serum creatinine is less than 265umol/L at the time of starting treatment.

B


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References

  1. 1.0 1.1 Dearnaley DP, Sydes MR, Mason MD, Stott M, Powell CS, 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 Sep 3;95(17):1300-11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12953084.
  2. 2.0 2.1 Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002 Oct 2;94(19):1458-68 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12359855.
  3. 3.0 3.1 Small EJ, Smith MR, Seaman JJ, Petrone S, Kowalski MO. Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 2003 Dec 1;21(23):4277-84 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14581438.
  4. Figg WD, Arlen P, Gulley J, Fernandez P, Noone M, Fedenko K, et al. A randomized phase II trial of docetaxel (taxotere) plus thalidomide in androgen-independent prostate cancer. Semin Oncol 2001 Aug;28(4 Suppl 15):62-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11685731.
  5. Elomaa I, Kylmälä T, Tammela T, Viitanen J, Ottelin J, Ruutu M, et al. Effect of oral clodronate on bone pain. A controlled study in patients with metastic prostatic cancer. Int Urol Nephrol 1992;24(2):159-66 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1385586.
  6. Kylmälä T, Taube T, Tammela TL, Risteli L, Risteli J, Elomaa I. 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(7):939-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9328156.
  7. Ernst DS, Tannock IF, Winquist EW, Venner PM, Reyno L, Moore MJ, et al. Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol 2003 Sep 1;21(17):3335-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12947070.
  8. Mason MD, Sydes MR, Glaholm J, Langley RE, Huddart RA, et al. Oral sodium clodronate for nonmetastatic prostate cancer--results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J Natl Cancer Inst 2007 May 16;99(10):765-76 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17505072.
  9. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004 Jun 2;96(11):879-82 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15173273.

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Appendices