What is the evidence for the use of bisphosphonates in the treatment of bone pain?
Castrate-resistant prostate cancer with existing bone pain
Seven low-quality randomised trials (five were double blind) focus on the treatment of existing pain of patients with painful bone metastases. Measurements of pain and pain outcomes varied. In three studies men in both arms received anti-neoplastic therapy. Due to many confounding factors and study limitations, no firm conclusions can be made regarding the ability of bisphosphonates to manage existing bone pain related to prostate cancer.
The two larger and more informative studies are presented below:
Small et al 2003 examining two multi-centred randomised placebo controlled trials reported that pamidronate disodium 90mg (iv) administered every three weeks for 27 weeks did not provide any improved palliation of worst (p=0.89) or average (p=0.71) bone pain compared with placebo in menwith bone pain at study entry. At nine weeks the mean decrease in worst pain score on a 0–10 pain scale was 0.86 in the pamidronate arm and 0.69 in the placebo group (p=0.58). No significant difference was seen in the use of radiation for bone pain relief (p=0.88). However a pre-planned subgroup analysis of men with stable or falling analgesia showed at nine weeks (n=121) a 2.13 unit decrease in mean worst pain score on a 0–10 scale in the pamidronate group, which was significantly (p=0.008) larger than the 0.79 unit decrease in the placebo group. Retrospective subgroup analysis for men with moderate rather than mild baseline pain was reported to show a significant reduction in pain (p=0.004) at nine weeks.
Ernst et al 2003 using a randomised double blind design (n=227) compared clodronate (1500 mg iv every three weeks) combined with mitoxantrone and prednisone with placebo and mitroxantrone and prednisone. Similar levels of pain control were noted in both arms; 43% experiencing pain improvement in the clodronate arm and 38% experiencing pain improvement in the placebo group (p=0.52). In this study analgesia was considered in determining the pain response. Similar proportions of men required local radiotherapy with over 12 months follow-up; 16% of men in the clodronate arm and 14% of the men in the placebo arm (p=0.85). However, in a subgroup analysis of men with moderate rather than mild baseline pain (n=49), 58% of men receiving clodronate treatment experienced pain palliation whereas only 26% of men receiving placebo experienced pain palliation (odds ratio=4.6, 95% CI=1.3 to 15.5, p=0.04).
For completeness and to appreciate the limitations of the remaining studies, a brief outline follows.
Smith 1989 examined the effect of sodium etidronate on the control of bone pain in a small (n=28) double-blind RCT. Men received either sodium etidronate (iv) 7.5 mg/kg/day for three days then orally 2x200mg/day for one month, or placebo. No significant differences were observed between the two groups (p=1.00).
Adami and Mian 1989 randomised 13 men with radiographic evidence of bone metastases to treatment with either 300mg of sodium clodronate (iv) daily or placebo for 14 days. It was reported that pain scores measured using a visual analogue scale and analgesic consumption fell in the treated group, but the statistical significance of the difference compared with the placebo group was not reported. In a multi-centre double-blind RCT without any documented chemotherapy, Strang et al 1997 treated 55 men with either sodium clodronate 300mg (iv) for three days followed by oral sodium clodronate at a dose of 3200mg daily or placebo for four weeks. They did not find a significant improvement in pain scores between groups at 32 days follow up, however their data suggested that patients with higher initial pain scores (n=20) may have a better response than those with lower scores. This trial was terminated prematurely because of recruitment difficulties and as a result numbers may not have been sufficient to show any statistically significant differences in men with high pain scores.
Elomaa et al 1992 and Kylmala et al 1993 reported a randomised trial of sodium clodronate 3.2g/day for one month followed by 1.6g/day for a further five months. At one month there was a reduction in pain from baseline in both the control and the clodronate arms. Although the reduction was greater in the treated group, with 28% of men no longer experiencing pain compared with 15% of men in the control arm, the difference was not statistically significant (p=0.26). The probable explanation for this finding (ie pain relief without clodronate in the control group) was that both groups were started on estramustine phosphate 2x280mg per day at the same time as the clodronate. The symptomatic improvement in the control group was almost certainly due to the effect of the extramustine, thus rendering it difficult to determine the true effect of clodronate.
Kylmala et al 1997 reported the results of a similar double-blind placebo controlled trial. Fifty-seven men, most of whom had painful bone metastases, began estramustine therapy and were randomised to either clodronate (iv) 300mg a day for five days and then oral clodronate 1.6g/day for 12 months, or placebo. Again, no significant difference was found between the groups, with mean pain scores in the treatment group not significantly improved from those in the control group over the 12 months.
Prevention/delay of bone pain in patients with hormone refractory disease which is either asymptomatic or with minimal symptoms from metastatic bone disease
In a quality double-blind multi-centre RCT, Saad et al 2002 and 2004  (N = 422) were unable to show consistent differences at 15 months follow up in reducing pain progression between men treated with 4mg zoledronic acid (iv) and placebo (p = 0.13). However, with a follow up of 24 months they were able to show significantly smaller increases in brief pain inventory scores at 21 (p = 0.01) and 24 months (p = 0.02) for the treated group when compared with placebo. As the authors point out, the study was not primarily designed to assess pain improvement.
Weinfurt et al 2006 published a re-analysis of the pain data from this trial. They found that a typical zoledronic acid patient had a 33% chance of a better pain response than a placebo patient, whereas a placebo patient had a 25% chance of a better pain response than a patient receiving zoledronic acid. This difference was statistically significant (p = 0.04). Nearly one third of patients in this trial had no baseline pain and for those experiencing baseline pain, changes in pain levels were not reported. Furthermore, many of these may have had osteoarthritis non-cancer-related pain at entry.
Side effects of bisphosphonate In most trials, the reported incidence of moderate to severe side effects for sodium clodronate, pamidronate and zoledronic acid is low. In randomised trials these agents were reported to cause hypocalcaemia in 2–4% of patients and in the zoledronic acid trial all men under study were given calcium supplement 500mg/day and vitamin D 400–500 IU/day. In the case of zoledronic acid, the incidence of fatigue, anaemia, myalgia, dizziness and lower limb oedema were at least 5% greater in the treated group than the control group. Also in their study, the dose of 8mg per treatment was discontinued because of the increased incidence of renal impairment at that dose level. No men were accepted onto the trial if they had a serum creatinine greater than 265umol/L. A case series reported by Oh et al 2007 indicates that renal impairment may be more frequent than previously appreciated in patients treated with zoledronic acid.
Recently, there have been reports of osteonecrosis of the jaw in patients undergoing treatment with bisphosphonates. In a case series of patients undergoing treatment with bisphosphonates for a variety of cancers, Bamias et al 2005 reported an incidence of 6.7% for osteonecrosis of the jaw, and an incidence of this condition in 6.5% of men with prostate cancer. They identified length of exposure as the most important risk factor and that zoledronic acid may be more prone to produce this complication than pamidronate. In a recent publication of a cohort study with matched controls, Wilkinson et al 2007 have confirmed the earlier case series reports. They showed that cancer patients treated with intravenously administered nitrogen containing bisphosphonates had an absolute risk at six years for any jaw toxicity of 5.48% compared with matched controls, who had an absolute risk of 0.30%. When adjustments were made for a number of potential confounders, the hazard ratio was 11.48 (95% CI = 6.49 to 20.33). They also confirmed that length of exposure was a risk factor for jaw toxicity with those receiving 14–21 infusions of bisphosphonates significantly more likely to experience jaw toxicity than those who received less than three infusions (hazard ratio = 3.02 with 95% CI = 1.28 to 7.10). They were unable to find a clear association between types of cancer, comorbidities, or with known risk factors for jaw and facial bone disease such as diabetes, alcoholism, smoking, obesity, hyperlipidaemia or parenteral corticosteroids. Atrial fibrillation may also be a concern. In a RCT of once-yearly infusions of zoledronic acid for the treatment of post-menopausal osteoporosis, there was a significant increase in ‘serious’ atrial fibrillation.
Evidence summary and recommendations
|For men with initially asymptomatic or mildly symptomatic bone metastases, zoledronic acid has been shown to be associated with less bone pain at 21 and 24 months. As the trials reported did not have pain control as their primary objective, this has diminished the power of these observations.||II||, , |
|Sodium etidronate has not been shown to be effective in controlling bone pain in metastatic prostate cancer.||II|||
|Three underpowered randomised controlled trials have failed to show a significant improvement in the control of metastatic bone pain over placebo either with clodronate alone or in combination with estramustine sulphate. A fourth study found a significant improvement with the addition of clodronate to mitoxantrone/prednisone only in a subgroup of men with moderate rather than mild baseline pain.||II||, , , , |
|Pamidronate disodium has not been shown to be effective in controlling bone pain in metastatic prostate cancer, except in a subgroup of men with stable or falling analgesia in which a significant but modest benefit was observed in worst pain.||II|||
|On the basis of the available evidence, bisphosphonates are not recommended for routine palliation of symptomatic bone disease in men, with hormone-resistant prostate cancer with a possible exception of zoledronic acid, where there is some evidence of a benefit in castrate-resistant men.||C|
In Australia, zoledronic acid (4mg in 5ml) is the only bisphosphonate listed on the PBS for ‘bone metastases from hormone-resistant prostate cancer with demonstration of biochemical progression of disease despite maximal therapy with hormonal treatments’. It is also listed along with clodronate for the ‘treatment of hypercalcemia of malignancy refractory to anti-neoplastic therapy’. (<www.pbs.gov.au> accessed 3/06/2009).
- 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.
- 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.
- Smith JA Jr. Palliation of painful bone metastases from prostate cancer using sodium etidronate: results of a randomized, prospective, double-blind, placebo-controlled study. J Urol 1989 Jan;141(1):85-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2462069.
- Adami S, Mian M. Clodronate therapy of metastatic bone disease in patients with prostatic carcinoma. Recent Results Cancer Res 1989;116:67-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2527401.
- Strang P, Nilsson S, Brändstedt S, Sehlin J, Borghede G, Varenhorst E, et al. The analgesic efficacy of clodronate compared with placebo in patients with painful bone metastases from prostatic cancer. Anticancer Res ;17(6D):4717-21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9494595.
- 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.
- Kylmälä T, Tammela T, Risteli L, Risteli J, Taube T, Elomaa I. Evaluation of the effect of oral clodronate on skeletal metastases with type 1 collagen metabolites. A controlled trial of the Finnish Prostate Cancer Group. Eur J Cancer 1993;29A(6):821-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7683480.
- 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.
- 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.
- 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.
- Weinfurt KP, Anstrom KJ, Castel LD, Schulman KA, Saad F. Effect of zoledronic acid on pain associated with bone metastasis in patients with prostate cancer. Ann Oncol 2006 Jun;17(6):986-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16533874.
- 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.
- Oh WK, Proctor K, Nakabayashi M, Evan C, Tormey LK, Daskivich T, et al. The risk of renal impairment in hormone-refractory prostate cancer patients with bone metastases treated with zoledronic acid. Cancer 2007 Mar 15;109(6):1090-6. Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17311345.
- Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005 Dec 1;23(34):8580-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16314620.
- Wilkinson GS, Kuo YF, Freeman JL, Goodwin JS. Intravenous bisphosphonate therapy and inflammatory conditions or surgery of the jaw: a population-based analysis. J Natl Cancer Inst 2007 Jul 4;99(13):1016-24 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17596574.
- Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007 May 3;356(18):1809-22 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17476007.