KQ 18. 거세저항성 전립선암 환자 중 골전이가 확인된 전립선암 환자에서 골보호제제(bone protective agents)를 사용하는 경우는 사용하지 않는 경우에 비해 골관련 합병증 (osseous complication)이 적은가? 문서 원본 보기

{| class="wikitable"
!권고사항
!권고수준
!근거수준
|-
|거세저항성 전립선암 환자 중 뼈전이가 확인된 경우, 골 보호제제(bone protective agents)를 사용하는 것이 뼈관련 합병증을 감소시키므로 골 보호제제 사용을 권고한다.
|B
|I
|}
==개요==
전립선암은 남성에 흔한 암 중 하나로<sup>[1]</sup> 진행된 전립선암에서 약 80% 정도는 골전이를 동반한다<sup>[2]</sup>. 골전이는 통증, 병적골절, 척수압박 등의 골관련 합병증을 유발할 수 있다<sup>[3]</sup>. 국한된 골전이에 대한 합병증의 치료로 방사선 치료나 수술을 이용할 수 있으며 광범위한 골전이의 경우 bone-seeking radionuclide을 이용하여 증상의 완화를 도모할 수 있다<sup>[4]</sup>. 전립선암의 골전이의 경우 전이 암세포에 의한 반응으로 골아세포가 과도하게 골을 생성하지만 골용해 역시 과도하게 나타나게 된다<sup>[5]</sup>. 골 보호제제(bone protective agents)란 병적인 골용해를 억제해함으로 뼈 관련 합병증을 예방할 목적으로 사용되는 약물들을 말한다<sup>[6,7]</sup>. 다발성 골수증과 유방암에서 골전이 병변의 골용해를 막아 효과적인 치료를 보인 2세대 bisphosphonate, pamidronate를<sup>[8,9]</sup> 전립선암의 골전이에서 골생성과 골용해를 막아 치료 효과를 기대하고 이에 대한 3상 연구가 있었다. 하지만 pamidronate는 전립선암의 골전이에서 골통증이나 골관련 합병증의 감소에 효과가 없었다<sup>[10]</sup>. 그 후 zoledronic acid, denosumab 등에 대해서 연구가 진행되었으며 이에 대한 보고들이 있었다<sup>[11-14]</sup>. 거세저항성 전립선암 환자 중 골전이가 동반된 경우 골보호제제를 사용하는 경우 골관련 합병증(osseous complication)이 적다는 점은 여러 대규모 무작위 대조군 시험에서 확인되었다<sup>[11,12,14]</sup>. 하지만 예방효과가 위약군에 비하여 현저하지 못하며 약물 부작용이 상당히 높다는 것 역시 보고되고 있다<sup>[13]</sup>. 이에 약물 시작 전 환자에게 효과에 부작용에 대한 충분한 설명과 주의가 필요하다.

==기존 가이드라인 요약 및 수용성, 적용성 평가==
2015년 대한비뇨기종양학회가 발간한 전립선암 진료지침에 따르면 골보호제제를 통한 골절을 감소시키는 치료는 골밀도를 증가시키므로 필요한 경우 실시하기를 권유하고 있다<sup>[13]</sup>. 또한 국외 EAU, NCCN 및 CCAACN에서 역시 사용을 권고하고 있다<sup>[11,14]</sup>. 하지만 NICE 가이드라인에서는 사용을 반대하는 상이한 지침을 발표하였다<sup>[15,16]</sup>. 또한 EAU, CCAACN 가이드라인에서도 부작용 가능성과 치료필요수(1명의 치료 효과를 올리기 위해 필요한 치료 환자수)가 9명 정도라는 점을 치료 시작 전 충분히 설명 후 시작할 것을 권고하고 있다<sup>[17]</sup>. 따라서 zoledronic acid와 denosumab같은 골보호제제 사용은 거세저항성 전립선암 환자에서 골전이가 동반한 경우 골관련 합병증을 줄일 수 있어 권유할 수 있으나 부작용에 대한 충분한 설명과 주위가 필요하다.

{| class="wikitable mw-collapsible"
! colspan="5" |KQ 18. 거세저항성 전립선암 환자 중 골전이가 확인된 전립선암 환자에서 골보호제제(bone protective agents)(비스포 스포네이트, 데노주맙 등)을 사용하는 경우는 사용하지 않는 경우에 비해 골관련 합병증(osseous complication)이 적은가?
|-
!지침(제목)
!권고
!권고등급
!근거수준
!page
|-
|1. 2015 KUOS
|골절을 감소시키는 치료는 골밀도를 증가시키므로 필요 한 경우 실시하여야 한다(denosumab 60 mg SQ every 6 mo, zoledronic acid 5 mg IV annually, alendronate 70 mg po weekly)
|없음
|없음
|74
|-
|2. EAU 2016
|Offer bone protective agents to patients with skeletal metastases to prevent osseous complications. However, the benefits must be balanced against the toxicity of these agents, and jaw necrosis in particular must be avoided.
|B
|I
|92
|-
|5. NCCN 2016
|Zoledronic acid every 3 to 4 weeks or denosumab 120mg every 4 weeks is recommended for with CRPC and bone metastases to prevent or delay disease- associated SREs.
|A
|I
|MS-36
|-
|6. NICE 2014
|Do not offer bisphosphonates to prevent or reduce the complications of bone metastases in men with hormone-relapsed prostate cancer
|C
|I
|356
|-
|9.CCAACN 2010
|Zoledronic acid may be considered for the prevention of skeletal related events in men with asymptomatic or mildly symptomatic hormone-resistant or 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 risk of osteonecrosis of the jaw occurring during treatment. Dental review is advised and be sought before commencing treatment.
|B
|I
|17
|}
{| class="wikitable"
! colspan="2" |지침(제목)
!2. EAU 2016
!5. NCCN 2016 
!6. NICE 2014
!9. CCAACN 2010
|-
| rowspan="4" |수용성
|인구 집단(유병률, 발생률 등)이 유사하다.
|예
|예
|예
|예
|-
|가치와 선호도가 유사하다.
|불확실
|예
|예
|예
|-
|권고로 인한 이득은 유사하다.
|예
|예
|예
|예
|-
|해당 권고는 수용할 만하다. 
|불확실
|예
|예
|예
|-
| rowspan="4" |적용성
|해당 중재/장비는 이용 가능하다. 
|예
|예
|예
|예
|-
|필수적인 전문기술이 이용 가능하다.
|예
|예
|예
|예
|-
|법률적/제도적 장벽이 없다. 
|예
|예
|예
|예
|-
|해당 권고는 적용할 만하다. 
|불확실
|예
|예
|예
|}
==업데이트 근거 요약==
전이성 전립성 환자에서 뼈는 가장 흔한 전이부위로 거세 저항성 전립선암의 경우 대부분 골전이를 동반하게 된다. 골전이는 통증, 병적골절, 척수압박 등의 골관련 합병증을 유발할 수 있으며 골보호제제에 대한 연구들이 있었다. Saad 등은 거세저항성 전립선암 환자 중 골전이가 확인된 경우 bisphosphonate를 사용하여 합병증 줄일 수 있다 보고하였다<sup>[11,12]</sup>. 해당 연구에서 거세 저항성 전립선암 환자 중 221명은 zoledronic acid를 8 mg, 221명은 4 mg, 208명은 위약을 매 3주간 15개월 간 복용하면서 관찰하였다. Zoledronic acid 8 mg을 복용한 환자들은 신장 독성으로 4 mg으로 감량하였으며 위약과 비교하여 합병증 발생 감소에 효과가 없었다. 4 mg은 합병증 발생 감소 효과가 있었으며 (44 vs. 33%, p=0.021) 병적 골절예방은 더욱 예방 효과가 있었다(13.1 vs. 22.1%, p=0.015). 하지만 zoledronic acid 사용 전, 치료필요수(1명의 치료 효과를 올리기 위해 필요한 치료 환자수)가 9명 정도이며 드물지만 치명적인 턱관절 괴사의 부작용이 발생 할 수 있는 점을 환자에게 충분히 설명함이 필요하다<sup>[17]</sup>. 최근 bisphosphonate에 대해 시행된 메타분석에서 통증조절 목적의 사용은 이득이 없으며 골관련 합병증과 병의 진행 예방에 이득이 있을 수 있으나 신기능 저하와 오심의 부작용을 고려하기를 권고하고 있다<sup>[18]</sup>. 

Denosumab은 파골세포의 형성, 기능, 생존을 조절하는 RANKL(receptor activator of nuclear factor κB ligand)에 대한 사람의 단클론항체이다<sup>[6]</sup>. 거세저항성 전립선암 환자 중 골전이가 확인된 전립선암 환자에서 Denosumab (n=950)과 zoledronic acid (n=951)를 비교한 3상 연구에서 denosumab 투여시 zoledronic acid 보다 골관련 합병증 발생시기를 20.7개월 17.1개월의 차이로 (HR: 0.82; p=0.008) 지연시켜 예방에 효과가 뛰어난 것으로 보고되었다<sup>[13]</sup>. 하지만 최근 사후재분 석(post-hoc re-evaluatoin)에서 denosumab과 zoledronic acid의 골관련 합병증 예방에 차이가 없다는 보고가 있었다<sup>[14]</sup>. 두 약제의 부작용은 동일 하게 97%로 보고 되었으며 빈혈, 허리통증, 식욕부진, 오심, 피로, 변비, 뼈통증이 흔하게 관찰되었다. CTCAE (Common Terminology Criteria for Adverse Events) 3 혹은 4단계 합병증은 denosumab와 zoledronic acid 각각 72%, 66% (p=0.01)에서 관찰되었으며 치명적인 부작용(fatal adverse events)은 각각 30%, 29% (p=0.72) 확인되었다<sup>[13]</sup>. 따라서 zoledronic acid와 denosumab의 사용은 거세저항성 전립선암 환자에서 골전이를 동반한 경우 다소 골관련 합병증을 줄일 수 있지만 부작용에 대한 충분한 설명과 주의가 필요하다.

==참고문헌==
1. Parkin DM, Laara E, Muir CS. Estimates of the worldwide frequency of sixteen major cancers in 1980. Int J Cancer 1988;41(2):184-97. 

2. Carlin BI, Andriole GL. The natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma. Cancer 2000;88(12 Suppl):2989-94. 

3. Scher HI, Chung LW. Bone metastases: improving the therapeutic index. Semin Oncol 1994;21(5):630-56. 

4. Hamdy NA, Papapoulos SE. The palliative management of skeletal metastases in prostate cancer: use of bone-seeking radionuclides and bisphosphonates. Semin Nucl Med 2001;31(1):62-8. 

5. Clarke NW, McClure J, George NJ. Morphometric evidence for bone resorption and replacement in prostate cancer. Br J Urol 1991;68(1):74-80. 

6. Fizazi K, Lipton A, Mariette X, Body JJ, Rahim Y, Gralow JR, Gao G, Wu L, Sohn W, Jun S. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 2009;27(10):1564-71. 

7. Belch AR, Bergsagel DE, Wilson K, O’Reilly S, Wilson J, Sutton D, Pater J, Johnston D, Zee B. Effect of daily etidronate on the osteolysis of multiple myeloma. J Clin Oncol 1991;9(8):1397-402. 

8. Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, Lipton A, Keller A, Ballester O, Kovacs MJ, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med 1996;334(8):488-93. 

9. Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton A, Sinoff C, Wheeler H, Simeone JF, Seaman J, Knight RD. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 1996;335(24):1785-91. 

10. Lipton A, Small E, Saad F, Gleason D, Gordon D, Smith M, Rosen L, Kowalski MO, Reitsma D, Seaman J. The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate. Cancer Invest 2002;20 Suppl 2:45-54. 

11. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Chen B, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94(19):1458-68. 

12. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Zheng M, 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;96(11):879-82. 

13. Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011;377(9768):813-22. 

14. Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, Miller K, Sieber P, Karsh L, Damiao R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012;379(9810):39-46. 

15. Dearnaley DP, Sydes MR, Mason MD, Stott M, Powell CS, Robinson AC, Thompson PM, Moffat LE, Naylor SL, Parmar MK, 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(17):1300-11. 

16. Yuen KK, Shelley M, Sze WM, Wilt T, Mason MD. Bisphosphonates for advanced prostate cancer. Cochrane Database Syst Rev 2006(4):CD006250. 

17. Aapro M, Abrahamsson PA, Body JJ, Coleman RE, Colomer R, Costa L, Crino L, Dirix L, Gnant M, Gralow J, et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 2008;19(3):420-32. 

18. Macherey S, Monsef I, Jahn F, Jordan K, Yuen KK, Heidenreich A, Skoetz N. Bisphosphonates for advanced prostate cancer. Cochrane Database Syst Rev 2017;12:CD006250.

==근거표==
{| class="wikitable"
!KQ18
!
|-
!Reference
|1. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. A randomized, placebo-controlled trial of zoledronic acidin patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458-68.
|-
!Study type
|Randomized controlled trial
|-
!Patients
|Zoledronic acid at 4 mg (N=214), zoledronic acid at 8 mg (subsequently reduced to 4 mg; 8/4) (N=221), or placebo (N=208)
|-
!Purpose of Study
|To studied the effect of a new bisphosphonate, zoledronic acid, which blocks bone destruction, on skeletal complications in prostate cancer patients with bone metastases
|-
!Study Results
|Approximately 38% of patients who received zoledronic acid at 4 mg, 28% who received zoledronic acid at 8/4 mg, and 31% who received placebo completed the study. A greater proportion of patients who received placebo had skeletal-related events than those who received zoledronic acid at 4 mg (44.2% versus 33.2%; difference=-11.0%, 95% confidence interval [CI]=-20.3% to -1.8%; P=.021) or those who received zoledronic acid at 8/4 mg (38.5%; difference versus placebo=-5.8%, 95% CI=-15.1% to 3.6%; P=.222). Median time to first skeletal-related event was 321 days for patients who received placebo, was not reached for patients who received zoledronic acid at 4 mg (P=.011 versus placebo), and was 363 days for those who received zoledronic acid at 8/4 mg (P=.491 versus placebo). Compared with urinary markers in patients who received placebo, urinary markers of bone resorption were statistically significantly decreased in patients who received zoledronic acid at either dose (P=.001). Pain and analgesic scores increased more in patients who received placebo than in patients who received zoledronic acid, but there were no differences in disease progression, performance status, or quality-of-life scores among the groups. Zoledronic acid at 4 mg given as a 15-minute infusion was well tolerated, but the 8-mg dose was associated with renal function deterioration.
|-
!Level of Study
|1
|-
!Reference
|2. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L ,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;96:879-82.
|-
!Study type
|Randomized controlled trial
|-
!Patients
|Zoledronic acid at 4 mg (N=214), zoledronic acid at 8 mg (subsequently reduced to 4 mg; 8/4) (N=221), or placebo (N=208)
|-
!Purpose of Study
|To examine long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer.
|-
!Study Results
|Among 122 patients who completed a total of 24 months on study, fewer patients in the 4-mg zoledronic acid group than in the placebo group had at least one SRE (38% versus 49%, difference=-11.0%, 95% confidence interval [CI]=-20.2% to -1.3%; P=.028), and the annual incidence of SREs was 0.77 for the 4-mg zoledronic acid group versus 1.47 for the placebo group (P=.005). The median time to the first SRE was 488 days for the 4-mg zoledronic acid group versus 321 days for the placebo group (P=.009). Compared with placebo, 4 mg of zoledronic acid reduced the ongoing risk of SREs by 36% (risk ratio=0.64, 95% CI=0.485 to 0.845; P=.002). Patients in the 4-mg zoledronic acid group had a lower incidence of SREs than did patients in the placebo group, regardless of whether they had an SRE prior to entry in the study. Long-term treatment with 4 mg of zoledronic acid is safe and provides sustained clinical benefits for men with metastatic hormone-refractory prostate cancer.
|-
!Level of Study
|1
|-
!Reference
|3. Aapro M, Abrahamsson PA, Body JJ, Coleman RE, Colomer R, Costa L, et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 2008;19:420-32.
|-
!Study type
|Review article
|-
!Patients
|Review article
|-
!Purpose of Study
|The purpose of this paper is to review the current evidence on the use of BP in solid tumours and provide clinical recommendations
|-
!Study Results
|Based on available evidence, the panel recommends amino-bisphosphonates for patients with metastatic bone disease from breast cancer and zoledronic acid for patients with other solid tumours as primary disease. Dosing of BP should follow approved indications with adjustments if necessary. While i.v. administration is most often preferable, oral administration (clodronate, IBA) may be considered for breast cancer patients who cannot or do not need to attend regular hospital care. Early-stage cancer patients at risk of developing CTIBL should be considered for preventative BP treatment. The strongest evidence in this setting is now available for ZOL. Overall, BP are well-tolerated, and most common adverse events are influenza-like syndrome, arthralgia, and when used orally, gastrointestinal symptoms. The dose of BP may need to be adapted to renal function and initial creatinine clearance calculation is mandatory according to the panel for use of any BP. Subsequent monitoring is recommended for ZOL and PAM, as described by the regulatory authority guidelines. Patients scheduled to receive BP (mainly every 3-4 weeks i.v.) should have a dental examination and be advised on appropriate measures for reducing the risk of jaw osteonecrosis. BP are well established as supportive therapy to reduce the frequency and severity of skeletal complications in patients with bone metastases from different cancers.
|-
!Level of Study
|6
|-
!Reference
|4. Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011;377:813-22.
|-
!Study type
|Randomized controlled trial
|-
!Patients
|1,904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid
|-
!Purpose of Study
|To compare denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration- resistant prostate cancer
|-
!Study Results
|Median duration on study at primary analysis cutoff date was 12.2 months (IQR 5.9-18.5) for patients on denosumab and 11.2 months (IQR 5.6-17.4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20.7 months (95% CI 18.8-24.9) with denosumab compared with 17.1 months (15.0-19.4) with zoledronic acid (hazard ratio 0.82, 95% CI 0.71-0.95; p=0.0002 for non-inferiority; p=0.008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0.0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p=0.09).
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!Level of Study
|I
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!Reference
|5. Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone- metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012;379:39-46.
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!Study type
|Randomized controlled tria
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!Patients
|1,432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo).
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!Purpose of Study
|To assess denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer.
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!Study Results
|Denosumab significantly increased bone-metastasis-free survival by a median of 4.2 months compared with placebo (median 29.5 [95% CI 25.4-33.3] vs 25.2 [22.2- 29.5] months; hazard ratio [HR] 0.85, 95% CI 0.73-0.98, p=0.028). Denosumab also significantly delayed time to first bone metastasis (33.2 [95% CI 29.5-38.0] vs 29.5 [22.4- 33.1] months; HR 0.84, 95% CI 0.71-0.98, p=0.032). Overall survival did not differ between groups (denosumab, 43.9 [95% CI 40.1-not estimable] months vs placebo, 44.8 [40.1-not estimable] months; HR 1.01, 95% CI 0.85-1.20, p=0.91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo.
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!Level of Study
|I
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!Reference
|6. Macherey S, Monsef I, Jahn F, Jordan K, Yuen KK, Heidenreich A, Skoetz N. Bisphosphonates for advanced prostate cancer. Cochrane Database Syst Rev 2017;12.
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!Study type
|Meta-Analysis Research
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!Patients
|We identified studies by electronic search of bibliographic databases including the Cochrane Controlled Trials Register and MEDLINE on 13 July 2017 and trial registries. We handsearched the Proceedings of American Society of Clinical Oncology (to July 2017) and reference lists of all eligible trials identified. This is an update of a review last published in 2006.
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!Purpose of Study
|To assess the effects of bisphosphonates in men with bone metastases from prostate cancer.
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!Study Results
|PRIMARY OUTCOME: there was no clear difference in the proportion of participants with pain response (RR 1.15, 95% CI 0.93 to 1.43; P=0.20; I2=0%; 3 trials; 876 participants; low quality evidence). In absolute terms, bisphosphonates resulted in a pain response in 40 more participants per 1000 (19 fewer to 114 more). SECONDARY OUTCOMES: bisphosphonates probably reduced the incidence of skeletal-related events in participants with prostate cancer metastatic to bone (RR 0.87, 95% CI 0.81 to 0.94; P=0.27; I2=19%; 9 trials; 3153 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 58 fewer SREs per 1000 (85 fewer to 27 fewer).We found no clinically relevant differences in mortality (RR 0.97, 95% CI 0.91 to 1.04; P=0.43; I2=1%; 9 trials; 2450 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 16 fewer deaths per 1000 (47 fewer to 21 more).Outcome definition of quality of life and the measurement tools varied greatly across trials and we were unable to extract any quantitative data for meta-analysis.Bisphosphonates probably increased the number of participants affected by nausea (RR 1.19, 95% CI 1.00 to 1.41; P=0.05; I2=0%; 9 trials; 3008 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in seven more cases of nausea per 1000 (0 fewer to 14 more). Bisphosphonates probably increased the number of renal adverse events (RR 1.65, 95% CI 1.11 to 2.46; P=0.01; I2=0%; 7 trials; 1794 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 22 more renal adverse events per 1000 (4 more to 50 more). We found no clear difference in the number of participants with osteonecrosis of the jaw between groups (RR 1.92, 95% CI 0.75 to 4.90; P=0.17; I2=0%; 5 trials; 1626 participants; very low quality evidence). In absolute terms, bisphosphonates resulted in seven more cases with osteonecrosis of the jaw per 1000 (2 fewer to 29 more). We observed no clinically relevant difference in the proportion of participants with decreased analgesic consumption (RR 1.19, 95% CI 0.87 to 1.63; P=0.28; I2=37%; 4 trials; 416 participants). Statistical analysis revealed that bisphosphonates probably reduced the number of participants with disease progression (RR 0.94, 95% CI 0.90 to 0.98; P=0.006; I2=0%; 7 trials; 2115 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 36 fewer cases of disease progression per 1000 (71 fewer to 7 fewer).Findings of our predefined subgroup and sensitivity analyses were no different from those of the primary analyses.
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!Level of Study
|1
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