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Meta-Analysis
. 2011 Dec 7;2011(12):CD009144.
doi: 10.1002/14651858.CD009144.pub2.

Bisphosphonates for osteoporosis in primary biliary cirrhosis

Jelena S Rudic  1 , Vanja Giljaca, Miodrag N Krstic, Goran Bjelakovic, Christian Gluud
Affiliations
Meta-Analysis

Bisphosphonates for osteoporosis in primary biliary cirrhosis

Jelena S Rudic et al. Cochrane Database Syst Rev. .

Abstract

Background: Bisphosphonates are widely used for treatment of postmenopausal osteoporosis. Patients with primary biliary cirrhosis often have osteoporosis - either postmenopausal or secondary to the liver disease. No systematic review or meta-analysis has assessed the effects of bisphosphonates for osteoporosis in patients with primary biliary cirrhosis.

Objectives: To assess the beneficial and harmful effects of bisphosphonates for osteoporosis in primary biliary cirrhosis.

Search methods: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, clinicaltrials.gov, the WHO International Clinical Trials Registry Platform, and full text searches were conducted until November 2011. Manufacturers and authors were contacted for additional studies during the conductance of the review.

Selection criteria: All randomised clinical trials of bisphosphonates in primary biliary cirrhosis compared with placebo or no intervention, or another bisphosphonate, or any other drug.

Data collection and analysis: Two authors extracted data. RevMan Analysis was used for statistical analysis of dichotomous data with risk ratio (RR) or risk difference (RD) and of continuous data with mean difference (MD) or standardised mean difference (SMD), all with 95% confidence intervals (CI). Methodological components were used to assess risk of systematic errors (bias). Trial sequential analysis was also used to control for random errors (play of chance).

Main results: Six trials were included. Three trials with 106 participants, of which two trials with high risk of bias, did not demonstrate significant effects of bisphosphonates (etidronate or alendronate) versus placebo or no intervention regarding mortality (RD 0.00; 95% CI -0.12 to 0.12, I² = 0%), fractures (RR 0.87; 95% CI 0.29 to 2.66, I² = 0%), or adverse events (RR 1.00; 95% CI 0.49 to 2.04). Two trials with 62 participants with high risk of bias compared one bisphosphonate (etidronate or alendronate) versus another (alendronate or ibandronate) and found no significant difference regarding mortality (RD -0.03; 95% CI -0.14 to 0.07, I² = 0%), fractures (RR 0.95; 95% CI 0.18 to 5.06, I² = 0%), or adverse events (RR 1.00; 95% CI 0.49 to 2.04, I² = 0%). Bisphosphonates had no significant effect on liver-related mortality, liver transplantation, or liver-related morbidity compared with placebo or no intervention, or another bisphosphonate. Bisphosphonates had no significant effect on bone mineral density compared with placebo or no intervention, or another bisphosphonate. Bisphosphonates compared with placebo or no intervention seem to decrease the urinary amino telopeptides of collagen I (NTx) concentration (MD -16.93 nmol bone collagen equivalents/mmol creatinine; 95% CI -23.77 to -10.10; 2 trials with 88 patients; I² = 0%) and serum osteocalcin (SMD -0.81; 95% CI -1.22 to -0.39; 3 trials with 100 patients; I² = 34 %) concentration. The former result was supported by trial sequential analysis, but not the latter. Alendronate compared with another bisphosphonate (ibandronate) had no significant effect on serum osteocalcin concentration (MD -3.61 ng/ml, 95% CI -9.41 to 2.18; 2 trials with 47 patients; I² = 82%) in a random-effects meta-analysis, but it significantly decreased serum osteocalcin (MD -4.40 ng/ml, 95% CI -6.75 to -2.05; 2 trials with 47 patients; I² = 82%), the procollagen type I N-terminal propeptide (MD -8.79 ng/ml, 95% CI -15.96 to -1.63; 2 trials with 47 patients; I² = 38%), and NTx concentration (MD -14.07 nmol bone collagen equivalents/mmol creatinine, 95% CI -24.23 to -3.90; 2 trials with 46 patients; I²=0%) in a fixed-effect model. The latter two results were not supported by trial sequential analyses. There was no statistically significant difference in the number of patients having bisphosphonates withdrawn due to adverse events compared with placebo or no intervention (RD -0.04; 95% CI -0.21 to 0.12; 2 trials with 46 patients; I² = 0%), or another bisphosphonate (RR 0.56; 95% CI 0.14 to 2.17; 2 trials with 62 patients; I² = 0%). One trial with 32 participants and with high risk of bias compared etidronate versus sodium fluoride without finding significant difference regarding mortality, fractures, adverse events, or bone mineral density. Etidronate compared with sodium fluoride significantly decreased serum osteocalcin, urinary hydroxyproline, and parathyroid hormone concentration.

Authors' conclusions: We did not find evidence to support or refute the use of bisphosphonates for patients with primary biliary cirrhosis. The data seem to indicate a possible positive intervention effect of bisphosphonates on decreasing urinary amino telopeptides of collagen I concentration compared with placebo or no intervention with no risk of random error. There is need for more randomised clinical trials assessing the effects of bisphosphonates for osteoporosis on patient-relevant outcomes in primary biliary cirrhosis.

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Conflict of interest statement

None known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Figure 4. Trial sequential analysis of the cumulative meta‐analysis of the effect of bisphosphonates versus placebo or no intervention on the urinary amino telopeptides of collagen I (NTx) concentration in participants with primary biliary cirrhosis. The diversity‐adjusted required information size (DARIS) of 168 patients is calculated based on a minimal relevant intervention effect (MIREDIF) of 11.5 nmol bone collagen equivalents (BCE)/mmol creatinine (Cr), a standard deviation of 23 nmol bone collagen equivalents/mmol creatinine, a risk of type 1 error of 5%, a power of 80%, and a diversity of 0%. The cumulated Z‐curve (blue curve) crosses the trial sequential monitoring boundary (red curve) implying that there is firm evidence for a beneficial effect of 11.5 nmol bone collagen equivalents/mmol creatinine decrease in NTx concentration when the cumulative meta‐analysis is adjusted for sparse data and multiple testing on accumulating data.
5
5
Figure 5. Trial sequential analysis of the cumulative meta‐analysis of the effect of alendronate versus another bisphosphonate on concentration of the procollagen type I N‐terminal propeptide (PINP) in participants with primary biliary cirrhosis. The diversity‐adjusted required information size (DARIS) of 168 patients is calculated based on a minimal relevant intervention effect (MIREDIF) of 9 ng/ml, a standard deviation of 18 ng/ml, a risk of type 1 error of 5%, a power of 80%, and a diversity of 38%. The cumulated Z‐curve (blue curve) does not cross the trial sequential monitoring boundary implying that there is no firm evidence for a beneficial effect of 9 ng/ml decrease in PINP concentration when the cumulative meta‐analysis is adjusted for sparse data and multiple testing on accumulating data.
6
6
Figure 6. Trial sequential analysis of the cumulative meta‐analysis of the effect of alendronate versus another bisphosphonate on concentration of the urinary amino telopeptides of collagen I (NTx) in participants with primary biliary cirrhosis. The diversity‐adjusted required information size (DARIS) of 87 patients is calculated based on a minimal relevant intervention effect (MIREDIF) of 12.5 nmol bone collagen equivalents/mmol creatinine, a standard deviation of 25 nmol bone collagen equivalents/mmol creatinine, a risk of type 1 error of 5%, a power of 80%, and a diversity of 0%. The cumulated Z‐curve (blue curve) does not cross the trial sequential monitoring boundary implying that there is no firm evidence for a beneficial effect of 12.5 nmol bone collagen equivalents/mmol creatinine decrease in NTx concentration when the cumulative meta‐analysis is adjusted for sparse data and multiple testing on accumulating data.
1.1
1.1. Analysis
Comparison 1 Bisphosphonates vs placebo or no intervention, Outcome 1 All‐cause mortality.
1.2
1.2. Analysis
Comparison 1 Bisphosphonates vs placebo or no intervention, Outcome 2 Fractures.
1.3
1.3. Analysis
Comparison 1 Bisphosphonates vs placebo or no intervention, Outcome 3 Adverse advents.
1.4
1.4. Analysis
Comparison 1 Bisphosphonates vs placebo or no intervention, Outcome 4 Lumbar spine bone mineral density (g/cm²).
1.5
1.5. Analysis
Comparison 1 Bisphosphonates vs placebo or no intervention, Outcome 5 Proximal femur bone mineral density (g/cm2).
1.6
1.6. Analysis
Comparison 1 Bisphosphonates vs placebo or no intervention, Outcome 6 Liver‐related mortality or liver transplantation.
1.7
1.7. Analysis
Comparison 1 Bisphosphonates vs placebo or no intervention, Outcome 7 Liver‐related morbidity.
1.8
1.8. Analysis
Comparison 1 Bisphosphonates vs placebo or no intervention, Outcome 8 Serum osteocalcin (ng/ml).
1.9
1.9. Analysis
Comparison 1 Bisphosphonates vs placebo or no intervention, Outcome 9 The urinary amino telopeptides of collagen I NTx (nmol bone collagen equivalents/mmol creatinine).
1.10
1.10. Analysis
Comparison 1 Bisphosphonates vs placebo or no intervention, Outcome 10 Number of patients having bisphosphonates withdrawn due to adverse events.
2.1
2.1. Analysis
Comparison 2 Bisphosphonates vs another bisphosphonate (alendronate vs etidronate or ibandronate), Outcome 1 All‐cause mortality.
2.2
2.2. Analysis
Comparison 2 Bisphosphonates vs another bisphosphonate (alendronate vs etidronate or ibandronate), Outcome 2 Fractures.
2.3
2.3. Analysis
Comparison 2 Bisphosphonates vs another bisphosphonate (alendronate vs etidronate or ibandronate), Outcome 3 Adverse advents.
2.4
2.4. Analysis
Comparison 2 Bisphosphonates vs another bisphosphonate (alendronate vs etidronate or ibandronate), Outcome 4 Lumbar spine bone mineral density (g/cm²).
2.5
2.5. Analysis
Comparison 2 Bisphosphonates vs another bisphosphonate (alendronate vs etidronate or ibandronate), Outcome 5 Proximal femur bone mineral density (g/cm2).
2.6
2.6. Analysis
Comparison 2 Bisphosphonates vs another bisphosphonate (alendronate vs etidronate or ibandronate), Outcome 6 Liver‐related mortality or liver transplantation.
2.7
2.7. Analysis
Comparison 2 Bisphosphonates vs another bisphosphonate (alendronate vs etidronate or ibandronate), Outcome 7 Liver‐related morbidity.
2.8
2.8. Analysis
Comparison 2 Bisphosphonates vs another bisphosphonate (alendronate vs etidronate or ibandronate), Outcome 8 Serum osteocalcin (ng/ml).
2.9
2.9. Analysis
Comparison 2 Bisphosphonates vs another bisphosphonate (alendronate vs etidronate or ibandronate), Outcome 9 The procollagen type I N‐terminal propeptide (PINP) (ng/ml).
2.10
2.10. Analysis
Comparison 2 Bisphosphonates vs another bisphosphonate (alendronate vs etidronate or ibandronate), Outcome 10 The urinary amino telopeptides of collagen I (NTx) (nmol bone collagen equivalents /mmol creatinine).
2.11
2.11. Analysis
Comparison 2 Bisphosphonates vs another bisphosphonate (alendronate vs etidronate or ibandronate), Outcome 11 Number of patients having alendronate withdrawn due to adverse events.
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Update of

  • doi: 10.1002/14651858.CD009144

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