Bisphosphonates in multiple myeloma: an updated network meta‐analysis

Rahul Mhaskar; Ambuj Kumar; Branko Miladinovic; Benjamin Djulbegovic

doi:10.1002/14651858.CD003188.pub4

Cochrane Database of Systematic Reviews

Bifosfonatos para el mieloma múltiple: un metanálisis en red actualizado

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DOI:

https://doi.org/10.1002/14651858.CD003188.pub4 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

18 diciembre 2017see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Hematología

Copyright:

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Rahul Mhaskar

Center for Evidence Based Medicine and Health Outcomes Research, University of South Florida, Tampa, USA
Ambuj Kumar

Correspondencia a: Center for Evidence Based Medicine and Health Outcomes Research, University of South Florida, Tampa, USA

[email protected]

[email protected]
Branko Miladinovic

Center for Evidence‐based Medicine, University of South Florida, Tampa, USA
Benjamin Djulbegovic

USF Program for Comparative Effectiveness Research & Dpt of Hematology, Moffitt Cancer Ctr, University of South Florida & Mofftt Cancer Center, Tampa, USA

Contributions of authors

For this update:

RM handsearched journals and references, extracted and analyzed data, wrote the initial and final drafts and participated in all phases of the project.

BD oversaw and co‐ordinated the group activity, maintained contact with Cochrane, provided vital content and methodological inputs, and edited the review.

AK extracted data, contacted a researcher regarding unpublished data, and maintained contact with Cochrane.

BM conducted the indirect comparisons using Bayesian methods.

BD, RM and AK discussed methodological problems.

All co‐authors interpreted data, provided constructive critiques and agreed on the final version of the paper.

Sources of support

Internal sources

Center for Evidence‐based Medicine,The University of South Florida, USA.
Department of Internal Medicine, University of Bonn, Germany.

External sources

Leukämie‐Initiative Bonn e.v., Germany.
Cochrane Haematological Malignancies Group (CHMG), Germany.

Declarations of interest

RM: None known.

AK: None known.

BM: None known.

BD: None known.

Acknowledgements

We want to thank Dr Terpos and Dr McCloskey for verification of extracted data from their papers, as well as Dr Ruiz‐Erenchun, Hoffmann‐La Roche Ltd, Basel, Switzerland, who provided additional data from the ibandronate trial. Dr Poglód provided additional information on the trials of his group. We also want to thank the Cochrane peer‐reviewers and editors for critical reading of our review and helpful feedback. We thank Dr Thomas A. Trikalinos for his suggestions regarding meta‐regression. We also thank the Cochrane Hematological Malignancies Group for their assistance in identifying the RCT by Garcia‐Sanz and colleagues.

Version history

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Title

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2017 Dec 18

Bisphosphonates in multiple myeloma: an updated network meta‐analysis

Review

Rahul Mhaskar, Ambuj Kumar, Branko Miladinovic, Benjamin Djulbegovic

https://doi.org/10.1002/14651858.CD003188.pub4

2012 May 16

Bisphosphonates in multiple myeloma: a network meta‐analysis

Review

Rahul Mhaskar, Jasmina Redzepovic, Keith Wheatley, Otavio Augusto Camara Clark, Branko Miladinovic, Axel Glasmacher, Ambuj Kumar, Benjamin Djulbegovic

https://doi.org/10.1002/14651858.CD003188.pub3

2010 Mar 17

Bisphosphonates in multiple myeloma

Review

Rahul Mhaskar, Jasmina Redzepovic, Keith Wheatley, Otavio Augusto Camara Clark, Branko Miladinovic, Axel Glasmacher, Ambuj Kumar, Benjamin Djulbegovic

https://doi.org/10.1002/14651858.CD003188.pub2

2002 Oct 21

Bisphosphonates in multiple myeloma

Review

Benjamin Djulbegovic, Keith Wheatley, Hamish Ross, Otavio Augusto Camara Clark, Gerard Bos, Hartmut Goldschmidt, Friedrich Cremer, Melissa Alsina, Axel Glasmacher

https://doi.org/10.1002/14651858.CD003188

Differences between protocol and review

Compared with the last version of this systematic review, we employed only the Bayesian method for the network meta‐analysis. That is, we have not used the frequentist method for performing adjusted indirect comparisons as described by Bucher, Glenny and Caldwell and colleagues. According to the revised guidelines for network meta analysis; we used the Bayesian methods under random‐effects multiple treatment comparisons (MTC) for indirect comparisons/network meta analysis (Higgins 1996; Lu 2004). Also, as per the peer reviewer's suggestions; we conducted additional sensitivity analyses based on the route of administration (oral versus intravenous) for gastrointestinal toxicity outcome (Analysis 3.8), which was not part of the protocol.

We also identified observational studies and case reports regarding bisphosphonate‐related ONJ in the MEDLINE database

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Bisphosphonate chemical structures

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Figure 2

Study flowchart

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Figure 3

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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Figure 4

Bisphosphonate potency metaregression for overall survival. HR: Hazard ratio.

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Figure 5

Randomized controlled trial (RCT) network for overall survival (OS), progression free survival (PFS) and skeletal related events (SREs).

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Figure 6

A: Ranking probabilities of competing bisphosphonates. The size of each bar corresponds to the probability of each treatment to be at a specific rank. OS: Overall survival; PFS: Progression‐free survival; SRE: Skeletal‐related events; Osteonecrosis; GI: Gastrointestinal toxicity; Hyper: Hypercalcemia.

B: Surface under the cumulative ranking curve (SUCRA) plots for each treatment. The outcomes are listed on the horizontal axis. SUCRA for each outcome are on the vertical axis.

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Figure 7

Funnel plot of comparison: 1 Bisphosphonates vs. control (efficacy), outcome: 1.6 Pain.

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Analysis 1.1

Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 1 Mortality.

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Analysis 1.2

Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 2 Progression‐free survival.

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$Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 3 Vertebral fractures.$

Analysis 1.3

Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 3 Vertebral fractures.

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$Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 4 Non‐vertebral fractures.$

Analysis 1.4

Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 4 Non‐vertebral fractures.

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Analysis 1.5

Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 5 Total skeletal‐related events.

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Analysis 1.6

Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 6 Pain.

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Analysis 1.7

Comparison 1 Bisphosphonates vs. control (efficacy), Outcome 7 Incidence of hypercalcemia.

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Analysis 2.1

Comparison 2 Bisphosphonates vs. control (adverse effects), Outcome 1 Osteonecosis of jaw.

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Analysis 2.2

Comparison 2 Bisphosphonates vs. control (adverse effects), Outcome 2 Gastrointestinal toxicity (grade III/IV).

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Analysis 2.3

Comparison 2 Bisphosphonates vs. control (adverse effects), Outcome 3 Hypocalcaemia.

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Analysis 2.4

Comparison 2 Bisphosphonates vs. control (adverse effects), Outcome 4 Renal dysfunction.

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$Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 1 Allocation concealment (vertebral fractures).$

Analysis 3.1

Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 1 Allocation concealment (vertebral fractures).

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$Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 2 Blinding (vertebral fractures).$

Analysis 3.2

Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 2 Blinding (vertebral fractures).

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$Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 3 Randomization method (vertebral fractures).$

Analysis 3.3

Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 3 Randomization method (vertebral fractures).

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$Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 4 Type of data analysis (vertebral fractures).$

Analysis 3.4

Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 4 Type of data analysis (vertebral fractures).

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$Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 5 Description of withdrawals and drop outs (vertebral fractures).$

Analysis 3.5

Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 5 Description of withdrawals and drop outs (vertebral fractures).

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$Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 6 Alpha error (vertebral fractures).$

Analysis 3.6

Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 6 Alpha error (vertebral fractures).

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$Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 7 Beta error (vertebral fractures).$

Analysis 3.7

Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 7 Beta error (vertebral fractures).

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Analysis 3.8

Comparison 3 Sensitivity analyses (assessment of bias: analysed outcome in brackets), Outcome 8 Gastrointestinal toxicity (grade III/IV: oral vs IV bisphosphonates)).

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Summary of findings for the main comparison. Summary of findings (direct comparisons)

Bisphosphonates in multiple myeloma
Patient or population: patients with multiple myeloma Intervention: bisphosphonates Control: no treatment/placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Control	Bisphosphonates
Overall survival##	Medium‐risk population#		HR 0.90 (0.76 to 1.07)	2706 (14 studies)	⊕⊕⊕⊝ moderate^1,2,3
	410 per 1000	378 per 1000 (330 to 431)
Progression‐free survival###	Medium‐risk population#		HR 0.75 (0.57 to 1.00)	908 (7 studies)	⊕⊕⊝⊝ low^1,4,11
	470 per 1000	379 per 1000 (304 to 470)
Vertebral fractures	Medium‐risk population#		RR 0.74 (0.62 to 0.89)	1116 (7 studies)	⊕⊕⊕⊝ moderate^1,5
	360 per 1000	266 per 1000 (223 to 320)
Non‐vertebral fractures	Medium‐risk population#		RR 1.03 (0.68 to 1.56)	1389 (6 studies)	⊕⊕⊕⊝ moderate^1,6
	140 per 1000	144 per 1000 (95 to 218)
Skeletal‐related events	Medium‐risk population#		RR 0.74 (0.63 to 0.88)	2141 (10 studies)	⊕⊕⊕⊝ moderate^1,7
	400 per 1000	296 per 1000 (252 to 352)
Pain	Medium‐risk population		RR 0.75 (0.60 to 0.95)	1281 (8 studies)	⊕⊝⊝⊝ very low^8,9
	540 per 1000	410 per 1000 (329 to 508)
Osteonecrosis of jaw	Medium‐risk population#		RR 4.61 (0.99 to 21.35)	1284 (6 studies)	⊕⊕⊝⊝ low^10,11
	NE	0 per 1000 (0 to 2)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; HR: Hazard ratio; NE: not estimable due to rarity of events in the control arm
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ A total of 20 RCTs were included in the direct meta‐analysis. Only 35% (7/20) of trials had adequate allocation concealment. Only 20% (4/20) of trials reported methods of randomization. Similarly, 15% (3/20) of trials reported blinding procedures and personnel who were blinded to the intervention assignment. However, sensitivity analyses based on the methodological quality domains did not change the estimates. Hence, the assessment of studies’ limitations may represent the poor quality of reporting rather than true biased estimates. ² Downgraded the quality of evidence for the outcome of overall survival (OS) by one for the observed inconsistency (I² = 65%). However we noticed that this heterogeneity in the pooled estimate is driven by studies by Aviles and colleagues (Aviles 2007; Aviles 2013); when we removed these RCTs heterogeneity disappeared. ³ Note that overall mortality data denotes the mortality rates, i.e. the number of events refers to the number of deaths. ⁴ Downgraded the quality of evidence by one level due to the potential for publication bias.The progression‐free survival data were extractable from only 35% (7/20) of studies eligible for direct meta‐analysis. ⁵ Downgraded the quality of evidence by one level due to the potential for publication bias. Data related to patients with vertebral fractures were extractable from only 35% (7/20) of studies eligible for direct meta‐analysis. ⁶ Downgraded the quality of evidence by one level due to the potential for publication bias. Data related to patients with non‐vertebral fractures were extractable from only 30% (6/20) of studies eligible for direct meta‐analysis. ⁷ Downgraded the quality of evidence by one level due to the potential for publication bias. Skeletal‐related events data were extractable from 50% (10/20) of studies. ⁸ Downgraded the quality of evidence by one level due to variation in assessment instruments.There was significant variation in the assessment methods used to measure pain. ⁹ Downgraded the quality of evidence by one level due to variation in assessment of pain based on blinding of the assessors. Only 15% (3/20) of trials reported blinding procedures and personnel who were blinded to the intervention assignment. Moreover, we found that RCTs with double‐blinding showed no significant benefit of bisphosphonates over placebo for amelioration of pain, while non‐blinded RCTs favored bisphosphonates over placebo for pain relief. We also downgraded the quality of evidence by one level due to imprecision. ¹⁰ Downgraded the quality of evidence by one level due to the potential for publication bias.The Osteonecrosis of jaw data were extractable from 30% (6/20) of studies eligible for direct meta‐analysis. ¹¹ Downgraded the quality of evidence by one level due to imprecision.All included RCTs and also the pooled estimate have wide confidence intervals. # The moderate control risk was calculated via GRADEpro software based on average risk in the control arm of the included studies. ## We have calculated and presented overall mortality instead of OS. The expected events represent a median timeline of 5 years. ### PFS events represent death or progress or relapse. The expected events represent a median timeline of 5 years.

Summary of findings for the main comparison. Summary of findings (direct comparisons)

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Table 1. Bisphosphonate potency

Type of bisphosphonates	Bisphosphontes	Relative potency
Nonaminobisphosphonates	Etidronate	1
	Clodronate	10
	Tiludronate	10
Aminobisphosphonates	Pamidronate	100
	Alendronate	500
	Ibandronate	1,000
	Risendronate	2,000
	Zoledronate	10,000
Based on information from (Drake 2008; Dunford 2001).

Table 1. Bisphosphonate potency

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Table 2. Type and content of reporting in RCTs on bisphosphonates in myeloma

Study ID	Adverse events (gastrointestinal symptoms)	Adverse events (hypocalcemia)	Adverse events (serum creatinine)	Adverse events (osteonecrosis of the jaw)
Belch 1991	No	No	No	No
Berenson 1998a	Yes	Yes	No	No
Brincker 1998	Yes	No	No	No
Delmas 1982	No	No	No	No
Daragon 1993	Yes	No	Yes	No
Heim 1995	No	No	No	No
Lahtinen 1992	Yes	No	Yes	No
McCloskey 2001	Yes	Yes	No	No
Terpos 2000	Yes	No	No	No
Terpos 2003	No	Yes	No	No
Kraj 2000	No	No	No	No
Attal 2006	No	No	No	Yes
Musto 2003	No	No	No	Yes
Musto 2008	No	No	No	Yes
Aviles 2007	No	No	No	No
Menssen 2002	No	No	No	No
Leng 2002	No	No	No	No
Morgan 2010	Yes	No	No	Yes
Rosen 2003	No	No	No	No
Gimsing 2010	No	No	No	Yes
Aviles 2013	No	No	No	Yes
Sezer 2010	Yes	No	No	Yes
Zhang 2012	No	No	No	No
Garcia‐Sanz 2015	No	No	No	Yes

Table 2. Type and content of reporting in RCTs on bisphosphonates in myeloma

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Table 3. Indirect comparisons

			MTC method (REM)
Outcome	Treatment1	Treatment2	NRCTs	Patients	HR/RR	95% LCRL	95% UCRL	Quality of the evidence (GRADE)
OS	PL	CLO	16	5260	1.19	0.88	1.63	⊕⊕⊕⊝ moderate
OS	ETI	CLO	16	5260	1.48	0.96	2.51	⊕⊕⊕⊝ moderate
OS	IBAN	CLO	16	5260	1.34	0.60	2.62	⊕⊕⊕⊝ moderate
OS	PAM 90 mg	CLO	16	5260	1.04	0.64	1.64	⊕⊕⊕⊝ moderate
OS	ZOL	CLO	16	5260	0.78	0.52	1.14	⊕⊕⊕⊝ moderate
OS	PAM 30 mg	CLO	16	5260	1.04	0.48	2.09	⊕⊕⊝⊝ low^*
OS	ETI	PL	16	5260	1.25	0.88	1.95	⊕⊕⊝⊝ low^*
OS	IBAN	PL	16	5260	1.13	0.54	2.06	⊕⊕⊝⊝ low^*
OS	PAM 90 mg	PL	16	5260	0.87	0.60	1.23	⊕⊕⊕⊝ moderate
OS	ZOL	PL	16	5260	0.67	0.46	0.91	⊕⊕⊕⊝ moderate
OS	PAM 30 mg	PL	16	5260	0.87	0.44	1.64	⊕⊕⊝⊝ low^*
OS	IBAN	ETI	16	5260	0.94	0.37	1.80	⊕⊕⊝⊝ low^*
OS	PAM 90 mg	ETI	16	5260	0.73	0.38	1.14	⊕⊕⊝⊝ low^*
OS	ZOL	ETI	16	5260	0.56	0.29	0.87	⊕⊕⊕⊝ moderate
OS	PAM 30 mg	ETI	16	5260	0.72	0.30	1.40	⊕⊕⊝⊝ low^*
OS	PAM 90 mg	IBAN	16	5260	0.87	0.39	1.74	⊕⊕⊝⊝ low^*
OS	ZOL	IBAN	16	5260	0.67	0.29	1.31	⊕⊕⊝⊝ low^*
OS	PAM 30 mg	IBAN	16	5260	0.87	0.32	2.06	⊕⊕⊝⊝ low^*
OS	ZOL	PAM 90 mg	16	5260	0.79	0.46	1.26	⊕⊕⊝⊝ low^*
OS	PAM 30 mg	PAM 90 mg	16	5260	1.00	0.57	1.74	⊕⊕⊝⊝ low^*
OS	PAM 30 mg	ZOL	16	5260	1.35	0.62	2.76	⊕⊕⊝⊝ low^*
PFS	PL	PAM 90 mg	9	3472	0.84	0.30	1.88	⊕⊝⊝⊝ very low ^{*^}
PFS	ZOL	PAM 90 mg	9	3472	0.59	0.20	1.39	⊕⊝⊝⊝ very low ^{*^}
PFS	CLO	PAM 90 mg	9	3472	0.66	0.16	1.71	⊕⊝⊝⊝ very low ^{*^}
PFS	PAM 30 mg	PAM 90 mg	9	3472	1.04	0.38	2.16	⊕⊝⊝⊝ very low ^{*^}
PFS	ZOL	PL	9	3472	0.70	0.46	1.03	⊕⊝⊝⊝ very low ^{*^}
PFS	CLO	PL	9	3472	0.77	0.30	1.47	⊕⊝⊝⊝ very low ^{*^}
PFS	PAM 30 mg	PL	9	3472	1.55	0.34	4.29	⊕⊝⊝⊝ very low ^{*^}
PFS	CLO	ZOL	9	3472	1.10	0.45	1.95	⊕⊝⊝⊝ very low ^{*^}
PFS	PAM 30 mg	ZOL	9	3472	2.30	0.45	6.78	⊕⊝⊝⊝ very low ^{*^}
PFS	PAM 30 mg	CLO	9	3472	2.38	0.43	8.15	⊕⊝⊝⊝ very low ^{*^}
SREs	PL	CLO	13	5727	1.27	0.81	1.84	⊕⊕⊝⊝ low^*
SREs	ETI	CLO	13	5727	1.01	0.37	2.20	⊕⊕⊝⊝ low^*
SREs	PAM 90 mg	CLO	13	5727	0.90	0.51	1.38	⊕⊕⊝⊝ low^*
SREs	IBAN	CLO	13	5727	1.37	0.68	2.55	⊕⊕⊝⊝ low^*
SREs	ZOL	CLO	13	5727	0.72	0.41	1.02	⊕⊕⊝⊝ low^*
SREs	PAM 30 mg	CLO	13	5727	0.89	0.44	1.62	⊕⊕⊝⊝ low^*
SREs	ETI	PL	13	5727	0.79	0.33	1.61	⊕⊕⊝⊝ low^*
SREs	PAM 90 mg	PL	13	5727	0.71	0.49	0.96	⊕⊕⊕⊝ moderate
SREs	IBAN	PL	13	5727	1.08	0.60	1.86	⊕⊕⊝⊝ low^*
SREs	ZOL	PL	13	5727	0.57	0.37	0.76	⊕⊕⊕⊝ moderate
SREs	PAM 30 mg	PL	13	5727	0.71	0.38	1.23	⊕⊕⊝⊝ low^*
SREs	PAM 90 mg	ETI	13	5727	1.06	0.40	2.25	⊕⊕⊝⊝ low^*
SREs	IBAN	ETI	13	5727	1.61	0.55	3.79	⊕⊕⊝⊝ low^*
SREs	ZOL	ETI	13	5727	0.84	0.31	1.76	⊕⊕⊝⊝ low^*
SREs	PAM30mg	ETI	13	5727	1.06	0.35	2.57	⊕⊕⊝⊝ low^*
SREs	IBAN	PAM 90 mg	13	5727	1.56	0.80	2.90	⊕⊕⊝⊝ low^*
SREs	ZOL	PAM 90 mg	13	5727	0.81	0.52	1.14	⊕⊕⊝⊝ low^*
SREs	PAM 30 mg	PAM 90 mg	13	5727	1.00	0.60	1.70	⊕⊕⊝⊝ low^*
SREs	ZOL	IBAN	13	5727	0.56	0.26	0.98	⊕⊕⊕⊝ moderate
SREs	PAM 90 mg	IBAN	13	5727	0.70	0.29	1.44	⊕⊕⊝⊝ low^*
SREs	PAM 30 mg	ZOL	13	5727	1.28	0.68	2.51	⊕⊕⊝⊝ low^*
Pain	ETI	CLO	8	1281	2.15	0.22	9.56	⊕⊝⊝⊝ very low ^{*^}
Pain	IBAN	CLO	8	1281	4.13	0.57	16.99	⊕⊝⊝⊝ very low ^{*^}
Pain	PAM 90 mg	CLO	8	1281	1.76	0.57	16.99	⊕⊝⊝⊝ very low ^{*^}
Pain	IBAN	ETI	8	1281	4.07	0.23	19.62	⊕⊝⊝⊝ very low ^{*^}
Pain	PAM 90 mg	ETI	8	1281	1.75	0.11	7.64	⊕⊝⊝⊝ very low ^{*^}
Pain	PAM 90 mg	IBAN	8	1281	0.75	0.06	3	⊕⊝⊝⊝ very low ^{*^}
Vertebral fractures	PL	CLO	8	3076	1.50	0.87	2.62	⊕⊕⊝⊝ low^*
Vertebral fractures	IBAN	CLO	8	3076	1.76	0.56	4.45	⊕⊕⊝⊝ low^*
Vertebral fractures	PAM 90 mg	CLO	8	3076	1.07	0.45	2.07	⊕⊕⊝⊝ low^*
Vertebral fractures	ZOL	CLO	8	3076	0.59	0.22	1.17	⊕⊕⊝⊝ low^*
Vertebral fractures	IBAN	PL	8	3076	1.16	0.41	2.56	⊕⊕⊝⊝ low^*
Vertebral fractures	PAM90mg	PL	8	3076	0.72	0.35	1.18	⊕⊕⊝⊝ low^*
Vertebral fractures	ZOL	PL	8	3076	0.42	0.12	0.94	⊕⊕⊕⊝ moderate
Vertebral fractures	PAM90mg	IBAN	8	3076	0.76	0.21	1.91	⊕⊕⊝⊝ low^*
Vertebral fractures	ZOL	IBAN	8	3076	0.45	0.08	1.29	⊕⊕⊝⊝ low^*
Vertebral fractures	ZOL	PAM 90 mg	8	3076	0.64	0.17	1.68	⊕⊕⊝⊝ low^*
Nonvertebral fractures	PL	CLO	7	3349	1.47	0.65	3.10	⊕⊕⊝⊝ low^*
Nonvertebral fractures	IBAN	CLO	7	3349	2.13	0.44	7.20	⊕⊕⊝⊝ low^*
Nonvertebral fractures	PAM 90 mg	CLO	7	3349	3.17	0.52	10.88	⊕⊕⊝⊝ low^*
Nonvertebral fractures	ZOL	CLO	7	3349	0.82	0.24	2.32	⊕⊕⊝⊝ low^*
Nonvertebral fractures	IBAN	PL	7	3349	1.46	0.40	3.98	⊕⊕⊝⊝ low^*
Non vertebral fractures	PAM 90 mg	PL	7	3349	2.01	0.46	6.32	⊕⊕⊝⊝ low^*
Non vertebral fractures	ZOL	PL	7	3349	0.66	0.13	2.30	⊕⊕⊝⊝ low^*
Non‐vertebral fractures	PAM 90 mg	IBAN	7	3349	1.98	0.25	7.66	⊕⊕⊝⊝ low^*
Non‐vertebral fractures	ZOL	IBAN	7	3349	0.64	0.07	2.82	⊕⊕⊝⊝ low^*
Non‐vertebral fractures	ZOL	PAM 90 mg	7	3349	0.49	0.04	2.14	⊕⊕⊝⊝ low^*
Hypercalcemia	PL	CLO	11	4146	1.64	0.71	3.58	⊕⊝⊝⊝ very low ^*$
Hypercalcemia	ETI	CLO	11	4146	2.59	0.51	8.80	⊕⊝⊝⊝ very low ^*$
Hypercalcemia	IBAN	CLO	11	4146	1.27	0.20	4.53	⊕⊝⊝⊝ very low ^*$
Hypercalcemia	PAM90mg	CLO	11	4146	1.14	0.32	3.05	⊕⊝⊝⊝ very low ^*$
Hypercalcemia	ZOL	CLO	11	4146	1.04	0.32	2.47	⊕⊝⊝⊝ very low ^*$
Hypercalcemia	ETI	PL	11	4146	1.55	0.40	4.27	⊕⊝⊝⊝ very low ^*$
Hypercalcemia	IBAN	PL	11	4146	0.76	0.16	2.27	⊕⊝⊝⊝ very low ^*$
Hypercalcemia	PAM 90 mg	PL	11	4146	0.70	0.26	1.40	⊕⊝⊝⊝ very low ^*$
Hypercalcemia	ZOL	PL	11	4146	0.73	0.16	1.92	⊕⊝⊝⊝ very low ^*$
Hypercalcemia	IBAN	ETI	11	4146	0.68	0.08	2.53	⊕⊝⊝⊝ very low ^*$
Hypercalcemia	PAM 90 mg	ETI	11	4146	0.62	0.11	1.92	⊕⊝⊝⊝ very low ^*$
Hypercalcemia	ZOL	ETI	11	4146	0.65	0.08	2.28	⊕⊝⊝⊝ very low ^*$
Hypercalcemia	PAM 90 mg	IBAN	11	4146	1.42	0.22	4.79	⊕⊝⊝⊝ very low ^*$
Hypercalcemia	ZOL	IBAN	11	4146	1.50	0.15	5.74	⊕⊝⊝⊝ very low ^*$
Hypercalcemia	ZOL	PAM 90 mg	11	4146	1.23	0.21	4.05	⊕⊝⊝⊝ very low ^*$
GIToxicity	PL	CLO	8	3789	0.87	0.45	1.49	⊕⊕⊝⊝ low^{* $$}
GIToxicity	ETI	CLO	8	3789	1.14	0.01	7.59	⊕⊕⊝⊝ low^{* $$}
GIToxicity	PAM 90 mg	CLO	8	3789	1.18	0.45	2.49	⊕⊕⊝⊝ low^{* $$}
GIToxicity	ZOL	CLO	8	3789	0.86	0.35	1.74	⊕⊕⊝⊝ low^{* $$}
GIToxicity	ETI	PL	8	3789	1.32	0.01	8.73	⊕⊕⊝⊝ low^{* $$}
GIToxicity	PAM 90 mg	PL	8	3789	1.36	0.69	2.39	⊕⊕⊝⊝ low^{* $$}
GIToxicity	ZOL	PL	8	3789	1.07	0.38	2.39	⊕⊕⊝⊝ low^{* $$}
GIToxicity	PAM 90 mg	ETI	8	3789	15.96	0.14	102.19	⊕⊕⊝⊝ low^{* $$}
GIToxicity	ZOL	ETI	8	3789	12.63	0.10	81.10	⊕⊕⊝⊝ low^{* $$}
GIToxicity	ZOL	PAM 90 mg	8	3789	0.86	0.24	2.27	⊕⊕⊝⊝ low^{* $$}
ONJ	PL	PAM 90 mg	8	3746	1.10	0.04	5.99	⊕⊝⊝⊝ very low ^{*^}
ONJ	ZOL	PAM 90 mg	8	3746	6.19	0.09	38.16	⊕⊝⊝⊝ very low ^{*^}
ONJ	CLO	PAM 90 mg	8	3746	0.77	0.01	4.94	⊕⊝⊝⊝ very low ^{*^}
ONJ	PAM 30 mg	PAM 90 mg	8	3746	0.44	0.05	1.83	⊕⊝⊝⊝ very low ^{*^}
ONJ	ZOL	PL	8	3746	5.70	0.72	21.26	⊕⊝⊝⊝ very low ^{*^}
ONJ	CLO	PL	8	3746	0.71	0.04	3.43	⊕⊝⊝⊝ very low ^{*^}
ONJ	PAM 30 mg	PL	8	3746	2.19	0.03	13.55	⊕⊝⊝⊝ very low ^{*^}
ONJ	CLO	ZOL	8	3746	0.13	0.02	0.44	⊕⊝⊝⊝ very low **
ONJ	PAM 30 mg	ZOL	8	3746	0.77	0.00	5.09	⊕⊝⊝⊝ very low ^{*^}
ONJ	PAM 30 mg	CLO	8	3746	11.14	0.04	76.15	⊕⊝⊝⊝ very low ^{*^}
REM: Random effects model, for multiple treatment comparison method: sigma˜Unif(0,1); ONJ: osteonecrosis of the jaw; PL: Placebo; #RCTS: Number of randomized controlled trials; LCRL: Lower credibility limit; UCRL: Upper credibility limit; OS: Overall survival; PFS: Progression‐free survival; SREs: Skeletal‐related events; HR: Hazard ratio; RR: Risk ratio; ETI: Etidronate; CLO: Clodronate; PAM 90 mg: Pamidronate 90 mg: PAM 30 mg: Pamidronate 30 mg; IBAN: Ibandronate: ZOL: Zoledronate; Randomized controlled trial with direct (head‐to‐head) comparison of zoledronate versus clodronate (Morgan 2010). Imprecision; ^ Contributing direct evidence of low quality;$ For the contributing direct evidence, the pooled estimate along with individual studies have wide confidence intervals. Therefore, we downgraded the quality of evidence by two levels resulting in low quality evidence. $$ For the contributing direct evidence, individual studies have wide confidence intervals. Therefore, we downgraded the quality of evidence by one level resulting in moderate quality evidence.**The results from head to head RCT comparing zoledronate with clodronate showed no difference in risk of ONJ (Morgan 2010). However, the results from network meta‐analysis showed an increased risk of ONJ with zoledronate over clodronate which is indicative of incoherence.

Table 3. Indirect comparisons

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Table 4. Included ONJ studies

Study	Study design	Type of bisphosphonate	Total number of patients	Number of patients with ONJ	Route, dose, frequency	Treatment duration	ONJ frequency
Badros 2006	Retrospective study	Pamidronate	17	3	Not reported	Not reported	17.65%
		Zoledronate	34	2			5.88%
		Pamidronate + zoledronate	33	17			51.51%
Berenson 2011	Retrospective study	Zoledronate	300	14	Not clear	Median: 18 months Range: 1‐121 months	5%
Calvo‐Villas 2006	Not clear	Zoledronate	64	7	Not reported	Not clear	9%
Cetiner 2009	Prospective study	Zoledronate	32	5	15 minute infusion of 4 mg IV zoledronate once a month	Mean duration: 26.5 months, SD 18.7 months	15%
Corso 2007	Retrospective study	Pamidronate	20	0	Not clear	23 months	0%
		Zoledronate	37	5	Not clear	28 months	11.9%
		Pamidronate + zoledronate	42	2	Not clear	47 months	4.55%
Dimopoulos 2006		Pamidronate	93	7	Not reported	39 months ONJ patients (11‐76) vs 28 (4.5‐123) months without ONJ	7.5%
		Zoledronate	33	1			3%
		Pamidronate + zoledronate	66	6			9.1%
		Ibandronate	1	0			0%
		Ibandronate + zoledronate	4	1			25%
		Clodronate + zoledronate	1	0			0%
		Alendronate + zoledronate	1	0			0%
Garcia‐Garay 2006	Retrospective study	Pamidronate	49	1	90 mg monthly	28 months	2%
		Zoledronate	64	6	4 mg monthly	12 months (7‐28)	9.3%
		Pamidronate + zoledronate	30	7		43.5 months (24‐59)	23.3%
Tosi 2006b	Retrospective study	Zoledronate	225	6	Not reported	10 months (4‐35)	2.7%
Zervas 2006	Retrospective study from 1991, prospective from 2001‐2006	Pamidronate	78	1	90 mg	24 months (4‐120)	1.28%
		Pamidronate	91	6	4 mg 4‐6 weeks		6.59%
		Pamidronate + zoledronate	85	21			24.71%
ONJ: Osteonecrosis of the jaw; SD: standard deviation; IV: intravenous.

Table 4. Included ONJ studies

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Table 5. Excluded ONJ studies

Study_ID	Reason for exclusion
Bujanda 2007	No multiple myeloma patients with ONJ
Hoff 2006	No extractable data for multiple myeloma patients (abstract)
Kut 2004	American Society of Hematology 2004 (abstract no 4933): Approximately 600 multiple myeloma patients. Teported frequency: 7 patients. Excluded due to imprecise reporting (e.g. approximately 600 multiple myeloma patients)
ONJ: Osteonecrosis of the jaw.

Table 5. Excluded ONJ studies

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Table 6. ONJ case reports/case series: data stratified by bisphosphonate type

Study	Total number of patients	Clodronate	Pamidronate	Zoledronate	Pamidronate /zoledronate	Not specified	Others
Bagan 2006	9		2	7
Battley 2006	1			1
Braun 2006	1			1
Broglia 2006	1				1
Capalbo 2006	9		2	4	3
Carneiro 2006	1			1
Carter 2005	1		1
Clarke 2007	21		12	1	8
Curi 2007	1			1
Dannemann 2007	7			2	5
Diego 2007	3			3
Dimitrakopoulos 2006	5			2	3
Elad 2006	22			17	4		1(A)
Ficarra 2005	2			1	1
Fortuna 2012	13			13
Gabbert 2015	101		18	78			5
Gander 2014	1			1
Hansen 2006	5			1	4
Hay 2006	2			2
Herbozo 2007	1			1
Junquera 2009	21		1	19			1(A)
Kademani 2006	1			1
Kamoh 2012	1					1
Katz 2005	2			1	1
Khamaisi 2006	6		6
Kumar 2007	2		2
Lazarovici 2009	101		30	31	23		17(16:A,1:U)
Lenz 2005	1			1
Lugassy 2004	3		1		2
Magopoulos 2007	33		6	19	7		1(P,I,Z)
Marunick 2005	2		1	1
Melo 2005	7		4	2	1
Merigo 2006	1			1
Migliorati 2005	3		1		2
Montazeri 2007	1	1
Mortensen 2007	4		2	2
Murad 2007	2			2
Pires 2005	4				4
Pozzi 2007	35		3	14	18
Purcell 2005	3		2	1
Ruggiero 2004	28		14	4	10
Pastor‐Zuazaga 2006	1				1
Phal 2007	3			1	1		1(P/C)
Polizzotto 2006	1		1
Saad 2012	6					6
Salesi 2006	2			2
Saussez 2009	34		3	20	5		6 (:I/Z,3:A,1:U)
Senel 2007	1	1
Sitters 2005	1			1
Tennis 2012	11					11
Then 2012	23					23
Thumbigere‐Math 2012	6					6
Treister 2006	1		1
Vannucchi 2005	1			1
Vescovi 2012	56					56
Walter 2007	9		1	1	7
Watters 2013	27					27
Wickham 2013	1	1
Wutzl 2006	12		2	8	2
Yeo 2005	2		2
Zarychanski 2006	10		10
Total	676	3	128	270	113	130	32
A: Alendronate; C: Clodronate; I: Ibandronate; P: Pamidronate; R: Risedronate; Z: Zoledronate; MM: multiple myeloma; U: Unknown.

Table 6. ONJ case reports/case series: data stratified by bisphosphonate type

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Comparison 1. Bisphosphonates vs. control (efficacy)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	14	2706	Hazard Ratio (Random, 95% CI)	0.90 [0.76, 1.07]

1.1 Etidronate	2	244	Hazard Ratio (Random, 95% CI)	1.24 [0.86, 1.80]
1.2 Clodronate	3	885	Hazard Ratio (Random, 95% CI)	0.93 [0.66, 1.29]
1.3 Pamidronate	5	977	Hazard Ratio (Random, 95% CI)	0.85 [0.67, 1.07]
1.4 Ibandronate	1	198	Hazard Ratio (Random, 95% CI)	1.07 [0.69, 1.64]
1.5 Zoledronate	3	402	Hazard Ratio (Random, 95% CI)	0.57 [0.43, 0.75]
2 Progression‐free survival Show forest plot	7	908	Hazard Ratio (Random, 95% CI)	0.75 [0.57, 1.00]

2.1 Clodronate	1	26	Hazard Ratio (Random, 95% CI)	0.63 [0.17, 2.34]
2.2 Pamidronate	1	177	Hazard Ratio (Random, 95% CI)	1.24 [0.66, 2.33]
2.3 Zoledronate	5	705	Hazard Ratio (Random, 95% CI)	0.70 [0.52, 0.95]
3 Vertebral fractures Show forest plot	7	1116	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.62, 0.89]

3.1 Clodronate	3	433	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.56, 0.89]
3.2 Pamidronate	3	485	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.40, 1.20]
3.3 Ibandronate	1	198	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.61, 1.81]
4 Non‐vertebral fractures Show forest plot	6	1389	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.68, 1.56]

4.1 Clodronate	3	752	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.42, 1.31]
4.2 Pamidronate	2	439	Risk Ratio (M‐H, Random, 95% CI)	1.65 [0.95, 2.87]
4.3 Ibandronate	1	198	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.79, 1.98]
5 Total skeletal‐related events Show forest plot	10	2141	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.63, 0.88]

5.1 Etidronate	1	78	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.39, 1.39]
5.2 Clodronate	1	204	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.65, 0.89]
5.3 Pamidronate	3	950	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.59, 0.91]
5.4 Ibandronate	1	198	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.80, 1.35]
5.5 Zoledronate	4	711	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.28, 0.89]
6 Pain Show forest plot	8	1281	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.60, 0.95]

6.1 Etidronate	1	78	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.26, 1.32]
6.2 Clodronate	4	566	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.29, 0.91]
6.3 Pamidronate	2	439	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.72, 1.01]
6.4 Ibandronate	1	198	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.86, 1.17]
7 Incidence of hypercalcemia Show forest plot	10	2174	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.56, 1.09]

7.1 Etidronate	1	166	Risk Ratio (M‐H, Random, 95% CI)	1.32 [0.73, 2.38]
7.2 Clodronate	3	831	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.45, 1.31]
7.3 Pamidronate	3	739	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.31, 1.33]
7.4 Ibandronate	1	198	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.27, 1.42]
7.5 Zoledronate	2	240	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.01, 3.91]

Comparison 1. Bisphosphonates vs. control (efficacy)

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Comparison 2. Bisphosphonates vs. control (adverse effects)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Osteonecosis of jaw Show forest plot	6	1284	Risk Ratio (M‐H, Random, 95% CI)	4.61 [0.99, 21.35]

1.1 Pamidronate	2	573	Risk Ratio (M‐H, Random, 95% CI)	3.06 [0.13, 74.69]
1.2 Zoledronate	4	711	Risk Ratio (M‐H, Random, 95% CI)	5.21 [0.91, 29.90]
2 Gastrointestinal toxicity (grade III/IV) Show forest plot	7	1829	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.95, 1.59]

2.1 Etidronate	1	78	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.94]
2.2 Clodronate	2	872	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.82, 1.72]
2.3 Pamidronate	3	739	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.90, 1.88]
2.4 Zoledronate	1	140	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.06, 15.23]
3 Hypocalcaemia Show forest plot	3	1090	Risk Ratio (M‐H, Random, 95% CI)	2.19 [0.49, 9.74]

3.1 Clodronate	1	536	Risk Ratio (M‐H, Random, 95% CI)	2.06 [0.38, 11.16]
3.2 Pamidronate	2	554	Risk Ratio (M‐H, Random, 95% CI)	2.71 [0.11, 66.19]
4 Renal dysfunction Show forest plot	2	414	Mean Difference (IV, Random, 95% CI)	‐0.36 [‐9.75, 9.03]

Comparison 2. Bisphosphonates vs. control (adverse effects)

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Comparison 3. Sensitivity analyses (assessment of bias: analysed outcome in brackets)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Allocation concealment (vertebral fractures) Show forest plot	7	1116	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.62, 0.89]

1.1 Adeqaute concealment of allocation	2	594	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.51, 0.82]
1.2 Inadequate concealment of allocation	5	522	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.67, 1.09]
2 Blinding (vertebral fractures) Show forest plot	7	1116	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.62, 0.89]

2.1 Double‐blind	5	1008	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.58, 0.85]
2.2 Not blinded	2	108	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.08, 3.72]
3 Randomization method (vertebral fractures) Show forest plot	7	1116	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.62, 0.89]

3.1 Randomization method is described	1	377	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.38, 0.85]
3.2 Randomization method is NOT described	6	739	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.65, 0.94]
4 Type of data analysis (vertebral fractures) Show forest plot	7	1116	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.62, 0.89]

4.1 Intention‐to‐treat analysis	3	463	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.55, 1.22]
4.2 Per protocol analysis	4	653	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.56, 0.89]
5 Description of withdrawals and drop outs (vertebral fractures) Show forest plot	7	1116	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.62, 0.89]

5.1 Withdrawals and dropouts well described	3	797	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.55, 0.82]
5.2 Withdrawals and dropouts NOT described	4	319	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.68, 1.29]
6 Alpha error (vertebral fractures) Show forest plot	7	1116	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.62, 0.89]

6.1 Alpha error pre‐specified	1	203	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.51, 1.08]
6.2 Alpha error NOT pre‐specified	6	913	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.59, 0.94]
7 Beta error (vertebral fractures) Show forest plot	7	1116	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.62, 0.89]

7.1 Beta error pre‐specified	1	203	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.51, 1.08]
7.2 Beta error NOT pre‐specified	6	913	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.59, 0.94]
8 Gastrointestinal toxicity (grade III/IV: oral vs IV bisphosphonates)) Show forest plot	7	1829	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.95, 1.59]

8.1 Oral route	4	1250	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.89, 1.70]
8.2 Intervenous route	3	579	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.81, 1.90]

Comparison 3. Sensitivity analyses (assessment of bias: analysed outcome in brackets)

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