Efficacy and safety of burosumab compared with conventional therapy in patients with X-linked hypophosphatemia: A systematic review

Dodamani, Manjunath Havalappa; Cheryl Kumar, Samantha; Bhattacharjee, Samiksha; Barnabas, Rohit; Kumar, Sandeep; Lila, Anurag Ranjan; Memon, Saba Samad; Karlekar, Manjiri; Patil, Virendra A.; Bandgar, Tushar R.

doi:10.20945/2359-4292-2023-0242

Manjunath Havalappa Dodamani

contributed equally to this work and are joint first authors

Department of Endocrinology, Seth G.S. Medical College & KEM Hospital, Mumbai, Maharashtra, India

https://orcid.org/0000-0002-6658-0269

Samantha Cheryl Kumar

contributed equally to this work and are joint first authors

Department of Child Health, Christian Medical College, Vellore, Tamil Nadu, India

https://orcid.org/0009-0005-7329-5027

Samiksha Bhattacharjee

Department of Clinical Pharmacology, Post-graduate Institute of Medical Education and Research, Chandigarh, India

https://orcid.org/0000-0002-2951-8861

Rohit Barnabas

Department of Endocrinology, Seth G.S. Medical College & KEM Hospital, Mumbai, Maharashtra, India

https://orcid.org/0000-0001-7612-506X

Sandeep Kumar

Department of Endocrinology, Seth G.S. Medical College & KEM Hospital, Mumbai, Maharashtra, India

https://orcid.org/0000-0002-7072-1896

Anurag Ranjan Lila

Department of Endocrinology, Seth G.S. Medical College & KEM Hospital, Mumbai, Maharashtra, India

https://orcid.org/0000-0001-7097-2831

Saba Samad Memon

Department of Endocrinology, Seth G.S. Medical College & KEM Hospital, Mumbai, Maharashtra, India

https://orcid.org/0000-0001-5199-6299

Manjiri Karlekar

Department of Endocrinology, Seth G.S. Medical College & KEM Hospital, Mumbai, Maharashtra, India

https://orcid.org/0000-0001-7277-7052

Virendra A. Patil

Department of Endocrinology, Seth G.S. Medical College & KEM Hospital, Mumbai, Maharashtra, India

https://orcid.org/0000-0003-1106-6809

Tushar R. Bandgar

Department of Endocrinology, Seth G.S. Medical College & KEM Hospital, Mumbai, Maharashtra, India

https://orcid.org/0000-0002-6902-4639

Correspondence to: Tushar R. Bandgar Department of Endocrinology, Seth G.S. Medical College & KEM Hospital, Parel, Mumbai, Maharashtra (4000012), India drtusharb@gmail.com

Disclosure: no potential conflict of interest relevant to this article was reported.

Authors (year)	Study subjects	Patients (n)	Age in years (mean ± SD)	Previous treatment (period)	Treatment (dose)	Treatment (duration)	Primary endpoint
Carpenter et al. (2018)	Pediatric patients (rickets)	26	8.7 ± 1.7	Conventional therapy^* * Conventional therapy includes neutral phosphorus (20-60 mg/kg/day) and calcitriol (20-40 ng/kg/day) or alfacalcidol (40-60 ng/kg/day). (7.0 ± 2.1 years)	Burosumab 0.98 mg/kg every 2 weeks	64 weeks	Change in TRS score from baseline to week 64
Carpenter et al. (2018)	Pediatric patients (rickets)	26	8.3 ± 2.0		Burosumab 1.5 mg/kg every 4 weeks	64 weeks	Change in TRS score from baseline to week 64
Imel et al. (2019)	Pediatric patients (rickets)	29	5.8 ± 3.4	Conventional therapy (3.3 ± 3.1 years)	Burosumab 0.8-1.2 mg/kg every 2 weeks	64 weeks	Change in rickets severity score (RGI-C) at the end of the study
Imel et al. (2019)	Pediatric patients (rickets)	32	6.3 ± 3.2	Conventional therapy (3.3 ± 3.1 years)	Conventional therapy	64 weeks
Whyte et al. (2022)	Pediatric patients (rickets)	13	1.7 ± 1.5	Conventional therapy (1.3 ± 1.2 years)	Burosumab 0.8-1.2 mg/kg every 2 weeks	64 weeks	Safety and change in fasting serum phosphorus level
Jin et al. (2022)	Pediatric patients (rickets)	30	6.5 ± 2.6	Most subjects received conventional therapy (2.25 years)	Conventional therapy (calcitriol 20 ng/kg/day)	2 years	Change in TRS score from baseline to the months 12 and 24
Jin et al. (2022)	Pediatric patients (rickets)	35	5.7 ± 2.9	Most subjects received conventional therapy (2.25 years)	Conventional therapy (calcitriol 40 ng/kg/day)	2 years	Change in TRS score from baseline to the months 12 and 24
Namba et al. (2022)	Pediatric patients (rickets)	15	6.7 ± 3.2	Phosphorus (0.3-3 g/day), vitamin D (0.15-4 µg/day)	Burosumab 0.8-1.2 mg/kg every 2 weeks	124 weeks	Safety and changes in TRS and RGI-C scores
Carpenter et al. (2014)	Adults	38	38 ± 13	Not available	Burosumab 0.1-1 mg/kg every 4 weeks	50 days	Safety and changes in serum and urinary mineral biochemistry
Imel et al. (2015)	Adults	28	41.9 ± 13.8	Conventional therapy	Burosumab 0.1-0.6 mg/kg every 4 weeks	22 months	Proportion of subjects achieving fasting serum Pi within the normal range
Insogna et al. (2018)	Adults	68	41.3 ± 11.6	Phosphorus (16.5 ± 10.4 years); active vitamin D (18.2 ± 11 years)	Burosumab 1 mg/kg every 4 weeks (≤90mg)	24 weeks	Change in serum Pi, 1,25(OH)₂D, and Tmp/GFR from baseline
Cheong et al. (2019)	Adults	6	37.3 (19-57)^ Mean (range).	Details regarding prior treatment were unavailable	Burosumab 0.3 mg/kg every 4 weeks	Sequential dose escalation single-dose study (29 days)	Change in serum Pi, 1,25(OH)₂D, and Tmp/GFR from baseline
		5	31.6 (19-49)^ Mean (range).		Burosumab 0.6 mg/kg every 4 weeks
		7	34.4 (19-57)^ Mean (range).		Burosumab 0.9 mg/kg every 4 weeks

Patients	Parameters	Treatment	SMD (95% CI)
Pediatric	Thacher's total rickets severity score	Burosumab	-1.46 (-1.76; −1.17)
	Thacher's total rickets severity score	Phosphorus and calcitriol	-0.86 (-1.45; −0.28)
	RGI-C score	Burosumab	1.83 (1.53; 2.14)
	RGI-C (deformity) score	Burosumab	1.10 (0.71; 1.49)
	Height SDS	Burosumab	0.16 (-0.11; 0.44)
	Height SDS	Phosphorus and calcitriol	0.06 (-0.17; 0.29)
	Phosphorus, mg/dL	Burosumab	1.83 (1.53; 2.14)
	Tmp/GFR	Burosumab	1.05 (0.7; 1.4)
	ALP, U/L	Burosumab	130.68 (125.26; 136.1)
	ALP, U/L	Phosphorus and calcitriol	26.21 (21.24; 31.18)

Parameters	SMD (95% CI)
Phosphorus, mg/dL	1.23 (0.98; 1.47)
Tmp/GFR	1.09 (0.88; 1.29)

Section and Topic	Item #	Checklist item	Location where item is reported
TITLE
Title	1	Identify the report as a systematic review.	Page 1, Line 2
ABSTRACT
Abstract	2	See the PRISMA 2020 for Abstracts checklist.	Page 1
INTRODUCTION
Rationale	3	Describe the rationale for the review in the context of existing knowledge.	Page 2
Objectives	4	Provide an explicit statement of the objective(s) or question(s) the review addresses.	Page 2
METHODS
Eligibility criteria	5	Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.	Page 3
Information sources	6	Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted.	Page 3
Search strategy	7	Present the full search strategies for all databases, registers and websites, including any filters and limits used.	Page 3
Selection process	8	Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.	Page 3
Data collection process	9	Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.	Page 3
Data items	10a	List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.	Page 4
Data items	10b	List and define all other variables for which data were sought (e.g., participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.	Page 4
Study risk of bias assessment	11	Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.	Page 3
Effect measures	12	Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results.	Page 4
Synthesis methods	13a	Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).	Table 1
	13b	Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.	Nothing specific
	13c	Describe any methods used to tabulate or visually display results of individual studies and syntheses.	"Escalc" function in Metafor
	13d	Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.	Random-effects model. We used standardized mean difference, as it is more generalizable
	13e	Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression).	---
	13f	Describe any sensitivity analyses conducted to assess robustness of the synthesized results.	---
Reporting bias assessment	14	Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).	---
Certainty assessment	15	Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.	---
RESULTS
Study selection	16a	Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.	Page 4
Study selection	16b	Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.	Page 4
Study characteristics	17	Cite each included study and present its characteristics.	Table 1
Risk of bias in studies	18	Present assessments of risk of bias for each included study.	Supplementary Table 2
Results of individual studies	19	For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimates and its precision (e.g. confidence/credible interval), ideally using structured tables or plots.	Table 2 and Figures 2 and 3
Results of syntheses	20a	For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.	Supplementary Table 2
	20b	Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect.	Table 2 and Pages 5 and 6
	20c	Present results of all investigations of possible causes of heterogeneity among study results.	-----
	20d	Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.	-----
Reporting biases	21	Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.	-----
Certainty of evidence	22	Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.	-----
DISCUSSION
Discussion	23a	Provide a general interpretation of the results in the context of other evidence.	Page 6
	23b	Discuss any limitations of the evidence included in the review.	Page 7
	23c	Discuss any limitations of the review processes used.	Page 7
	23d	Discuss implications of the results for practice, policy, and future research.	Page 8
OTHER INFORMATION
Registration and protocol	24a	Provide registration information for the review, including register name and registration number, or state that the review was not registered.	Pages 2 and 3
	24b	Indicate where the review protocol can be accessed, or state that a protocol was not prepared.	Page 3 (PROSPERO registration)
	24c	Describe and explain any amendments to information provided at registration or in the protocol.	-----
Support	25	Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review.	None
Competing interests	26	Declare any competing interests of review authors.	None
Availability of data, code and other materials	27	Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.	Data will be made available upon request to the corresponding author

	Randomization process	Deviations from intended interventions	Missing outcome data	Measurement of the outcome	Selection of the reported result	Overall bias
Assignment to intervention (the "intention-to-treat" effect)
Low risk of bias	50	100	100	87.5	100	50
Some concern	37.5	0	0	12.5	0	37.5
High risk of bias	0	0	0	0	0	0

[1] Correspondence to: Tushar R. Bandgar Department of Endocrinology, Seth G.S. Medical College & KEM Hospital, Parel, Mumbai, Maharashtra (4000012), India drtusharb@gmail.com

Brasil

Brasil

Efficacy and safety of burosumab compared with conventional therapy in patients with X-linked hypophosphatemia: A systematic review

ABSTRACT