Parathyroidectomy for adults with primary hyperparathyroidism

Joseph M Pappachan; Ian M Lahart; Ananth K Viswanath; Farzad Borumandi; Ravinder Sodi; Maria-Inti Metzendorf; Brenda Bongaerts

doi:10.1002/14651858.CD013035.pub2

Cochrane Database of Systematic Reviews

Paratiroidectomía para adultos con hiperparatiroidismo primario

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DOI:

https://doi.org/10.1002/14651858.CD013035.pub2 Copiar DOI

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Cochrane Database of Systematic Reviews

Versión publicada:

08 marzo 2023see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Trastornos metabólicos y endocrinos

Copyright:

Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Joseph M Pappachan

Correspondencia a: Department of Endocrinology & Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston, UK

[email protected]

Faculty of Science, Manchester Metropolitan University, Manchester, UK

University of Manchester Medical School, Manchester, UK
Ian M Lahart

Faculty of Education, Health and Wellbeing, University of Wolverhampton, Walsall, UK
Ananth K Viswanath

Endocrinology, New Cross Hospital, Wolverhampton, UK
Farzad Borumandi

Department of Oral and Maxillofacial Surgery, University Hospitals Sussex NHS Foundation Trust, St. Richard's Hospital, Chichester and Worthing Hospital, Worthing, UK
Ravinder Sodi

Biochemistry, Pathology Department, Broomfield Hospital, Mid & South Essex NHS Foundation Trust, Chelmsford, UK
Maria-Inti Metzendorf

Institute of General Practice, Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
Brenda Bongaerts

Institute of General Practice, Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany

Contributions of authors

JMP: protocol draft, search strategy development, acquisition of study reports, study selection, data extraction, data interpretation, review of the draft and review updates
IML: protocol draft, search strategy development, acquisition of study reports, data analysis, review of the draft and review updates
AKV: protocol draft, search strategy development, study selection, data interpretation, review of the draft and review updates
FB: acquisition of study reports, study selection, data extraction, review of the draft and review updates
RS: protocol draft, search strategy development, study selection, review of the draft and review updates
MIM: search strategy development, data interpretation, review of the draft and review updates
BB: data extraction, data analysis, data interpretation, review of the draft and review updates

Sources of support

Internal sources

Department of Endocrinology & Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston, UK

External sources

No sources of support provided

Declarations of interest

JMP: none known
IML: none known
AKV: received speakers fees for providing diabetes educational meetings for GPS/Primary care colleagues. These events were supported by various pharmaceutical companies. Received support from pharmaceutical companies to attend international diabetes conferences.
FB: none known
RS: received speakers fees for providing biochemistry educational meetings for GPS/Primary care colleagues.
MIM: none known
BB: none known. She is the Co‐ordinating Editor of the CMED Group. Nevertheless, she was excluded from the editorial processing of this protocol, and an independent editor acted as Sign‐off Editor.

Acknowledgements

Cochrane Metabolic and Endocrine Disorders Group supported the authors in the development of this Review.

The following people conducted the editorial process for this article:

Sign‐off Editor (final editorial decision): René Rodríguez Gutierrez
Managing Editor (selected peer reviewers, collated peer‐reviewer comments, provided editorial guidance to authors, edited the article): Juan Victor Ariel Franco, Institute of General Practice, Medical Faculty of the Heinrich‐Heine‐University Düsseldorf, Düsseldorf, Germany
Copy Editor (copy‐editing and production): Julia Turner
Peer‐reviewers (provided comments and recommended an editorial decision): Yuan Chi, Cochrane Campbell Global Ageing Partnership; Mattabhorn Phimphilai, Division of Endocrinology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Eric Mirallié, Chirurgie Cancérologique, Digestive et Endocrinienne, IMD, Hôtel Dieu, 44093 Nantes, France; Nisha Nigil Haroon, Northern Ontario School of Medicine, Canada; Carolyn Dacey Seib, MD, MAS, Stanford University School of Medicine.

Version history

Published

Title

Stage

Authors

Version

2023 Mar 08

Parathyroidectomy for adults with primary hyperparathyroidism

Review

Joseph M Pappachan, Ian M Lahart, Ananth K Viswanath, Farzad Borumandi, Ravinder Sodi, Maria-Inti Metzendorf, Brenda Bongaerts

https://doi.org/10.1002/14651858.CD013035.pub2

2018 May 24

Parathyroidectomy for adults with primary hyperparathyroidism

Protocol

Joseph M Pappachan, Ravinder Sodi, Ananth K Viswanath, Ian M Lahart

https://doi.org/10.1002/14651858.CD013035

Differences between protocol and review

See Pappachan 2018 (review protocol).

We simplified the objective to: "To evaluate the benefits and harms of parathyroidectomy for adults with PHPT compared to simple observation or medical therapy."
We deleted "We will define any follow‐up period going beyond the original time frame for the primary outcome measure as specified in the power calculation of the trial's protocol as an extended follow‐up period (also called open‐label extension study) (Buch 2011; Megan 2012)." as it did not apply to our review.
We deleted the outcome 'Socioeconomic effects' because MECIR guidance indicates that additional methods are needed to include them.
We changed the outcome 'Adverse events of surgery' to 'Serious adverse events', considering that the formulation would be better suited for both arms of the main comparison (where one arm did not undergo surgery)
We specified that we would use risk ratio as a measure of treatment effect.
We added more specifications to the section on risk of bias, assessment of heterogeneity, data synthesis and GRADE based on the updated Cochrane Handbook for Systematic Reviews of Interventions, and we corrected the references (Higgins 2022). We restricted sensitivity analysis to considerations of the risk of bias.

We planned to investigate the effects of parathyroidectomy on PHPT‐related morbidities such as osteoporosis, osteopenia or acute kidney injury. However, the included RCTs did not report these parameters directly, so we were unable to meta‐analyse these outcomes. We performed a post‐hoc analysis to examine BMD outcomes as a surrogate marker for these morbidities (we downgraded the certainty of the evidence due to indirectness).

We also planned to compare the effects of different types of parathyroidectomy, such as minimally invasive parathyroidectomy and bilateral neck exploration; however, no studies provided the necessary data for this subgroup analysis. There was also insufficient data to perform sensitivity analysis.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Aged; Female; Humans; Male;

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

The Search strategy and the study flow diagram

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (blank cells indicate that the particular outcome was not measured in some studies).

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study (blank cells indicate that the particular outcome was not measured in some studies).

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Analysis 1.1

Comparison 1: Parathyroidectomy versus observation, Outcome 1: Cure of primary hyperparathyroidism

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Analysis 1.2

Comparison 1: Parathyroidectomy versus observation, Outcome 2: Morbidity related to primary hyperparathyroidism

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Analysis 1.3

Comparison 1: Parathyroidectomy versus observation, Outcome 3: Serious adverse events

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Analysis 1.4

Comparison 1: Parathyroidectomy versus observation, Outcome 4: All‐cause mortality

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Analysis 1.5

Comparison 1: Parathyroidectomy versus observation, Outcome 5: Hospitalisation for correction of hypercalcaemia

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Summary of findings 1. Parathyroidectomy compared to observation in adults with primary hyperparathyroidism

Outcomes	Anticipated absolute effects (95% CI)*		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comment
Parathyroidectomy compared to observation for primary hyperparathyroidism
Patient or population: people with primary hyperparathyroidism Settings: inpatients/outpatient follow‐up Intervention: parathyroidectomy Comparison: observation
Outcomes	Risk with observation	Risk with parathyroidectomy	Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comment
Cure of PHPT Assessed with: normalisation of hypercalcaemia Follow‐up: 6–24 months	0 per 1000	994 per 1000 (163 to 164)	RR 0.04 (0.02 to 0.08)	333 (8)	⊕⊕⊕⊝ Moderate^a	—
Morbidity related to PHPT Assessed with: osteoporosis, kidney dysfunction/urolithiasis, cognitive function and cardiovascular disease Follow‐up: 12–24 months	Mean BMD of the lumbar spine ranged across control groups from 0.68 to 1.12 g/cm².	Mean BMD at the lumbar spine in the intervention groups was on average 0.03 g/cm² higher (95% CI 0.05 lower to 0.12 higher).	—	287 (5)	⊕⊝⊝⊝ Very low^b	—
	Mean BMD of the femoral neck ranged across control groups from 0.79 to 0.82 g/cm².	Mean BMD at the femoral neck in the intervention groups was on average 0.01 g/cm² lower (95% CI 0.13 lower to 0.11 g/cm² higher).	—	216 (3)	⊕⊝⊝⊝ Very low^b	—
	Mean LVEF ranged across control groups from 65.7 to 68.0%.	Mean LVEF in the intervention groups was on average 2.38% lower (95% CI 4.77% lower to 0.01% higher).	—	121 (3)	⊕⊝⊝⊝ Very low^c	Ambrogini 2007 did not provide mean values for the echocardiographic parameters but reported that all parameters were within the normal range and did not change during follow‐up in either group. We could not include this study in the statistical analysis.
Serious adverse events Follow‐up: 6–24 months	0 per 1000	12 per 1000 (1 to 164)	RR3.35 (0.14 to 78.60)	168 (4)	⊕⊕⊝⊝ Low^d	The pooled relative effect is based on only 1 study, the other three could not be included as they had zero events in both intervention and control group.
All‐cause mortality Follow‐up: 6–24 months	15 per 1000	31 per 1000 (3 to 339)	RR2.11 (0.20 to 22.60)	133 (2)	⊕⊝⊝⊝ Very low^e	The pooled relative effect is based on only 1 study, the other study could not be included as it had zero events in both intervention and control group.
Health‐related quality of life Assessed with: SF‐36 scores (higher scores indicate better quality of life) Follow‐up: 12–24 months	See comment	See comment	See comment	195 (3)	⊕⊝⊝⊝ Very low^c	1 study observed no differences in scores for in any SF‐36 domains between groups; 1 study reported higher scores for the parathyroidectomy group in 2 domains (social and emotional role function); 1 study showed higher scores for the parathyroidectomy group in 4 domains (bodily pain, general health, vitality and mental health).
Hospitalisation for hypercalcaemia, renal impairment or pancreatitis Follow‐up: 6–24 months	54 per 1000	35 per 1000 (1 to 164)	RR 0.91 (0.20 to 4.25)	287(6)	⊕⊕⊝⊝ Low^d	All reported hospitalisations were due to (recurrent) hypercalcaemia. The pooled relative effect was based on 4 studies, the other 2 could not be included as they had zero events in both intervention and control group.
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% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BMD: bone mineral density; CI: confidence interval; LVEF: left ventricular ejection fraction; MD: mean difference; PHPT: primary hyperparathyroidism; RR: risk ratio; SF‐36: 36‐Item Short Form Health Survey.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^a Downgraded one level due to unclear risk of bias (sequence generation, allocation concealment and selective reporting). ^b Downgraded three levels due to unclear risk of bias (sequence generation, allocation concealment and selective reporting), inconsistency in the direction of the effect, indirectness (surrogate outcome) and serious imprecision (small sample size). ^c Downgraded three levels due to unclear risk of bias (sequence generation, allocation concealment and selective reporting), indirectness (surrogate outcome) and serious imprecision (small sample size). ^d Downgraded two levels due to unclear risk of bias (sequence generation, allocation concealment and selective reporting) and imprecision (low sample size). ^e Downgraded three levels due to high risk of bias (sequence generation, allocation concealment and lack of blinding of the outcome assessor) and serious imprecision (low median sample size).

Summary of findings 1. Parathyroidectomy compared to observation in adults with primary hyperparathyroidism

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Table 1. Overview of study populations

Study ID (study design)	Study groups	Screened/ eligible (n)	Randomised (n)	Analysed for primary outcome (n)	Randomised finishing study (n (%))	Duration of follow‐up (extended follow‐up)
Almqvist 2004 (parallel RCT)	Parathyroidectomy	200/50^a	25	23	25 (100%)	12 months
	Observation	200/50^a	25	25	24 (96%)^b
	Total:		50	48	49 (98%)
Ambrogini 2007 (parallel RCT)	Parathyroidectomy	412/50^c	24	24 (24)	24 (100%)	6 months (12 months)
	Observation	412/50^c	26	25 (25)	26 (100%)
	Total:		50	49 (49)	50 (100%)
Bollerslev 2007 (parallel RCT)	Parathyroidectomy	191^a	96	56 (47)	82 (85%)^d	12 months (24 months)
	Observation	191^a	95	59 (48)	82 (86%)^e
	Total:		191	115 (95)	164 (86%)
Horiuchi 2002 (parallel RCT)	Parathyroidectomy	22^a	13	13	13 (100%)	12 months
	Etidronate therapy	22^a	9	9	9 (100%)
	Total:		22	22	22 (100%)
Morris 2010 (parallel RCT)	Parathyroidectomy	54/21^a	10	9	9 (90%)^f	6 months
	Observation	54/21^a	11	9	9 (82%)^f,g
	Total:		21	18	18 (86%)
Pepe 2013 (parallel RCT)	Parathyroidectomy	37/30^a	15	12	12 (80%)^h	6 months
	Observation	37/30^a	15	12	12 (80%)^h
	Total:		30	24	24 (80%)
Pepe 2018 (parallel RCT)	Parathyroidectomy	33/30^a	15	13^ag	13 (87%)^h	6 months
	Observation	33/30^a	15	13^ag	13 (87%)^h
	Total:		30	26	26 (87%)
Talpos 2000 (parallel RCT)	Parathyroidectomy	283/53^a	25	25	25 (100%)	24 months
	Observation	283/53^a	28	28	28 (100%)
	Total:		53	53	53 (100%)
All studies	All interventions		223		203 (91%)
	All controls		224		203 (91%)
	Interventions + controls		447		406 (91%)
^a Sample size calculation not performed. ^b One participant was withdrawn from the study after one year because of progressive angina pectoris. ^c Sample size calculation was based on a pilot study; for ≥ 5% difference between groups in mean lumbar spine bone mineral density at 1 year with 90% power and significance level of 0.05 using 2‐sided t‐test, each group should have ≥ 22 people. Assuming 10% dropout rate, investigators planned to include 24 people in each group. ^d One participant died, 12 withdrew. ^e One participant died, 12 withdrew and one was excluded because of parathyroid cancer. ^f One participant did not receive the allocated intervention and was excluded from the study. ^g One participant withdrew from the study. ^h Participants who violated the protocol left the study. RCT: randomised controlled trial.

Table 1. Overview of study populations

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Comparison 1. Parathyroidectomy versus observation

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Cure of primary hyperparathyroidism Show forest plot	8	333	Risk Ratio (M‐H, Random, 95% CI)	0.04 [0.02, 0.08]

1.2 Morbidity related to primary hyperparathyroidism Show forest plot	6		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.2.1 Bone mineral density at lumbar spine (g/cm 2)	5	287	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.07, 0.10]
1.2.2 Bone mineral density at femoral neck (g/cm 2)	3	216	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.13, 0.11]
1.2.3 Left ventricular ejection fraction (%)	3	121	Mean Difference (IV, Random, 95% CI)	‐2.38 [‐4.77, 0.01]
1.3 Serious adverse events Show forest plot	4		Risk Ratio (IV, Random, 95% CI)	Totals not selected

1.4 All‐cause mortality Show forest plot	2		Risk Ratio (IV, Random, 95% CI)	Totals not selected

1.5 Hospitalisation for correction of hypercalcaemia Show forest plot	6	287	Risk Ratio (IV, Random, 95% CI)	0.91 [0.20, 4.25]

Comparison 1. Parathyroidectomy versus observation

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Paratiroidectomía para adultos con hiperparatiroidismo primario

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