Evidence review for monitoring

National Guideline Centre (UK)

Evidence review for monitoring

Hyperparathyroidism (primary): diagnosis, assessment and initial management

Evidence review I

NICE Guideline, No. 132

Authors

National Guideline Centre (UK).

London: National Institute for Health and Care Excellence (NICE); 2019 May.

ISBN-13: 978-1-4731-3415-7

1. Monitoring

1.1. Review question: What is the optimum type and frequency of monitoring for people with primary hyperparathyroidism (for example, pre-operative, postoperative, non-surgical)?

1.2. Introduction

There is uncertainty regarding the long-term sequelae of primary hyperparathyroidism (PHPT) even in people who have undergone successful parathyroidectomy. This is reflected in variation in practice regarding what should be monitored and for how long. Monitoring for end organ damage is more established although monitoring for cardiovascular events and cancer is less clear. The purpose of this review is to identify the optimum type and frequency of monitoring for people with PHPT. One approach to this question is to understand the long-term outcomes in people with PHPT.

1.2.1. PICO table

For full details see the review protocol in appendix A.

Table 1

PICO characteristics of review question.

1.3. Review question: What are the long-term outcomes in people with primary hyperparathyroidism?

1.3.1. PICO table

For full details see the review protocol in appendix A.

Table 2

PICO characteristics of review question.

1.4. Clinical evidence

1.4.1. Included studies

A search was conducted for assessing the optimum type and frequency of monitoring for people with PHPT. No evidence was identified for this review question. See the study selection flow chart in appendix C.

A second search of the original PHPT search was conducted to determine whether PHPT is associated with poor long-term outcomes and to determine what monitoring strategies they need to undergo. The aim of the review was to look at the incidence of outcomes in people with PHPT compared with healthy controls. It was thought that any difference in all/some of the outcomes would mean that someone with PHPT would need to be monitored.

Eleven comparative studies: Clifton-Bligh 2015²¹; De Geronimo 2006²⁶; Hedback 1998³⁸; Kenny 1995⁴¹; Khosla 1999⁴²; Larsson 1993⁴⁵; Melton 1992⁴⁹; Ronni-Sivula 1985⁶⁰; Su 2008⁶⁹; Wilson 1988⁷⁹; Yu 2011⁸⁰ were included.

Only one prospective cohort study, Yu 2011⁸⁰, adjusted for all key confounders. This study evaluated the risk of mortality and morbidity among untreated mild PHPT patients compared with a matched cohort. The study adjusted for a number of potential confounding variables (multiple deprivation index [SIMD], history of bisphosphonates prescription, history of hospital admitted CVD, cerebrovascular disease, hypertension, renal failure, renal stones, psychiatric disease, fractures, cancer and diabetes) and the propensity of having calcium checked in the analysis. In 5 studies (Clifton-Bligh, 2015²¹; De Geronimo, 2006²⁶; Hedback 1998³⁸; Melton, 1992⁴⁹; Ronni-Sivula, 1985⁶⁰) the control group was matched for factors such as age and gender but these studies did not adjust for serum calcium level and absence/presence of end organ effects (no multivariate analysis conducted). The remaining 5 studies did not match or adjust for any key confounders (no multivariate analysis conducted).

The definition of mild and non-mild PHPT was not consistent across the studies. The definitions reported in the studies are noted in their respective evidence tables.

The studies were stratified as non-surgical, pre-operative, mixed pre and post-operative (including surgery and non-surgery patients) and post-operative.

There were 2 studies in the strata non-surgical (mild asymptomatic patients) (Yu 2011; Wilson 1988); 1 study in pre-operative (Suh 2008); 5 studies in the mixed pre and post-operative (mild and non-mild patients): (Melton 1992; De Geronimo 2006; Clifton-Bligh 2015; Khosla 1999; Larsson 1993); and 3 studies in the post-operative (Ronni-Sivula 1985; Kenny 1995; Hedback 1998). No evidence was available for people on calcimimetics, bisphosphonates and normocalcaemic patients.

Evidence from the studies are summarised in the clinical evidence summary tables below (Table 4, Table 5, Table 6, Table 7, Table 8, Table 9). See also the study selection flow chart in appendix C, study evidence tables in appendix D, forest plots in appendix E, and GRADE tables in appendix F.

1.4.2. Excluded studies

See the excluded studies list in appendix I.

1.4.3. Summary of clinical studies included in the evidence review

Table 3

Summary of studies included in the evidence review (comparative studies).

See appendix D for full evidence tables.

1.4.4. Quality assessment of clinical studies included in the evidence review

Table 4

Clinical evidence summary: PHPT cases compared to matched comparators (adjusted for key confounders) (Stratum-Non-surgical).

Table 5

Clinical evidence summary: PHPT compared to control (no multivariate analysis) (Stratum – Pre-surgery).

Table 6

Clinical evidence summary: PHPT compared to control (no multivariate analysis) – Mixed strata – Pre and post-operative (surgery and non-surgery patients).

Table 7

Clinical evidence summary (modified GRADE table): PHPT compared to control (no multivariate analysis) – Mixed strata-Pre and post-operative (surgery and surgery patients).

Table 8

Clinical evidence summary (modified GRADE table): PHPT (observed) versus expected numbers in the general population (no multivariate analysis) – Mixed strata – Pre and post-operative (surgery and non-surgery patients).

Table 9

Clinical evidence summary: PHPT patients compared to control (no multivariate analysis) – Stratum post-operative.

Narrative data

1. Clifton-Bligh 2015²¹

n=561

448 had surgery and 113 did not have surgery.

There was no significant difference in the relative survival between surgically and non-surgically treated patients over a 10 year period (figures, no data). The average number of years of life lost by hyperparathyroid patients compared to control population was 7.5 years. There was no significant difference in the death rate between those with an initial serum calcium of >3.00 mmol/l compared with those with an initial serum calcium of <3.00 mmol/l (no data).

In a multivariate analysis in the surgically treated group, the serum calcium did not significantly influence survival (HR 1.57, 95% CI 0.30–8.30, p=0.593). In a multivariate analysis, risk factors associated with death in the surgically treated group were diabetes mellitus (HR 4.09, 95% CI 1.42–6.74, P=0.001), congestive cardiac failure (HR 5.46, 95% CI 1.31–22.87, P=0.002), coronary heart disease (HR 2.16, 95% CI 1.080.044). The presence of kidney stones before surgery was associated with reduced mortality (HR 0.364, 95% CI 0.22–0.68, P=0.001).

In the non-surgically treated group, death was significantly associated with a high serum PTH (HR 1.59, 95% CI 1.20–2.11, p=0.001), coronary heart disease (HR 3.10, 95% CI 1.42–6.74, P=0.004), and kidney stones (HR 2.48, 95% CI 1.07–5.76, p=0.035). This difference between the surgically treated and non-surgically treated group with respect to the impact of kidney stones is not clear. Compared with the non-surgically treated group, the hazard ratio of death for the surgically treated group adjusted for age, sex and time of diagnosis was 0.67 (95% 0.38–1.18, p=0.167).

Using a 20 year follow-up for the whole group, multivariate analysis did not show any survival difference between male and female, surgery versus non-surgery (p=0.867), serum calcium >3 mmol/l versus <3 mmol/l (p=0.794), or serum PTH analysed as quartiles (no data).

2. Hedback 1992³⁸

Yearly death reduction

Hyperparathyroid population operated on in 1987–94: mean (range)

Male: 17% (95% 7–26)

Female: 8% (2.00–13)

Swedish population 1974–1983: male: 0.95% (95% CI 0.81–1.09)

Female: 1.68% (1.53–1.83)

Swedish population 1987–94: male: 1.51% (1.34–1.67)

Female: 0.88% (0.70–1.05)

3. Melton 1992⁴⁹

Fracture risk (after diagnosis)

Overall: PHPT 50/90; control 52/90; RR 1.0 (95% CI 0.7–1.4)

Calcium ≥2.74 mmol/l: PHPT 34/90; control 24/90; RR 1.4 (95% CI 0.8–2.4)

Calcium <2.74 mmol/l: PHPT 16/90; control 27/90; RR 0.6 (95% CI 0.3–1.1)

Operated on: PHPT 19/90; control 26/90; RR 0.7 (95% CI 0.4–1.3)

Not operated on: PHPT 31/90; control 26/90; RR 1.2 (95% CI 0.7–2.0)

Comorbid conditions: PHPT 44/90; control 38/90; RR 1.2 (95% CI 0.8–1.8)

No comorbid conditions: PHPT 6/90; control 14/90; RR 0.4 (95% CI 0.2–1.1)

Women: 43/90; 42/90; RR 1.0 (95% CI 0.7–1.6)

Men: 7/90; 10/90; RR 0.7 (95% CI 0.3–1.8)

In a multivariate analysis, only age at diagnosis was an independent predictor of fracture risk in PHPT (P<0.2). A 10 year increase in age corresponded to a 36% increase in fracture risk.

4. Ronni-Sivula⁶⁰

Mortality

PHPT patients 34/334; control 21/334; RR 1.62 (0.96 to 2.73)

The mean age of PHPT patients at death was 65 years, 61 years in men and 66 years in women.

The mean age of control patients at death was 67 years, 62 years in men and 69 years in women.

The deceased patients in the PHPT group had a higher mean value of serum calcium pre-operatively than patients in the entire PHPT group (3.31 mmol/l versus 3.08 mmol/l).

In the deceased patients in the PHPT group, serum creatinine was elevated (>115 mmol/l) pre-operatively in 15 (44%) of the deceased patients. In the entire PHPT group serum creatinine was elevated pre-operatively in 57 patients (17%). In the deceased patients serum creatinine was most often elevated in the groups with hypercalcaemic crises (4/6) and cystic bone changes (3/4) and most rarely in the renal stone group (1/5).

PHPT patients who died had more severe form of disease: 55% had hypercalcaemic crises and 24% had cystic bone changes, 4% had renal stones.

Causes of death:

PHPT: n=18 cardiac disease; n=4 cerebrovascular death; n=1 vascular disease; n=4 uraemia; n=2 malignant tumour; n=2 hypercalcaemic crisis; n=3 other causes

Control: n=8 cardiac disease; n=5 malignant tumour; n=8 other causes

1.5. Economic evidence

1.5.1. Included studies

No relevant health economic studies were identified.

1.5.2. Excluded studies

No health economic studies that were relevant to this question were excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in appendix G.

1.5.3. Unit costs

Unit costs for common clinical tests for monitoring PHPT were presented to the committee for consideration of cost effectiveness.

Table 10

UK costs of monitoring procedures.

Table 11

UK cost of clinical events associated with PHPT.

1.6. Resource costs

The recommendations made by the committee based on this review are not expected to have a substantial impact on resources.

1.7. Evidence statements

1.7.1. Clinical evidence statements

1.7.1.1. Monitoring

No evidence was identified for assessing the optimum type and frequency of monitoring for people with PHPT.

1.7.1.2. Monitoring long term outcomes

1.7.1.2.1. PHPT cases versus matched comparators (adjusted for key confounders) in non-surgical stratum

Evidence from one study (n=8544, median follow up 2.9 years, Low quality) suggested that there was increased risk of all-cause mortality, fatal CVD, non-fatal CVD, hypertension, cerebrovascular disease, renal stones, renal failure, all fractures and osteoporotic fracture associated with PHPT (all patients diagnosed but untreated, mild asymptomatic PHPT).

No evidence was identified for the outcomes of renal tract calcification, pancreatitis, myocardial infarction, number of people meeting the criteria for surgery, serum calcium (>2.85 mmol/litre), 24-hour urine for calcium (>10 mmol/dl) and BMD of proximal femur.

1.7.1.2.2. PHPT cases versus controls (no multivariate analysis) in pre-surgery stratum

Evidence from one study (n=771, Very Low quality) suggested that there was increased risk of renal stones associated with PHPT.

No evidence was identified for the outcomes of mortality, fragility fracture, renal tract calcification, pancreatitis, stroke, hypertension, myocardial infarction, number of people meeting the criteria for surgery, serum calcium (>2.85 mmol/litre), 24-hour urine for calcium (>10 mmol/dl) and BMD of proximal femur.

1.7.1.2.3. PHPT cases versus controls (no multivariate analysis) in mixed pre and post-operative stratum

Evidence for fractures (all) was inconsistent. One study (n=180, Very Low quality) suggested that there was no difference between PHPT and controls for fractures; another study (n=407, Very Low quality) suggested that there was increased risk of fractures associated with PHPT.

Evidence from one study (n=114, Very Low quality) suggested there was a reduced risk of non-vertebral fractures associated with mild PHPT. Evidence from two studies (n=114 for mild PHPT; n=162 for non-mild PHPT, Very Low quality) suggested that there was no difference between PHPT and controls for the outcome lumbar spine BMD. Evidence from one study (n=114, Very Low quality) suggested that there was no difference between PHPT and controls for the outcomes femoral neck BMD, total femur BMD, and non-vertebral fractures associated with non-mild PHPT.

Evidence from 3 studies (n=343; n=407; n=162, Very Low quality) suggested that there was increased risk of vertebral fractures associated with PHPT (both mild and non-mild).

Evidence from one study (n=1373 women; n=551 men, Very Low quality) suggested that there was no difference between PHPT and control for the outcome hip fractures in both men and women.

No evidence was identified for the outcomes of mortality, renal stones, renal tract calcification, pancreatitis, stroke, hypertension, myocardial infarction, number of people meeting the criteria for surgery, serum calcium (>2.85 mmol/litre) and 24-hour urine for calcium (>10 mmol/dl).

1.7.1.2.4. PHPT cases versus controls (no multivariate analysis) in post-operative stratum

The evidence for the outcome mortality was not consistent. One study (n=668, Very Low quality) suggested that there was no difference between those PHPT patients who had surgery and healthy controls; another study (n=4461, Very Low quality) suggested that there was increased mortality in surgery patients compared to healthy controls.

Evidence from one study (n=90, Very Low quality) suggested that there was increased risk of fracture in PHPT patients compared to healthy controls.

No evidence was identified for the outcomes of renal stones, renal tract calcification, pancreatitis, stroke, hypertension, myocardial infarction, number of people meeting the criteria for surgery, serum calcium (>2.85 mmol/litre), 24-hour urine for calcium (>10 mmol/dl) and BMD of proximal femur.

1.7.2. Health economic evidence statements

No relevant economic evaluations were identified.

1.8. The committee’s discussion of the evidence

1.8.1. Interpreting the evidence

1.8.1.1. The outcomes that matter most

For the monitoring review the committee considered the outcomes of health-related quality of life and mortality as critical outcomes for decision making. Other important outcomes included deterioration in renal function, fractures (vertebral or long bone), occurrence of kidney stones, persistent hypercalcaemia, bone mass density (BMD) of the distal radius or the lumbar spine, cardiovascular events, adverse events (to include voice change, hypoparathyroidism, hypothyroidism/hyperthyroidism), cancer incidence and re-operation (for post-surgery stratum). No evidence was available for this review.

For the monitoring long-term outcomes review the committee considered the outcomes of mortality, fragility fracture, renal stones, renal tract calcification, pancreatitis, stroke, hypertension, myocardial infarction, number of people who become eligible for surgery/meet the criteria for surgery as critical outcomes for decision making. Other important outcomes included serum calcium (>2.85 mmol/litre), 24-hour urine for calcium (>10 mmol/dl) and BMD of proximal femur (T-score <2.5; Z score <2).

No evidence was identified for the outcomes of pancreatitis, myocardial infarction, number of people meeting the criteria for surgery, serum calcium (>2.85 mmol/litre) and 24-hour urine for calcium (>10 mmol/dl).

1.8.1.2. The quality of the evidence

All the evidence in this review included the incidence of outcomes in people with primary hyperparathyroidism compared with healthy controls.

There were 11 observational studies, of which one was a prospective cohort study and the rest were retrospective cohort studies. The majority of evidence was of Very Low quality due to risk of bias and also, in most cases, imprecision. Only one prospective cohort study adjusted for all key confounders; in five studies the control group was matched for factors such as age and gender but these studies did not adjust for serum calcium level and absence/presence of end organ effects (no multivariate analysis conducted) and the remaining five studies did not have matched controls or adjust for any key confounders (no multivariate analysis conducted). These limitations were taken into account by the committee when interpreting the evidence.

1.8.1.3. Benefits and harms

The studies in this review were stratified as non-surgical, pre-operative, mixed pre- and post-operative and post-operative. No evidence was available for people on calcimimetics, bisphosphonates and normocalcaemic patients.

Non-surgical: The evidence for this group suggested that compared to healthy controls there was increased risk of all-cause mortality, fatal and nonfatal cardiovascular disease (CVD), hypertension, cerebrovascular disease, all fractures, osteoporotic fractures, renal failure and renal stones in patients with asymptomatic primary hyperparathyroidism, with the risk of renal failure and renal stones being the highest.

Pre-operative: There was evidence from only one study for this stratum. The evidence suggested that there was an increased risk of renal stones in people with primary hyperparathyroidism compared to healthy controls.

Mixed pre and post-operative: The studies in this strata included both mild and non-mild primary hyperparathyroidism patients. Data were not available separately for surgical and non-surgical/pre-surgery patients. However, for some outcomes the evidence was reported separately for mild and non-mild patients. The evidence suggested that there was increased risk of vertebral fractures in both mild and non-mild primary hyperparathyroidism patients compared to healthy controls and there was no difference between the primary hyperparathyroidism and healthy controls for lumbar spine BMD, femoral neck BMD and total femur BMD for both mild and non-mild patients. The evidence for all fractures was not consistent; one study suggested that there was no difference and one study suggested that there was increased risk in primary hyperparathyroidism patients compared to healthy controls. The evidence suggested there was a reduced risk for non-vertebral fractures in mild primary hyperparathyroidism patients compared to healthy controls and there was no difference in non-vertebral fractures between non-mild primary hyperparathyroidism patients and healthy controls. The evidence also suggested that there was no difference between the primary hyperparathyroidism and healthy controls for the outcome hip fractures in both men and women.

Post-operative: The evidence for the outcome mortality was not consistent; one study suggested that there was no difference between those primary hyperparathyroidism patients who had surgery and healthy controls and one study suggested that there was increased mortality in surgery patients compared to healthy controls and this was mainly attributed to cardiovascular disease. The evidence also suggested that there was increased risk of fracture in primary hyperparathyroidism patients compared to healthy controls.

Overall the evidence suggested that there was increased risk of mortality, fractures, renal stones, renal failure, cardiovascular disease, low bone density and hypertension associated with untreated asymptomatic primary hyperparathyroidism patients. Due to the low quality of the evidence, the committee also took their clinical experiences into account when making their recommendations.

Based on their experience, the committee agreed that all patients diagnosed with primary hyperparathyroidism will need baseline assessment of their symptoms, BMD by DXA scan, and ultrasound of the renal tract to help determine the optimal management pathway. The committee considered that monitoring serum calcium level and symptoms of hypercalcaemia would support discussion of the most appropriate treatment strategy including surgery. Ultrasound of the kidneys would help in identifying cause for specific interventions or appropriate referral, and DXA scan would help in assessing fracture risk and/or the need for bisphosphonates.

The committee discussed the increased risk of mortality due to cardiovascular causes both before and after parathyroidectomy and hence felt that there is a need for monitoring cardiovascular risk in this group of patients. The committee also discussed the increased risk of renal stones and fractures in people with primary hyperparathyroidism (both before and after surgery) and therefore agreed that these people need to be monitored accordingly and consideration given to adjunctive treatments.

Based on their knowledge and experience, the committee agreed that people who have had parathyroid surgery can be considered biochemically cured if their albumin-adjusted serum calcium level is within the reference range 3 to 6 months after surgery. The committee considered that the risk of recurrent disease following successful removal of a solitary adenoma is very low and that, after the 6-month check, it is sufficient for calcium to be checked as part of routine blood testing to a maximum of once a year. The committee highlighted that for people with multigland disease there is a higher risk of recurrence than in those who had a single adenoma and in monitoring of such patients specialist opinion should be sought. However, the committee noted that the risk is still very low if the person has normal adjusted calcium at 3 to 6 months after surgery. The committee agreed that for people with osteoporosis, although bone density improves after surgery, skeletal recovery can take some time and would need specialist monitoring. Based on their experience, the committee discussed that risk of kidney stones decreases after successful surgery, but the residual risk persists and hence specialist opinion should be sought for monitoring of such patients.

The committee noted that in patients with multigland disease, a specialist will be aware of associated syndromes (for example multiple endocrine neoplasia type 1 [MEN1], MEN2A, familial isolated hyperparathyroidism, autosomal dominant mild hyperparathyroidism, familial hypocalciuric hypercalcaemia), and hence would be in a better position to make individualised assessment and determine the frequency of monitoring. The committee stated that for those patients with multigland disease discharged back to primary care, serum calcium tests will need to be conducted annually as part of their routine biochemical testing. Current practice is to conduct biochemical tests annually if there is no end organ damage.

The committee stated that in patients with genetic diseases such as MEN-1, primary hyperparathyroidism could be the first presentation so early detection of the disease, correct treatment, and continued care are of great importance; but noted that such cases are infrequent and beyond the scope of this guideline.

The committee discussed from clinical experience that there are no clinical factors that would predict the prognosis of patients with asymptomatic primary hyperparathyroidism. Evidence from the review suggested that around 35% of asymptomatic patients develop indications for surgery during follow-up. Hence the committee agreed that long-term medical monitoring for asymptomatic patients was essential to assess progression to meeting eligibility criteria for surgery and/or any evidence of end organ damage. The committee recommended the following monitoring strategies including assessment of symptoms and comorbidities annually; annual measurement of serum calcium test, estimated glomerular filtration rate (eGFR) or serum creatinine test; DXA scan every 2 to 3 years; ultrasound of the renal tract if renal stones are suspected (see NICE’s guideline on renal and ureteric stones). The committee recognised that measurement of renal function is important in assessing calcium and PTH levels. Most patients will have eGFR measured with serum calcium. An elevated serum calcium should be investigated irrespective of eGFR and the proposed algorithms are designed to ensure that if eGFR has not been checked early in the diagnostic odyssey, it is done so as part of the investigation and assessment of patients with hypercalcaemia. Such monitoring may detect clinically relevant changes that may necessitate reconsideration of surgery and/or adjunctive medical therapies. The committee discussed that assessment of symptoms will be annually or when the patients presents with any of the symptoms of primary hyperparathyroidism such as fatigue, depression, abdominal pain, constipation, muscle weakness, loss of concentration, mild confusion etc. The committee discussed that for suspected renal stones patients could present with colic/severe pain, asymptomatic haematuria, passing grit, discomfort etc. Based on the evidence and their experience, the committee agreed that there was an increased risk of fracture associated with primary hyperparathyroidism and hence agreed that DXA scan should be done every 2–3 years in these patients.

The committee agreed that these recommendations could also apply to those people who have refused surgery and in people after failed primary surgery to assess progression of disease in these patients.

The committee also discussed the current National Institutes of Health (NIH) criteria¹⁶ for monitoring in patients with asymptomatic primary hyperparathyroidism who do not undergo parathyroid surgery (2013). The current NIH criteria include the following monitoring strategies: serum calcium annually; skeletal – every 1–2 years (3 sites), X-ray or VFA of spine if clinically indicated (for example height loss, back pain); renal – eGFR, annually; serum creatinine, annually. If renal stones are suspected: 24-hour biochemical stone profile, renal imaging by X-ray, ultrasound, or CT.

The committee noted that there are no established guidelines/definitions of cure for primary hyperparathyroidism. The committee from their experience discussed that patients are considered to be biochemically cured if their PTH is in the reference range immediately following surgery and their serum calcium is within the reference range 3–6 months after surgery. The committee stated that post-operative PTH would still be performed if an intraoperative PTH was taken as a very small proportion of patients would show a change from intraoperative PTH level. Overall the committee did not think that a PTH test at 3–6 months would offer any additional clinical value. The committee noted that persistently high calcium at 3–6 months would trigger testing of plasma PTH (as per the recommendations on diagnosis). The committee considered that a 3–6 month post-operative calcium test could be done in secondary care.

1.8.2. Cost effectiveness and resource use

No previously published economic evaluations were identified for the cost-effectiveness of monitoring people with primary hyperparathyroidism. Unit costs of monitoring procedures were presented to the committee for consideration. Costs of clinical events associated with primary hyperparathyroidism – including cardiovascular events, renal events and fragility fractures – were also presented to provide a more comprehensive picture of potential healthcare resource use of primary hyperparathyroidism if the condition is left unchecked. However, as there is no clinical evidence for the extent to which monitoring will prevent such events, cost effectiveness of monitoring could not be evaluated and therefore is highly uncertain.

For people who have had parathyroid surgery, the committee noted that a PTH test immediately following surgery provides a timely indication of whether a patient has been cured of primary hyperparathyroidism due to the short half-life of PTH compared to calcium in the blood and is the most clinically relevant indication of cure. The committee also highlighted that further confirmation of cure at 3 to 6 months is necessary to assess recurrent disease. However, they agreed that this can be achieved with a lower cost test for albumin-adjusted serum calcium rather than a repeated PTH test.

The committee discussed that those with successful parathyroid surgery are generally considered to return to general population risk levels for end organ disease such as renal stones and fractures and therefore do not require further monitoring. However, the committee considered that there may be cases where specialist endocrine opinion should be sought with regards to monitoring due to more complex issues such as multi-gland disease and recurrent disease, or due to comorbidities such as osteoporosis and renal stones. In these cases decisions on monitoring should be made on a case-by-case basis.

In addition, the committee considered that in the event that people who have been cured after parathyroid surgery have a routine blood test for another cause, incidental testing for serum calcium as part of these blood tests could be cost effective. The committee discussed that there is minimal added expense to such testing as this does not require additional time in taking blood, only in analysing the sample (estimated around an additional £0.30 to additionally analyse calcium). The committee highlighted that such incidental testing should be limited to once a year to avoid unnecessary testing for those who may have frequent routine blood tests. The committee discussed that incidental calcium testing could help identify recurrent disease prior to the onset of symptoms or potential consequential end organ damage as a result of hypercalcaemia and therefore avoid potential decrements in quality of life and associated costs of such events. The committee was of the consensus that this practice could therefore be cost effective. However, as there is no clinical evidence available to assess this, this is highly uncertain.

For patients who are either not eligible for surgery, or have chosen not to undergo surgery, consensus from the committee was that monitoring should occur. However, the committee noted that there is some variation in current practice with respect to some of the items tested as part of the monitoring regime. While most practitioners adopt a fairly standard practice of including tests as specified in the NIH guidance – including annual tests for serum calcium and serum creatinine – some practitioners also test for PTH as part of routine practice. The committee indicated that testing for serum calcium and serum creatinine as part of routine monitoring is sufficient to detect any signs of change in a patient’s condition, and are also less costly. It was noted that healthcare providers should use their judgement in determining whether a patient will require a further PTH test based on the results of their tests for serum calcium. Hence, routine testing of PTH levels has not been recommended. This is a potential area for some cost savings.

The committee considered that these recommendations are generally in line with current practice and therefore are not expected to have a significant impact on healthcare resource use.

1.8.3. Other factors the committee took into account

The committee noted that the pre-operative population awaiting surgery are not considered to be in a monitoring setting (see recommendations on surgery).

The committee was aware of two studies⁶¹^,⁷⁶ assessing long-term outcomes in patients with and without parathyroid surgery which were included in the indications for surgery evidence review.. The study⁷⁶ reported that the risks of mortality, fractures and gastric ulcers were lower in patients treated surgically than those treated conservatively. However there was a higher risk of kidney or urinary tract stones in patients treated surgically than patients treated conservatively. Another study⁶¹ was a long-term prospective cohort study of asymptomatic primary hyperparathyroidism patients. The study reported that at 10 years, 25% of the asymptomatic primary hyperparathyroidism patients did show evidence of progressive disease with worsening hypercalcemia, hypercalciuria, and reductions in BMD being the most common complications. The study reported that 37% of asymptomatic patients developed new surgical criteria at any time point over the 15 years of observation. Meeting surgical criteria at study baseline did not predict who would have progressive disease. BMD did not change at any measurement site during the first 8 years of follow-up in the asymptomatic patients. The lumbar spine BMD was stable for the entire 15 years of follow-up. Overall, 59% of the asymptomatic patients had more than a 10% decline in BMD at one or more sites over the 15-year period. The study also reported that 15% of the patients who underwent surgery were symptomatic with kidney stones. At 15 years, serum calcium, PTH, and urinary calcium excretion were all significantly lower in comparison with the individual subjects’ baseline values and all well within normal limits. Post-operative increases in BMD were sustained with BMD remaining significantly above baseline for the entire 15 years of follow-up at all three skeletal sites. The committee noted that the findings of these studies were consistent with their clinical experience.

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Appendices

Appendix A. Review protocols

Table 12. Review protocol: Monitoring strategies

Table 13. Monitoring long term outcomes protocol

Table 14. Health economic review protocol

Appendix B. Literature search strategies

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual 2014, updated 2017 https://www.nice.org.uk/guidance/pmg20/resources/developing-nice-guidelines-the-manual-pdf-72286708700869

For more detailed information, please see the Methodology Review.

B.1. Clinical search literature search strategy

Searches were constructed using a PICO framework where population (P) terms were combined with Intervention (I) and in some cases Comparison (C) terms. Outcomes (O) are rarely used in search strategies for interventions as these concepts may not be well described in title, abstract or indexes and are therefore difficult to retrieve. Search filters were applied to the search where appropriate.

Table 15. Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

Cochrane Library (Wiley) search terms

CINAHL (EBSCO) search terms

PsycINFO (ProQuest) search terms

B.2. Health Economics literature search strategy

Health economic evidence was identified by conducting a broad search relating to primary hyperparathyroidism population in NHS Economic Evaluation Database (NHS EED – this ceased to be updated after March 2015) and the Health Technology Assessment database (HTA) with no date restrictions. NHS EED and HTA databases are hosted by the Centre for Research and Dissemination (CRD). Additional searches were run on Medline and Embase for health economics papers published since 2002.

Table 16. Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

NHS EED and HTA (CRD) search terms

Appendix C. Clinical evidence selection

Figure 1. Flow chart of clinical study selection for the review of Monitoring strategies

Figure 2. Flow chart of clinical study selection for the review of Monitoring long-term outcomes

Appendix D. Clinical evidence tables

Download PDF (383K)

Appendix E. Forest plots

E.1. PHPT cases versus matched comparators (adjusted for key confounders) Strata – Non-surgical

Figure 3. All-cause mortality

Figure 4. Fatal CVD

Figure 5. Non-fatal CVD

Figure 6. Cerebrovascular disease

Figure 7. Hypertension

Figure 8. Renal failure

Figure 9. Renal stones

Figure 10. All fractures

Figure 11. Osteoporotic fractures

E.2. PHPT versus control (no multivariate analysis) Stratum-Pre-surgery

Figure 12. Renal stones

E.3. PHPT cases versus control (no multivariate analysis)-Strata – Pre-operative and post-operative (surgery and non-surgery patients)

Figure 13. Fractures (all)

Figure 14. Lumbar spine-BMD (gm/cm²) (mild PHPT versus healthy women)

Figure 15. FN BMD (mg/cm²) (mild PHPT versus healthy women)

Figure 16. FT BMD (mg/cm²) (mild PHPT versus healthy women)

Figure 17. Vertebral fractures (mild PHPT versus control)

Figure 18. Vertebral fractures (non-mild PHPT versus healthy women)

Figure 19. Non-vertebral fractures (mild PHPT versus healthy women)

Figure 20. Non-vertebral fractures (non-mild PHPT versus healthy women)

Figure 21. LS-BMD (mg/cm²) (non-mild PHPT versus healthy women)

Figure 22. Femur neck-BMD (mg/cm²) (non-mild PHPT versus healthy women)

Figure 23. Total femur-BMD (mg/cm²) (non-mild PHPT versus healthy women)

E.4. PHPT cases versus control (no multivariate analysis) – strata post-operative

Figure 24. Mortality

Figure 25. Fractures

Appendix F. GRADE tables

Table 17. Clinical evidence profile: PHPT cases versus matched comparators (adjusted for key confounders) – non-surgical

Table 18. Clinical evidence profile: PHPT versus control (no multivariate analysis) – Pre-operative

Table 19. Clinical evidence profile: PHPT versus control (no multivariate analysis) – Mixed pre-operative and post-operative (surgical and non-surgical patients)

Table 20. Clinical evidence profile: PHPT versus control (no multivariate analysis) – strata post-operative

Appendix G. Health economic evidence selection

Figure 26. Flow chart of health economic study selection for the guideline

Appendix H. Health economic evidence tables

No economic studies were included in this review.

Appendix I. Excluded studies

I.1. Excluded clinical studies

Table 21. Studies excluded from the clinical review

I.2. Excluded health economic studies

None.

Appendix J. Research recommendations

J.1. Long-term consequences of management strategies for PHPT

Research question: What are the long-term outcomes of different management strategies for primary hyperparathyroidism? What strategies are most cost-effective?

Why this is important

There is limited evidence on the long-term outcomes of the different management strategies such as surgery, calcimimetics and bisphosphonates (see evidence report C, evidence report G and evidence report H). In order for people to make an informed choice regarding their treatment research is needed on this topic.

Criteria for selecting high-priority research recommendations

Final

Intervention evidence review

This evidence review was developed by the National Guideline Centre

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK577896PMID: 35167213

Table 1PICO characteristics of review question

Population	Adults (18 years or over) with primary hyperparathyroidism Strata: Pre-operative Post-operative Non-surgical Previous surgery Pregnant women
Interventions	Different techniques/tools/variables being monitored blood tests (adjusted serum calcium, serum creatinine), imaging (DXA for bone disease (±VFA) US for kidney stones, renal tract calcification x-ray for fragility fracture for vertebral fracture other (24-hour urinary calcium, creatinine clearance) CV variables (BP, lipids, ECG), vitamin D (for post-operative monitoring) renal function Different frequencies of monitoring (this may differ for the different tests – e.g. bloods 6–12 months, DXA 2–3 years) Different durations of monitoring (for post-surgery stratum, e.g. for 3 months or 6 months – to include the optimum timing of serum calcium assessment post-surgery to determine cure)
Comparisons	Comparing types of monitoring strategies to each other Comparing different frequencies of the same strategy
Outcomes	Critical outcomes: HRQOL (continuous outcome) Mortality (dichotomous outcome) Important outcomes: Deterioration in renal function (continuous – study may also report renal replacement) Fractures (vertebral or long bone) (dichotomous outcome) Occurrence of kidney stones (dichotomous outcome) Persistent hypercalcaemia (dichotomous outcome) BMD of the distal radius or the lumbar spine (continuous) Cardiovascular events (dichotomous outcome) Adverse events (to include voice change, hypoparathyroidism, hypothyroidism/hyperthyroidism; dichotomous outcome) Cancer incidence (dichotomous outcome) Reoperation (for post-surgery stratum)
Study design	RCTs and systematic reviews of RCTs In the absence of RCT evidence for the critical outcomes, NRSs will be included (only if the following key confounders are matched for or adjusted for in the analysis) Key confounders: Age Absence/presence of end-organ effects Adjusted serum calcium level

Table 2PICO characteristics of review question

Population	Adults (18 years or over) with primary hyperparathyroidism Strata: Preoperative Non-surgical Post-operative People on calcimimetics People on bisphosphonates Previous surgery Normocalcaemic patients Subgroup: People on HRT
Interventions and comparisons	This review will be looking at the incidence of outcomes in people with PHPT compared with healthy controls
Outcomes	Critical outcomes: mortality (dichotomous outcome) fragility fracture (dichotomous outcome) renal stones (dichotomous outcome) renal tract calcification (dichotomous outcome) pancreatitis (dichotomous outcome) stroke (dichotomous outcome) hypertension (dichotomous outcome) myocardial infarction (dichotomous outcome) Number of people who become eligible for surgery/meet the criteria for surgery (dichotomous) serum calcium (>2.85 mmol/l) (dichotomous) (continuous if dichotomous not available) 24-hour urine for calcium (>10 mmol/dl) (dichotomous) (continuous if dichotomous not available) BMD of proximal femur (T-score <2.5; Z score <2) (dichotomous) (continuous if dichotomous not available) Follow-up: minimum 2 years
Study design	Prospective cohort studies Retrospective cohort studies will be included only if insufficient prospective cohort studies are identified Key confounders: Age Absence/presence of end-organ effects Adjusted serum calcium level

Table 3Summary of studies included in the evidence review (comparative studies)

Study

Comparison

Population

Outcomes

Comments

Yu 2011⁸⁰

Prospective cohort study

Setting: Tayside, Scotland, 1997–2006

Each of the selected patients was then matched with five individuals, or comparators, by age, gender and calendar year of PHPT diagnosis, from the general Tayside population, with either no calcium records or normal serum calcium concentration during the study period. The calendar year of the matching was the index date for each comparator.

All Tayside residents over 20 years of age were considered as potential cases.

In conjunction with hospital admission records, nuclear medicine and histology data, the PHPT cohort was primarily diagnosed if they met either of the following biochemical criteria: albumin-corrected serum calcium >2.55 mm (10.22 mg/dl, reference range 2.10–2.55 mm) on at least two occasions, with plasma parathyroid hormone (PTH) concentration >3 pm (13.5 ng/l, reference range 1.0–6.9 pm); or, albumin-corrected serum calcium >2.55 mm (10.22 mg/dl) on a single occasion, with plasma PTH concentration >6.9 pm (31.05 ng/l).

A subgroup of ‘mild PHPT’ patients was further selected for this study, these being patients with untreated PHPT, low concentrations of hypercalcaemia and an absence of renal stones, renal failure and osteoporotic fractures, at diagnosis.

Mild untreated group were defined as untreated PHPT patients whose serum calcium concentrations were <2.9 mmol/l within the first 6 months after a positive diagnosis with absence of previous (prior to PHPT diagnosis) fracture fragility, renal stones and renal failure and not treated with cinacalcet.

Further exclusion criteria were applied to the mild untreated group: serum calcium was followed up for >6 months; less than two serum calcium measurements within the first 6 months.

All-cause mortality
Fatal CVD
Non-fatal CVD
Cerebrovascular disease
Hypertension
Renal failure
Renal stones
All fractures
Osteoporotic fractures

PHPT patients not fitting NIH criteria for referral.

Study used individual data for both cases and comparators.

Clifton-Bligh, 2015²¹

Retrospective cohort study

Australia

n=561 patients with PHPT

Patients diagnosed with PHPT between 1961 and 1994 were identified, medical records were obtained and examined, and a determination was made as to whether or not they were alive at the end of 1994.

Survival data of individuals with PHPT compared with expected survival in the general Australian population was obtained from the Life Tables.

The control population was the Australian population at large for whom Life Tables from 1961–1994 existed at the time (Life Tables are published by the Australian Government Actuary).

Control population matched for age, sex, the year observation began, and the duration of the observation.

Survival rate over a 10 and 20 year period

Follow-up: 10 years and 20 years

The relative survival over a 20 year time interval was calculated for the patients studied between 1972 and 2011. The group was divided into 2 cohorts: those diagnosed between 1972 and 1981 and those diagnosed between 1982 and 1991, and 20 year relative survival was calculated for each cohort.

Before 1972 diagnosis of PHPT was made if surgical removal of a parathyroid gland restored eucalcaemia, or if a full investigation failed to find another cause for hypercalcaemia. After 1972, the diagnosis of PHPT was made if the serum calcium and serum PTH was above the upper limit of the reference range.

Because of the concept that a person with mild PHPT might not require surgery, 113 of the patients with mild PHPT were not subjected to neck exploration and 448 patients had parathyroid surgery.

De Geronimo, 2006²⁶

Cohort study

Italy

Setting: Mineral metabolic centre

n=98 post-menopausal women with PHPT and 89 healthy women.

98 consecutive post-menopausal patients with PHPT. They were grouped as mild or non-mild according to criteria established by the Consensus Development conference on the management of asymptomatic primary hyperparathyroidism:

Serum calcium greater than 1m g/dl above the upper limits of normal; 24-h total urine calcium excretion of more than 400 mg; creatinine clearance reduced by more than 30% compared to age-matched persons; bone density at lumbar spine, hip or distal radius that is more than 2.5 SD below peak bone mass; patients under 50 years of age.

Based on these criteria, only 25 of the 98 patients were considered as suffering from mild disease. In this group of patients hypercalcaemia was occasionally detected in the course of the standard biochemical evaluation performed on all subjects undergoing BMD measurement.

None of the mild patients reported either height loss or clinical vertebral fractures at history.

In the remaining 73 patients, a severe disease was present; 13 of them had a history of nonvertebral fractures; 7 referred by GPs for nephrolithiasis; 21 referred by GPs for osteoporosis; 15 patients renal stones shown by ultrasonography; 3 were referred for hypercalcaemia; 2 had a life threatening episode of pancreatitis. The remaining 12 patients complained of bone pain and/or neuromuscular symptoms.

Mild or non-mild PHPT postmenopausal women

Healthy subjects - 89 healthy postmenopausal women, matched for age, years since menopause, BMI. They were randomly selected from ambulatory post-menopausal women sent by their GPs to the hospital as part of a menopause-screening programme.

Vertebral fracture
Non-vertebral fractures
Lumbar spine – BMD
Femoral neck – BM
Total femur – BMD

Control patients matched for age, years since menopause and BMI. Not adjusted for absence/presence of end-organ effects and serum calcium level.

Diagnosis of PHPT was made according to the conventional clinical and lab data, including a history of at least 1 year of prolonged hypercalcaemia without evidence of non-parathyroid aetiology and unsuppressed serum levels of immunoreactive PTH.

Headback 1998³⁸

Retrospective cohort study

Sweden

n=4461 (915 men and 3546 women)

Patients diagnosed as having PHPT or parathyroid adenoma according to the International Classification of Diseases during 1987–94 from the Swedish national patient registry.

The patient series studied consisted of those individuals who at the same time were reported to have undergone removal of a parathyroid gland or adenoma. The inclusion date of a patient was the date of arrival at the hospital before surgery.

PHPT patients

Control

Whole Swedish population matched for age, sex and calendar year.

Strata: Post-operative

Death

Number of patients operated for PHPT

Total number of observation years was 3205 giving mean follow-up times of 3.6 and 3.5 years respectively (range 0–8 years)

Kenny 1995⁴¹

Retrospective cohort study

USA

n=46 Post-menopausal women who had undergone parathyroidectomy for hyperparathyroidism during a 5 year period (1986 to 1991)

Control – n=44 postmenopausal women without hyperparathyroidism contacted by random digit dialling and interviewed as controls.

PHPT patients vs control

Strata: Post-operative

Fracture incidence

Follow-up: 5 years

The women in the control were group were similar to those with PHPT in regard to age, weight, and height.

Not adjusted for key confounders.

Khosla 1999⁴²

USA

Retrospective Cohort study

n=407 patients with PHPT

Patients with PHPT:

The database the Rochester Epidemiology Project was used to identify 435 Rochester residents with PHPT during period, 1965–1992. Seven of these patients refused subsequent authorisation for chart review, and 21 had no follow-up after age 35 years, resulting in a final cohort of 407 subjects. These subjects were then followed forward in time through their linked medical records in the community (retrospective cohort study) until death or the most recent clinical contact and backward in time to the first medical record entry in the community.

Age related fractures in patients with PHPT (1965–1992)

Age related fractures in general population

The majority were women (344, 775) and most were 45 years of age or older at the diagnosis of HPT (335, 82%). The mean age at diagnosis was 57.8 years. The average maximum serum calcium level was 10.9 (0.6) mg/dl. Median serum PTH, measured by a C-terminal assay, was 47 µl.eq/ml (25–75% interval, 33–71 µl.eq/ml; normal ≤50 µl.eq/ml). The majority of the patients were asymptomatic.

Fractures

Study - 28 year period

No multivariate analysis

Diagnosis of vertebral fracture was accepted on the basis of a radiologists’ report of compression or collapse of one or more thoracic or lumbar vertebrae. All fractures were classified according to the circumstances of the injury.

Larsson, 1993⁴⁵

Sweden

Retrospective cohort study

n=1373 patients with PHPT

All patients who were admitted to hospital with the diagnosis of PHPT.

1318 patients (69%) had been subjected to parathyroidectomy at the same or a subsequent admission.

Mean serum calcium at the time of diagnosis for women with PHPT was 2.91 (0.22), and for men 2.79 (0.18) mmol/l; p<0.01. The serum calcium levels at diagnosis were stable during the study period.

For each patient the observation period started in 1965, or at the age of 30 for those below this age in 1965 and ended at the date of hip fracture diagnosis, death, or at the end of 1983.

Patients with PHPT

Entire background population

Hip fracture

Follow-up - 19 years

No multivariable analysis

Melton, 1992⁴⁹

Rochester, USA

Population based retrospective cohort study

n=90 patients with PHPT; n=90 matched control subjects

90 cases of PHPT newly diagnosed during the life among Rochester during 1965 through 1976; 83 subjects had histopathologic proof of parathyroid adenoma or hyperplasia or had hypercalcaemia with pathognomonic radiographic signs and/or elevated serum parathyroid hormone concentrations. The remainder had hypercalcaemia for more than a year without another cause being found after careful evaluation. Patients with an incidental autopsy diagnosis of parathyroid adenoma or hyperplasia were excluded.

The 90 patients were matched by age and gender to control subjects from the local population who had no evidence of PHPT.

Patients with PHPT

matched control subjects

Controls matched by age and gender.

Fractures

Age interaction (narrative)

Proportional hazards model was used to determine the relative influence of various clinical characteristics on subsequent fracture risk among those with HPT. The factors evaluated included age at diagnosis, gender, initial serum calcium (<2.74 vs >2.74 mmol/L), comorbid conditions related to HPT and parathyroid surgery.

Not adjusted for serum calcium level and absence/presence of end organ effects.

Ronni-Sivula, 1985⁶⁰

Finland

Retrospective cohort study

Setting: department of surgery

n=334 (PHPT); n= 334 healthy controls

334 patients (83 men and 251 women) were operated on for PHPT in the years 1956–79. A follow-up study of this material was performed in the years 1980–82. 34 patients had died before the end of the year 1980. All clinical data as well as causes of death of these patients were collected and examined.

PHPT patients operated in the years 1956–79

Control.

Each PHPT patient in the original material was given a pair who was sex and age matched and operated on for appendicitis, varicose veins or haemorrhoids in the same year

Strata: Post-operative

Mortality

No multivariate analysis

Not adjusted for serum calcium level and absence/presence of end organ effects.

Suh 2008⁶⁹

Retrospective cohort study

USA

n=271

All patients who had undergone renal imaging within 6 months before parathyroid surgery for PHPT

n=500

Age matched subjects who had right upper quadrant sonograms obtained for various reasons

Strata: Post-operative

Renal stones

No multivariate analysis

Wilson, 1988⁷⁹

Retrospective cohort study

USA

Setting: Outpatient department of a bone and mineral metabolism clinic.

n=174 PHPT; n=200 control

All patients with mild asymptomatic PHPT.

Diagnostic criteria for PHPT:

persistent hypercalcaemia (calcium ≥2.65 mmol/L), with no clinical indication of another cause, and evidence of parathyroid hormone hypersecretion, with increased or non-suppressed values of radioimmunoassay of parathyroid hormone or nephrogenous cyclic adenosine monophosphate excretion per unit of glomerular filtrate.

The diagnosis was made at the clinic between 1 January 1976 and December 1985.

None of the post-menopausal women were receiving oestrogen replacement therapy at the time of initial diagnosis.

Inclusion criteria:

Absence of symptoms due to PHPT, no current kidney stone disease, a plasma calcium level of less than 3.00 mmol/L, a plasma creatinine level of less than 133µmol/L, no radiographic evidence of osteitis fibrosa, and a forearm bone densitometry not more than 2.5 standard deviations below the mean value expected for age, sex and race.

PHPT group

Healthy white women. These data had been obtained in 200 ambulatory white female patients having routine annual physical examination.

In almost every patient hypercalcaemia was an incidental finding. The mean plasma calcium level was 2.77 (0.09) mmol/L (reference value, 2.40 [0.08]).

Prevalence of vertebral fractures

Follow-up: 10 years

A reduction in anterior height of more than 20% compared with an adjacent vertebra was classified as a fracture.

Prospectively collected data were retrospectively analysed and compared with data from historical control group.

No multivariate analysis

Table 4Clinical evidence summary: PHPT cases compared to matched comparators (adjusted for key confounders) (Stratum-Non-surgical)

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with Control	Risk difference with Cases (95% CI)
All-cause mortality	8544 (1 study) median 2.9 years	LOW^c	HR 1.64 (1.43 to 1.87)^b	Moderate
All-cause mortality	8544 (1 study) median 2.9 years	LOW^c	HR 1.64 (1.43 to 1.87)^b		-^a
Fatal CVD	8544 (1 study) median 2.9 years	LOW^c	HR 1.64 (1.32 to 2.04)^b	Moderate
Fatal CVD	8544 (1 study) median 2.9 years	LOW^c	HR 1.64 (1.32 to 2.04)^b		-^a
Nonfatal CVD	8544 (1 study) median 2.9 years	LOW^c	HR 2.48 (2.13 to 2.89)^b	Moderate
Nonfatal CVD	8544 (1 study) median 2.9 years	LOW^c	HR 2.48 (2.13 to 2.89)^b		-^a
Hypertension	8544 (1 study) median 2.9 years	LOW^c	HR 2.60 (2.04 to 3.31)^b	Moderate
Hypertension	8544 (1 study) median 2.9 years	LOW^c	HR 2.60 (2.04 to 3.31)^b		-^a
Cerebrovascular disease	8544 (1 study) median 2.9 years	LOW^c	HR 2.51 (1.95 to 3.22)^b	Moderate
Cerebrovascular disease	8544 (1 study) median 2.9 years	LOW^c	HR 2.51 (1.95 to 3.22)^b		-^a
Renal failure	8544 (1 study) median 2.9 years	LOW^c	HR 13.83 (10.41 to 18.37)^b	Moderate
Renal failure	8544 (1 study) median 2.9 years	LOW^c	HR 13.83 (10.41 to 18.37)^b		-^a
Renal stones	8544 (1 study) median 2.9 years	LOW^c	HR 5.15 (2.69 to 9.83)^b	Moderate
Renal stones	8544 (1 study) median 2.9 years	LOW^c	HR 5.15 (2.69 to 9.83)^b		-^a
All fractures	8544 (1 study) median 2.9 years	LOW^c	HR 1.75 (1.36 to 2.26)^b	Moderate
All fractures	8544 (1 study) median 2.9 years	LOW^c	HR 1.75 (1.36 to 2.26)^b		-^a
Osteoporotic fractures	8544 (1 study) median 2.9 years	LOW^c	HR 1.63 (1.22 to 2.19)^b	Moderate
Osteoporotic fractures	8544 (1 study) median 2.9 years	LOW^c	HR 1.63 (1.22 to 2.19)^b		-^a

a: Absolute effect cannot be calculated as adjusted control group event rate not reported.

b: Confounding covariates considered were multiple deprivation index, history of bisphosphonates prescription, history of hospital-admitted CVD, cerebrovascular disease, hypertension, renal failure, renal stones, psychiatric disease, fractures, cancer and diabetes.

c: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias (used the non-randomised studies checklist on evibase for assessment for risk of bias).

: Note: All patients with diagnosed but untreated, mild asymptomatic PHPT.

Table 5Clinical evidence summary: PHPT compared to control (no multivariate analysis) (Stratum – Pre-surgery)

Outcomes

No of Participants (studies) Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with Control

Risk difference with Monitoring long term outcomes - PHPT (95% CI)

Renal stones

(definitive calculi)

771

(1 study)

VERY LOW^a

due to risk of bias

RR 4.38

(1.94 to 9.88)

Moderate

16 per 1000

54 more per 1000

(from 15 more to 142 more)

PHPT group: 19/271

Control: 8/500

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias (used the non-randomised studies checklist on evibase for assessment for risk of bias).

Table 6Clinical evidence summary: PHPT compared to control (no multivariate analysis) – Mixed strata – Pre and post-operative (surgery and non-surgery patients)

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with Control	Risk difference with Monitoring long term outcomes - PHPT (95% CI)
Fractures (all)	180 (1 study)	VERY LOW^a due to risk of bias,	RR 0.96 (0.74 to 1.24)	Moderate
Fractures (all)	180 (1 study)	VERY LOW^a due to risk of bias,	RR 0.96 (0.74 to 1.24)	414 per 1000	17 fewer per 1000 (from 108 fewer to 99 more)
Lumbar spine BMD (mg/cm²) (mild PHPT vs healthy women)	114 (1 study)	VERY LOW^a due to risk of bias	-	-	The mean lumbar spine BMD (mg/cm²) (mild PHPT vs healthy women) in the intervention groups was 77.1 higher (31.61 to 122.59 higher)
Femoral neck-BMD (mg/cm²) (mild PHPT vs healthy women)	114 (1 study)	VERY LOW^a^,^c due to risk of bias, imprecision	-	-	The mean femoral neck - BMD (mg/cm²) (mild PHPT vs healthy women) in the intervention groups was 18.4 higher (24.43 lower to 61.23 higher)
Total femur - BMD (mg/cm²) (mild PHPT vs healthy women)	114 (1 study)	VERY LOW^a^,^c due to risk of bias, imprecision	-	-	The mean total femur - BMD (mg/cm²) (mild PHPT vs healthy women) in the intervention groups was 21.2 higher (30.33 lower to 72.73 higher)
Vertebral fractures (mild PHPT vs healthy controls)	343 (2 studies)	VERY LOW^a^,^b due to risk of bias, inconsistency	RR 2.31 (1.26 to 4.21)	Moderate
Vertebral fractures (mild PHPT vs healthy controls)	343 (2 studies)	VERY LOW^a^,^b due to risk of bias, inconsistency	RR 2.31 (1.26 to 4.21)	72 per 1000	94 more per 1000 (from 19 more to 231 more)
Vertebral fractures (non-mild PHPT vs healthy women)	162 (1 study)	VERY LOW^a due to risk of bias	RR 5.33 (2.64 to 10.77)	Moderate
Vertebral fractures (non-mild PHPT vs healthy women)	162 (1 study)	VERY LOW^a due to risk of bias	RR 5.33 (2.64 to 10.77)	90 per 1000	390 more per 1000 (from 148 more to 879 more)
Non-vertebral fractures (mild PHPT vs healthy women)	114 (1 study)	VERY LOW^a^,^c due to risk of bias, imprecision	Peto OR 0.22 (0.07 to 0.78)	Moderate
Non-vertebral fractures (mild PHPT vs healthy women)	114 (1 study)	VERY LOW^a^,^c due to risk of bias, imprecision	Peto OR 0.22 (0.07 to 0.78)	191 per 1000	190 fewer per 1000 (from 290 to 90 fewer)
Non-vertebral fractures (non-mild PHPT vs healthy women)	162 (1 study)	VERY LOW^a^,^c due to risk of bias, imprecision	RR 0.93 (0.49 to 1.79)	Moderate
Non-vertebral fractures (non-mild PHPT vs healthy women)	162 (1 study)	VERY LOW^a^,^c due to risk of bias, imprecision	RR 0.93 (0.49 to 1.79)	191 per 1000	13 fewer per 1000 (from 97 fewer to 151 more)
Lumbar spine-BMD (mg/cm²) (non-mild PHPT vs healthy women)	162 (1 study)	VERY LOW^a due to risk of bias	-	-	The mean lumbar spine - BMD (mg/cm²) (non-mild PHPT vs healthy women) in the intervention groups was 73.6 lower (116.15 to 31.05 lower)
Femoral neck-BMD (mg/cm²) (non-mild PHPT vs healthy women)	162 (1 study)	VERY LOW^a due to risk of bias	-	-	The mean femoral neck - BMD (mg/cm²) in the intervention groups was 89.3 lower (121.96 to 56.64 lower)
Total femur-BMD (mg/cm²) (non-mild PHPT vs healthy women)	162 (1 study)	VERY LOW^a due to risk of bias	-	-	The mean total femur - BMD (mg/cm²) in the intervention groups was 102.5 lower (140.13 to 64.87 lower)

a: Downgraded by 1 increment if the majority of studies were at high risk of bias, and downgraded by 2 increments if the majority of studies were at very high risk of bias (used the non-randomised studies checklist on evibase for assessment for risk of bias).

b: Heterogeneity, I²=90%

c: Downgraded by 1 increment if the confidence interval crossed 1 MID, and downgraded by 2 increments if the confidence interval crossed both MIDs.

Table 7Clinical evidence summary (modified GRADE table): PHPT compared to control (no multivariate analysis) – Mixed strata-Pre and post-operative (surgery and surgery patients)

Outcomes

No of Participants (studies) Follow up

Quality of the evidence (GRADE)

Relative survival rate^* for the PHPT group compared to control

Anticipated absolute effects

Relative survival

561 (1 study)

VERY LOW^a

due to risk of bias

86.8% (95% CI 84.9–86.2, p<0.001)

(10 years)

124/561 patients died between 1961 and 1994^b

Relative survival

561 (1 study)

VERY LOW^a

due to risk of bias

62.9% (95% CI 58.5–67.4, P<0.001).

(20 years)

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias (used the non-randomised studies checklist on evibase for assessment of risk of bias).

b: Control group event rate not reported

*: Relative survival rate - is a way of comparing the survival of people who have a specific disease with those who do not, over a certain period of time.

: It is calculated by dividing the percentage of patients with the disease who are still alive at the end of the period of time by the percentage of people in the general population/control who are alive at the end of the same time period.

Table 8Clinical evidence summary (modified GRADE table): PHPT (observed) versus expected numbers in the general population (no multivariate analysis) – Mixed strata – Pre and post-operative (surgery and non-surgery patients)

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Standardised Incidence Ratio^* (SIR) 95% CI and Risk ratio (RR)	Anticipated absolute effects
Any Fracture (at all skeletal sites)^b	407 (1 study)	VERY LOW^a due to risk of bias	SIR 1.3 (95% CI 1.1–1.5)^*	observed: n=202; expected: n=154.6
Vertebral fracture	407 (1 study)	VERY LOW^a due to risk of bias	SIR 3.2 (95% CI 2.5–4.0)	observed: n=79; expected: n= 24.6
Hip fractures (women)	1373 (1 study)	VERY LOW^a due to risk of bias	RR 0.93 (95% CI 0.72–1.19)	observed: 67/1373; expected: 71.76
Hip fractures (men)	551 (1 study)	VERY LOW^a due to risk of bias	RR 1.39 (95% CI 0.69–2.50)	observed 11/551; expected 7.9

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias (used the non-randomised studies checklist on evibase for assessment of risk of bias).

b: A total of 471 fractures occurred in 202 patients after the index date. The majority of fractures of the vertebrae (92%), distal forearm (91%), pelvis (75%), and proximal femur (90%) were due to mild or moderate trauma.

*: Predictors of the risk of mild/moderate trauma, vertebral, distal forearm or proximal femur fractures:
Multivariate model
Age (per 10 year increase): relative hazard 1.6 (95% 1.4–1.9)
Female gender: relative hazard 2.3 (95% CI 1.2–4.1)
By multivariate analysis, only age and female gender were significant independent predictors of fracture risk.

**: Fracture risk was assessed by comparing new fractures at each site to the number expected from gender and age specific fracture incidence rates for the general population (SIRs).

Table 9Clinical evidence summary: PHPT patients compared to control (no multivariate analysis) – Stratum post-operative

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with Control	Risk difference with Monitoring - no MV analysis-strata post-operative (95% CI)
Mortality	668 (1 study)	VERY LOW^a^,^b due to risk of bias, imprecision	RR 1.62 (0.96 to 2.73)	Moderate
Mortality	668 (1 study)	VERY LOW^a^,^b due to risk of bias, imprecision	RR 1.62 (0.96 to 2.73)	63 per 1000	39 more per 1000 (from 3 fewer to 109 more) PHPT: 34/334 Control: 21/334
mortality^c	4461 (1 study)	VERY LOW^a due to risk of bias	Male: RR 1.30 (95% CI 1.07–1.57) Female: RR 1.61 (95% CI 1.46–1.78)	-	Male: observed: n=107; expected: n=82.2 Female: observed: n=396; expected: n=245.6 Altogether: observed: n-=503; expected: n=327.8
Fracture^d	90 (1 study)	VERY LOW^a^,^b due to risk of bias, imprecision	RR 1.91 (1.06 to 3.47)	Moderate
Fracture^d	90 (1 study)	VERY LOW^a^,^b due to risk of bias, imprecision	RR 1.91 (1.06 to 3.47)	250 per 1000	227 more (from 15 more to 618 more) PHPT: 22/46 Control: 11/44

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias (used the non-randomised studies checklist on evibase for assessment of risk of bias).

b: Downgraded by 1 increment if the confidence interval crossed 1 MID, and downgraded by 2 increments if the confidence interval crossed both MIDs.

c: The cause of increased risk of death was cardiovascular disease
Men: RR 1.71 (95% CI 1.34–2.15)
Women: RR 1.85 (955 CI 1.62–2.11)

d: 92% of the total fractures and all of the post-menopausal fractures occurred after minor trauma.

Table 10UK costs of monitoring procedures

Monitoring procedure	Cost (average)	Notes	Source
GP consultation	£37.00	Assumed average duration of 9.22 minutes	PSSRU 2017²⁴
Blood tests (adjusted serum calcium, serum creatinine, renal function, lipids)	£1.13	Clinical biochemistry test	NHS Reference Costs 16/17²⁸
PTH test	£8.00	Average of 12 test costs sought by the committee from laboratories in their local areas.	Committee estimate
Vitamin D	£16.50	Average of two NHS hospitals^(b)	Filby 2014³⁶
DXA scan	£83.00	Performed in an outpatient setting	NHS Reference Costs 16/17²⁸
Ultrasound	£52.00	US with duration <20 minutes, without contrast, outpatient setting	NHS Reference Costs 16/17²⁸
X-ray	£30.00	Direct access plain film	NHS Reference Costs 16/17²⁸
Blood pressure	£6.00	Calculation based on average cost of 15min contact with community or hospital based nurse	PSSRU 2017²⁴
ECG	£ 37.00	ECG not included in 16/17 NHS reference costs. The committee did not consider it is likely to have changed significantly in cost since 2010/11.	NHS Reference costs 10/11²⁹.

Table 11UK cost of clinical events associated with PHPT

Event	Cost	Notes	Source
Cardiovascular events
Acute coronary syndrome (including myocardial infarction)	£4,933	Cost of initial 6 months	NICE Hypertension Guideline (update 2011)⁵²
Stroke	£10,190
Heart failure	£2,649
Renal events
Renal dysfunction	£803	General renal disorders without interventions, national average, day case, CC score 0–2	NHS Reference costs 16/17²⁸
Renal stones – shockwave therapy	£452	Day case	NHS Reference costs 16/17²⁸
Renal stones – ureteroscopy	£2,172	50% elective weighted average, and 50% day case weighted average to reflect UK practice
Renal stones – percutaneous nephrolithotomy	£5,195	Elective weighted average
Fragility fractures^(a)
Hip	£15,722	Total cost of initial hospitalisation and costs in year following fracture.	NICE TA464⁵⁴
Vertebrae	£8,019
Proximal humerus	£6,625
Wrist	£4,523

Table 12Review protocol: Monitoring strategies

Field	Content
Review question	6.1 What is the optimum type and frequency of monitoring for people with PHPT (for example, pre-operative, postoperative, non-surgical)?
Type of review question	Intervention The optimum use of monitoring for people with PHPT – looking at patient outcomes for different strategies or frequencies of monitoring. This will cover pre-operative, post-operative and non-surgical monitoring.
Objective of the review	To determine the clinical and cost effectiveness of different strategies or frequencies of monitoring, at the pre-operative and postoperative stage as well as in people with PHPT not undergoing surgery.
Eligibility criteria – population	Adults (18 years or over) with primary hyperparathyroidism Strata: Pre-operative Post-operative Non-surgical Previous surgery Pregnant women Exclude people: with secondary and tertiary HPT with multiple endocrine neoplasia with familial hyperparathyroidism with parathyroid carcinoma on medications interfering with calcium metabolism (lithium). Studies including mixed populations of people with primary and secondary or tertiary hyperparathyroidism will be excluded unless subgroups reported separately by type of hyperparathyroidism.
Eligibility criteria – intervention(s)	Different techniques/tools/variables being monitored: Blood tests (adjusted serum calcium, serum creatinine) Imaging (DXA for bone disease) (±VFA) US for kidney stones, renal tract calcification X-ray for fragility fracture for vertebral fracture Other (24-hour urinary calcium, creatinine clearance CV variables (BP, lipids, ECG) Vitamin D (for post-operative monitoring) Renal function Different frequencies of monitoring (acceptable frequencies – this may differ for the different tests – e.g. bloods 6–12 months, DXA 2–3 years) Different durations of monitoring (for post-surgery stratum, e.g. for 3 months or 6 months – to include the optimum timing of serum calcium assessment post-surgery to determine cure)
Eligibility criteria – comparator(s)	Comparing types of strategies to each other Comparing different frequencies of the same strategy
Outcomes and prioritisation	Report all outcomes separately for <6 months and ≥6 months Critical outcomes: HRQOL (continuous outcome) Mortality (dichotomous outcome) Important outcomes: Deterioration in renal function (continuous – study may also report renal replacement) Fractures (vertebral or long bone) (dichotomous outcome) Occurrence of kidney stones (dichotomous outcome) Persistent hypercalcaemia (dichotomous outcome) BMD of the distal radius or the lumbar spine (continuous) Cardiovascular events (dichotomous outcome) Adverse events (to include voice change, hypoparathyroidism, hypothyroidism/hyperthyroidism; dichotomous outcome) Cancer incidence (dichotomous outcome) Reoperation (for post-surgery stratum)
Eligibility criteria – study design	RCTs and systematic reviews of RCTs In the absence of RCT evidence for the critical outcomes, NRSs will be included (only if the following key confounders are matched for or adjusted for in the analysis) Key confounders: Age Absence/presence of end-organ effects Adjusted serum calcium level
Other inclusion exclusion criteria	Non-English language articles Conference abstracts
Proposed sensitivity / subgroup analysis, or meta-regression	N/A
Selection process – duplicate screening / selection / analysis	Studies are sifted by title and abstract. Potentially significant publications obtained in full text are then assessed against the inclusion criteria specified in this protocol.
Data management (software)	Pairwise meta-analyses were performed using Cochrane Review Manager (RevMan5). GRADEpro was used to assess the quality of evidence for each outcome. Endnote for bibliography, citations, sifting and reference management. Data extractions performed using EviBase, a platform designed and maintained by the National Guideline Centre (NGC).
Information sources – databases and dates	Clinical search databases to be used: Medline, Embase, Cochrane Library, CINAHL, PsycINFO Date: all years Health economics search databases to be used: Medline, Embase, NHSEED, HTA Date: Medline, Embase from 2002 NHSEED, HTA – all years Language: Restrict to English only Supplementary search techniques: backward citation searching Key papers: Not known
Identify if an update	N/A
Author contacts	https://www.nice.org.uk/guidance/indevelopment/gid-ng10051
Highlight if amendment to previous protocol	N/A
Search strategy – for one database	For details please see appendix B
Data collection process – forms / duplicate	A standardised evidence table format will be used, and published as appendix D of the evidence report.
Data items – define all variables to be collected	For details please see evidence tables in appendix D (clinical evidence tables) or H (health economic evidence tables).
Methods for assessing bias at outcome / study level	Standard study checklists were used to critically appraise individual studies. For details please see section 6.2 of Developing NICE guidelines: the manual The risk of bias across all available evidence was evaluated for each outcome using an adaptation of the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE) toolbox’ developed by the international GRADE working group http://www.gradeworkinggroup.org/
Criteria for quantitative synthesis	For details please see section 6.4 of Developing NICE guidelines: the manual.
Methods for quantitative analysis – combining studies and exploring (in)consistency	For details please see the separate Methods report for this guideline.
Meta-bias assessment – publication bias, selective reporting bias	For details please see section 6.2 of Developing NICE guidelines: the manual.
Confidence in cumulative evidence	For details please see sections 6.4 and 9.1 of Developing NICE guidelines: the manual.
Rationale / context – what is known	For details please see the introduction to the evidence review.
Describe contributions of authors and guarantor	A multidisciplinary committee developed the evidence review. The committee was convened by the National Guideline Centre (NGC) and chaired by Jonathan Mant in line with section 3 of Developing NICE guidelines: the manual. Staff from the NGC undertook systematic literature searches, appraised the evidence, conducted meta-analysis and cost-effectiveness analysis where appropriate, and drafted the evidence review in collaboration with the committee. For details please see Developing NICE guidelines: the manual.
Sources of funding / support	The NGC is funded by NICE and hosted by the Royal College of Physicians.
Name of sponsor	The NGC is funded by NICE and hosted by the Royal College of Physicians.
Roles of sponsor	NICE funds the NGC to develop guidelines for those working in the NHS, public health and social care in England.
PROSPERO registration number	Not registered

Table 13Monitoring long term outcomes protocol

Field	Content
Review question	What are the long-term outcomes in people with PHPT?
Type of review question	Prognostic
Objective of the review	To determine whether PHPT is associated with poor long-term outcomes to determine what monitoring they need to undergo
Eligibility criteria – population / disease / condition / issue / domain	Adults (18 years or over) with primary hyperparathyroidism Strata: Preoperative Non-surgical Post-operative People on calcimimetics People on bisphosphonates Previous surgery Normocalcaemic patients Subgroup: People on HRT Exclude people: with secondary and tertiary HPT with multiple endocrine neoplasia with familial hyperparathyroidism with parathyroid carcinoma people on medications interfering with calcium metabolism (lithium).
Outcomes and prioritisation	Mortality (dichotomous) Fragility fracture (dichotomous) Renal stones (dichotomous) Renal tract calcification (dichotomous) Pancreatitis (dichotomous) Stroke (dichotomous) Hypertension (dichotomous) Myocardial infarction (dichotomous) Number of people who become eligible for surgery/meet the criteria for surgery (dichotomous) Serum calcium (>2.85 mmol/L) (dichotomous) (continuous if dichotomous not available) 24-hour urine for calcium (>10 mmol/dl) (dichotomous) (continuous if dichotomous not available) BMD of proximal femur (T-score <2.5; Z score <2) (dichotomous) (continuous if dichotomous not available) Report age interaction (this will be a narrative – how age interacts with the outcome of interest) Follow-up: minimum 2 years
Eligibility criteria – study design	Prospective cohort studies Retrospective cohort studies will be included only if insufficient prospective cohort studies are identified. Key confounders: Age Absence/presence of end-organ effects Adjusted serum calcium level
Other inclusion exclusion criteria	Exclusions: Non-English language papers Conference abstracts Not compared to healthy controls Studies <50 participants Note: This review will be looking at the incidence of outcomes in people with PHPT compared with healthy controls. We will not be looking at studies reporting the incidence in people with PHPT as this is less informative.
Proposed sensitivity / subgroup analysis, or meta-regression	N/A
Selection process – duplicate screening / selection / analysis	Studies are sifted by title and abstract. Potentially significant publications obtained in full text are then assessed against the inclusion criteria specified in this protocol.
Data management (software)	Pairwise meta-analyses were performed using Cochrane Review Manager (RevMan5). GRADEpro was used to assess the quality of evidence for each outcome. Endnote for bibliography, citations, sifting and reference management Data extractions performed using EviBase, a platform designed and maintained by the National Guideline Centre (NGC).
Information sources – databases and dates	Clinical search databases to be used: Medline, Embase, Cochrane Library Date: all years Health economics search databases to be used: Medline, Embase, NHSEED, HTA Date: Medline, Embase from 2014 NHSEED, HTA – all years Language: Restrict to English only Supplementary search techniques: backward citation searching Key papers: Not known
Identify if an update	N/A
Author contacts	https://www.nice.org.uk/guidance/indevelopment/gid-ng10051
Highlight if amendment to previous protocol	For details please see section 4.5 of Developing NICE guidelines: the manual.
Search strategy – for one database	For details please see appendix B
Data collection process – forms / duplicate	A standardised evidence table format will be used, and published as appendix D of the evidence report.
Data items – define all variables to be collected	For details please see evidence tables in appendix D (clinical evidence tables) or H (health economic evidence tables).
Methods for assessing bias at outcome / study level	Standard study checklists were used to critically appraise individual studies. For details please see section 6.2 of Developing NICE guidelines: the manual. The risk of bias across all available evidence was evaluated for each outcome using an adaptation of the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE) toolbox’ developed by the international GRADE working group http://www.gradeworkinggroup.org/
Criteria for quantitative synthesis	For details please see section 6.4 of Developing NICE guidelines: the manual.
Methods for quantitative analysis – combining studies and exploring (in)consistency	For details please see the separate Methods report for this guideline.
Meta-bias assessment – publication bias, selective reporting bias	For details please see section 6.2 of Developing NICE guidelines: the manual.
Confidence in cumulative evidence	For details please see sections 6.4 and 9.1 of Developing NICE guidelines: the manual.
Rationale / context – what is known	For details please see the introduction to the evidence review.
Describe contributions of authors and guarantor	A multidisciplinary committee developed the evidence review. The committee was convened by the National Guideline Centre (NGC) and chaired by Jonathan Mant in line with section 3 of Developing NICE guidelines: the manual. Staff from the NGC undertook systematic literature searches, appraised the evidence, conducted meta-analysis and cost-effectiveness analysis where appropriate, and drafted the evidence review in collaboration with the committee. For details please see Developing NICE guidelines: the manual.
Sources of funding / support	The NGC is funded by NICE and hosted by the Royal College of Physicians.
Name of sponsor	The NGC is funded by NICE and hosted by the Royal College of Physicians.
Roles of sponsor	NICE funds the NGC to develop guidelines for those working in the NHS, public health and social care in England.
PROSPERO registration number	Not registered

Table 14Health economic review protocol

Review question	All questions – health economic evidence
Objectives	To identify health economic studies relevant to any of the review questions.
Search criteria	Populations, interventions and comparators must be as specified in the clinical review protocol above. Studies must be of a relevant health economic study design (cost–utility analysis, cost-effectiveness analysis, cost–benefit analysis, cost–consequences analysis, comparative cost analysis). Studies must not be a letter, editorial or commentary, or a review of health economic evaluations (recent reviews will be ordered although not reviewed. The bibliographies will be checked for relevant studies, which will then be ordered). Unpublished reports will not be considered unless submitted as part of a call for evidence. Studies must be in English.
Search strategy	A health economic study search will be undertaken using population-specific terms and a health economic study filter – see appendix B below.
Review strategy	Studies not meeting any of the search criteria above will be excluded. Studies published before 2002, abstract-only studies and studies from non-OECD countries or the USA will also be excluded. Each remaining study will be assessed for applicability and methodological limitations using the NICE economic evaluation checklist which can be found in appendix H of Developing NICE guidelines: the manual (2014).⁵³ Inclusion and exclusion criteria If a study is rated as both ‘Directly applicable’ and with ‘Minor limitations’ then it will be included in the guideline. A health economic evidence table will be completed and it will be included in the health economic evidence profile. If a study is rated as either ‘Not applicable’ or with ‘Very serious limitations’ then it will usually be excluded from the guideline. If it is excluded then a health economic evidence table will not be completed and it will not be included in the health economic evidence profile. If a study is rated as ‘Partially applicable’, with ‘Potentially serious limitations’ or both then there is discretion over whether it should be included. Where there is discretion The health economist will make a decision based on the relative applicability and quality of the available evidence for that question, in discussion with the guideline committee if required. The ultimate aim is to include health economic studies that are helpful for decision-making in the context of the guideline and the current NHS setting. If several studies are considered of sufficiently high applicability and methodological quality that they could all be included, then the health economist, in discussion with the committee if required, may decide to include only the most applicable studies and to selectively exclude the remaining studies. All studies excluded on the basis of applicability or methodological limitations will be listed with explanation in the excluded health economic studies appendix below. The health economist will be guided by the following hierarchies. Setting: UK NHS (most applicable). OECD countries with predominantly public health insurance systems (for example, France, Germany, Sweden). OECD countries with predominantly private health insurance systems (for example, Switzerland). Studies set in non-OECD countries or in the USA will be excluded before being assessed for applicability and methodological limitations. Health economic study type: Cost–utility analysis (most applicable). Other type of full economic evaluation (cost–benefit analysis, costeffectiveness analysis, cost–consequences analysis). Comparative cost analysis. Non-comparative cost analyses including cost-of-illness studies will be excluded before being assessed for applicability and methodological limitations. Year of analysis: The more recent the study, the more applicable it will be. Studies published in 2002 or later but that depend on unit costs and resource data entirely or predominantly from before 2002 will be rated as ‘Not applicable’. Studies published before 2002 will be excluded before being assessed for applicability and methodological limitations. Quality and relevance of effectiveness data used in the health economic analysis: The more closely the clinical effectiveness data used in the health economic analysis match with the outcomes of the studies included in the clinical review the more useful the analysis will be for decision-making in the guideline.

Table 15Database date parameters and filters used

Database	Dates searched	Search filter used
Medline (OVID)	1946 – 06 August 2018	Exclusions
Embase (OVID)	1974 – 06 August 2018	Exclusions
The Cochrane Library (Wiley)	Cochrane Reviews to 2018 Issue 8 of 12 CENTRAL to 2018 Issue 7 of 12 DARE, and NHSEED to 2015 Issue 2 of 4 HTA to 2016 Issue 4 of 4	None
CINAHL, Current Nursing and Allied Health Literature (EBSCO)	Inception – 06 August 2018	Exclusions
PsycINFO (ProQuest)	Inception – 06 August 2018	Exclusions

Medline (Ovid) search terms

1.	hyperparathyroidism/ or hyperparathyroidism, primary/
2.	((primary or asymptomatic or symptomatic or mild or familial or maternal) adj6 (HPT or hyperparathyroidis*)).ti,ab.
3.	PHPT.ti,ab.
4.	Parathyroid Neoplasms/
5.	(parathyroid* adj3 (adenoma* or carcinoma* or hyperplasia* or neoplas* or tumo?r* or cancer* or metasta* or hypercalc?emi*)).ti,ab.
6.	or/1–5
7.	letter/
8.	editorial/
9.	news/
10.	exp historical article/
11.	Anecdotes as Topic/
12.	comment/
13.	case report/
14.	(letter or comment*).ti.
15.	or/7–14
16.	randomized controlled trial/ or random*.ti,ab.
17.	15 not 16
18.	animals/ not humans/
19.	exp Animals, Laboratory/
20.	exp Animal Experimentation/
21.	exp Models, Animal/
22.	exp Rodentia/
23.	(rat or rats or mouse or mice).ti.
24.	or/17–23
25.	not 24
26.	limit 25 to English language

Embase (Ovid) search terms

1.	hyperparathyroidism/ or primary hyperparathyroidism/
2.	((primary or asymptomatic or symptomatic or mild or familial or maternal) adj6 (HPT or hyperparathyroidis*)).ti,ab.
3.	PHPT.ti,ab.
4.	parathyroid tumor/ or parathyroid adenoma/ or parathyroid carcinoma/
5.	(parathyroid* adj3 (adenoma* or carcinoma* or hyperplasia* or neoplas* or tumo?r* or cancer* or metasta* or hypercalc?emi*)).ti,ab.
6.	or/1–5
7.	letter.pt. or letter/
8.	note.pt.
9.	editorial.pt.
10.	Case report/ or Case study/
11.	(letter or comment*).ti.
12.	or/7–11
13.	randomized controlled trial/ or random*.ti,ab.
14.	12 not 13
15.	animal/ not human/
16.	Nonhuman/
17.	exp Animal Experiment/
18.	exp Experimental animal/
19.	Animal model/
20.	exp Rodent/
21.	(rat or rats or mouse or mice).ti.
22.	or/14–21
23.	6 not 22
24.	limit 23 to English language

Cochrane Library (Wiley) search terms

#1.	MeSH descriptor: [Hyperparathyroidism] explode all trees
#2.	MeSH descriptor: [Hyperparathyroidism, Primary] explode all trees
#3.	((primary or asymptomatic or symptomatic or mild or familial or maternal) near/6 (HPT or hyperparathyroidis*)):ti,ab
#4.	PHPT:ti,ab
#5.	MeSH descriptor: [Parathyroid Neoplasms] explode all trees
#6.	(parathyroid* near/3 (adenoma* or carcinoma* or hyperplasia* or neoplas* or tumo?r* or cancer* or metasta* or hypercalc?emi*)):ti,ab
#7.	(or #1-#6)

CINAHL (EBSCO) search terms

S1.	(MH “Hyperparathyroidism”)
S2.	((primary or asymptomatic or symptomatic or mild or familial or maternal) n6 HPT) OR ((primary or asymptomatic or symptomatic or mild or familial or maternal) n6 hyperparathyroidis*)
S3.	PHPT
S4.	(MH “Parathyroid Neoplasms”)
S5.	(parathyroid* n3 (adenoma* or carcinoma* or hyperplasia* or neoplas* or tumor* or tumour* or cancer* or metasta* or hypercalcemi* or hypercalcaemi*))
S6.	S1 OR S2 OR S3 OR S4 OR S5
S7.	PT anecdote or PT audiovisual or PT bibliography or PT biography or PT book or PT book review or PT brief item or PT cartoon or PT commentary or PT computer program or PT editorial or PT games or PT glossary or PT historical material or PT interview or PT letter or PT listservs or PT masters thesis or PT obituary or PT pamphlet or PT pamphlet chapter or PT pictorial or PT poetry or PT proceedings or PT “questions and answers” or PT response or PT software or PT teaching materials or PT website
S8.	S6 NOT S7

PsycINFO (ProQuest) search terms

1.	su.Exact(“parathyroid neoplasms” OR “hyperparathyroidism” OR “hyperparathyroidism, primary”)
2.	PHPT
3.	((primary or asymptomatic or symptomatic or mild or familial or maternal) Near/6 (HPT or hyperparathyroidis*))
4.	(parathyroid* near/3 (adenoma* or carcinoma* or hyperplasia* or neoplas* or tumor* or tumour* or cancer* or metasta* or hypercalcaemi* or hypercalcemi*))
5.	1 or 2 or 3 or 4
6.	(su.exact.explode(“rodents”) or su.exact.explode(“mice”) or (su.exact(“animals”) not (su.exact(“human males”) or su.exact(“human females”))) or ti(rat or rats or mouse or mice))
7.	(s1 or s2 or s3 or s4) NOT (su.exact.explode(“rodents”) or su.exact.explode(“mice”) or (su.exact(“animals”) not (su.exact(“human males”) or su.exact(“human females”))) or ti(rat or rats or mouse or mice))

Table 16Database date parameters and filters used

Database

Dates searched

Search filter used

Medline

2002 – 06 August 2018

Exclusions

Health economics studies

Embase

2002 – 06 August 2018

Exclusions

Health economics studies

Centre for Research and Dissemination (CRD)

HTA - Inception – 06 August 2018

NHSEED - Inception to March 2015

None

Medline (Ovid) search terms

1.	hyperparathyroidism/ or hyperparathyroidism, primary/
2.	((primary or asymptomatic or symptomatic or mild or familial or maternal) adj6 (HPT or hyperparathyroidis*)).ti,ab.
3.	PHPT.ti,ab.
4.	Parathyroid Neoplasms/
5.	(parathyroid* adj3 (adenoma* or carcinoma* or hyperplasia* or neoplas* or tumo?r* or cancer* or metasta* or hypercalc?emi*)).ti,ab.
6.	or/1–5
7.	letter/
8.	editorial/
9.	news/
10.	exp historical article/
11.	Anecdotes as Topic/
12.	comment/
13.	case report/
14.	(letter or comment*).ti.
15.	or/7–14
16.	randomized controlled trial/ or random*.ti,ab.
17.	15 not 16
18.	animals/ not humans/
19.	exp Animals, Laboratory/
20.	exp Animal Experimentation/
21.	exp Models, Animal/
22.	exp Rodentia/
23.	(rat or rats or mouse or mice).ti.
24.	or/17–23
25.	6 not 24
26.	limit 25 to English language
27.	Economics/
28.	Value of life/
29.	exp “Costs and Cost Analysis”/
30.	exp Economics, Hospital/
31.	exp Economics, Medical/
32.	Economics, Nursing/
33.	Economics, Pharmaceutical/
34.	exp “Fees and Charges”/
35.	exp Budgets/
36.	budget*.ti,ab.
37.	cost*.ti.
38.	(economic* or pharmaco?economic*).ti.
39.	(price* or pricing*).ti,ab.
40.	(cost* adj2 (effective* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab.
41.	(financ* or fee or fees).ti,ab.
42.	(value adj2 (money or monetary)).ti,ab.
43.	or/27–42
44.	26 and 43

Embase (Ovid) search terms

1.	hyperparathyroidism/ or primary hyperparathyroidism/
2.	((primary or asymptomatic or symptomatic or mild or familial or maternal) adj6 (HPT or hyperparathyroidis*)).ti,ab.
3.	PHPT.ti,ab.
4.	parathyroid tumor/ or parathyroid adenoma/ or parathyroid carcinoma/
5.	(parathyroid* adj3 (adenoma* or carcinoma* or hyperplasia* or neoplas* or tumo?r* or cancer* or metasta* or hypercalc?emi*)).ti,ab.
6.	or/1–5
7.	letter.pt. or letter/
8.	note.pt.
9.	editorial.pt.
10.	Case report/ or Case study/
11.	(letter or comment*).ti.
12.	or/7–11
13.	randomized controlled trial/ or random*.ti,ab.
14.	12 not 13
15.	animal/ not human/
16.	Nonhuman/
17.	exp Animal Experiment/
18.	exp Experimental animal/
19.	Animal model/
20.	exp Rodent/
21.	(rat or rats or mouse or mice).ti.
22.	or/14–21
23.	6 not 22
24.	limit 23 to English language
25.	health economics/
26.	exp economic evaluation/
27.	exp health care cost/
28.	exp fee/
29.	budget/
30.	funding/
31.	budget*.ti,ab.
32.	cost*.ti.
33.	(economic* or pharmaco?economic*).ti.
34.	(price* or pricing*).ti,ab.
35.	(cost* adj2 (effective* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab.
36.	(financ* or fee or fees).ti,ab.
37.	(value adj2 (money or monetary)).ti,ab.
38.	or/25–37
39.	24 and 38

NHS EED and HTA (CRD) search terms

#1.	MeSH DESCRIPTOR Hyperparathyroidism EXPLODE ALL TREES
#2.	MeSH DESCRIPTOR Hyperparathyroidism, Primary EXPLODE ALL TREES
#3.	(((primary or asymptomatic or symptomatic or mild or familial or maternal) adj6 (HPT or hyperparathyroidis*)))
#4.	(PHPT)
#5.	MeSH DESCRIPTOR Parathyroid Neoplasms EXPLODE ALL TREES
#6.	((parathyroid* adj3 (adenoma* or carcinoma* or hyperplasia* or neoplas* or tumo?r* or cancer* or metasta* or hypercalc?emi*)))
#7.	#1 OR #2 OR #3 OR #4 OR #5 OR #6
#8.	* IN NHSEED
#9.	* IN HTA
#10.	#7 AND #8
#11.	#7 AND #9

Figure 1Flow chart of clinical study selection for the review of Monitoring strategies

Figure 2Flow chart of clinical study selection for the review of Monitoring long-term outcomes

Figure 3All-cause mortality

Figure 4Fatal CVD

Figure 5Non-fatal CVD

Figure 6Cerebrovascular disease

Figure 7Hypertension

Figure 8Renal failure

Figure 9Renal stones

$Figure 10. All fractures.$

Figure 10All fractures

$Figure 11. Osteoporotic fractures.$

Figure 11Osteoporotic fractures

Figure 12Renal stones

Figure 13Fractures (all)

Figure 14. Lumbar spine-BMD (gm/cm2) (mild PHPT versus healthy women).

Figure 14Lumbar spine-BMD (gm/cm²) (mild PHPT versus healthy women)

Figure 15. FN BMD (mg/cm2) (mild PHPT versus healthy women).

Figure 15FN BMD (mg/cm²) (mild PHPT versus healthy women)

Figure 16. FT BMD (mg/cm2) (mild PHPT versus healthy women).

Figure 16FT BMD (mg/cm²) (mild PHPT versus healthy women)

$Figure 17. Vertebral fractures (mild PHPT versus control).$

Figure 17Vertebral fractures (mild PHPT versus control)

$Figure 18. Vertebral fractures (non-mild PHPT versus healthy women).$

Figure 18Vertebral fractures (non-mild PHPT versus healthy women)

$Figure 19. Non-vertebral fractures (mild PHPT versus healthy women).$

Figure 19Non-vertebral fractures (mild PHPT versus healthy women)

$Figure 20. Non-vertebral fractures (non-mild PHPT versus healthy women).$

Figure 20Non-vertebral fractures (non-mild PHPT versus healthy women)

Figure 21. LS-BMD (mg/cm2) (non-mild PHPT versus healthy women).

Figure 21LS-BMD (mg/cm²) (non-mild PHPT versus healthy women)

Figure 22. Femur neck-BMD (mg/cm2) (non-mild PHPT versus healthy women).

Figure 22Femur neck-BMD (mg/cm²) (non-mild PHPT versus healthy women)

Figure 23. Total femur-BMD (mg/cm2) (non-mild PHPT versus healthy women).

Figure 23Total femur-BMD (mg/cm²) (non-mild PHPT versus healthy women)

Figure 24Mortality

Figure 25Fractures

Table 17Clinical evidence profile: PHPT cases versus matched comparators (adjusted for key confounders) – non-surgical

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Cases	Control	Relative (95% CI)	Absolute	Quality	Importance
All-cause mortality (follow-up median 2.9 years)
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	no serious imprecision	None	NR	NR	HR 1.64 (1.43 to 1.87)^b	-^c	⊕⊕◯◯ LOW	CRITICAL
Fatal CVD (follow-up median 2.9 years)
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	no serious imprecision	None	NR	NR	HR 1.64 (1.32 to 2.04)^b	-^c	⊕⊕◯◯ LOW	CRITICAL
Non-fatal CVD (follow-up median 2.9 years)
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	no serious imprecision	None	NR	NR	HR 2.48 (2.13 to 2.89)^b	-^c	⊕⊕◯◯ LOW	CRITICAL
Hypertension (follow-up median 2.9 years)
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	no serious imprecision	None	NR	NR	HR 2.60 (2.04 to 3.31)^b	-^c	⊕⊕◯◯ LOW	CRITICAL
Cerebrovascular disease (follow-up median 2.9 years)
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	no serious imprecision	None	NR	NR	HR 2.51 (1.95 to 3.22)^b	-^c	⊕⊕◯◯ LOW	CRITICAL
Renal failure (follow-up median 2.9 years)
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	no serious imprecision	None	NR	NR	HR 13.83 (10.41 to 18.37)^b	-^c	⊕⊕◯◯ LOW	CRITICAL
Renal stones (follow-up median 2.9 years)
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	no serious imprecision	None	NR	NR	HR 5.15 (2.69 to 9.83)^b	-^c	⊕⊕◯◯ LOW	CRITICAL
All fractures (follow-up median 2.9 years)
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	no serious imprecision	None	NR	NR	HR 1.75 (1.36 to 2.26)^b	-^c	⊕⊕◯◯ LOW	CRITICAL
Osteoporotic fractures (follow-up median 2.9 years)
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	no serious imprecision	None	NR	NR	HR 1.63 (1.22 to 2.19)^b	-^c	⊕⊕◯◯ LOW	CRITICAL

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias.

b: Confounding covariates considered were multiple deprivation index, history of bisphosphonates prescription, history of hospital admitted CVD, cerebrovascular disease, hypertension, renal failure, renal stones, psychiatric disease, fractures, cancer and diabetes.

c: Absolute effect cannot be calculated as adjusted control group event rate not reported.

*: All patients with diagnosed but untreated, mild asymptomatic PHPT.

Table 18Clinical evidence profile: PHPT versus control (no multivariate analysis) – Pre-operative

Quality assessment

No of patients

Effect

Quality

Importance

No of studies

Design

Risk of bias

Inconsistency

Indirectness

Imprecision

Other considerations

PHPT

Control

Relative (95% CI)

Absolute

Renal stones

observational studies

very serious^a

no serious inconsistency

no serious indirectness

no serious imprecision

None

19/271 (7%)

1.6%

RR 4.38 (1.94 to 9.88)

54 more per 1000 (from 15 more to 142 more)

⊕◯◯◯

VERY LOW

CRITICAL

a: Downgraded by 1 increment if the majority of studies were at high risk of bias, and downgraded by 2 increments if the majority of studies were at very high risk of bias.

Table 19Clinical evidence profile: PHPT versus control (no multivariate analysis) – Mixed pre-operative and post-operative (surgical and non-surgical patients)

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	PHPT	CONTROL	Relative (95% CI)	Absolute	Quality	Importance
Fracture
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	no serious imprecision	None	50/90 (55.6%)	41.4%	RR 0.96 (0.74 to 1.24)	17 fewer per 1000 (from 108 fewer to 99 more)	⊕◯◯◯ VERY LOW	CRITICAL
Lumbar spine BMD (mg/cm²) (mild PHPT vs healthy women) (Better indicated by higher values)
1	observational studies	Serious^c	no serious inconsistency	no serious indirectness	no serious imprecision	None	25	89	-	MD 77.1 higher (31.61 to 122.59 higher)	⊕◯◯◯ VERY LOW	CRITICAL
Femoral neck-BMD (mg/cm²) (mild PHPT vs healthy women) (Better indicated by higher values)
1	observational studies	Serious^c	no serious inconsistency	no serious indirectness	Serious^c	None	25	89	-	MD 18.4 higher (24.43 lower to 61.23 higher)	⊕◯◯◯ VERY LOW	CRITICAL
Total femur-BMD (mg/cm²) (mild PHPT vs healthy women) (Better indicated by higher values)
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	Serious^c	None	25	89	-	MD 21.2 higher (30.33 lower to 72.73 higher)	⊕◯◯◯ VERY LOW	CRITICAL
Vertebral fractures (mild PHPT vs control)
2	observational studies	Serious^a	very serious^b	no serious indirectness	no serious imprecision	None	14/199 (7%)	7.2%	RR 2.31 (1.26 to 4.21)	94 more per 1000 (from 19 more to 231 more)	⊕◯◯◯ VERY LOW	CRITICAL
Vertebral fractures (non-mild PHPT vs healthy women)
1	observational studies	Serious^c	no serious inconsistency	no serious indirectness	no serious imprecision	None	35/73 (47.9%)	9%	RR 5.33 (2.64 to 10.77)	390 more per 1000 (from 148 more to 879 more)	⊕◯◯◯ VERY LOW	CRITICAL
Non-vertebral fractures (mild PHPT vs healthy women)
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	very serious^c	None	0/25 (0%)	19.1%	Peto OR 0.22 (0.07 to 0.78)	190 fewer per 1000 (from 290 to 90 fewer)	⊕◯◯◯ VERY LOW	CRITICAL
Non-vertebral fractures (non-mild PHPT vs healthy women)
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	very serious^c	None	13/73 (17.8%)	19.1%	RR 0.93 (0.49 to 1.79)	13 fewer per 1000 (from 97 fewer to 151 more)	⊕◯◯◯ VERY LOW	CRITICAL
Lumbar spine-BMD (mg/cm²) (non-mild PHPT vs healthy women) (Better indicated by higher values)
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	no serious imprecision	None	73	89	-	MD 73.6 lower (116.15 to 31.05 lower)	⊕◯◯◯ VERY LOW	CRITICAL
Femoral neck-BMD (mg/cm²) (non-mild PHPT vs healthy women) (Better indicated by higher values)
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	no serious imprecision	None	73	89	-	MD 89.3 lower (121.96 to 56.64 lower)	⊕◯◯◯ VERY LOW	CRITICAL
Total femur-BMD (mg/cm²) (non-mild PHPT vs healthy women) (Better indicated by higher values)
1	observational studies	Serious^a	no serious inconsistency	no serious indirectness	no serious imprecision	None	73	89	-	MD 102.5 lower (140.13 to 64.87 lower)	⊕◯◯◯ VERY LOW	CRITICAL

a: Downgraded by 1 increment if the majority of studies were at high risk of bias, and downgraded by 2 increments if the majority of studies were at very high risk of bias.

b: Heterogeneity, I²=90%.

c: Downgraded by 1 increment if the confidence interval crossed 1 MID, and downgraded by 2 increments if the confidence interval crossed both MIDs.

Table 20Clinical evidence profile: PHPT versus control (no multivariate analysis) – strata post-operative

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	PHPT	Control	Relative (95% CI)	Absolute	Quality	Importance
Mortality
1	observational studies	very serious^a	no serious inconsistency	no serious indirectness	serious imprecision^b	None	34/334 (10.2%)	6.3%	RR 1.62 (0.96 to 2.73)	39 more per 1000 (from 3 fewer to 109 more)	⊕◯◯◯ VERY LOW	CRITICAL
Fracture
1	observational studies	very serious^a	no serious inconsistency	no serious indirectness	serious imprecision^b	None	22/46 (47.8%)	25%	RR 1.91 (1.06 to 3.47)	227 more (from 15 more to 618 more)	⊕◯◯◯ VERY LOW	CRITICAL

a: Downgraded by 1 increment if the majority of studies were at high risk of bias, and downgraded by 2 increments if the majority of studies were at very high risk of bias.

b: Downgraded by 1 increment if the confidence interval crossed 1 MID, and downgraded by 2 increments if the confidence interval crossed both MIDs

Figure 26Flow chart of health economic study selection for the guideline

* Non-relevant population, intervention, comparison, design or setting; non-English language

Table 21Studies excluded from the clinical review

Study	Exclusion reason
Abdulkader 2012¹	Conference abstract
Agarwal 2003²	Incorrect study design. Case report.
Ahsan 2017³	n=25. Excluding studies less than 50 participants.
Alvarez-Allende 2014⁴	Conference abstract
Amaral 2012⁵	Inappropriate comparison. Study compared the clinical and laboratory data between the normocalcaemic and mild hypercalcaemic patients.
Antonelli 2011⁶	Conference abstract
Babey 2010⁷	Conference abstract
Bai 2012⁸	Incorrect study design – literature review to explore association between primary hyperparathyroidism (PHPT) and acute or chronic pancreatitis.
Bailey 1974⁹	Incorrect study design
Bandeira 2009¹⁰	Inappropriate comparison. Study aims to determine the prevalence of cortical osteoporosis in patients with symptomatic PHPT and compare it with the asymptomatic form.
Bandeira 2016¹¹	Conference abstract
Bao 2013¹²	Conference abstract
Battersby 1969¹³	Incorrect study design – case report (of pancreatitis with PHPT)
Beard 1950¹⁴	Incorrect study design – case series
Bhadada 2018¹⁵	Non-comparative study
Bonzelaar 2016¹⁷	Conference abstract
Cannon 2010¹⁸	Inappropriate comparison. Study describes the surgical outcome and long term results of hypercalcaemic crisis patients after parathyroidectomy compared to non-crisis patients.
Carnaille 1998¹⁹	Incorrect comparison. Study looked at association of pancreatitis with PHPT.
Cassibba 2014²⁰	Incorrect study design – retrospective analysis of a case series
Corlew 1985²²	n=47. Excluding studies less than 50 participants.
Csupor 2005²³	Inappropriate comparison. Study aimed to assess the potential association between the surgically confirmed location of the disease and the presence of kidney stone.
Danzi 1974²⁵	Incorrect study design – case report.
Deaconson 1987²⁷	Inappropriate population group. Study reports the influence of parathyroidectomy on the natural history of nephrolithiasis and changes in the rates of new stone formation.
Diaz de la Guardia 2010³⁰	Not in English
Dimkovic 2002³¹	Inappropriate population. Study aimed to examine patients with kidney stone disease, elevated iPTH, but normal serum calcium level and normal urinary excretion of calcium.
Dolgin 1979³²	Study analysed the effect of routine screening of calcium and phosphate levels on the incidence and spectrum of PHPT. No useable outcomes.
Dumitrescu 2008³³	Incorrect population. Study aimed to determine the prevalence of contributors to secondary osteoporosis in patients presenting with a clinical vertebral or non-vertebral fracture.
Eufrazino 2013³⁴	Incorrect study design – cross-sectional study
Falko 1984³⁵	No comparison group. Study assessed clinical and biochemical spectrum of patients with PHPT who had surgery.
Heath 1991³⁷	Incorrect study design – case series
Hedback 2002³⁹	Incorrect study design – case series
Jha 2016⁴⁰	Non-comparative study
Kobayashi 1997⁴³	Non-comparative study
Larsson 1989⁴⁴	No useable outcomes
Lowe 2007⁴⁶	No comparison group. Study described the clinical course of 37 patients with normocalcaemic PHPT who were followed for up to 8 years.
Lueg 1982⁴⁷	Incorrect study design – case series
Marques 2011⁴⁸	Incorrect study design. Retrospective review of medical records to describe the characteristics of normocalcaemic primary hyperparathyroidism (NPHPT) in patients seen for osteoporosis evaluation.
Misiorowski 2012⁵⁰	No useable outcomes. The aim of the study was to evaluate the diagnostic power of the bone densitometry in diagnosis of PHPT.
Mollerup 1999⁵¹	Inappropriate comparison – before and after surgery. The study aimed to evaluate the risk of renal stone recurrence after successful surgical treatment of PHPT.
Nilsson 2005⁵⁵	Inappropriate population and outcomes. Study explored long-term effects of parathyroidectomy on cardiovascular functions in PHPT.
Pradeep 2008⁵⁶	Non-comparative study
Pratley 1973⁵⁷	Incorrect study design – case series.
Purnell 1971⁵⁸	Non-comparative study
Rajeevan 2014⁵⁹	Incorrect study design – series review
Rubin 2008⁶¹	Inappropriate comparison. Study compared PHPT patients who had undergone surgery vs those without surgery.
Scholz 1981⁶²	Non-comparative study
Siilin 2011⁶³	Study assessed BMD between PHPT and men without PHPT. No clinical outcomes.
Silverberg 1990⁶⁵	No comparison group
Silverberg 1995⁶⁴	Non-comparative study
Siminovitch 1980⁶⁶	Study assessed the effect of parathyroidectomy in patients with normocalcaemic calcium stones. No useable outcomes.
Soreide 1997⁶⁷	Inappropriate comparison. The study evaluated survival after surgical treatment for primary hyperparathyroidism.
Strewler 1995⁶⁸	Literature review. Screened for references.
Turchi 1962⁷⁰	Incorrect study design – case report.
Vanderwalde 2006⁷¹	Study aimed to determine the effect of parathyroidectomy on fracture risk in patients with PHPT. Inappropriate comparison-comparison groups were parathyroidectomy vs observation.
Vanderwalde 2009⁷²	Inappropriate comparison – comparison groups were parathyroidectomy vs observation
Vestergaard 2000⁷³	Inappropriate comparison
Vestergaard 2003⁷⁵	Study included in surgery review

Criteria for selecting high-priority research recommendations

PICO question	Population: People diagnosed with PHPT Intervention(s): Surgery, calcimimetics and bisphosphonates (or any combination, no treatment (surveillance/conservative management) Comparison: Compared to each other Outcome(s): Health-related quality of life, mortality, preservation of end organ function (bone mineral density, fractures, renal stones and renal function), persistent hypercalcaemia, cardiovascular events, adverse events, cancer incidence.
Importance to patients or the population	There is limited evidence on the long-term outcomes of the different management strategies. In order for people to make an informed choice regarding their treatment research is needed on this topic.
Relevance to NICE guidance	Limited recommendations were made on surgery, calcimimetics and bisphosphonates.
Relevance to the NHS	Altered guidance may have a financial impact on the NHS depending on whether the evidence either supports or does not support certain management strategies.
National priorities	None
Current evidence base	The majority of randomised evidence compared parathyroidectomy versus conservative management. The longest follow up period was 5 years. One very small study reported at 17 years but only a very limited number of outcomes were reported.
Equality	None
Study design	RCT
Feasibility	20-year follow up period to ensure all patient outcomes are captured.
Other comments	None
Importance	High: the research is essential to inform future updates of key recommendations in the guideline.

Evidence review for monitoring

Authors

1. Monitoring

1.1. Review question: What is the optimum type and frequency of monitoring for people with primary hyperparathyroidism (for example, pre-operative, postoperative, non-surgical)?

1.2. Introduction

1.2.1. PICO table

1.3. Review question: What are the long-term outcomes in people with primary hyperparathyroidism?

1.3.1. PICO table

1.4. Clinical evidence

1.4.1. Included studies

1.4.2. Excluded studies

1.4.3. Summary of clinical studies included in the evidence review

1.4.4. Quality assessment of clinical studies included in the evidence review

Narrative data

1. Clifton-Bligh 201521

2. Hedback 199238

Yearly death reduction

3. Melton 199249

Fracture risk (after diagnosis)

4. Ronni-Sivula60

Mortality

1.5. Economic evidence

1.5.1. Included studies

1.5.2. Excluded studies

1.5.3. Unit costs

1.6. Resource costs

1.7. Evidence statements

1.7.1. Clinical evidence statements

1.7.1.1. Monitoring

1.7.1.2. Monitoring long term outcomes

1.7.1.2.1. PHPT cases versus matched comparators (adjusted for key confounders) in non-surgical stratum

1.7.1.2.2. PHPT cases versus controls (no multivariate analysis) in pre-surgery stratum

1.7.1.2.3. PHPT cases versus controls (no multivariate analysis) in mixed pre and post-operative stratum

1.7.1.2.4. PHPT cases versus controls (no multivariate analysis) in post-operative stratum

1.7.2. Health economic evidence statements

1.8. The committee’s discussion of the evidence

1.8.1. Interpreting the evidence

1.8.1.1. The outcomes that matter most

1.8.1.2. The quality of the evidence

1.8.1.3. Benefits and harms

1.8.2. Cost effectiveness and resource use

1.8.3. Other factors the committee took into account

References

Appendices

Appendix A. Review protocols

Appendix B. Literature search strategies

B.1. Clinical search literature search strategy

B.2. Health Economics literature search strategy

Appendix C. Clinical evidence selection

Appendix D. Clinical evidence tables

Appendix E. Forest plots

E.1. PHPT cases versus matched comparators (adjusted for key confounders) Strata – Non-surgical

E.2. PHPT versus control (no multivariate analysis) Stratum-Pre-surgery

E.3. PHPT cases versus control (no multivariate analysis)-Strata – Pre-operative and post-operative (surgery and non-surgery patients)

E.4. PHPT cases versus control (no multivariate analysis) – strata post-operative

Appendix F. GRADE tables

Appendix G. Health economic evidence selection

Appendix H. Health economic evidence tables

Appendix I. Excluded studies

I.1. Excluded clinical studies

I.2. Excluded health economic studies

Appendix J. Research recommendations

J.1. Long-term consequences of management strategies for PHPT

Research question: What are the long-term outcomes of different management strategies for primary hyperparathyroidism? What strategies are most cost-effective?

Why this is important

Table 1PICO characteristics of review question

Table 2PICO characteristics of review question

Table 3Summary of studies included in the evidence review (comparative studies)

Table 4Clinical evidence summary: PHPT cases compared to matched comparators (adjusted for key confounders) (Stratum-Non-surgical)

Table 5Clinical evidence summary: PHPT compared to control (no multivariate analysis) (Stratum – Pre-surgery)

Table 6Clinical evidence summary: PHPT compared to control (no multivariate analysis) – Mixed strata – Pre and post-operative (surgery and non-surgery patients)

Table 7Clinical evidence summary (modified GRADE table): PHPT compared to control (no multivariate analysis) – Mixed strata-Pre and post-operative (surgery and surgery patients)

Table 8Clinical evidence summary (modified GRADE table): PHPT (observed) versus expected numbers in the general population (no multivariate analysis) – Mixed strata – Pre and post-operative (surgery and non-surgery patients)

Table 9Clinical evidence summary: PHPT patients compared to control (no multivariate analysis) – Stratum post-operative

Table 10UK costs of monitoring procedures

Table 11UK cost of clinical events associated with PHPT

Table 12Review protocol: Monitoring strategies

Table 13Monitoring long term outcomes protocol

Table 14Health economic review protocol

Table 15Database date parameters and filters used

1. Clifton-Bligh 2015²¹

2. Hedback 1992³⁸

3. Melton 1992⁴⁹

4. Ronni-Sivula⁶⁰

Figure 14Lumbar spine-BMD (gm/cm²) (mild PHPT versus healthy women)

Figure 15FN BMD (mg/cm²) (mild PHPT versus healthy women)

Figure 16FT BMD (mg/cm²) (mild PHPT versus healthy women)

Figure 21LS-BMD (mg/cm²) (non-mild PHPT versus healthy women)

Figure 22Femur neck-BMD (mg/cm²) (non-mild PHPT versus healthy women)

Figure 23Total femur-BMD (mg/cm²) (non-mild PHPT versus healthy women)