What is primary hyperparathyroidism?
Primary hyperparathyroidism (PHPT) is a disorder in which the parathyroid glands (four glands located near or on the thyroid in the neck) become enlarged and produce too much parathyroid hormone. The disease affects 1% of adults. Overproduction of parathyroid hormone disrupts calcium levels in the body, which can lead to various other health issues, such as osteoporosis (a health condition that weakens bones) and bone fractures, chronic kidney disease, cardiovascular disease, and cognitive dysfunction (decline in mental ability), along with a reduced health-related quality of life.
How is hyperparathyroidism treated?
Parathyroidectomy (surgical removal of the abnormal parathyroid gland or glands) is a well-established treatment option for people with PHPT. Parathyroidectomy is expected to cure PHPT and improve the unwanted complications of the disease.
What did we want to find out?
We wanted to know if parathyroidectomy was better than medical therapy or simple observation for curing mild PHPT with no symptoms and improving disease-associated complications such as osteoporosis, low bone density, kidney stones, kidney disease, cardiovascular disease (conditions affecting the heart and blood vessels) and cognitive dysfunction. We also wanted to determine if parathyroidectomy had any unwanted effects and whether it improved the health-related quality of life of people with PHPT.
What did we do?
We searched for randomised controlled trials (RCTs) that examined parathyroidectomy compared to non-surgical treatment options in adults with PHPT. We compared and summarised the results of the studies and rated our confidence in the evidence based on factors such as study methods and sizes.
What did we find?
We identified only eight RCTs, which enrolled 433 adults. In total, 164 adults had a parathyroidectomy, and 163 (99%) were cured after six to 24 months. Compared to medical therapy or simple observation, parathyroidectomy probably results in a large increase in cure rates. We have no information on the effect of parathyroidectomy on osteoporosis or cardiovascular disease. However, the included studies reported measures that are closely related to these conditions. Parathyroidectomy may have little or no effect on the bone mineral density of the lower spine and hip after one to two years, but we are very uncertain about the results. The evidence on the effect of parathyroidectomy on left ventricular ejection fraction (the percentage of blood leaving the left heart chamber at each heartbeat) was also very uncertain. Parathyroidectomy, compared to observation, may have little or no effect on unwanted severe events or the occurrence of hospitalisation for the correction of abnormally high calcium levels in the blood. The evidence is very uncertain about the impact of parathyroidectomy on death from any cause. Finally, three RCTs reported results for health-related quality of life. The findings differed widely, and we are uncertain about the effect of parathyroidectomy on health-related quality of life compared to observation.
What are the limitations of the evidence?
We are moderately confident in the evidence on cure rates because the reports of the RCTs did not contain enough information to prove their methods were reliable. However, we have little or very little confidence in the other results because the methods may have been unreliable, the studies did not measure complications of PHPT directly, and the studies enrolled few people.
How up-to-date is the evidence?
The evidence is up to date to 26 November 2021.
In accordance with the literature, our review findings suggest that parathyroidectomy, compared to simple observation or medical (etidronate) therapy, probably results in a large increase in cure rates of PHPT (with normalisation of serum calcium and parathyroid hormone levels to laboratory reference values). Parathyroidectomy, compared with observation, may have little or no effect on serious adverse events or hospitalisation for hypercalcaemia, and the evidence is very uncertain about the effect of parathyroidectomy on other short-term outcomes, such as BMD, all-cause mortality and quality of life. The high uncertainty of evidence limits the applicability of our findings to clinical practice; indeed, this systematic review provides no new insights with regard to treatment decisions for people with (asymptomatic) PHPT. In addition, the methodological limitations of the included studies, and the characteristics of the study populations (mainly comprising white women with asymptomatic PHPT), warrant caution when extrapolating the results to other populations with PHPT.
Large-scale multi-national, multi-ethnic and long-term RCTs are needed to explore the potential short- and long-term benefits of parathyroidectomy compared to non-surgical treatment options with regard to osteoporosis or osteopenia, urolithiasis, hospitalisation for acute kidney injury, cardiovascular disease and quality of life.
Primary hyperparathyroidism (PHPT), a disorder in which the parathyroid glands produce excessive amounts of parathyroid hormone, is most common in older adults and postmenopausal women. While most people with PHPT are asymptomatic at diagnosis, symptomatic disease can lead to hypercalcaemia, osteoporosis, renal stones, cardiovascular abnormalities and reduced quality of life. Surgical removal of abnormal parathyroid tissue (parathyroidectomy) is the only established treatment for adults with symptomatic PHPT to prevent exacerbation of symptoms and to be cured of PHPT. However, the benefits and risks of parathyroidectomy compared to simple observation or medical therapy for asymptomatic and mild PHPT are not well established.
To evaluate the benefits and harms of parathyroidectomy in adults with PHPT compared to simple observation or medical therapy.
We searched CENTRAL, MEDLINE, LILACS, ClinicalTrials.gov and WHO ICTRP from their date of inception until 26 November 2021. We applied no language restrictions.
We included randomised controlled trials (RCTs) comparing parathyroidectomy with simple observation or medical therapy for the treatment of adults with PHPT.
We used standard Cochrane methods. Our primary outcomes were 1. cure of PHPT, 2. morbidity related to PHPT and 3. serious adverse events. Our secondary outcomes were 1. all-cause mortality, 2. health-related quality of life and 3. hospitalisation for hypercalcaemia, acute renal impairment or pancreatitis. We used GRADE to assess the certainty of the evidence for each outcome.
We identified eight eligible RCTs that included 447 adults with (mostly asymptomatic) PHPT; 223 participants were randomised to parathyroidectomy. Follow-up duration varied from six months to 24 months.
Of the 223 participants (37 men) randomised to surgery, 164 were included in the analyses, of whom 163 were cured at six to 24 months (overall cure rate 99%). Parathyroidectomy compared to observation probably results in a large increase in cure rate at six to 24 months follow-up: 163/164 participants (99.4%) in the parathyroidectomy group and 0/169 participants in the observation or medical therapy group were cured of their PHPT (8 studies, 333 participants; moderate certainty).
No studies explicitly reported intervention effects on morbidities related to PHPT, such as osteoporosis, osteopenia, kidney dysfunction, urolithiasis, cognitive dysfunction or cardiovascular disease, although some studies reported surrogate outcomes for osteoporosis and cardiovascular disease. A post-hoc analysis revealed that parathyroidectomy, compared to observation or medical therapy, may have little or no effect after one to two years on bone mineral density (BMD) at the lumbar spine (mean difference (MD) 0.03 g/cm2,95% CI −0.05 to 0.12; 5 studies, 287 participants; very low certainty). Similarly, compared to observation, parathyroidectomy may have little or no effect on femoral neck BMD after one to two years (MD −0.01 g/cm2, 95% CI −0.13 to 0.11; 3 studies, 216 participants; very low certainty). However, the evidence is very uncertain for both BMD outcomes. Furthermore, the evidence is very uncertain about the effect of parathyroidectomy on improving left ventricular ejection fraction (MD −2.38%, 95% CI −4.77 to 0.01; 3 studies, 121 participants; very low certainty).
Four studies reported serious adverse events. Three of these reported zero events in both the intervention and control groups; consequently, we were unable to include data from these three studies in the pooled analysis. The evidence suggests that parathyroidectomy compared to observation may have little or no effect on serious adverse events (RR 3.35, 95% CI 0.14 to 78.60; 4 studies, 168 participants; low certainty).
Only two studies reported all-cause mortality. One study could not be included in the pooled analysis as zero events were observed in both the intervention and control groups. Parathyroidectomy compared to observation may have little or no effect on all-cause mortality, but the evidence is very uncertain (RR 2.11, 95% CI 0.20 to 22.60; 2 studies, 133 participants; very low certainty).
Three studies measured health-related quality of life using the 36-Item Short Form Health Survey (SF-36) and reported inconsistent differences in scores for different domains of the questionnaire between parathyroidectomy and observation.
Six studies reported hospitalisations for the correction of hypercalcaemia. Two studies reported zero events in both the intervention and control groups and could not be included in the pooled analysis. Parathyroidectomy, compared to observation, may have little or no effect on hospitalisation for hypercalcaemia (RR 0.91, 95% CI 0.20 to 4.25; 6 studies, 287 participants; low certainty). There were no reported hospitalisations for renal impairment or pancreatitis.