Hyperparathyroidism

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Hyperparathyroidism
Thyroid and parathyroid.
ICD-10 E21
ICD-9 252.0
DiseasesDB 20710
MeSH D006961

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omar Elshafei, MD[2] Anmol Pitliya, M.B.B.S. M.D.[3] Synonyms and keywords: Hyperparathyroid; parathyroid hormone levels raised; parathyroid related hypercalcemia; overactive parathyroid glands

Overview

Hyperparathyroidism is the excessive secretion of parathyroid hormone by one or more of the parathyroid glands. It is conventionally divided into three forms. Primary hyperparathyroidism arises from autonomous, clonally dysregulated parathyroid tissue and produces hypercalcemia with an elevated or inappropriately normal parathyroid hormone concentration. Secondary hyperparathyroidism is an appropriate compensatory response to a chronic hypocalcemic stimulus, most often chronic kidney disease or vitamin D deficiency, and is characterised by a raised parathyroid hormone level with a low or normal serum calcium. Tertiary hyperparathyroidism develops when long-standing secondary stimulation gives rise to autonomous parathyroid function, classically after kidney transplantation.

Primary hyperparathyroidism is among the most common endocrine disorders and predominantly affects postmenopausal women. Where routine biochemical testing is widespread, most patients are now identified incidentally and are asymptomatic or minimally symptomatic, in contrast to the historical presentation dominated by nephrolithiasis, osteitis fibrosa cystica, and fragility fracture. Classical target organ involvement affects the skeleton and the kidney; a range of neuropsychiatric, cardiovascular, and neuromuscular features has also been described, although a causal relationship for many of these remains unproven.

The diagnosis is biochemical rather than radiological. Concurrent measurement of albumin-adjusted serum calcium and intact parathyroid hormone establishes parathyroid-dependent hypercalcemia, after which familial hypocalciuric hypercalcemia and drug-related causes must be excluded. Imaging serves to localise abnormal glands before an operation and never to confirm or refute the diagnosis, so non-localising imaging does not exclude the disease and is not by itself a reason to withhold surgery.

Parathyroidectomy is the only definitive cure for primary and tertiary disease and achieves biochemical cure in the great majority of patients. For those who decline or are unfit for surgery, calcimimetic therapy lowers serum calcium without improving bone mineral density, while antiresorptive agents improve bone mineral density without lowering serum calcium, so the choice is directed by which target organ is of greater concern. Secondary hyperparathyroidism of chronic kidney disease is managed medically with phosphate control, vitamin D therapy, and calcimimetics, with surgery reserved for refractory disease. Parathyroid carcinoma is rare and is managed by en bloc resection.

Historical Perspective

  • The clinical profile of primary hyperparathyroidism changed profoundly across the four decades from 1980 to 2020. In regions where serum calcium and parathyroid hormone assays became widely available, the disease shifted from a symptomatic disorder with overt skeletal and renal involvement to a predominantly asymptomatic biochemical diagnosis.[1]
  • Symptomatic presentation still predominates in several Eastern regions, where a similar transition toward asymptomatic disease is anticipated as biochemical screening becomes more accessible. The population selected for testing, whether in general practice or in a tertiary referral centre, strongly influences reported epidemiological figures.[1]
  • International guidance has been revised at successive expert workshops. The guidelines published in 2014 were superseded by the Fifth International Workshop, whose summary statement and recommendations were issued in 2022 and included revised renal criteria for surgery.[2]
  • Pathological nomenclature was substantially revised in the 2022 World Health Organization classification of parathyroid tumours. The concept of "parathyroid hyperplasia" is no longer supported in the setting of primary hyperparathyroidism, because the affected glands are generally composed of multiple clonal neoplastic proliferations rather than a hyperplastic response, and the term is now applied principally to secondary hyperplasia caused by chronic renal failure. The designation "atypical parathyroid adenoma" was retired and replaced by "atypical parathyroid tumor", denoting a neoplasm of uncertain malignant potential.[3]

Classification

Classification by Mechanism

Type Mechanism Serum calcium Parathyroid hormone Typical setting
Primary Autonomous, clonally dysregulated overgrowth of one or more glands with reduced expression of the calcium-sensing receptor Elevated (or normal in the normocalcemic variant) Elevated or inappropriately normal Sporadic solitary neoplasm; multiglandular disease; hereditary syndromes
Secondary Appropriate compensatory hypersecretion driven by a chronic hypocalcemic or phosphate-retaining stimulus Low or normal Elevated Chronic kidney disease; vitamin D deficiency; malabsorption
Tertiary Acquired autonomy after prolonged secondary stimulation Elevated Elevated Long-standing dialysis; after kidney transplantation

Pathological Classification of Parathyroid Tumours (2022 WHO)

Entity Defining features
Parathyroid adenoma Benign clonal neoplasm; the usual cause of sporadic primary hyperparathyroidism
Multiglandular parathyroid disease (multiglandular multiple parathyroid adenomas) Regarded as germline susceptibility-driven multiglandular parathyroid neoplasia rather than hyperplasia; morphological and immunohistochemical clues may point to MEN1, CDKN1B, MAX, or CDC73 related disease
Atypical parathyroid tumor Neoplasm of uncertain malignant potential; replaces the former term "atypical parathyroid adenoma"
Parafibromin deficient parathyroid neoplasm Complete absence of nuclear parafibromin immunoreactivity; nucleolar loss is abnormal and warrants molecular testing
Parathyroid carcinoma Requires angioinvasion, lymphatic invasion, perineural (intraneural) invasion, local malignant invasion of adjacent structures, or documented metastatic disease; mitotic activity and Ki67 labelling index should be recorded
Parathyroid hyperplasia Term now reserved principally for secondary hyperplasia, most often caused by chronic renal failure

[3]

Classification by Clinical and Biochemical Phenotype

  • Symptomatic primary hyperparathyroidism: overt manifestations such as nephrolithiasis, fragility fracture, or osteitis fibrosa cystica.
  • Asymptomatic disease with evidence of target organ involvement: subclinical nephrolithiasis, nephrocalcinosis, reduced bone mineral density, or vertebral fracture identified on evaluation.
  • Asymptomatic disease without target organ involvement: no end organ damage after a complete standard evaluation. Separating these two asymptomatic phenotypes was proposed to clarify natural history and response to intervention, since both may occur with or without non-classical manifestations.[4]
  • Normocalcemic primary hyperparathyroidism: persistently normal albumin-adjusted and ionised calcium with an elevated parathyroid hormone level, diagnosed only after all secondary causes of a raised parathyroid hormone have been excluded. It is frequently diagnosed without fulfilment of rigorous criteria.[4] The entity is heterogeneous, and a proportion of cases revert spontaneously, revealing previously unrecognised secondary hyperparathyroidism, so caution is advised before recommending surgery.[5]

Pathophysiology

Normal Physiology

Parathyroid hormone occupies a pivotal position in calcium homeostasis. Small changes in extracellular ionised calcium are detected by parathyroid cells through the calcium-sensing receptor, which adjusts hormone secretion accordingly. Parathyroid hormone raises serum calcium by increasing osteoclastic bone resorption, enhancing renal tubular calcium reabsorption, promoting renal phosphate excretion, and stimulating synthesis of 1,25-dihydroxyvitamin D, which in turn increases intestinal calcium absorption.[1]

Primary Hyperparathyroidism

  • The central lesion is clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of the calcium-sensing receptor, so that secretion is no longer appropriately suppressed by a normal or elevated extracellular calcium concentration.[1]
  • Skeletal involvement reflects varying degrees of dysregulated bone remodelling, with a characteristic pattern of preferential cortical bone loss and relative preservation of cancellous bone at the lumbar spine.[1][6]
  • Intestinal calcium hyperabsorption combined with increased bone resorption raises the filtered calcium load which, with other metabolic factors, predisposes to calcium-containing kidney stones.[1]
  • A genetic basis is identifiable in roughly 10% of all cases. These occur within the multiple endocrine neoplasia syndromes (MEN1 to MEN4) or the hyperparathyroidism jaw tumour syndrome, or as non-syndromic isolated endocrinopathy such as familial isolated primary hyperparathyroidism and neonatal severe hyperparathyroidism.[1]
  • In parathyroid carcinoma, mutations of the CDC73 gene, which encodes the loss-of-function protein parafibromin, are the dominant genomic alteration and have been detected in up to 80% of sporadic cases. Other reported alterations involve mTOR, KMT2D, CDKN2C, THRAP3, PIK3CA, and EZH2, together with CCND1 amplification.[7][8]

Secondary and Tertiary Hyperparathyroidism

  • In chronic kidney disease, phosphate retention, reduced 1,25-dihydroxyvitamin D synthesis, and altered fibroblast growth factor 23 signalling combine to lower ionised calcium and drive sustained parathyroid stimulation and gland hyperplasia, the parathyroid component of chronic kidney disease mineral and bone disorder.[9][10]
  • Vitamin D deficiency with consequent secondary hyperparathyroidism is associated with accelerated deterioration of bone microarchitecture. In a prospective study of 826 older men followed with high-resolution peripheral quantitative computed tomography over 8 years, participants with 25-hydroxyvitamin D of 20 ng/mL or less showed more rapid loss of total and cortical bone mineral density at the distal radius than those above 30 ng/mL, and men with parathyroid hormone above the median of 44 pg/mL declined faster than those in the lowest quartile of 34 pg/mL or less.[11]
  • Prolonged secondary stimulation may culminate in autonomous secretion with frank hypercalcemia, defining tertiary hyperparathyroidism, which is most often recognised after successful kidney transplantation.[12]

Chronic lithium therapy alters the set point of the calcium-sensing receptor and is associated with a measurable rise in both calcium and parathyroid hormone. In a systematic review and meta-analysis of 385 studies, lithium treatment was associated with an increase in blood calcium of 0.09 mmol/L (95% CI 0.02 to 0.17, p = 0.009) and in parathyroid hormone of 7.32 pg/mL (3.42 to 11.23, p < 0.0001).[13]

Causes

Category Causes
Primary, sporadic Solitary parathyroid adenoma (the usual cause); multiglandular parathyroid disease; atypical parathyroid tumor; parathyroid carcinoma
Primary, hereditary Multiple endocrine neoplasia types 1 to 4; hyperparathyroidism jaw tumour syndrome (CDC73); familial isolated primary hyperparathyroidism; neonatal severe hyperparathyroidism
Secondary Chronic kidney disease; vitamin D deficiency; malabsorption syndromes; renal hypercalciuria; inadequate dietary calcium
Tertiary Long-standing secondary hyperparathyroidism, particularly on maintenance dialysis and after kidney transplantation
Drug-related Chronic lithium therapy

[1][3][9][13]

Differentiating Hyperparathyroidism from other Diseases

The first discriminating step is the parathyroid hormone level measured concurrently with an albumin-adjusted serum calcium. A suppressed parathyroid hormone level directs attention to non-parathyroid causes of hypercalcemia, whereas an elevated or inappropriately normal level indicates parathyroid-dependent disease, within which familial hypocalciuric hypercalcemia is the principal mimic.

Condition Serum calcium Parathyroid hormone Serum phosphate Urinary calcium Distinguishing features
Primary hyperparathyroidism Elevated Elevated or inappropriately normal Low or low-normal Normal or elevated Usually postmenopausal women; skeletal and renal target organ involvement; cure follows parathyroidectomy
Normocalcemic primary hyperparathyroidism Persistently normal (albumin-adjusted and ionised) Elevated Variable Variable Diagnosis of exclusion; requires multiple determinations and exclusion of all secondary causes; may revert spontaneously
Familial hypocalciuric hypercalcemia Elevated (usually mild, lifelong) Normal or mildly elevated Normal Low Inactivating CASR mutation; asymptomatic relatives; not cured by parathyroidectomy; distinguished by the calcium to creatinine clearance ratio and confirmed by CASR sequencing
Hypercalcemia of malignancy Elevated, often markedly and of rapid onset Suppressed Variable Elevated Advanced malignancy usually evident; parathyroid hormone related peptide mediated or osteolytic. Ectopic parathyroid hormone secretion by non-parathyroid tumours is a rare exception accounting for less than 1% of hypercalcemia of malignancy
Secondary hyperparathyroidism (chronic kidney disease) Low or normal Elevated Elevated Low Reduced glomerular filtration rate; hyperphosphatemia; low 1,25-dihydroxyvitamin D
Secondary hyperparathyroidism (vitamin D deficiency) Low or normal Elevated Low or normal Low Low 25-hydroxyvitamin D; parathyroid hormone falls after repletion
Tertiary hyperparathyroidism Elevated Elevated Variable Variable Antecedent chronic kidney disease or transplantation; autonomous secretion persisting after the stimulus is corrected
Lithium-associated hypercalcemia Mildly elevated Elevated or inappropriately normal Normal Normal or low Chronic lithium exposure; multiglandular involvement is common, favouring bilateral neck exploration if surgery is required
Thiazide-associated hypercalcemia Mildly elevated Normal or mildly elevated Normal Low Resolves or unmasks underlying primary disease after withdrawal and repeat testing
Granulomatous disease and vitamin D excess Elevated Suppressed Normal or elevated Elevated Elevated 1,25-dihydroxyvitamin D in granulomatous disease; elevated 25-hydroxyvitamin D in intoxication

[2][14][8][15]

Calcium to Creatinine Clearance Ratio

The calcium to creatinine clearance ratio is the standard initial discriminator between primary hyperparathyroidism and familial hypocalciuric hypercalcemia, but it does not separate the two conditions cleanly. In a study of 54 patients with clinically significant CASR mutations and 97 patients with histologically verified primary hyperparathyroidism, the ratio had an area under the receiver operating characteristic curve of 0.923 ± 0.021. The optimal cut-off for diagnosing familial hypocalciuric hypercalcemia was below 0.0115, yielding a diagnostic specificity of 0.88 and a sensitivity of 0.80. A more permissive cut-off below 0.020 captured 98% (53 of 54) of patients with familial hypocalciuric hypercalcemia but also included 35% (34 of 97) of those with primary hyperparathyroidism. A two-step procedure is therefore recommended, using the ratio with a cut-off below 0.020 as the first step and CASR gene analysis as the second.[16]

Epidemiology and Demographics

  • Primary hyperparathyroidism is typically a disease of postmenopausal women, but its measured prevalence and incidence vary globally and depend heavily on the availability of serum calcium and parathyroid hormone testing and on the population screened.[1]
  • In a descriptive epidemiological study of 3.5 million enrollees within an integrated health system, initial case finding identified 15,234 patients with chronic hypercalcemia, of whom 13,327 (87%) had primary hyperparathyroidism. Incidence fluctuated from 34 to 120 per 100,000 person-years (mean 66) among women and from 13 to 36 (mean 25) among men. Prevalence tripled during the study period, rising from 76 to 233 per 100,000 women and from 30 to 85 per 100,000 men.[17]
Incidence of primary hyperparathyroidism by age (per 100,000 person-years)
Age group Women Men
Younger than 50 years 12 to 24 for both sexes
50 to 59 years 80 36
70 to 79 years 196 95
Incidence by race (per 100,000 person-years)
Group Women Men
Black 92 46
White 81 29
Asian 52 28
Hispanic 49 17
Other 25 6

[17]

  • Parathyroid carcinoma accounts for less than 1% of all cases of sporadic primary hyperparathyroidism and for up to 15% of cases in the hereditary hyperparathyroidism jaw tumour syndrome.[7]
  • Among patients receiving chronic lithium therapy, hypercalcemia was detected in 26% of a cohort of bipolar patients, with an adjusted odds ratio of 13.45 (95% CI 3.09 to 58.55, p = 0.001) compared with bipolar patients not exposed to lithium.[15]

Risk Factors

  • Female sex and postmenopausal status.[1]
  • Advancing age, with a pronounced widening of the sex difference after the age of 50 years.[17]
  • Black race, which carried the highest incidence in a large racially mixed cohort.[17]
  • Chronic lithium therapy.[13][15]
  • Chronic kidney disease and maintenance dialysis, for secondary and tertiary disease.[9]
  • Vitamin D deficiency, for secondary disease.[11]
  • A germline predisposition or family history of hypercalcemia, parathyroid tumours, or associated syndromic tumours.[1][18]

Screening

  • Population-wide screening for primary hyperparathyroidism is not recommended. Most cases are identified through case finding, when serum calcium is measured as part of routine biochemical testing for another indication.[2]
  • Individuals with a confirmed MEN1 mutation and their first-degree relatives should undergo genetic testing followed by periodic clinical, biochemical, and radiological surveillance, since early tumour detection and intervention mitigate the morbidity and premature mortality of untreated disease.[18][19]
  • Because of the consistent finding of a high prevalence of hyperparathyroidism in lithium-treated patients, calcium concentrations should be checked before and during lithium treatment.[13]
  • In chronic kidney disease, serum calcium, phosphate, parathyroid hormone, and alkaline phosphatase activity should be monitored, with the frequency of testing guided by the stage of disease and by the presence and rate of progression of abnormalities.[9][20]
  • DNA testing has value in confirming a clinical diagnosis in a proband, for example by distinguishing primary hyperparathyroidism from familial hypocalciuric hypercalcemia, in mutation-specific carrier testing of relatives, and in ruling out phenocopies that would otherwise confound the diagnosis.[1]

Natural History, Complications and Prognosis

Natural History of Untreated Asymptomatic Disease

  • In a 10-year prospective study of 121 patients, of whom 101 (83%) were asymptomatic, 14 of 52 asymptomatic patients who did not undergo surgery (27%) showed progression of disease, defined as development of at least one new indication for parathyroidectomy. The remainder had no change in serum calcium concentration, urinary calcium excretion, or bone mineral density.[21]
  • With observation extended to 15 years, 37% of asymptomatic patients showed disease progression at some time point. Lumbar spine bone mineral density remained stable, but density fell at cortical sites even before 10 years, ultimately decreasing by 10 ± 3% at the femoral neck and by 35 ± 5% at the distal radius among the few patients observed for the full 15 years. Meeting surgical criteria at baseline did not predict who would progress.[6]

Effect of Surgery on Long-Term Outcomes

The randomised evidence and the large observational evidence point in different directions, and both are presented here.

  • In the Scandinavian Investigation of Primary Hyperparathyroidism, a randomised controlled trial of 191 patients with mild disease, parathyroidectomy produced a significant treatment effect on bone mineral density at all analysed compartments over 10 years, most clearly at the lumbar spine and femoral neck (p < 0.001), with mean changes in T-score from baseline greater in the surgical group by 0.41 for the 33% radius site to 0.58 for the lumbar spine. There was, however, no difference between groups in fracture frequency at 10 years, and the authors concluded that observation could be considered a safe option for many patients with mild disease from the standpoint of bone health.[22][23]
  • At 5 years within the same trial, five new clinically unrecognised vertebral fractures were identified, all of them in the observation group, a difference that did not reach statistical significance (p = 0.058).[24]
  • The mortality and morbidity endpoints of the same trial showed no benefit of surgery. After 10 years, 15 patients had died (8 in the parathyroidectomy group and 7 in the observation group). Over an extended observation period, 44 deaths occurred, evenly distributed between groups (24 and 20). A total of 101 morbidity events, comprising cardiovascular events, cerebrovascular events, cancer, peripheral fractures, and renal stones, were also similarly distributed (52 and 49), and 16 vertebral fractures occurred in 14 patients (7 in each group).[25]
  • Secondary analyses of the same trial detected no difference between groups in the development of renal function or in markers of vascular and systemic inflammation over 10 years.[26]
  • By contrast, a population-based longitudinal cohort study of 210,206 Medicare beneficiaries diagnosed with primary hyperparathyroidism found that parathyroidectomy was associated with a lower incidence of major adverse cardiovascular events (hazard ratio 0.92, 95% CI 0.90 to 0.94), of cardiovascular disease related hospitalisation (hazard ratio 0.89, 95% CI 0.87 to 0.91), and of cardiovascular hospitalisation associated mortality (hazard ratio 0.76, 95% CI 0.71 to 0.81) compared with non-operative management. At 10 years the adjusted absolute risk reductions were 1.7% (95% CI 1.3% to 2.1%), 2.5% (95% CI 2.1% to 2.9%), and 1.4% (95% CI 1.2% to 1.6%) respectively.[27]
  • These two bodies of evidence differ in design rather than in quality. The randomised trial has the stronger internal validity but was not powered for mortality, while the cohort study has far greater statistical power but remains subject to confounding by indication. Both should inform, and neither alone should determine, the decision in an individual patient.

Complications

  • Skeletal: reduced bone mineral density with preferential cortical loss, vertebral and peripheral fractures, and in advanced disease osteitis fibrosa cystica. Subclinical vertebral fractures are common in patients otherwise classified as asymptomatic.[4]
  • Renal: nephrolithiasis, nephrocalcinosis, and impaired glomerular filtration rate. Subclinical nephrolithiasis is common in asymptomatic disease.[4]
  • Non-classical: observational and cross-sectional studies continue to report associations with cardiovascular and neuropsychological abnormalities across disease phenotypes, but their causal relationship to hyperparathyroidism is uncertain, and randomised trials have not demonstrated a consistent long-term benefit of parathyroidectomy on these outcomes.[4]
  • Hypercalcemic crisis: severe symptomatic hypercalcemia with volume depletion, altered mental status, and renal impairment.
  • Post-operative hungry bone syndrome: rapid, profound, and prolonged hypocalcemia with hypophosphatemia and hypomagnesemia following parathyroidectomy. It is reported in 25% to 90% of patients with radiological evidence of hyperparathyroid bone disease compared with 0% to 6% of patients without skeletal involvement.[28]

Prognosis

  • Parathyroidectomy achieves biochemical cure in 96.1% of patients with asymptomatic primary hyperparathyroidism, a finding graded as high quality evidence.[29]
  • Following successful surgery, lumbar spine bone mineral density increased by 8 ± 2% after 1 year and 12 ± 3% after 10 years, and femoral neck bone mineral density by 6 ± 1% after 1 year and 14 ± 4% after 10 years, while radial density did not change significantly. Of 12 symptomatic patients with kidney stones who underwent parathyroidectomy, none had recurrent stones, whereas 6 of 8 who did not undergo surgery did.[21]
  • Post-operative complications are few and uncommon, occurring in under 3% of patients in centres performing more than 40 parathyroidectomies per year.[30]
  • For parathyroid carcinoma, reported 5-year and 10-year survival has ranged from 77% to 100% and from 49% to 91% respectively.[7] In a population-based cohort of 590 patients, 5-year and 10-year overall survival were 80.8% and 67.1%, and cancer-specific survival was 93.6% and 92.1%. Age, absence of surgery, and debulking surgery were consistent predictors of poorer survival.[31]

Diagnosis

History and Symptoms | Physical Examination | Laboratory Findings | EKG | X ray | CT | MRI | Ultrasound | Other Imaging Findings | Other Diagnostic Studies

Diagnostic Approach

 
 
Elevated albumin-adjusted serum calcium on more than one occasion, or an incidentally elevated parathyroid hormone level
 
 
 
 
 
 
 
 
 
 
 
 
Measure concurrently: albumin-adjusted and ionised calcium, intact parathyroid hormone, phosphate, 25-hydroxyvitamin D, creatinine and eGFR; review medications (lithium, thiazides)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parathyroid hormone suppressed → non-parathyroid hypercalcemia: malignancy, granulomatous disease, vitamin D excess, thyrotoxicosis
 
Parathyroid hormone elevated or inappropriately normal → parathyroid-dependent hypercalcemia
 
 
Parathyroid-dependent hypercalcemia confirmed
 
 
 
 
 
 
 
 
 
 
 
 
Calculate the calcium to creatinine clearance ratio and repeat the medication review
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ratio below 0.020 → proceed to CASR gene analysis to identify familial hypocalciuric hypercalcemia; note that 35% of patients with primary disease also fall below this threshold
 
Ratio above 0.020 → primary hyperparathyroidism; complete target organ assessment with DXA at three sites, vertebral imaging, and renal imaging

Laboratory Findings

  • Diagnosis rests on concurrent measurement of albumin-adjusted serum calcium and intact parathyroid hormone. Hypercalcemia with an elevated or inappropriately normal parathyroid hormone establishes parathyroid-dependent disease.[2]
  • Initial evaluation should include measurement of 25-hydroxyvitamin D, a 24-hour urine calcium, and dual-energy X-ray absorptiometry, with supplementation for vitamin D deficiency.[32]
  • For suspected normocalcemic disease, multiple albumin-adjusted and ionised calcium determinations should be obtained and all secondary causes of an elevated parathyroid hormone excluded before the diagnosis is accepted.[4][5]
  • Genetic testing should be considered in young patients, in multiglandular disease, and where there is a suggestive family history, to distinguish syndromic and familial forms and to exclude phenocopies.[1]

Imaging and Localisation

Imaging is performed to guide the operation and not to establish the diagnosis. Patients with non-localising imaging remain surgical candidates, and pre-operative parathyroid biopsy should be avoided.[32]

Modality Role
Cervical ultrasound First-line, widely available, operator dependent; also assesses concurrent thyroid disease
Dual-phase or dual-tracer parathyroid scintigraphy with SPECT/CT Established functional localisation; performance falls appreciably in multiglandular disease
Four-dimensional computed tomography Anatomical localisation, useful when ultrasound and scintigraphy are discordant or negative
Choline-labelled PET/CT and PET/MRI Higher-sensitivity functional imaging, particularly valuable in persistent or recurrent disease and in negative conventional imaging
Magnetic resonance imaging Adjunct where radiation exposure is a concern, including pregnancy

[33][32]

Intraoperative Parathyroid Hormone Monitoring

In a series of 617 patients of whom 603 (97.7%) were cured, the sensitivity of ultrasound was higher than that of sestamibi scintigraphy (78.2% versus 70%, p < 0.05), but both were inferior to intraoperative parathyroid hormone monitoring (98.6%, p < 0.05). Ultrasound and scintigraphy were markedly less sensitive in multigland disease than in single gland disease (55% versus 85% and 45.5% versus 77.5% respectively, p < 0.05), whereas intraoperative monitoring performed well in both situations (96.7% versus 98.8%, p > 0.05).[34]

Treatment

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Management Algorithm

 
 
Confirmed primary hyperparathyroidism
 
 
 
 
 
 
 
 
 
 
 
 
Assess guideline criteria for parathyroidectomy: symptoms, age, degree of hypercalcemia, skeletal involvement, and renal involvement
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptomatic, or asymptomatic meeting criteria → refer for parathyroidectomy, the only definitive cure
 
Criteria not met, or surgery declined or contraindicated → structured surveillance; add a calcimimetic if hypercalcemia requires control and an antiresorptive agent if bone mineral density is low

Initial Management

  • Confirm the biochemical diagnosis, exclude familial hypocalciuric hypercalcemia and drug-related causes, and complete the assessment of skeletal and renal target organs before deciding on management.[2]
  • Correct vitamin D deficiency. Vitamin D repletion in primary hyperparathyroidism is safe and beneficial: in a randomised placebo-controlled trial, daily supplementation with 70 μg (2800 IU) of cholecalciferol decreased parathyroid hormone by 17% before parathyroidectomy (p = 0.01), increased lumbar spine bone mineral density by 2.5% (p = 0.01), and decreased C-terminal β-CrossLaps by 22% (p < 0.005), while plasma creatinine and plasma and urinary calcium did not differ from placebo.[35]
  • Severe symptomatic hypercalcemia requires volume repletion with isotonic saline, withdrawal of contributing drugs, and an antiresorptive agent. The supporting randomised evidence for these agents derives from populations with hypercalcemia of malignancy rather than from primary hyperparathyroidism.
    • In a pooled analysis of two randomised controlled trials in 275 evaluable patients with corrected serum calcium of 3.00 mmol/L (12.0 mg/dL) or higher, complete response rates by day 10 were 88.4% with zoledronic acid 4 mg (p = 0.002), 86.7% with zoledronic acid 8 mg (p = 0.015), and 69.7% with pamidronate 90 mg. Median duration of complete response was 32, 43, and 18 days respectively.[36]
    • For hypercalcemia refractory to intravenous bisphosphonate, denosumab 120 mg subcutaneously lowered corrected serum calcium to 11.5 mg/dL (2.9 mmol/L) or below in 21 of 33 patients (64%) by day 10, with an estimated median response duration of 104 days.[37]

Medical Therapy

Medical therapy is indicated for patients with symptomatic or asymptomatic disease who are not candidates for, or who decline, parathyroid surgery. The two drug classes address different targets and are not interchangeable.

Agent Effect on serum calcium and parathyroid hormone Effect on bone mineral density
Cinacalcet Reduces both No change
Alendronate No significant change Increases at lumbar spine and hip
Denosumab No significant change Increases at lumbar spine, total hip, and femoral neck
Vitamin D repletion Reduces parathyroid hormone without raising calcium Increases at lumbar spine
  • Calcimimetics. In a randomised, double-blind, placebo-controlled study of 78 patients, 73% of those treated with cinacalcet achieved normocalcemia compared with 5% of placebo-treated patients (p < 0.001), while fasting predose parathyroid hormone decreased by 7.6% with cinacalcet and increased by 7.7% with placebo (p < 0.01). Bone mineral density was unchanged.[38] Normocalcemia was maintained for up to 5.5 years of continued treatment, again without significant effect on areal bone mineral density.[39]
  • Bisphosphonates. In a double-blind randomised placebo-controlled trial, alendronate 10 mg daily over 2 years was associated with a significant increase in lumbar spine bone mineral density of 6.85% from baseline (p < 0.001), an increase in total hip density of 4.01% at 12 months (p < 0.001) that remained stable thereafter, and a gain of 3.67% at the femoral neck at 24 months (p = 0.038). Density at the one-third radius did not change significantly, and serum calcium, parathyroid hormone, and urine calcium were unaltered.[40]
  • Denosumab. In the DENOCINA randomised, double-blind, placebo-controlled phase 3 trial, bone mineral density improved at 1 year compared with placebo in both denosumab-containing groups: lumbar spine 6.9% (95% CI 4.2 to 9.6) with denosumab and 5.4% (95% CI 2.7 to 8.1) with denosumab plus cinacalcet (p < 0.0001); total hip 4.1% (2.5 to 5.8) and 5.0% (3.0 to 6.9) respectively (p < 0.0001); femoral neck 3.8% (1.4 to 6.3, p = 0.0022) and 4.5% (1.9 to 7.9, p = 0.0008). Denosumab was effective irrespective of concomitant cinacalcet treatment.[41]
  • Pooled assessment. A systematic review and meta-analysis of randomised controlled trials, comprising 11 trials in 438 patients for medical therapy, concluded that alendronate, denosumab, vitamin D, and estrogen therapy all increased bone density, and that cinacalcet probably reduced serum calcium and parathyroid hormone levels. Cinacalcet and vitamin D may cause a small or no increase in overall adverse events; very-low-quality evidence raised the possibility of an increase in serious adverse events with alendronate and denosumab, and low-quality evidence indicated increased bleeding and mastalgia with estrogen therapy.[29]

Medical Therapy of Secondary Hyperparathyroidism in Chronic Kidney Disease

Management follows the KDIGO framework and combines control of hyperphosphatemia, maintenance of serum calcium, and treatment of the parathyroid hormone abnormality itself with calcitriol, vitamin D analogues, or calcimimetics.[9][20] The recommendations of the 2017 update were judged to remain largely consistent with the available evidence at a subsequent controversies conference, although a reframing of the field around chronic kidney disease associated osteoporosis and chronic kidney disease associated cardiovascular disease was proposed, with emphasis on personalised management.[10]

  • Cinacalcet and cardiovascular outcomes. In a randomised trial of 3883 patients on hemodialysis with moderate to severe secondary hyperparathyroidism (median intact parathyroid hormone 693 pg/mL, 10th to 90th percentile 363 to 1694), the primary composite endpoint of death, myocardial infarction, hospitalisation for unstable angina, heart failure, or a peripheral vascular event was reached in 938 of 1948 patients (48.2%) receiving cinacalcet and 952 of 1935 (49.2%) receiving placebo (relative hazard 0.93, 95% CI 0.85 to 1.02, p = 0.11). Hypocalcemia and gastrointestinal adverse events were significantly more frequent with cinacalcet.[42]
  • Etelcalcetide. In two parallel phase 3 randomised placebo-controlled trials in 1023 patients, a reduction of more than 30% in parathyroid hormone was achieved in 188 of 254 patients (74.0%) versus 21 of 254 (8.3%) in trial A, and 192 of 255 (75.3%) versus 25 of 260 (9.6%) in trial B (both p < 0.001). A parathyroid hormone level of 300 pg/mL or lower was achieved in 126 of 254 (49.6%) versus 13 of 254 (5.1%) and in 136 of 255 (53.3%) versus 12 of 260 (4.6%).[43] In a head-to-head randomised trial of 683 patients, intravenous etelcalcetide was non-inferior and then superior to oral cinacalcet: 232 of 340 patients (68.2%) versus 198 of 343 (57.7%) achieved a reduction in parathyroid hormone of more than 30% (p for non-inferiority < 0.001, p for superiority = 0.004), and 178 patients (52.4%) versus 138 (40.2%) achieved a reduction of more than 50% (p = 0.001).[44]

Procedural / Surgical Therapy

  • Parathyroidectomy is the treatment of choice for symptomatic primary hyperparathyroidism and for asymptomatic disease with evidence of target organ involvement.[30] Surgery is indicated for all symptomatic patients, should be considered for most asymptomatic patients, and is more cost-effective than observation or pharmacological therapy.[32]
  • Guideline criteria for operating on asymptomatic disease are built on four domains: age, the degree of hypercalcemia, skeletal involvement, and renal involvement. The renal criteria were revised in the 2022 guidelines, and the current thresholds within each domain should be taken from the guideline itself.[2]
  • Both focused, image-guided (minimally invasive) parathyroidectomy and bilateral neck exploration are appropriate operations that achieve high cure rates. Minimally invasive parathyroidectomy requires intraoperative parathyroid hormone monitoring under a reliable protocol and is not routinely recommended for known or suspected multigland disease.[32]
  • Surgeons performing a high volume of operations achieve better outcomes; complications occur in under 3% of patients in centres performing more than 40 parathyroidectomies per year.[32][30]
  • Defined operative approaches include selective parathyroidectomy, bilateral neck exploration for non-localised or multigland disease, subtotal parathyroidectomy, total parathyroidectomy with immediate or delayed autotransplantation, and transcervical thymectomy with extended en bloc parathyroidectomy for parathyroid carcinoma.[30]
  • Devascularised normal parathyroid tissue should be autotransplanted, ex vivo aspiration of resected tissue may be used to confirm parathyroid tissue intraoperatively, and clinically relevant thyroid disease should be assessed pre-operatively and addressed during the operation.[32]
  • En bloc resection of the parathyroid tumour is the initial mainstay of treatment for parathyroid carcinoma. Multiple surgical procedures may be required, with surgical morbidity taken into account, and medical management of hypercalcemia becomes pivotal once the tumour is no longer resectable.[7]

Long-Term Management

  • Patients should be observed post-operatively for haematoma, evaluated for hypocalcemia and its symptoms, and followed to assess for cure, which is defined as eucalcemia at more than 6 months. Calcium supplementation may be indicated post-operatively.[32]
  • Hungry bone syndrome should be anticipated in patients with severe disease, high pre-operative bone turnover, or radiological hyperparathyroid bone disease. Treatment aims to replenish the calcium deficit with high doses of calcium supplemented by high doses of active vitamin D metabolites, with correction of magnesium deficiency; resolution may take several months.[28] Among patients with advanced chronic kidney disease, a systematic review of nine studies, none of them randomised, found insufficient evidence to establish the effectiveness of any pre-operative intervention aimed at reducing post-operative hypocalcemia.[45]
  • Patients managed without surgery require structured surveillance of serum calcium, renal function, and bone mineral density, with imaging repeated if new symptoms or biochemical deterioration emerge, since roughly one quarter to one third of asymptomatic patients develop a new indication for surgery over 10 to 15 years and progression cannot be predicted from baseline criteria.[2][21][6]
  • Persistent or recurrent disease after an initial operation requires re-evaluation of the diagnosis, high-quality localisation imaging, and referral for reoperative surgery in an experienced centre.[30][14]

Special Populations

  • Pregnancy and lactation. The physiological changes in calcium metabolism during pregnancy and lactation modify both the presentation and the management of parathyroid disorders, and an interdisciplinary approach is recommended for pregnant and lactating women and their newborn children.[14][46]
  • Chronic kidney disease and dialysis. Management is directed by the KDIGO framework, with parathyroidectomy reserved for severe hyperparathyroidism refractory to medical or pharmacological therapy.[9][10]
  • After kidney transplantation. In a cohort study of adult kidney transplant recipients with tertiary hyperparathyroidism, patients treated with cinacalcet (n = 162) had a 77% higher risk of persistent hypercalcemia and a 73% higher risk of elevated parathyroid hormone than those who underwent parathyroidectomy (n = 338). Parathyroidectomy performed within 1 year of transplant (n = 132) was associated with a 57% lower risk of kidney stone formation than surgery performed 1 to 3 years after transplant (n = 57), and parathyroidectomy within 6 months of transplant (n = 55) showed a 62% lower risk of persistent hypercalcemia, hyperphosphatemia, and kidney stone formation than surgery performed between 6 months and 1 year (n = 77).[12]
  • Multiple endocrine neoplasia type 1. Primary hyperparathyroidism is the most frequent endocrinopathy in MEN1 and its surgical management is challenging because of multiglandular involvement and the risk of recurrence. Care should be delivered by multidisciplinary teams experienced in endocrine tumours, with genetic testing of patients and first-degree relatives and periodic surveillance of mutation carriers.[18][19]
  • Patients on chronic lithium therapy. Multiglandular involvement and recurrence are common, and bilateral neck exploration should be considered if surgery becomes necessary.[15]
  • Older adults. In this group the observational evidence of a cardiovascular benefit from parathyroidectomy is most directly relevant to surgical decision making, particularly for patients with a long life expectancy.[27]

Case Studies

Case #1

de:Hyperparathyreoidismus it:Iperparatiroidismo

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 Minisola S, Arnold A, Belaya Z, Brandi ML, Clarke BL, Hannan FM, Hofbauer LC, Insogna KL, Lacroix A, Liberman U, Palermo A, Pepe J, Rizzoli R, Wermers R, Thakker RV (2022). "Epidemiology, Pathophysiology, and Genetics of Primary Hyperparathyroidism". J Bone Miner Res. 37 (11): 2315–2329. doi:10.1002/jbmr.4665. PMID 36245271 Check |pmid= value (help).
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Bilezikian JP, Khan AA, Silverberg SJ, El-Hajj Fuleihan G, Marcocci C, Minisola S, Perrier N, Sitges-Serra A, Thakker RV, Guyatt G, Mannstadt M, Potts JT, Clarke BL, Brandi ML (2022). "Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop". J Bone Miner Res. 37 (11): 2293–2314. doi:10.1002/jbmr.4677. PMID 36245251 Check |pmid= value (help).
  3. ↑ 3.0 3.1 3.2 Erickson LA, Mete O, Juhlin CC, Perren A, Gill AJ (2022). "Overview of the 2022 WHO Classification of Parathyroid Tumors". Endocr Pathol. 33 (1): 64–89. doi:10.1007/s12022-022-09709-1. PMID 35175514 Check |pmid= value (help).
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 El-Hajj Fuleihan G, Chakhtoura M, Cipriani C, Eastell R, Karonova T, Liu JM, Minisola S, Mithal A, Moreira CA, Peacock M, Schini M, Silva B, Walker M, El Zein O, Marcocci C (2022). "Classical and Nonclassical Manifestations of Primary Hyperparathyroidism". J Bone Miner Res. 37 (11): 2330–2350. doi:10.1002/jbmr.4679. PMID 36245249 Check |pmid= value (help).
  5. ↑ 5.0 5.1 Zavatta G, Clarke BL (2020). "Normocalcemic Hyperparathyroidism: A Heterogeneous Disorder Often Misdiagnosed?". JBMR Plus. 4 (8): e10391. doi:10.1002/jbm4.10391. PMID 32803112 Check |pmid= value (help).
  6. ↑ 6.0 6.1 6.2 Rubin MR, Bilezikian JP, McMahon DJ, Jacobs T, Shane E, Siris E, Udesky J, Silverberg SJ (2008). "The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years". J Clin Endocrinol Metab. 93 (9): 3462–3470. doi:10.1210/jc.2007-1215. PMID 18544625.
  7. ↑ 7.0 7.1 7.2 7.3 Cetani F, Pardi E, Marcocci C (2018). "Parathyroid Carcinoma". Front Horm Res. 51: 63–76. doi:10.1159/000491039. PMID 30641523.
  8. ↑ 8.0 8.1 Cetani F, Pardi E, Marcocci C (2021). "Parathyroid Carcinoma and Ectopic Secretion of Parathyroid Hormone". Endocrinol Metab Clin North Am. 50 (4): 683–709. doi:10.1016/j.ecl.2021.07.001. PMID 34774241 Check |pmid= value (help).
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group (2017). "KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)". Kidney Int Suppl (2011). 7 (1): 1–59. doi:10.1016/j.kisu.2017.04.001. PMID 30675420.
  10. ↑ 10.0 10.1 10.2 Ketteler M, Evenepoel P, Holden RM, Isakova T, Jørgensen HS, Komaba H, Nickolas TL, Sinha S, Vervloet MG, Cheung M, King JM, Grams ME, Jadoul M, Moysés R (2025). "Chronic kidney disease-mineral and bone disorder: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference". Kidney Int. 107 (3): 405–423. doi:10.1016/j.kint.2024.11.013. PMID 39864017 Check |pmid= value (help). Vancouver style error: initials (help)
  11. ↑ 11.0 11.1 Bobillier A, Wagner P, Whittier DE, Ecochard R, Boyd SK, Chapurlat R, Szulc P (2022). "Association of Vitamin D and Parathyroid Hormone Status With the Aging-Related Decline of Bone Microarchitecture in Older Men: The Prospective Structure of Aging Men's Bones (STRAMBO) Study". J Bone Miner Res. 37 (10): 1903–1914. doi:10.1002/jbmr.4657. PMID 35880628 Check |pmid= value (help).
  12. ↑ 12.0 12.1 Zhao HH, Wilhelm SM (2024). "Timing of parathyroidectomy for tertiary hyperparathyroidism after kidney transplant". Surgery. 176 (6): 1617–1622. doi:10.1016/j.surg.2024.08.010. PMID 39299856 Check |pmid= value (help).
  13. ↑ 13.0 13.1 13.2 13.3 McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR (2012). "Lithium toxicity profile: a systematic review and meta-analysis". Lancet. 379 (9817): 721–728. doi:10.1016/S0140-6736(11)61516-X. PMID 22265699.
  14. ↑ 14.0 14.1 14.2 Bollerslev J, Rejnmark L, Zahn A, Heck A, Appelman-Dijkstra NM, Cardoso L, Hannan FM, Cetani F, Sikjaer T, Formenti AM, Björnsdottir S, Schalin-Jantti C, Belaya Z, Gibb FW, Lapauw B, Amrein K, Wicke C, Grasemann C, Krebs M, Ryhänen EM, Makay O, Minisola S, Gaujoux S, Bertocchio JP, Hassan-Smith ZK, Linglart A, Winter EM, Kollmann M, Zmierczak HG, Tsourdi E, Pilz S, Siggelkow H, Gittoes NJ, Marcocci C, Kamenicky P (2022). "European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders". Eur J Endocrinol. 186 (2): R33–R63. doi:10.1530/EJE-21-1044. PMID 34863037 Check |pmid= value (help).
  15. ↑ 15.0 15.1 15.2 15.3 Meehan AD, Udumyan R, Kardell M, Landén M, Järhult J, Wallin G (2018). "Lithium-Associated Hypercalcemia: Pathophysiology, Prevalence, Management". World J Surg. 42 (2): 415–424. doi:10.1007/s00268-017-4328-5. PMID 29260296.
  16. ↑ Christensen SE, Nissen PH, Vestergaard P, Heickendorff L, Brixen K, Mosekilde L (2008). "Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods". Clin Endocrinol (Oxf). 69 (5): 713–720. doi:10.1111/j.1365-2265.2008.03259.x. PMID 18410554.
  17. ↑ 17.0 17.1 17.2 17.3 Yeh MW, Ituarte PH, Zhou HC, Nishimoto S, Liu IL, Harari A, Haigh PI, Adams AL (2013). "Incidence and prevalence of primary hyperparathyroidism in a racially mixed population". J Clin Endocrinol Metab. 98 (3): 1122–1129. doi:10.1210/jc.2012-4022. PMID 23418315.
  18. ↑ 18.0 18.1 18.2 Brandi ML, Pieterman C, English KA, Lines KE, Shariq OA, Marini F, Cuny T, Lewis MA, Stratakis CA, Perrier ND, Waguespack SG, Castinetti F, Valk GD, Thakker RV (2025). "Multiple endocrine neoplasia type 1 (MEN1): recommendations and guidelines for best practice". Lancet Diabetes Endocrinol. 13 (8): 699–721. doi:10.1016/S2213-8587(25)00119-6. PMID 40523372 Check |pmid= value (help). Vancouver style error: initials (help)
  19. ↑ 19.0 19.1 Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML (2012). "Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1)". J Clin Endocrinol Metab. 97 (9): 2990–3011. doi:10.1210/jc.2012-1230. PMID 22723327.
  20. ↑ 20.0 20.1 Ketteler M, Block GA, Evenepoel P, Fukagawa M, Herzog CA, McCann L, Moe SM, Shroff R, Tonelli MA, Toussaint ND, Vervloet MG, Leonard MB (2017). "Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters". Kidney Int. 92 (1): 26–36. doi:10.1016/j.kint.2017.04.006. PMID 28646995.
  21. ↑ 21.0 21.1 21.2 Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP (1999). "A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery". N Engl J Med. 341 (17): 1249–1255. doi:10.1056/NEJM199910213411701. PMID 10528034.
  22. ↑ Lundstam K, Pretorius M, Bollerslev J, Godang K, Fagerland MW, Mollerup C, Fougner SL, Pernow Y, Aas T, Hessman O, Rosén T, Nordenström J, Jansson S, Hellström M, Heck A (2023). "Positive Effect of Parathyroidectomy Compared to Observation on BMD in a Randomized Controlled Trial of Mild Primary Hyperparathyroidism". J Bone Miner Res. 38 (3): 372–380. doi:10.1002/jbmr.4763. PMID 36593641 Check |pmid= value (help).
  23. ↑ Lundstam K, Heck A, Godang K, Mollerup C, Baranowski M, Pernow Y, Aas T, Hessman O, Rosén T, Nordenström J, Jansson S, Hellström M, Bollerslev J (2017). "Effect of Surgery Versus Observation: Skeletal 5-Year Outcomes in a Randomized Trial of Patients With Primary HPT (the SIPH Study)". J Bone Miner Res. 32 (9): 1907–1914. doi:10.1002/jbmr.3177. PMID 28543873.
  24. ↑ Lundstam K, Heck A, Mollerup C, Godang K, Baranowski M, Pernow Y, Varhaug JE, Hessman O, Rosén T, Nordenström J, Jansson S, Hellström M, Bollerslev J (2015). "Effects of parathyroidectomy versus observation on the development of vertebral fractures in mild primary hyperparathyroidism". J Clin Endocrinol Metab. 100 (4): 1359–1367. doi:10.1210/jc.2014-3441. PMID 25636048.
  25. ↑ Pretorius M, Lundstam K, Heck A, Fagerland MW, Godang K, Mollerup C, Fougner SL, Pernow Y, Aas T, Hessman O, Rosén T, Nordenström J, Jansson S, Hellström M, Bollerslev J (2022). "Mortality and Morbidity in Mild Primary Hyperparathyroidism: Results From a 10-Year Prospective Randomized Controlled Trial of Parathyroidectomy Versus Observation". Ann Intern Med. 175 (6): 812–819. doi:10.7326/M21-4416. PMID 35436153 Check |pmid= value (help).
  26. ↑ Heck A, Pretorius M, Lundstam K, Godang K, Hellström M, Ueland T, Bollerslev J (2024). "No effect of surgery on kidney and cardiovascular risk factors in mild primary hyperparathyroidism: secondary analyses from a 10-year randomized controlled trial". Eur J Endocrinol. 191 (3): 354–360. doi:10.1093/ejendo/lvae109. PMID 39189547 Check |pmid= value (help).
  27. ↑ 27.0 27.1 Seib CD, Meng T, Cisco RM, Suh I, Lin DT, Harris A, Trickey AW, Tamura MK, Kebebew E (2023). "Adverse Cardiovascular Outcomes Among Older Adults With Primary Hyperparathyroidism Treated With Parathyroidectomy Versus Nonoperative Management". Ann Surg. 278 (2): e302–e308. doi:10.1097/SLA.0000000000005691. PMID 36005546 Check |pmid= value (help). Vancouver style error: initials (help)
  28. ↑ 28.0 28.1 Witteveen JE, van Thiel S, Romijn JA, Hamdy NA (2013). "Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature". Eur J Endocrinol. 168 (3): R45–R53. doi:10.1530/EJE-12-0528. PMID 23152439.
  29. ↑ 29.0 29.1 Ye Z, Silverberg SJ, Sreekanta A, Tong K, Wang Y, Chang Y, Zhang M, Guyatt G, Tangamornsuksun W, Zhang Y, Manja V, Bakaa L, Couban RJ, Brandi ML, Clarke B, Khan AA, Mannstadt M, Bilezikian JP (2022). "The Efficacy and Safety of Medical and Surgical Therapy in Patients With Primary Hyperparathyroidism: A Systematic Review and Meta-Analysis of Randomized Controlled Trials". J Bone Miner Res. 37 (11): 2351–2372. doi:10.1002/jbmr.4685. PMID 36053960 Check |pmid= value (help).
  30. ↑ 30.0 30.1 30.2 30.3 30.4 Perrier N, Lang BH, Farias L, Poch LL, Sywak M, Almquist M, Vriens MR, Yeh MW, Shariq O, Duh QY, Yeh R, Vu T, LiVolsi V, Sitges-Serra A (2022). "Surgical Aspects of Primary Hyperparathyroidism". J Bone Miner Res. 37 (11): 2373–2390. doi:10.1002/jbmr.4689. PMID 36054175 Check |pmid= value (help). Vancouver style error: initials (help)
  31. ↑ Zhang K, Su A, Wang X, Zhao W, He L, Wei T, Li Z, Zhu J, Chen YW (2022). "Non-Linear Correlation Between Tumor Size and Survival Outcomes for Parathyroid Carcinoma: A SEER Population-Based Cohort Study". Front Endocrinol (Lausanne). 13: 882579. doi:10.3389/fendo.2022.882579. PMID 35846299 Check |pmid= value (help).
  32. ↑ 32.0 32.1 32.2 32.3 32.4 32.5 32.6 32.7 Wilhelm SM, Wang TS, Ruan DT, Lee JA, Asa SL, Duh QY, Doherty GM, Herrera MF, Pasieka JL, Perrier ND, Silverberg SJ, Solórzano CC, Sturgeon C, Tublin ME, Udelsman R, Carty SE (2016). "The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism". JAMA Surg. 151 (10): 959–968. doi:10.1001/jamasurg.2016.2310. PMID 27532368.
  33. ↑ Petranović Ovčariček P, Giovanella L, Carrió Gasset I, Hindié E, Huellner MW, Luster M, Piccardo A, Weber T, Talbot JN, Verburg FA (2021). "The EANM practice guidelines for parathyroid imaging". Eur J Nucl Med Mol Imaging. 48 (9): 2801–2822. doi:10.1007/s00259-021-05334-y. PMID 33839893 Check |pmid= value (help).
  34. ↑ Shawky M, Abdel Aziz T, Morley S, Beale T, Bomanji J, Soromani C, Lam F, Philips I, Matias M, Honour J, Smart J, Kurzawinski TR (2019). "Impact of intraoperative parathyroid hormone monitoring on the management of patients with primary hyperparathyroidism". Clin Endocrinol (Oxf). 90 (2): 277–284. doi:10.1111/cen.13882. PMID 30346646.
  35. ↑ Rolighed L, Rejnmark L, Sikjaer T, Heickendorff L, Vestergaard P, Mosekilde L, Christiansen P (2014). "Vitamin D treatment in primary hyperparathyroidism: a randomized placebo controlled trial". J Clin Endocrinol Metab. 99 (3): 1072–1080. doi:10.1210/jc.2013-3978. PMID 24423366.
  36. ↑ Major P, Lortholary A, Hon J, Abdi E, Mills G, Menssen HD, Yunus F, Bell R, Body J, Quebe-Fehling E, Seaman J (2001). "Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials". J Clin Oncol. 19 (2): 558–567. doi:10.1200/JCO.2001.19.2.558. PMID 11208851.
  37. ↑ Hu MI, Glezerman IG, Leboulleux S, Insogna K, Gucalp R, Misiorowski W, Yu B, Zorsky P, Tosi D, Bessudo A, Jaccard A, Tonini G, Ying W, Braun A, Jain RK (2014). "Denosumab for treatment of hypercalcemia of malignancy". J Clin Endocrinol Metab. 99 (9): 3144–3152. doi:10.1210/jc.2014-1001. PMID 24915117.
  38. ↑ Peacock M, Bilezikian JP, Klassen PS, Guo MD, Turner SA, Shoback D (2005). "Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism". J Clin Endocrinol Metab. 90 (1): 135–141. doi:10.1210/jc.2004-0842. PMID 15522938.
  39. ↑ Peacock M, Bolognese MA, Borofsky M, Scumpia S, Sterling LR, Cheng S, Shoback D (2009). "Cinacalcet treatment of primary hyperparathyroidism: biochemical and bone densitometric outcomes in a five-year study". J Clin Endocrinol Metab. 94 (12): 4860–4867. doi:10.1210/jc.2009-1472. PMID 19837909.
  40. ↑ Khan AA, Bilezikian JP, Kung AW, Ahmed MM, Dubois SJ, Ho AY, Schussheim D, Rubin MR, Shaikh AM, Silverberg SJ, Standish TI, Syed Z, Syed ZA (2004). "Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial". J Clin Endocrinol Metab. 89 (7): 3319–3325. doi:10.1210/jc.2003-030908. PMID 15240609.
  41. ↑ Leere JS, Karmisholt J, Robaczyk M, Lykkeboe S, Handberg A, Steinkohl E, Brøndum Frøkjær J, Vestergaard P (2020). "Denosumab and cinacalcet for primary hyperparathyroidism (DENOCINA): a randomised, double-blind, placebo-controlled, phase 3 trial". Lancet Diabetes Endocrinol. 8 (5): 407–417. doi:10.1016/S2213-8587(20)30063-2. PMID 32333877 Check |pmid= value (help).
  42. ↑ Chertow GM, Block GA, Correa-Rotter R, Drüeke TB, Floege J, Goodman WG, Herzog CA, Kubo Y, London GM, Mahaffey KW, Mix TC, Moe SM, Trotman ML, Wheeler DC, Parfrey PS (2012). "Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis". N Engl J Med. 367 (26): 2482–2494. doi:10.1056/NEJMoa1205624. PMID 23121374.
  43. ↑ Block GA, Bushinsky DA, Cunningham J, Drueke TB, Ketteler M, Kewalramani R, Martin KJ, Mix TC, Moe SM, Patel UD, Silver J, Spiegel DM, Sterling L, Walsh L, Chertow GM (2017). "Effect of Etelcalcetide vs Placebo on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: Two Randomized Clinical Trials". JAMA. 317 (2): 146–155. doi:10.1001/jama.2016.19456. PMID 28097355.
  44. ↑ Block GA, Bushinsky DA, Cheng S, Cunningham J, Dehmel B, Drueke TB, Ketteler M, Kewalramani R, Martin KJ, Moe SM, Patel UD, Silver J, Sun Y, Wang H, Chertow GM (2017). "Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: A Randomized Clinical Trial". JAMA. 317 (2): 156–164. doi:10.1001/jama.2016.19468. PMID 28097356.
  45. ↑ Landsberg A, Brockman NK, Sevinc E, McClurg C, Elliott MJ, Girard LP, James MT, Leung AA, Pannu NI, Pasternak M, Ronksley PE, Tonelli M, Harrison TG (2025). "Interventions to Reduce the Risk of Hypocalcemia After Parathyroidectomy for People With Advanced Chronic Kidney Disease: A Systematic Review". Can J Kidney Health Dis. 12: 20543581251358144. doi:10.1177/20543581251358144. PMID 40756446 Check |pmid= value (help).
  46. ↑ Vantyghem MC, Mirallié E, Al-Salameh A, Aubert S, Barraud S, Baud G, Ben Hamou A, Bertocchio JP, Borson-Chazot F, Bouillet B, Briet C, Buffet C, Caiazzo R, Cardot-Bauters C, Cariou B, Chabre O, Chanson P, Charbit J, Chéreau N, Chevalier B, Brunaud L, Kamenicky P (2025). "French expert consensus statement on diagnosis and management of primary hyperparathyroidism". Ann Endocrinol (Paris). 86 (5): 102449. doi:10.1016/j.ando.2025.102449. PMID 40889554 Check |pmid= value (help).

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