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Parathyroid hormone (PTH) is an 84-amino acid (aa) polypeptide hormone with a molecular weight of approximately 9,500 Daltons. It is synthesized as a 115-aa preprohormone in the chief cells of the parathyroid glands. In the endoplasmic reticulum, 25 aa are cleaved to produce a prohormone, and in the Golgi apparatus, an additional 6 aa are removed to generate the mature 84-aa PTH, which is then stored in secretory granules (). PTH consists of an amino-terminal fragment comprising residues 1–34 (which confers biological activity) and a carboxy-terminal fragment comprising residues 50–84. The PTH gene is located on the short arm of chromosome 11 (11p15). Once stored in secretory granules, PTH can follow two fates: it is either secreted into the bloodstream in response to calcium concentrations or degraded by calcium-sensitive proteases into carboxy-terminal fragments (C-terminal fragments). After secretion into the circulation, PTH has a half-life of approximately 2 to 5 minutes ().

The synthesis and secretion of PTH are regulated by the calcium-sensing receptor (CaSR), which detects minimal changes in plasma calcium concentrations. CaSR is a seven-transmembrane domain G protein–coupled receptor (GPCR) expressed on the surface of parathyroid chief cells and renal tubular cells (). When calcium binds to the extracellular domain of CaSR, a conformational change is induced, which facilitates the recruitment of heterotrimeric G protein subunits: Gαq11, Gαq, and to a lesser extent, Gαi. The Gαq proteins activate phospholipase C, leading to mobilization of intracellular calcium stores and an increase in cytosolic calcium, whereas Gαi inhibits adenylate cyclase activity, resulting in decreased cyclic AMP (cAMP) synthesis. These signaling changes, through mechanisms not yet fully understood, rapidly inhibit (within minutes) both the secretion of preformed PTH and its synthesis. Transcription of the PTH gene is suppressed in states of hypercalcemia and it is also suppressed by 1,25-dihydroxyvitamin D (). In contrast, an acute drop in circulating calcium levels triggers PTH secretion within seconds. Additionally, elevated phosphate concentrations also stimulate PTH secretion. The relationship between serum calcium and PTH follows a sigmoidal curve, whereby a small decrease in serum calcium results in a large increase in PTH secretion. This tight regulation helps maintain calcium levels within the physiological range of 8.5 to 10.3 mg/dL, which is very important, since calcium plays a critical role in normal cellular function, membrane stability, intracellular signaling, endocrine and exocrine secretory processes, blood coagulation, platelet adhesion, neuromuscular activity, the electrophysiological function of the heart and smooth muscle, and in maintaining bone structure ().

PTH exerts its biological effects by binding to its receptor, PTHR1, which is expressed in osteoblasts and renal tubular cells. This receptor is recognized by both PTH and PTHrP (parathyroid hormone-related protein). PTHR1 activates multiple intracellular signaling pathways; however, its calciotropic actions are primarily mediated through activation and coupling of the Gαs subunit of the G protein, which stimulates adenylate cyclase, increasing cyclic AMP (cAMP) production. This in turn activates protein kinase A (PKA). Under conditions of hypocalcemia, PTH acts directly on the kidney and bone, and indirectly on the intestine, to restore serum calcium levels (). In the kidney, PTH promotes calcium reabsorption and phosphate excretion in the urine, increases the production of 1,25-dihydroxyvitamin D (1,25(OH) 2 D), and interferes with sodium and water reabsorption in the proximal tubule. Approximately 10,000 mg of calcium are filtered daily by the glomeruli, with only 100–200 mg excreted in the urine, representing 1–2% of the filtered load. However, in PHPT, the filtered calcium load is increased due to enhanced bone resorption stimulated by PTH and elevated intestinal calcium absorption mediated by 1,25-dihydroxyvitamin D ().

In the proximal tubule (PT), most solutes and water are reabsorbed. Calcium reabsorption in this segment is closely linked to sodium (Na + ) reabsorption, which is primarily mediated by the sodium/hydrogen exchanger isoform 3 (NHE3) (). However, other sodium-dependent cotransporters also contribute, including the sodium-phosphate (NaPi), sodium-glucose (SGLT), and sodium–amino acid cotransporters. In the early segments of the PT, sodium, water, glucose, amino acids, and bicarbonate are reabsorbed, leading to an increase in luminal chloride relative to plasma and the development of negative luminal potential. This environment promotes passive paracellular chloride reabsorption, likely through claudin-10a (). The reabsorption of chloride establishes a positive luminal electrochemical gradient that facilitates calcium reabsorption in the more distal segments of the PT via claudin-2 (, ). In summary, approximately 65% of filtered calcium is reabsorbed in the PT through passive paracellular diffusion, driven by favorable electrochemical and concentration gradients—the latter being the dominant force (, , ). Additionally, calcium reabsorption in this segment is aided by solute drag, which occurs as water is reabsorbed (). Water reabsorption in the PT is triggered by solute reabsorption, particularly sodium and chloride.

In the PT, PTH exerts at least three actions, none of which are directly related to calcium reabsorption: 1) PTH stimulates 1α-hydroxylase, which converts 25-hydroxyvitamin D (25(OH)D) into its active form, 1,25-dihydroxyvitamin D (1,25(OH) 2 D); 2) PTH downregulates the NaPi IIa and IIc cotransporters through phosphorylation of the sodium–hydrogen exchanger regulatory factor 1 (NHERF1). NHERF1 acts as a scaffolding protein linking NaPi IIa to the actin cytoskeleton, enabling its retention at the apical membrane. When NHERF1 is phosphorylated, NaPi IIa is internalized, endocytosed, and degraded in lysosomes, resulting in reduced phosphate reabsorption, increased phosphaturia, and potentially hypophosphatemia; 3) PTH inhibits NHE3, which normally reabsorbs Na + and secretes H + , establishing a gradient for water reabsorption. Inhibition of NHE3 leads to decreased sodium and water reabsorption and promotes urinary alkalinization. This reduction in water reabsorption ultimately lowers calcium reabsorption in the PT, an effect opposite to that observed in the loop of Henle, where PTH enhances calcium reabsorption (). See .

In the thick ascending limb (TAL) of the loop of Henle, approximately 25% of filtered calcium and 70% of magnesium are reabsorbed via the paracellular pathway, a process promoted by parathyroid hormone (PTH) and inhibited by the calcium-sensing receptor (CaSR) (). Calcium reabsorption depends on a positive luminal voltage generated by ROMK (a potassium channel that allows K + efflux into the lumen) and claudin-10b, a paracellular tight junction protein that enables bidirectional sodium transport. In the initial segment of the TAL (outer medulla), sodium is reabsorbed from the lumen into the interstitial space through claudin-10b. However, in the more distal segment (cortex), sodium moves from the interstitium into the lumen, also through claudin-10b. This movement contributes to the generation of a highly positive luminal transepithelial voltage (~30 mV), which facilitates paracellular calcium and magnesium reabsorption via claudins 16 and 19 (). Conversely, claudin-14 inhibits the expression of claudins 16 and 19 (,). PTH, via cAMP generation, stimulates the activity of both ROMK and NKCC2 (the Na + /K + /2Cl − cotransporter). NKCC2 facilitates the reabsorption of sodium, potassium, and chloride, while ROMK promotes K + efflux into the lumen, establishing the positive voltage required for calcium and magnesium reabsorption through claudins 16 and 19. PTH also enhances the translocation of claudin-14 from the membrane to the cytosol, thus favoring the membrane expression of claudins 16 and 19. In contrast, CaSR promotes claudin-14 expression and inhibits the activity of ROMK and NKCC2 (). Most chloride is reabsorbed via the transcellular route, while sodium is reabsorbed approximately equally through transcellular and paracellular pathways (). See .

In the distal tubule, approximately 8% of the filtered calcium load is reabsorbed through three transcellular steps: 1) Calcium entry through the apical membrane via the transient receptor potential vanilloid type 5 (TRPV5) channel, 2) Intracellular transport bound to the calcium-binding protein calbindin-D28k, and 3) Extrusion across the basolateral membrane into the interstitial space through the plasma membrane Ca 2+ -ATPase (PMCA1b) and the sodium-calcium exchanger (NCX) located on the basolateral side of epithelial cells (). See .

In bone, PTH stimulates bone resorption and increases plasma concentrations of calcium and phosphate. However, osteoclasts do not express receptors for PTH; instead, PTH binds to the PTHR1 receptor on osteoblasts to promote the expression of RANKL (Receptor Activator of Nuclear Factor κB Ligand) and decreases the secretion of osteoprotegerin, a decoy receptor that binds RANKL and prevents its interaction with RANK. By upregulating RANKL, PTH facilitates the binding of RANKL to RANK on the surface of osteoclast precursors, triggering their differentiation into mature osteoclasts capable of resorbing bone by dissolving hydroxyapatite. The degradation products: calcium, phosphate, and alkaline phosphatase are taken up by osteoclasts via endocytosis and subsequently released into circulation ().

In the intestine, PTH does not exert a direct effect on calcium metabolism. However, 1,25-dihydroxyvitamin D significantly enhances the intestinal absorption of dietary calcium and phosphate. Daily calcium intake is approximately 1000 mg, of which 25–35% is absorbed. This absorption occurs via two mechanisms: a saturable transcellular transport pathway located primarily in the duodenum, and a no saturable paracellular pathway occurring throughout the small and large intestines (, ).

Calciotropic hormone production and calcium balance decrease with aging. On the other hand, the skeletal mass increases until growth is completed and then decreases at a constant rate during the rest of life. Parathyroid hormone, vitamin D and calcium can contribute to these changes.

Serum concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)D] decrease with age and are associated with reduction in vertebral mineral content and a rise in serum concentrations of intact PTH. The mechanisms behind these changes are multifactorial (). Skin absorption and vitamin D synthesis decrease with age, by an estimated 13% per decade. Reduced kidney conversion of 25(OH)D to 1,25(OH)D, along with partial resistance to the effects of 1,25(OH)D on the intestinal calcium absorption, also contribute to the decline in vitamin D activity in the elderly.

As we get older, the serum concentration of intact PTH increases (-) and correlates with a rise of urinary cAMP and the decrease in tubular reabsorption of phosphorus (P). The estimated PTH increase is 5 to 6% per decade, from 20 to 98 years of age () without gender difference. This change has been explained by the decreased efficiency in absorption, metabolism and action of vitamin D in the elderly which potentially lead to a decrease in ionized calcium and by renal retention of phosphate (). However, increased PTH levels with age have been shown to be independent of serum concentrations of 25(OH)D, ionized calcium, and serum P concentrations (); neither seems to depend on the decrease in glomerular filtration. An increase in serum PTH concentrations can affect the assessment of parathyroid function in older adults, making it an important factor to consider.

Multiple factors, like reduced calcium intake, lower intestinal absorption, or diminished action and serum levels of 1,25(OH)D, often result in a negative calcium balance in the elderly (-, ). Hyponatremia, which is more common in older adults, also plays a role in increasing renal calcium excretion. The increase in serum P concentrations, albeit within the normal range in older individuals without kidney disease, is associated with a higher risk of fractures (). Whether the fracture risk is related to the P or to the regulatory hormones of phosphate such as fibroblast growth factor 23 (FGF-23) produced by osteocytes or its co-factor α-Klotho, PTH, or 1,25(OH)D3, is unclear (). FGF-23 inhibits P reabsorption and renal production of 1,25(OH)D, from early stages of chronic renal failure (); the consequences of this phenomenon on the bones of the elderly are unknown.

Primary hyperparathyroidism (PHPT) is a disorder characterized by the autonomous secretion of parathyroid hormone (PTH) from one or more parathyroid glands, resulting in hypercalcemia or high-normal serum calcium levels ().

PHPT is a common endocrine disorder that occurs most frequently in individuals over the age of 50. Its incidence and prevalence are difficult to determine due to a large number of undiagnosed asymptomatic cases (, ); however, in recent decades, both the incidence and prevalence have increased, largely due to the incorporation of serum calcium measurements in routine medical checkups (–). The prevalence of PHPT varies by sex, age, and population group (, ), with the most influential factor being the availability of serum calcium and PTH testing (). PHPT is more common in women than in men, with a ratio of 3:1; however, among individuals under the age of 45, the sex distribution is equal (, ). The highest incidence is observed in Black individuals, followed by White, Asian, and Hispanic populations.

In 2010, the prevalence in the United States was 233 per 100,000 women and 85 per 100,000 men; however, among women aged 70 to 79, the prevalence rose to 1,409 per 100,000 Black women and 1,110 per 100,000 White women (, ). No population-based studies are available to determine the prevalence in South America (). In Western Europe, incidence has also increased: from 2003 to 2017, Spain reported an incidence of 40.3 per 100,000 women/year and 13.7 per 100,000 men/year (). In 2010, the reported incidence in Denmark was 16 per 100,000 people/year (). In Scandinavia, the prevalence was found to be 1.07% among individuals over 25 years of age, and 2.6% among women aged 55 to 75 years (, ). In Eastern Europe, the Czech Republic reported an incidence of 24 cases per 100,000 people/year (). In China, the reported prevalence was 0.2% (). In Australia, the number of parathyroidectomies has increased, although there are no epidemiological data reporting the prevalence of PHPT. Likewise, there are no data available for the African continent. An autopsy study reported a parathyroid adenoma prevalence of 7% in the elderly population ().

PHPT may present as a single adenoma (85%), multiglandular disease, which can manifest as hyperplasia or multiple adenomas (14%), or, in rare cases, as carcinoma (<1%). However, in older adults, multiglandular disease occurs in 20–30% of PHPT cases (). Kebebew reported that 26% of octogenarian patients exhibited multiglandular disease (). In most cases, unregulated monoclonal or oligoclonal proliferation occurs, along with reduced expression of the calcium-sensing receptor (CaSR) in chief cells of the parathyroid glands. This results in both a mass effect and an altered set point (, ). Most factors involved in this proliferative process remain unknown.

Among the genetic mechanisms involved in the development of sporadic parathyroid adenoma are loss-of-function mutations in tumor suppressor genes and gain-of-function mutations in proto-oncogenes. To date, only mutations in MEN1 and CCND1 (menin and cyclin D1, respectively, a tumor suppressor and an oncogene, both located on chromosome 11) have been recognized as established drivers in the pathogenesis of parathyroid adenomas. Other genes confer predisposition and may contribute to tumorigenesis when combined with a second mutational event. These include: CDKN1B ( cyclin-dependent kinase inhibitor 1B : p27), CDKN2C ( cyclin-dependent kinase inhibitor 2C : p18), GCM2 ( glial cells missing 2 ), CDC73 ( cell division cycle 73 , formerly known as HRPT2 : parafibromin), and CASR ( calcium-sensing receptor ). Finally, several genes have been proposed as candidate driver or candidate predispositon genes that may contribute to tumor initiation or predisposition. These include: ZFX ( zinc finger X-chromosomal protein ), EZH2 ( enhancer of zeste 2 polycomb repressive complex 2 subunit ), CTNNB1 ( catenin beta 1 : β-catenin), CDKN1A ( cyclin-dependent kinase inhibitor 1A : p21), and CDKN2B ( cyclin-dependent kinase inhibitor 2B : p15) ().

PHPT is the most common cause of hypercalcemia (). Hypercalcemia results from PTH stimulation of PTHR1 receptors expressed on osteoblasts, leading to increased synthesis of RANKL. RANKL binds to the RANK receptor on osteoclasts, promoting their differentiation and activity. This enhances bone resorption and mobilizes calcium and phosphate from bone into the circulation (). Hypercalcemia also results from increased renal tubular calcium reabsorption, both at the thick ascending limb of the loop of Henle and in the distal tubule (, ). Additionally, PTH increases the synthesis of 1,25-dihydroxyvitamin D in the proximal tubule, leading to enhanced intestinal absorption of calcium and phosphate (). PHPT may present as asymptomatic hypercalcemia in 70–80% of patients (, ), as normocalcemic hyperparathyroidism , or as classic hyperparathyroidism . The clinical presentation of PHPT depends on the duration of the disease at the time of diagnosis and its association with other endocrine syndromes, such as MEN1, MEN4, MEN2A, and hyperparathyroidism-jaw tumor syndrome.

Currently, asymptomatic hypercalcemia is the most common presentation of PHPT across all age groups, including adults over 65 years of age. Patients typically present with stable calcium and PTH levels, and serum calcium rarely exceeds 1 mg/dL above the upper limit of the normal range. Fewer than 5% of patients will experience progressive hypercalcemia over time (); however, patients may present with osteoporosis, primarily affecting the forearm and cortical bone (–), vertebral fractures, hypercalciuria, and nephrolithiasis (). Older adults may report nonspecific constitutional, neuropsychiatric, or cognitive symptoms including weakness, fatigue, joint pain, depression, anxiety, sleep disturbance, and perceived cognitive decline (, -). While severe hypercalcemia in symptomatic PHPT is clearly associated with altered mental status (), it remains uncertain whether more subtle neurocognitive or neuropsychiatric manifestations are specifically attributable to PHPT in the absence of marked hypercalcemia. Moreover, older adults are particularly susceptible to bone demineralization and fractures (, ).

An Italian study compared the clinical presentation of PHPT in 462 patients, of whom 54.1% were under 65 years and 45.9% were older than 65. No significant differences were found in serum calcium, PTH, or vitamin D levels. Urinary calcium excretion was lower in older adults (205 vs 308 mg/day), and renal involvement was also less frequent (25% vs 49.2%). However, skeletal involvement was more prevalent in older adults (58% vs 44%). Compared to younger patients, older adults exhibited a lower frequency of classic presentation (44.4% vs 57.2%) and a higher frequency of asymptomatic disease without surgical criteria (18.4% vs 5.6%). Skeletal involvement was more pronounced in older adults, with the forearm being the most affected site, whereas the lumbar spine was more commonly involved in younger patients. Osteitis fibrosa cystica was also more frequent in individuals over 65 years. Finally, positive parathyroid imaging findings were less common in elderly patients with mild asymptomatic disease ().

Neuromuscular symptoms , such as proximal myopathy, fatigue, and weakness. Chronic hyperparathyroidism can lead to proximal muscle weakness due to atrophy of type II muscle fibers (). Neurocognitive symptoms , including depression, anxiety, psychosis, cognitive dysfunction, dementia, reduced social interaction, confusion, delirium, and lethargy (, –). Gastrointestinal symptoms , such as anorexia, nausea, vomiting, epigastric pain, constipation, and, occasionally, pancreatitis (1–10%) (). Skeletal manifestations including osteitis fibrosa cystica, osteoporosis, and pathological fractures. Renal manifestations , particularly nephrolithiasis. Cardiovascular manifestations , such as left ventricular hypertrophy (LVH) with diastolic dysfunction, arterial hypertension (AH), vascular dysfunction (both endothelial and smooth muscle), atherosclerosis, thickening of the intimal and medial layers with arterial stiffening, which may lead to coronary artery disease and acute myocardial infarction, arrhythmias, and myocardial, valvular, and vascular calcifications, contributing to increased cardiovascular (CV) mortality (, –). The most common skeletal manifestation is osteoporosis, which increases the risk of fractures by 2–3 times, particularly in the vertebrae, distal forearm, and pelvis. Osteoporosis is present in 58% of patients over 75 years of age, compared to 21% in those under 75 ().

Hypercalciuria is observed in 30–40% of patients with PHPT, though it is less prevalent in older adults. PTH promotes tubular calcium reabsorption at the thick ascending limb of the loop of Henle and the distal tubule, which would be expected to reduce calciuria. However, two mechanisms counteract this effect: first, the filtered calcium load increases due to hypercalcemia; second, sodium and calcium reabsorption in the proximal tubule, where approximately 65% of filtered calcium is normally reabsorbed, is reduced. This occurs due to PTH-mediated inhibition of the Na+/H+ exchanger (NHE3). The incidence of nephrolithiasis has declined and currently occurs in 15–25% of cases. When stratified by age, it is more common in younger individuals and occurs in only 15% of patients older than 75 years (). Most stones are composed of calcium oxalate; however, alkaline urine promotes the precipitation of calcium phosphate. Other contributing factors to urolithiasis include dehydration and elevated levels of calcitriol. Nephrocalcinosis is another renal manifestation, resulting from calcium phosphate deposition in the renal parenchyma. Some patients may also exhibit reduced creatinine clearance ().

Normocalcemic PHPT is defined as elevated PTH levels with normal total and ionized serum calcium, in the absence of secondary causes of PTH elevation such as vitamin D deficiency, chronic kidney disease with a glomerular filtration rate < 60 ml/min, use of medications such as thiazides, bisphosphonates, denosumab, and lithium, hypercalciuria, and malabsorption syndromes. The diagnosis should include measurements of total calcium, ionized calcium, and PTH on multiple occasions, with at least two additional measurements beyond the initial one over a period of 3 to 6 months. In 4–10% of cases, ionized calcium will be elevated, and up to 19% of patients will develop hypercalcemia within a 3-year follow-up period. Patients with normocalcemic PHPT should be monitored annually with calcium and PTH measurements, as well as bone mineral density assessments every 1 to 2 years. If hypercalcemia develops, current guidelines should be followed to determine whether surgical treatment is indicated or continued observation is appropriate. Conversely, if progression occurs at the skeletal level (e.g., fractures or progressive reduction in BMD) or at the renal level (e.g., nephrolithiasis or nephrocalcinosis), parathyroid surgery should be considered ().

The diagnosis of PHPT is biochemical and is confirmed by the presence of hypercalcemia in the setting of elevated or inappropriately normal parathyroid hormone (PTH) levels. Between 8% and 12% of patients with PHPT will have PTH values within the normal range, typically in the upper half; only about 1% will have PTH levels below 40 pg/mL (). Additional laboratory and imaging findings include: Serum phosphorus is often at the lower limit of normal, with frank hypophosphatemia observed in approximately one-third of patients. Magnesium excretion is mildly increased, and some patients may exhibit mild hypomagnesemia. Vitamin D deficiency is common in patients with PHPT, particularly in mild cases (up to 50%), and may blunt hypercalcemia, resulting in high-normal serum calcium levels that can obscure or complicate the diagnosis. Patients with vitamin D deficiency tend to have larger parathyroid glands, higher PTH levels, increased osteoclastic activity, and a higher incidence of pathological fractures (). 1,25-dihydroxyvitamin D levels are elevated in 24% of patients and within the high-normal range in the remainder. These elevated levels are associated with increased urinary calcium excretion and lower bone mineral density (BMD).

PTH decreases bicarbonate reabsorption in the proximal tubule. This may contribute to decreased serum bicarbonate concentrations, potentially causing hyperchloremic metabolic acidosis. However, this is usually counterbalanced by the release of alkali from bone as a result of increased osteoclastic activity, so metabolic acidosis typically occurs only in patients with renal impairment or markedly elevated PTH levels. Hypercalciuria is present in 30–40% of patients. Bone turnover markers of formation and resorption are elevated or in the high-normal range, depending on the extent of skeletal involvement. Bone densitometry (DXA) is essential in the assessment of PHPT and typically shows reduced BMD at cortical bone-rich sites such as the one-third distal radius. The differential diagnosis of PHPT includes familial hypocalciuric hypercalcemia (FHH) , characterized by mild hypercalcemia, PTH levels in the high-normal or slightly elevated range, a calcium/creatinine clearance ratio < 0.01, and usually urinary calcium < 100 mg/24 hours (, ). The recommended diagnostic tests are detailed in .

Imaging studies are not used to diagnose PHPT, but rather for the preoperative localization of the pathological gland, which helps in planning the surgical approach and minimizing surgical time and trauma. Localization of the parathyroid glands can be challenging despite the available imaging techniques, especially when the glands are small (<5 mm and <500 mg), ectopic, supernumerary, or when multiglandular disease or coexisting thyroid nodular disease is present. Typically, there are four parathyroid glands (though 3 to 8 may be found), located posterior to the thyroid gland at the superior and inferior poles of each thyroid lobe. The average weight is 30–70 mg, while adenomas generally range from 500 to 5000 mg in weight (). Techniques used for localizing adenomas include: dual-phase technetium-99m sestamibi scintigraphy (99mTc-MIBI), 99mTc-MIBI with specialized imaging acquisition methods (such as pinhole and SPECT), dual-tracer scintigraphy, neck ultrasound, positron emission tomography (PET), four-dimensional computed tomography (4D-CT), magnetic resonance imaging (MRI), and hybrid techniques like 99mTc-MIBI SPECT-CT and PET-CT (). PET-CT may use tracers such as 11 C-methionine, 11 C-choline, and 18 F-choline. The choice of localization technique depends on the experience and resources of each medical center.

Parathyroidectomy (PTX) is the only curative treatment for patients with PHPT. It cures approximately 97.8% of cases in patients with asymptomatic PHPT (, ). PTX is considered safe, well-tolerated and, with only a minimal increase in complication risk among older adults (, ). PTX should be performed by an experienced (high-volume) surgeon, defined as one who performs at least 50 parathyroidectomies annually (). Surgery is recommended for all symptomatic patients with PHTP. For patients with an asymptomatic presentation, surgical indications have been established since 1991, with the most recent update presented in the management guidelines of the 5th International Workshop and summarized in (). The surgical indications for asymptomatic presentation aim to provide benefits that outweigh the risk of complications and are based on the risk of disease progression. However, surgery remains an option for any patient seeking a definitive cure, as long as no contraindications are present (). There is insufficient evidence to recommend surgery for the improvement of neurocognitive function, quality of life, or cardiovascular indices, as will be detailed later.

In patients over 70 years of age, referral for PTX is less frequent, even in the absence of formal contraindications. This more conservative approach is largely driven by concerns regarding surgical risk and the high prevalence of comorbidities in this age group, including hypertension, type 2 diabetes mellitus, and cardiovascular disease (, , ). Indeed, more than two-thirds of patients with PHPT present with or are treated for these conditions (–). Other factors influencing decisions against surgery include advanced age, mild or asymptomatic disease, stable hypercalcemia, and severe frailty (). Importantly, the likelihood of undergoing surgery decreases with advancing age, regardless of disease severity or fulfillment of established surgical criteria ().

Dombrowsky reviewed the medical records of 25 patients over 75 years old with PHPT who were referred for surgery and compared them with 25 who were not. The average follow-up was 5.5 years. The goal was to identify the reasons for diagnostic delays and lack of surgical referrals. Hypercalcemia was unrecognized in 58% of cases. A diagnosis of PHPT was not made in 28% of patients, despite elevated calcium and PTH levels. In 16% of cases, the diagnosis was also missed in patients with clear PHPT-related symptoms such as fractures, osteoporosis, and kidney stones. Reasons for not choosing surgery included age (14%), comorbidities (20%), mild or asymptomatic disease (14%), and mild or stable hypercalcemia (14%) ().