Primary hyperparathyroidism: Management

INTRODUCTION — Primary hyperparathyroidism (PHPT) is often recognized as a result of biochemical screening or during evaluation for decreased bone mass. Most patients with PHPT have serum calcium concentrations within 1 to 1.5 mg/dL (0.25 to 0.375 mmol/L) above the upper limit of normal with an elevated or inappropriately normal parathyroid hormone (PTH) level. Among such patients, the majority are women over age 50 years who are asymptomatic. This topic reviews the management of PHPT in general and the risks and benefits of medical versus surgical management in asymptomatic patients. The clinical manifestations and diagnosis of PHPT, diagnostic localization of abnormal parathyroid glands, and the methods of surgical removal are discussed in greater detail elsewhere.

The decision regarding medical versus surgical treatment does not apply to patients who have familial hypocalciuric hypercalcemia. Patients with this disorder have mild hypercalcemia, few if any symptoms, no evidence of end organ damage from their disease, and consequently, no benefit from parathyroidectomy.

●(See "Primary hyperparathyroidism: Clinical manifestations".)

●(See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

●(See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism".)

●(See "Parathyroid exploration for primary hyperparathyroidism".)

●(See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)

SYMPTOMATIC — Patients with symptomatic PHPT (nephrolithiasis, fractures, symptomatic hypercalcemia) should have parathyroid surgery, which is the only definitive therapy. Parathyroidectomy is an effective therapy that cures the disease, decreases the risk of kidney stones, improves bone mineral density (BMD), and may decrease fracture risk and modestly improve some quality-of-life measurements. (See 'Surgical procedure' below.)

Observational studies report a marked reduction in formation of kidney stones after successful surgery [1,2]. Furthermore, over a 10-year follow-up period, all patients with a history of nephrolithiasis who did not choose to have parathyroidectomy had progression of disease [2]. Thus, a history of nephrolithiasis is regarded as a clear indication for surgery.

Some patients may have nonspecific symptoms that are difficult to quantify. These symptoms include fatigue, a sense of weakness, mild depression, and memory impairment. Because of the largely subjective nature of these symptoms, the distinction between asymptomatic and symptomatic PHPT is not always clear-cut. Patients may deny symptoms, whereas a family member may say the patient has been mildly symptomatic in some way [3-5]. Nonspecific neuropsychiatric symptoms alone are not indications for surgery. (See 'Nonclassic end organ effects' below.)

If there are comorbidities, contraindications, or prior unsuccessful neck explorations that preclude surgery, or if the patient refuses surgery, preventive measures and adequate monitoring are important. (See 'Preventive measures' below and 'Monitoring' below.)

In addition, for such patients who are unable to have surgery and whose primary indication for surgery is symptomatic and/or severe hypercalcemia (particularly those in whom bone density is normal), we suggest cinacalcet rather than bisphosphonates. (See 'Poor surgical candidates' below.)

ASYMPTOMATIC — Although patients with symptomatic PHPT should undergo parathyroid surgery, the widespread identification of asymptomatic individuals raises the question of need for and timing of surgical intervention in this population [6,7]. In some patients with asymptomatic disease, surgery is not mandatory. Most asymptomatic patients do not have progression of disease, as defined by worsening hypercalcemia, hypercalciuria, bone disease, and/or nephrolithiasis [8]. However, some individuals do progress and would benefit from surgical cure. The primary goal is to identify the asymptomatic individuals at risk for disease progression, as well as those who have features of the disease that may improve following parathyroidectomy. These two groups of individuals would likely benefit from surgical intervention.

Candidates for surgery — All patients with PHPT are "candidates" for surgery, which offers the only established option for long-term cure of the disease [9]. For asymptomatic individuals who meet the Fifth International Workshop on Asymptomatic Primary Hyperparathyroidism guidelines (table 1), we suggest surgical intervention as opposed to observation [10-12]. Patients need to meet only one of the following criteria for surgery:

●Serum calcium concentration of >1 mg/dL (0.25 mmol/L) above the upper limit of normal.

●Skeletal indications:

•Bone density at the hip, lumbar spine, or distal radius that is at least 2.5 standard deviations below peak bone mass (T-score ≤-2.5).

•Previous asymptomatic vertebral fracture (by radiograph, computed tomography [CT], magnetic resonance imaging [MRI], or vertebral fracture assessment).

●Kidney indications:

•Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m².

•Twenty-four-hour urinary calcium >250 mg/day (6.25 mmol/day) in women and >300 mg/day (7.5 mmol/day) in men.

•Nephrolithiasis or nephrocalcinosis by radiograph, ultrasound, or CT.

●Age less than 50 years.

Patients with asymptomatic PHPT who do not meet surgical intervention criteria may still choose parathyroidectomy because it is the only definitive therapy.

These criteria were chosen based on clinical experience and observational and clinical trial data as to which patients are more likely to have end-organ effects of PHPT (nephrolithiasis, skeletal involvement) if surgery is deferred and the most benefit from surgery. Parathyroidectomy should be performed by surgeons who are highly experienced and skilled in the operation.

Surgery versus nonsurgical management — The debate regarding treatment of asymptomatic PHPT revolves around the effect of intervention on outcomes, such as symptoms, bone disease, and biochemical abnormalities. Although parathyroidectomy improves bone density and may have modest effects on some quality-of-life symptoms, long-term, observational data and short-term, randomized trial data clearly demonstrate that a large subgroup of patients with asymptomatic PHPT can be followed safely without surgery because they do not have disease progression, as evidenced by stable biochemical abnormalities and bone mineral density (BMD) for up to a decade of observation [8]. However, disease may progress (worsening hypercalcemia, hypercalciuria, newly diagnosed nephrolithiasis) in as many as one-third of patients over the first years of observation, and these patients would benefit from surgical intervention. In addition, BMD may decline in patients observed for longer than 8 to 10 years. Although these observational data are based upon a small number of patients, they do suggest that long-term (>8 to 10 years) observation in asymptomatic patients is not optimal for skeletal outcomes. (See 'Subclinical bone disease' below.)

The ability to identify criteria that are predictive of disease progression would improve management strategies, but these factors (other than age <50 years at presentation) are as yet unknown. Proponents of surgery for asymptomatic individuals argue that many untreated patients are lost to follow-up after 5 to 10 years and that the cost of follow-up visits and tests may ultimately exceed the costs of surgery [13,14]. Some argue that parathyroidectomy is an attractive strategy for nearly all patients, particularly given significant progress in techniques for minimally invasive surgical extirpation [15,16]. Proponents who favor nonoperative management for asymptomatic individuals cite the lack of disease progression in most patients and the ability to treat, if necessary, with alternative therapies as reasons to avoid an invasive procedure. (See 'Poor surgical candidates' below.)

Biochemical abnormalities — There is little evidence that hypercalcemia worsens in the majority of asymptomatic patients followed for two to three years [17,18]. However, in one trial, 8 percent of asymptomatic patients randomly assigned to observation developed worsening hypercalcemia requiring surgery over a two-year interval [17].

Observational studies of longer duration (up to 15 years) report similar findings [19-23]. Biochemical abnormalities remain stable in the majority of patients, but patients occasionally become spontaneously normocalcemic during follow-up, and a small proportion develop worsening biochemical parameters requiring surgical intervention [2,20,22,23].

Among 52 asymptomatic patients followed for up to 10 years, there was no change in mean serum calcium and parathyroid hormone (PTH) concentrations and urinary calcium excretion (or BMD), but one or more of these measures increased substantially in 14 patients (27 percent) [2], and after 15 years of observation, 37 percent of patients had evidence of disease progression [8]. These patients were younger at baseline than those without disease progression (52 versus 60 years of age), and several became menopausal during follow-up. Thus, younger age (<50 years) at diagnosis has been identified as a risk factor for disease progression [24].

Subclinical kidney disease — Important subclinical kidney manifestations of PHPT include asymptomatic nephrolithiasis, hypercalciuria, nephrocalcinosis, and chronic kidney impairment (see "Primary hyperparathyroidism: Clinical manifestations", section on 'Kidney'). Patients with subclinical kidney disease are regarded as having symptomatic disease and are candidates for surgery, even in the absence of symptoms [10,25-27].

●Kidney function – In randomized trials, there is no evidence that kidney function deteriorates in asymptomatic patients followed for two to three years without surgery, nor definitive evidence that kidney function improves in asymptomatic patients who are cured following parathyroidectomy [17,18,28]. Similarly, data are lacking to support a specific threshold of kidney impairment at which parathyroidectomy should be performed. In an observational study in 43,697 predominantly asymptomatic individuals with PHPT (approximately 88 percent male, mean age 66.8 years), the rate of a sustained decline (≥50 percent) in eGFR over 10 years of follow-up did not differ between individuals who underwent parathyroidectomy within one year of diagnosis and those who underwent initial nonsurgical management [29]. In subgroup analyses, a kidney protective benefit of parathyroidectomy was evident in individuals aged <60 years. Nonetheless, these findings were observational and primarily confined to males. Limited data show that reductions in eGFR can have adverse skeletal and biochemical effects in PHPT and that patients with eGFR <60 mL/min/1.73 m² have improvement in these outcomes after surgery. These data have led to the recommendation that those with eGFR <60 mL/min/1.73 m² be referred for surgery [30,31].

●Kidney stones and hypercalciuria – While kidney stones remain the most common presentation of symptomatic PHPT, asymptomatic stones are present in 11 to 35 percent of patients [25]. Most stones in patients with hyperparathyroidism are composed of calcium oxalate; some have calcium phosphate or mixed calcium phosphate and oxalate. A contributing factor for stone formation in hyperparathyroidism is hypercalciuria. However, urinary calcium excretion per gram creatinine does not necessarily differentiate patients with or without stones, nor does it predict the development of kidney stones in an individual patient [10,32]. Other risk factors include hypomagnesuria, urinary calcium/magnesium ratio, and genetic factors, possibly including polymorphisms in the calcium-sensing receptor (CaSR) gene [33]. Nevertheless, most experts believe that urinary calcium excretion >250 mg/day in women and >300 mg/day in men raises sufficient concern about long-term kidney complications to warrant a recommendation for parathyroidectomy [10].

Subclinical bone disease — Patients with asymptomatic hyperparathyroidism may have decreased BMD, in particular at more cortical sites (forearm and hip) as compared with more trabecular sites (spine). In addition, observations from large case-control and cohort studies suggest that there may be increased fracture risk at vertebral and other skeletal sites [25]. The prevalence of vertebral fractures varies widely across studies and does not consistently correlate with disease severity. (See "Primary hyperparathyroidism: Clinical manifestations", section on 'Skeletal'.)

Randomized trials have demonstrated increased BMD following parathyroidectomy [17,18,34-36]. In one trial, lumbar spine BMD increased in the surgical group compared with the observation group two years after surgery; spine BMD remained unchanged in the observation group [17]. A similar but nonsignificant trend was noted at the femoral neck. In another randomized trial, BMD after two years was slightly better at the femoral neck and total hip (but not spine) in the surgical compared with the nonsurgical group (group differences of 0.8 and 1.0 percent per year at the femoral neck and hip, respectively) [18].

Significant improvement in BMD post-parathyroidectomy has also been noted in observational studies [2,21,37-39]. In one prospective study of a cohort of 121 patients with hyperparathyroidism followed for up to 10 years, there were substantial increments in BMD of 12 to 15 percent in those who underwent parathyroidectomy [2]. Most of the increments occurred within the first year at the lumbar spine and within the first two years at the hip. Importantly, not only bone density improves after parathyroidectomy. Using the noninvasive imaging technology of high-resolution peripheral quantitative CT, skeletal microarchitecture and bone strength were both found to improve through two years after surgery [40].

In most [2,37,38,41-43], but not all [44,45], studies, the initial years of observation without surgical intervention were not associated with progressive bone loss. In a 15-year follow-up of the prospective cohort study described above, lumbar spine BMD remained stable in the six patients observed without intervention [8]. In contrast, BMD started to fall at cortical sites, ultimately decreasing at the femoral neck and distal radius by 10 and 35 percent, respectively. Although the sample size after 10 years was limited, these data suggest that nonsurgical management of PHPT is not a lifelong strategy and requires careful reevaluation in stable patients after ten years [16,46].

Observational data suggest that fracture risk is decreased after parathyroidectomy [47-53]. A prospective randomized study also suggested fewer vertebral fractures following parathyroidectomy as compared with observation [54].

There are very limited data from trials directly comparing parathyroidectomy with medical therapy (eg, bisphosphonates) for the treatment of low BMD [55]. In the short term, bisphosphonates improve bone density in patients with PHPT. However, documentation that the bone density benefit is sustained and accompanied by fracture reduction is lacking (see 'Osteoporosis' below). PHPT is a chronic disease, and patients with PHPT and osteoporosis require a long-term solution. There is concern about the adverse effects of long-term use of bisphosphonates. For these reasons, surgery remains the treatment of choice for osteoporotic patients with PHPT. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Duration of therapy'.)

Nonclassic end organ effects

●Neuropsychiatric – International guidelines do not include neuropsychiatric symptoms as a specific indication for parathyroidectomy [10,12].

Although only a minority of patients with mild PHPT have the classic symptoms of the disease (nephrolithiasis or overt bone disease, osteitis fibrosa cystica), many have nonspecific symptoms. These symptoms include fatigue, a sense of weakness, mild depression, and memory impairment; their reversal after surgery in some patients suggests that they were caused by the hypercalcemia or the hypersecretion of parathyroid hormone (PTH) [56-65]. However, most of the studies reporting symptomatic improvement were observational and limited by selection bias, inclusion of subjects with symptomatic hyperparathyroidism, or by lack of an adequate control group or validated instruments to describe neuropsychiatric symptoms.

Randomized trials in PHPT have been difficult to conduct and have limitations, including difficulty recruiting asymptomatic patients who will accept randomization to surgery. Subjects who choose to participate may well differ from those who decline enrollment, decreasing the generalizability of the results to all patients with asymptomatic PHPT [66]. In addition, withdrawal rates are high due to a variety of reasons, including discontent with initial treatment assignment. Despite these limitations, the results of randomized trials assessing the benefit of surgery versus observation on neuropsychiatric symptoms in individuals with asymptomatic PHPT provide important information [34,67,68].

In a meta-analysis of three trials in 225 patients with PHPT, patients randomly assigned to surgery showed modest improvements in certain quality-of-life domains without consistent findings across trials [11]. As examples of the included trials:

•Long-term (10 year) data on 120 subjects was reported from a prospective, randomized trial comparing surgery versus no surgery in 191 Scandinavian patients with PHPT [68]. There was modest improvement in some of the mental domains of the Short Form 36 (SF-36) quality-of-life scale. Although these changes were statistically significant, the treatment effects were subtle and of uncertain clinical significance. Further, there were no significant differences in the Comprehensive Psychopathological Rating Scale (CPRS) between the two groups.

•In another trial, 53 of 283 potentially eligible patients (calcium between 10.1 and 11.5 mg/dL [2.52 to 2.87 mmol/L]) agreed to be randomly assigned to surgery or observation [18,67]. At baseline, mean SF-36 Health Survey scores were similar to published normals. Those who underwent successful surgery (traditional neck exploration) had little change in psychosocial functioning two years later, but there was a significant decline over time in the observation group. After a median follow-up of 42 months, there was a significant benefit of surgery compared with no surgery in two of nine domains of the SF-36 survey (social functioning and emotional problems) [18].

•In a one-year trial of 50 patients (mean calcium 10.2 mg/dL [2.55 mmol/L]) randomly assigned to observation or parathyroidectomy, there was modest improvement in some SF-36 quality-of-life domains (bodily pain, general health, vitality, and mental health) in patients assigned to surgery compared with observation [34].

Taken together, these short- and long-term randomized trial data suggest minimal to modest differences in some domains of the SF-36, favoring surgical intervention. The fact that improvements were noted in differing domains of the SF-36 in the different trials suggests that individual patients cannot have specific expectations regarding surgical outcome for neuropsychiatric symptoms. In addition, the differences were small and of uncertain clinical significance. It should be noted that while international guidelines do not include neuropsychiatric symptoms as a specific indication for parathyroidectomy, more liberal guidelines were issued by the American Association of Endocrine Surgeons in 2016 [69]. These guidelines suggest intervention for neurocognitive and/or neuropsychiatric symptoms that "are attributable to PHPT," although the evidence supporting this recommendation is of low quality, and no guidance was included as to how to determine attribution.

●Cardiovascular – Cardiovascular features of classical PHPT include hypertension, arrhythmia, ventricular hypertrophy, vascular stiffening, and vascular and valvular calcification. In addition, several studies in Europe have reported increased cardiovascular morbidity and mortality in patients with otherwise asymptomatic hyperparathyroidism. (See "Primary hyperparathyroidism: Clinical manifestations".)

The extent to which other cardiovascular findings persist after parathyroidectomy is unclear. The available data are mostly observational, and definitive evidence for an improvement in cardiovascular function post-parathyroidectomy is lacking.

•A meta-analysis of 15 studies, including four randomized trials and 457 patients undergoing parathyroidectomy, supported a modest reduction in left ventricular mass after surgery [70].

•Although hypertension is frequently seen in patients with PHPT, even among those with mild and normocalcemic disease, a clear causal link between the two conditions is lacking in patients without multiple endocrine neoplasia (MEN). Most, but not all, observational studies indicate that hypertension is not reversible with surgical cure and should not be used as an indication for parathyroidectomy [12,20,71,72].

There are few randomized trials with cardiovascular endpoints. In a two-year analysis of a randomized trial of parathyroidectomy versus observation in 116 patients with asymptomatic PHPT, mean arterial and diastolic blood pressure declined in both groups with no significant difference between groups [35]. There were also no differences between the two groups in cardiovascular risk factors, including lipids, adiponectin, leptin, C-reactive protein, or biochemical markers of endothelial function (eg, vascular cell adhesion molecule 1, Von Willebrand factor). There were only minor differences in echocardiogram findings in 49 patients in whom echocardiography was performed (a significant reduction in diastolic dimension of the interventricular septum and a nonsignificant reduction in left ventricular mass, both in the parathyroidectomy group) [73]. Although data are limited, the impact of parathyroidectomy on cardiovascular risk factors has been mixed [74,75].

Additional research is focusing on more subtle abnormalities of the cardiovascular system. The nature of such involvement and the extent to which any abnormalities improve postoperatively need to be elucidated before recommending surgery based upon such considerations [76].

Mortality — Survival benefit has been demonstrated post-parathyroidectomy in several large cohort studies from Sweden and Denmark [47,77-79]. Similarly, in a Scottish study, risk of mortality was lower in patients with PHPT who were treated surgically versus those who did not undergo surgery [80]. However, in the largest published study, the survival benefit was not observed until 15 years post-parathyroidectomy [78].

Surgical procedure — The goal of parathyroid surgery is excision of the overactive parathyroid tissue (adenoma[s] or hyperplasia) and thereby biochemical cure of PHPT. The standard surgical approach for most patients with PHPT had been bilateral neck exploration, usually under general anesthesia [6]. Bilateral exploration relies on visual and weight-based estimations of gland size to distinguish a single adenoma from multiglandular disease. However, with increased experience, improved imaging modalities, and the use of adjuncts such as intraoperative parathyroid hormone monitoring (IOPTH), minimally invasive parathyroidectomy (MIP) is emerging as the procedure of choice in those with positive preoperative localization [69]. The success of a targeted parathyroidectomy is dependent upon studies that permit the surgeon to limit the operative field to the region where a single radiologic focus is identified. (See "Parathyroid exploration for primary hyperparathyroidism", section on 'Focused parathyroid exploration' and "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism", section on 'Role of preoperative localization'.)

Nonoperative management — For the patient who will not undergo surgery (due to clinician recommendation or patient choice), it is appropriate to recommend supportive-preventive measures with adequate monitoring. Asymptomatic patients who do not undergo surgery require long-term monitoring for worsening hypercalcemia, kidney impairment, and bone loss. The development of any of these findings indicates disease progression and the need for surgical intervention. We monitor serum calcium and creatinine annually, and bone density (hip, spine, and forearm) every one to two years (see 'Monitoring' below). If disease progression occurs (table 1), we would suggest surgery, as described above.

Preventive measures — A number of measures should be recommended to patients who do not undergo surgery, including the following:

●Avoid factors that can aggravate hypercalcemia if possible, including thiazide diuretic and lithium carbonate therapy, volume depletion, prolonged bed rest or inactivity, and a high-calcium diet (>1000 mg/day). (See "Diuretics and calcium balance".)

●Encourage physical activity to minimize bone resorption.

●Encourage adequate hydration (at least six to eight glasses of water per day) to minimize the risk of nephrolithiasis and worsened hypercalcemia.

●Maintain a moderate calcium intake (1000 mg/day) (see "Calcium and vitamin D supplementation in osteoporosis", section on 'Primary hyperparathyroidism'). A low calcium diet may lead to further increases in PTH secretion and could aggravate bone disease [81]. However, in patients with high serum calcitriol concentrations, the recommended calcium intake has been shown to exacerbate hypercalcemia or hypercalciuria. Thus, moderate calcium restriction (eg, <800 mg/day) is probably warranted when the serum calcitriol concentration is high [82].

●Maintain moderate vitamin D intake (400 to 800 international units daily) to maintain a serum 25-hydroxyvitamin D (25[OH]D) level >30 ng/mL (75 mmol/L) but <50 ng/mL (125 nmol/L). Vitamin D deficiency stimulates PTH secretion and bone resorption and, therefore, is deleterious in patients with PHPT. In such patients, higher doses of vitamin D up to 2800 international units per day have been reported to be safe and did not increase serum or urinary calcium [83]. (See 'Concomitant vitamin D deficiency' below.)

Monitoring — Periodic monitoring should be performed for disease progression and development of indications for surgery (table 1).

Measurements of serum calcium, creatinine, and eGFR annually and bone density (hip, spine, and forearm) every one to two years is sufficient [10]. While exclusion of nephrocalcinosis or silent nephrolithiasis (with radiograph, ultrasound, or CT) at the time of the original evaluation is recommended by some, repeat imaging should only be performed if clinically indicated [10]. After initial evaluation, if development of a kidney stone is suspected on clinical grounds (eg, flank pain, hematuria), kidney imaging (radiograph, ultrasound, CT) should be repeated. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Kidney imaging'.)

For patients who are initially followed without surgery, parathyroidectomy is indicated if any of the following occur during follow-up [10]:

●Consistent elevation in serum calcium >1 mg/dL (0.25 mmol/L) above the upper limit of the reference range

●Interim low trauma fracture

●Interim kidney stone(s)

●Progression to osteoporosis (T-score ≤-2.5) at any site

●Reduction in eGFR (decrement of ≥3 mL/min/1.73 m² per year over one to two years)

POOR SURGICAL CANDIDATES — For certain patients who meet surgical criteria (either due to symptoms or to consensus guideline criteria) but who cannot or will not have surgery, we prescribe medical therapy for the indications described immediately below. The following recommendations are in keeping with the Fifth International Workshop on Asymptomatic Primary Hyperparathyroidism guidelines [10,84]:

●For patients whose primary indication for surgery is symptomatic and/or severe hypercalcemia, we typically use cinacalcet rather than bisphosphonates, particularly for those in whom bone density is not in the osteoporotic range.

●For individuals who are unable to have surgery and whose primary indication for surgery is osteoporosis and risk for fracture, we suggest bisphosphonates. Among the bisphosphonates, alendronate has been most extensively evaluated in patients with PHPT. Denosumab also increases BMD in patients with PHPT, although substantially less evidence supports its use in this setting [85,86].

●If there is no need to improve bone density or to lower the serum calcium, we do not use pharmacologic therapy.

Certain medications have been used in patients with PHPT (eg, patients who do not meet surgical criteria, who are unable to undergo surgery, or who prefer to avoid surgery), although they are not primarily indicated for this purpose. They include bisphosphonates, denosumab, and estrogen plus progestin, which inhibit bone resorption and can increase bone density and possibly lower serum calcium concentrations in patients with hyperparathyroidism [12,83]. Other medications, such as calcimimetics or vitamin D analogs, suppress parathyroid hormone (PTH) release or counteract the effects of hyperparathyroidism at the level of the PTH receptor and thereby reduce serum calcium.

Although thiazides may raise serum calcium levels in patients with PHPT [87,88], low dose thiazides (eg, 12.5 mg daily) have been studied for the treatment of hypercalciuria in poor surgical candidates [89]. Close monitoring of serum calcium is required [89].

Indications for medical therapy

Severe hypercalcemia — Cinacalcet can be used to normalize serum calcium in patients with severe hypercalcemia who are unable to undergo parathyroidectomy [10,84].

●For patients who are unable to have surgery and whose primary indication for surgery is symptomatic and/or severe hypercalcemia (particularly those in whom bone density is normal), we suggest cinacalcet rather than bisphosphonates.

●In such patients, we typically give cinacalcet at a dose of 30 mg twice daily.

●Serum calcium should be measured within one week after initiation or any dose adjustment.

Calcimimetic agents activate the calcium-sensing receptor in the parathyroid gland, thereby inhibiting PTH secretion [90]. Functions of the calcium-sensing receptor are reviewed elsewhere (see "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia"). Only one calcimimetic drug, cinacalcet, is available for the treatment of secondary hyperparathyroidism associated with kidney failure, for hypercalcemia in parathyroid cancer, and for the treatment of severe hypercalcemia in patients with PHPT unable to undergo parathyroidectomy. (See "Parathyroid carcinoma" and "Management of secondary hyperparathyroidism in adult patients on dialysis", section on 'Calcimimetics'.)

Cinacalcet reduces serum calcium in the majority of patients with PHPT [91-95]. In a meta-analysis of three trials in 114 patients with PHPT who were randomly assigned to cinacalcet or placebo, cinacalcet reduced serum levels of both calcium (mean difference [MD] -1.6 mg/dL, 95% CI -2.1 to -1.1 [-0.4 mmol/L, -0.5 to -0.3 mmol/L]) and PTH (MD -30 pg/mL, 95% CI -41 to -19 [-3.2 pmol/L, -4.3 to -2]) relative to placebo [11]. In one of the larger trials in the meta-analysis (78 patients with PHPT randomly assigned to cinacalcet or placebo), cinacalcet therapy normalized serum calcium in 73 percent of subjects compared with only 5 percent in the placebo group. Serum PTH concentrations decreased by 7.5 percent with cinacalcet but increased in the placebo group. BMD was unchanged in both groups, and there was no significant difference in the 24-hour urinary calcium-creatinine ratio between the two groups [93]. In an open-label extension study, 45 patients (21 and 24 of those originally assigned to cinacalcet and placebo, respectively) were treated with cinacalcet (30 to 50 mg twice daily) for up to 4.5 years [96]. Cinacalcet maintained normocalcemia and reduced PTH in most patients (74 to 92 percent), with no changes in BMD.

In a pooled analysis of data from three trials, cinacalcet was equally effective in reducing serum calcium in patients across a broad spectrum of disease severity [97].

Side effects most commonly reported included nausea, arthralgia, diarrhea, myalgia, and paresthesia, occurring in 36, 30, 22, 22, and 22 percent of patients, respectively, sometimes requiring discontinuation of the medication. Thus, cinacalcet is not the medical equivalent of parathyroidectomy, because it is not permanent and does not improve BMD or reduce urinary calcium excretion [11]. Furthermore, PTH concentrations do not normalize, and data are lacking on any salutary effect of cinacalcet on nephrolithiasis.

No data exist on the effects of cinacalcet on subtle neuropsychiatric or cognitive abnormalities in the disease or in patient-reported quality-of-life outcomes. Thus, cinacalcet is not indicated in patients with mild, asymptomatic PHPT.

Osteoporosis

●Bisphosphonates (preferred) – For patients with PHPT and osteoporosis (or those with low bone mineral density [BMD] that would warrant intervention) who prefer to avoid surgery, we suggest bisphosphonates. In the short term (two years), the increases in BMD with bisphosphonate therapy match those seen after parathyroidectomy [98]. However, documentation that the bone density benefit is sustained and accompanied by fracture reduction is needed. In addition, PHPT is a chronic problem, and there is concern about the adverse effects of long-term use of bisphosphonates (see "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Duration of therapy'). Thus, surgery remains the treatment of choice for patients with PHPT and osteoporosis.

Bisphosphonates are potent inhibitors of bone resorption and may be useful to improve low bone mass in patients with untreated PHPT.

In three trials in which patients with generally mild PHPT were randomly assigned to alendronate or placebo for one to two years, alendronate increased bone density at the hip and lumbar spine [99-101] (but not radius [101]) compared with no treatment or placebo. In a meta-analysis of these trials (95 patients with PHPT), alendronate increased BMD at the lumbar spine (mean difference [MD] 5.6 percent, 95% CI 2.9-8.2) and femoral neck (MD 3.6 percent, 95% CI 2.1-5.2) [11]. None of the included trials were designed to assess fracture outcomes. In the same meta-analysis, alendronate did not affect 24-hour urinary calcium excretion or serum levels of PTH or calcium [11].

The influence of prior bisphosphonate use on postsurgical bone density improvement, should surgery become necessary, is unknown. In studies of recombinant PTH for the treatment of osteoporosis, the prior administration of bisphosphonate blunts the improvement in BMD attained with PTH alone (see "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Combination therapy not recommended'). Thus, bone remodeling is necessary for the intermittent administration of recombinant PTH to exert its beneficial effects on bone density and fracture prevention.

●Denosumab – In patients who are unable to tolerate bisphosphonate therapy, denosumab may be used as an alternative. However, limited evidence supports denosumab use in patients with PHPT, and risk of accelerated bone loss and vertebral fracture after discontinuation of denosumab or treatment interruption raise concern for its use in this setting. (See "Denosumab for osteoporosis", section on 'Discontinuation or delay of denosumab'.)

Denosumab has been used successfully to treat resistant hypercalcemia in patients with parathyroid carcinoma, and the drug may have the potential to improve bone at cortical sites impacted by PHPT. A retrospective study comparing surgery with denosumab in 39 patients reported improved BMD with denosumab, although significantly greater increases were seen with parathyroidectomy (spine 11.2 versus 6 percent with denosumab; total hip 7.5 versus 3.7 percent) [85]. PTH levels rose in those treated with denosumab, but calcium levels did not decline. Another study in 50 patients demonstrated better BMD response to denosumab in older females with PHPT compared with older females with osteoporosis but without PHPT [86]. Further investigation of this drug in PHPT is warranted. (See "Parathyroid carcinoma", section on 'Denosumab'.)

Severe hypercalcemia and osteoporosis — Cinacalcet reduces serum calcium in most patients with PHPT but does not improve bone density, whereas the antiresorptive agents improve bone density but do not reduce serum calcium. There are no randomized trials evaluating the benefits and risks of combination therapy with cinacalcet and alendronate. In small observational studies, treatment of patients with both drugs improved bone density and reduced serum calcium levels [84,102,103]. A randomized, placebo-controlled study of cinacalcet and denosumab in 45 patients (15 placebo-placebo, 16 denosumab-placebo, 14 cinacalcet-denosumab) demonstrated normalization of serum calcium in 64 percent of patients on combination therapy and an increase in spine and hip BMD in denosumab groups comparison with placebo [104]. Thus, for patients with severe hypercalcemia and very low bone density who are unable to have surgery, treatment with both cinacalcet and an antiresorptive agent is an option [10].

Other medications

●Estrogen-progestin therapy – Although estrogen or estrogen-progestin therapy reduces bone resorption in postmenopausal women with PHPT, neither should be a first-line medical therapy for women with PHPT. However, women with PHPT who choose to take estrogen-progestin therapy for menopausal symptoms will have the added skeletal benefit. There are significant risks associated with estrogen-progestin therapy. (See "Menopausal hormone therapy: Benefits and risks" and "Treatment of menopausal symptoms with hormone therapy".)

Estrogen-progestin therapy is beneficial in postmenopausal women with PHPT because of its ability to reduce bone resorption. In two trials, serum calcium concentrations decreased by 0.5 to 1.0 mg/dL (0.12 to 0.24 mmol/L) and bone density increased slightly [105,106]. In a third, larger, randomized, controlled trial, there was no change in serum calcium or PTH concentrations with estrogen-progestin therapy [44]. In this trial, 42 women with mild hyperparathyroidism were randomly assigned to treatment with placebo or conjugated estrogens (0.625 mg/day) plus medroxyprogesterone acetate (5 mg/day) for two years [44]. Total body and forearm bone density fell by 2.3 and 3.5 percent, respectively, in the placebo group and increased by 1.3 and 3.4 percent, respectively, in the estrogen-progestin group. Lumbar spine and femoral neck bone density also increased in the latter group. Twenty-three of the 42 women then participated in an extension study for an additional two years (total of four years) [107]. The beneficial effect of hormone therapy on bone density persisted at year 4, with between-group differences in hip, lumbar spine, and forearm bone density that ranged from 7 to 8.2 percent. In addition, a small prospective trial suggested that improvements in BMD after parathyroidectomy are most substantial in a subset of women given concomitant menopausal hormone therapy [108].

There are no data evaluating the effect of estrogen-progestin therapy on fracture risk in women with PHPT.

●Raloxifene – Raloxifene, a selective estrogen receptor modulator (SERM), is available in many countries for the prevention and treatment of osteoporosis (see "Selective estrogen receptor modulators for prevention and treatment of osteoporosis"). In a short-term study of 18 postmenopausal women with asymptomatic PHPT, raloxifene (60 mg/day for eight weeks) reduced mean serum calcium concentration by 0.4 mg/dL at a single time point (eight weeks) [109]. Further data are needed before recommending raloxifene for this indication.

●Drugs in development – Drugs in development include calcitriol analogs that inhibit PTH secretion directly but do not stimulate gastrointestinal calcium or phosphate absorption [110] and drugs that block the PTH receptor [111,112].

CONCOMITANT VITAMIN D DEFICIENCY — Due to the significant prevalence of vitamin D insufficiency in individuals with PHPT, the Fifth International Workshop on Primary Hyperparathyroidism recommends measuring 25-hydroxyvitamin D (25[OH]D) in all patients with PHPT and supplementing vitamin D as needed to maintain serum levels >30 ng/mL (70 nmol/L) and below the upper limit of the reference range (usually 50 ng/mL [125 nmol/L]) [10,12,84,113]. Specific repletion recommendations are not available from clinical trial data. Until such information becomes available, we suggest cautiously repleting vitamin D (600 to 1000 international units daily) in patients with underlying hyperparathyroidism, since worsening hypercalcemia and hypercalciuria have been reported in this setting [114]. We do not favor repletion of vitamin D deficiency in PHPT using high-dose (50,000 international units) vitamin D preparations.

Vitamin D deficiency is common in patients with PHPT. Some individuals with vitamin D deficiency and hyperparathyroidism have more clinically significant disease. (See "Primary hyperparathyroidism: Clinical manifestations", section on 'Symptomatic primary hyperparathyroidism'.)

Vitamin D repletion may improve some of the clinical manifestations [115], although there is concern that repleting vitamin D will worsen hypercalcemia and hypercalciuria [116]. However, in a systematic review of nine observational studies (547 patients with hyperparathyroidism and hypovitaminosis D), vitamin D replacement improved serum 25-hydroxyvitamin D levels, while parathyroid hormone (PTH) levels were unchanged, and there was no worsening of hypercalcemia or hypercalciuria [117]. In a subsequent systematic review of 11 studies in 388 patients with PHPT and vitamin D deficiency or insufficiency, serum PTH levels decreased with vitamin D supplementation and 24-hour urinary calcium excretion was unchanged [118]. In one randomized trial of cholecalciferol (2800 international units/day) versus placebo in 46 patients with PHPT and hypovitaminosis D (mean 25[OH]D 21.6 ng/mL [54 nmol/L]), vitamin D supplementation raised the serum 25(OH)D to 37 ng/mL, while reducing PTH by 17 percent and improving lumbar spine BMD [83]. There was no difference between groups in serum or urinary calcium levels.

Regardless of the vitamin D dose, particular caution must be exercised in those individuals with vitamin D deficiency whose urinary calcium excretion is in the upper range of normal or frankly elevated. Once these individuals are vitamin D replete, their urinary calcium levels can rise quickly, increasing their risk for kidney stone formation. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Coexisting primary hyperparathyroidism'.)

NORMOCALCEMIC HYPERPARATHYROIDISM — Patients with normocalcemic hyperparathyroidism (elevated parathyroid hormone [PTH], normal serum albumin-adjusted calcium) typically come to medical attention in the setting of an evaluation for low bone mineral density (BMD). In order to make this diagnosis, certain conditions must be met. In particular, all secondary causes for hyperparathyroidism (table 2) must be ruled out, and ionized calcium levels should be normal [10]. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Secondary hyperparathyroidism'.)

The natural history of the disorder is unclear, in part because of lack of consistent definitions for this phenotype, as well as inadequate exclusion of all secondary causes for hyperparathyroidism. In one prospective study of 37 patients with normocalcemic hyperparathyroidism, 41 percent developed evidence for progressive hyperparathyroid disease during a median of three years (range one to eight years) of observation [119]. However, less than 20 percent of patients became hypercalcemic during the observation period. Instead, some persistently normocalcemic patients developed other indications of progressive disease, such as kidney stones, hypercalciuria, bone loss, and fracture. Furthermore, four individuals with normal serum calcium levels had successful parathyroid surgery.

There are insufficient longitudinal data on patients with this phenotype of PHPT to support definite guidelines for management. In practice, however, most patients with symptomatic (ie, kidney stones, overt skeletal involvement) normocalcemic hyperparathyroidism should undergo parathyroid surgery, as is recommended for patients with symptomatic hypercalcemic PHPT. Patients with asymptomatic normocalcemic PHPT may develop symptomatic disease and, therefore, require monitoring for disease progression and development of indications for surgery (see 'Monitoring' above). Again, in the absence of sufficient data to support accepted surgical criteria, experts generally consider surgery when one or more of the indications used in asymptomatic PHPT is met (table 1).

For such patients who meet surgical criteria, we routinely obtain a localization study with ultrasonography, technetium-99m sestamibi, CT, or MRI to facilitate unilateral exploration or minimally invasive surgery. However, localization studies may have a lower success rate for normocalcemic than for hypercalcemic PHPT [12]. As is true in hypercalcemic disease, patients with normocalcemic hyperparathyroidism and negative preoperative localization studies require bilateral exploration by an experienced parathyroid surgeon. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism", section on 'Negative imaging'.)

If osteoporosis is the only indication for surgery, some clinicians treat patients who have negative localization studies with a bisphosphonate rather than surgery. In a trial in 30 postmenopausal women with normocalcemic PHPT, combined treatment for one year with alendronate and vitamin D led to increased BMD at the lumbar spine and femoral neck, whereas treatment with vitamin D alone did not [120].

PREGNANCY — PHPT is uncommon during pregnancy [121-124]. However, moderate to severe hypercalcemia during pregnancy may carry significant maternal and fetal risks. In case reports and case series, maternal presentation included hyperemesis, nephrolithiasis, recurrent urinary tract infection, and pancreatitis. Neonatal complications included hypocalcemia and tetany, secondary to fetal parathyroid hormone (PTH) suppression, preterm delivery, low birth weight, and fetal demise [122,125]. These outcomes are very uncommon in pregnancies of patients with mild hypercalcemia.

As in nonpregnant patients, treatment is based upon severity and symptoms, but consideration of gestational age is also important. When interpreting the severity of serum calcium elevations in pregnant women, it is important to remember that total serum calcium declines across gestation, likely due to plasma volume expansion. The upper limit of normal for total serum calcium is 9.5 mg/dL in pregnancy. The active, ionized calcium level does not change significantly during a normal pregnancy. For pregnant individuals with mild hypercalcemia, pregnancy-associated hypercalciuria may prevent the distinction between familial hypocalciuric hypercalcemia and mild PHPT on the basis of calcium excretion and therefore necessitate genetic testing or deferral of diagnosis until post-pregnancy [12].

Surgery during the second trimester is the preferred treatment for symptomatic patients or those with a serum calcium level consistently >11 mg/dL (2.75 mmol/L) [10]; however, observation with adequate hydration may be appropriate in some circumstances (for some patients with asymptomatic, very mild hypercalcemia) [126]. In one small series, surgery was successfully performed in 15 of 16 patients during the third trimester [127]. In pregnant patients undergoing minimally invasive parathyroid surgery (MIP), localization is done with ultrasound rather than sestamibi. If a woman with diagnosed PHPT plans a pregnancy, parathyroidectomy should be done prior to conception. If a patient is followed through her pregnancy with very mild hypercalcemia, it is important to alert neonatologists to the possibility of hypocalcemia in the newborn (due to possible suppression of the fetal parathyroid gland). In such patients, parathyroidectomy should be recommended after delivery or prior to any subsequent pregnancy.

Pregnant individuals should not receive medical therapy with bisphosphonates, denosumab, or cinacalcet [12].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary hyperparathyroidism".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Primary hyperparathyroidism (The Basics)")

●Beyond the Basics topic (see "Patient education: Primary hyperparathyroidism (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Symptomatic primary hyperparathyroidism – Patients with symptomatic primary hyperparathyroidism (PHPT; nephrolithiasis, symptomatic hypercalcemia) should have parathyroid surgery, which is the only definitive therapy. Parathyroidectomy is an effective therapy that cures the disease, decreases the risk of kidney stones, improves bone mineral density (BMD), and may decrease fracture risk and modestly improve some quality-of-life measurements. (See 'Symptomatic' above.)

●Asymptomatic primary hyperparathyroidism – Surgical guidelines for asymptomatic PHPT have been developed based upon risk for end-organ effects and disease progression, as well as upon data regarding likelihood of improvement after surgery. Parathyroidectomy should be performed only by surgeons who are highly experienced and skilled in the operation. (See 'Asymptomatic' above.)

•For asymptomatic individuals who meet any of the Fifth International Workshop on Primary Hyperparathyroidism guidelines (table 1), we suggest surgical intervention as opposed to observation (Grade 2C). (See 'Candidates for surgery' above.)

•For asymptomatic individuals who do not meet surgical criteria, we monitor serum calcium and creatinine annually and bone density (hip, spine, and forearm) every one to two years. If disease progression occurs (table 1), we would proceed to surgery, as described above. (See 'Monitoring' above.)

Patients with asymptomatic PHPT who do not meet surgical intervention criteria may still choose parathyroidectomy because it is the only definitive therapy.

●Poor surgical candidates – For patients who are unable to have surgery and whose primary indication for surgery is symptomatic and/or severe hypercalcemia or osteoporosis and high risk for fracture, we recommend medical therapy rather than observation (Grade 1B). If there is no need to improve bone density or to lower the serum calcium, we do not use pharmacologic therapy. (See 'Poor surgical candidates' above.)

•Severe hypercalcemia – For such patients who are unable to have surgery and whose primary indication for surgery is symptomatic and/or severe hypercalcemia (particularly those in whom bone density is normal), we suggest cinacalcet rather than antiresorptive medications (Grade 2C). (See 'Severe hypercalcemia' above.)

•Osteoporosis – For individuals (symptomatic or asymptomatic) who are unable to have surgery and whose primary indication for surgery is osteoporosis and risk for fracture, we suggest bisphosphonates (Grade 2B). Bisphosphonates are generally the treatment of choice for adults with osteoporosis and high fracture risk. Denosumab is an option for patients who cannot tolerate bisphosphonate therapy. (See 'Osteoporosis' above.)

•Severe hypercalcemia and osteoporosis – For patients with severe hypercalcemia and very low bone density who are unable to have surgery, treatment with both cinacalcet and an antiresorptive agent is an option. (See 'Severe hypercalcemia and osteoporosis' above.)

●Concomitant vitamin D deficiency – For individuals with PHPT and a serum vitamin D level (25-hydroxyvitamin D [25(OH)D] ≤30 ng/mL [75 nmol/L]), we suggest vitamin D supplementation (Grade 2C). The goal is to maintain a 25(OH)D level >30 ng/mL (75 nmol/L) but <50 ng/mL (125 nmol/L). In such individuals, monitoring of serum and urine calcium to identify worsening hypercalcemia and/or hypercalciuria is necessary. (See 'Concomitant vitamin D deficiency' above.)