PHPT is the most common endocrine disorder after thyroid diseases and diabetes and is the most common cause of hypercalcemia [4]. The estimated prevalence ranges between 1 and 4 cases per 1,000 persons in different countries and may reach up 2.6 % in older women in Sweden. The incidence of PHPT peaks in the sixth-seventh decade and is most common in women (female/male ratio 3:1). PHPT is most often caused by a single adenoma (80–85 %) and less frequently by multiple gland disease (10–15 %) or carcinoma (less than 1 %). It mainly occurs as a sporadic disease (90–95 %), but may be part of hereditary disorders (multiple endocrine neoplasia types 1 and 2A or the hyperparathyroidism–jaw tumor syndrome).

In the Western Countries the clinical profile has shifted from a symptomatic disease (hypercalcemic symptoms, kidney stones, overt bone disease) to one with absent or nonspecific manifestations (asymptomatic PHPT).

The diagnosis is usually made by the finding of a mild increase of albumin-adjusted serum calcium on routine biochemistry or in evaluating women with postmenopausal osteoporosis.

Plasma PTH measurement is the next step in the differential diagnosis of hypercalcemia. The simultaneous elevation of serum calcium and PTH (or an inappropriately normal PTH level) indicates the diagnosis of PHPT. Exceptions to this rule are the use of lithium or thiazides, tertiary hyperparathyroidism of end-stage renal failure, and familial hypocalciuric hypercalcemia.

Patients may complain of weakness and easy fatigability, anxiety, and cognitive impairment. Abnormalities of glucose and lipid metabolism are seen. Low-bone mineral density (BMD), particularly at sites enriched in cortical bone (e.g., distal 1/3 radius), is found in most patients. Nephrolithiasis has been reported in up to 7 % of patients with asymptomatic PHPT undergoing renal ultrasonographic evaluation.

Recently, another phenotype of PHPT, with increased PTH concentration in the absence of hypercalcemia (normocalcemic PHPT), has been detected particularly in women evaluated for low BMD [5]. Normocalcemic PHPT should be diagnosed only after exclusion of all causes of secondary hyperparathyroidism.

The natural course of PHPT depends upon its severity. Worsening usually occurs in symptomatic patients not undergoing parathyroidectomy. Conversely, studies most patients with asymptomatic mild PHPT have shown stability of serum calcium, PTH, creatinine, urinary calcium, and BMD for up to 8 years. Progression of the disease occurs in about one-third of patients, particularly in those aged less than 50 years [6].

Parathyroidectomy, with removal of all hyperfunctioning parathyroid tissue, is indicated in all patients with symptomatic PHPT and should be recommended in those with asymptomatic disease who met the criteria for surgery established by international guidelines [7] (Table 24.1). In experienced hand parathyroidectomy is successful in up to 95–98 %, with a low rate (1–3 %) of complications (laryngeal nerve injury and less frequently permanent hypocalcemia). A minimally invasive approach can be offered to most patients. Intraoperative PTH monitoring may be helpful in this setting. A single, benign chief-cell adenoma is usually found at histology. When histology is equivocal or suggests a possible malignancy, molecular studies may help to define the diagnosis [8]. Successful surgery is followed by a prompt normalization of PTH and serum and urinary calcium. BMD increases, mostly during the first few postoperative years. Recurrence of nephrolithiasis is rare. Recurrence of PHPT is rare in patients with sporadic PHPT, but it may occur in familial cases, unless total parathyroidectomy is performed.

A normal calcium intake should be recommended in patients not undergoing parathyroidectomy. Vitamin D deficiency, which appears to be associated with a more severe disease, should be corrected. Monitoring of serum calcium and creatinine every year and measurement of BMD every 1–2 years should be recommended to patients not undergoing parathyroidectomy. Vertebral fracture assessment should be done is clincally indicated. If renal stones suspetced, 24-h biochemical stone profile and renal imaging should be performed.

Medical therapy might be considered to reduce serum calcium or increase BMD in some of these patients. Beneficial effects of antiresorptive therapy have been shown in placebo-controlled clinical trials in postmenopausal women. In one trial of 2 years duration estrogen therapy (0.625 mg conjugated estrogen associated with 5 mg medroxyprogesterone daily) increased femoral neck and lumbar spine BMD [9], but long-term treatment with estrogen is no longer used because of the increased cardiovascular and breast-cancer risks. In another trial alendronate (10 mg daily for 2 years) reduced bone turnover markers and increased BMD at the lumbar spine and hip, but not at the distal radius. Serum calcium and PTH did not change significantly [10]. The calcimimetic cinacalcet may be considered in patients in whom BMD is not low. It has been show to decrease and often normalize serum calcium levels across a broad range of disease severity [11, 12], including patients with parathyroid carcinoma [13]. PTH levels declined only modestly and generally remained elevated. BMD did not change in patients given cinacalcet for up to 5.5 years. Cinacalcet may be associated with antiresorptive therapy in patients with low BMD. It is worth noting that no single or combined medical therapy is associated with a complete cure of PHPT and therefore medical therapy should not be offered as an alternative to patients who met the criteria for parathyroidectomy.