Patients with asymptomatic or minimally symptomatic hypocalcemia can be managed in the outpatient setting. Calcium carbonate and calcium citrate are widely accepted forms of calcium supplementation (Table 35.1). In general, studies on the bioavailability of calcium carbonate and calcium citrate demonstrate conflicting results depending on the population studied and the methodology [10–12]. Premenopausal women treated with calcium carbonate exhibited improved calcium bioavailability measured by serum total and ionized calcium and PTH compared to treatment with calcium citrate [12]. Studies in postmenopausal women have demonstrated no difference or superior bioavailability of calcium citrate [10, 11, 13]. In addition to menopausal status, gastric acid secretion may account for some of these differences. In the presence of achlorhydria or diminished gastric acid output, as can be seen with proton-pump inhibitors and H₂ blockers, calcium citrate provides superior bioavailability because calcium carbonate requires an acidic environment for absorption [14]. Calcium carbonate and calcium citrate contain 40 and 21 % of elemental calcium, respectively. In general, 1–2 g of elemental calcium is administered three times a day.

In addition to calcium, treatment with vitamin D metabolites or analogs is critical in the management of hypoparathyroidism by improving intestinal calcium absorption and potentially by promoting bone remodeling ([15, 16]; reviewed in [17]). Vitamin D is available in several forms, which differ in onset of action, half-life, and cost (Table 35.2). Cholecalciferol (viamin D₃), which is cutaneously formed or obtained in the diet, has a half-life of approximately 20 h. Ergocalciferol (vitamin D₂), which is manufactured from yeast, has been used to treat severe vitamin D deficiency because historically it has been available in higher doses than cholecalciferol. However, several studies suggest that ergocalciferol is 3 times less potent, has a slower onset of action (3 days vs. 14 days) and has a shorter duration of action than cholecalciferol [18–21]. Calcidiol (25-hydroxyvitamin D₃), which is not commonly used for pharmacologic replacement, is produced by hydroxylation of cholecalciferol in the liver and has low biologic activity, but is the major metabolite in the bloodstream. Calcidiol is further hydroxylated in a PTH-dependent manner by renal 1α-hydroxylase in the kidney resulting in formation of the most active metabolite, calcitriol. Because of a rapid onset of action and no requirement for PTH-dependent conversion, calcitriol results in improvement of hypocalcemia within hours. The potency of calcitriol can result in hypercalcemia, however, this is quickly reversed upon discontinuation of calcitriol due to the short half-life of 4–6 h. Alfacalcidol (1-hydroxyvitamin D₃) and doxercalciferol (1-hydroxyvitamin D₂) are synthetic analogs that can be converted to calcitriol in the liver. Like calcitriol, alfacalcidol and doxercalciferol (1) do not require PTH-mediated activation, (2) have a rapid onset of action and short half-life, and (3) can induce hypercalcemia [22–26]. Doxercalciferol appears to be less prone to hypercalcemic episodes than calcitriol and alfacalcidol; however, these studies were performed in patients with secondary hyperparathyroidism and animals models, so their applicability to hypoparathyroidism is limited [26–28]. Prior to the availability of metabolically active forms of vitamin D, high doses of cholecalciferol or ergocalciferol were used to treat hypoparathyroidism with some success, perhaps due to (1) low affinity binding of cholecalciferol or ergocalciferol to the vitamin D receptor when supplemented at high doses and (2) limited conversion of cholecalciferol or ergocalciferol to calcitriol despite absence of PTH. At present, active metabolites of vitamin D are primarily used in the treatment of hypoparathyroidism. Cholecalciferol or ergocalciferol supplementation in addition to active metabolites of vitamin D may be beneficial because of a longer half-life and limited peripheral tissue-mediated conversion to calcitriol; however, further studies are needed to substantiate this possibility [29, 30].

Most complications that occur due to treatment of hypoparathyroidism are related to vitamin D toxicity, which can result in hyperphosphatemia, hypercalcemia, and hypercalciuria. Vitamin D supplementation enhances intestinal absorption of calcium and phosphorus. If hyperphosphatemia occurs, initial treatment is to reduce dietary intake. Phosphate binders are reserved for severe situations. Hypercalcemia may be short-lived or prolonged depending on the form of vitamin D replacement. Hypercalciuria can occur in the absence of hypercalcemia due to poor renal calcium resorption [25]. Thiazide diuretics are used in prevention and treatment of hypercalcemia and hypercalciuria.

Activation of the parathyroid CaSR results in increased intracellular Ca²⁺ and decreased PTH secretion. CaSR is expressed in parathyroid chief cells and in all nephron segments in the kidney. Activating CaSR mutations cause inappropriately low PTH levels in the setting of hypocalcemia. Although activation of renal CaSR primarily increases urinary calcium excretion, it also inhibits resorption of potassium, sodium, and water (reviewed by [37]). Calcimimetics potentiate the CaSR and inhibit PTH secretion and are useful in treatment of hyperparathyroidism whereas calcilytics inhibit the CaSR and can treat certain forms of hypoparathyroidism [38]. One of the early calcilytics, NPS 2143, reduced intracellular calcium in human embryonic kidney cells, stimulated PTH secretion from bovine parathyroid cells in vitro, and increased serum calcium in parathyroidectomized rats [38–41]. Because of promiscuous action against norepinephrine, dopamine, and serotonin monoamine transporters by NPS-2143, three other calcilytics, ronacaleret (SB-751689), NPSP795, and JTT-305/MK-5442, with a more desirable selectivity profile were developed. Ronacaleret administration in a randomized placebo-controlled trial of 569 postmenopausal women with osteoporosis resulted in increased serum calcium, PTH, and lumbar spine bone mineral density [42]. However, decreases in bone mineral density of the total hip, femoral neck, and trochanter were seen. The effects of ronacaleret in hypoparathyroidism have yet to be studied. Similarly, treatment with JTT-305/MK-5442 increased serum calcium, PTH, and bone formation markers in a randomized placebo-controlled trial on 383 postmenopausal women with osteoporosis [43]. NPSP795 is currently in Phase II clinical trials for treatment of hypoparathyroidism secondary to activating CaSR mutations. The efficacy of these medications in patients with hypoparathyroidism due to activating CaSR mutations will be critical because of the complications caused by calcium and vitamin D replacement, as well as the ineffectiveness of PTH replacement.

Treatment of hypoparathyroidism with the standard agents of calcium and vitamin D leaves patients vulnerable to psychiatric illnesses and increased morbidity from infections while exposing patients to the risks of renal and vascular disease. A retrospective U.S. study of patients with hypoparathyroidism indicated increased risk of chronic renal insufficiency and hospital admission related to hypoparathyroidism [44]. Nationwide Danish case-control studies in patients with postsurgical hypoparathyroidism demonstrated a fivefold increased risk of renal stones and renal insufficiency, twofold increased incidence of depression or bipolar disease, and increased risk of hospitalizations due to infection or seizure [45, 46]. In nonsurgical hypoparathyroidism, there was an increased risk of renal insufficiency, cardiac ischemia and arrhythmia, stroke, depression, and hospitalization due to infection in a similarly structured Danish case-control study [47]. One small case-control study demonstrated that intimal thickening of arteries was elevated in patients with hypoparathyroidism suggesting intimal thickening as a mechanism for risk of cardiovascular disease [48]. Together, these data imply that treatment of hypoparathyroidism with calcium and vitamin D cannot adequately replace PTH. Thus, interest in PTH replacement therapy has increased. Currently available pharmacologic replacement therapies include recombinant human PTH 1-34 and PTH 1-84 (Table 35.1, Fig. 35.1). Both proteins must be administered subcutaneously due to poor oral bioavailability.

The ideal treatment for hypoparathyroidism in most patients is replacement of functional, calcium-responsive parathyroid tissue. Although PTH hormone replacement therapy may provide some benefits over treatment with calcium and vitamin D, dosing regimens are still not physiologic. Several clinical and experimental models for transplantation of parathyroid tissue exist to prevent and treat hypoparathyroidism. Autotransplantation is performed in patients routinely, whereas allotransplantation is less common because of potential need for immunosuppression. Stem cell-derived parathyroid cells may offer restoration of physiologic parathyroid function in the future.

Maintenance of calcium homeostasis is essential for normal fetal development. Hypocalcemia attributable to undertreatment of hypoparathyroidism during pregnancy can result in fetal hyperparathyroidism, bone malformation, and death [126, 127]. Overtreatment resulting in maternal hypercalcemia can cause fetal parathyroid hypoplasia and miscarriage. During pregnancy, normal maternal calcium levels are maintained despite calcium mobilization to the fetal skeleton due to elevated levels of vitamin D metabolites and PTH related protein [128, 129]. Calcitriol requirements may be reduced or increased in the pregnant hypoparathyroid patient [126, 130–136]; however, calcitriol requirements generally decrease during lactation [130–132, 134, 137]. Historically, calcitriol was withheld during pregnancy due to concern for teratogenicity; however, recent studies have suggested that this is unlikely [126, 138]. Because of fluctuating calcitriol requirements, serum calcium levels should be assessed frequently during pregnancy and lactation. Generally, calcitriol requirements return to baseline after cessation of lactation.