Calcimimetic Use in Familial Hypocalciuric Hypercalcemia-A Perspective in Endocrinology.

Context: Familial hypocalciuric hypercalcemia (FHH) causes lifelong hypercalcemia that even persists after subtotal parathyroidectomy. Symptoms are usually mild. Past recommendations have often been for monitoring and against surgical or pharmacologic treatments.
Methods: Review of publications about FHH, calcium-sensing receptors (CaSRs), and calcimimetics.
Results: FHH reflects heterozygous germline mutation of CASR, GNA11, or AP2S1. These mutations inactivate the CaSRs in the parathyroid cell. Thereby, they shift the serum calcium set point to higher values and cause hypercalcemia. Calcimimetic drugs enhance the effects of calcium on the CaSRs and thereby inhibit the parathyroid cell. Calcimimetic drugs are indicated in adults with primary hyperparathyroidism without a good surgical option. Calcimimetic safety and efficacy are not established in children younger than age 18 years. Recent case reports have described treatment of FHH with calcimimetics. Success was classified as combinations of subjective improvements and decreases of serum calcium levels, but not necessarily into the normal range. Treatment was successful in 14 of 16 cases (88%).
Conclusion: Deductions based on these case reports have limitations. For example, failures of therapy may not have been reported. Cost of the drug might be rate limiting. Calcimimetics can be offered to adults with FHH and those in whom the serum calcium level is >0.25 mM (1 mg/dL) beyond the upper limit of normal or with possible symptoms of hypercalcemia. Calcimimetics can now be offered to more adults with FHH.

Familial benign hypercalcemia or familial hypocalciuric hypercalcemia (FHH) is a hereditary disorder that involves lifelong hypercalcemia, a usually mild course, and resistance of hypercalcemia to subtotal parathyroidectomy (1, 2). It constitutes ~2% of cases of primary hyperparathyroidism (PHPT). Past recommendations were for use of medications in FHH rarely or not at all. Recent experiences with calcimimetic drugs suggest that these may be used in a larger fraction of cases of FHH than previously.

FHH causes lifelong hypercalcemia of varying degrees and similar to that in typical PHPT. Symptoms of FHH (e.g., fatigue, weakness, or thought disturbances) may be frequent, but they are usually mild (3, 4). Occasionally, FHH causes chondrocalcinosis or pancreatitis (3, 5, 6). The frequency of urolithiasis or osteopenia is not increased. Hypercalcemia begins in the first week of life and remains stable throughout adulthood. Serum parathyroid hormone (PTH) level is normal to mildly elevated; this indicates failure of parathyroid cell suppression, considering the simultaneous hypercalcemia. Urine calcium level is low to normal; this represents a relative hypocalciuria, considering the simultaneous hypercalcemia (7).

The usual cause of FHH (or FHH1) is a heterozygous inactivating germline mutation of the CASR gene that encodes the extracellular calcium-sensing receptor (CaSR). The CaSRs are expressed mainly on the parathyroid cells (8). They are sensors for extracellular calcium, and they regulate PTH secretion (1). They are the main determinant of the set point for blood calcium concentration. Inactivation of the mutant CaSRs in parathyroid cells of FHH causes hypercalcemia. Inactivation of the mutant CaSRs in the kidney accounts for the relative hypocalciuria in FHH (9).

Less frequently, FHH is caused by inactivating mutation of GNA11 or AP2S1 and this is termed FHH2 or FHH3, respectively; the latter two genes encode two molecules that are likely to be immediately downstream of the CaSR in the calcium sensing pathway of the parathyroid cell (10). The average hypercalcemia level is somewhat higher in FHH3 than in FHH1 (11).

The same heterozygous CASR mutations occasionally present as neonatal severe primary hyperparathyroidism (NSHPT), with a maximal serum calcium level of 3 to 4 mM (12). These cases show hyperparathyroid bone disease around the time of birth, with rib fractures, bell-shaped chest, and high PTH concentration. This more severe presentation is believed to be caused by superimposed secondary hyperparathyroidism in the mutant parathyroid cells of the affected fetus; the parathyroid cells inappropriately sense calcium deficiency from the normocalcemic mother and cause pathologic oversecretion of PTH in utero (12). With successful management and without parathyroidectomy, NSHPT from a heterozygous CASR mutation can evolve to become more typical neonatal FHH without secondary hyperparathyroidism. An even more severe form of NSHPT, with a maximal serum calcium level of 4 to 9 mM is rarely caused by biallelic CASR mutation (10, 13). DNA analysis is required to differentiate the two forms of NSHPT. Sometimes, finding hypercalcemia in both parents (each with FHH) can be a fast surrogate for the DNA information about biallelic CASR mutation in the neonate.

Several pharmacologic therapies had little affect on the hypercalcemia in FHH and were often recommended against (14–17). Subtotal parathyroidectomy in FHH is virtually always followed by persistent hypercalcemia, and this treatment is not recommended. Total parathyroidectomy in FHH leads to hypoparathyroidism and is recommended only for the most severe and rare cases, such as in most cases of NSHPT with biallelic mutation of the CASR (1, 2).

Calcimimetic drugs, such as cinacalcet, are allosteric agonists at the CaSR (10, 18). They enhance the effect of extracellular calcium at the CaSR in the parathyroid cell; in particular, they can decrease PTH secretion and serum calcium levels. They are approved by the US Food and Drug Administration in adults with secondary hyperparathyroidism who undergo dialysis (since 2004), in adults with PHPT without a good surgical option (since 2011), and in adults with PHPT resulting from parathyroid carcinoma (since 2004) (18). Their safety and efficacy in children younger than age 18 years is not established. Clinical trials of cinacalcet in children were suspended in 2013 after an unexplained death of a 14-year-old patient with hypocalcemia who was participating in a clinical trial of chronic renal failure and dialysis (19).

Calcimimetic efficacy in all these states probably reflects their action on the remaining wild-type CaSRs in pathologic parathyroid cells; the CaSRs are downregulated in these states (20). A beneficial action of a calcimimetic on the wild-type or even on some of the mutant CaSRs in FHH is a possibility. This is supported by data in vitro and in vivo (10, 12).

Principal adverse effects in treatment of PHPT include hypocalcemia (6% vs 0% in placebo), nausea (30% vs 18% in placebo), and vomiting (21–23). Physicians should read the full prescribing information (21). Cost of the drug might be rate limiting, particularly considering the possibility for long-term use in FHH (24).

The first case report of successful use of a calcimimetic in FHH was by Timmers et al. (25) in 2006, with normalization of serum calcium levels during a 12-month follow-up. Mayr et al. (13) reviewed case reports of calcimimetics for FHH or NSHPT into 2016. Usually the criteria for intervention included serum calcium level of 2.8 mM (11.2 mg/dL) or higher and symptoms possibly attributable to hypercalcemia. Because these were case reports, there were no uniform criteria for inclusion or for success. Success was generally ascribed to subjective improvement of symptoms and to a decrease, but not necessarily normalization, of serum calcium. There were reports of 16 cases of FHH treated by calcimimetics, with success reported in 14 (88%) (13, 26). This included success in each of four cases with FHH from mutation in AP2S1 (13, 27). In addition, recurrent pancreatitis remitted during calcimimetic maintenance in two FHH cases with recurrent pancreatitis (28, 29). Calcimimetics were used in four cases of NSHPT from heterozygous CASR mutation, with success in each (13, 30). Calcimimetics were ineffective in each of three cases with the most serious variant of NSHPT from biallelic CASR mutation (13).

The overall impression is of a high likelihood of success from calcimimetics in adults with FHH. Adverse effects were mild. Because these were all case reports, the possibility of various biases should be considered. More severe cases may have been selected for treatment, some treatment failures may not have been reported, and placebo effects were not excluded. A controlled trial would be highly desirable.

The successes with calcimimetics seem meaningful, even after considering possible weaknesses of the collection of case reports. The laboratory data and the clinical data about calcimimetics support an updating of the management recommendations in FHH (13). Cinacalcet is the only calcimimetic currently available for oral administration (19). It can be offered to many adults with FHH, particularly those with possible symptoms from hypercalcemia and particularly those whose serum calcium level is >0.25 mM (1 mg/dL) beyond the upper limit of normal. The calcium cutoff of 0.25 mM is derived from the cutoff for offering surgical intervention in asymptomatic PHPT, a condition related to FHH (2, 31). Recurrent pancreatitis in FHH would be a rare indication. Cinacalcet for FHH can be initiated and increased as in the product prescribing information for PHPT (22). If there is improvement of symptoms or serum calcium level during a trial of 8 to 12 weeks, the decision to continue the drug should be made by discussion with the patient. Although normalization of serum calcium levels is desirable, it is not an obligatory criterion for success. Similarly, serum PTH level often decreases during treatment, but it may not decrease during successful therapy in some cases. In long-term use, periodic holidays of 1 to 3 weeks off the drug should be tried at 1- to 2-year intervals.