Update on Genetic and Clinical Aspects of Primary Hyperparathyroidism: Update on Genetic and Clinical Aspects of Primary Hyperparathyroidism

S. Miedlich, K. Krohn, R. Paschke

Disclosures

Clin Endocrinol. 2003;59(5) 

In This Article

Alternative Medical Approaches to Treat Patients With pHPT

The classical treatment and definitive cure of pHPT is the surgical removal of the pathological parathyroid glands. The success rate of the standard procedure, four-gland exploration, when carried out by an experienced endocrine surgeon is about 95% (Krubsack et al., 1989; Clark, 1994; Strewler, 1995). Recently, minimally invasive, unilateral surgical approaches using endoscopic techniques have been introduced promising a reduction in operative time, overall risk and stay in hospital (Mourad et al., 2001; Lorenz et al., 2001; Miccoli, 2002). Intraoperative PTH assays are highly predictive of successful removal of the pathological glands; a decrease of more than 50% predicts cure in more than 95% (Boggs et al., 1996; Mandell et al., 2001). However, preoperative localization studies (ultrasonography and sestamibi scintigraphy), not necessarily required prior to the standard procedure, are mandatory for the minimally invasive approaches. Therefore, the efficacy and cost-effectiveness of the new techniques compared to the standard procedure of parathyroidectomy have to be evaluated in future studies.

The growing percentage of oligo- and asymptomatic patients with pHPT and the slow progression of the disease have raised the question whether it is possible to monitor these patients without surgery, and to treat them medically. To date, studies of carefully selected, small groups of patients with pHPT have demonstrated beneficial effects on biochemical and physical parameters by use of oral phosphate, bisphosphonates, oestrogens, SERMs, vitamin D and calcimimetics.

Administration of oral phosphate to patients with mild pHPT led to reductions of serum calcium and 1,25-dihydroxyvitamin D concentrations. Although PTH levels increased, treatment with phosphate revealed a trend towards a reduction in bone turnover after 1 year (Broadus et al., 1983). However, long-term treatment with oral phosphate in patients with pHPT may increase the risk of nephrocalcinosis; and case reports describe the development of tertiary hyperparathyroidism as well as ectopic cardiac calcifications in patients with X-linked hypophosphatemic ricketts after prolonged therapy with oral phosphate (Huang et al., 2000; Wu et al., 2000; Moltz et al., 2001; Younis et al., 2001).

By their antiresorptive effects on bone, bisphosphonates supposedly have been shown to lower serum and urinary calcium levels in patients with pHPT. Thereby, they acutely stimulate hypersecretion of PTH which seemed to limit their potential use in patients with pHPT (Douglas et al., 1983; Hamdy et al., 1987; Adami et al., 1990, 1994; Reasner et al., 1993; Kotzmann et al., 1994; LoCascio et al., 1994; Rossini et al., 2001). However, despite an increase in PTH concentrations, a 2-year controlled study of oral alendronate confirmed significant gains in BMD in patients with mild pHPT (Rossini et al., 2001). Another small study of patients with pHPT confirmed this positive effect on BMD for the bisphosphonate etidronate without significant changes in serum calcium and PTH (Horiuchi et al., 2002).

As stated earlier, postmenopausal women with pHPT have been treated successfully with oestrogens and/or progestagens. Long-term hormone replacement therapy significantly reduced urinary calcium excretion, markers of bone turnover and increased bone mass (Selby & Peacock, 1986; Horowitz et al., 1987; McDermott et al., 1994; Diamond et al., 1996; Grey et al., 1996; Guo et al., 1996; Orr-Walker et al., 2000). Basal serum calcium and PTH levels were not influenced, which indicates that the above-mentioned changes could be mediated by the known osteoprotective effects of oestrogens. Some (Boucher et al., 1989; Zofkova et al., 1993) but not all (Prince et al., 1990) studies of oestrogen replacement therapy in healthy postmenopausal women report an increased suppressibility of PTH levels and a decrease of the calcium set-point, respectively. Therefore, direct effects of oestrogens on parathyroid cell function were suggested. However, the absence of significant quantities of oestrogen receptors in parathyroid tissue from patients with pHPT argues against a direct influence of oestrogens on parathyroid cell function (Prince et al., 1991; Sandelin et al., 1992).

SERMs were first introduced to treat patients with breast cancer (for review see Dhingra, 2001; O'Regan & Gradishar, 2001). They also mediate antiresorptive effects on bone in womenwith osteoporosis (Delmas et al., 1997; Ettinger et al., 1999). Preliminary studies of SERMs in patients with pHPT (n = 4) have shown a reduction in bone turnover and an increase in bone mass (Kristensen et al., 1989; Zanchetta & Bogado, 2001). Similarly to hormone replacement therapy, biochemical markers of bone turnover and urinary calcium decreased without significant changes of ionized serum calcium and PTH levels (Zanchetta & Bogado, 2001).

Administration of vitamin D reverses bone loss and reduces fracture risk in patients with low bone mass and vitamin D deficiency(Adams et al., 1999; Wasnich & Miller, 2000). In patients with pHPT and coexisting hypovitaminosis D, administration of vitamin D also increased BMD without significant changes of serum calcium and PTH levels (n = 5). It indicates that the persistence of hyperparathyroidism does not diminish the effectiveness of vitamin D replacement on bone (Kantorovich et al., 2000). However, frank hypercalciuria was induced in three patients. This effect may increase the risk of nephrolithiasis and thereby limit the usefulness of vitamin D supplements in patients with pHPT. However, a balanced nutritional intake (1000-1200 mg/day calcium, 400-600 U/day vitamin D), rather than the traditionally advocated avoidance of calcium and vitamin D, should be recommended for patients with mild pHPT.

Small organic compounds, like NPS R-467or NPS R-568, activate CaR in the presence of calcium by binding to a site distinct from the agonist-binding site (Nemeth et al., 1998). These compounds are therefore referred to as allosteric activators of the CaR. Application of NPS R-568 in the presence of extracellular calcium inhibits PTH secretion as well as cellular proliferation in vitro and in vivo (Wada et al., 1997, 2000; Nemeth et al., 1998; Roussanne et al., 2001). NPS R-568, and a second-generation compound AMG 073, have been subject of clinical trials for the treatment of various hyperparathyroid disorders such as primary and secondary hyperparathyroidism (Silverberg et al., 1997; Antonsen et al., 1998; Goodman et al., 2000; Shoback et al., 2000, 2001).

To date, oestrogens and bisphosphonates have been investigated in a number of studies in patients with pHPT. Due to their beneficial effects on bone metabolism and urinary calcium excretion, they may be approved as alternative therapeutic options for patients with pHPT. However, further long-term studies have yet to address potential negative effects of these drugs (such as stimulation of PTH secretion by bisphosphonates) on the course of pHPT. Oestrogens might be a treatment option for younger, postmenopausal women with asymptomatic pHPT. Bisphosphonates seem to be useful for elderly patients with mild to moderate pHPT, or patients with pHPT who are unwilling to undergo surgery. The long-term effects of SERMs and calcimimetics in patients with pHPT are currently under investigation. Bisphosphonates are also beneficial for the immediate treatment of severe hypercalcaemia in patients with pHPT. It should be noted that medical management of patients with pHPT requires a highly committed patient. Regular monitoring of biochemical and clinical parameters is mandatory in order to detect progression of the disease, and to prevent severe hypercalcaemia (Bilezikian et al., 2002).

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