Secondary Hyperparathyroidism: Pathogenesis and Latest Treatment

Abstract

The classic pathogenesis of secondary hyperparathyroidism (SHPT) began with the trade‐off hypothesis based on parathyroid hormone hypersecretion brought about by renal failure resulting from a physiological response to correct metabolic disorder of calcium, phosphorus, and vitamin D. In dialysis patients with failed renal function, physiological mineral balance control by parathyroid hormone through the kidney fails and hyperparathyroidism progresses. In this process, many significant genetic findings have been established. Abnormalities of Ca‐sensing receptor and vitamin D receptor are associated with the pathogenesis of SHPT, and fibroblast growth factor 23 has also been shown to be involved in the pathogenesis. Vitamin D receptor activators (VDRAs) are widely used for treatment of SHPT. However, VDRAs have calcemic and phosphatemic effects that limit their use to a subset of patients, and calcimimetics have been developed as alternative drugs for SHPT. Hyperphosphatemia also affects progression of SHPT, and control of hyperphosphatemia is, therefore, thought to be fundamental for control of SHPT. Currently, a combination of a VDRA and a calcimimetic is recognized as the optimal strategy for SHPT, and for other outcomes such as reduced cardiovascular disease and improved survival. The latest findings on the pathogenesis and treatment of SHPT are summarized in this review.

Evocalcet: A New Oral Calcimimetic for Dialysis Patients With Secondary Hyperparathyroidism

“…The resulting phosphorus accumulation enhances the production and secretion of fibroblast growth factor 23 (FGF‐23) and decreases the production of active vitamin D. Consequently, there is decreased Ca 2+ absorption in the intestinal tract and decreased blood Ca 2+ concentrations, leading to a disruption of Ca 2+ and phosphorus homeostasis. These changes—namely increased phosphorus, and decreased vitamin D and Ca 2+ levels—promote the synthesis and hypersecretion of PTH as well as parathyroid cell proliferation, resulting in secondary hyperparathyroidism (SHPT) .…”

Effects of Orai3-Mediated Store-Operated Calcium Entry on Parathyroid Hormone Release in Secondary Hyperparathyroidism

“…Phosphate accumulation, increased FGF23 levels, decreased vitamin D activity, and hypocalcemia are persistent stimulants of parathyroid hyperplasia and increased PTH secretion [25,26]. Calcitriol, a metabolite of vitamin D, inhibits the cell cycle regulator c-MYC, inhibits transforming growth factor α, and induces p21 to act as cell cycle inhibitor [27]. In breast cancer cells, Orai3 can also change the cell proliferation process through the c-MYC pathway [23].…”

<p>Erythropoietin Resistance in Patients with Chronic Kidney Disease: Current Perspectives</p>

“…In the final stages of CKD, parathyroid hormone (PTH) synthesis and secretion are continuously stimulated, causing secondary hyperparathyroidism (HPTS). 36 Although CKD-MBD is the most widely recognized consequence of HPTS in these patients, consistent evidence shows that PTH and fibroblast growth factor 23 (FGF23), both with markedly elevated levels in HPTS, have multiple adverse effects on extraskeletal tissues, including the pathological development of anemia. 37 The classical pathogenesis of anemia associated with HPTS in hemodialysis patients with CKD is established by excessive PTH secretion, which leads to bone marrow fibrosis and a consequent interference in erythropoiesis.…”

“…Several treatment options are available, including vitamin D receptor activators, cinacalcet hydrochloride, and parathyroidectomy. 36 However, the Mineral and Bone Disorders Outcomes Study for Japanese Chronic Kidney Disease Stage 5D Patients, a multicenter prospective cohort study conducted with hemodialysis patients with HPTS, showed that the use of a calcimimetic drug promoted a relatively small increase in Hb level and that further investigations are needed to define the role of calcimimetic drugs to control anemia. 39 Other Important Factors…”