Outcomes Of Therapeutic Intervention For Secondary Hyperparathyroidism (renal Hyperparathyroidism)
Feb 26, 2024
Since the introduction of cinacalcet in 2008, the treatment of secondary hyperparathyroidism (SHPT) has shifted from total parathyroidectomy (PTx), which had been the mainstream, to medical treatment. The effectiveness of PTx has been reported for some time, and the effectiveness of cinacalcet has also been reported in various studies. As a result, the number of PTx surgeries has decreased dramatically, with national statistics now showing less than 100 surgeries per year. Gastrointestinal symptoms caused by cinacalcet have also been reported, but recently, evocalcet, which causes fewer gastrointestinal symptoms, has also appeared. These medical treatments are expected to further reduce the number of PTx surgeries in the future. However, there are many patients who require PTx because they are unable or resistant to medical treatment. Therefore, PTx will continue to be one of the essential surgical techniques for endocrine surgeons. In this review, we would like to discuss the outcomes of medical and surgical treatments.
Key words: secondary hyperparathyroidism, calcimimetics, parathyroidectomy, mortality
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Introduction
To date, various complications have been reported due to secondary hyperparathyroidism (SHPT), including abnormalities in bone metabolism, as well as an increase in cardiovascular events and overall mortality due to its advanced progression [ 1-3]. In Japan, around 2008, cinacalcet, a treatment for SHPT, was introduced, leading to a major shift in treatment from surgical treatment, which had been the main treatment method up until then, to medical treatment, and total parathyroidectomy (total parathyroidectomy) for SHPT. PTx) decreased dramatically. According to national statistics from the PTx Study Group for Hyperparathyroidism, PTx was performed in 1,754 cases in 2007 (including cases of reoperation), but in 2019 the number increased to 90 cases (including cases of reoperation). It has been shown that this has decreased to (Figs. 1 and 2) [4]. Furthermore, with the advent of new calcimimetics, it is easy to predict that PTx will continue to decline. This review examines the outcomes of therapeutic interventions for secondary hyperparathyroidism.
①Treatment intervention criteria for SHPT
②Treatment methods for SHPT (a. medical treatment, b. surgical treatment)
③Describe the outcomes of each treatment method for SHPT in order.
1 . Annual number of parathyroidectomy for renal hyperparathyroidism in Japan. * Proposition of Japanese Society for Dialysis Therapy guideline.
Figure 2. Details of trends in the number of PTx cases in the PSSJ survey
PSSJ: PTx Study Group for Hyperparathyroidism PTx Study Group for Hyperparathyroidism (PSSJ) Working Group: Current status of PTx for SHPT in PSSJ survey 2019 http://2hpt-japs.jp/pdf/genkyo_v210107.pdf Reference May 6, 2021
①Treatment intervention criteria for SHPT
There are various treatment guidelines for bone mineral metabolism abnormalities, such as the K/DOQI and KIDIGO guidelines, but in Japan, the Japanese Society for Dialysis Medicine published the ``Guidelines for the Treatment of Secondary Hyperparathyroidism in Dialysis Patients'' in 2006. In 2012, the ``Clinical Guidelines for Bone and Mineral Metabolism Abnormalities Associated with Chronic Kidney Disease'' was published. Regarding the treatment of SHPT, the 2012 "Clinical Guidelines for Bone and Mineral Metabolism Abnormalities Associated with Chronic Kidney Disease" lists Chapter 2: Management target values for P and Ca, Chapter 3: Evaluation and management of parathyroid function, and Chapter 4: The chapter ``Indications and methods of parathyroid intervention'' provides detailed information, and it is appropriate to follow the ``Clinical guidelines for bone and mineral metabolic abnormalities associated with chronic kidney disease'' for the treatment intervention criteria and selection of treatment methods for SHPT. it is conceivable that.
②Treatment method for SHPT
a. Medical treatment method
These include traditional phosphate binders, vitamin D receptor agonists (VDRAs), and calcimimetics. Calcimimetics currently include the oral drugs cinacalcet and evocalcet, and the intravenous drug etelcalcetide.
b. surgical treatment
Total parathyroidectomy, total parathyroidectomy + autotransplantation, and subtotal parathyroidectomy are commonly performed. In Japan, total parathyroidectomy + autotransplantation is the most commonly performed surgical procedure.
③ Outcomes for each treatment method for SHPT
a. Outcome of medical treatment method (calcimimetics) 1. Outcomes of treatment with cinacalcetCinacalcet was the first calcimimetic available. Cinacalcet suppresses PTH production by acting allo sterically on Ca receptors in the parathyroid glands [5]. The MBD-5D study in Japan showed that the combination of cinacalcet and reduced doses of vitamin D preparations not only increased the effect of lowering serum PTH, but also showed the possibility of better control of serum Ca and serum P [6]. As a direct effect of cinacalcet on the parathyroid glands, it has been shown that it may cause histological changes in the parathyroid glands and reduce the volume of the enlarged parathyroid glands [7, 8].
The histological therapeutic effects of cinacalcet on bone are demonstrated in the Bone Biopsy Study For Dialysis Patients with Secondary Hyperparathyroidism of End Stage Renal Disease (BONAFIDE). In patients with high-turn over bone disease, long-term administration of cinacalcet has been shown to optimize the bone formation rate, and also to improve markers of high-turn over bone and bone tissue findings [9]. . Regarding clinical fracture events, the secondary endpoint of the Evaluation of Cinacalcet Hydrochloride Herapy to Lower Cardiovascular Events (EVOLVE) trial, intention-to-treat analysis showed no significant difference between the cinacalcet and placebo groups, but the prespecified lag -cen soring analysis showed that cinacalcet significantly lowers fracture risk [10]. Regarding the effect on mortality and cardiovascular events, which is the primary end point of the EVOLVE trial, intention-to-treat analysis did not show that cinacalcet was effective, but lag-censoring analysis showed that cinacalcet improved mortality. [11] Furthermore, in a sub-analysis of the EVOLVE trial, no significant difference was observed in atherosclerotic cardiovascular events, but cinacalcet was found to be effective in improving non-atherosclerotic cardiovascular events such as sudden death and heart failure [12 ]. On the other hand, the ADAVNCE study also showed that cinacalcet plus low dose vitamin D sterols may suppress cardiovascular calcification compared to treatment with only low dose vitamin D sterols through flexible dosing [ 13]. Studies conducted in Japan and Australia also showed that it reduced mortality and cardiovascular event mortality [14, 15]. There have also been reports that cinacalcet has an anemia-improving effect [16]. However, while these effects are observed, many gastrointestinal symptoms such as nausea and vomiting are observed, and it has been pointed out that the drug may not be fully taken in the end [11, 13, 17].
2. Outcomes of treatment with etelcalcetide
Following the oral drug cinacalcet, etelcalcetide was introduced as an intravenous drug. A randomized, double-blind, double-dummy clinical trial comparing cinacalcet and etelcalcetide was conducted in patients with SHPT in the United States, Canada, Europe, Russia, and New Zealand. Achievement rate of reducing serum PTH by 30% or more
In addition to the non-inferiority of etelcalcetide, the superiority of etelcalcetide is also demonstrated in its achievement rate of reducing serum PTH by 30% or more and 50% or more [18]. Etelcalcetide has also been shown to lower FGF23 more significantly than cinacalcet [19]. SHPT can be managed even in patient groups with poor medication adherence to cinacalcet.
The efficacy of etelcalcetide has also been shown [20].
However, similar to cinacalcet, gastrointestinal symptoms were observed, and the frequency was almost the same as with cinacalcet [18].
3. Outcomes of treatment with evocalcet
Evocalcet is the third oral calcimimetics to appear after etelcalcetide, which can be administered intravenously. Evocalcet was developed with the aim of reducing the gastrointestinal symptoms caused by cinacalcet and etelcalcetide.
A head-to-head comparison of cinacalcet and evocalcet showed that evocalcet was non-inferior to cinacalcet in achieving control of intact PTH within the target range, and gastrointestinal symptoms were 32.8% with cinacalcet. Evocalcet showed a significant reduction of 18.6% [21]. In addition, comparable reductions in FGF23, serum corrected Ca, serum P, and bone metabolism markers were observed with cinacalcet and evocalcet, and good clinical outcomes are expected in the future [21]. Switching from cinacalcet to evocalcet and long-term use of evocalcet are also expected to be safe and effective [22].
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