International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 5/2014 (360-368)
Original ©2014 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965 DOI 10.5414/CP202020 e-pub: February 26, 2014
Active vitamin D analogs, maxacalcitol and alfacalcidol, as maintenance therapy for mild secondary hyperparathyroidism in hemodialysis patients – a randomized study Hirokazu Honda1, Fumihiko Koiwa2, Hiroaki Ogata3, Kanji Shishido4, Takashi Sekiguchi5, Tetsuo Michihata6, Hajime Ogawa7, Masanori Mukai8, Keiko Takahashi4, Ryuji Suzuki9, Kyoko Kino10, Kenichi Kato11, Koji Yamamoto12, Eriko Kinugasa3, and Tadao Akizawa1 1Division
of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, 2Division of Nephrology, Department of Medicine, Showa University Fujigaoka Hospital, 3Department of Internal Medicine, Showa University Northern Yokohama Hospital, Yokohama, 4Kawasaki Clinic, Kawasaki, 5Sekiguchi Naika Clinic, Hachinohe, 6Ebara Clinic, 7Ogawa Clinic, 8Yukigaya Sanwa Clinic, 9Hitotsubashi Hospital, Tokyo, 10Bousei Hospital, Saitama, 11Yamanashi Red Cross Hospital, Minamituru, and 12Hatanodai Koike Clinic, Tokyo, Japan
Key words alfacalcidol – CKD-MBD – hemodialysis – maxacalcitol – secondary hyperparathyroidism
Received August 7, 2013; accepted November 20, 2013 Correspondence to Hirokazu Honda, MD, PhD Division of Nephrology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 141-8666, Japan hondah@ med.showa-u.ac.jp
Abstract. Background: The present randomized study was designed to compare the efficacy between two active vitamin D analogs, alfacalcidol (ACD) and maxacalcitol (OCT), for the management of mild secondary hyperparathyroidism (SHPT) in dialysis patients. Methods: SHPT in all 32 patients analyzed in the study was initially treated with OCT. Once patients’ intact PTH levels decreased to the target range of 150 – 180 pg/ mL, they were randomized either to switch to ACD at 0.5 µg/day (n = 14), or to remain on an effectively unchanged dose of OCT (n = 13). Phosphate, calcium, and intact PTH levels were measured every 2 weeks for 12 weeks and vitamin D doses were changed according to target ranges of phosphate (3.5 – 6.0 mg/dL), calcium (albuminadjusted calcium: 8.4 – 10.0 mg/dL), and intact parathyroid hormone (60 – 180 pg/ mL). Achievement rates of the target ranges of the parameters were estimated. Results: Baseline calcium levels in the OCT group were significantly higher than in the ACD group. Changes in achievement rates of target ranges of intact PTH and calcium during the study did not differ significantly between the vitamin D drugs. Changes in calcium levels in the OCT and ACD groups were similar during the study. Achievement rates of the target range of phosphate in both groups were also similar until 8 weeks, although the rate in the OCT group declined at 10 weeks. Conclusions: The efficacy and safety of OCT for the treatment of mild SHPT are similar to those of ACD in hemodialysis patients.
Introduction Chronic kidney disease mineral-bone disorder (CKD-MBD) is a systemic disorder characterized by abnormal serum levels of mineral-related biochemistries, bone abnormalities and extra skeletal calcification. CKDMBD is a significant cause of morbidity due to valvular heart disease and vascular calcification, and influences the quality of life as well as the prevalence of bone disease in CKD patients, especially those under dialysis [1]. Secondary hyperparathyroidism (SHPT) is the main abnormality related to CKD-MBD. Hence, adequate management of SHPT is required to prevent complications and improve clinical outcomes in these patients [2]. The Kidney Disease Outcomes Quality Initiative (KDOQI) was the first to provide evidence-based clinical practice guidelines for the management of SHPT, with several other guidelines being proposed after the KDOQI guidelines [3]. Finally, in recognition of the need to adapt international guidelines for each country, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines were established in 2009 [4]. However, Japanese dialysis patients show unique characteristics that are different from those in patients in the USA and Europe, including a much lower mortality and longer dialysis duration; in ad-
361
Vitamin D therapy for SHPT in HD patients
dition, there has been a limited availability of new drugs in Japan. Thus, the Japanese Society for Dialysis Therapy (JSDT) proposed the first guidelines for the management of SHPT in chronic dialysis patients [5]. The JSDT guidelines were mainly based on observational studies using the JSDT database, with an aim to set the target ranges of phosphate, calcium and intact parathyroid hormone (PTH), depending, as much as possible, upon the best survival rate [5]. However, some questions remain regarding the management of SHPT in terms of compliance with the target range of parameters. Danese et al. [6] demonstrated that maintenance of target PTH concentration could prevent bone fractures, which is an important risk factor for mortality and hospitalization in hemodialysis patients [7]. Thus, adequate and persistent treatment for SHPT is required to prevent bone fractures in these patients as well as in the general population [8]. In order to prevent or slow the development of SHPT, treatment of phosphate retention or hyperphosphatemia and adequate supplements of vitamin D should be considered. Active vitamin D analogs, such as alfacalcidol (ACD), are often used for the treatment of vitamin D deficiency in patients with SHPT [9]. However, ACD can cause dose-dependent increase in phosphate and calcium absorption in the intestines and worsening of the hyperphosphatemia [10]. Hence, it is not always possible to administer appropriate doses of ACD that are adequate for the disease severity of SHPT. Moreover, the efficacy of ACD in patients with moderate to severe SHPT is possibly weak compared with that of other active vitamin D analogs [11]. Maxacalcitol (OCT), another of the active vitamin D analogs, has shown less calcemic action and a strong suppressive effect on PTH secretion in uremic animal models. OCT also dose-dependently suppresses PTH secretion in human SHPT. In some cases, increased serum calcium levels could be observed, although, usually, this is an unphysiological change 12). Thus, OCT is also used to treat SHPT, especially moderate to severe SHPT, in hemodialysis patients [13, 14]. Studies between OCT and active vitamin D, calcitriol, have been performed in hemodialysis (HD) patients [15, 16, 17]. Hayashi et al. [15] reported that OCT is equally effective as calcitriol for the treatment of SHPT,
when used as initial and maintenance therapies. Regarding OCT and ACD, Adachi et al. [18] demonstrated the efficacy of maintenance ACD therapy after intravenous OCT for SHPT. However, the efficacy of OCT as maintenance therapy in patients with mild SHPT is uncertain. Therefore, the present study was designed to clarify the efficacy and safety of the active vitamin D analogs, ACD and OCT, for the management of mild SHPT in HD patients.
Methods Subjects The ethics committee of Showa University School of Medicine approved the study protocol (approval number, 07504), and each patient provided written informed consent to participate in the study. The study was performed according to the 2004 revised Helsinki Declaration. 32 patients undergoing maintenance HD were recruited from nine HD clinics for this randomized, prospective study between December 1, 2007 and October 31, 2009. Inclusion criteria were stable patients on HD who were ≥ 18 years and ≤ 75 years of age, with intact PTH levels between 180 and 500 pg/mL, phosphate levels between 3.5 and 7.0 mg/dL, and albumin-adjusted calcium levels between 8.4 and 10.5 mg/dL at the time of pre-HD measurement, indicative of mild SHPT. Exclusion criteria comprised moderate to severe heart failure or liver dysfunction, pregnant or lactating women, history of drug allergy, aluminum bone diseases, primary HPT, malignancy, and presence of acute or severe chronic infectious disease at the time of recruitment. Patients with SHPT who were treated by cinacalcet, parathyroidectomy, or direct percutaneous parathyroid gland ethanol (or vitamin D) injection therapy, or who participated in another clinical study within 3 months of this study were also excluded. All patients were similarly managed in terms of medical treatment and medication according to the JSDT guidelines, including management of CKD-MBD [5]. All recruited patients underwent three sessions of HD per week (3 – 4 hours per session) using standard high-flux polysulfone or cellulose acetate membranes. The type of dialyzer membrane
362
Honda, Koiwa, Ogata, et al.
and HD dose remained unchanged during the study. Patients were recommended to maintain a daily protein intake of 1.0 – 1.2 g/kg body weight and a daily phosphate intake of 800 mg/ day. Dialysate calcium concentration did not differ among the facilities and all facilities used the calcium concentration of 2.5 mEq/L.
(or vitamin D) infusion therapy, patients were excluded from analysis. During the study, patients were not allowed to simultaneously receive vitamin D or its other analogs, bisphosphonates or drugs containing calcitonin. Use of lanthanum carbonate and/or calcimimetics was not permitted during the study as well.
Study design
Outcome
This randomized study was planned as an exploratory study; thus, we did not estimate a pre-specified expected size for the trial and an expected effect of the randomization by statistical methods. The total anticipated enrollment in this study was 40 patients, based on the expected total number of mild SHPT patients per year in the nine HD clinics. Finally, however, 32 patients with mild SHPT were enrolled in this study during the enrollment period. Initial treatment for SHPT in all 32 patients was by intravenous OCT. Randomization was performed using the randomization plan made by the first (and original) generator (http://www.randomization.com). The randomization plan for the two treatment labels, ACD or OCT, was created with 25 blocks of 4 subjects each per 100 subjects. When patients’ intact PTH levels decreased to between 150 and 180 pg/mL, they were randomized into two groups for further treatment (2 weeks before baseline): the ACD group, in which patients were essentially switched to oral ACD at a dose of 0.5 µg/day from baseline, and the OCT group, in which the dose of OCT at randomization was essentially continued. However, doses of ACD and OCT could be adjusted from baseline, depending on phosphate, albumin-adjusted calcium and intact PTH levels. Phosphate, calcium, and intact PTH levels were followed up every 2 weeks. Doses of vitamin D and phosphate binders, such as calcium containing phosphate binders or sevelamer HCl, were adjusted according to the JSDT guideline [5] and the target ranges of phosphate (3.5 – 6.0 mg/dL), calcium (albumin-adjusted calcium: 8.4 – 10.0 mg/ dL), and intact PTH (60 – 180 pg/mL). Minimum doses of ACD and OCT were 0.25 µg/ day and 2.5 µg/once a week, respectively. If the parameters could not be controlled by the minimum dose of vitamin D or if patients required alternative treatment for SHPT, such as parathyroidectomy or percutaneous ethanol
The primary outcome was achievement of the target range of intact PTH levels during the observation period, while secondary outcomes were changes in phosphate, calcium levels and intact-PTH, achievement rates of the target range of phosphate and calcium levels, and combined achievement rates of the three parameters during the observation period. Changes in the biomarkers of bone turnover, bone alkaline phosphatase, intact osteocalcin and whole PTH, between baseline and 12 weeks after the start of therapy, were also estimated as secondary outcomes.
Measurement of biological markers Baseline venous blood samples were obtained before HD on the 3rd day after the previous dialysis session and every 2 weeks thereafter, to measure routine biochemical parameters, including albumin, phosphate, calcium and intact PTH. Alkaline phosphatase was measured at baseline, 4, 8, and 12 weeks. Serum samples obtained from each patient at baseline and 12 weeks were immediately frozen and stored at –80 °C until analysis for bone alkaline phosphatase, intact osteocalcin, and whole PTH, as biomarkers of bone turnover.
Statistical analysis Data are presented as means ± SD or median (range), unless otherwise noted, with p
Original ©2014 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965 DOI 10.5414/CP202020 e-pub: February 26, 2014
Active vitamin D analogs, maxacalcitol and alfacalcidol, as maintenance therapy for mild secondary hyperparathyroidism in hemodialysis patients – a randomized study Hirokazu Honda1, Fumihiko Koiwa2, Hiroaki Ogata3, Kanji Shishido4, Takashi Sekiguchi5, Tetsuo Michihata6, Hajime Ogawa7, Masanori Mukai8, Keiko Takahashi4, Ryuji Suzuki9, Kyoko Kino10, Kenichi Kato11, Koji Yamamoto12, Eriko Kinugasa3, and Tadao Akizawa1 1Division
of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, 2Division of Nephrology, Department of Medicine, Showa University Fujigaoka Hospital, 3Department of Internal Medicine, Showa University Northern Yokohama Hospital, Yokohama, 4Kawasaki Clinic, Kawasaki, 5Sekiguchi Naika Clinic, Hachinohe, 6Ebara Clinic, 7Ogawa Clinic, 8Yukigaya Sanwa Clinic, 9Hitotsubashi Hospital, Tokyo, 10Bousei Hospital, Saitama, 11Yamanashi Red Cross Hospital, Minamituru, and 12Hatanodai Koike Clinic, Tokyo, Japan
Key words alfacalcidol – CKD-MBD – hemodialysis – maxacalcitol – secondary hyperparathyroidism
Received August 7, 2013; accepted November 20, 2013 Correspondence to Hirokazu Honda, MD, PhD Division of Nephrology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 141-8666, Japan hondah@ med.showa-u.ac.jp
Abstract. Background: The present randomized study was designed to compare the efficacy between two active vitamin D analogs, alfacalcidol (ACD) and maxacalcitol (OCT), for the management of mild secondary hyperparathyroidism (SHPT) in dialysis patients. Methods: SHPT in all 32 patients analyzed in the study was initially treated with OCT. Once patients’ intact PTH levels decreased to the target range of 150 – 180 pg/ mL, they were randomized either to switch to ACD at 0.5 µg/day (n = 14), or to remain on an effectively unchanged dose of OCT (n = 13). Phosphate, calcium, and intact PTH levels were measured every 2 weeks for 12 weeks and vitamin D doses were changed according to target ranges of phosphate (3.5 – 6.0 mg/dL), calcium (albuminadjusted calcium: 8.4 – 10.0 mg/dL), and intact parathyroid hormone (60 – 180 pg/ mL). Achievement rates of the target ranges of the parameters were estimated. Results: Baseline calcium levels in the OCT group were significantly higher than in the ACD group. Changes in achievement rates of target ranges of intact PTH and calcium during the study did not differ significantly between the vitamin D drugs. Changes in calcium levels in the OCT and ACD groups were similar during the study. Achievement rates of the target range of phosphate in both groups were also similar until 8 weeks, although the rate in the OCT group declined at 10 weeks. Conclusions: The efficacy and safety of OCT for the treatment of mild SHPT are similar to those of ACD in hemodialysis patients.
Introduction Chronic kidney disease mineral-bone disorder (CKD-MBD) is a systemic disorder characterized by abnormal serum levels of mineral-related biochemistries, bone abnormalities and extra skeletal calcification. CKDMBD is a significant cause of morbidity due to valvular heart disease and vascular calcification, and influences the quality of life as well as the prevalence of bone disease in CKD patients, especially those under dialysis [1]. Secondary hyperparathyroidism (SHPT) is the main abnormality related to CKD-MBD. Hence, adequate management of SHPT is required to prevent complications and improve clinical outcomes in these patients [2]. The Kidney Disease Outcomes Quality Initiative (KDOQI) was the first to provide evidence-based clinical practice guidelines for the management of SHPT, with several other guidelines being proposed after the KDOQI guidelines [3]. Finally, in recognition of the need to adapt international guidelines for each country, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines were established in 2009 [4]. However, Japanese dialysis patients show unique characteristics that are different from those in patients in the USA and Europe, including a much lower mortality and longer dialysis duration; in ad-
361
Vitamin D therapy for SHPT in HD patients
dition, there has been a limited availability of new drugs in Japan. Thus, the Japanese Society for Dialysis Therapy (JSDT) proposed the first guidelines for the management of SHPT in chronic dialysis patients [5]. The JSDT guidelines were mainly based on observational studies using the JSDT database, with an aim to set the target ranges of phosphate, calcium and intact parathyroid hormone (PTH), depending, as much as possible, upon the best survival rate [5]. However, some questions remain regarding the management of SHPT in terms of compliance with the target range of parameters. Danese et al. [6] demonstrated that maintenance of target PTH concentration could prevent bone fractures, which is an important risk factor for mortality and hospitalization in hemodialysis patients [7]. Thus, adequate and persistent treatment for SHPT is required to prevent bone fractures in these patients as well as in the general population [8]. In order to prevent or slow the development of SHPT, treatment of phosphate retention or hyperphosphatemia and adequate supplements of vitamin D should be considered. Active vitamin D analogs, such as alfacalcidol (ACD), are often used for the treatment of vitamin D deficiency in patients with SHPT [9]. However, ACD can cause dose-dependent increase in phosphate and calcium absorption in the intestines and worsening of the hyperphosphatemia [10]. Hence, it is not always possible to administer appropriate doses of ACD that are adequate for the disease severity of SHPT. Moreover, the efficacy of ACD in patients with moderate to severe SHPT is possibly weak compared with that of other active vitamin D analogs [11]. Maxacalcitol (OCT), another of the active vitamin D analogs, has shown less calcemic action and a strong suppressive effect on PTH secretion in uremic animal models. OCT also dose-dependently suppresses PTH secretion in human SHPT. In some cases, increased serum calcium levels could be observed, although, usually, this is an unphysiological change 12). Thus, OCT is also used to treat SHPT, especially moderate to severe SHPT, in hemodialysis patients [13, 14]. Studies between OCT and active vitamin D, calcitriol, have been performed in hemodialysis (HD) patients [15, 16, 17]. Hayashi et al. [15] reported that OCT is equally effective as calcitriol for the treatment of SHPT,
when used as initial and maintenance therapies. Regarding OCT and ACD, Adachi et al. [18] demonstrated the efficacy of maintenance ACD therapy after intravenous OCT for SHPT. However, the efficacy of OCT as maintenance therapy in patients with mild SHPT is uncertain. Therefore, the present study was designed to clarify the efficacy and safety of the active vitamin D analogs, ACD and OCT, for the management of mild SHPT in HD patients.
Methods Subjects The ethics committee of Showa University School of Medicine approved the study protocol (approval number, 07504), and each patient provided written informed consent to participate in the study. The study was performed according to the 2004 revised Helsinki Declaration. 32 patients undergoing maintenance HD were recruited from nine HD clinics for this randomized, prospective study between December 1, 2007 and October 31, 2009. Inclusion criteria were stable patients on HD who were ≥ 18 years and ≤ 75 years of age, with intact PTH levels between 180 and 500 pg/mL, phosphate levels between 3.5 and 7.0 mg/dL, and albumin-adjusted calcium levels between 8.4 and 10.5 mg/dL at the time of pre-HD measurement, indicative of mild SHPT. Exclusion criteria comprised moderate to severe heart failure or liver dysfunction, pregnant or lactating women, history of drug allergy, aluminum bone diseases, primary HPT, malignancy, and presence of acute or severe chronic infectious disease at the time of recruitment. Patients with SHPT who were treated by cinacalcet, parathyroidectomy, or direct percutaneous parathyroid gland ethanol (or vitamin D) injection therapy, or who participated in another clinical study within 3 months of this study were also excluded. All patients were similarly managed in terms of medical treatment and medication according to the JSDT guidelines, including management of CKD-MBD [5]. All recruited patients underwent three sessions of HD per week (3 – 4 hours per session) using standard high-flux polysulfone or cellulose acetate membranes. The type of dialyzer membrane
362
Honda, Koiwa, Ogata, et al.
and HD dose remained unchanged during the study. Patients were recommended to maintain a daily protein intake of 1.0 – 1.2 g/kg body weight and a daily phosphate intake of 800 mg/ day. Dialysate calcium concentration did not differ among the facilities and all facilities used the calcium concentration of 2.5 mEq/L.
(or vitamin D) infusion therapy, patients were excluded from analysis. During the study, patients were not allowed to simultaneously receive vitamin D or its other analogs, bisphosphonates or drugs containing calcitonin. Use of lanthanum carbonate and/or calcimimetics was not permitted during the study as well.
Study design
Outcome
This randomized study was planned as an exploratory study; thus, we did not estimate a pre-specified expected size for the trial and an expected effect of the randomization by statistical methods. The total anticipated enrollment in this study was 40 patients, based on the expected total number of mild SHPT patients per year in the nine HD clinics. Finally, however, 32 patients with mild SHPT were enrolled in this study during the enrollment period. Initial treatment for SHPT in all 32 patients was by intravenous OCT. Randomization was performed using the randomization plan made by the first (and original) generator (http://www.randomization.com). The randomization plan for the two treatment labels, ACD or OCT, was created with 25 blocks of 4 subjects each per 100 subjects. When patients’ intact PTH levels decreased to between 150 and 180 pg/mL, they were randomized into two groups for further treatment (2 weeks before baseline): the ACD group, in which patients were essentially switched to oral ACD at a dose of 0.5 µg/day from baseline, and the OCT group, in which the dose of OCT at randomization was essentially continued. However, doses of ACD and OCT could be adjusted from baseline, depending on phosphate, albumin-adjusted calcium and intact PTH levels. Phosphate, calcium, and intact PTH levels were followed up every 2 weeks. Doses of vitamin D and phosphate binders, such as calcium containing phosphate binders or sevelamer HCl, were adjusted according to the JSDT guideline [5] and the target ranges of phosphate (3.5 – 6.0 mg/dL), calcium (albumin-adjusted calcium: 8.4 – 10.0 mg/ dL), and intact PTH (60 – 180 pg/mL). Minimum doses of ACD and OCT were 0.25 µg/ day and 2.5 µg/once a week, respectively. If the parameters could not be controlled by the minimum dose of vitamin D or if patients required alternative treatment for SHPT, such as parathyroidectomy or percutaneous ethanol
The primary outcome was achievement of the target range of intact PTH levels during the observation period, while secondary outcomes were changes in phosphate, calcium levels and intact-PTH, achievement rates of the target range of phosphate and calcium levels, and combined achievement rates of the three parameters during the observation period. Changes in the biomarkers of bone turnover, bone alkaline phosphatase, intact osteocalcin and whole PTH, between baseline and 12 weeks after the start of therapy, were also estimated as secondary outcomes.
Measurement of biological markers Baseline venous blood samples were obtained before HD on the 3rd day after the previous dialysis session and every 2 weeks thereafter, to measure routine biochemical parameters, including albumin, phosphate, calcium and intact PTH. Alkaline phosphatase was measured at baseline, 4, 8, and 12 weeks. Serum samples obtained from each patient at baseline and 12 weeks were immediately frozen and stored at –80 °C until analysis for bone alkaline phosphatase, intact osteocalcin, and whole PTH, as biomarkers of bone turnover.
Statistical analysis Data are presented as means ± SD or median (range), unless otherwise noted, with p
