Restoration of Parathyroid Function After Change of Phosphate Binder From Calcium Carbonate to Lanthanum Carbonate in Hemodialysis Patients With Suppressed Serum Parathyroid Hormone

ICURT PROCEEDINGS

Restoration of Parathyroid Function After Change of Phosphate Binder From Calcium Carbonate to Lanthanum Carbonate in Hemodialysis Patients With Suppressed Serum Parathyroid Hormone Masaaki Inaba, MD, PhD,*,† Senji Okuno, MD, PhD,*,† Harumi Nagayama, MD,*,† Shinsuke Yamada, MD, PhD,*,† Eiji Ishimura, MD, PhD,*,† Yasuo Imanishi, MD, PhD,*,† and Shigeichi Shoji, MD, PhD*,† Control of phosphate is the most critical in the treatment of chronic kidney disease with mineral and bone disorder (CKD-MBD). Because calcium-containing phosphate binder to CKD patients is known to induce adynamic bone disease with ectopic calcification by increasing calcium load, we examined the effect of lanthanum carbonate (LaC), a non-calcium containing phosphate binder, to restore bone turnover in 27 hemodialysis patients with suppressed parathyroid function (serum intact parathyroid hormone [iPTH] & 150 pg/ mL). At the initiation of LaC administration, the dose of calcium-containing phosphate binder calcium carbonate (CaC) was withdrawn or reduced based on serum phosphate. After initiation of LaC administration, serum calcium and phosphate decreased significantly by 4 weeks, whereas whole PTH and iPTH increased. A significant and positive correlation between decreases of serum calcium, but not phosphate, with increases of whole PTH and iPTH, suggested that the decline in serum calcium with reduction of calcium load by LaC might increase parathyroid function. Serum bone resorption markers, such as serum tartrate–resistant acid phosphatase 5b, and Ntelopeptide of type I collagen increased significantly by 4 weeks after LaC administration, which was followed by increases of serum bone formation markers including serum bone alkaline phosphatase, intact procollagen N-propeptide, and osteocalcin. Therefore, it was suggested that LaC attenuated CaC-induced suppression of parathyroid function and bone turnover by decreasing calcium load. In conclusion, replacement of CaC with LaC, either partially or totally, could increase parathyroid function and resultant bone turnover in hemodialysis patients with serum iPTH & 150 pg/mL. Ó 2015 by the National Kidney Foundation, Inc. All rights reserved.

I

T IS INCREASINGLY recognized that the prevalence rate of chronic kidney disease (CKD), a potent cardiovascular disease risk, is rather high around 13% of the general Japanese population,1 which is complicated with CKD-mineral and bone disorder (CKD-MBD).2 Among the various abnormalities, phosphate load is thought as an initial event to cause CKD-MBD. Phosphate load into circulation becomes more remarkable in CKD patients as renal function decreases.3 In addition, oral phosphate loading to CKD patients might form vicious cycle to further increase phosphate release from bone by inducing hyperparathyroidism.4 Therefore, it is important to restrict oral phosphate intake to subside phosphate load particularly *

Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan. † Department of Nephrology, Shirasagi Hospital, Osaka, Japan. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Masaaki Inaba, MD, Department of Metabolism, Endocrinology and Molecular Medicine, Internal Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. E-mail: [email protected] Ó 2015 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2014.10.013

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in CKD patients to protect against the development of secondary hyperparathyroidism and vascular calcification. Lanthanum carbonate (LaC), a non-calcium containing phosphate binder, differs from CaC in that it does not increase calcium load to induce adynamic bone disease (ABD) or aortic calcification in hemodialysis (HD) patients.5 We recently reported that initiation of LaC administration to HD patients with ABD restored normal bone formation on bone histomorphometrical analysis.6 The present study was performed to examine (i) whether LaC might increase serum parathyroid hormone (PTH) and bone metabolic markers in HD patients with suppressed serum intact PTH (iPTH) ,100 pg/mL, (ii) what mechanism might be involved in the LaC-restored parathyroid function.

Methods Patients A total of 27 HD patients (17 males and 10 females) were enrolled in the study after informed consent was obtained. The main entry criteria were mean iPTH &150 pg/mL (target lower limit based on K/DOQI clinical practice guidelines7) before treatment with LaC. Patients with acute illness, significant infection, or malignancy and those who had received HD for ,1 year were excluded. For 4 weeks Journal of Renal Nutrition, Vol 25, No 2 (March), 2015: pp 242-246

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before initiation of the study and 24 weeks during the study period, the regimen of drugs that could affect calcium metabolism was not changed except for the dose of CaC. All 27 HD patients completed the study. The study was approved by the Ethics Review Committee of Osaka City University Graduate School of Medicine.

Study Design For HD patients with serum phosphate levels &6.0 mg/ dL on the basis of Japanese Clinical practice guideline for the management of CKD-MBD,8 CaC was totally replaced with LaC at the starting oral daily dose of 750 mg after each meal during 24 weeks. For those with serum phosphate levels .6.0 mg/dL, LaC at the daily dose of 750 mg was administered in addition to the prescribed CaC to restore serum phosphate levels to target range &6.0 mg/dL. In the replacement group, CaC at the daily dose of 2080 6 840 mg was replaced initially with LaC at the daily dose of 750 mg and did not change essentially to 770 6 160 mg during the study period of 24 weeks. In the add-on groups, the daily dose of CaC at the start of this study was 3190 6 1330 mg which was reduced to 2810 6 1450 mg/day at the end of the study, whereas the dose of LaC was increased form 750 mg/day to 910 6 460 mg/day. Blood was drawn in the morning after an overnight fast. Biochemical Markers for Calcium and Bone Metabolism Biochemical markers for calcium and bone metabolism were measured as described previously. Serum tartrate–resistant acid phosphatase 5b activity and N-telopeptide of type 1 collagen (NTX) was measured by fragments absorbed immunocapture enzymatic assay and enzyme-linked immunosorbent assay (Osteomark), respectively. Serum bone alkaline phosphatase (BAP), intact osteocalcin (IOC), and type I pro-

collagen N-terminal propeptide (P1NP) were measured by enzyme immunoassay (Alkphase-B), immunoradiometric assay (Mitsubishi Kagaku), and radioimmunoassay (Orion Diagnostica), respectively.9-11

PTH Assay Serum active PTH(1-84) was measured using a whole PTH (wPTH) assay (Scantibodies Laboratory, Santee, CA) as described previously. Serum iPTH, which reflects both biologically active PTH(1-84) and the large C-terminal fragment, was measured by electrochemiluminescence immunoassay (Roche Diagnostics, Tokyo, Japan).11 Statistical Analysis Data were analyzed using StatView 5.0 J (Abacus Concepts, Inc, Piscataway, NJ). Each result is expressed as a mean 6 standard deviation unless otherwise indicated. Correlation coefficients were calculated by simple regression analysis. Comparisons of changes in parameters were analyzed by Tukey-Kramer multiple comparison analysis of variance test, with P values , .05 considered statistically significant.

Results Clinical Characteristics of the HD Patients The baseline characteristics of the HD patients are shown in Table 1. The mean serum calcium and phosphate were 9.5 6 0.6 mg/dL and 5.8 6 1.6 mg/dL, respectively, and the median serum iPTH and wPTH were 59 (range: 13150) and 28.5 (range: 6.8-92.0) pg/mL, respectively. Considering for the target levels of serum iPTH 150 to 300 pg/mL by kidney disease outcomes quality initiatives CKD-MBD guideline, the enrolled subjects are assumed to exhibit suppressed parathyroid function. However, the median serum bone markers, such as BAP, P1NP, and TRAP-5b, were all within their respective normal ranges,

Table 1. Clinical Characteristics of the Enrolled Hemodialysis Patients Variable Age (y) Gender (male/female) Hemodialysis duration (mo) Diabetes (1/2) Body mass index (kg/m2) La carbonate (change/add) Calcium (mg/dL) Phosphate (mg/dL) Intact PTH (pg/mL) Whole PTH (pg/mL) BAP (mg/L) P1NP (mg/L) Intact OC (ng/mL) TRACP-5b (mU/L) NTX (nmol BCE/L)

Mean 6 SD or Median (Range)

Normal Range

64.0 6 12.2 17/10 78.5 6 66.5 14/11 21.6 6 2.8 12/15 9.5 6 0.6 5.8 6 1.6 59 (13-150) 28.5 (6.8-92.0) 10.4 (6.2-22.1) 46.1 (14.7-148.0) 19.0 (8.5-98.0) 303 (115-940) 54.0 (14.0-143.0)

8.5-10.2 2.4-4.3 10-65 9-39 Male: 3.7-20.9, female premenopause: 2.9-14.5 Male: 19.0-83.5, female premenopause: 14.9-68.8 2.5-13.0 Male: 170-590, female premenopause: 120-420 Male: 9.5-17.7, female premenopause: 7.5-16.5

BAP, bone alkaline phosphatase; La, lanthanum; NTX, N-telopeptide of type 1 collagen; OC, osteocalcium; P1NP, type I procollagen N-terminal propeptide; PTH, parathyroid hormone; SD, standard deviation; TRACP, tartrate-resistant acid phosphatase. Data are expressed as mean 6 standard deviation for the variables with normal distribution or median (range) for the variables with nonnormal distribution.

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as the secondary event to that of bone resorption via a coupling phenomenon.

although iOC and NTX, which accumulate in serum due to impaired urinary excretion12 were significantly above the normal upper limit.

Correlations Between Changes in PTH and Bone Markers During 24 Weeks of LaC Treatment Changes in serum wPTH and iPTH were significantly and positively correlated with those in serum bone metabolic markers at 24 weeks after initiation of LaC, whereas the correlation of change in serum wPTH with those of bone markers seemed stronger than that of iPTH (data not shown), suggesting wPTH as a more reliable marker. Supportive of this notion is the finding that changes in wPTH-to-iPTH ratio, a clinically reliable marker of parathyroid function,11 exhibited a significant and positive correlation with change in iOC during 24 weeks of LaC treatment (r 5 0.457, P 5 .0198).

Time Course of the Effects of LaC on Serum phosphate, Calcium, and PTH Time course changes in serum phosphate, calcium, and PTH are shown (Fig. 1). Serum phosphate and calcium decreased significantly in a time-dependent manner. Serum wPTH and iPTH increased significantly by 4 weeks after initiation of LaC and then increased in a time-dependent manner until week 24. Correlations Between Changes in Serum PTH, Calcium, and Phosphate at 24 Weeks After Initiation of LaC Administration At 24 weeks after initiation of LaC, the changes in wPTH (r 5 20.491, P 5 .0123) and iPTH (r 5 20.514, P 5.0088) were significantly and negatively correlated with those in serum calcium, but not with those in serum phosphate, supporting the notion that the lowered calcium load by LaC could stimulate parathyroid function either measured by iPTH or wPTH assay.

Discussion The study showed that treatment by LaC in place of CaC simulated parathyroid function with the resultant increase of bone turnover as reflected by significant increases of bone metabolic markers in HD patients with suppressed parathyroid function as reflected by their serum iPTH & 150 pg/ m.7 (Figs. 1 and 2). The mechanism by which the switch of phosphate binder from calcium-containing one to noncalcium-containing one stimulated parathyroid function could be explained by decreased calcium load as represented by the significant correlation between the reduction of serum

6 4 2 0 pre

serum Ca (mg/dL)

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10 P = 0.036 8

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12 w 24 w

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300

P < 0.001

*

200

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Effect of LaC on Bone Metabolism Serum TRAP-5b and NTX, both bone resorption markers, had increased significantly 4 weeks after initiation of LaC (Fig. 2), which was followed by increases of bone formation markers, serum BAP, P1NP and iOC, suggesting LaC-induced stimulation of bone formation

200 150

4w

12 w 24 w

P < 0.001

*

100

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Figure 1. Time courses of changes in serum calcium, phosphate, and PTH during the 24-week study period. Serum calcium and phosphate decreased significantly in a time-dependent manner. The serum PTH, either measured by intact PTH or wPTH assay, increased significantly in a time-dependent manner. Values are expressed as median with range. Significant differences between values at pretreatment value and at each time point are indicated (*P , .05 vs. pretreatment value). PTH, parathyroid hormone.

RESTORATION OF PARATHYROID FUNCTION BY LaC

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Figure 2. Time courses of changes of serum bone markers during the 24-week study period. Serum TRACP-5b and NTX, which are bone resorption markers, both increased significantly by 4 weeks after initiation of LaC administration and then increased thereafter in a time-dependent manner. Serum BAP, P1NP, and osteocalcin, all bone formation markers, increased after 12, 12, and 24 weeks, respectively after LaC treatment, suggesting increases of bone formation markers were secondary to those of bone resorption markers. Values are expressed as median with range. Significant differences between values at pretreatment value and at each time point are indicated. BAP, bone alkaline phosphatase; LaC, lanthanum carbonate; NTX, N-telopeptide of type 1 collagen; OC, osteocalcin; P1NP, type I procollagen N-terminal propeptide; TRACP; tartrate-resistant acid phosphatase.

calcium and the increase of serum PTH (Fig. 2). It was suggested that the increased PTH after replacement with LaC might be responsible for the increased bone turnover because constitutive increase of PTH directly stimulates bone resorption and consequently bone formation, as represented by the sequential increase of bone markers. Together with the significant correlation between changes of serum PTH and bone markers at 24 weeks after LaC treatment, it was suggested that decreased calcium load by LaC administration stimulated parathyroid function in HD patients with suppressed parathyroid function. Supportive of this notion is our recent report that LaC treatment of HD patients with ABD increased mineralization of either the periosteal surface or the minimodeling surface at the endocortical surface on bone histomorphometric analysis of bone specimens obtained before and 10 months after LaC treatment.6 To avoid the calcium load of calcium-based phosphate binder, the non–calcium-containing LaC has been introduced into clinical practice. Indeed, bone histomorphometric analysis demonstrated that LaC protected against the development of ABD in the HD patients in comparison with CaC .13 Furthermore, LaC was associated with reduced progression of vascular calcification not only at aorta but also superficial femoral artery compared with CaC in HD patients.14 Although previous studies indicated that calciumcontaining phosphate binders was associated with vascular calcifications,15 suppressed bone turnover state, in addition

to calcium overload, is responsible for the development of vascular calcification. The associations between calcium load and arterial wall stiffening or aorta calcification were stronger in patients with ABD, indicating that the presence of suppressed bone turnover conferred significantly greater influence of calcium overload on aortic calcifications and arterial wall stiffening. Increased calcium overload stimulates bone calcification in the absence of vitamin D16 not only by increasing the availability of calcium for bone calcification but also by elongating calcification process by parathyroid suppression.17 We recently reported that the impaired secretion of fibroblast growth factor-23 and PTH after oral phosphate administration test in the patients with type 2 diabetes mellitus (DM) might be responsible for an increase of serum phosphate,4 and that PTH is a major stimulator of FGF23 secretion in HD patients.18 Furthermore, we reported that parathyroidectomy in HD patients with secondary hyperparathyroidism increased osteocyte death and empty lacunae, supporting the notion that PTH is a trophic factor for osteocytes. These data together suggested that calcium overload due to the administration of calcium-containing phosphate binder might induce ABD not only by directly stimulating calcification process but also by impairing osteocyte/osteoblast. The resultant development of ABD might cause vascular calcification because of the decreased capacity of bone to absorb surplus calcium and phosphate.15 Based on our report showing the significant association of

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vascular calcification with increased cardiovascular mortality,19 it was suggested that LaC might be superior to CaC in improving mortality in HD patients. Supporting this notion is the recently reported meta-analysis showed that non–calcium-based phosphate binders are associated with a decreased risk of all-cause mortality compared with calcium-based phosphate binders in CKD patients.20 In conclusion, administration of LaC, a non-calcium containing phosphate binder in place of CaC, might normalize parathyroid function and thus bone turnover in HD patients with low PTH (&150 pg/mL).

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9. Inaba M, Okuno S, Imanishi Y, et al. Significance of Bio-intact PTH(1-84) assay in hemodialysis patients. Osteoporos Int. 2005;16:517-525. 10. Okuno S, Inaba M, Kitatani K, Ishimura E, Yamakawa T, Nishizawa Y. Serum levels of C-terminal telopeptide of type I collagen: a useful new marker of cortical bone loss in hemodialysis patients. Osteoporos Int. 2005;16:501-509. 11. Kurajoh M, Inaba M, Yamada S, et al. Association of increased active PTH(1-84) fraction with decreased GFR and serum Ca in predialysis CRF patients: modulation by serum 25-OH-D. Osteoporos Int. 2008;19:709-716. 12. Yamada S, Inaba M, Kurajoh M, et al. Utility of serum tartrate-resistant acid phosphatase (TRACP5b) as a bone resorption marker in patients with chronic kidney disease: independence from renal dysfunction. Clin Endocrinol (oxf). 2008;69:189-196. 13. Malluche HH, Siami GA, Swanepoel C, et al. Improvements in renal osteodystrophy in patients treated with lanthanum carbonate for two years. Clin Nephrol. 2008;70:284-295. 14. Toussaint ND, Lau KK, Polkinghorne KR, Kerr PG. Attenuation of aortic calcification with lanthanum carbonate versus calcium-based phosphate binders in haemodialysis: a pilot randomized controlled trial. Nephrology (Carlton). 2011;16:290-298. 15. London GM, Marchais SJ, Guerin AP, Boutouyrie P, Metivier F, de Vernejoul MC. Association of bone activity, calcium load, aortic stiffness, and calcifications in ESRD. J Am Soc Nephrol. 2008;19:1827-1835. 16. Balsan S, Garabedian M, Larchet M, et al. Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D. J Clin Invest. 1986;77:1661-1667. 17. Boivin G, Lips P, Ott SM, et al. Contribution of raloxifene and calcium and vitamin D3 supplementation to the increase of the degree of mineralization of bone in postmenopausal women. J Clin Endocrinol Metab. 2003;88:4199-4205. 18. Imanishi Y, Inaba M, Nakatsuka K, et al. FGF-23 in patients with end-stage renal disease on hemodialysis. Kidney Int. 2004;65:1943-1946. 19. Okuno S, Ishimura E, Kitatani K, et al. Presence of abdominal aortic calcification is significantly associated with all-cause and cardiovascular mortality in maintenance hemodialysis patients. Am J Kidney Dis. 2007;49:417-425. 20. Jamal SA, Vandermeer B, Raggi P, et al. Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet. 2013;382:1268.