Journal of Orthopedic Research and Therapy (ISSN: 2575-8241)

Article / research article

"Increased Bone Mineral Density and Improved Metabolic Bone Markers in Patients with Hypophosphatemic Rickets/Osteomalacia Treated with the Calcimimetic, Cinacalcet"

Noriyuki Hayashi, Yasuo Imanishi*, Masaya Ohara, Daichi Miyaoka, Yuki Nagata, Masanori Emoto, Masaaki Inaba

Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Japan

*Corresponding author: Yasuo Imanishi, Department of Metabolism, Endocrinology and Molecular Medicine,

Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. Tel: +81666453806; Fax: +81666453808; Email: imanishi@med.osaka-cu.ac.jp

Received Date: 15 May, 2018; Accepted Date: 19 May, 2018; Published Date: 25 May, 2018

1.       Abstract

Hypophosphatemic rickets/osteomalacia is a rare disorder characterized by renal phosphate wasting and low 1,25-dihydroxyvitamin D levels, leading to hypophosphatemia and abnormal bone mineralization. Patients are conventionally treated with a Vitamin D Receptor Activator (VDRA), but dosing is often limited because of side effects, such as hypercalcemia and/or hypercalciuria. This study aimed to assess the efficacy of the calcimimetic, cinacalcet, in the treatment of four adult patients with hypophosphatemic rickets/osteomalacia over a 2-year period. Patients continued VDRA (alfacalcidol) therapy, doses of which were adjusted to ensure that hypercalcemia or hypercalciuria was not present prior to cinacalcet administration. These doses were fixed for the first year but could be adjusted in the second. In the first year, cinacalcet 25 mg/day reduced serum Parathyroid Hormone (PTH) and Calcium (Ca) levels by 46% and 9%, respectively. Reduced serum PTH levels increased the tubular maximum reabsorption of phosphate to glomerular filtration rate by 112%; as a result, serum phosphorus levels increased by 38%. Reduced serum Ca levels enabled mean doses of alfacalcidol to be increased from 2.4 ± 1.3 to 3.3 ± 1.1 µg/day in the second year. Reduced serum bone-specific alkaline phosphatase levels indicated improved osteoblast maturation and bone calcification. In addition, cinacalcet administration increased bone mineral density by 26% and 16% in the lumbar spine and femur, respectively. Although the interpretation of these data is limited by the small number of participants and absence of controls, our results indicate the potential of this new therapeutic approach for patients with hypophosphatemic rickets/osteomalacia.

2.       Keywords: Calcimimetic; Cinacalcet; Hypophosphatemic Osteomalacia; Hypophosphatemic Rickets; PTH; Vitamin D Receptor Activator



Figures 1(A-E): Changes in clinical parameters after the initiation of cinacalcet. A) wPTH, B) cCa, C) TmP/GFR, D) serum P, and E) serum BAP. Data are presented as mean ± SD. Changes in all parameters were statistically significant by repeated-measures one-way ANOVA. *P < 0.05 vs baseline by Dunnett’s test. wPTH, whole parathyroid hormone; cCa, corrected calcium; TmP/GFR, tubular maximum reabsorption of phosphate per glomerular filtration rate; P, phosphate; BAP, bone-specific alkaline phosphatase.



Figure 2: Alfacalcidol dosing over the study period. Alfacalcidol dose was fixed for the first year of cinacalcet administration; in the second year, the maximal doses of alfacalcidol were determined every 3 months for each participants, while ensuring that patients did not exhibit hypercalcemia (cCa > 10.4 mg/dL) or hypercalciuria (urinary calcium/creatinine ratio > 0.3 mg/mg). Data are presented as mean ± SD. *P < 0.05 vs baseline by Mann-Whitney’s U test.



Figure 3: Change in BMD and TBS after the initiation of cinacalcet. Changes in Lumber Spine (LS) BMD, Total Hip (TH) BMD, and TBS were observed after 2 years’ cinacalcet therapy. Data are presented as mean ± SD. *P < 0.05 vs baseline by Mann-Whitney’s U test.



 

 

Case 1

Case 2

Case 3

Case 4

Mean ± SD

Diagnosis

Rickets

Rickets

Osteomalacia

Osteomalacia

 

Gender

Female

Female

Female

Male

 

Age, years

40

56

62

66

56 ± 10

cCa, mg/dL

9.8

10.2

9.5

9.8

9.8 ± 0.2

P, mg/dL

1.7

2.6

2.2

1.6

2.0 ± 0.1

TmP/GFR, mg/dL

0.92

0.89

1.10

1.53

1.11 ± 0.30

wPTH, pg/mL

19.4

82.5

20.2

20.2

35.6 ± 31.3

BAP, µg/L

34.3

77.9

151.0

299.9

140.8 ± 116.5

LS-BMD, g/cm2

1.093

0.709

0.511

1.123

0.859 ± 0.299

TH-BMD, g/cm2

0.698

0.602

0.339

0.779

0.601 ± 0.191

TBS

1.414

1.182

1.120

1.265

1.245 ± 0.077

cCa, corrected calcium; P, phosphorus; TmP/GFR, tubular maximum reabsorption of phosphate per glomerular filtration rate; wPTH, whole parathyroid hormone; BAP, bone-specific alkaline phosphatase; LS-BMD, lumbar spine bone mineral density; TH-BMD, total hip bone mineral density; TBS, trabecular bone score.

 

Table 1: Patient baseline characteristics.

 

 

Baseline

1 year

2 years

Alb, g/dL

4.1 ± 0.5

4.4 ± 0.3

4.3 ± 0.1

Cr, mg/dL

0.53 ± 0.06

0.57 ± 0.08

0.58 ± 0.10

eGFR, mL/min/1.73 m2

97.8 ± 2.5

92.0 ± 14.3

90.8 ± 18.7

ALP, IU/L

952 ± 662

553 ± 236

419 ± 256

OC, U/L

7.2 ± 1.3

7.6 ± 2.9

7.3 ± 5.4

CTX, ng/mL

1.042 ± 0.367

1.029 ± 0.499

1.113 ± 0.634

FGF23, pg/mL

346 ± 128

276 ± 118

328 ± 94

25OHD, ng/mL

12.7 ± 5.8

12.5 ± 4.9

14.0 ± 5.0

1,25(OH)2D, pg/mL

56.3 ± 18.7

76.8 ± 32.3

88.0 ± 31.1

U-Ca/Cr, mg/mgCr

0.22 ± 0.20

0.17 ± 0.07

0.25 ± 0.09

Alb, albumin; Cr, creatinine; eGFR, estimated glomerular filtration rate; ALP, alkaline phosphatase; OC, osteocalcin; CTX, collagen C-terminal telopeptide; FGF23, fibroblast growth factor 23; 25OHD, 25-hydroxyvitamin D; 1,25(OH)2D, 1,25-dihydroxyvitamin D; U-Ca/Cr, urinary calcium/creatinine ratio. No significant change was observed in these parameters by repeated-measures one-way ANOVA.

 

Table 2: Changes in clinical parameters during cinacalcet treatment.

 

1.       Fukumoto S, Ozono K, Michigami T, Minagawa M, Okazaki R, et al. (2015) Pathogenesis and diagnostic criteria for rickets and osteomalacia--proposal by an expert panel supported by the Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research, and the Japan Endocrine Society. J Bone Miner Metab 33: 467-473.

2.       Baroncelli GI, Bertelloni S, Sodini F, Galli L, Vanacore T, et al. (2004) Genetic advances, biochemical and clinical features and critical approach to treatment of patients with X-linked hypophosphatemic rickets. Pediatr Endocrinol Rev 1: 361-379.

3.       Cho HY, Lee BH, Kang JH, Ha IS, Cheong HI, et al. (2005) A clinical and molecular genetic study of hypophosphatemic rickets in children. Pediatr Res 58: 329-333.

4.       Imel EA, Zhang X, Ruppe MD, Weber TJ, Klausner MA, et al. (2015) Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23. J Clin Endocrinol Metab 100: 2565-2573.

5.       Ruppe MD, Zhang X, Imel EA, Weber TJ, Klausner MA, et al. (2016) Effect of four monthly doses of a human monoclonal anti-FGF23 antibody (KRN23) on quality of life in X-linked hypophosphatemia. Bone Rep 5: 158-162.

6.       Nemeth EF, Steffey ME, Hammerland LG, Hung BC, Van Wagenen BC, et al. (1998) Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc Natl Acad Sci U S A 95: 4040-4045.

7.       Kawata T, Imanishi Y, Kobayashi K, Onoda N, Okuno S, et al. (2006) Direct in vitro evidence of the suppressive effect of cinacalcet HCl on parathyroid hormone secretion in human parathyroid cells with pathologically reduced calcium-sensing receptor levels. J Bone Miner Metab 24: 300-306.

8.       Alon US, Levy-Olomucki R, Moore WV, Stubbs J, Liu S, et al. (2008) Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets. Clin J Am Soc Nephrol 3: 658-664.

9.       Geller JL, Khosravi A, Kelly MH, Riminucci M, Adams JS, et al. (2007) Cinacalcet in the management of tumor-induced osteomalacia. J Bone Miner Res 22: 931-937.

10.    Imai E, Horio M, Nitta K, Yamagata K, Iseki K, et al. (2007) Modification of the Modification of Diet in Renal Disease (MDRD) Study equation for Japan. Am J Kidney Dis 50: 927-937.

11.    Gao P, Scheibel S, D'Amour P, John MR, Rao SD, et al. (2001) Development of a novel immunoradiometric assay exclusively for biologically active whole parathyroid hormone 1-84: implications for improvement of accurate assessment of parathyroid function. J Bone Miner Res 16: 605-614.

12.    Genant HK, Jergas M, Palermo L, Nevitt M, Valentin RS, et al. (1996) Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis The Study of Osteoporotic Fractures Research Group. J Bone Miner Res 11: 984-996.

13.    Miyaoka D, Imanishi Y, Ohara M, Hayashi N, Nagata Y, et al. (2017) Effects of Teriparatide and Sequential Minodronate on Lumbar Spine Bone Mineral Density and Microarchitecture in Osteoporosis. Calcif Tissue Int 101: 396-403.

14.    Kobayashi K, Imanishi Y, Miyauchi A, Onoda N, Kawata T, et al. (2006) Regulation of plasma fibroblast growth factor 23 by calcium in primary hyperparathyroidism. Eur J Endocrinol 154: 93-99.

15.    Kawata T, Imanishi Y, Kobayashi K, Miki T, Arnold A, et al. (2007) Parathyroid hormone regulates fibroblast growth factor-23 in a mouse model of primary hyperparathyroidism. J Am Soc Nephrol 18: 2683-2688.

16.    Clinkenbeard EL, Cass TA, Ni P, Hum JM, Bellido T, et al. (2016) Conditional Deletion of Murine Fgf23: Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia. J Bone Miner Res 31: 1247-1257.

17.    Murali SK, Roschger P, Zeitz U, Klaushofer K, Andrukhova O, et al. (2016) FGF23 Regulates Bone Mineralization in a 1,25(OH)2D3 and Klotho-Independent Manner. J Bone Miner Res 31: 129-142.

18.    Saji F, Shigematsu T, Sakaguchi T, Ohya M, Orita H, et al. (2010) Fibroblast growth factor 23 production in bone is directly regulated by 1α,25-dihydroxyvitamin D, but not PTH. Am J Physiol Renal Physiol 299: 1212-1217.

19.    Hansen D, Rasmussen K, Pedersen SM, Rasmussen LM, Brandi L (2012) Changes in fibroblast growth factor 23 during treatment of secondary hyperparathyroidism with alfacalcidol or paricalcitol. Nephrol Dial Transplant 27: 2263-2269.

20.    Nagata Y, Imanishi Y, Ishii A, Kurajoh M, Motoyama K, et al. (2011) Evaluation of bone markers in hypophosphatemic rickets/osteomalacia. Endocrine 40: 315-317.

21.    Shanbhogue VV, Hansen S, Jorgensen NR, Beck-Nielsen SS (2018) Impact of Conventional Medical Therapy on Bone Mineral Density and Bone Turnover in Adult Patients with X-Linked Hypophosphatemia: A 6-Year Prospective Cohort Study. Calcif Tissue Int 102: 321-328.

22.    Leifheit-Nestler M, Kucka J, Yoshizawa E, Behets G, D'Haese P, et al. (2017) Comparison of calcimimetic R568 and calcitriol in mineral homeostasis in the Hyp mouse, a murine homolog of X-linked hypophosphatemia. Bone 103: 224-232.

23.    Colares Neto GP, Pereira RM, Alvarenga JC, Takayama L, Funari MF, et al. (2017) Evaluation of bone mineral density and microarchitectural parameters by DXA and HR-pQCT in 37 children and adults with X-linked hypophosphatemic rickets. Osteoporos Int 28: 1685-1692.

24.    Iki M, Tamaki J, Sato Y, Winzenrieth R, Kagamimori S, et al. (2015) Age-related normative values of trabecular bone score (TBS) for Japanese women: the Japanese Population-based Osteoporosis (JPOS) study. Osteoporos Int 26: 245-252.

Citation: Hayashi N, Imanishi Y, Ohara M, Miyaoka D, Nagata Y, et al. (2018) Increased Bone Mineral Density and Improved Metabolic Bone Markers in Patients with Hypophosphatemic Rickets/Osteomalacia Treated with the Calcimimetic, Cinacalcet. J Orthop Res Ther 2018: 199. DOI: 10.29011/2575-8241.000199

free instagram followers instagram takipçi hilesi