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
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
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.