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Secondary hyperparathyroidism from inadequate calcium absorption in the gut, is the underlying pathophysiology for rachitic changes in hereditary vitamin D–resistant rickets (HVDRR). We describe a novel use of Cinacalcet to treat a child with HVDRR in whom conventional modes of therapy had to be discontinued. Cinacalcet therapy with high-dose oral calcium effectively normalized the metabolic abnormalities and bone condition. The relative ease of administration of the calcimimetic as a once- or twice-daily oral preparation, compared with traditional intravenous calcium administration, should encourage its move to the frontline of treatment of the disorder. © 2013 American Society for Bone and Mineral Research.
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- Case Report
Hereditary vitamin D–resistant rickets (HVDRR) is a rare autosomal recessive disease (OMIM 277440), and is characterized by early-onset rickets, hypocalcemia, hypophosphatemia, and secondary hyperparathyroidism in the face of elevated serum 1,25(OH)2-D3 concentration.1–3 A subset of children have total/partial alopecia and dermal cysts.1–3 The disorder results from loss of function mutation in vitamin D–receptor (VDR) gene, leading to target organ resistance to 1,25(OH)2-D3.1 Several mutations have been described, and individuals with alopecia are generally unresponsive to oral calcium and 1,25(OH)2-D3 therapy, and are currently being treated with intravenous calcium via a central line.(4–7) Secondary hyperparathyroidism from inadequate calcium absorption in the gut, is the underlying pathophysiology for rachitic changes in HVDRR.8 Preliminary studies showed the calcimimetic Cinacalcet to be safe and effective therapy in children with secondary hyperparathyroidism, as a result of other conditions, such as renal failure, X-linked hypophosphatemic rickets (XLH), and familial hypocalciuric hypercalcemia.9–12 In this report, we describe our novel experience with Cinacalcet therapy in a child with HVDRR that is resistant to 1,25(OH)2-D3, as a result of a missense mutation affecting the DNA-binding domain of VDR, in which all other modes of therapy were exhausted.
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- Case Report
A 13-month-old male child was brought to the hospital for evaluation of failure to thrive. At presentation, his weight was 8.025 kg (Z-score –4.8) and length 65 cm (Z-score –2.6). He had rachitic rosary over the chest wall, widening of wrists and ankles, and bowing of upper and lower extremities. His head appeared disproportionately large (head circumference 51 cm, Z-score 3.2) with open anterior fontanel and frontal bossing. He had patches of scalp that were devoid of hair, whereas other regions had sparse hair, and scant eyebrows. He also exhibited delayed dentition, a large umbilical hernia, and generalized developmental delay. At presentation, his serum chemistry panel showed normal serum electrolytes, albumin, magnesium, BUN, and creatinine. Serum calcium (Ca) was 7.4 mg/dL, iCa 0.96 mmol/L (normal 1.13 to 1.37), phosphorus (P) 2.4 mg/dL, parathyroid hormone (PTH) 1103 pg/mL, and alkaline phosphatase (ALP) 893 U/L (Table 1). His serum 25(OH)-D3 concentration was 15 ng/mL and 1,25(OH)2-D3 200 pg/mL. The skeletal survey showed generalized osteopenia with advanced features of rickets manifested by cupping and fraying at the metaphyseal ends of long bones of upper and lower extremities, and widening of growth plates (Fig. 1C). Kidney ultrasound showed no evidence of nephrocalcinosis.
Table 1. Effect of Therapy With Elemental Calcium, Ergocalciferol, Calcitriol, and Cinacalcet Over Four Time Periods on Serum Total Calcium, Phosphorus, Parathyroid Hormone, and Alkaline Phosphatase
|Age (months)||Elemental Calcium (mg/day)||Ergocalciferol (units/day)||Calcitriol (µg/day)||Cinacalcet (mg/day)||Serum Ca (mg/dL)||Serum P (mg/dL)||Serum ALP (U/L)||Serum PTH (pg/mL)|
| ||Reference Range|| || || ||8.6–10.5||3.5–6.8||110–320||7–75|
|Period I: Oral Treatment with Vitamin D, Calcium, and Calcitriol|
|Median for the period|| || || || ||7.8||2.4||725||815|
|Mean for the last three visits|| || || || ||7.9||2.4||580||895|
|Period II: Treatment with Intravenous Calcium|
|20||550 mg over 10 hrs||400||0|| ||7.8||2.9||851||799|
|21||600 mg over 10 hrs||400||0|| ||8.3||2.2||1039||360|
|22||450 mg over 15 hrs||400||0|| ||8.2||2.8||805||158|
|23||400 mg over 20 hrs||400||0|| ||8.5||5.0||532||193|
|24||400 mg over 20 hrs||400||0|| ||9.0||4.0||348||99|
|25||400 mg over 20 hrs||400||0|| ||9.2||6.6||383||94|
|26||400 mg over 20 hrs||400||0|| ||8.8||4.9||332||136|
|27||400 mg over 20 hrs||400||0|| ||9.1||5.9||294||115|
|Median for the period|| || || || ||8.5||4.0||432||165|
|Mean for the last three visits|| || || || ||9.0||5.8||336||115|
|Period III: Off Intravenous Calcium Therapy|
|Median for the period|| || || || ||8.9||4.5||460||268|
|Mean for the last three visits|| || || || ||9.0||3.6||506||479|
|Period IV: Novel Therapy with Cinacalcet|
|Median for the period|| || || || ||8.4||4.5||280||122|
|Mean for the last three visits|| || || || ||9.1||4.7||230||35|
Figure 1. The clinical course of the child with HVDRR has been divided into four periods based on key therapies during each period. The locally weighted regression-smoothing scatter plot (LOESS) regression, based on the Epanechnikov kernel function and piecewise change-point regression model, was used to best fit the data for serum PTH, ALP, Ca, and P. (A) Scatter plot for serum parathyroid hormone (PTH) and serum alkaline phosphatase (ALP). Individual results of serum PTH are represented by (○) and LOESS regression line by (), and of serum ALP by (▵) and LOESS regression line by (---). (B) Scatter plot for serum calcium (Ca) and serum phosphorus (P). Individual results of serum Ca are represented by (○) and LOESS regression line by (), and for serum P by (▵) and LOESS regression line by (---). (C) Radiological changes over the four time periods. Period I: Oral treatment with vitamin D, calcium, and calcitriol, during which the child had received ergocalciferol and escalating doses of calcium and calcitriol with minimal/poor response to therapy, as shown by persistent marked elevation in serum PTH and ALP; low serum P concentration; and rachitic changes on X-rays. Period II: Treatment with intravenous calcium for HVDRR, during which the child achieved almost normalization of serum PTH, ALP, Ca, and P, and healing of rachitic changes on X-ray. Period III: Off intravenous calcium therapy because of recurrent line infections/sepsis. The child received high oral dose of calcium and, subsequently, extremely high doses of calcitriol therapy, which could not prevent slow deterioration of his mineral metabolism and recurrence of early changes of rickets on X-ray. Period IV: Cinacalcet combined with oral calcium therapy led to normalization of all biochemical parameters with complete healing of rickets.
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Period I: Oral treatment with vitamin D, calcium, and calcitriol
To eliminate the possibility of nutritional rickets, the child was initially treated with standard doses of ergorcalciferol, calcium, and calcitriol (Table 1). However, even after normalization of 25(OH)-D3 level, there was no evidence of healing of rickets on X-rays, nor correction of serum Ca, P, ALP, and PTH levels. Next, an attempt was made to treat with incrementally increasing supra-physiological doses of calcium and calcitriol reaching elemental calcium of 8000 mg/day and calcitriol 6 µg/day. During this 6 months of oral therapy, his 25(OH)-D3 levels rose to 117 ng/mL and 1,25(OH)2-D3 to 669 pg/mL, but no improvement on X-rays was observed, and the child's chemistry panel continued to show unresponsiveness. Toward the end of this period we evaluated him for VDR gene mutation. A single G to A missense mutation was identified in exon 2 that changed the codon for valine to methionine at amino acid 26 (V26M) in the DNA-binding domain confirming the diagnosis of HVDRR.13 The functional impact of this mutation has been previously described.13
Period II: Treatment with intravenous calcium
Once HVDRR was confirmed, and with family's consent, we embarked on intravenous calcium therapy. Calcium gluconate was initiated at 550 mg of elemental calcium daily, infused via a central line over a period of 10 hours. Over the next 8 months, the dose of calcium was titrated based on biochemical response, ranging between 450 and 600 mg per day, infused over 10 to 20 hours. He responded to treatment with significant improvement, albeit not complete normalization, of his serum Ca, P, ALP, and PTH, and radiological healing of rickets (Table 1 and Fig. 1A–C. During this period, 25(OH)-D3 levels ranged between 33 and 47 ng/mL and 1,25(OH)2-D3 between 99 and 243 pg/mL. However, intravenous calcium therapy was complicated by repeated severe central-line infections with various organisms, including Serratia, Citrobacter, Enterobacter, Enterococcus, and Staphylococcus species that failed to respond to conventional antibiotic therapy, each time necessitating central-line removal and replacement. An extensive work-up failed to detect any immunological malfunction. After the seventh life-threatening line infection, we agreed with the family to discontinue intravenous treatment.
Period III: Off intravenous calcium therapy
After discontinuation of intravenous calcium therapy, and while on maintenance dose of 400 units of ergocalciferol, we observed a gradual increase in ALP and PTH despite normal serum calcium levels (Table 1). The addition of high-dose of oral calcium did not affect the trend of rising ALP and PTH, and decline in serum P. It was evident that the improvement achieved previously with intravenous calcium therapy was slowly dissipating by increasing severity of secondary hyperparathyroidism, and therefore calcitriol at highly supra-physiological doses was added.14 However, after 20 months of this mode of treatment, no significant impact on serum levels of ALP and PTH could be observed, and X-rays showed increased flaring and cupping of the metaphyses consistent with early manifestations of rickets. Serum 25(OH)-D3 levels ranged between 32 and 52 ng/mL, and 1,25(OH)2-D3 level ranged between 129 and 2430 pg/mL during this period. FGF-23 was undetectable.
Period IV: Cinacalcet therapy
After a thorough discussion with the family, a decision was made to try Cinacalcet as part of the child's treatment. Although the manufacturer does not recommend crushing the tablet, having no other choices of how to administer it, we prepared a suspension daily by crushing 30 mg tablet into 10 mL water. The treatment was started in the hospital for close monitoring of serum iCa, because of the possibility of hypocalcemia induced by Cinacalcet therapy. The starting dose of Cinacalcet was 4 mg (∼0.25 mg/kg) once a day. We did not appreciate a significant decrease in serum iCa, and the dose was incrementally increased based on serum PTH levels, reaching 4.5 mg twice a day by the end of the week, when the child was discharged. The dose was further increased over the next 6 weeks to 9 mg twice a day (∼1 mg/kg/day) as an outpatient. Over the next year, we observed sustained control of secondary hyperparathyroidism and healing of the patient's rachitic changes on X-rays (Table 1 and Fig. 1A–C. At the age of 62 months, calcitriol therapy was discontinued. Nevertheless, the patient continued to maintain normal values of all biochemical parameters and normal-appearing bones on radiographs, and consequently the Cinacalcet dose was decreased to once a day at 8 mg (∼0.4 mg/kg/day) (Table 1). The bone turnover markers obtained before the initiation of Cinacalcet therapy were elevated; namely Bone Specific-ALP was 187.1 µg/L (normal 25 to 124), osteocalcin was 48 ng/mL (normal 9 to 38), and urine N-telopeptide was 1412 nmol/mmolCr (normal 56 to 1763). They decreased to 78.9 µg/L, 29 ng/mL, and 530 nmol/mmolCr, respectively, on last follow-up. Serum FGF-23 was undetectable throughout this period, while 25(OH)-D3 levels ranged between 38 and 64 ng/mL (64 ng/mL on last follow-up), and 1,25(OH)2-D3 ranged between 246 and 2630 pg/mL (246 ng/mL on last follow-up). On last follow up the patient's weight was 20.7 kg (Z-score 0.1), length 102.3 cm (Z-score –2.4); he had normal chemistries, resolution of rachitic changes and no nephrocalcinosis, but no change in alopecia.
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HVDRR results from loss of function of VDR leading to target organ resistance to 1,25(OH)2-D3.1 The nature of the mutation impacts alopecia and response to therapy.1 As described before, in vitro studies on our patient's fibroblasts revealed that the mutant V26M VDR failed to induce CYP24A1 gene in response to treatment with up to 1000 nM 1,25(OH)2-D3.13 Indeed, as was found in period I, and again while on extremely high oral doses of elemental calcium (∼200 to 250 mg/kg/day) and calcitriol 20 µg/day in period III, there was no improvement in the patient's biochemical and radiological abnormalities, indicating complete resistance to 1,25(OH)2-D3, similar to other children with alopecia and mutation in the DNA-binding domain.1
Recently Tiosano and Hochberg have proposed a mechanistic classification of rickets, namely PTH-dependent, FGF 23–dependent, and Renal, all leading to a common denominator of hypophosphatemia causing rickets by interfering with apoptosis of chondrocytes.8 They proposed HVDRR to be a form of PTH-dependent rickets. The secondary hyperparathyroidism develops because of decreased gastrointestinal calcium absorption and leads to both hypophosphatemia and increased bone turnover, as was evident in our patient while he was off effective treatment (Table 1). In HVDRR the defect in calcium absorption can be overcome by intravenous calcium infusion, which bypasses the gut.4–7 We could replicate this observation in period II, when the child received intravenous calcium therapy resulting in marked, albeit incomplete, reversal of the biochemical and skeletal abnormalities. The fulminant life-threatening infections led to a comprehensive immunological workup, which failed to detect any abnormality and consequently resulted in withdrawal of this line of therapy.
In period III, we attempted to maximize the use of vitamin D–independent, nonsaturable paracellular pathway of calcium absorption in the gut by supplementing our patient with 200 to 250 mg/kg/day of oral calcium, in spite of which there was a slow and steady worsening of his mineral and skeletal status (Table 1 and Fig. 1A–C). Thus, because of circumstances beyond our control, period III resulted in an ineffective treatment providing a “washout” period between periods II and IV.
The VDR mutation causing HVDRR results in poor calcium absorption from the gut.15 Based on the concept that skeletal pathophysiology is a form of PTH-dependent rickets, which develops in response to the poor absorption of calcium in the gut, we considered the use of a calcimimetic as a mean to normalize serum PTH. The safety and efficacy of Cinacalcet in children has been shown in a few small series and anecdotal cases of secondary hyperparathyroidism in other disorders.9–12. Because of the concern that Cinacalcet therapy might cause hypocalcemia, the high dose of oral calcium supplementation was not interrupted. However, because of the potential adverse effect of sequestration of dietary phosphate in the gut, we recommend that future studies try to use lower doses of supplementary calcium. Supplementation with phosphate was not necessary because serum phosphate normalized with suppression of the parathyroid gland with either intravenous calcium or Cinacalcet therapy (Table 1 and Fig. 1).2, 3, 15–17 Cinacalcet exerted its effect rapidly, resulting in suppression of PTH and resolution of the radiological changes of rickets. This effect was further corroborated by suppression of bone turnover markers, and also by an apparent increase in bone mineralization on X-rays. Not unexpected, the beneficial effect of the calcimimetic agent was unaffected by the discontinuation of supplementation with 1,25(OH)2-D3. We did not observe any difficulties in the preparation or administration of the medication to the young child.
The patient described in this report exhibited the classical clinical pattern of HVDRR from a VDR mutation that caused complete target organ resistance to 1,25(OH)2-D3. The successful treatment with Cinacalcet shows that the skeletal pathophysiology of rickets in HVDRR is PTH dependent, and that successful control of the secondary hyperparathyroidism is sufficient to heal the rickets, even though resistance to 1,25(OH)2-D3 remains unaffected. Considering its relative easiness of the administration as a once-a-day or twice-a-day oral preparation, compared with the cumbersome and at times risks-associated intravenous calcium therapy, one can consider Cinacalcet to be an adjunct to calcium therapy in management of children with HVDRR.