Oral Phosphate Supplementation Research Articles

#3060 Assessment of differences in management and outcomes of severe hypophosphatemia secondary to refeeding syndrome

Abstract Background and Aims Refeeding syndrome is a severe, potentially life-threatening condition characterized by fatal shifts in fluids and electrolytes that may occur in malnourished patients receiving parenteral or enteral artificial refeeding. This condition may present with hypokalemia, hypomagnesemia, thiamine deficiency and changes in glucose and fat metabolism, but the hallmark of the syndrome is hypophosphatemia. The rise in insulin during refeeding may lead to a significant uptake and utilization of phosphorus into the cells, leading to a deficit in intracellular and extracellular phosphorus. The best method for phosphate repletion has not yet been determined. In this study we describe the different management strategies and outcomes of severe hypophosphatemia secondary to refeeding syndrome observed at our centre. Method We performed a retrospective observational study of patients admitted at out tertiary hospital from December 2022 and May 2023 who presented severe hypophosphatemia (defined as serum phosphate level <1.2 mg/dl) secondary to refeeding syndrome. We collected demographic data, comorbidities, changes in electrolytes and kidney function and treatments received during in-hospital admission. Our outcomes were development of complications associated with severe hypophosphatemia (convulsions, myopathy, fractures, haemolytic anemia, and major cardiovascular events) and death. Results We identified 16 cases of severe hypophosphatemia secondary to refeeding syndrome during the study period, with a mean phosphate level of 0.81 ± 0.26 mg/dl. Mean age was 54.7 ± 16.4 years, and females were predominant (62.5%), and all were associated with parenteral nutrition. 18.8% of patients had had previous episodes of severe hypophosphatemia, 25% presented diarrhoea as well and 18.8% had also received intravenous iron previous to the episode. At presentation, mean serum creatinine was 0.64 ± 0.3 mg/dl, mean potassium levels were 3.5 ± 0.9 mmol/l, mean sodium 141.7 ± 6.3 mmol/l, mean calcium was 8.62 ± 0.37 mg/dl and mean magnesium was 2.05 ± 0.45 mg/dl. Most patients (75%) were treated by discontinuation of parenteral nutrition and intravenous phosphate, while 18.8% of patients were only treated by temporary discontinuation of parenteral nutrition and only 1 patient (6.3%) was treated with oral phosphate supplementation. Regarding complications, 18.8% of patients presented myopathy, 12.5% presented convulsions, 25% presented major cardiovascular events, and 18.8% of patients died during hospitalization. Conclusion Refeeding syndrome is a potential fatal condition that frequently presents with severe hypophosphatemia, however it frequently passes unrecognized. Prompt detection and management is essential, especially in patients receiving parenteral nutrition, to prevent complications and death. Further research is needed to determine the best management strategy in refeeding syndrome to improve outcomes.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a complex disorder in need of precision medicine

Hereditary hypophosphatemic rickets with hypercalciuria is an autosomal recessive phosphate-wasting disorder, associated with kidney and skeletal pathologies, which is caused by pathogenic variants of SLC34A3. In this issue, Zhu etal. describe a pooled analysis of 304 individuals carrying SLC34A3 variants. Their study underscores the complexity of hereditary hypophosphatemic rickets with hypercalciuria, as kidney and bone phenotypes generally do not coexist, heterozygous carriers of SLC34A3 variants also can be affected, and the response to oral phosphate supplementation is dependent on the genetic status.

An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH)

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

Growth hormone treatment improves final height in children with X-linked hypophosphatemia

Background/aimDespite optimal conventional treatment (oral phosphate supplements and active vitamin D analogs), about 40–50% of children with well-controlled X-linked hypophosphatemia (XLH) show linear growth failure, making them less likely to achieve an acceptable final height. Here, we studied the hypothesis that rhGH treatment improves final height in children with XLH and growth failure.MethodsTwo cohorts of children with XLH were included in this retrospective longitudinal analysis: (1) a cohort treated with rhGH for short stature (n = 34) and (2) a cohort not treated with rhGH (n = 29). The mean duration of rhGH treatment was 4.4 ± 2.9 years. We collected the auxological parameters at various time points during follow-up until final height.ResultsIn rhGH-treated children, 2 years of rhGH therapy was associated with a significant increase in height from − 2.4 ± 0.9 to − 1.5 ± 0.7 SDS (p < 0.001). Their mean height at rhGH discontinuation was − 1.2 ± 0.9 SDS and at final height was − 1.3 ± 0.9 SDS corresponding to 165.5 ± 6.4 cm in boys and 155.5 ± 6.3 cm in girls. Notably, the two groups had similar final heights; i.e., the final height in children not treated with rhGH being − 1.2 ± 1.1 SDS (165.4 ± 6.8 cm in boys and 153.7 ± 7.8 cm in girls), p = 0.7.ConclusionTreatment with rhGH permits to improve final height in children with XLH and growth failure, despite optimal conventional treatment. We propose therefore that rhGH therapy could be considered as an option for short stature in the context of XLH.

PSAT189 Severe Hypocalcemia and Hypophosphatemia Associated with Denosumab use in a Chronic Myeloid Leukemia Patient on Imatinib

Abstract Background Hypocalcemia and hypophosphatemia are known side effects of Denosumab, especially in presence of risk factors including underlying chronic kidney disease, osteoblastic metastasis, high bone turnover states, vitamin D deficiency and preexisting hypocalcemia. We report a unique case of prolonged severe hypocalcemia and hypophosphatemia in a patient with CML on Imatinib, treated with Denosumab for osteoporosis. Clinical case A 73-year-old lady with history of CML, on Imatinib for 4 years and osteoporosis with a chronic L1 compression fracture treated with her second dose of Denosumab 3-months back, presented with complaints of numbness and tingling involving the entire body. Labs revealed severe hypocalcemia (calcium 5.6 mg/dL, ionized calcium 2.93 mg/dL), severe hypophosphatemia, (phosphorus of 0.5mg/dL) and a low normal magnesium level of 1.5mg/dL, with normal ALP, liver and kidney function parameters. Of note she had normal calcium, phosphorus and vitamin D levels before receiving denosumab. Further work-up revealed an elevated PTH level of 241 pg/mL, normal 25 hydroxy vitamin D level of 26.0 ng/ml, slightly low 1,25 (OH) vitamin D of 16pg/ml and an elevated FGF 23 of 299RU/mL (normal &amp;lt;180RU/mL). Her calcium and phosphorus levels remained suboptimal despite treatment with up to 24 grams of calcium carbonate supplementation daily, K-phos 1 packet QID and calcitriol 0.25 mcg TID. 24-hour urine calcium and phosphorus levels were low at 4mg/day and 0.2mg/day respectively. Fractional excretion of phosphate was 13.63%, suggesting renal phosphorus wasting, likely from an elevated FGF23. Bone scan showed no metastatic lesion. After discussion with oncology, Imatinib was held inpatient and she was started on intravenous calcium gluconate infusion, and continued on Calcitriol, vitamin D3 and K-phos supplementation. After receiving almost 18gm of calcium gluconate intravenously over 2 days, her hypocalcemia and hypophosphatemia resolved with improvement in symptoms. Conclusion Hypocalcemia is a recognized adverse effect of Denosumab that is seen in patients with underlying risk factors. Emerging data now suggests the deregulatory effect of long term Imatinib therapy on bone formation by inhibition of osteoclastic activity along with transient increase in osteoblastic activity leading to retention and sequestration of calcium and phosphate in bone, resulting in hypocalcemia and hypophosphatemia. Ours is the first reported case of severe hypocalcemia and hypophosphatemia observed in a CML patient on Imatinib after receiving Denosumab, with resistance to high dose oral calcium and phosphate supplementation, requiring intravenous supplementation and transient discontinuation Imatinib. The elevated FGF 23 likely played a key role in severe hypophosphatemia. This unique case addresses the prospect of occurrence of severe hypocalcemia and hypophosphatemia in patients on Imatinib receiving Denosumab, while questioning the possibility of potentiation of the osteoclast inhibitory effect of this medication when used in patients on long term Imatinib therapy. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Growth hormone treatment improves final height in children with X-linked hypophosphatemia

Despite optimal conventional treatment (oral phosphate supplements and active vitamin D analogs), about 40–50% of children with well-controlled X-linked hypophosphatemia (XLH) show linear growth failure, making them less likely to achieve an acceptable final height. Here, we studied the hypothesis that rhGH treatment improves final height in children with XLH and growth failure. Two cohorts of children with XLH were included in this retrospective longitudinal analysis: (1) a cohort treated with rhGH for short stature ( n = 34); and (2) a cohort not treated with rhGH ( n = 29). The mean duration of rhGH treatment was 4.4 ± 2.9 years. We collected the auxological parameters at various time points during follow-up to final height. In rhGH-treated children, 2 years of rhGH therapy was associated with significant increases in height from −2.4 ± 0.9 to −1.5 ± 0.7 SDS ( P < 0.001). Their mean height at rhGH discontinuation was −1.2 ± 0.9 SDS and at final height was −1.3 ± 0.9 SDS (160.4 ± 8.0 cm). Notably, the two groups had similar final heights, the final height in children not treated with rhGH being −1.2 ± 1.1 SDS (157.8 ± 9.2 cm), P = 0.7. Treatment with rhGH significantly increases final height in children with XLH and growth failure, despite optimal conventional treatment. We propose therefore that rhGH therapy could be an appropriate option for short stature in the context of XLH.

X-linked hypophosphatemia and burosumab: Practical clinical points from the French experience.

Hereditary hypophosphatemia with increased FGF23 levels are rare inherited metabolic diseases characterized by low serum phosphate because of impaired renal tubular phosphate reabsorption. The most common form is X-linked hypophosphatemia (XLH), secondary to a mutation in the PHEX gene. In children, XLH is often manifested by rickets, delayed development of gait, lower limb deformities, growth retardation, craniosynostosis, and spontaneous dental abscesses. In adults, patients present diffuse musculoskeletal pain (bone and joints), early osteoarthritis, entesopathies, pseudo-fractures, muscular weakness, and severe dental damage. Conventional medical management is based on the combined administration of oral phosphate supplementation with active vitamin D analogs. Treatment with the recently approved anti-FGF23 burosumab is an alternative, especially in severe forms. Burosumab restores phosphate reabsorption in the proximal tubule and stimulates the endogenous synthesis of calcitriol. In Europe, burosumab has been approved for the treatment of XLH with radiographic evidence of bone disease in pediatric patients from one year of age and in adults. This manuscript will discuss the specific management of burosumab in children and adolescents in daily practice.

METABOLIC AND ORTHOPEDIC ASPECT OF X-LINKED VITAMIN D-RESISTANT HYPOPHOSPHATEMIC RICKETS

INTRODUCTION: - The X-linked vitamin D-resistant hypophosphatemic rickets (VDXLR) is a metabolic disorder. Medication treatment consists of oral phosphate substitution and supplementation of active vitamin D compounds. Our study aimed to review our patients with VDXLR, focusing on those undergoing surgery, mainly lengthening procedures. The main parameters of interest were growth, height, the axis of the lower limbs, pain, and degenerative arthropathy. METHODS: - Twelve patients with VDXLR were followed at our institution. Eight patients underwent surgical correction, and three of them in combination with bone lengthening. The corrections were executed at the end of growth in the patients. Clinical end points were height, leg axis, and pain. RESULTS: - Single bilateral surgical correction was performed in six patients; one patient had three and ve corrections. Bone lengthening was performed in three patients. At the last follow-up, the height of seven operated patients was within normal range. In addition, the leg axis was normalized in six patients with mild genua vara in two. Bone healing was excellent, and no surgical complications. There was no one radiological evidence of degenerative arthropathy. CONCLUSIONS: - In case of bone deformity, surgery can safely be performed, independent of age or bone maturation. All patients were happy with the outcomes of axial corrective surgery and bone lengthening, and in the majority. Only one corrective intervention was needed.

The Metabolic Bone Disease X-linked Hypophosphatemia: Case Presentation, Pathophysiology and Pharmacology.

The authors present a stereotypical case presentation of X-linked hypophosphatemia (XLH) and provide a review of the pathophysiology and related pharmacology of this condition, primarily focusing on the FDA-approved medication burosumab. XLH is a renal phosphate wasting disorder caused by loss of function mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). Typical biochemical findings include elevated serum levels of bioactive/intact fibroblast growth factor 23 (FGF23) which lead to (i) low serum phosphate levels, (ii) increased fractional excretion of phosphate, and (iii) inappropriately low or normal 1,25-dihydroxyvitamin D (1,25-vitD). XLH is the most common form of heritable rickets and short stature in patients with XLH is due to chronic hypophosphatemia. Additionally, patients with XLH experience joint pain and osteoarthritis from skeletal deformities, fractures, enthesopathy, spinal stenosis, and hearing loss. Historically, treatment for XLH was limited to oral phosphate supplementation, active vitamin D supplementation, and surgical intervention for cases of severe bowed legs. In 2018, the United States Food and Drug Administration (FDA) approved burosumab for the treatment of XLH and this medication has demonstrated substantial benefit compared with conventional therapy. Burosumab binds circulating intact FGF23 and blocks its biological effects in target tissues, resulting in increased serum inorganic phosphate (Pi) concentrations and increased conversion of inactive vitamin D to active 1,25-vitD.

MO054EFFICACY OF ORAL PHOSPHATE SUPPLEMENTATION IN CHILDREN WITH HEREDITARY HYPOPHOSPHATEMIC RICKETS WITH HYPERCALCIURIA

Abstract Background and Aims Hereditary hypophosphatemic rickets with hypercalciuria (HHRH; MIM #241530) is an autosomal recessive renal phosphate-wasting disorder caused by mutations in the SLC34A3/NPT2c gene. HHRH characterized by increased urinary phosphate excretion leading to hypophosphatemic rickets, short stature and elevated serum 1,25(OH)2D levels which result in hypercalciuria leads to nephrocalcinosis/urolithiasis due to enhanced intestinal calcium absorption and reduced PTH-dependent calcium reabsorption in the distal renal tubules. Treatment of HHRH involves administration of oral phosphate supplements alone to normalize of serum phosphate, alkaline phosphatase activity (ALP), PTH levels, urine calcium excretion for prevention of renal calcifications and progression of rickets. Currently there is no consensus on the optimal dose of oral phosphate in patients with HHRH. The aim of the study was to evaluate the efficacy of oral phosphate supplements in Russian cohort of children with HHRH. Method 9 children (7M/2F) with homozygous (n=6) and compound heterozygous (n=3) SLC34A3 mutations from unrelated families were examined. Treatment with oral phosphate supplements was started at the median age of patients 12.0 (IQR: 9.0; 13.0) years. The median dosage of oral phosphate supplements was 14.1 (IQR: 13.8; 14.8) mg/kg/day based on elemental phosphorus. The duration of follow-up was 36.0 (IQR: 16; 49) months. Blood electrolytes levels, ALP, PTH and 24-hour-urine excretion of calcium were evaluated in all children. ALP Z-scores were calculated using age- and sex-specific mean/standard deviation (SD) lab reference data. Bone mineral density with Z-score were measured in lumbar spine and whole body for all patients using a dual energy X-ray absorptiometry device. Molecular genetic analysis was performed in all children using by next generation sequencing. Results The median SD score of height at the first and last follow-up was -1.35 (IQR: -1.8; -0.87) and -1.51 (IQR: -2.0; -0.66) (p=0.6), respectively, short stature had 33.3% (3/9) of patients at first and 44.4% (4/9) at last follow-up (p=0.7). Treatment with low doses of oral phosphate supplements did not led to normalization of serum phosphorus:1.05 (IQR: 0.97; 1.39) vs. 0.93 (IQR: 0.81; 1.27) mmol/l (p=0.13), PTH: 8.3 (IQR: 5.8; 13.8) vs. 12.9 (IQR: 12.0; 16.0) pg/ml (p=0.34), Z-score in lumbar spine: -1.2 (IQR: -2.7; -0.1) vs. -1.8 (IQR: -2.8; -1.1) (p=0.48) and Z-score in total body: -2.1 (IQR -2.6; -1.5) vs. -2.4 (IQR: -3.0; -2.0) (p=0.37). Hypercalciuria had 88.8% (8/9) of children (0.15 (IQR: 0.12; 0.19) mmol/kg/day) at first follow-up and 44.4% (4/9) (0.09 (IQR: 0.08; 0.16) mmol/kg/day) in last examination (p=0.13). ALP blood levels were elevated in all patients (9/9) at first and most recent visit, but ALP Z-score were significant lower at last follow-up: 3.9 (IQR: 1.2; 5.1) vs. 0.57 (IQR: -0.36; 2.1) (p=0.04). There were significant correlations between doses of oral phosphate supplements and ALP Z-score (r=-0.68; p=0.04) and total body Z-score (r=0.78; p=0.03). There was no significant correlations between ALP Z-score and total body Z-score (r=-0.3) or lumbar spine Z-score (r=-0.1). Conclusion The present study demonstrated that treatment of HHRH with low doses (&amp;lt;20 mg/kg/day) of oral phosphorus supplements led to decreasing of ALP Z-score in 7/9 (77.8%) and hypercalciuria in 5/9 (55.6%) of patients. However, that therapy didn’t improve significantly height and severity of rickets, as well didn’t led to normalization of serum phosphorus in children with HHRH. It is therefore conceivable that higher daily doses of phosphate supplements are needed to normalize all clinical and radiological features of disease. Lack of association between ALP Z-score and bone mineral density severity on radiographs limits the value of serum ALP as the indicator of rickets activity.

Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice.

Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).

SUN-929 An Unusual Presentation of Insulinomas-Profound Hypophosphatemia

BACKGROUND: Insulin induces intracellular shift of phosphorus, causing hypophosphatemia. This is mild, transient and quiescent in normal persons. Persistent hyperinsulinemia in patients with depleted phosphorus stores can cause profound symptomatic hypophosphatemia. Clinical Case: A 36yr old man with MEN 1 presented in follow-up. His original manifestation of MEN 1 was familial primary hyperparathyroidism (pHPT) for which he had parathyroidectomy in 2009. At one of his endocrine clinic visits, he was noted to have asymptomatic hypophosphatemia with serum phosphorus of 2.4 (2.7–4.5 mg/dL) and mildly elevated PTH of 89 (9–77 pg/mL). This was presumed to be due to mild persistent/recurrent pHPT, and he was advised to increase dietary phosphorus intake. About a year later, he presented to the emergency room (ER) with palpitations and marked asthenia. Serum phosphorus was 1.0. He was treated with intravenous phosphorus and discharged on oral phosphorus replacement with advice to increase his dietary phosphate intake. Despite this, he continued to have recurrent spells of dizziness, weakness, palpitations, and marked hypophosphatemia several requiring repeat ER visits. His degree of mild pHPT remained stable and imaging studies to identify a possible cause for tumor induced osteomalacia with phosphate wasting was unrevealing. He volunteered at a follow up visit that he had a long history of low blood sugar spells (confirmed by fingerstick) that he had learnt to manage with frequent carbohydrate rich snacks. This prompted the consideration of a possible insulinoma as the cause for his persistent hypophosphatemia. Despite significant hypoglycemia on an abbreviated supervised fast, an OGTT and mixed meal test showed profound severe insulin mediated hypoglycemia. CGMS also showed multiple extended early morning severe hypoglycemic spells <50mg/dl over a 2 wk period. Multiple imaging tests were negative but a Gallium Dotatate scan revealed multiple areas of uptake in his pancreas. Endoscopic ultrasound of the pancreas demonstrated multiple masses in the pancreas: one 7 x 5 cm mass in the body and one 4 x 4 cm mass near the neck of the pancreas. Fine needle aspiration biopsy revealed well-differentiated neuroendocrine tumors. He had distal pancreatectomy and tumor enucleation of 5 tumors identified on intraoperative sonography. Histopathology confirmed multiple neuroendocrine tumors, with immunostaining for insulin. He has had no further episodes of hypophosphatemia since despite being off oral phosphate supplements. Conclusion: Profound hypophosphatemia can be the dominant presentation of persistent hyperinsulinemia seen in patients with insulinoma. Insulinomas and other causes of persistent hyperinsulinemia need to be considered in the differential diagnosis of persistent/recurrent hypophosphatemia.

SUN-345 Use of Anti-FGF23 Monoclonal Antibody in the Treatment of Children and Adolescents with X-Linked Hypophosphatemic Rickets

Background: X-linked hypophosphataemia is the most common heritable form of rickets in children, disorder caused by mutations in PHEX, leading to elevated secretion of FGF23, renal phosphate wasting with consequent hypophosphataemia, diminish synthesis of 1,25(OH)2 vitamin D, rickets/osteomalacia, and disproportionate short stature. Conventional treatment with oral phosphate supplementation and active vitamin D heals rickets, prevents progressive growth failure, but in a substantial proportion of patients treatment is unsuccessful and/or associated with adverse effects. Since 2018, burosumab, a human monoclonal antibody against FGF23, was approved for the treatment of X-linked hypophosphataemia.Aim: We report a pilot experience on the efficacy and safety of treatment with burosumab in children and adolescents with X-linked hypophosphataemia (XLH). Methods and patients: Eight XLH patients (5 males) (5 pre pubertal and 3 Tanner IV) with an age range from 2.9 to 16.2 years, were recruited, 6/8 had family history of XLH, the remaining two were confirmed with molecular study. All discontinue conventional therapy at least 7 days before treatment with Burosumab which was administered every 2 weeks SC for 6 months, at a starting dose of 0.8 mg/kg/dose. Growth velocity, Thacher Rickets Severity Score, fasting serum calcium (mg/dl), phosphorus (P)(mg/dl), alkaline phosphatase (ALP)(IU/L), PTH (pg/dl), 25OH Vitamin D (ng/ml) and tubular phosphate reabsorption (TPR) (X±SD) were evaluated at basal, 3, and 6 months of treatment. Results: All patients had normal 25OH2 Vitamin D: 35.3±8.6 ng/ml at the start of therapy and had significantly improvement of serum P: basal 2.2±0.51, 3 months: 3.24±0.43 and at 6 months 3.01±0.38 mg/dl (p<0.005). The mean serum ALP level decreased from 686.9±410.8 to 535.8±302.4 and 402.5±106.7 IU/L (p<0.05) respectively. TPR normalized during treatment: 67.3±9, 86±3.1, and 86.9±6.1 %(p<0.001). The severity of rickets, as well, showed a significant improvement: 4.0±2.0, 2.3±1.2, and 1.0±0.8 (p<0.005), respectively. The non-pubertal children increased their growth velocity from 3.7±1.2 cm/yr to 7.0±1.4, and 7.9±2.0 cm/yr (p<0.05) respectively. Serum calcium and PTH levels did not show any significantly variation. Mild adverse events such as local reactions and headaches were observed. Conclusions: 1) Treatment with burosumab restores phosphate metabolism, 2) Growth and the Thacher Rickets Severity Score improved during treatment, 3) all patients showed a good safety profile with only minor adverse events. This is the first report of children with XLH treated with burosumab in Latin-America.

SAT-376 Secondary Hyperparathyroidism, an Untoward Complication of High Dose Phosphate Supplementation in Hereditary Hypophosphatemic Rickets

Background: Hereditary hypophosphatemic rickets is a debilitating disease with multiple skeletal abnormalities. Children exhibit rickets and growth failure, while adults exhibit bone pain, enthesopathy, HTN, and arthritis. Gene mutations involving renal phosphate reabsorption(PHEX, FGF23, SLC34A3) leads to renal phosphate wasting. Modes of inheritance include X-linked dominant (most common), autosomal dominant, and autosomal recessive. High dose oral phosphate supplements along with calcitriol are the mainstay of treatment. This can lead to complications of secondary hyperparathyroidism. Clinical Case: An 81-year-old Caucasian woman with PMH of X-linked dominant hypophosphatemic rickets (XLH), secondary osteoarthritis of both knees, HTN, and neuropathy was seen in the Endocrinology clinic. She was diagnosed with XLH 47 years ago and was taking calcitriol 0.5 mcg daily along with a phosphate supplement of 250 mg, 2 tablets 5 times a day. She underwent multiple corrective orthopedic procedures and bilateral knee replacements. On exam, she had short stature (height of 149.9 cm), arthritic changes of bilateral hand joints, and dentures. Starting in 2015, there was a rise in PTH to 101 pg/ml (normal 18.4-80 pg/ml). Over the next 4 years her PTH continued to rise to 182.6 pg/ml, 244.4 pg/ml, 350.6 in 2016, 2017, and 2019 respectively. A 24-hour urine collection revealed a calcium level of 175 mg (normal 100-250 mg/24 hours) and a phosphorus level of 2191 mg (normal 900-1300 mg/24 hours). In December of 2018, she developed hypercalcemia with a serum calcium level of 10.9 mg/dl(normal 8.5-10.5 mg/dl). We then tapered off calcitriol and decreased the phosphate supplements to TID. Despite these measures, her PTH continued to rise, but phosphorus remained normal. A Sestamibi scan showed hyperplasia of all four parathyroid glands, and a DXA scan showed normal bone mineral density. Serum alkaline phosphatase was normal. We decreased her phosphate supplements to BID and started cinacalcet at 30 mg BID. Conclusion: This case illustrates the challenges of primary and secondary hyperparathyroidism when treating XLH. It is proposed that an increased oral phosphate load transiently lowers ionized calcium in serum, which then stimulates PTH secretion. Increased mineralization of bone is another possible explanation of this phenomenon. Persistent parathyroid stimulation can cause hyperplasia of parathyroid glands, nephrocalcinosis, hypertension, and renal failure. Early identification, temporary discontinuation of oral phosphate, and an increase of calcitriol will lower PTH. The FDA approved burosumab for the treatment of XLH in 2018. Future studies are needed to see if burosumab therapy prevents the above complications associated with traditional treatment.

X-Linked Hypophosphataemic Rickets and Growth.

X-linked hypophosphataemia (XLH) is the most prevalent form of hereditary rickets characterized by an alteration of phosphate metabolism which frequently leads to the appearance of fractures, bone deformities and growth delay. Although the mechanism of growth impairment in patients with XLH still needs to be clarified, it is known that this alteration is not due to genetic or endocrine factors. A potential explanation for the impairment of growth in this disease is the alteration of the growth plate, a structure responsible for longitudinal growth of bones. Some of the findings in the growth plate of patients with XLH include atypical organization of chondrocytes due to low rates of proliferation and apoptosis and disturbance of chondrocyte hypertrophy, overactivation of the mitogen-activated protein kinase (MAPK) signalling pathway and upregulation of phosphorylated extracellular signal-regulated kinase (pERK). Conventional treatment of XLH (consisting of oral phosphate supplements and active vitaminD analogues) is often insufficient for the longitudinal growth of bone, but other strategies based on recombinant growth hormone or therapies targeting fibroblast growth factor23 (FGF23) or its receptor, such as burosumab, have shown promising results. This article briefly describes the relationship between XLH and growth retardation, and how to address this alteration in patients with XLH.

High Risk of Hypophosphatemia in Patients with Previous Bariatric Surgery Receiving Ferric Carboxymaltose: A Prospective Cohort Study.

Iron deficiency is a common finding in patients with previous bariatric surgery, and parenteral supplementation is frequently required. Ferric carboxymaltose (FCM) is among the preferred compounds used but may be associated with new-onset hypophosphatemia. This study was undertaken to study the prevalence of hypophosphatemia following FCM in patients with previous bariatric surgery, a population that may be at particular risk due to highly prevalent secondary hyperparathyroidism. Patients with previous bariatric surgery and iron depletion scheduled for FCM infusion were prospectively studied before and one week after FCM application. The primary endpoint was new-onset hypophosphatemia. Patients were followed until plasma phosphate had normalized without replacement. Fifty-two patients (40 females) following Roux-en-Y gastric bypass (n = 50) or sleeve gastrectomy (n = 2), with a median age of 46years (range 22-68) and a BMI of 32.2kg/m2 (27.5-37.3), were analyzed. Fifteen patients (29%) developed new-onset hypophosphatemia, with 11 (21%) requiring oral phosphate supplementation for a median duration of 14days (14-25). The plasma phosphate decreased by 0.3mmol/l (-0.5--0.2; p < 0.001) secondary to a 56% increase in the fractional urinary phosphate excretion (p < 0.001). This was associated with a significant increase in serum intact FGF23 (+30%; p < 0.001) and a decrease in serum 1,25(OH)2 vitamin D3 concentrations (-37.6%; p < 0.001). Patients with previous bariatric surgery receiving FCM are at considerable risk of developing significant hypophosphatemia secondary to increased renal phosphate wasting through a mechanism involving FGF23. Monitoring plasma phosphate should be considered following FCM in patients with previous bariatric surgery. ISRCTN registry, ISRCTN12291677, https://www.isrctn.com.

New Developments in the Treatment of X-Linked Hypophosphataemia: Implications for Clinical Management.

X-linked hypophosphataemia (XLH) is due to mutations in phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and represents the most common heritable form of rickets. In this condition, the hormone fibroblast growth factor 23 (FGF23) is produced in excessive amounts for still unknown reasons, and causes renal phosphate wasting and suppression of 1,25-dihydroxyvitamin D, leading to low serum phosphate concentrations. Prolonged hypophosphataemia decreases apoptosis of hypertrophic chondrocytes in growth plates (causing rickets) and decreases mineralisation of existing bone (causing osteomalacia). In contrast to historical conventional treatment with oral phosphate supplements and active vitamin D for the last 50 years, the new anti-FGF23 antibody treatment (burosumab) targets the primary pathology by blocking FGF23, thereby restoring phosphate homeostasis. In this review, we describe the changes in treatment monitoring, treatment targets and long-term treatment goals, including future opportunities and challenges in the treatment of XLH in children.

Description of a novelSLC34A3.c.671delTmutation causing hereditary hypophosphatemic rickets with hypercalciuria in two adolescent boys and response to recombinant human growth hormone

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive disorder characterized by hypophosphatemia, rickets, hyperphosphaturia, elevated 1,25(OH)2D, and hypercalciuria. Mutations in SLC34A3, the gene encoding the sodium-dependent cotransporter NPT2c, have previously been described as a cause of HHRH. Here, we describe two male siblings with rickets and hypercalciuric nephrolithiasis born to unrelated parents, and their response to oral phosphate supplementation and growth hormone therapy. Whole exome sequencing of the oldest brother, and polymerase chain reaction and Sanger sequence analysis of the identified SLC34A3 mutations, was performed for confirmation and to evaluate his siblings and parents. Serum and urine biochemical parameters of mineral homeostasis before and after therapy were evaluated. Whole exome sequencing analysis identified a previously reported heterozygous deletion SLC34A3.g.2259-2359del101bp on the maternal allele, and a novel heterozygous single nucleotide deletion SLC34A3.c.671delT on the paternal allele of the two affected brothers. The parents and the unaffected brother are heterozygous carriers. Recombinant human growth hormone (rHGH) plus oral phosphate in one affected brother improved the renal phosphate leak and resulted in accelerated linear growth superior to that seen with oral phosphate supplementation alone in the other affected brother. Our case study is the first to demonstrate that rHGH can be considered in addition to oral supplementation with phosphorus to improve linear growth in patients with this disorder, and suggests that renal phosphate reabsorption in response to rHGH is NPT2c-independent.

CKD-MBD post kidney transplantation

Complications of chronic kidney disease-associated mineral and bone disorders (CKD-MBD) are frequently observed in pediatric kidney transplant recipients and are associated with high morbidity, including growth failure, leg deformities, bone pain, fractures, osteonecrosis, and vascular calcification. Post-transplant CKD-MBD is mainly due to preexisting renal osteodystrophy and cardiovascular changes at the time of transplantation, glucocorticoid treatment, and reduced graft function. In addition, persistent elevated levels of parathyroid hormone (PTH) and fibroblast growth factor 23 may cause hypophosphatemia, resulting in impaired bone mineralization. Patient monitoring should include assessment of growth, leg deformities, and serum levels of calcium, phosphate, magnesium, alkaline phosphatase, 25-hydroxyvitamin D, and PTH. Therapy should primarily focus on regular physical activity, preservation of transplant function, and steroid-sparing immunosuppressive protocols. In addition, adequate monitoring and treatment of vitamin D and mineral metabolism including vitamin D supplementation, oral phosphate, and/or magnesium supplementation, in case of persistent hypophosphatemia/hypomagnesemia, and treatment with active vitamin D in cases of persistent secondary hyperparathyroidism. The latter should be done using the minimum PTH-suppressive dosages aiming at the recommended CKD stage-dependent PTH target range. Finally, treatment with recombinant human growth hormone should be considered in patients lacking catch-up growth within the first year after transplantation.

Mineralized tissues in hypophosphatemic rickets.

Hypophosphatemic rickets is caused by renal phosphate wasting that is most commonly due to X-linked dominant mutations in PHEX. PHEX mutations cause hypophosphatemia indirectly, through the increased expression of fibroblast growth factor 23 (FGF23) by osteocytes. FGF23 decreases renal phosphate reabsorption and thereby increases phosphate excretion. The lack of phosphate leads to a mineralization defect at the level of growth plates (rickets), bone tissue (osteomalacia), and teeth, where the defect facilitates the formation of abscesses. The bone tissue immediately adjacent to osteocytes often remains unmineralized ("periosteocytic lesions"), highlighting the osteocyte defect in this disorder. Common clinical features of XLH include deformities of the lower extremities, short stature, enthesopathies, dental abscesses, as well as skull abnormalities such as craniosynostosis and Chiari I malformation. For the past four decades, XLH has been treated by oral phosphate supplementation and calcitriol, which improves rickets and osteomalacia and the dental manifestations, but often does not resolve all aspects of the mineralization defects. A newer treatment approach using inactivating FGF23 antibodies leads to more stable control of serum inorganic phosphorus levels and seems to heal rickets more reliably. However, the long-term benefits of FGF23 antibody treatment remain to be elucidated.