No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Effect of Paricalcitol on Circulating Parathyroid Hormone in X-Linked Hypophosphatemia: A Randomized, Double-Blind, Placebo-Controlled Study
Abstract
Context:
Hyperparathyroidism occurs frequently in X-linked hypophosphatemia (XLH) and may exacerbate phosphaturia, potentially affecting skeletal abnormalities.
Objective:
The objective of the study was to suppress elevated PTH levels in XLH patients.
Design:
This was a prospective, randomized, placebo-controlled, double-blind, 1-year trial of paricalcitol, with outcomes measured at entry and 1 year later.
Setting:
PATIENTS were recruited from the investigators' clinics or referred from throughout the United States. Data were collected in an in-patient hospital research unit.
Patients:
Subjects with a clinical diagnosis of XLH and hyperparathyroidism were offered participation and were eligible if they were 9 years old or older and not pregnant, and their serum calcium level was less than 10.7 mg/dL, their 25-hydroxyvitamin D level was 20 ng/mL or greater, and their creatinine level was 1.5 mg/dL or less.
Intervention:
The intervention for this study was the use of paricalcitol or placebo for 1 year.
Main outcome measures:
Determined prior to trial onset was the change in PTH area under the curve. Secondary outcomes included renal phosphate threshold per glomerular filtration rate, serum phosphorus, serum alkaline phosphatase activity, and (99m)Tc-methylenediphosphonate bone scans.
Results:
PTH area under the curve decreased 17% with paricalcitol, differing (P = .007) from the 20% increase with placebo. The renal phosphate threshold per glomerular filtration rate increased 17% with paricalcitol and decreased 21% with placebo (P = .05). Serum phosphorus increased 12% with paricalcitol but did not differ from placebo. Paricalcitol decreased alkaline phosphatase activity in adults by 21% (no change with placebo, P = .04). Bone scans improved in 6 of 17 paricalcitol subjects, whereas no placebo-treated subject improved. Hypercalciuria developed in six paricalcitol subjects and persisted from baseline in one placebo subject.
Conclusions:
Suppression of PTH may be a useful strategy for skeletal improvement in XLH patients with hyperparathyroidism, and paricalcitol appears to be an effective adjunct to standard therapy in this setting. Although paricalcitol was well tolerated, urinary calcium and serum calcium and creatinine should be monitored closely with its use.
... (10) In support of this observation, it was determined in XLH cases with secondary hyperparathyroidism that the administration of paricalcitol, a vitamin D analog, compared with placebo, suppressed PTH and increased TmP/GFR despite an increase in intact FGF23 (iFGF23). (11) Similarly, case reports of hypoparathyroidism postparathyroidectomy in both TIO and XLH normalized TmP/GFR, despite high cFGF23. (12)(13)(14) This phenomenon, with hindsight, was evident in earlier case reports of XLH in the era prior to FGF23 discovery, even including the original publication by Albright and colleagues that reported normalization of serum phosphate after parathyroidectomy. ...
... (12)(13)(14) This phenomenon, with hindsight, was evident in earlier case reports of XLH in the era prior to FGF23 discovery, even including the original publication by Albright and colleagues that reported normalization of serum phosphate after parathyroidectomy. (15)(16)(17) The opposite effect is seen when there is PTH excess caused by secondary hyperparathyroidism in the setting of XLH that leads to further lowering of serum phosphate (11,18) and TmP/GFR. (11) The potential for an independent effect of extracellular calcium on TmP/GFR must be considered based on earlier studies: Conflicting results about the effect of calcium on renal phosphate wasting in XLH have been reported. ...
... (15)(16)(17) The opposite effect is seen when there is PTH excess caused by secondary hyperparathyroidism in the setting of XLH that leads to further lowering of serum phosphate (11,18) and TmP/GFR. (11) The potential for an independent effect of extracellular calcium on TmP/GFR must be considered based on earlier studies: Conflicting results about the effect of calcium on renal phosphate wasting in XLH have been reported. Increasing serum calcium in XLH by calcium infusions reduced renal phosphate wasting, which suggested an indirect effect consequent upon lowering of PTH by the calcium infusion. ...
ABSTRACT Excess fibroblast growth factor 23 (FGF23), excess PTH, and an increase in extracellular calcium cause hypophosphatemia by lowering the maximum renal phosphate reabsorption threshold (TmP/GFR). We recently reported two cases of X‐linked hypophosphatemia (XLH) with severe tertiary hyperparathyroidism who had normalization of TmP/GFR upon being rendered hypoparathyroid following total parathyroidectomy, despite marked excess in both C‐terminal FGF23 (cFGF23) and intact FGF23 (iFGF23). We explored the effects of FGF23, PTH, and calcium on TmP/GFR in a cross‐sectional study (n = 74) across a spectrum of clinical cases with abnormalities in TmP/GFR, PTH, and FGF23. This comprised three groups: FGF23‐dependent hypophosphatemia (n = 27), hypoparathyroidism (HOPT; n = 17), and chronic kidney disease (n = 30). Measurements included TmP/GFR, cFGF23, PTH, ionized calcium, vitamin D metabolites, and bone turnover markers. The combined effect of cFGF23, PTH, and ionized calcium on TmP/GFR was modeled using hierarchical multiple regression and was probed by moderation analysis with PROCESS. Modeling analysis showed independent effects on TmP/GFR by cFGF23, PTH, and ionized calcium in conjunction with a weak but significant effect of the interaction term for PTH and FGF23; probing showed that the effect was most prominent during PTH deficiency. Teriparatide 20 μg daily was self‐administered for 28 days by one case of X‐linked hypophosphatemia with hypoparathyroidism (XLH‐HOPT) to assess the response of TmP/GFR, cFGF23, iFGF23, nephrogenous cyclic adenosine monophosphate (NcAMP), vitamin D metabolites, and bone turnover markers. After 28 days, TmP/GFR was lowered from 1.10 mmol/L to 0.48 mmol/L; this was accompanied by increases in NcAMP, ionized calcium, and bone turnover markers. In conclusion, the effect of FGF23 excess on TmP/GFR is altered by PTH such that the effect is ameliorated by hypoparathyroidism and the effect is augmented by hyperparathyroidism. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
... (2) Secondary and tertiary hyperparathyroidism have been described in XLH patients, mainly in case reports and small cohort studies. (3)(4)(5)(6)(7)(8)(9)(10) In two recent retrospective cohorts, elevated serum parathyroid hormone (PTH) concentrations were detected in 59% and 83% of the pediatric and adult patients evaluated. (11,12) Hyperparathyroidism has been mostly linked to long-term phosphate supplementation. ...
... Hypercalcemia related to parathyroid gland autonomy is often reported in these cases. (3)(4)(5)(6)(7)(8)(9)(10) In two recent retrospective studies in pediatric and adult patients with XLH, Results are expressed as numbers (n). ...
... In centers without access to experienced surgeon, cinacalcet can be a therapeutic alternative as it seems to improve the biochemical profile in combination with standard therapy. (21,28) Paricalcitol, a vitamin D analog, could also be an effective adjunct to standard therapy as it efficiently suppressed PTH secretion in a prospective, randomized, placebo-controlled trial in XLH patients with previous evidence of secondary hyperparathyroidism. (9) Burosumab, a recombinant human monoclonal IgG1 antibody directed against FGF-23, has recently proved its efficacy to improve phosphate homeostasis, vitamin D metabolism in XLH adult patients. (30) PTH concentrations decreased in the burosumab-treated group and increased at week 24 in the placebo group, suggesting that burosumab could improve hyperparathyroidism in these patients. ...
X-linked hypophosphatemia (XLH) is characterized by increased activity of circulating FGF23 resulting in renal phosphate wasting and abnormal bone mineralization. Hyperparathyroidism may develop in XLH patients; however its prevalence, pathogenesis and clinical presentation are not documented. This observational study (CNIL 2171036 v 0) recruited XLH adult patients in a single tertiary referral center. Each patient was explored in standardized conditions and compared with two healthy volunteers, matched for sex, age and 25-OH vitamin D concentrations. The primary endpoint was the proportion of patients with hyperparathyroidism. The secondary endpoints were the factors influencing serum PTH concentrations and the prevalence of hypercalcemic hyperparathyroidism. Sixty-eight patients (51 women, 17 men) were enrolled and matched with 136 healthy volunteers. Patients had higher PTH concentrations compared with healthy controls (53.5 ng/L, IQR 36.7-72.7 vs 36.0 ng/L, IQR 27.7-44.0, P < 0.0001). Hyperparathyroidism was observed in 17 patients out of 68 (25%). In patients, a positive relationship between PTH and calcium concentrations and a negative relationship between PTH and phosphate concentrations were observed. Seven (10%) patients (3 premenopausal women, 1 postmenopausal woman and 3 men) were diagnosed with hypercalcemic hyperparathyroidism. All underwent parathyroid surgery, with consecutive normalization of calcium and PTH concentrations. Hyperparathyroidism is a frequent complication in XLH adult patients. Disruption of the physiological regulation of PTH secretion contributes to parathyroid disease. Early-onset hypercalcemic hyperparathyroidism can be effectively and safely cured by surgical resection. This article is protected by copyright. All rights reserved.
... In contrast to calcipenic rickets, parathyroid hormone (PTH) levels are usually at the upper limit of the normal range or even slightly elevated. Circulating levels of 1,25(OH) 2 vitamin D are low or inappropriately normal in the setting of hypophosphataemia 6,[62][63][64] . ...
... Therefore, potassium citrate should be used with caution in XLH. Secondary hyperparathyroidism, which might aggravate phosphaturia and promote bone resorption, results from the long-term stimulation of parathyroid cells by FGF23 and phosphate supplements and from the suppression of 1,25(OH) 2 vitamin D levels by FGF23, especially in patients not treated with active vitamin D 62,64,[86][87][88]104,[126][127][128] . Conversely, suppressed PTH levels secondary to excessive vitamin D therapy and/or insufficient oral phosphate intake might decrease bone turnover and compromise rickets healing and growth. ...
... A single evening dose might help prevent excessive calcium absorption after food intake and thus hypercalciuria120 . Several other vitamin D analogues are also available62,117,121,122 . As in healthy children, 25(OH) vitamin D deficiency in children with XLH should be corrected by supplementation with native vitamin D.Calcium supplements.Nutritional calcium intake should be kept within the normal range for age. ...
X-linked hypophosphataemia (XLH) is the most common cause of inherited phosphate wasting and is associated with severe complications such as rickets, lower limb deformities, pain, poor mineralization of the teeth and disproportionate short stature in children as well as hyperparathyroidism, osteomalacia, enthesopathies, osteoarthritis and pseudofractures in adults. The characteristics and severity of XLH vary between patients. Because of its rarity, the diagnosis and specific treatment of XLH are frequently delayed, which has a detrimental effect on patient outcomes. In this Evidence-Based Guideline, we recommend that the diagnosis of XLH is based on signs of rickets and/or osteomalacia in association with hypophosphataemia and renal phosphate wasting in the absence of vitamin D or calcium deficiency. Whenever possible, the diagnosis should be confirmed by molecular genetic analysis or measurement of levels of fibroblast growth factor 23 (FGF23) before treatment. Owing to the multisystemic nature of the disease, patients should be seen regularly by multidisciplinary teams organized by a metabolic bone disease expert. In this article, we summarize the current evidence and provide recommendations on features of the disease, including new treatment modalities, to improve knowledge and provide guidance for diagnosis and multidisciplinary care. In this Evidence-Based Guideline on X-linked hypophosphataemia, the authors identify the criteria for diagnosis of this disease, provide guidance for medical and surgical treatment and explain the challenges of follow-up.
... Nadczynność przytarczyc bywa dość częstym powikłaniem nie tyle krzywicy hipofosfatemicznej, co jej leczenia. Wśród powikłań opisywano też pojawianie się zwapnień ektopowych, głównie wapnicy nerek [13,15,18]. Wydaje się jednak, że były to przypadki, w których leczenie prowadzono korzystając z gotowych schematów bez faktycznej i częstej kontroli metabolicznej przebiegu terapii, lub też sytuacje, w których należało dokonywać kompromisów wynikających z braku akceptacji rodziny dla częstego, w ciągu doby, podawania leków. ...
... Wysokie stężenie PTH często zmusza do redukcji doustnej podaży fosforanów (zapobieganie hipokalcemii, a w dalszej perspektywie zmniejszenieryzyka trzeciorzędowej nadczynnościprzytarczyc) [19], co z kolei może prowadzić do gorszej mineralizacji kości (brak substratu dla powstawania hydroksyapatytu). Pożądane obniżenie poziomu parathormonu powoduje Paricalcitol -analog 1,25-dihydroksycholekalcyferolu, aktywna postać witaminy D 2 [18]. ...
... Kilka opisów przypadków i obserwacji krótkoterminowych sugeruje, że również Cynakalcet ma korzystny wpływ na zmniejszenie stężenia PTH i FGF23 w surowicy. Jednak obawy co do bezpieczeństwa stosowania tego leku u dzieci stale rosną, nie ma też w tej dziedzinie badań prospektywnych, długoterminowych [18]. Opisany przypadek poważnej w skutkach hipokalcemii w przebiegu leczenia tym preparatem spowodował wstrzymanie badań klinicznych z udziałem dzieci [15]. ...
... Le alterazioni biochimiche tipiche associate all'XLH includono ipofosfatemia, perdita renale di fosfato con ridotto rapporto TmP/GFR, elevata attività della fosfatasi alcalina sierica (ALP) e livelli alti o inappropriati di FGF23 [3]. I livelli sierici di 1,25(OH) 2 D 3 tendono ad essere inappropriatamente bassi o normali nel contesto dell'ipofosfatemia, mentre la 25(OH)D 3 sierica è solitamente normale [26]. Le concentrazioni sieriche di calcio sono generalmente nell'intervallo normale inferiore e l'escrezione urinaria di calcio è tendenzialmente bassa, a causa della ridotta sintesi di 1,25(OH) 2 D 3 (Tabella 1) [27]. ...
Sommario
Il rachitismo ipofosfatemico legato al cromosoma X (XLH) è una rara malattia congenita caratterizzata da perdita renale del fosfato e conseguente ipofosfatemia. I pazienti adulti con XLH possono presentare manifestazioni cliniche molto variabili da forme lievi a più gravi, comprendenti: osteomalacia, fratture e pseudofratture, deformità ossee, dolore osseo, malattie dentali, entesopatie (calcificazioni dei legamenti e giunzioni teno-ossee), debolezza muscolare, malattie articolari degenerative, rigidità, ridotta mobilità articolare e ridotta funzionalità fisica, e perdita dell’udito. La risposta al trattamento convenzionale con supplementazioni di fosfato e calcitriolo/alfacalcidolo risulta insoddisfacente in molti pazienti, senza alcun effetto sostanziale sul decorso della patologia e con potenziali complicanze endocrinologiche e renali a lungo termine. Recentemente, sono state pubblicate delle linee guida comprendenti raccomandazioni e suggerimenti sulla gestione clinica e farmacologica dei pazienti affetti da XLH anche in età adulta. Tuttavia, ad oggi, non c’è un consenso generale sulle indicazioni di trattamento nei pazienti adulti. In questa Rassegna descriveremo le principali caratteristiche cliniche dell’XLH nell’adulto, vantaggi e limiti della terapia convenzionale, delle nuove terapie e le prospettive future.
... If availa ble, paricalcitol could be added to conventional therapy for PTH suppression. Paricalcitol was tested in a ran domized trial in patients with XLH without prevalent hypercalcaemia 133 . Tertiary hyperparathyroidism should primarily be treated by parathyroid surgery 132 . ...
0123456789();: Renal phosphate wasting syndromes comprise a hetero geneous group of diseases with multiple causes that manifest biochemically as hypophosphataemia. The differential diagnoses of hypophosphataemia are many and the first step is to check whether reduced serum levels of phosphate are due to decreased renal tubular reabsorption of phosphate (TRP). After exclusion of parathyroid hormone (PTH)driven decreased renal tubular phosphate reabsorption, two other main causes of renal phosphate wasting should be investigated: defects in intrinsic renal phosphate transport and fibro blast growth factor 23 (FGF23)related causes, such as Xlinked hypophosphataemia (XLH) 1. This Consensus Statement focuses on XLH as a cause of renal phosphate wasting and mentions acquired tumourinduced osteomalacia (TIO) as a differential Interdisciplinary management of FGF23-related phosphate wasting syndromes: a Consensus Statement on the evaluation, diagnosis and care of patients with X-linked hypophosphataemia Abstract | X-linked hypophosphataemia (XLH) is the most frequent cause of hypophosphataemia-associated rickets of genetic origin and is associated with high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23). In addition to rickets and osteomalacia, patients with XLH have a heavy disease burden with enthesopathies, osteoarthritis, pseudofractures and dental complications, all of which contribute to reduced quality of life. This Consensus Statement presents the outcomes of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, and provides robust clinical evidence on management in XLH, with an emphasis on patients' experiences and needs. During growth, conventional treatment with phosphate supplements and active vitamin D metabolites (such as calcitriol) improves growth, ameliorates leg deformities and dental manifestations, and reduces pain. The continuation of conventional treatment in symptom-free adults is still debated. A novel therapeutic approach is the monoclonal anti-FGF23 antibody burosumab. Although promising, further studies are required to clarify its long-term efficacy, particularly in adults. Given the diversity of symptoms and complications, an interdisciplinary approach to management is of paramount importance. The focus of treatment should be not only on the physical manifestations and challenges associated with XLH and other FGF23-mediated hypophosphataemia syndromes, but also on the major psychological and social impact of the disease. ✉
... If availa ble, paricalcitol could be added to conventional therapy for PTH suppression. Paricalcitol was tested in a ran domized trial in patients with XLH without prevalent hypercalcaemia 133 . Tertiary hyperparathyroidism should primarily be treated by parathyroid surgery 132 . ...
X-linked hypophosphataemia (XLH) is the most frequent cause of hypophosphataemia-associated rickets of genetic origin and is associated with high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23). In addition to rickets and osteomalacia, patients with XLH have a heavy disease burden with enthesopathies, osteoarthritis, pseudofractures and dental complications, all of which contribute to reduced quality of life. This Consensus Statement presents the outcomes of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, and provides robust clinical evidence on management in XLH, with an emphasis on patients’ experiences and needs. During growth, conventional treatment with phosphate supplements and active vitamin D metabolites (such as calcitriol) improves growth, ameliorates leg deformities and dental manifestations, and reduces pain. The continuation of conventional treatment in symptom-free adults is still debated. A novel therapeutic approach is the monoclonal anti-FGF23 antibody burosumab. Although promising, further studies are required to clarify its long-term efficacy, particularly in adults. Given the diversity of symptoms and complications, an interdisciplinary approach to management is of paramount importance. The focus of treatment should be not only on the physical manifestations and challenges associated with XLH and other FGF23-mediated hypophosphataemia syndromes, but also on the major psychological and social impact of the disease. This Consensus Statement provides robust clinical evidence on the multidisciplinary management of children and adults with X-linked hypophosphataemia, with an emphasis on patients’ experiences and needs. It is the outcome of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases.
... 41 In addition, secondary hyperparathyroidism may evolve into tertiary hyperparathyroidism, 42 requiring parathyroid surgery. 43,44 Phosphate oral intake also induces digestive disorders such as nausea, vomiting, and abdominal pain in a dose-dependent manner. These side effects together with the need to take the treatment several times a day are a substantial hurdle to optimal patient compliance. ...
X-linked hypophosphatemia (XLH) is a genetic disease mostly related to PHEX gene mutations which increases FGF23 serum levels, leading to hypophosphatemia and osteomalacia in adults, while affected children, in addition, develop rickets. Most of adults with XLH suffer from reduced quality of life and physical disability due to chronic bone and joint pain related to limb deformities, early osteoarthritis, delayed-healing of insufficiency fractures, and enthesopathies. Dental infections, muscle dysfunction, and deafness are also frequent. The current treatment consists of 2–5 times daily oral administration of phosphate combined to active vitamin D, often badly tolerated with immediate digestive side effects, responsible for poor compliance. In the long term, it may induce nephrocalcinosis and hyperparathyroidism. Burosumab, an anti-FGF23 blocking antibody, was approved for treating children with XLH in many countries. A randomized 24-week-long placebo-controlled trial, followed by an open-label period of equal duration was conducted in 134 XLH adults treated with 1 mg/kg burosumab/4 weeks. During burosumab treatment, 94% of the patients normalized serum phosphate values versus 7% in the placebo group. Fracture healing was increased 16.7 times compared with placebo-treated patients. All pain and disability tests improved significantly in a time-dependent manner. Burosumab for 48 weeks improved histological lesions of osteomalacia in a single-arm longitudinal study analyzing paired bone biopsies. Another single-arm, open-label study investigated the long-term safety and efficacy of burosumab in 20 adult patients followed for 3.2 years. Burosumab was beneficial on pain and disability scores and on bone remodeling markers. No major side effects especially no hyperphosphatemic episodes were reported. Overall, the benefit/risk ratio of burosumab is positive in adult patients with clinical and/or biological complications of XLH. Burosumab corrects hypophosphatemia, promotes fracture healing, and induces a modest but significant effect on XLH-induced subjective pain and disability symptoms.
Plain language title and summary
Effects of conventional treatment and burosumab in adults with X-linked hypophosphatemia. X-linked hypophosphatemia (XLH) is a disease of genetic origin that affects mineralized tissues (skeleton and teeth) and impairs muscle function. It induces a decrease in blood phosphate levels. This leads to under mineralization of bones and insufficiency fractures that heal slowly, associated with poor dental health characterized by spontaneous dental abscesses. Adults with XLH suffer from chronic pain and limb deformities that alter their quality of life. They are currently treated with daily administration of vitamin D and several daily doses of phosphate. This treatment may induce parathyroid gland dysfunction and mineral deposits in the kidney. If not tightly monitored, these side effects may lead to tertiary hyperparathyroidism and the need for parathyroid gland surgery, or to nephrocalcinosis which may proceed to chronic kidney disease. Burosumab is an antibody that blocks the action of FGF23 the factor that circulates in excess in blood and is responsible for phosphate renal leak in XLH. Three studies demonstrated that burosumab, injected every 4 weeks, is efficient and safe for treating adults with XLH.
... The primary search yielded 1773 references, of which 67 were assessed in full. Fourty trials were subsequently excluded: 20 had an ineligible study design [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52], seven examined vitamin D co-supplementation [53][54][55][56][57][58][59], two was conducted in children [60,61], one was a review study [62], and three did not provide values for serum FGF-23 concentration at endline [23][24][25]. Ten reports from three trials were identified [63][64][65][66][67][68][69][70][71][72][73]; only the most completed of each was included in the analyses [68,70,72]. ...
Previous studies of the effect of vtamin D on serum levels of fibroblast growth factor- 23 (FGF-23) have yeilded an inconsistent findings. This systematic review and meta-analysis of randomized controlled trials (RCTs) sought to investigate the effect of vitamin D supplementation on serum levels of FGF-23. PubMed, Scopus, ISI Web of Science, and the Cochrane Library were searched, from database inception to November 2020, for RCTs that evaluated the effects of native or active vitamin D supplementation on serum levels of FGF-23 in adults. Weighted mean difference (WMD) were calculated and random effects meta-analysis was used to estimate the overall effects. Twenty-seven trials were included in the meta-analysis. Supplementation with native vitamin D (23 studies, n = 2247 participants; weighted mean difference [WMD] = 0.5 pg/mL, 95 % CI: -0.52 to 1.51, P = 0.33; I² = 29.9 %), and active vitamin D (5 studies, n = 342 participants, WMD = 29.45 pg/mL, 95 % CI: -3.9 to 62.81, P = 0.08; I² = 99.3%) had no significant effects on serum FGF-23 concentration. In subgroup analyses, supplementation with ergocalciferol (3 studies, n = 205 participants; WMD = 18.27 pg/mL, 95 % CI: 5.36–31.17, P = 0.006), and daily dosing regimens (9 studies, n = 1374 participants; WMD = 0.41 pg/mL, 95 % CI: 0.22 to 0.59, P < 0.001) increased serum FGF-23 levels compared to control. Overall, our findings revealed no significan effect of vitamin D supplementation on serum FGF-23 concentration. However, further high quality, large-scale studies are needed to better elucidate this relationship.
... Persistent secondary hyperparathyroidism may play a role in increased skeletal turnover in adults. When paricalcitol was added to standard therapy to suppress PTH in adults with XLH, the renal phosphate threshold improved and blood alkaline phosphatase levels fell, in spite of the expected rise in FGF23 levels [50]. This study demonstrated that secondary hyperparathyroidism appears to worsen the biochemical abnormalities in XLH. ...
FGF23 is a hormone produced by osteocytes in response to an elevation in the concentration of extracellular phosphate. Excess production of FGF23 by bone cells, or rarely by tumors, is the hormonal basis for several musculoskeletal syndromes characterized by hypophosphatemia due to renal phosphate wasting. FGF23-dependent chronic hypophosphatemia causes rickets and osteomalacia, as well as other skeletal complications. Genetic disorders of FGF23-mediated hypophosphatemia include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), fibrous dysplasia of bone, McCune-Albright syndrome, and epidermal nevus syndrome (ENS), also known as cutaneous skeletal hypophosphatemia syndrome (CSHS). The principle acquired form of FGF23-mediated hypophosphatemia is tumor-induced osteomalacia (TIO). This review summarizes current knowledge about the pathophysiology and clinical presentation of the most common FGF23-mediated conditions, with a focus on new treatment modalities. For many decades, calcitriol and phosphate supplements were the mainstay of therapy. Recently, burosumab, a monoclonal blocking antibody to FGF23, has been approved for treatment of XLH in children and adults, and an active comparator trial in children has shown good efficacy and safety for this drug. The remainder of FGF23-mediated hypophosphatemic disorders continue to be treated with phosphate and calcitriol, although ongoing trials with burosumab for treatment of tumor-induced osteomalacia show early promise. Burosumab may be an effective treatment for the remainder of FGF23-mediated disorders, but clinical trials to support that possibility are at present not available.
... Typical biochemical alterations associated with XLH include hypophosphatemia, renal phosphate wasting with reduced TmP/GFR ratio (tubular maximal reabsorption of phosphate adjusted for glomerular filtration rate), and high serum alkaline phosphatase (ALP) activity and FGF23 levels [33,47]. Serum 1,25(OH) 2 D 3 levels tend to be inappropriately low or normal in the setting of hypophosphatemia, while serum 25-vitamin D [25-(OH) 2 D 3 ] is usually normal [48]. Serum calcium concentrations are generally in the lower normal range, and urinary calcium excretion is tendentially low, due to impaired 1,25(OH) 2 D 3 synthesis [51]. ...
The main congenital conditions of hypophosphatemia expressed in adulthood include several forms of hereditary hypophosphatemic rickets and a congenital disorder of vitamin D metabolism characterized by osteomalacia and hypophosphatemia in adult patients. Hypophosphatemia in adults is defined as serum phosphate concentration < 0.80 mmol/L. The principal regulators of phosphate homeostasis, as is well known, are parathyroid hormone (PTH), activated vitamin D, and Fibroblast Growth Factor 23 (FGF23). Differential diagnosis of hypophosphatemia is based on the evaluation of mechanisms leading to this alteration, such as high PTH activity, inadequate phosphate absorption from the gut, or renal phosphate wasting, either due to primary tubular defects or high FGF23 levels. The most common inherited form associated to hypophosphatemia is X-linked hypophosphatemic rickets (XLH), caused by PHEX gene mutations with enhanced secretion of the FGF23. Until now, the management of hypophosphatemia in adulthood has been poorly investigated. It is widely debated whether adult patients benefit from the conventional treatments normally used for pediatric patients. The new treatment for XLH with burosumab, a recombinant human IgG1 monoclonal antibody that binds to FGF23, blocking its activity, may change the pharmacological management of adult subjects with hypophosphatemia associated to FGF23-dependent mechanisms.
... -the absence of correction of the phosphate wasting with continued hypophosphatemia [20,30,80,85]; -the risk of nephrocalcinosis and/or urolithiasis; large doses of active vitamin D and oral phosphate supplements have both been associated with an increased rate of nephrocalcinosis in children [67,[91][92][93][94][95]; -the risk of hyperparathyroidism; large oral doses of phosphate supplements are associated with the development of secondary and tertiary hyperparathyroidism by yet unknown mechanisms [8,86,91,92,[96][97][98][99][100]] -the insufficient, or lack of, response of some children, leading to corrective surgeries of lower limbs [101]; -and the incomplete correction of muscle function deficits [75,76]. ...
Early diagnosis, optimal therapeutic management and regular follow up of children with X-linked hypophosphatemia (XLH) determine their long term outcomes and future quality of life. Biochemical screening of potentially affected newborns in familial cases and improving physician's knowledge on clinical signs, symptoms and biochemical characteristics of XLH for de novo cases should lead to earlier diagnosis and treatment initiation. The follow-up of children with XLH includes clinical, biochemical and radiological monitoring of treatment (efficacy and complications) and screening for XLH-related dental, neurosurgical, rheumatological, cardiovascular, renal and ENT complications. In 2018, the European Union approved the use of burosumab, a humanized monoclonal anti-FGF23 antibody, as an alternative therapy to conventional therapy (active vitamin D analogues and phosphate supplements) in growing children with XLH and insufficiently controlled disease. Diagnostic criteria of XLH and the principles of disease management with conventional treatment or with burosumab are reviewed in this paper.
... Cinacalcet has been variably tolerated in our experience, and rebound hyperparathyroidism following discontinuation of the drug may occur. We have also used paricalcitol (a 1,25(OH) 2 D analogue) in the setting of intolerance or unresponsiveness to cinacalcet with monitoring of serum and urinary calcium 175 . Parathyroidectomy may be required if hyper parathyroidism with hypercalcaemia is persistent and unresponsive to medical therapy. ...
Rickets is a bone disease associated with abnormal serum calcium and phosphate levels. The clinical presentation is heterogeneous and depends on the age of onset and pathogenesis but includes bowing deformities of the legs, short stature and widening of joints. The disorder can be caused by nutritional deficiencies or genetic defects. Mutations in genes encoding proteins involved in vitamin D metabolism or action, fibroblast growth factor 23 (FGF23) production or degradation, renal phosphate handling or bone mineralization have been identified. The prevalence of nutritional rickets has substantially declined compared with the prevalence 200 years ago, but the condition has been re-emerging even in some well-resourced countries; prematurely born infants or breastfed infants who have dark skin types are particularly at risk. Diagnosis is usually established by medical history, physical examination, biochemical tests and radiography. Prevention is possible only for nutritional rickets and includes supplementation or food fortification with calcium and vitamin D either alone or in combination with sunlight exposure. Treatment of typical nutritional rickets includes calcium and/or vitamin D supplementation, although instances infrequently occur in which phosphate repletion may be necessary. Management of heritable types of rickets associated with defects in vitamin D metabolism or activation involves the administration of vitamin D metabolites. Oral phosphate supplementation is usually indicated for FGF23-independent phosphopenic rickets, whereas the conventional treatment of FGF23-dependent types of rickets includes a combination of phosphate and activated vitamin D; an anti-FGF23 antibody has shown promising results and is under further study.
... Elevated FGF-23 levels following PTH infusion and reduced FGF-23 levels following parathyroidectomy underscore a cardinal role of PTH in mediating FGF-23 elevations [18]. The normalization of TP/GFR and serum P with declines in PTH, despite marked FGF-23 elevations following reinstitution of calcitriol (Table 1), underscore the dominant role of PTH as a cause for the phosphaturia, in agreement with observations in patients with X-linked hypophosphatemia treated with paricalcitol [21], and point to the utmost importance of controlling hyperparathyroidism in VDRR-I. ...
Background:
As 1,25(OH)2D3 vitamin D3 induces fibroblast growth factor-23 (FGF-23) production and suppresses the renin-angiotensin-aldosterone system (RAAS), its absence in vitamin-D-dependent rickets type I (VDDR-I) may have adverse health consequences.
Case description:
An infant presented at age 8 months with hypocalcemia and rickets and very low 1,25(OH)2D3 levels. Genetic analysis confirmed VDRR-I, and calcitriol therapy was initiated. During periods of nonadherence to therapy, chemical measurements revealed detectable FGF-23 levels, with undetectable 1,25(OH)2D3, hypophosphatemia, low tubular reabsorption of phosphate, hypocalcemia, and very elevated parathyroid hormone (PTH) levels. These changes, in addition to elevated RAAS levels, normalized during calcitriol therapy despite elevated FGF-23 levels. At age 12 years, all rachitic manifestations were absent, and bone mineral density (BMD) and the echocardiogram were normal.
Conclusions:
Whereas 1,25(OH)2D3 is not indispensable for FGF-23 production, PTH in the absence of vitamin D may maintain FGF-23 secretion despite hypocalcemia. Normalization of urinary phosphate losses despite elevated FGF-23 during calcitriol-mediated suppression of secondary hyperparathyroidism points to a cardinal role of PTH as a cause of the phosphaturia in VDRR-I. Normalization of RAAS by calcitriol may conceivably prevent adverse cardiovascular outcomes.
... There are reports of successful treatment of tertiary HPT with cinacalcet in children (24,76) and adults (77,78), but safety concerns have stopped further clinical trials investigating the effects of cinacalcet in children (79). A recent report suggests the vitamin D analog paricalcitol to suppress elevated PTH secondary to treatment in XLHR (80). However, careful monitoring of treatment, to ensure lowest efficient phosphate dose is very important to heal rickets and at the same time reduce the risk of tertiary HPT. ...
Objective:
Hereditary hypophosphatemias are rare monogenic conditions characterized by decreased renal tubular phosphate reabsorption. The aim of this study was to explore the prevalence, genotypes, phenotypic spectrum, treatment response and complications of treatment in the Norwegian population of children with hereditary hypophosphatemia.
Design:
Retrospective national cohort study.
Methods:
Sanger sequencing and multiplex ligand-dependent probe amplification (MLPA) analysis of PHEX, and Sanger sequencing of FGF23, DMP1, ENPP1 KL and FAM20C were performed to assess genotype in patients with hereditary hypophosphatemia with or without rickets in all pediatric hospital departments across Norway. Patients with hypercalcuria were screened for SLC34A3 mutations. In one family exome sequencing was performed. Information from the patients' medical records was collected for the evaluation of phenotype.
Results:
28 patients with hereditary hypophosphatemia (18 female, 10 male) from 19 different families were identified. X-linked dominant hypophosphatemic rickets (XLHR) was confirmed in 21 children from 13 families. The total number of inhabitants in Norway aged 18 or below by January 1st, 2010 was 1.109,156, giving an XLHR prevalence of approximately 1 in 60.000 Norwegian children. FAM20C mutations were found in two brothers, and SLC34A3 mutations in one patient. In XLHR growth was compromised in spite of treatment with oral phosphate and active vitamin D compounds, with males tending to be more affected than females. Nephrocalcinosis was slightly more common in patients starting treatment before one year of age, and was associated with higher average treatment doses of phosphate. However, none of these differences reached statistical significance.
Conclusions:
We present the first national cohort of hereditary hypophosphatemia in children. The prevalence of XLHR seems to be lower in Norwegian children than reported earlier.
Beyond its functions in locomotion, support and protection of vital organs, bone also interacts with other organs to adjust mineral balance in response to physiological requirements. Bone remodelling is a continuous process of bone resorption and formation for the purpose of maintaining healthy bone mass and growth. Any derangement in this process can cause bone disorders with important clinical consequences. The most prominent features of bone diseases in children include early bone fractures, deformities and pain, which can persist and worsen later in life if an accurate and timely diagnosis is not achieved. Biochemical and genetic testing usually help to discriminate the aetiology of the disease, which determines the subsequent management and follow-up. This review focuses on major genetic metabolic bone diseases in children, their pathophysiological mechanisms, the potential therapeutic interventions and the possible consequences in adulthood of the disease and its treatments.
X-linked hypophosphatemia (XLH) is caused by mutations in the PHEX gene which result in Fibroblast Growth Factor-23 (FGF23) excess and phosphate wasting. Clinically, XLH children present with rickets, bone deformities and short stature. In adulthood, patients may still be symptomatic with bone and joint pain, osteomalacia-related fractures or pseudofractures, precocious osteoarthrosis, entesopathy, muscle weakness and severe dental anomalies. Besides these musculoskeletal and dental manifestations, adult XLH patients are also prone to secondary and tertiary hyperparathyroidism, cardiovascular and metabolic disorders. Pathophysiology of hyperparathyroidism is only partially understood, ….. Similarly, the pathophysiological mechanisms of potential cardiovascular and metabolic involvements are not clear, but FGF-23 excess may play an essential role. Treatment should be considered in symptomatic patients, patients undergoing orthopedic or dental surgery and women during pregnancy and lactation. Treatment with oral phosphate salts and active vitamin D analogs has incomplete efficacy and potential risks. Burosumab, a recombinant human monoclonal antibody against FGF 23, has proven its efficacy in phase 2 and phase 3 clinical trials in adult patients with XLH, but currently its position as first line or second line treatment differ among the countries.
Rickets derives from the old English word “wrikken” meaning to twist or bend and refers to conditions of impaired mineralization of growing bones, ultimately resulting in their bowing and twisting. Rickets and osteomalacia refer to similar processes occurring in different compartments of the bone. Rickets is evident histologically and radiographically as a disorganized and expanded growth plate (physis) of the growing bone, together with the accompanying osteomalacia (accumulation of excess unmineralized osteoid matrix due to a delayed mineral apposition rate) of the trabecular and cortical bone. Children with untreated rickets may develop severe curvature deformities of the lower extremities, primarily due to the effect of weight bearing on an under-mineralized skeleton. This chapter will describe the pathophysiology and clinical diagnostic and treatment approach to rickets from a variety of calciopenic and phosphopenic causes.
Apart from the classic forms of rickets, there are rare genetic disorders from the group of vitamin D-resistant rickets where the clinical picture is very similar to the classic forms. Diagnosis of genetically conditioned rickets is often delayed. It is very important to know that a disorder of genetic background may be the cause of the failure of classic treatment in patients with rachitic symptoms. In the group of genetically conditioned rickets there are, among others, congenital hypophosphatemic rickets and vitamin D-dependent rickets type I and II. Congenital hypophosphatemic rickets is characterised by bone mineralisation disturbances related to hypophosphatemia secondary to renal loss of phosphates. The term "hypophosphatemic rickets" covers a group of diseases with similar phenotype but with different genotypes, inheritance models and etiopathogeneses. Mutation of at least ten genes underlying this disease entity have been described. Vitamin D-dependent rickets are caused by defects of vitamin D metabolism. There are four forms described in literature that are distinguished by their genetic causes: type 1A (VDDR1A), type 1B (VDDR1B), and type 2A (VDDR2A), type 2B (VDDR2B). A detailed family history in combination with a physical examination, biochemistry and X-ray imaging helps in differential diagnostics of rare forms of rickets.
Fibroblast growth factor-23 (FGF23) regulates phosphate reabsorption in the kidney and therefore plays an essential role in phosphate balance in humans. There is a host of defects that ultimately lead to excess FGF23 levels and thereby cause renal phosphate wasting and hypophosphatemic rickets. We describe the genetic, pathophysiologic, and clinical aspects of this group of disorders with a focus on X-linked hypophosphatemia (XLH), the best characterized of these abnormalities. We also discuss autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR) and tumor-induced osteomalacia (TIO) in addition to other rarer FGF23-mediated conditions. We contrast the FGF23-mediated disorders with FGF23-independent hypophosphatemia, specifically hypophosphatemic rickets with hypercalciuria (HHRH). Errant diagnosis of hypophosphatemic disorders is common. This review aims to enhance the recognition and appropriate diagnosis of hypophosphatemia and to guide appropriate treatment.
Fibroblast growth factor-23 (FGF23) is a bone-derived endocrine regulator of phosphate homeostasis which inhibits renal tubular phosphate reabsorption. Binding of circulating FGF23 to FGF receptors in the cell membrane requires the concurrent presence of the co-receptor αKlotho. It is still controversial whether αKlotho is expressed in the kidney proximal tubule, the principal site of phosphate reabsorption. Hence, it has remained an enigma as to how FGF23 downregulates renal phosphate reabsorption. Here, we show that renal proximal tubular cells do express the co-receptor αKlotho together with cognate FGF receptors, and that FGF23 directly downregulates membrane expression of the sodium-phosphate cotransporter NaPi-2a by serine phosphorylation of the scaffolding protein Na(+)/H(+) exchange regulatory cofactor (NHERF)-1 through ERK1/2 and serum/glucocorticoid-regulated kinase-1 signaling.
X-linked dominant hypophosphatemic rickets (XLH) is the most prevalent genetic form of hypophosphatemic rickets. Standard treatment of XLH patients includes long-term administration of phosphate and calcitriol. Treated patients usually respond well to the conventional therapy and demonstrate amelioration of rachitic symptoms and improved growth. However, long-term administration of phosphate and vitamin D preparations is sometimes complicated with nephrocalcinosis, secondary or tertiary hyperparathyroidism and arterial hypertension. We describe a patient with XLH, caused by a rare missense mutation of the PHEX gene. The patient, while under treatment with alphacalcidol and oral phosphate, developed hypercalciuria, nephrocalcinosis, secondary hyperparathyroidism and arterial hypertension. Cinacalcet was added to the therapeutic regimen and the long-term effects on calciotropic parameters and FGF23 levels are herein reported.
Phosphate is critical for the maintenance of skeletal integrity, is a necessary component of important biomolecules, and is central to signal transduction and cell metabolism. It is becoming clear that endocrine communication between the skeleton, kidney, and the intestine is involved in maintaining appropriate serum phosphate concentrations, and that the kidney is the primary site for minute-to-minute regulation of phosphate levels. The identification of genetic alterations in Mendelian disorders of hypophosphatemia and hyperphosphatemia has led to the isolation of novel genes and the identification of new roles for existing proteins--such as fibroblast growth factor 23 and its processing systems, the co-receptor alpha-klotho, and phosphate transporters--in the control of renal phosphate handling. Recent findings also indicate that fibroblast growth factor 23 has feedback mechanisms involving parathyroid hormone and vitamin D that control phosphate homeostasis. This Review will highlight genetic, in vitro and in vivo findings, and will discuss how these clinical and experimental discoveries have uncovered novel aspects of renal phosphate handling and opened new research and therapeutic avenues.
In contrast to the regulation of calcium homeostasis, which has been extensively studied over the past several decades, relatively little is known about the regulation of phosphate homeostasis. Fibroblast growth factor 23 (FGF23) is part of a previously unrecognized hormonal bone-parathyroid-kidney axis, which is modulated by PTH, 1,25(OH)(2)-vitamin D (1,25(OH)(2)D), dietary and serum phosphorus levels. Synthesis and secretion of FGF23 by osteocytes are positively regulated by 1,25(OH)(2)D and serum phosphorus and negatively regulated, through yet unknown mechanisms, by the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and by dentin matrix protein 1 (DMP1). In turn, FGF23 inhibits the synthesis of 1,25(OH)(2)D, and it may negatively regulate the secretion of parathyroid hormone (PTH) from the parathyroid glands. However, FGF23 synergizes with PTH to increase renal phosphate excretion by reducing expression of the renal sodium-phosphate cotransporters NaPi-IIa and NaPi-IIc in the proximal tubules. Most insights gained into the regulation of phosphate homeostasis by these factors are derived from human genetic disorders and genetically engineered mice, which are reviewed in this paper.
In hypophosphatemic rickets, there are both inherited and acquired forms, where X-linked dominant hypophosphatemic rickets (XLH) is the most prevalent genetic form and caused by mutations in the phosphate-regulating endopeptidase (PHEX) gene. XLH is associated with growth retardation and bone deformities. The renal tubular cells have an important role in calcium and phosphate metabolism, where the 1alpha-hydroxylase enzyme metabolizes the conversion of 25 (OH)-vitamin D to potent 1,25 (OH)2-vitamin D, whereas the sodium-phosphate transporter controls tubular phosphate reabsorption. The pathophysiological defect in XLH is speculated to cause an increase in a circulating phosphate regulating hormone termed phosphatonin (fibroblast growth factor 23 is the primary phosphatonin candidate), which leads to inhibition of 1alpha-hydroxylase, and simultaneously to inhibition of the sodium-phosphate transporter domain NPT2c leading to parathyroid hormone-independent phosphaturia. Hence, current treatment of XLH is 1,25 (OH)2-vitamin D or the vitamin D analog alfacalcidol and elementary phosphorus. Unfortunately, patients with XLH may develop nephrocalcinosis, secondary or tertiary hyperparathyroidism, and in some situations also hypertension and cardiovascular abnormalities. We describe a patient with XLH caused by a novel missense mutation in the PHEX gene, who on treatment with alfacalcidol and oral phosphate had normal growth and minimal bone deformities, but who subsequently developed moderate nephrocalcinosis, significant hyperparathyroidism, hypercalcemia, renal failure, and hypertension. We also report the use of the calcimimetic drug cinacalcet in the successful treatment of hypercalcemia and hyperparathyroidism.
Parathyroid function is described as normal in patients with phosphopenic rickets before initiation of therapy with phosphate salts; however, hyperparathyroidism is an occasional complication of treatment. We observed a higher than expected frequency of hyperparathyroidism in patients with phosphate-wasting rickets, present before treatment in some patients and, more frequently, after the onset of treatment. To better define parathyroid status in hypophosphatemic rickets, we sampled 12 affected children and 7 affected adults every 4 h for 1 day and measured PTH in assays detecting midmolecule fragments (cPTH) and intact hormone (iPTH). All children and 4 adults were receiving a vitamin D preparation and phosphate salts; 3 adults were untreated. Mean cPTH, iPTH, and nephrogenous cAMP excretions in each group of patients were greater than in controls. Exaggerated nocturnal rises in both cPTH and iPTH characterized the profile in patients. Seventeen patients demonstrated frankly elevated cPTH at night, with peak values at midnight, whereas no control individual did. Although mean iPTH values in patients increased at night, they did not exceed the upper limit of normal. Hyperparathyroidism in hypophosphatemic rickets occurs in both children and adults, may be present in untreated patients, is predominantly nocturnal, and is characterized by exaggerated secretion of midmolecule fragments. This manifestation of hypophosphatemic rickets is more widespread than currently recognized; we speculate that it may contribute to the pathogenesis of nephrocalcinosis and precede the development of tertiary hyperparathyroidism.
This chapter provides an overview of the prototype X-linked hypophosphatemic disease (XLH). The chapter discusses key elements central to the pathophysiology of XLH and its related disorders, including the putative function of the mutated endopeptidase PHEX and the substances that appear to be important candidates for mediation of the disease. The chapter reviews the biochemistry of FGF23 with respect to its role in the related disorder, autosomal-dominant hypophosphatemic rickets (ADHR). Clinical features of related disorders, including ADHR, hereditary hypophosphatemic rickets with hypercalciuria (HHRH), and tumor-induced osteomalacia (TIO) are compared to those observed in XLH. XLH is one of the most common bone diseases seen in children. XLH is characterized by renal phosphate wasting leading to hypophosphatemia and low or normal concentrations of 1,25-dihydroxyvitamin D [1,25(OH)2D], an inappropriate response to hypophosphatemia. In children, the disorder first becomes apparent with the development of rickets, skeletal deformities, short stature, and dental abscesses. In adults, manifestations of XLH include osteomalacia, degenerative joint disease, enthesopathy, bone and joint pain, and continued dental disease.
The findings in seventy subjects with vitamin D-resistant rickets in twenty-four different families have been analyzed. In five families, previously reported on, additional information has been obtained. Hypophosphatemia, as previously reported, was found to be the best means for identifying positively those with the disorder. Statistical analysis indicated that nonfasting plasma phosphorus levels could be utilized for this differentiation. In thirteen of the twenty-four families a hereditary origin transmitted by a sex-linked dominant gene was clearly established by chemical and clinical classification of parents and progeny; in three additional families clinical and partial chemical classification indicated the same mechanism. Only eight subjects were detectably affected in the remaining families, and hence these cases were probably sporadic. In addition, two mothers with affected children were apparently the initial affected members in their respective pedigrees; this was less certainly the case in two other mothers with affected children. It is impossible from the data available to distinguish whether phenocopy or mutation was responsible for the sporadic cases. Estimates of mutation rates, assuming ten subjects were mutants, were within expected ranges.
Paricalcitol (Zemplar®) is a synthetic vitamin D2 analogue that inhibits the secretion of parathyroid hormone (PTH) through binding to the vitamin D receptor. It is approved in the US and in most European nations for intravenous use in the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure in adult, and in the US paediatric, patients.
Paricalcitol effectively reduced elevated serum PTH levels and was generally well tolerated in children and adults with secondary hyperparathyroidism associated with chronic renal failure. In well designed clinical trials, paricalcitol was as effective as calcitriol and as well tolerated in terms of the incidence of prolonged hypercalcaemia and/or elevated calcium-phosphorus product (Ca × P). Thus, paricalcitol is a useful option for the management of secondary hyperparathyroidism in adults and children with chronic renal failure.
Pharmacological Properties
Paricalcitol (19-nor-1,25-dihyroxyvitamin D2) mimics the actions of 1,25-dihydroxyvitamin D3 (calcitriol), at the vitamin D receptor. This receptor heterodimerises the retinoid X receptor to regulate transcriptional activity of vitamin D-responsive genes.
In rats, paricalcitol inhibits the secretion of PTH in a dose-dependent manner, and suppresses parathyroid hyperplasia. Paricalcitol stimulates less osteoclastic activity than calcitriol and induces similar inhibition of osteoblast maturation in vitro. In rodent models, paricalcitol stimulates less intestinal calcium uptake and is 10-fold less active in the mobilisation of skeletal calcium and phosphorus in vivo than calcitriol.
Intravenous paricalcitol absorption is dose proportional, with little evidence of accumulation of the drug after repeated doses in healthy volunteers or in haemodialysis patients. Mean maximum plasma concentration and area under the plasma concentration-time curve from 0 to 44 hours were 4566 pg/mL and 18 232 pg · h/mL after 4 weeks’ treatment with paricalcitol 0.16 μg/kg three times weekly in haemodialysis patients. The drug is extensively bound to plasma proteins (>99.9%).
Paricalcitol elimination, primarily by biliary excretion, is biphasic. Paricalcitol was metabolised by the cytochrome P450 enzyme 24-hydroxylase in vitro, and only 5.7% of an intravenous dose of the drug was excreted unchanged in healthy volunteers. In patients undergoing haemodialysis, paricalcitol clearance was 0.58–0.91 L/h, and the terminal elimination half-life was 11–32 hours; clearance did not appear to be altered by haemodialysis, indicating that paricalcitol may be administered at any time during haemodialysis.
Therapeutic Efficacy
Intravenous paricalcitol is effective in the treatment of secondary hyperparathyroidism associated with chronic renal failure. In patients undergoing maintenance haemodialysis, paricalcitol reduced mean serum intact PTH (iPTH) levels from ≥650 pg/mL to <300 pg/mL in 18–19 weeks and these reductions were proportionally similar to those evoked by calcitriol therapy.
In calcitriol-resistant patients on maintenance haemodialysis, a switch to paricalcitol therapy elicited a sustained reduction in serum iPTH levels, while in children and young adults, paricalcitol reduced serum iPTH levels without increasing the incidence of elevated serum calcium or phosphorus levels.
Both paricalcitol and calcitriol evoked reductions in serum alkaline phosphatase levels, indicating reductions in bone turnover.
Tolerability
Morbidity and mortality data from analysis of a historical cohort indicate that, over a 36-month period in patients undergoing haemodialysis, paricalcitol provided a 16% survival advantage over calcitriol. Therapy with paricalcitol had little effect on serum calcium and phosphorus levels, and differences in the effect of paricalcitol compared with calcitriol on the induction of single episodes or prolonged periods of hypercalcaemia and/or elevated Ca × P were equivocal.
In calcitriol-resistant patients switched to paricalcitol therapy, use of a calcitriol: paricalcitol dose conversion ratio of 1: 3 minimised increases in serum calcium levels. In children and young adults receiving maintenance haemodialysis, paricalcitol use did not cause increases in serum calcium or phosphorus levels.
Other adverse events reported by patients treated with paricalcitol included nausea, vomiting and oedema.
The aim of this article is to describe the intriguing action of fibroblast growth factor 23 on the parathyroid.
Fibroblast growth factor 23 inhibits renal phosphate reabsorption and calcitriol production. It is the principal phosphaturic factor in a bone-kidney axis coordinating systemic phosphate homeostasis and bone mineralization. Fibroblast growth factor 23 acts at its target tissues by binding to the Klotho-FGFR1c complex and it has recently been confirmed that the fibroblast growth factor 23 receptor is present not only in renal tissue but also in the parathyroid. Fibroblast growth factor 23 leads to a decrease in parathyroid hormone mRNA and serum parathyroid hormone levels by the mitogen-activated protein kinase pathway both in vivo and in vitro.
Fibroblast growth factor 23 is secreted by osteocytes and acts through its receptor the heterodimer of Klotho-FGFR1c in the kidney and parathyroid. In the kidney it leads to phosphaturia and decreased calcitriol synthesis, and in the parathyroid it activates the mitogen-activated protein kinase pathway to decrease parathyroid hormone gene expression and secretion. The decreased parathyroid hormone levels would then also contribute to a decrease in calcitriol synthesis. A bone-kidney-parathyroid hormonal network is now apparent which regulates phosphate, calcium and calcitriol homeostasis. Fibroblast growth factor 23 is the major factor regulating phosphate, and parathyroid hormone the major factor for calcium and calcitriol balances between these factors.
Circulating fibroblast growth factor (FGF)-23 is variably elevated in individuals with X-linked hypophosphatemia (XLH), and klotho has recently been shown to effect renal phosphate handling, yet limited data are available on circulating FGF23 and klotho in XLH.
The objective of the study was to characterize circulating FGF23 and klotho in XLH.
Children and adults with XLH withheld medication for 14 d. Fasting serum FGF23, PTH, klotho, phosphate, and 1,25 dihydroxyvitamin D were obtained. Treated adults were also sampled, and circadian sampling was performed in selected individuals.
The study was conducted at a hospital research unit at an academic medical center. Patients and Other
Participants included 23 individuals with XLH and eight controls.
There were no interventions.
Serum klotho and FGF23 were measured.
FGF23 was greater in XLH than in controls and greater in treated XLH subjects compared with XLH subjects not receiving medical therapy. Children had higher klotho levels than adults, but values in XLH were similar to controls. A strong positive correlation between FGF23 and PTH was found in XLH subjects, whereas there was no relationship between these variables in controls. Circulating klotho, but not FGF23, has a diurnal pattern.
Serum klotho declines with age and demonstrates circadian variation but is normal in XLH. Serum FGF23 is similar in children and adults, is elevated in XLH, further increases with therapy, and demonstrates no diurnal variation. The direct relationship between FGF23 and PTH in subjects with XLH suggests that FGF23 regulation of PTH secretion is aberrant in this disorder.
X-linked hypophosphatemia (XLH), characterized by renal phosphate wasting, is the most common cause of vitamin D-resistant rickets. It has been postulated that some phosphaturic factor plays a causative role in XLH and its murine homolog, the Hyp mouse. Fibroblast growth factor 23 (FGF23) is a physiological phosphaturic factor; its circulatory level is known to be high in most patients with XLH and Hyp mice, suggesting its pathophysiological role in this disease. To test this hypothesis, we treated Hyp mice with anti-FGF23 antibodies to inhibit endogenous FGF23 action. A single injection of the antibodies corrected the hypophosphatemia and inappropriately normal serum 1,25-dihydroxyvitamin D. These effects were accompanied by increased expressions of type IIa sodium-phosphate cotransporter and 25-hydroxyvitamin-D-1alpha-hydroxylase and a suppressed expression of 24-hydroxylase in the kidney. Repeated injections during the growth period ameliorated the rachitic bone phenotypes typically observed in Hyp mice, such as impaired longitudinal elongation, defective mineralization, and abnormal cartilage development. Thus, these results indicate that excess actions of FGF23 underlie hypophosphatemic rickets in Hyp mice and suggest a novel therapeutic potential of the FGF23 antibodies for XLH.
We investigated the acute effects of oral administration of 1,25-dihydroxyvitamin D (1,25-(OH)2D) and phosphate on the major mineral metabolism indexes in six children with vitamin D-resistant rickets treated with a long-term regimen of phosphate and calcitriol. Two acute tests were performed in which plasma calcium, phosphate, immunoreactive parathyroid hormone (iPTH) (intact molecule), 25-hydroxyvitamin D (25-OHD), and 1,25-(OH)2D levels were measured: the first after an oral phosphate load (20 mg/kg) was administered after calcitriol had been discontinued for 10 days, and the second after a calcitriol load (0.03 microgram/kg) plus the same phosphate load but with the children receiving the usual combination treatment. There were no significant differences in basal levels of calcium, phosphate, iPTH, 25-OHD, or 1,25-(OH)2D between the two tests, nor were delta percent calcium and 25-OHD values significantly different. The delta percent plasma phosphate concentration at 60 minutes was significantly higher during test 2 than during test 1 (p less than 0.01) and delta percent iPTH concentration at 60 minutes was significantly higher during test 1 than during test 2 (p less than 0.01). In test 2 the iPTH level returned to baseline at 180 minutes. Higher delta percent 1,25-(OH)2D values at 60 minutes were observed in test 2 than in test 1 (p less than 0.01). Furthermore, the delta percent 1,25-(OH)2D levels were still higher at 180 minutes in test 2 than during test 1 (p less than 0.01). Our study indicates that oral calcitriol has an inhibitory effect on iPTH secretion in the hours immediately after oral phosphate administration in children with vitamin D-resistant rickets.
Orally administered phosphate supplements are the mainstay of therapy for hypophosphatemic osteomalacia of diverse causes and are generally believed to be free from harmful side effects. Two cases are reported, however, in which long-term therapy (14 and 10 years, respectively) resulted in hypercalcemic hyperparathyroidism associated with surgically proved adenomatous hyperplasia. This complication occurred despite concomitant treatment with pharmacologic doses of vitamin D. Thus, long-term oral phosphate therapy can produce tertiary hyperparathyroidism in susceptible patients.
Controversy exists over the role that PTH and extracellular fluid calcium concentration may play in modulation of the renal phosphate transport defect in X-linked hypophosphatemic rickets. In previous studies, administration of PTH to affected subjects resulted in an increase or no effect on renal phosphate excretion, while calcium infusion increased renal tubular phosphate transport. In contrast, patients with X-linked hypophosphatemic rickets and hyperparathyroidism have no change in their renal phosphate wasting after parathyroidectomy. However, none of these were permanently hypoparathyroid postoperatively. We describe a patient with idiopathic hypoparathyroidism in whom we proved the coexistence of X-linked hypophosphatemic rickets using family history and dental abnormalities. Initially, the patient had a mean serum calcium level of 5.6 +/- 0.07 (+/- SE) mg/dl and a renal tubular maximum for reabsorption of phosphate per liter glomerular filtrate (TmP/GFR) of 6.5 +/- 0.46 mg/dl. Hypoparathyroidism was confirmed, and therapy with vitamin D (50,000 U/day) and calcium (1,000 mg/day) was begun. On this regimen, serum calcium rose to 8.1 +/- 0.2 mg/dl, and TmP/GFR declined to 2.59 +/- 0.12 mg/dl. Bone biopsy revealed the persistence of osteomalacia. Subsequently, therapy with 1,25-dihydroxyvitamin D3 (1.0 microgram/day) was initiated, and serum calcium rose to 9.6 +/- 0.07 mg/dl, and TmP/GFR declined to 1.79 +/- 0.16 mg/dl. The prevailing serum calcium level correlated inversely with the TmP/GFR (r2 = 0.91; P less than 0.001). These data indicate that calcium and/or PTH are involved in modulation of the renal phosphate transport defect in X-linked hypophosphatemic rickets.
A controlled metabolic study to examine the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment on the renal handling of phosphate was conducted in nine patients with X-linked dominant hypophosphatemic rickets, including one with autonomous secondary hyperparathyroidism. Administration of 1,25(OH)2D3 resulted in uniform reduction in serum PTH from 63.6 +/- 14.7 (SD) to 49.3 +/- 14.8 muleq/ml (P less than 0.01), elevation of the tubular threshold for phosphate (TmP/GFR) from 1.41 +/- 0.30 to 1.90 +/- 0.31 mg/dl (P less than 0.01) and increase in serum phosphate from 2.6 +/- 0.7 to 3.4 +/- 1.1 mg/dl (P less than 0.01) in eight PTH-suppressible patients. Four patients treated with phosphate before and during the study (group A) excreted significantly more phosphate than those not treated with phosphate (group B) (P less than 0.001). In the control period, group A also had depressed TmP/GFR and higher concentrations of serum phosphate and PTH. With 1,25(OH)2D3 treatment, serum phosphate in group A became remarkably higher than in group B, 4.28 +/- 0.99 vs. 2.55 +/- 0.31 mg/dl (P less than 0.02), whereas serum PTH and TmP/GFR were similar in both groups. A good inverse linear correlation was found between mean serum PTH and mean TmP/GFR of the groups before and after treatment (r = 0.947); whereas, no correlation was found between TmP/GFR and serum calcium. The patient with autonomous secondary hyperparathyroidism, who was also treated with phosphate, had the lowest TmP/GFR. Administration of 1,25(OH)2D3 had no effect on the serum PTH and phosphate concentrations or on TmP/GFR. We conclude that in patients with X-linked dominant hypophosphatemic rickets PTH modulates to some extent the tubular handling of phosphate, and that the importance of this mechanism increases with therapeutic phosphate supplementation. Simultaneous administration of 1,25(OH)2D3 suppressed PTH activity, raised serum phosphate concentrations, and elevated TmP/GFR.
Four patients with familial hypophosphataemic rickets developed significant hypercalcaemia which persisted after discontinuation of vitamin D therapy. They had increased PTH levels and were operated for hyperparathyroidism at the ages of 18, 20, 24 and 45 years, respectively. Three of the patients had previously received phosphate treatment and one patient developed hyperparathyroidism 7 years after treatment with calcitriol. Histological evaluation revealed different degrees of parathyroid hyperplasia in all patients, with persistently increased PTH and/or calcium levels after surgery. The possibility of autonomous hyperparathyroidism should be evaluated in the follow-up of patients with X-linked hypophosphataemic rickets.
Parathyroid function is described as normal in patients with phosphopenic rickets before initiation of therapy with phosphate salts; however, hyperparathyroidism is an occasional complication of treatment. We observed a higher than expected frequency of hyperparathyroidism in patients with phosphate-wasting rickets, present before treatment in some patients and, more frequently, after the onset of treatment. To better define parathyroid status in hypophosphatemic rickets, we sampled 12 affected children and 7 affected adults every 4 h for 1 day and measured PTH in assays detecting midmolecule fragments (cPTH) and intact hormone (iPTH). All children and 4 adults were receiving a vitamin D preparation and phosphate salts; 3 adults were untreated. Mean cPTH, iPTH, and nephrogenous cAMP excretions in each group of patients were greater than in controls. Exaggerated nocturnal rises in both cPTH and iPTH characterized the profile in patients. Seventeen patients demonstrated frankly elevated cPTH at night, with peak values at midnight, whereas no control individual did. Although mean iPTH values in patients increased at night, they did not exceed the upper limit of normal. Hyperparathyroidism in hypophosphatemic rickets occurs in both children and adults, may be present in untreated patients, is predominantly nocturnal, and is characterized by exaggerated secretion of midmolecule fragments. This manifestation of hypophosphatemic rickets is more widespread than currently recognized; we speculate that it may contribute to the pathogenesis of nephrocalcinosis and precede the development of tertiary hyperparathyroidism.
Secondary hyperparathyroidism contributes to significant morbidity in patients with chronic renal failure. The treatment of this disorder with vitamin D compounds, such as calcitriol, although effective at suppressing parathyroid hormone (PTH) secretion, may promote the development of hypercalcemia and hyperphosphatemia, thus increasing the risk for metastatic calcification. A new vitamin D analogue, 19-nor-1alpha,25-(OH)2D2 (paricalcitol; Zemplar, Abbott Laboratories, Inc, Chicago, IL) has recently been developed for the treatment of secondary hyperparathyroidism, and, in experimental animals, it was found to be less calcemic and phosphatemic than calcitriol. In double-blind clinical trials, paricalcitol effectively decreased the levels of PTH by 60%, yet the mean serum calcium values remained within the normal range. The few episodes of hypercalcemia that occurred in the paricalcitol-treated patients (8 of 400 determinations > or =11.0 mg/dL in 7 patients) were associated with marked decreases in PTH levels (87% +/- 2% less than baseline) and absolute values of PTH less than 100 pg/mL in four of the seven patients. PTH values less than 100 pg/mL, however, occurred in 15 patients, but were not invariably associated with frank hypercalcemia, although serum calcium levels increased to 10.63 +/- 0.3 mg/dL, slightly greater than the upper limits of normal. Additional studies to evaluate the conversion from calcitriol to paricalcitol therapy showed that a dose ratio of 1:4 (calcitriol:paricalcitol) could maintain control of high levels of PTH without significant alterations in serum calcium and phosphorus levels. These studies indicate that effective control of hyperparathyroidism can be achieved with paricalcitol therapy with minimal perturbation of serum calcium and phosphorus levels, and may have a therapeutic advantage over current treatment strategies.
An adolescent with hypophosphatemic rickets developed cardiac calcifications in the absence of hypercalcemia or elevation of the phosphocalcic product (the product of the total serum calcium and phosphorus concentrations). Cardiac calcifications led to aortic and mitral valve dysfunction, myocardial calcification, and arrhythmia. Hyperparathyroidism probably played a significant role in the development of this complication, which emphasizes the necessity for intermittent assessment of parathyroid status in individuals receiving medical therapy for hypophosphatemic rickets.
Mutations in fibroblast growth factor 23 (FGF-23) cause autosomal dominant hypophosphatemic rickets. Clinical and laboratory findings in this disorder are similar to those in oncogenic osteomalacia, in which tumors abundantly express FGF-23 messenger RNA, and to those in X-linked hypophosphatemia, which is caused by inactivating mutations in a phosphate-regulating endopeptidase called PHEX. Recombinant FGF-23 induces phosphaturia and hypophosphatemia in vivo, suggesting that it has a role in phosphate regulation. To determine whether FGF-23 circulates in healthy persons and whether it is elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, an immunometric assay was developed to measure it.
Using affinity-purified, polyclonal antibodies against [Tyr223]FGF-23(206-222)amide and [Tyr224]FGF-23(225-244)amide, we developed a two-site enzyme-linked immunosorbent assay that detects equivalently recombinant human FGF-23, the mutant form in which glutamine is substituted for arginine at position 179 (R179Q), and synthetic human FGF-23(207-244)amide. Plasma or serum samples from 147 healthy adults (mean [+/-SD] age, 48.4+/-19.6 years) and 26 healthy children (mean age, 10.9+/-5.5 years) and from 17 patients with oncogenic osteomalacia (mean age, 43.0+/-13.3 years) and 21 patients with X-linked hypophosphatemia (mean age, 34.9+/-17.2 years) were studied.
Mean FGF-23 concentrations in the healthy adults and children were 55+/-50 and 69+/-36 reference units (RU) per milliliter, respectively. Four patients with oncogenic osteomalacia had concentrations ranging from 426 to 7970 RU per milliliter, which normalized after tumor resection. FGF-23 concentrations were 481+/-528 RU per milliliter in those with suspected oncogenic osteomalacia and 353+/-510 RU per milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia.
FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, suggesting that this growth factor has a role in phosphate homeostasis. FGF-23 measurements might improve the management of phosphate-wasting disorders.
The findings in seventy subjects with vitamin D-resistant rickets in twenty-four different families have been analyzed. In five families, previously reported on, additional information has been obtained. Hypophosphatemia, as previously reported, was found to be the best means for identifying positively those with the disorder. Statistical analysis indicated that nonfasting plasma phosphorus levels could be utilized for this differentiation. In thirteen of the twenty-four families a hereditary origin transmitted by a sex-linked dominant gene was clearly established by chemical and clinical classification of parents and progeny; in three additional families clinical and partial chemical classification indicated the same mechanism. Only eight subjects were detectably affected in the remaining families, and hence these cases were probably sporadic. In addition, two mothers with affected children were apparently the initial affected members in their respective pedigrees; this was less certainly the case in two other mothers with affected children. It is impossible from the data available to distinguish whether phenocopy or mutation was responsible for the sporadic cases. Estimates of mutation rates, assuming ten subjects were mutants, were within expected ranges.
Paricalcitol (Zemplar) is a synthetic vitamin D(2) analogue that inhibits the secretion of parathyroid hormone (PTH) through binding to the vitamin D receptor. It is approved in the US and in most European nations for intravenous use in the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure in adult, and in the US paediatric, patients. Paricalcitol effectively reduced elevated serum PTH levels and was generally well tolerated in children and adults with secondary hyperparathyroidism associated with chronic renal failure. In well designed clinical trials, paricalcitol was as effective as calcitriol and as well tolerated in terms of the incidence of prolonged hypercalcaemia and/or elevated calcium-phosphorus product (Ca x P). Thus, paricalcitol is a useful option for the management of secondary hyperparathyroidism in adults and children with chronic renal failure.
Although increased circulating levels of PTH with mild hypocalcemia has been reported in Hyp mice, hyperparathyroidism in X-linked hypophosphatemic rickets is postulated to arise from the standard use of phosphate salts, which induce chronic stimulation of PTH secretion. In this study, we sought to examine the role of PTH in the metabolic derangements associated with Hyp by generating hemizygous hypophosphatemic (Hyp/Y) mice homozygous for the Pth-null allele (Pth(-/-);Hyp/Y). Early postnatal lethality was observed in the Pth(-/-);Hyp/Y mice. Within the first 6 h, postpartum serum phosphorus increased to levels comparable to those in the Pth(-/-) mice, whereas in Hyp mice, it decreased during the first 48 h after birth. Serum calcium concentration started low after birth and remained reduced in both Pth(-/-);Hyp/Y and Pth(-/-) mice although more profoundly so in the former group, whereas in Hyp/Y mice, the levels were initially lower than but reached wild-type levels by 24 h. Circulating PTH levels in Hyp/Y mice were higher than wild-type levels throughout the first 48 h after birth and continued to be so well into adulthood. Twice-daily administration of PTH 1-34 to Pth(-/-);Hyp/Y newborn mice increased serum calcium levels and prevented their early demise. The findings here indicate that the cause of death in the Pth(-/-);Hyp/Y mice is severe hypocalcemia. A potential role for fibroblast growth factor 23 in promoting secondary hyperparathyroidism by suppressing renal 25-hydroxyvitamin D(3)-1alpha-hydroxylase (Cyp27b1) activity while increasing that of renal 25-hydroxyvitamin D(3) 24-hydroxylase (Cyp24) is proposed. Hyperparathyroidism, therefore, is an integral component in the pathophysiology of Hyp, and likely X-linked hypophosphatemic rickets and serves to prevent severe hypocalcemia in mice and perhaps in patients afflicted with the disorder.
The treatment for X-linked hypophosphatemia (XLH) with phosphate and calcitriol can be complicated by secondary hyperparathyroidism and nephrocalcinosis. Furthermore, vitamin D and phosphate stimulate FGF23 production, the pathogenic factor causing XLH. We investigated in XLH patients: 1) whether treatment with the calcimimetic agent, cinacalcet, will block the rise in parathyroid hormone (PTH) caused by phosphate administration; and 2) whether treatment with oral phosphate and calcitriol increases FGF23 levels.
Eight subjects with XLH were given a single oral dose of phosphate, followed the next day by combined treatment with phosphate and cinacalcet. Serum measurements of ionized calcium (Ca), phosphate, creatinine, intact PTH, 1,25(OH)(2)D, FGF23, and tubular threshold for phosphate/glomerular filtration rate (TP/GFR) were assessed in response to short-term treatment with phosphate and cinacalcet and compared with long-term administration of phosphate and calcitriol.
Oral phosphate load increased serum phosphate, decreased ionized calcium, and increased PTH. Twenty-four hours later, FGF23 significantly increased and 1,25(OH)(2)D decreased. The concomitant administration of phosphate and cinacalcet resulted in further decrease in serum Ca(2+) but suppression of PTH and greater increase in serum phosphate and TP/GFR. Chronic treatment with phosphate and calcitriol resulted in a smaller increment in serum phosphate and high serum FGF23.
Traditional therapy of XLH with phosphate and calcitriol elevates FGF23 and has the potential to stimulate PTH. Short-term treatment with cinacalcet suppresses PTH, leading to increase in TP/GFR and serum phosphate. Thus, long-term clinical studies are needed to investigate whether cinacalcet may be a useful adjuvant in the treatment of XLH, allowing the use of lower doses of phosphate and calcitriol.
Familial hypophosphatemia and related disorders Pediatric Bone: Biology, Diseases
- Holm Ia
- Mj
- Carpenter
- To
Holm IA, Econs MJ, Carpenter TO. Familial hypophosphatemia and related disorders. In: Glorieux FH, Juppner H, Pettifor JM, eds. Pediatric Bone: Biology, Diseases. 2nd ed. San Diego: Elsevier; 2012:699 –726.
Autonomous hyperparathy- 3110 Carpenter et al Paricalcitol Treatment in XLH
- J Knudtzon
- J Halse
- E Monn
Knudtzon J, Halse J, Monn E, et al. Autonomous hyperparathy-
3110
Carpenter et al
Paricalcitol Treatment in XLH
J Clin Endocrinol Metab, September 2014, 99(9):3103–3111
Downloaded from press.endocrine.org by [${individualUser.displayName}] on 21 September 2015. at 23:06 For personal use only. No other uses without permission. . All rights reserved. roidism in X-linked hypophosphataemia
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 21 September 2015. at 23:06 For personal use only. No other uses without permission.. All rights reserved.
roidism in X-linked hypophosphataemia. Clin Endocrinol (Oxf).
1995;42:199 –203.
Familial hypophosphatemia and related disorders
- Holm
Familial hypophosphatemia and related disorders
- IA Holm
- MJ Econs
- TO Carpenter
- FH Glorieux
- H Juppner
- JM Pettifor