What is wrong in doing good?

Hypophosphataemia is a common side-effect in patients with iron deficiency anaemia treated with ferric carboxymaltose, which is not a class effect of all intravenous (IV) iron formulations. The report by Chu et al. shows that moderate and severe hypophosphataemia is common and can even require IV supplementation of phosphate with unknown long-term consequences. Commentary on: Chu et al. Incidence and predictors of hypophosphataemia after ferric carboxymaltose use-a 3-year experience from a single institution in Singapore. Br J Haematol 2023;202:1199-1204.

Incidence and predictors of hypophosphataemia after ferric carboxymaltose use-A 3-year experience from a single institution in Singapore.

Ferric carboxymaltose (FCM) administration helps reduce transfusion requirements in the perioperative situation, which improves patient outcomes and reduces healthcare costs. However, there is increasing evidence of hypophosphataemia after FCM use. We aim to determine the incidence of hypophosphataemia after FCM administration and elucidate potential biochemical factors associated with the development of subsequent hypophosphataemia. A retrospective review of anonymised data of all FCM administrations in a single institution was conducted from August 2018 to August 2021. Each unique FCM dose administered was examined to assess its effect on Hb and serum phosphate levels within the subsequent 28 days from each FCM administration. Phosphate levels were repeatedly measured within the 28-day interval and the lowest phosphate level within that period was determined. Patients' serum phosphate levels within 28 days of FCM administration were compared against normal serum phosphate levels within 2 weeks before FCM administration. The odds ratios of various pre-FCM serum markers were calculated to elucidate potential biochemical predictors of post-FCM hypophosphataemia. In 3 years, a total of 1296 doses of FCM were administered to 1069 patients. The mean improvement in Hb was 2.45 g/dL (SD = 1.94) within 28 days of FCM administration, with the mean time taken to peak Hb levels being 6.3 days (SD = 8.63), which is earlier than expected, but was observed in this study and hence reported. The incidence of hypophosphataemia <0.8 mmol/L was 22.7% (n = 186), and <0.4 mmol/L was 1.6% (n = 9). This figure is lower than the numbers reported in previously published meta-analyses given that routine checks of serum phosphate levels were not conducted initially and hence could possibly be higher. The odds of developing hypophosphataemia (<0.8 mmol/L) were 27.7 (CI: 17.3-44.2, p < 0.0001) if baseline serum phosphate was less than 1 mmol/L. The odds of developing hypophosphataemia (<0.8 mmol/L) were 1.3 (CI: 1.08-1.59, p < 0.01) if the change in Hb levels observed after FCM administration were more than 4 g/dL. Hypophosphataemia after FCM administration is significant and FCM should be used by clinicians with caution.

Interaction between ferric carboxymaltose and denosumab causing severe hypocalcaemia and hypophosphataemia in a patient without chronic kidney disease.

Coadministration of ferric carboxymaltose and denosumab may cause hypocalcaemia and hypophosphataemia; however, this interaction is not well-described in the literature and has typically been described in patients with chronic kidney disease (CKD). We present a case of this interaction in a patient without preexisting CKD. We suggest the use of alternative iron preparations and an interval of at least 4 weeks between administrations.

Osmotic demyelination syndrome: novel risk factors and proposed pathophysiology.

BACKGROUND: Osmotic demyelination syndrome (ODS) is non-inflammatory demyelination in response to an osmotic challenge. It can be pontine or extrapontine in presentation. AIMS: To retrospectively review cases involving ODS and define the spectrum of causes, risk factors, clinical and radiological presentations, and functional outcomes. RESULTS: The study utilised data from 15 patients with a mean age of 53.6 years. Malnutrition (9; 60%) and chronic alcoholism (10; 66.7%) were the most common associated disorders. Two (13.3%) patients had severe hyponatraemia (<120 mmol/L). The average highest single-day change was 5.1 mmol/L. Radiologically, 14 (93.3%) had pontine and 6 (40%) had extra-pontine lesions. Hypokalaemia (14; 93.3%) and hypophosphataemia (9; 60%) were commonly associated. Common clinical manifestations include altered consciousness/encephalopathy (9; 60%), dysphagia (4; 26.7%) and limb weakness (4; 26.7%). At 3 months, two (14.3%) had died and six (40%) were functionally independent (modified Rankin scale 0-2). CONCLUSION: We found that ODS occurred despite appropriate correction rates of hyponatraemia. Factors such as malnutrition, chronic alcoholism, hypokalaemia and hypophosphataemia are thought to play a role in its pathogenesis. Approximately half of the patients survived and became functionally independent.

Hypophosphataemia definitions, incidence and associated outcomes in paediatric intensive care: A retrospective cohort study in post-cardiac surgical patients <2 years of age.

AIM: Hypophosphataemia has been linked to higher morbidity and mortality in intensive care but there is inconsistency in the definition of hypophosphataemia for infants and children. We aimed to determine the incidence of hypophosphataemia in a group of at-risk children in paediatric intensive care unit (PICU) and associations with patient characteristics and clinical outcomes using three different hypophosphataemia thresholds. METHODS: Retrospective cohort study of 205 post-cardiac surgical patients <2 years of age admitted to Starship Child Health PICU, Auckland, New Zealand. Patient demographics and routine daily biochemistry for 14 days after PICU admission were collected. Rates of sepsis, mortality and length of mechanical ventilation were compared between groups with different serum phosphate concentrations. RESULTS: Out of 205 children, 6 (3%), 50 (24%) and 159 (78%) had hypophosphataemia at thresholds of <0.7, <1.0 and <1.4 mmol/L, respectively. There were no differences in gestational age at birth, sex, ethnicity or mortality in those with and without hypophosphataemia at any threshold. Children with a serum phosphate <1.4 mmol/L had more mean (SD) total hours of mechanical ventilation (85.2 (79.6) vs. 54.9 (36.2) h, P = 0.02) and those with mean serum phosphate <1.0 mmol/L had more mean hours of mechanical ventilation (119.4 (102.8) vs. 65.2 (54.8) h, P < 0.0001), episodes of sepsis (14% vs. 5%, P = 0.03) and longer length of stay (6.4 (4.8-20.7) vs. 4.9 (3.9-6.8) days, P = 0.02). CONCLUSIONS: Hypophosphataemia is common in this PICU cohort and serum phosphate <1.0 mmol/L is associated with increased morbidity and length of stay.

Relationship of blood thiamine pyrophosphate to plasma phosphate and the response to enteral nutrition plus co-administration of intravenous thiamine during critical illness.

BACKGROUND: Hypovitamin B1 occurs frequently during critical illness but is challenging to predict or rapidly diagnose. The aim of this study was to evaluate whether plasma phosphate concentrations predict hypovitamin B1, enteral nutrition prevents hypovitamin B1 and intravenous thiamine supplementation achieves supraphysiological concentrations in critically ill patients. METHODS: Thirty-two enterally fed critically ill patients, with a plasma phosphate concentration ≤0.65 mmol/L, formed a nested cohort within a larger randomised clinical trial. Patients were assigned to receive intravenous thiamine (200 mg) twice daily, and controls were not administered intravenous thiamine. Thiamine pyrophosphate concentrations were measured at four time points (pre- and post-infusion and 4- and 6-h post-infusion) on days 1 and 3 in those allocated to thiamine and once in the control group. RESULTS: Baseline thiamine pyrophosphate concentrations were similar (intervention 88 [67, 93] vs. control 89 [62, 110] nmol/L, p = 0.49). Eight (25%) patients had hypovitamin B1 (intervention 3 vs. control 5), with two patients in the control group remaining insufficient at day 3. There was no association between baseline phosphate and thiamine pyrophosphate concentrations. Intravenous thiamine achieved supraphysiological concentrations 6 h post first infusion, with concentrations increasing to day 3. In the control group, thiamine pyrophosphate concentrations were not statistically different between baseline and day 3 (mean change: 8.6 [-6.0, 23.1] nmol/L, p = 0.25). CONCLUSIONS: Phosphate concentrations did not predict hypovitamin B1, which was observed in 25% of the participants. Enteral nutrition alone prevented the development of new hypovitamin B1. Administration of a single 200-mg dose of intravenous thiamine achieved supraphysiological concentrations of thiamine pyrophosphate, with repeated dosing sustaining this effect.

Hypophosphatemia in critically ill patients undergoing Sustained Low-Efficiency Dialysis with standard dialysis solutions.

BACKGROUND: In patients admitted to the Intensive Care Unit (ICU), Kidney Replacement Therapy (KRT) is an important risk factor for hypophosphataemia. However, studies addressing the development of hypophosphatemia during prolonged intermittent KRT modalities are lacking. Thus, we evaluated the incidence of hypophosphatemia during Sustained Low-Efficiency Dialysis (SLED) in ICU patients; we also examined the determinants of post-SLED serum phosphate level (s-P) and the relation between s-P and phosphate supplementation and ICU mortality. METHODS: We conducted a retrospective analysis on a cohort of critically ill patients with severe renal failure and KRT need, who underwent at least three consecutive SLED sessions at 24-72 h time intervals with daily monitoring of s-P concentration. SLED with Regional Citrate Anticoagulation (RCA) was performed with either conventional dialysis machines or continuous-KRT monitors and standard dialysis solutions. When deemed necessary by the attending physician, intravenous phosphate supplementation was provided by sodium glycerophosphate pentahydrate. We used mixed-effect models to examine the determinants of s-P and Cox proportional hazards regression models with time-varying covariates to examine the adjusted relation between s-P, intravenous phosphate supplementation and ICU mortality. RESULTS: We included 65 patients [mean age 68 years (SD 10.0); mean Acute Physiology and Chronic Health Evaluation II score 25 (range 9-40)] who underwent 195 SLED sessions. The mean s-P before the start of the first SLED session (baseline s-P) was 5.6 ± 2.1 mg/dL (range 1.5-12.3). Serum phosphate levels at the end of each SLED decreased with increasing age, SLED duration and number of SLED sessions (P < .05 for all). The frequency of hypophosphatemia increased after the first through the third SLED session (P = .012). Intravenous phosphate supplementation was scheduled after 12/45 (26.7%) SLED sessions complicated by hypophosphataemia. The overall ICU mortality was 23.1% (15/65). In Cox regression models, after adjusting for potential confounders and for current s-P, intravenous phosphate supplementation was associated with a decrease in ICU mortality [adjusted hazard ratio: 0.24 (95% confidence interval: 0.06 to 0.89; P = 0.033)]. CONCLUSIONS: Hypophosphatemia is a frequent complication in critically ill patients undergoing SLED with standard dialysis solutions, that worsens with increasing SLED treatment intensity. In patients undergoing daily SLED, phosphate supplementation is strongly associated with reduced ICU mortality.

Intravenous iron: do we adequately understand the short- and long-term risks in clinical practice?

Intravenous (IV) iron as a therapeutic agent is often administered but not always fully understood. The benefits of IV iron are well proven in many fields, particularly in nephrology. IV iron is beneficial not only for true iron deficiency but also for iron-restricted anaemia (functional iron deficiency). Yet, the literature on intravenous iron has many inconsistencies regarding its adverse effects. Over the last several years, newer forms of iron have been developed, leading to the more regular use of iron and in larger doses. This review will summarize some of the older and newer literature regarding the differences among iron products, including the mechanisms and frequency of their adverse events (AEs). The pathway and frequency of an underrecognized adverse event (hypophosphataemia) will be discussed. Recent insights on infection risk and iron handling by macrophages are examined. Potential but presently unproven risks of iron overload due to IV iron are discussed. The impact of these on the risk:benefit ratio and dosing of intravenous iron are considered in different clinical settings, including pregnancy and cancer. IV iron is an essential component of the therapy of anaemia and understanding these issues will enable more informed treatment decisions and knowledgeable use of these drugs.

Higher prevalence of non-skeletal comorbidity related to X-linked hypophosphataemia: a UK parallel cohort study using CPRD.

OBJECTIVES: X-Linked hypophosphataemic rickets (XLH) is a rare multi-systemic disease of mineral homeostasis that has a prominent skeletal phenotype. The aim of this study was to describe additional comorbidities in XLH patients compared with general population controls. METHODS: The Clinical Practice Research Datalink (CPRD) GOLD was used to identify a cohort of XLH patients (1995-2016), along with a non-XLH cohort matched (1 : 4) on age, sex and GP practice. Using the CALIBER portal, phenotyping algorithms were used to identify the first diagnosis (and associated age) of 273 comorbid conditions during patient follow-up. Fifteen major disease categories were used and the proportion of patients having ≥1 diagnosis was compared between cohorts for each category and condition. Main analyses were repeated according to the Index of Multiple Deprivation (IMD). RESULTS: There were 64 and 256 patients in the XLH and non-XLH cohorts, respectively. There was increased prevalence of endocrine [OR 3.46 (95% CI: 1.44, 8.31)] and neurological [OR 3.01 (95% CI: 1.41, 6.44)] disorders among XLH patients. Across all specific comorbidities, four were at least twice as likely to be present in XLH cases, but only depression met the Bonferroni threshold: OR 2.95 (95% CI: 1.47, 5.92). Distribution of IMD among XLH cases indicated greater deprivation than the general population. CONCLUSION: We describe a higher risk of mental illness in XLH patients compared with matched controls, and greater than expected deprivation. These findings may have implications for clinical practice guidelines and decisions around health and social care provision for these patients.

Burden of disease associated with X-linked hypophosphataemia in adults: a systematic literature review.

This systematic review collated evidence on the burden of XLH in adults. Data captured highlight the substantial ongoing burden of XLH in adulthood and identified unmet needs. Greater awareness and understanding of the impact of XLH in adulthood are needed to improve care and outcomes in adults with XLH. INTRODUCTION: X-linked hypophosphataemia (XLH) is a rare metabolic bone disease characterized by renal phosphate wasting and musculoskeletal manifestations. Whilst the disease's impact in children is well documented, information on the effects of this progressive, debilitating condition on adults is lacking. This systematic review aimed to collate existing evidence on the burden of XLH in adulthood to identify unmet needs. METHODS: MEDLINE, Embase and Cochrane Library databases and recent congress reports were searched on 19 February 2019 for English-language publications describing the medical, humanistic and socio-economic impact of XLH in adults (≥ 18 years old). In addition, a structured Internet search was conducted. RESULTS: Of the 2351 articles identified, 91 met the selection criteria along with 44 congress abstracts. Data show that adults with XLH experience a range of clinical manifestations, particularly skeletal deformities and (pseudo)fractures, along with pain, dental abnormalities and impaired physical function and mobility. XLH in adulthood impacts on quality of life and places limitations on daily activities. The level of healthcare resource utilization among adults with XLH is indicative of substantial socio-economic burden; further research is needed to quantitate the economic impact on the healthcare system, society and patients. Adults with XLH may not receive appropriate care and treatment; a possible explanation for this is a lack of awareness among healthcare professionals. CONCLUSION: XLH in adults is associated with considerable disease burden and unmet needs. Forthcoming studies and increased awareness of the impact of XLH in adulthood should help to improve management of XLH in adulthood and patient outcomes.

Hypophosphataemia is common in patients with aneurysmal subarachnoid haemorrhage.

INTRODUCTION: Hypophosphataemia is common in critically ill patients, but neither its prevalence nor its association with outcome have been investigated specifically in patients with aneurysmal subarachnoid haemorrhage (aSAH). METHODS: Patients with aSAH and at least one phosphate measurement were included from two independent cohorts; an American cohort extracted from two open-access databases (Medical Information Mart for Intensive Care-III and eICU Collaborative Research Database v. 2.0) and a Danish cohort consisting of patients with aSAH admitted to Rigshospitalet, Denmark over a 4-year period. In each cohort, we calculated the prevalence of mild (0.32-0.80 mmol/L) and severe (<0.32 mmol/L) hypophosphataemia and their association with in-hospital mortality before and after propensity-score matching. RESULTS: Hypophosphataemia occurred in 72.4% (95% CI: 68.1-76.3) of patients in the American cohort (n = 471) and 54.9% (50.0-59.7) in the Danish cohort (n = 419). However, it was not associated with mortality in neither full (American: Mild, Odds ratio (OR) 0.99 (0.91-1.07), Severe OR 1.20 (0.95-1.51); Danish: Mild, OR 1.01 (0.95-1.08), Severe OR 1.20 (0.95-1.51)) nor propensity-score matched cohorts (American (n = 168): Mild, OR 1.06 (0.88-1.28), Severe OR 1.46 (0.96-2.12); Danish (n = 44): Mild, OR 1.16 (0.82-1.65), Severe OR 0.45 (0.13-1.55)). CONCLUSION: In this retrospective study of patients with aSAH, hypophosphataemia was common.

Serum phosphate and mortality in incident dialysis patients in Australia and New Zealand.

AIM: Hyperphosphataemia is associated with increased adverse outcomes, including mortality. Re-examining this association using up-to-date data reflecting current and real-world practices, across different global regions and in both haemodialysis and peritoneal dialysis patients, is important. METHODS: We describe the association between serum phosphate and all-cause and cardiovascular mortality in incident dialysis patients between 2008 and 2018 using the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. Time-dependent Cox proportionate hazards models were used. Models were adjusted for available covariates and fitted for the overall cohort, and also each dialysis modality. RESULTS: 31 989 patients were followed over 97 122 person-years at risk (mean age at first dialysis 61 years, 38% female, 67% haemodialysis). We observed a U-shaped association between serum phosphate and all-cause mortality. In the fully adjusted model, categories of serum phosphate above and below 1.25-1.99 mmol/L were associated with progressively higher risk, reaching a hazard ratio of 2.13 (95% CI 1.93-2.36, p < .001) for serum phosphate ≥2.75 mmol/L, and 1.56 (95% CI 1.44-1.69, p < .001) for serum phosphate <1.00 mmol/L. Low and high levels of serum phosphate were also associated with increased risk of cardiovascular mortality, however the association with high serum phosphate was more pronounced ("J-shaped relationship"). The associations were consistent across sub-analyses of patients receiving haemodialysis and peritoneal dialysis treatment. CONCLUSION: In this large contemporary dialysis cohort, both high and low levels of serum phosphate were independently associated with increased risk of mortality. Future studies are required to determine whether treatment of abnormal serum phosphate levels improves mortality.

Clinical factors associated with early and persistent hypocalcaemia after parathyroidectomy in patients on dialysis with severe hyperparathyroidism.

AIM: Severe hypocalcaemia following parathyroidectomy for secondary or tertiary hyperparathyroidism (SHPT/THPT) is scarcely studied. We aimed to describe and identify risk factors for early and persistent hypocalcaemia after parathyroidectomy. METHODS: Retrospective pair-matched cohort study. We assessed 87 dialysis patients with SHPT (n = 73) or THPT (n = 14) paired with 146 subjects with primary hyperparathyroidism (PHPT) who underwent parathyroidectomy and were followed for 12 months. Early severe hypocalcaemia was defined as a free Ca ≤0.8 mmol/L [3.2 mg/dl] or corrected Ca ≤1.87 mmol/L [7.5 mg/dl] within 48 h. After parathyroidectomy and persistent hypocalcaemia, as an elemental Ca intake >3.0 g/day to achieve corrected Ca >2 mmol/L [8.0 mg/dl]. RESULTS: Early severe hypocalcaemia occurred in 77% (67/87) versus 6.8% (10/146) of subjects with SHPT/THPT and PHPT, respectively (p < .001). In SHPT/THPT cases, persistent hypocalcaemia occurred in 77% (49/64) and 64% (35/54) after 6 and 12 months of parathyroidectomy, respectively. In PHPT cases, persistent hypocalcaemia occurred in 6.8% (10/146) after 4-12 months of parathyroidectomy. Preoperative serum alkaline phosphatase (ALP) was the only risk factor associated to early severe hypocalcaemia (OR 7.3, 95% C.I. 1.7-10.9, p = .006) and persistent hypocalcaemia (OR 7.1, 95% C.I: 2.1-14.2, p = .011). Subjects with persistently low intact parathormone (iPTH) (<5.3 pmol/L [50 ng/ml]), suggestive of adynamic bone disease) showed higher Ca increases and less oral calcium requirements compared to those who progressively increased iPTH after parathyroidectomy. CONCLUSION: Early and persistent hypocalcaemia after parathyroidectomy in severe HPT were a common event associated directly to preoperative ALP levels. Subjects with persistently low postoperative iPTH normalized serum Ca more frequently after 1 year of follow up.

Clinical factors associated with severe hypophosphataemia after kidney transplant.

BACKGROUND: The mechanism by which hypophosphataemia develops following kidney transplantation remains debated, and limited research is available regarding risk factors. This study aimed to assess the association between recipient and donor variables, and the severity of post-transplantation hypophosphataemia. METHODS: We performed a single-centre retrospective observational study. We assessed the association between demographic, clinical and biochemical variables and the development of hypophosphataemia. We used linear regression analysis to assess association between these variables and phosphate nadir. RESULTS: 87.6% of patients developed hypophosphataemia. Patients developing hypophosphataemia were younger, had a shorter time on renal replacement therapy, were less likely to have had a parathyroidectomy or to experience delayed graft function, were more likely to have received a living donor transplant, from a younger donor. They had higher pre-transplantation calcium levels, and lower alkaline phosphatase levels. Receipt of a living donor transplant, lower donor age, not having had a parathyroidectomy, receiving a transplant during the era of tacrolimus-based immunosuppression, not having delayed graft function, higher pre-transplantation calcium, and higher pre-transplantation phosphate were associated with lower phosphate nadir by multiple linear regression. CONCLUSIONS: This analysis demonstrates an association between variables relating to better graft function and hypophosphataemia. The links with biochemical measures of mineral-bone disease remain less clear.

Oral health-related quality of life in X-linked hypophosphataemia and osteogenesis imperfecta.

X-linked hypophosphataemia (XLH) and osteogenesis imperfecta (OI) are rare congenital disorders characterised by skeletal dysplasia. The two disorders may include dental anomalies potentially affecting individual well-being. The aims of study were (a) to assess the oral health-related quality of life (OHRQoL) in Danish adults with XLH or OI, and (b) to compare the results of the groups. A cross-sectional study including 35 adults with XLH, 56 adults with OI type I and 17 adults with OI types III-IV was conducted. The OHRQoL was assessed by the 49-item version of the questionnaire Oral Health Impact Profile (OHIP). Summed domain scores (seven) were compared between XLH and OI groups. Prevalence of severe impact on OHRQoL (scores 3-4) was compared between groups. The median scores in XLH group exceeded the medians in OI (P < .05) in the domains functional limitation (XLH:6.5; OI:4.0), pain (XLH:9.5; OI:5.0), psychological discomfort (XLH:5.5; OI:2.0), psychological disability (XLH:2.0; OI:0.0), handicap (XLH:2.0; OI:0.0) and total OHIP (XLH:35.0; OI:14.0). Differences in domains physical disability (XLH: 4.0; OI: 1.0) and social disability (XLH: 0.0; OI: 0.0) were not significant. Prevalence of severe impact on OHRQoL in the XLH group significantly exceeded the level in OI group in the domains functional limitation (XLH: 59%; OI: 35%), psychological discomfort (XLH: 38%; OI: 20%) and physical disability (XLH: 32%; OI: 13%). In conclusion, adults with XLH experience a higher negative impact on their OHRQoL than adults with OI. Only to a minor degree, individuals with OI types III-IV experience a higher impact on OHRQoL than individuals with OI type I.

Is hypophosphataemia an independent predictor of mortality in critically ill patients with bloodstream infection? A multicenter retrospective cohort study.

BACKGROUND: Hypophosphataemia affects up to one-third of patients in the intensive care unit (ICU) and is particularly common during sepsis. Experimental data suggest that hypophosphataemia leads to an acquired dysfunction of leukocytes, thus promoting infections and increasing the risk of death during sepsis. OBJECTIVES: The aim of our study was to investigate the association between hypophosphataemia and mortality in critically ill patients with a bloodstream infection (BSI). METHODS: We performed a retrospective study in three ICUs during an 18-month period. All adults with a BSI diagnosed in the ICU were eligible. Patients with and without hypophosphataemia, defined as phosphataemia below 0.8 mmol/L, were compared. A multivariate survival analysis using a Cox proportional hazard regression model was conducted to study the association between hypophosphataemia and 90-d mortality. RESULTS/FINDINGS: Among the 3783 patients admitted to the three participating ICUs within the 18-month study period, 203 met the inclusion criteria and 193 were analysed. Fifty-four patients had hypophosphataemia. After adjusting for confounders, hypophosphataemia was significantly associated with a twofold increased risk of 90-d mortality (hazard ratio = 2.10 [1.177-3.80], p = 0.013). This association is particularly strong in patients without shock. CONCLUSIONS: Hypophosphataemia was independently associated with a twofold increase in 90-d mortality in ICU patients with a BSI. These results suggest that investigators and physicians should include phosphataemia as a predictor of the severity of BSIs. Further research is warranted to better understand this association and to determine the potential benefits of systematic monitoring of phosphataemia and phosphorus supplementation. CLINICAL TRIAL REGISTRATION: NCT03529058.

Tumor induced osteomalacia.

Tumor induced osteomalacia (TIO) is a rare paraneoplastic syndrome typically caused by small endocrine tumors that secrete fibroblast growth factor 23(FGF23). TIO is clinically characterized by progressive muskuloskeletal pain, fatigue, proximal muscle weakness, and multiple fractures that lead to long-term disability. Due to the non-specific symptoms of the disease, it may take several years for them to be properly diagnosed and treated, so it is important to better inform about this rare paraneoplastic syndrome.

Hypophosphataemia after ferric carboxymaltose is unrelated to symptoms, intestinal inflammation or vitamin D status.

BACKGROUND: Intravenous iron replacement is recommended for iron-deficient patients with inflammatory bowel disease (IBD), but may be associated with hypophosphataemia, predisposing to osteomalacia and fractures. This study aimed to evaluate the incidence and risk factors for hypophosphataemia following intravenous ferric carboxymaltose (FCM) in patients with IBD. METHODS: This prospective observational study of patients with and without IBD evaluated serum phosphate for 28 days following intravenous FCM, and assessed associations with symptoms, markers of inflammation and vitamin D status. RESULTS: Twenty-four patients with IBD (11 with Crohn's disease [CD], 13 with ulcerative colitis [UC], mean age 45 years [range 19-90], 7 female), and 20 patients without IBD (mean age 56 [22-88] y, 11 female), were included. Overall, serum phosphate declined by a mean of 36% at Day 7, with a mean fall of 42% (SD 19%) at some time point over 28 days (p <  0.001). Twenty-four of 44 (55%) patients developed moderate to severe hypophosphataemia (serum phosphate < 0.6 mmol/L). No differences between patients with and without IBD were seen, but patients with CD had greater decline in phosphate than those with UC. There was no association between hypophosphataemia and symptomatic adverse events, faecal calprotectin, C-reactive protein, albumin, platelet count, 25(OH) vitamin D, or 1,25(di-OH) vitamin D. Serum phosphate < 1.05 mmol/L on Day 2 predicted susceptibility to moderate-severe hypophosphataemia (OR 7.0). CONCLUSIONS: Hypophosphataemia following FCM is common, unrelated to symptomatic adverse events, baseline intestinal or systemic inflammation, or vitamin D status.

Pharmacological management of X-linked hypophosphataemia.

The most common heritable disorder of renal phosphate wasting, X-linked hypophosphataemia (XLH), was discovered to be caused by inactivating mutations in the phosphate regulating gene with homology to endopeptidases on the X-chromosome (PHEX) gene in 1995. Although the exact molecular mechanisms by which PHEX mutations cause disturbed phosphate handling in XLH remain unknown, focus for novel therapies has more recently been based upon the finding that the bone-produced phosphaturic hormone fibroblast growth factor-23 is elevated in XLH patient plasma. Previous treatment strategies for XLH were based upon phosphate repletion plus active vitamin D analogues, which are difficult to manage, fail to address the primary pathogenesis of the disease, and can have deleterious side effects. A novel therapy for XLH directly targeting fibroblast growth factor-23 via a humanized monoclonal antibody (burosumab-twza/CRYSVITA, henceforth referred to just as burosumab) has emerged as an effective, and recently approved, pharmacological treatment for both children and adults. This review will provide an overview of the clinical manifestations of XLH, the molecular pathophysiology, and summarize its current treatment.

Congenital hypophosphataemia in adults: determinants of bone turnover markers and amelioration of renal phosphate wasting following total parathyroidectomy.

Congenital hypophosphataemia (CH) is a collection of disorders that cause defective bone mineralisation manifesting with rickets in childhood and osteomalacia in adulthood. Bone turnover markers (BTMs) are surrogate measures of metabolic bone disease severity. We explored the utility of BTMs in 27 adults with CH: 23 had X-linked hypophosphataemia (XLH), of whom 2 were hypoparathyroid post-total parathyroidectomy (PTx); 2 had autosomal dominant hypophosphataemic rickets (ADHR), and 2 had none of the known mutations. We measured the renal tubular maximum reabsorption rate of phosphate (TmP/GFR), C-terminal fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), ionised calcium, 1,25-dihydroxyvitamin D [1,25(OH)2D], and a panel of BTMs: serum bone-specific alkaline phosphatase (bone ALP), osteocalcin (Oc), total procollagen type I amino-terminal propeptide (PINP), and carboxy-terminal telopeptide of type I collagen (CTX); and urine amino-terminal telopeptides of type I collagen (uNTX). After excluding 2 patients with XLH and PTx, the frequency of abnormal elevation in BTMs was: bone ALP (96%); CTX (72%); PINP (52%); uNTX (48%); Oc (28%). The strongest association with bone ALP was TmP/GFR. Those patients receiving phosphate supplements and alfacalcidol had significant elevation in CTX. The 2 patients with XLH and PTx had normalisation of TmP/GFR and near normalisation of BTMs post-operatively, despite marked elevation in both C-terminal and intact FGF23. In conclusion, BTMs in our CH patients indicated that most have abnormalities consistent with osteomalacia and many have mild secondary hyperparathyroidism; and the normalisation of TmP/GFR after total PTx in 2 cases of XLH remains unexplained, but possible causes are speculated.