Increased Serum Phosphate Research Articles

Fibroblast Growth Factor-23-Klotho Axis in Cardiorenal Syndrome: Mediators and Potential Therapeutic Targets.

Cardiorenal syndrome (CRS) is a complex disorder that refers to the category of acute or chronic kidney diseases that induce cardiovascular disease, and inversely, acute or chronic heart diseases that provoke kidney dysfunction. There is a close relationship between renal and cardiovascular disease, possibly due to the presence of common risk factors for both diseases. Thus, it is well known that renal diseases are associated with increased risk of developing cardiovascular disease, suffering cardiac events and even mortality, which is aggravated in those patients with end-stage renal disease or who are undergoing dialysis. Recent works have proposed mineral bone disorders (MBD) as the possible link between kidney dysfunction and the development of cardiovascular outcomes. Traditionally, increased serum phosphate levels have been proposed as one of the main factors responsible for cardiovascular damage in kidney patients. However, recent studies have focused on other MBD components such as the elevation of fibroblast growth factor (FGF)-23, a phosphaturic bone-derived hormone, and the decreased expression of the anti-aging factor Klotho in renal patients. It has been shown that increased FGF-23 levels induce cardiac hypertrophy and dysfunction and are associated with increased cardiovascular mortality in renal patients. Decreased Klotho expression occurs as renal function declines. Despite its expression being absent in myocardial tissue, several studies have demonstrated that this antiaging factor plays a cardioprotective role, especially under elevated FGF-23 levels. The present review aims to collect the recent knowledge about the FGF-23-Klotho axis in the connection between kidney and heart, focusing on their specific role as new therapeutic targets in CRS.

Recombinant growth hormone therapy for X-linked hypophosphatemia in children.

Conventional treatment of X-linked hypophosphatemia with oral phosphate and calcitriol can heal rickets, but it does not always raise serum phosphate concentrations significantly, nor does it always normalize linear growth. Some clinical trials suggest that combining recombinant human growth hormone therapy with conventional treatment improves growth velocity, phosphate retention, and bone mineral density, but some clinical trials suggest that it appears to aggravate the pre-existent disproportionate stature of such children. This is an updated version of a previously published review. To determine whether recombinant human growth hormone therapy for children with X-linked hypophosphatemia is associated with changes in longitudinal growth, mineral metabolism, endocrine function, renal function, bone mineral density, body proportions, and also with any adverse effects. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. In addition, we searched the Cochrane Central Register of Controlled Trials, Ovid MEDLINE and the reference lists of identified trials and other reviews. We also undertook some additional handsearching of relevant journals and conference proceedings. Date of the most recent search: 12 January 2021 SELECTION CRITERIA: All randomized controlled studies or quasi-randomized controlled studies comparing growth hormone (alone or combined with conventional treatment) with either placebo or conventional treatment alone in children with X-linked hypophosphatemia. Two authors independently assessed studies for risk of bias and extracted data from eligible studies. GRADE criteria were used to assess the certainty of the evidence for each outcome. We included two studies (20 participants) in the review. In one cross-over study, results showed that recombinant human growth hormone therapy may improve the height standard deviation (SDS) score (z score), but we are unsure whether the intervention was the reason behind a transient increase in serum phosphate and tubular maximum for phosphate reabsorption. In the second, parallel study, treatment may also have improved the height SDS from baseline in the rhGH group compared to the control group, although no significant difference was seen between groups after three years, MD 0.50 SDS (95 % CI -0.54 to 1.54) (low-certainty evidence). The treatment was possibly well-tolerated during both studies with only transient adverse effects seen in three participants (low-certainty evidence). We are uncertain whether growth hormone improves serum phosphate levels or change in TmP/GFR (very low-certainty evidence). The treatment may make little or no difference to alkaline phosphatase levels (low-certainty evidence). We do not have enough high-certainty evidence to recommend the use of recombinant human growth hormone therapy in children with X-linked hypophosphatemia.

Serum phosphate and chronic kidney and cardiovascular disease: Phosphorus potential implications in general population.

It has already been established that in end-stage renal disease, hyperphosphatemia causes soft tissue calcification including vascular calcifications. It has also been supported that there is a connection between increased serum phosphate and morbidity in subjects, who suffer from renal disease. However, studies in these populations conferred mixed results. Several warnings are included in the role of serum phosphorus on cardiovascular disease in normal populations. Homeostasis of serum phosphate is obtained by the cooperation between regulatory hormones, cellular receptors and bone metabolic factors. There is the probability that one or more phosphate regulatory factors, rather than phosphate directly, may be responsible for observed associations with calcification and cardiovascular events in normal populations. Experimental studies have shown that the restriction of dietary phosphate prevents the progression of kidney dysfunction, although high dietary phosphate aggravates the renal function. In the current review, we discuss the role of serum phosphorus on progression of renal dysfunction and cardiovascular outcomes in chronic kidney disease patients and its involvement in important health risks in the general population.

Basal Ganglia Calcification in Hypoparathyroidism Is Associated With Low Serum Calcium/Phosphate Ratio

Background: Basal ganglia calcification (BGC) is a well-known complication of hypoparathyroidism. It is currently thought that increased serum phosphate or calcium x phosphate product may be major risk factors. However, the pathophysiology of BGC is still unclear, since the literature is largely based on limited case series or case reports. Methods: We identified a large cohort of patients with hypoparathyroidism diagnosed between 2000 and 2020 and evaluated those with head CT scans performed over this interval. Etiology and date of onset of hypoparathyroidism were determined by medical records review. All head CT scan images were reviewed to confirm radiology reports reporting BGC. We retrieved laboratory data within 10 years before the first head CT that showed incident BGC. Three age- and sex- matched controls with head CT scans were selected for each patient, and compared to the patients with hypoparathyroidism. Results: Of 1014 unique patients with a verified diagnosis of hypoparathyroidism, 142 had a head CT scan performed between 2000 and 2020. Head CT scans were performed for reasons unrelated to hypoparathyroidism in 96.5% of patients. In this cohort, 80.3% of patients (n=114) had post-surgical hypoparathyroidism. Age at which the first head CT in patients was done was 62±20.6 (range 11–97), and duration of hypoparathyroidism at the time of first head CT was 11.0±14.4 years (0–71). Prevalence of BGC in patients with hypoparathyroidism was 25.4% (n=36), as compared with 7.3% in the control group (31/426) (P<0.001). Patients and controls were similar in terms of cardiovascular risk factors (diabetes, hypertension, dyslipidemia, alcohol consumption, smoking status and BMI). In patients with non-surgical hypoparathyroidism (n=28), prevalence of BGC was 71.4% vs. 14.0% in the postsurgical cohort (OR 15.4; 95% CI 5.8–40, P<0.001). Compared to patients with hypoparathyroidism without BGC, those with BGC had lower time-weighted average serum calcium (8.4±0.8 vs. 8.8±0.8, P=0.002; normal range, 8.6–10.2 mg/dL), and lower time-weighted average calcium/phosphate ratio (Ca/P) (1.83±0.52 vs. 2.13±0.47, P=0.007). Conclusions: Basal ganglia calcification in hypoparathyroidism is associated with low serum calcium and low Ca/P ratio. This may allow increased bioavailability of phosphate in the extracellular space, leading to calcium phosphate crystal formation within the basal ganglia. Assessing Ca/P ratio may be useful to identify patients at risk for BGC. Prevalence of BGC is significantly higher in patients with non-surgical hypoparathyroidism.

Effects of Active Vitamin D or FGF23 Antibody on Hyp Mice Dentoalveolar Tissues

Mutations in the PHEX gene lead to X-linked hypophosphatemia (XLH), a form of inherited rickets featuring elevated fibroblast growth factor 23 (FGF23), reduced 1,25-dihydroxyvitamin D (1,25D), and hypophosphatemia. Hyp mutant mice replicate the XLH phenotype, including dentin, alveolar bone, and cementum defects. We aimed to compare effects of 1,25D versus FGF23-neutralizing antibody (FGF23Ab) monotherapies on Hyp mouse dentoalveolar mineralization. Male Hyp mice, either injected subcutaneously with daily 1,25D or thrice weekly with FGF23 blocking antibody from 2 to 35 d postnatal, were compared to wild-type (WT) controls and untreated Hyp mice. Mandibles were analyzed by high-resolution micro–computed tomography (micro-CT), histology, and immunohistochemistry. Both interventions maintained normocalcemia, increased serum phosphate levels, and improved dentoalveolar mineralization in treated versus untreated Hyp mice. 1,25D increased crown dentin volume and thickness and root dentin/cementum volume, whereas FGF23Ab effects were limited to crown dentin volume. 1,25D increased bone volume fraction, bone mineral density, and tissue mineral density in Hyp mice, whereas FGF23Ab failed to significantly affect these alveolar bone parameters. Neither treatment fully attenuated dentin and bone defects to WT levels, and pulp volumes remained elevated regardless of treatment. Both treatments reduced predentin thickness and improved periodontal ligament organization, while 1,25D promoted a more profound improvement in acellular cementum thickness. Altered cell densities and lacunocanalicular properties of alveolar and mandibular bone osteocytes and cementocytes in Hyp mice were partially corrected by either treatment. Neither treatment normalized the altered distributions of bone sialoprotein and osteopontin in Hyp mouse alveolar bone. Moderate improvements from both 1,25D and FGF23Ab treatment regimens support further studies and collection of oral health data from subjects receiving a newly approved anti-FGF23 therapy. The inability of either treatment to fully correct Hyp mouse dentin and bone prompts further experiments into underlying pathological mechanisms to identify new therapeutic approaches.

Phosphate as a Pathogen of Arteriosclerosis and Aging.

During the evolution of skeletons, terrestrial vertebrates acquired strong bones made of calcium–phosphate. By keeping the extracellular fluid in a supersaturated condition regarding calcium and phosphate ions, they created the bone when and where they wanted simply by providing a cue for precipitation. To secure this strategy, they acquired a novel endocrine system to strictly control the extracellular phosphate concentration. In response to phosphate intake, fibroblast growth factor–23 (FGF23) is secreted from the bone and acts on the kidney through binding to its receptor Klotho to increase urinary phosphate excretion, thereby maintaining phosphate homeostasis. The FGF23–Klotho endocrine system, when disrupted in mice, results in hyperphosphatemia and vascular calcification. Besides, mice lacking Klotho or FGF23 suffer from complex aging-like phenotypes, which are alleviated by placing them on a low-phosphate diet, indicating that phosphate is primarily responsible for the accelerated aging. Phosphate acquires the ability to induce cell damage and inflammation when precipitated with calcium. In the blood, calcium–phosphate crystals are adsorbed by serum protein fetuin-A and prevented from growing into large precipitates. Consequently, nanoparticles that comprised calcium–phosphate crystals and fetuin-A, termed calciprotein particles (CPPs), are generated and dispersed as colloids. CPPs increase in the blood with an increase in serum phosphate and age. Circulating CPP levels correlate positively with vascular stiffness and chronic non-infectious inflammation, raising the possibility that CPPs may be an endogenous proaging factor. Terrestrial vertebrates with the bone made of calcium–phosphate may be destined to age due to calcium–phosphate in the blood.

Acute effects of dietary phosphorus intake on markers of mineral metabolism in hemodialysis patients: post hoc analysis of a randomized crossover trial

Background Long-term dietary phosphorus excess influences disturbances in mineral metabolism, but it is unclear how rapidly the mineral metabolism responds to short-term dietary change in dialysis populations. Methods This was a post hoc analysis of a randomized crossover trial that evaluated the short-term effects of low-phosphorus diets on mineral parameters in hemodialysis patients. Within a 9-day period, we obtained a total of 4 repeated measurements for each participant regarding dietary intake parameters, including calorie, phosphorus, and calcium intake, and markers of mineral metabolism, including phosphate, calcium, intact parathyroid hormone (iPTH), intact fibroblast growth factor 23 (iFGF23), and C-terminal fibroblast growth factor 23 (cFGF23). The correlations between dietary phosphorus intake and serum mineral parameters were assessed by using mixed-effects models. Results Thirty-four patients were analyzed. In the fully adjusted model, we found that an increase in dietary phosphorus intake of 100 mg was associated with an increase in serum phosphate of 0.3 mg/dL (95% confidence intervals [CI], 0.2–0.4, p < .001), a decrease in serum calcium of 0.06 mg/dL (95% CI, −0.11 to −0.01, p = .01), an increase in iPTH of 5.4% (95% CI, 1.4–9.3, p = .01), and an increase in iFGF23 of 5.0% (95% CI, 2.0–8.0, p = .001). Dietary phosphorus intake was not related to cFGF23. Conclusions Increased dietary phosphorus intake acutely increases serum phosphate, iPTH, and iFGF23 levels and decreases serum calcium levels, highlighting the important role of daily fluctuations of dietary habits in disturbed mineral homeostasis in hemodialysis patients.

Cardiovascular Risk Factors in Pre-dialysis Chronic Kidney Disease patients of Nepal

Background and Aims: Cardiovascular disease (CVD) is the commonest cause of morbidity and mortality in patients with chronic kidney disease (CKD) due to increased prevalence of traditional and nontraditional CVD risk factors. Our study aimed to evaluate these risk factors in pre-dialysis Nepalese CKD patients.&#x0D; Methods: This was a cross-sectional study conducted in Department of Nephrology, Bir hospital. Total 100 consecutive pre-dialysis CKD patients were enrolled. Ten traditional and six nontraditional CVD risk factors were analyzed and compared between CKD stages. Descriptive statistics was used to illustrate the socio-demographic and clinical characteristics, chi square test for categorical variables and multiple logistic regression analysis was done to determine the risk factors of CVD in CKD patients. p-value&lt;0.05 was considered to be statistically significant.&#x0D; Results: Mean patient age was 52.03}13.64 years with majority (60%) of the patients being male. Comparison of traditional risk factors in different stages depicted similar trend except for old age in Stage 3 CKD (p=0.002). Anemia (p&lt;0.001), hyperphosphatemia (p=0.01), hyperparathyroidism (p&lt;0.01) and cumulative nontraditional risk factors were significantly higher (p=0.01) in stage 5 CKD. The predicted CVD events by Framingham risk score showed high risk in 37% with no significant difference among the stages. Multiple logistic regression analysis showed increased body mass index, low serum albumin and increased serum phosphate as the three significant predictors for left ventricular hypertrophy.&#x0D; Conclusion: Our study shows that the CVD risk factors were prevailing along the various stages of CKD. The occurrence of non-traditional risk factors increased with increasing stage of CKD.

Sclerostin antibody treatment increases bone mass and normalizes circulating phosphate levels in growing Hyp mice

X-linked hypophosphatemia (XLH), caused by a loss-of-function mutation in the phosphate regulating gene with homology to endopeptidase located on the X chromosome (PHEX), is the most common form of vitamin D-resistant rickets. Loss of functional PHEX results in elevated fibroblast growth factor 23 (FGF23) levels, impaired phosphate reabsorption, and inhibited skeletal mineralization. Sclerostin, a protein produced primarily in osteocytes, suppresses bone formation by antagonizing Wnt signaling and is reported to be elevated in XLH patients. This study used the Hyp mouse model to investigate sclerostin's role in the pathophysiology of XLH by evaluating the use of a monoclonal antibody to sclerostin in a mouse model of XLH, the Hyp mouse. Male and female wild-type and Hyp littermates were injected with 25 mg/kg of vehicle or sclerostin antibody (Scl-Ab) twice weekly, beginning at 4 weeks of age and euthanized at 8 weeks of age. Scl-Ab treatment increased serum phosphate levels and suppressed circulating levels of intact FGF23 in treated wild-type and Hyp mice of both sexes. Cortical area, trabecular bone volume fraction (BV/TV), metaphyseal apparent density, and the peak load increased with Scl-Ab treatment in both sexes. This short-term treatment study suggests that Scl-Ab treatment can effectively improve some of the pathologies associated with XLH, including normalization of phosphate, and that sclerostin may play a role in regulating FGF23 and phosphate metabolism in XLH. © 2019 American Society for Bone and Mineral Research.

Iron deficiency plays essential roles in the trigger, treatment, and prognosis of autosomal dominant hypophosphatemic rickets.

Autosomal dominant hypophosphatemic rickets (ADHR) is unique for its incomplete penetrance, variety of disease onsets, and waxing and waning phenotypes. Iron deficiency is a trigger of ADHR. This study aimed to clarify the role of iron deficiency in ADHR. Data of clinical manifestations and laboratory examinations were collected from patients among eight kindreds with ADHR. Multiple regression and Pearson's correlation tests were performed to test the relationships of serum phosphate levels and other laboratory variables during the patients' follow-ups. Among 23 ADHR patients with fibroblast growth factor 23 (FGF23) mutations, 14 patients presented with obvious symptoms. Ten patients had iron deficiency at the onset of ADHR, coinciding with menarche, menorrhagia, pregnancy, and chronic gastrointestinal bleeding. Two patients who did not have their iron status tested presented with symptoms after abortion and pregnancy in one patient each, which suggested that they also had iron deficiency at onset. Patients were treated with ferrous succinate tablets, vitamin C, and neutral phosphate and calcitriol. With correction of the iron status, the patients' symptoms showed notable improvement, with increased serum phosphate levels. Two patients' FGF23 levels also declined to the normal range. There were strong correlations between serum phosphate and serum iron levels (r = 0.7689, p < 0.0001), serum ferritin levels (r = 0.5312, p = 0.002), iron saturation (r = 0.7907, p < 0.0001), and transferrin saturation (r = 0.7875, p < 0.001). We also examined the relationships between serum phosphate levels and hemoglobin-related indices, which were significant (hemoglobin: r = 0.71, p < 0.0001; MCV: r = 0.7589, p < 0.0001; MCH: r = 0.8218, p < 0.0001; and MCHC: r = 0.7751, p < 0.0001). Longitudinal data of six patients' follow-up also showed synchronous changes in serum phosphate with serum iron levels. Iron deficiency plays an important role in triggering ADHR. Monitoring and correcting the iron status are helpful for diagnosing and treating ADHR. Iron metabolism parameters and hemoglobin-related parameters are positively correlated with serum phosphate levels in patients with ADHR and iron deficiency, and these might serve as good indicators of prognosis of ADHR.

Interim Analysis of a Phase 2 Open-Label Trial Assessing Burosumab Efficacy and Safety in Patients With Tumor-Induced Osteomalacia

ABSTRACTPatients with tumor‐induced osteomalacia (TIO), an acquired paraneoplastic condition characterized by osteomalacia due to hypophosphatemia, exhibit a similar clinical picture to those with X‐linked hypophosphatemic rickets/osteomalacia (XLH). The human monoclonal anti‐fibroblast growth factor 23 (FGF23) antibody burosumab (KRN23) increases serum phosphate and improves bone turnover, fracture healing, pain, and physical function in XLH patients by inhibiting circulating FGF23; thus, burosumab is expected to be an effective treatment for TIO. We report here an interim analysis of a multicenter, open‐label, intraindividual dose‐adjustment study of burosumab (0.3 to 2.0 mg/kg every 4 weeks) in Japanese and Korean TIO patients. The primary endpoint was the fasting serum phosphate level at each visit. Key secondary endpoints were changes over time in bone biomarkers, pharmacodynamic markers, bone histomorphometric parameters, motor function, and patient‐reported outcomes. Safety was assessed based on treatment‐emergent adverse events (TEAEs). Thirteen patients received burosumab treatment, of whom 4 underwent bone biopsy. The mean dose after week 112 was approximately 1.0 mg/kg. After the first burosumab administration, mean serum phosphate levels increased and remained above the lower limit of normal and in the normal range from weeks 14 to 112. Bone biomarkers initially increased, reaching maximum values at week 16 or 24, and then gradually decreased. After burosumab treatment, patients were able to walk further (evaluated by the 6‐minute walk test), reported decreased pain levels, and showed a tendency toward healing of baseline fractures and pseudofractures. Two patients discontinued, one each due to disease progression and consent withdrawal. Burosumab was generally well tolerated, with no treatment‐related TEAEs of grade ≥3 and no treatment‐related serious AEs. In conclusion, the interim results of this first study of burosumab to treat TIO patients indicate that this drug has the potential to provide clinical benefit for patients with unresectable tumors. The full study results are eagerly anticipated. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..

P0891META-ANALYSIS OF NUTRITIONAL VITAMIN D FOR THE TREATMENT OF SECONDARY HYPERPARATHYROIDISM IN PATIENTS WITH NON-DIALYSIS CHRONIC KIDNEY DISEASE

Abstract Background and Aims Chronic kidney disease (CKD) is commonly associated with mineral and bone disorder (CKD-MBD). Secondary hyperparathyroidism (SHPT) is a critical component of CKD-MBD characterized by excessive PTH secretion and parathyroid hyperplasia. SHPT develops in CKD because of disturbances in CKD-MBD parameters such as increases in serum phosphate and fibroblast growth factor 23, and reductions in 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D) and serum calcium. Low vitamin D levels play a critical role in the development and progression of SHPT. Nutritional vitamin D (NVD) supplements are being frequently used to address SHPT, especially in early CKD. The objective of this meta-analysis (MA) was to evaluate the effectiveness of the NVDs cholecalciferol and ergocalciferol in reducing PTH and increasing 25(OH)D in patients with non-dialysis CKD (ND-CKD). Method A systematic literature search was performed in PubMed to identify relevant randomized control trials (RCTs) to be included in the MA. All analyses were performed using both random and fixed effects models with inverted-variance weighting. Comparisons were made between the effects of NVDs relative to placebo-treated or untreated patients and between the baseline and end-of-study values of the patients treated with the NVDs, i.e. the effects in treated patients only. Results A total of 14 RCTs comprising 974 patients were included in the analyses. Overall reductions in PTH were small when compared to baseline (reduction of 10.95 pg/ml, 95 % confidence interval (CI): -15.99 to -5.91 pg/ml), while reductions in PTH were approximately three times larger when compared to placebo-treated or untreated patient groups (reduction of 34.35 pg/ml, 95 % CI:-47.47 to -21.24 pg/ml). This indicated a limited potential to actively lower PTH with NVDs as the relative effect on PTH when compared to placebo-treated or untreated patient groups was driven to a large degree by increases in PTH in the comparator arms. Treatment with NVDs tended to increase levels of 25(OH)D both when compared to placebo-treated or untreated patients (increase of 26.54 ng/ml, 95 % CI: 24.62 to 28.46 ng/ml) and when only the changes in treated patients were considered (increase of 21.49 ng/ml, 95 % CI: 20.54 to 22.44 ng/ml). However, large variations in effect sizes on levels of 25(OH)D were observed, making judgements about the size of any true treatment effect difficult. Average levels of 25(OH)D in treated patients at the end of the study period were &amp;gt;30 ng/ml in all but two RCTs and &amp;gt;50 ng/ml in only five of the included RCTs. No clear relationship was observed between study length (range: 4 to 144 weeks) or doses administered (range: 14 000 to 75 000 UI weekly average) and effects on 25(OH)D or PTH. Conclusion Our results suggest that treatment with NVDs is not efficacious to reliably and consistently lower PTH in ND-CKD patients with SHPT. Although treatment with NVDs can potentially be used to correct vitamin D insufficiency, our results suggest that the potential of NVD treatment to raise 25(OH)D levels to &amp;gt;50 ng/ml, a level needed to reduce PTH, is limited.

P0894OBESITY IMPAIRS THE ACUTE RESPONSE TO AN ORAL PHOSPHATE CHALLENGE

Abstract Background and Aims T Obesity is an increasing health problem world-wide. People who are overweight or obese are at greater risk of developing chronic diseases including cardiovascular disease (CVD). Factors associated with dysregulated phosphate metabolism have been linked to the presence of vascular calcification in people with type 2 diabetes (T2D) with normal kidney function. Insulin resistance and abdominal obesity are associated with increased circulating levels of phosphaturic hormones including fibroblast growth factor 23 (FGF-23) and parathyroid hormone (PTH). Abnormalities in phosphate regulation may not be reflected in single circulating measurements of serum phosphate, but can be revealed by the acute circulating and mineral response to an oral challenge of phosphate. The aim of this study was to determine if obesity and insulin resistance impact the acute capacity to excrete an oral phosphate challenge. Method Community-dwelling people (N=78) free of T2D and symptomatic CVD (∼10 males and ∼10 females from each decade between 40 and 80 years) with normal kidney function were recruited from Kingston, Ontario, Canada. Following a 12-hour fast, participants consumed a 1250 mg phosphate drink (sodium phosphate) where blood and urine were collected at baseline, 1, 2 and 3 hours following the oral challenge. Participants with a high-risk metabolic profile characterized by an elevated waist-to-height ratio (WHtR) (&amp;gt; 0.58) were matched by age and sex to participants with a low risk WHtR (&amp;lt;0.5). Results The results reveal a significant impact of obesity on phosphate excretion in response to an oral phosphate challenge. There was an association between WHtR ratio and the level of iFGF-23 (R=-0.34 p&amp;lt;0.01) but not PTH. After adjustment for age and sex, WHtR ratio was inversely correlated with urinary phosphate excretion in response to the phosphate challenge (R=-0.29, p=0.02) and the change in fractional excretion of phosphate (r=-0.34, p=0.007). From the larger cohort, an age- and sex- matched subset was selected for 12 high risk and 12 low risk metabolic profiles with WHtR of 0.66±0.02 and 0.46±0.01, respectively. Kidney function was the same between the two groups (eGFR 92.3±13.1 versus 95.8±13.6 ml/min/1.73m2 respectively) but high risk participants had significantly higher homeostatic model assessment of insulin resistance (HOMA-IR) (1.61±0.81 versus 0.68±0.3, p&amp;lt;0.01). Participants with a high risk metabolic profile had a greater increase in serum phosphate from baseline (29% increase in the area under the curve, p=0.04) and a significantly blunted increase in the fractional excretion of phosphate in response to the oral phosphate challenge (35% reduction in area under the curve [AUC], p=0.03) compared to the matched low risk profile participants. Conclusion Overweight/obese individuals demonstrate impaired response to an oral phosphate challenge, whereby phosphate excretion was impaired and there was increased exposure to new circulating phosphate. An impaired acute phosphate response may contribute to the initiation or propagation of vascular calcification. Dysregulated phosphate homeostasis may be an under-recognized cardiovascular risk factor in obese people that could be modified by diet and weight loss. Whether insulin enhances renal phosphate reabsorption requires further study.

Serum phosphate: Does it more closely reflect the true state of acromegaly?

An increased serum phosphate (P) level is common in acromegaly patients, however, the relationships among P, growth hormone (GH), insulin-like growth factor 1 (IGF-1) and disease status remain unknown. To reveal these relationships, we examined the association of P with comprehensive clinical data. We measured the serum P, calcium, GH, oral glucose tolerance test-GH (OGTT-GH), IGF-1, and insulin-like growth factor binding protein-3 (IGBP-3) levels in 103 acromegaly patients. SAGIT® was used to assess the disease status comprehensively. Spearman’s rank correlation coefficient was obtained to evaluate the associations among the above parameters. Stepwise multiple linear regression analysis was performed to investigate factors independently associated factors with the SAGIT scores. The area under the receiver operating characteristic curve (AUCROC) was used to evaluate the efficacy of the percentage change in the serum phosphate level in predicting remission in patients with postoperatively discordant GH and IGF-1 levels. Hyperphosphatemia was found in 68.9% of patients at baseline. The serum P level was higher in the non-remission group, but no correlation was found between hyperphosphatemia and remission. We revealed a significant correlation between the P level and SAGIT® score in patients both preoperatively (r = 0.659, p = 0.000) and 1-year postoperatively without remission patients (r = 0.534, p = 0.027). All biochemical levels decreased significantly postoperatively, and the GH and OGTT-GH levels achieved early stability (1 month); however, the P, IGF-1 and IGBP-3 levels showed a gradual decline. A percentage change in P of −8.12% is recommended as a cut-off value for predicting remission in patients with postoperatively discordant GH and IGF-1 levels. As a metabolic product which affected by the GH/IGF-1 axis, serum P appears to more closely reflect the comprehensive disease status in acromegaly. When the GH and IGF-1 levels are discordant during follow-up, perioperative change in the P level may be a potential predictor of remission.

Sclerostin Antibody Treatment Increases Bone Mass and Normalizes Circulating Phosphate Levels in Growing Hyp Mice.

X-linked hypophosphatemia (XLH), caused by a loss-of-function mutation in the phosphate regulating gene with homology to endopeptidase located on the X chromosome (PHEX), is the most common form of vitamin D-resistant rickets. Loss of functional PHEX results in elevated fibroblast growth factor 23 (FGF23) levels, impaired phosphate reabsorption, and inhibited skeletal mineralization. Sclerostin, a protein produced primarily in osteocytes, suppresses bone formation by antagonizing Wnt signaling and is reported to be elevated in XLH patients. This study used the Hyp mouse model to investigate sclerostin's role in the pathophysiology of XLH by evaluating the use of a monoclonal antibody to sclerostin in a mouse model of XLH, the Hyp mouse. Male and female wild-type and Hyp littermates were injected with 25 mg/kg of vehicle or sclerostin antibody (Scl-Ab) twice weekly, beginning at 4 weeks of age and euthanized at 8 weeks of age. Scl-Ab treatment increased serum phosphate levels and suppressed circulating levels of intact FGF23 in treated wild-type and Hyp mice of both sexes. Cortical area, trabecular bone volume fraction (BV/TV), metaphyseal apparent density, and the peak load increased with Scl-Ab treatment in both sexes. This short-term treatment study suggests that Scl-Ab treatment can effectively improve some of the pathologies associated with XLH, including normalization of phosphate, and that sclerostin may play a role in regulating FGF23 and phosphate metabolism in XLH. © 2019 American Society for Bone and Mineral Research.

Mineral and Electrolyte Disorders With SGLT2i Therapy.

ABSTRACTThe newly developed sodium‐glucose cotransporter 2 inhibitors (SGLT2is) effectively modulate glucose metabolism in diabetes. Although clinical data suggest that SGLT2is (empagliflozin, dapagliflozin, ertugliflozin, canagliflozin, ipragliflozin) are safe and protect against renal and cardiovascular events, very little attention has been dedicated to the effects of these compounds on different electrolytes. As with other antidiabetic compounds, some effects on water and electrolytes balance have been documented. Although the natriuretic effect and osmotic diuresis are expected with SGLT2is, these compounds may also modulate urinary potassium, magnesium, phosphate, and calcium excretion. Notably, they have had no effect on plasma sodium levels and promoted only small increases in serum potassium and magnesium concentrations in clinical trials. Moreover, SGLT2is may induce an increase in serum phosphate, FGF‐23, and PTH; reduce 1,25‐dihydroxyvitamin D; and generate normal serum calcium. Some published and preliminary reports, as well as unconfirmed reports have suggested an association with bone fractures. Some homeostasis perturbations are transient, whereas others may persist, suggesting that the administration of SGLT2is may affect electrolyte balances in exposed subjects. Although current evidence supports their safety, additional efforts are needed to elucidate the long‐term impact of these compounds on chronic kidney disease, mineral metabolism, and bone health. Indeed, the limited follow‐up studies and the heterogeneity of the case‐mix of different randomized controlled trials preclude a definitive answer on the impact of these compounds on long‐term outcomes such as the risk of bone fracture. Here we review the current understanding of the mechanisms involved in electrolyte handling and the available data on the clinical implications of electrolytes and mineral metabolism perturbations induced by SGLT2i administration. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Chronic kidney disease and aging differentially diminish bone material and microarchitecture in C57Bl/6 mice.

Chronic kidney disease (CKD) is a common disease of aging and increases fracture risk over advanced age alone. Aging and CKD differently impair bone turnover and mineralization. We thus hypothesize that the loss of bone quality would be greatest with the combination of advanced age and CKD. We evaluated bone from young adult (6 mo.), middle-age (18 mo.), and old (24 mo.) male C57Bl/6 mice three months following either 5/6th nephrectomy, to induce CKD, or Sham procedures. CKD exacerbated losses of cortical and trabecular microarchitecture associated with aging. Aging and CKD each resulted in thinner, more porous cortices and fewer and thinner trabeculae. Bone material quality was also reduced with CKD, and these changes to bone material were distinct from those due to age. Aging reduced whole-bone flexural strength and modulus, micrometer-scale nanoindentation modulus, and nanometer-scale tissue and collagen strain (small-angle x-ray scattering [SAXS]. By contrast, CKD reduced work to fracture and variation in bone tissue modulus and composition (Raman spectroscopy), and increased percent collagen strain. The increased collagen strain burden was associated with loss of toughness in CKD. In addition, osteocyte lacunae became smaller, sparser, and more disordered with age for Sham mice, yet these age-related changes were not clearly observed in CKD. However, for CKD, larger lacunae positively correlated with increased serum phosphate levels, suggesting that osteocytes play a role in systemic mineral homeostasis. This work demonstrates that CKD reduces bone quality, including microarchitecture and bone material properties, and that loss of bone quality with age is compounded by CKD. These findings may help reconcile why bone mass does not consistently predict fracture in the CKD population, as well as why older individuals with CKD are at high risk of fragility.

DMP1 prevents osteocyte alterations, FGF23 elevation and left ventricular hypertrophy in mice with chronic kidney disease

During chronic kidney disease (CKD), alterations in bone and mineral metabolism include increased production of the hormone fibroblast growth factor 23 (FGF23) that may contribute to cardiovascular mortality. The osteocyte protein dentin matrix protein 1 (DMP1) reduces FGF23 and enhances bone mineralization, but its effects in CKD are unknown. We tested the hypothesis that DMP1 supplementation in CKD would improve bone health, prevent FGF23 elevations and minimize consequent adverse cardiovascular outcomes. We investigated DMP1 regulation and effects in wild-type (WT) mice and the Col4a3−/− mouse model of CKD. Col4a3−/− mice demonstrated impaired kidney function, reduced bone DMP1 expression, reduced bone mass, altered osteocyte morphology and connectivity, increased osteocyte apoptosis, increased serum FGF23, hyperphosphatemia, left ventricular hypertrophy (LVH), and reduced survival. Genetic or pharmacological supplementation of DMP1 in Col4a3−/− mice prevented osteocyte apoptosis, preserved osteocyte networks, corrected bone mass, partially lowered FGF23 levels by attenuating NFAT-induced FGF23 transcription, and further increased serum phosphate. Despite impaired kidney function and worsened hyperphosphatemia, DMP1 prevented development of LVH and improved Col4a3−/− survival. Our data suggest that CKD reduces DMP1 expression, whereas its restoration represents a potential therapeutic approach to lower FGF23 and improve bone and cardiac health in CKD.

SUN-524 Burosumab Initiation In A UK XLH Cohort: Real-World Use Resonates With Research Evidence

Objectives X-linked hypophosphatemia (XLH) is a rare inherited form of osteomalacia characterised by low blood phosphate levels which lead to inadequate mineralization of bone:rickets leading in turn to a spectrum of skeletal abnormalities, physical impairment, weakness, and pain. Burosumab is an anti-FGF23 fully human monoclonal antibody, and the first treatment to target the underlying pathophysiology of XLH. Real world evidence has an important role in validating the findings of clinical research studies; more data on dose regimen and relevant biochemical outcomes outside of the clinical research study environment is required. We report these criteria following the first three months of burosumab treatment in a real-world setting. Methods An early access program (EAP) for burosumab was made available for children in the United Kingdom with XLH in 12 specialist centres. Inclusion criteria for the EAP included radiographic evidence of disease, XLH confirmed by genetic PHEX mutation, confirmed familial X-linked inheritance mutation or family history. Patients must have also had an unsatisfactory response to conventional treatment. EAP enrolment was between January and March 2018. 135 of 142 applications were approved.1 Of the 7 declined, 4 failed to meet diagnostic criteria and 3 had insufficient radiological evidence.1 132 have commenced treatment (dose in accordance with EMA marketing authorisation), of whom 41 have completed the initial 12-week burosumab titration period. Results The mean age enrolled was 7.2 years (range <1.6-16.7), 45% female, 43% male and 12% unspecified. The mean height and weight at week 0 was 110.45 cm (75-153 cm) and 25.36 kg respectively. The mean dose administered was 0.57 mg/kg at week 0 and 0.94 mg/kg at week 12 (end of the initial titration period). Mean serum phosphorus was 0.66 mmol/L (0.35-0.85 mmol/L) in week 0 rising to 1.00 mmol/L (0.57-1.58 mmol/L) at week 12 representing a 51.5% increase in serum phosphate. Mean serum ALP fell from 635.48 IU/L (269-2124 IU/L) at week 0 to 522.42 IU/L (190-1473 IU/L) at week 12, representing 18% decrease in ALP. No patients discontinued treatment due to adverse events.1Conclusions Early data from treating children and young people with XLH with burosumab in a real-world UK setting demonstrate that key biochemical responses are in line with the clinical research program findings. Ongoing monitoring and research is required to confirm the biochemical response translates to the expected subsequent impact on skeletal and non-skeletal outcomes, including linear growth and deformities.

FGF23 Synthesis and Activity.

The phosphaturic hormone FGF23 is produced primarily in osteoblasts/osteocytes and is known to respond to increases in serum phosphate and 1,25(OH)2 vitamin D (1,25D). Novel regulators of FGF23 were recently identified, and may help explain the pathophysiologies of several diseases. This review will focus on recent studies examining the synthesis and actions of FGF23. The synthesis of FGF23 in response to 1,25D is similar to other steroid hormone targets, but the cellular responses to phosphate remain largely unknown. The activity of intracellular processing genes control FGF23 glycosylation and phosphorylation, providing critical functions in determining the serum levels of bioactive FGF23. The actions of FGF23 largely occur through its co-receptor αKlotho (KL) under normal circumstances, but FGF23 has KL-independent activity during situations of high concentrations. Recent work regarding FGF23 synthesis and bioactivity, as well as considerations for diseases of altered phosphate balance will be reviewed.