A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults With X-Linked Hypophosphatemia: Week 24 Primary Analysis.

In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia. Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy. Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia. This report summarizes results from a double-blind, placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH. Participants with hypophosphatemia and pain were assigned 1:1 to burosumab 1 mg/kg (n = 68) or placebo (n = 66) subcutaneously every 4 weeks (Q4W) and were comparable at baseline. Across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p < 0.001). Burosumab significantly reduced the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with placebo (least squares [LS] mean ± standard error [SE] difference, -8.1 ± 3.24; p = 0.012). Reductions in WOMAC physical function subscale (-4.9 ± 2.48; p = 0.048) and Brief Pain Inventory worst pain (-0.5 ± 0.28; p = 0.092) did not achieve statistical significance after Hochberg multiplicity adjustment. At week 24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group (p < 0.001). Biochemical markers of bone formation and resorption increased significantly from baseline with burosumab treatment compared with placebo. The safety profile of burosumab was similar to placebo. There were no treatment-related serious adverse events or meaningful changes from baseline in serum or urine calcium, intact parathyroid hormone, or nephrocalcinosis. These data support the conclusion that burosumab is a novel therapeutic addressing an important medical need in adults with XLH.© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

The Parathyroid Gland and Heart Disease.

The parathyroid glands are critical to maintaining calcium homeostasis through actions of parathyroid hormone (PTH). Recent clinical and molecular research has shown that direct and indirect actions of PTH also affect the heart and vasculature through downstream actions of G protein-coupled receptors in the myocardium and endothelial cells. Patients with disorders of the parathyroid gland have higher incidences of hypertension, arrhythmias, left ventricular hypertrophy, heart failure, and calcific disease which translate into increased cardiac morbidity and mortality. Importantly, clinical research also suggests that early treatment of parathyroid disorders through medical or surgical management may reverse cardiovascular remodeling and mitigate cardiac risk factors.

FRACTURE LIAISON SERVICES: MULTIDISCIPLINARY APPROACHES TO SECONDARY FRACTURE PREVENTION.

OBJECTIVE: A well-recognized gap exists between evidence-based recommendations for post-fracture care and actual clinical practice, demonstrated by the high percentage of fragility fracture patients who are neither diagnosed nor treated for osteoporosis. Our purpose is to review fracture liaison service (FLS) models and to evaluate national and international experiences in secondary fracture prevention. METHODS: We performed a systematic search of publication databases (MEDLINE, SCOPUS) and included randomized controlled trials, meta-analyses, and review articles using the following keywords: Fracture liaison services, Secondary prevention of fracture, Post-fracture healthcare gap, and fragility fractures. References were included from 2001-2015. We subsequently performed reference searches of retrieved articles and available literature was reviewed. RESULTS: The efficacy of secondary fracture prevention programs correlates strongly with their intensity. Type A FLS Models are most successful in initiating diagnostic and treatment plans for fragility fracture patients. Adoption of FLS programs improves care by lowering mortality and refracture rates while also lowering healthcare costs. The quality of evidence supporting associations between FLS programs and improved outcomes was moderately strong due to the availability of longitudinal data from nationalized health systems. CONCLUSION: As our population ages and challenges to the healthcare system loom ever larger, it is imperative that we fund and champion fracture liaison services. The fracture liaison service has recently emerged as a novel clinical approach that uses coordinated, multidisciplinary care to improve post-fracture outcomes and reduce recurrent fractures. These programs are simple, targeted, high-yield and have the potential to protect our most vulnerable patients. ABBREVIATIONS: DXA = dual-energy x-ray absorptiometry FLS = fracture liaison service NCQA = National Committee of Quality Assurance NHS = National Health Service PCP = primary care physician PQRS = Physician Quality Reporting System QCDR = Qualified Clinical Data Registry.

Pharmacokinetics and pharmacodynamics of a human monoclonal anti-FGF23 antibody (KRN23) in the first multiple ascending-dose trial treating adults with X-linked hypophosphatemia.

In X-linked hypophosphatemia (XLH), serum fibroblast growth factor 23 (FGF23) is increased and results in reduced renal maximum threshold for phosphate reabsorption (TmP), reduced serum inorganic phosphorus (Pi), and inappropriately low normal serum 1,25 dihydroxyvitamin D (1,25[OH]2 D) concentration, with subsequent development of rickets or osteomalacia. KRN23 is a recombinant human IgG1 monoclonal antibody that binds to FGF23 and blocks its activity. Up to 4 doses of KRN23 were administered subcutaneously every 28 days to 28 adults with XLH. Mean ± standard deviation KRN23 doses administered were 0.05, 0.10 ± 0.01, 0.28 ± 0.06, and 0.48 ± 0.16 mg/kg. The mean time to reach maximum serum KRN23 levels was 7.0 to 8.5 days. The mean KRN23 half-life was 16.4 days. The mean area under the concentration-time curve (AUCn ) for each dosing interval increased proportionally with increases in KRN23 dose. The mean intersubject variability in AUCn ranged from 30% to 37%. The area under the effect concentration-time curve (AUECn ) for change from baseline in TmP per glomerular filtration rate, serum Pi, 1,25(OH)2 D, and bone markers for each dosing interval increased linearly with increases in KRN23 AUCn . Linear correlation between serum KRN23 concentrations and increase in serum Pi support KRN23 dose adjustments based on predose serum Pi concentration.

Effect of four monthly doses of a human monoclonal anti-FGF23 antibody (KRN23) on quality of life in X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is characterized by lower extremity deformities that lead to bone and/or joint pain that result from decreased renal tubular reabsorption leading to hypophosphatemia caused by elevated levels of fibroblast growth factor 23 (FGF23). OBJECTIVE: Validate the use of SF-36v2 Health Survey (SF-36v2) and the Western Ontario and McMaster Osteoarthritis Index (WOMAC) to measure previously unstudied health-related quality of life (HRQoL) in XLH patients and determine the change in HRQoL before and after treatment with KRN23, a human monoclonal anti-FGF23 antibody. METHODS: Twenty-eight adult outpatients with XLH received up to four doses of KRN23 administered subcutaneously every 28 days. General HRQoL was measured with the SF-36v2 and condition-related HRQoL with the WOMAC at baseline and study endpoint as a secondary outcome of a Phase 1/2, open-label, multicenter, dose-escalation trial. RESULTS: Testing for scale discriminant validity and convergent-divergent validity supported the use of these scales in the assessment of HRQoL in XLH. Both instruments indicated impairment of physical function at baseline with all mean scores showing a trend to improved health at study endpoint compared to baseline. When corrected for multiple comparisons, the score for Role Limitations due to physical health on the SF-36v2 which measures the patient's perception of their own chronic functional impairments due to poor physical health remained significantly improved (P < 0.05), increasing to the mean score of US adults. For the WOMAC, Physical Functioning and Stiffness scores were significantly improved (P < 0.05). CONCLUSION: KRN23 administration was associated with significantly improved patient perception of their Physical Functioning and Stiffness due to their disease. This study demonstrates that the SF-36v2 and WOMAC are valid tools for assessing HRQoL in XLH.

Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23.

CONTEXT: In X-linked hypophosphatemia (XLH), elevated fibroblast growth factor 23 (FGF23) decreases the renal tubular maximum reabsorption rate of phosphate/glomerular filtration rate (TmP/GFR) and serum inorganic phosphorus (Pi), resulting in rickets and/or osteomalacia. OBJECTIVE: The objective was to test the hypothesis that monthly KRN23 (anti-FGF23 antibody) would safely improve serum Pi in adults with XLH. DESIGN: Two sequential open-label phase 1/2 studies were done. SETTING: Six academic medical centers were used. PARTICIPANTS: Twenty-eight adults with XLH participated in a 4-month dose-escalation study (0.05-0.6 mg/kg); 22 entered a 12-month extension study (0.1-1 mg/kg). INTERVENTION: KRN23 was injected sc every 28 days. MAIN OUTCOME MEASURE: The main outcome measure was the proportion of subjects attaining normal serum Pi and safety. RESULTS: At baseline, mean TmP/GFR, serum Pi, and 1,25-dihydroxyvitamin D [1,25(OH)2D] were 1.6 ± 0.4 mg/dL, 1.9 ± 0.3 mg/dL, and 36.6 ± 14.3 pg/mL, respectively. During dose escalation, TmP/GFR, Pi, and 1,25(OH)2D increased, peaking at 7 days for TmP/GFR and Pi and at 3-7 days for 1,25(OH)2D, remaining above (TmP/GFR, Pi) or near [1,25(OH)2D] pre-dose levels at trough. After each of the four escalating doses, peak Pi was between 2.5 and 4.5 mg/dL in 14.8, 37.0, 74.1, and 88.5% of subjects, respectively. During the 12-month extension, peak Pi was in the normal range for 57.9-85.0% of subjects, and ≥25% maintained trough Pi levels within the normal range. Serum Pi did not exceed 4.5 mg/dL in any subject. Although 1,25(OH)2D levels increased transiently, mean serum and urinary calcium remained normal. KRN23 treatment increased biomarkers of skeletal turnover and had a favorable safety profile. CONCLUSIONS: Monthly KRN23 significantly increased serum Pi, TmP/GFR, and 1,25(OH)2D in all subjects. KRN23 has potential for effectively treating XLH.

Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia.

BACKGROUND: X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia. XLH-associated mutations in phosphate-regulating endopeptidase (PHEX) result in elevated serum FGF23, decreased renal phosphate reabsorption, and low serum concentrations of phosphate (inorganic phosphorus, Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. KRN23 is a human anti-FGF23 antibody developed as a potential treatment for XLH. Here, we have assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of KRN23 following a single i.v. or s.c. dose of KRN23 in adults with XLH. METHODS: Thirty-eight XLH patients were randomized to receive a single dose of KRN23 (0.003-0.3 mg/kg i.v. or 0.1-1 mg/kg s.c.) or placebo. PK, PD, immunogenicity, safety, and tolerability were assessed for up to 50 days. RESULTS: KRN23 significantly increased the maximum renal tubular threshold for phosphate reabsorption (TmP/GFR), serum Pi, and 1,25(OH)2D compared with that of placebo (P<0.01). The maximum serum Pi concentration occurred later following s.c. dosing (8-15 days) compared with that seen with i.v. dosing (0.5-4 days). The effect duration was dose related and persisted longer in patients who received s.c. administration. Changes from baseline in TmP/GFR, serum Pi, and serum 1,25(OH)2D correlated with serum KRN23 concentrations. The mean t1/2 of KRN23 was 8-12 days after i.v. administration and 13-19 days after s.c. administration. Patients did not exhibit increased nephrocalcinosis or develop hypercalciuria, hypercalcemia, anti-KRN23 antibodies, or elevated serum parathyroid hormone (PTH) or creatinine. CONCLUSION: KRN23 increased TmP/GFR, serum Pi, and serum 1,25(OH)2D. The positive effect of KR23 on serum Pi and its favorable safety profile suggest utility for KRN23 in XLH patients. Trial registration. Clinicaltrials.gov NCT00830674. Funding. Kyowa Hakko Kirin Pharma, Inc.

Kaposi sarcoma in the setting of cushing disease.

OBJECTIVE: To report a case of a human immunodeficiency virus (HIV)-negative Kaposi sarcoma (KS) associated with Cushing disease (CD). METHODS: The details of case presentation, evaluation, diagnosis, and treatment are presented and cases of KS and CD published before November 1, 2010 on PubMed and Scopus are reviewed. RESULTS: A 54-year-old Hispanic HIV-negative man presented with typical signs and symptoms of CD (easy bruisability, proximal muscle wasting, and abdominal fat pads). Numerous raised, purplish, nonblanching plaques 0.5 to 2 cm in diameter extended throughout his lower extremities. Biochemical tests and pituitary magnetic resonance imaging confirmed CD. A lesion biopsy showed atypical vascular proliferation positive by immunohistochemistry for human herpesvirus 8 (HHV-8), consistent with KS. He underwent 2 transsphenoidal surgeries followed by a bilateral adrenalectomy. After recovery, his KS was treated with a systemic combination of liposomal doxorubicin and paclitaxel. CONCLUSION: The occurrence of CD and KS is rare. Specific therapy for CD and chemotherapy for KS are effective in the treatment of KS associated with CD.

Vitamin D receptors and parathyroid glands.

OBJECTIVE: To describe the function and metabolism of the vitamin D hormone and the role of the vitamin D receptor and the calcium-sensing receptor in the secretion of parathyroid hormone. METHODS: A review of the literature was undertaken regarding the function and metabolism of vitamin D; the role of the vitamin D receptor and calcium-sensing receptor in the secretion of parathyroid hormone; and the contemporary research regarding the interaction of vitamin D and parathyroid hormone in patients with vitamin D deficiency, primary hyperparathyroidism, and secondary hyperparathyroidism. RESULTS: Over the last several years, great interest has been generated about the interaction of vitamin D and the parathyroid glands, gastrointestinal tract, kidney, and bone in relation to calcium and parathyroid hormone levels. Vitamin D has an important role in calcium and parathyroid hormone metabolism. Likewise, the vitamin D axis appears to be involved with the development of both primary and secondary hyperparathyroidism. The specific mechanism by which vitamin D interacts with the parathyroid gland to bring about observed effects is not yet fully understood. CONCLUSION: Future studies investigating the relationship of the vitamin D receptor, calcium-sensing receptor, and parathyroid glands are needed to enhance our knowledge of vitamin D deficiency and primary and secondary vitamin D deficiency.

Medications that affect calcium.

OBJECTIVE: To review medications that can affect serum calcium concentrations. METHODS: The literature was reviewed for articles pertaining to medications that affect calcium concentrations. RESULTS: The serum calcium concentration is tightly regulated because of the importance of this mineral in diffuse cellular processes. Many medications have been reported to cause changes in serum calcium levels by influencing intestinal calcium absorption, renal calcium resorption, and bone remodeling or through altering parathyroid or 1,25-dihydroxyvitamin D-mediated regulation. Some medications are used specifically to alter serum calcium as a therapeutic intervention. With others, the calcium disturbances are viewed as a side effect of the treatment. CONCLUSION: It is important to be aware of the influence that medications can have on serum calcium levels when evaluating patients with disorders of calcium homeostasis.

Mutational analysis of PHEX, FGF23 and DMP1 in a cohort of patients with hypophosphatemic rickets.

BACKGROUND: X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets and autosomal recessive hypophosphatemic rickets make up a group of renal phosphate wasting disorders with common clinical and biochemical characteristics. These three types of rickets are related to mutations in PHEX, FGF23 and dentin matrix protein 1 (DMP1), respectively. OBJECTIVE: The objective of the study was to evaluate the frequency of mutations that occur in these three genes associated with hypophosphatemic rickets. PATIENTS AND METHODS: In this study, we sequenced these genes in 76 members of 46 kindreds from a large hypophosphatemic rickets cohort. RESULTS: Forty-two individuals from 27 kindreds were found to have mutations in PHEX; 16 of which were novel. One subject had an FGF23 mutation. No individuals were found to have mutations in DMP1 consistent with the presence of recessive hypophosphatemic rickets. CONCLUSIONS: Our data highlight the wide spectrum of genetic variation that can be seen in PHEX, FGF23 and DMP1 when screening a large cohort with hypophosphatemic rickets.

Consumptive hypothyroidism caused by paraneoplastic production of type 3 iodothyronine deiodinase.

Consumptive hypothyroidism is characterized by excessive inactivation of thyroid hormone by type 3 iodothyronine deiodinase (D3). Previously this rare syndrome was described in association with massive hemangiomas in children and in a single case of a hemangioendothelioma in an adult. Here we report the first case of consumptive hypothyroidism from a nonvascular tumor in a patient who required supraphysiologic doses of levothyroxine prior to the resection of a large malignant solitary fibrous tumor. The tumor expressed D3 message, protein and exhibited functional D3 enzymatic activity. The clinical presentation of this patient expands the differential diagnosis of hypothyroidism, adds to the growing list of paraneoplastic syndromes that impact the endocrine system, and extends the spectrum of tumor types associated with consumptive hypothyroidism.

Reduced bone mineral density in human immunodeficiency virus-infected patients and its association with increased central adiposity and postload hyperglycemia.

Reduced bone mineral density (BMD) and abnormalities in fat redistribution, glucose homeostasis, and lipid metabolism are prevalent among HIV-infected patients on highly active antiretroviral therapy (HAART). The relationship between the metabolic and skeletal complications of HIV is unclear. Fifty-one HIV patients on HAART (aged 30-54 yr, 86% male) and 21 HIV-negative control subjects (aged 31-51 yr, 82% male) were examined with oral glucose tolerance testing, a fasting lipid profile, and dual x-ray absorptiometry, and markers of bone formation (serum osteocalcin) and resorption (urinary deoxypyridinoline). HIV-infected subjects had a higher prevalence of either osteopenia or osteoporosis (World Health Organization criteria) at the spine, hip, or forearm, compared with HIV-negative controls (63% vs. 32%, P = 0.02) and evidence of increased bone resorption (urine deoxypyridinoline, 14.7 +/- 6.5 vs. 10.9 +/- 2.5 nmol/mmol creatinine, P = 0.012). Among the HIV-infected patients, those with reduced bone mineral density (n = 32) were similar to the group with normal BMD (n = 19) in the use of protease inhibitors, duration of HAART therapy, or other demographic variables. Plasma glucose 2 h after a glucose load (odds ratio 1.02 per 1 mg/dl increase, 95% confidence interval 1.01-1.05, P = 0.009) and central adiposity (trunk fat/total fat) (odds ratio 1.09 per 1% ratio increase, 95% confidence interval 1.00-1.18, P = 0.012) were associated with reduced BMD. These associations remained significant in a multivariate model including age and body mass index. Bone resorption was associated with female gender (P < 0.001) and non-high-density lipoprotein cholesterol (P = 0.034) in a multivariate linear regression model controlling for age, body mass index, protease inhibitor use, duration of HAART, and extremity fat. Reduced BMD is prevalent in HIV-infected patients on HAART and is related to central adiposity and postload hyperglycemia. Bone resorption is independently associated with female gender and dyslipidemia. HIV-infected patients with metabolic abnormalities may represent a population that would benefit from bone density screening.