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Acknowledgment of Commercial Support
This activity is supported by an educational grant from Ultragenyx Pharmaceutical Inc.
Clinical Briefings™: X-Linked Hypophosphatemia: Diagnosing and Addressing the Underlying Cause of the Disease
Original Release Date: December 31, 2018
Review Date: June 10, 2019
Re-Release Date: June 20, 2019
Expiration Date: June 30, 2020
Media: Internet - based
X-linked hypophosphatemia (XLH) is a lifelong condition that requires long-term treatment and monitoring. Clinical presentation is variable, causing significant morbidity in patients with XLH as they age. This morbidity may result from impairment in mobility, osteoarthritis, enthesopathy, stress fractures in weakened bones, and pain and discomfort. Current treatment consists of conventional therapy, which includes vitamin D supplementation and oral phosphate, aimed at improving growth, lessening the severity of symptoms, and preventing skeletal abnormalities; and burosumab, an anti-FGF23 fully human monoclonal antibody, and the first-in-class treatment targeting the underlying pathophysiology of XLH.
This activity has recently been updated to include the latest data from the 64-week extension trial, which found that burosumab exhibited superior improvement of bone disease in children with XLH as compared to conventional therapy using oral phosphate and active vitamin D. As a result of the addition of new data, Physician’s Education Resource®, LLC, has extended the accreditation for this program from December 31, 2019, to June 30, 2020.
Acknowledgement of Commercial Support
This activity is supported by an educational grant from Ultragenyx Pharmaceutical Inc.
Instructions for This Activity and Receiving Credit
This online educational activity is directed toward primary care physicians, pediatricians, endocrinologists, nephrologists, dentists, nurse practitioners (NPs), physician assistants (PAs), nurses and other healthcare professionals who would be involved in the diagnosis and management of XLH.
Upon successful completion of this activity, you should be better prepared to:
- Utilize clinical trial data concerning novel therapy for X-linked hypophosphatemia (XLH) in clinical care of patients
- Evaluate the medical needs of patients with XLH and appropriate multidisciplinary approach to care
- Apply the knowledge of adverse drug reactions, toxicities, and relative risks of pharmacologic and nonpharmacologic therapies to select appropriate interventions
Faculty, Staff, and Planners' Disclosures
Thomas O. Carpenter, MD
Professor of Pediatrics
Professor of Orthopedics and Rehabilitation
Yale University School of Medicine
New Haven, Connecticut
Disclosures: Grant/Research Support: Ultragenyx Pharmaceutical (Investigator in clinical trials) Consultant: Clementia, Inozyme, Pharmacosmos, Ultragenyx Pharmaceutical Spouse’s employment role: Consultant for Thermo-Fisher Investigational/Off-Label Use of Drugs/Devices Disclosure: Alfacalcidol; Calcitriol; various oral phosphate salts
The staff of PER® have no relevant financial relationships with commercial interests to disclose.
Disclosure Policy and Resolution of Conflicts of Interest (COI)
As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME/CE activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME/CE activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.
Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.
Off-Label Disclosure and Disclaimer
This CME/CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME/CE activity is for continuing medical and nursing education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER®.
PER Pulse™ Recaps
1 of 3
Join renowned medical expert Thomas O. Carpenter, MD, in the online continuing medical education activity X-Linked Hypophosphatemia: Diagnosing and Addressing the Underlying Cause of the Disease. You will engage with the faculty through an expert discussion to gain insight into emerging therapies and their impact on the treatment paradigm and investigate best practices for the management of X-linked hypophosphatemia.
This first of 3 PER Pulse™ Recaps will focus on the application of evidence-based clinical decision making relative to applying emerging clinical trial data to the treatment paradigm of X-linked hypophosphatemia (XLH).
XLH manifests in approximately 1 in 20,000 live births and typically presents in early childhood.1 In the United States, approximately 3000 children and 12,000 adults have XLH.2 The primary goal of treatment in the pediatric patient with XLH is to correct or minimize rickets/osteomalacia, radiographic abnormalities, and skeletal deformities.2 XLH is a lifelong condition that typically requires long-term treatment and monitoring.
Initial treatment dosages recommended for XLH are 20 to 30 mg/kg of calcitriol (divided into 3 daily doses) and 20 to 40 mg/kg of elemental phosphorus (divided into 3-5 daily doses) to correct vitamin D and phosphorus deficiencies.2 The multiple daily doses recommended are ideal for optimal bone mineralization and help to reduce gastrointestinal adverse effects due to phosphate supplementation.1
Burosumab is the first and only therapy addressing the underlying cause of XLH. It is the first recombinant immunoglobulin G1 monoclonal antibody to inhibit fibroblast growth factor 23 (FGF23) and has been indicated for patients ≥1 years.3-5 This agent’s inhibition of FGF23 aids in restoring phosphate homeostasis by enhancing renal phosphate reabsorption through increased renal expression of sodium phosphate cotransporters and by increasing the renal expression of 1α-hydroxylase, a vitamin D–metabolizing enzyme involved in vitamin D production.4
Recombinant human growth hormone (rhGH) is an adjunctive therapy used in pediatric patients with XLH. Results from several studies have shown that regular rhGH doses improved growth velocity and phosphate concentrations, but evidence for efficacy is unclear.6-8 Surgery is indicated for patients only after medical treatment has failed. Specifically, children with progressive skeletal deformities that cause significant gait disturbances, limitations in daily activities, and pain are indicated for surgical treatment.1,2
- Sharkey MS, Grunseich K, Carpenter TO. Contemporary medical and surgical management of X-linked hypophosphatemic rickets. J Am Acad Orthop Surg. 2015;23(7):433-442. doi: 10.5435/JAAOS-D-14-00082.
- Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res. 2011;26(7):1381-1388. doi: 10.1002/jbmr.340.
- FDA approves first therapy for rare inherited form of rickets, x-linked hypophosphatemia [news release]. Silver Spring, MD: FDA; April 17, 2018. www.fda.gov/newsevents/newsroom/pressannouncements/ucm604810.htm. Accessed December 14, 2018.
- Ultragenyx Pharmaceutical Inc. Crysvita website. crystiva.com. Accessed December 21, 2018.
- Carpenter TO, Whyte MP, Imel EA, et al. Burosumab therapy in children with X-linked hypophosphatemia. N Engl J Med. 2018;378(21):1987-1998. doi: 10.1056/NEJMoa1714641.
- Zivičnjak M, Schnabel D, Billing H, et al; Hypophosphatemic Rickets Study Group of Arbeitsgemeinschaft für Pädiatrische Endokrinologie and Gesellschaft für Pädiatrische Nephrologie. Age-related stature and linear body segments in children with X-linked hypophosphatemic rickets. Pediatr Nephrol. 2011;26(2):223-231. doi: 10.1007/s00467-010-1705-9.
- Baroncelli GI, Bertelloni S, Ceccarelli C, Saggese G. Effect of growth hormone treatment on final height, phosphate metabolism, and bone mineral density in children with X-linked hypophosphatemic rickets. J Pediatr. 2001;138(2):236-243. doi: 10.1067/mpd.2001.108955.
- Cameron FJ, Sochett EB, Caneman A, Kooh SW. A trial of growth hormone therapy in well-controlled hypophosphataemic rickets. Clin Endocrinol (Oxf). 1999;50(5):577-582.
2 of 3
As a follow-up to the online continuing medical education activity X-Linked Hypophosphatemia: Diagnosing and Addressing the Underlying Cause of the Disease, this second of 3 PER Pulse™ Recaps will focus on the clinical management of multidisciplinary aspects of care in patients with X-linked hypophosphatemia.
The following diagnostic criteria should be considered:
- Metaphyses: widened, frayed, or cupped
- Rachitic rosary or beading of the ribs due to poor skeletal mineralization
- Low serum phosphate concentration
Reduced tubular resorption of phosphate
- The calculation of tubular maximum reabsorption rate of phosphate to glomerular filtration rate has relied on the nomogram-based method.
Additional laboratory findings1
- Normal serum calcium and 25-hydroxyvitamin D levels
- Normal serum calcitriol level in the presence of hypophosphatemia
Normal parathyroid hormone level
- Slightly elevated in some patients
- Absence of glycosuria, bicarbonaturia, proteinuria, or amino-aciduria
- A hemizygous PHEX pathogenic variant in a male proband
- A heterozygous PHEX pathogenic variant in a female proband
- Genetic testing can include single-gene testing, multigene panel, or more comprehensive genomic testing.1
- Ruppe MD. X-Linked hypophosphatemia. National Center for Biotechnology Information website. ncbi.nlm.nih.gov/books/NBK83985/. Updated April 13, 2017. Accessed January 8, 2018.
3 of 3
As a follow-up to the online continuing medical education activity X-Linked Hypophosphatemia: Diagnosing and Addressing the Underlying Cause of the Disease, this third of 3 PER Pulse™ Recaps will focus on the toxicities and the risks of different therapeutic interventions for X-linked hypophosphatemia and associated comorbid conditions.
Dosage adjustments of conventional therapy with calcitriol should occur based on therapeutic outcomes and not on specific phosphorus levels. If a child continues to have decreased height velocity or increased bowing, treatment adherence should be assessed and dosage adjustments made, if necessary. In contrast, children who maintain acceptable height velocity and show improvement in skeletal deformities can generally be considered as having received satisfactory dosing.1
Secondary hyperparathyroidism is commonly seen during conventional treatment despite phosphorus levels being within normal limits. Hypercalciuria, hypercalcemia, and nephrocalcinosis are complications also observed in these patients. As a result, it is recommended to conduct laboratory monitoring every 3 months and include parathyroid hormone , phosphate, calcium, creatinine, and urinary calcium/creatinine.2
In addition, a decrease in alkaline phosphatase can be used as a marker for skeletal response to treatment (acute increases can occur after initiation of therapy).2 A renal ultrasound should also be conducted every 2 to 5 years to detect nephrocalcinosis.2 A radiograph of the knees should be taken prior to initiation of therapy and then several months later to determine the extent of growth plate response. Thereafter, repeat radiographs should be conducted every 1 to 2 years to determine any therapeutic changes or evidence of disease progression.2
- Carpenter TO, Imel EA, Holm IA, et al. A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res. 2011;26(7):1381-1388. doi: 10.1002/jbmr.340.
- Sharkey MS, Grunseich K, Carpenter TO. Contemporary medical and surgical management of X-linked hypophosphatemic rickets. J AM Acad Orthop Surg. 2015;23(7):433-442. doi: 10.5435/JAAOS-D-14-00082.
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