What is the treatment and management approach for a male patient with X-linked hypophosphatemia, characterized by low phosphate levels, softening of the bones, and a family history of similar bone health issues?

Treatment and Management of X-Linked Hypophosphatemia

Burosumab is now the preferred first-line treatment for X-linked hypophosphatemia in both children (≥6 months) and adults, having largely replaced conventional therapy with oral phosphate and active vitamin D due to superior efficacy and improved quality of life outcomes. 1

Diagnosis Confirmation

Before initiating treatment, confirm the diagnosis through:

• Genetic testing of the PHEX gene is the gold standard for diagnosis confirmation 1
• If genetic testing unavailable, measure intact FGF23 levels (non-suppressed levels in the setting of hypophosphatemia support XLH diagnosis) 1
• Exclude Fanconi syndrome by testing for glucosuria, aminoaciduria, and low molecular weight proteinuria 1
• Document renal phosphate wasting via TmP/GFR calculation (fractional phosphate excretion >15%) 2

Treatment Approach

First-Line: Burosumab (Anti-FGF23 Antibody)

Burosumab directly addresses the underlying pathophysiology by neutralizing excess FGF23, normalizing phosphate levels and improving skeletal mineralization. 1

Pediatric Dosing (≥6 months to <18 years):

• For patients <10 kg: Start at 1 mg/kg subcutaneously every 2 weeks, rounded to nearest 1 mg 3
• For patients ≥10 kg: Start at 0.8 mg/kg subcutaneously every 2 weeks, rounded to nearest 10 mg (minimum 10 mg, maximum 90 mg) 3
• Titrate dose every 4 weeks based on fasting serum phosphorus to maintain within age-appropriate reference range 3
• Maximum dose: 2 mg/kg every 2 weeks (up to 90 mg) 3

Adult Dosing:

• Follow similar weight-based dosing principles as pediatric patients 1

Pre-Treatment Requirements:

• Discontinue oral phosphate and active vitamin D analogs 1 week before starting burosumab 3
• Confirm fasting serum phosphorus is below reference range for age 3

Alternative: Conventional Therapy

Conventional therapy (oral phosphate + active vitamin D) is now reserved for patients who cannot access burosumab or have contraindications, as it has limited efficacy and significant adverse effects. 1

• Requires frequent daily dosing (multiple times per day) of phosphate supplements 1
• Active vitamin D analogs (calcitriol, alfacalcidol) to prevent secondary hyperparathyroidism 1
• Major limitation: Both phosphate and vitamin D further stimulate FGF23 secretion, creating a vicious cycle 1
• Common complications: Secondary/tertiary hyperparathyroidism (83.3% prevalence), nephrocalcinosis (more common with tertiary hyperparathyroidism at 60%), and chronic kidney disease 4

Multidisciplinary Care Coordination

All patients require care organized by a metabolic bone disease expert with multidisciplinary team involvement. 1

Essential team members include:

• Metabolic bone disease specialist (coordinator) 1
• Endocrinology (pediatric or adult) 5
• Nephrology for monitoring renal complications 1
• Orthopedic surgery for skeletal deformities and pseudofractures 1
• Dentistry for dental abscesses and hypomineralization 1
• Physical therapy for musculoskeletal symptoms and mobility 6
• Neurosurgery if craniosynostosis develops 1
• Audiology for hearing assessment (starting age 8 years) 1

Monitoring Protocol

Initial Phase (First 3 Months):

• Fasting serum phosphorus every 4 weeks 3
• Serum calcium, creatinine, alkaline phosphatase, PTH 1, 2
• 25(OH) vitamin D and 1,25(OH)₂ vitamin D 1, 2
• Renal ultrasound for nephrocalcinosis 1

Ongoing Monitoring:

• Continue biochemical monitoring at appropriate intervals based on stability 1
• Radiological assessment for rickets severity, osteomalacia, pseudofractures 1
• Growth parameters (height, weight, BMI) in children 1
• Intermalleolar/intercondylar distance for leg deformities 1
• Dental examination regularly 1
• Hearing assessment from age 8 years 1

Management of Specific Complications

Hyperparathyroidism:

• Secondary hyperparathyroidism is extremely common (83.3% of patients) with conventional therapy 4
• Tertiary hyperparathyroidism develops in 16.7% of patients 4
• Parathyroidectomy has poor outcomes: 75% have persistent/recurrent hypercalcemia after surgery 4
• Prevention strategy: Burosumab avoids this complication by eliminating need for phosphate/vitamin D supplementation 1

Growth Impairment:

• Recombinant human growth hormone (rhGH) can be considered in children with compromised height prognosis 7
• Combined burosumab + rhGH therapy appears safe and may provide additive height benefits (mean height gain 0.2 SDS in first year of combination) 7
• Burosumab alone shows minimal height improvement (0.0-0.1 SDS change) 7

Musculoskeletal Symptoms:

• Physical therapy focused on pain relief, improving function, and reducing disability 6
• Address enthesopathies, osteoarthritis, and muscle weakness 1, 8
• Orthopedic intervention for severe deformities or pseudofractures 1

Dental Management:

• Regular dental surveillance for abscesses and periodontitis 1
• Preventive care to address hypomineralization 1

Critical Pitfalls to Avoid

• Never combine burosumab with oral phosphate or active vitamin D (contraindicated due to risk of severe hypercalcemia) 3
• Do not delay genetic testing when clinical suspicion exists, as it confirms diagnosis and enables family screening 1
• Avoid assuming normal phosphate levels exclude disease in infants <3-4 months, as age-related reference ranges differ 2
• Do not perform parathyroidectomy without careful consideration, as recurrence rates are 75% 4
• Screen all first-degree relatives (except sons of affected males, who cannot inherit X-linked disease) 1

Special Populations

Pregnancy and Lactation:

• Requires specialized management protocols 1
• Genetic counseling should be offered, especially during transition to adult care 1

Transition from Pediatric to Adult Care:

• Ensure continuity with adult metabolic bone specialist 1
• Offer genetic counseling at this critical juncture 1