X-linked hypophosphatemia (XLH) is a rare, progressive genetic disease that is characterized by low levels of phosphate in the blood. Phosphorus in phosphate is an important mineral for proper bone and teeth development.
In XLH, mutations in the PHEX gene, which is situated on the X-chromosome, result in excess production of another protein called fibroblast growth factor 23 (FGF23). The growth factor is synthesized by the FGF23 gene and inhibits kidneys from reabsorbing phosphate back into the bloodstream. This results in the excretion of phosphate in the urine, leading to low phosphate levels in the blood and causing bone deformities and weakness.
Although no cure has been found yet for XLH, several treatment options are available to manage symptoms and correct skeletal defects.
Treatment in children
Treatment in children with XLH should begin as soon as a diagnosis is confirmed and should last until they complete their bone growth.
Standard therapy of phosphate and active vitamin D
The standard treatment for children is a combination of phosphate salts taken orally between three to five times daily along with an appropriate dose of calcitriol, the active form of vitamin D. The number of times phosphate is taken is adjusted based on serum alkaline phosphatase activity which can be determined using blood tests.
The calcitriol dosage is usually started low (between 20 and 30 ng per kg daily). A high dose of calcitriol (between 50 and 70 ng per kg daily) may also be prescribed. The initial dose of phosphate ranges between 20 and 60 mg per kg and is adjusted as needed. Doses greater than 80 mg per kg should be avoided to prevent gastrointestinal side effects and hyperparathyroidism.
Side effects of this standard treatment include nephrocalcinosis (calcium deposition in the kidneys), hypercalcemia (excess calcium in the blood), hypercalciuria (excess calcium in the urine), secondary hyperparathyroidism (excess production of the parathyroid hormone due to vitamin D deficiency), and high blood pressure. Secondary hyperparathyroidism can be treated with calcimimetics (medicines that signal the body to produce less parathyroid hormone) such as Sensipar (cinacalcet).
XLH drastically affects body height. Research has shown that the administration of recombinant human growth hormone for up to two years before the onset of puberty can increase height.
Children with bowed legs can be treated with hemiepiphysiodesis, a minimally invasive surgery to insert metal plates for proper bone growth and alignment, before the onset of puberty. The metal plates are removed once the bone is straight and normal growth continues. This is followed by physiotherapy and regular assessment of bone function until the bones mature.
About 30% to 60% of children with XLH show craniosynostosis (early closure of skull joints leading to problems in skull growth) and Chiari type 1 malformation (protrusion of a part of the cerebellum into the base of the skull where the spinal cord begins). Both conditions can be corrected with surgery to relieve pressure in the skull and spinal cord.
Treatment in adults
Treatment in adults targets the symptoms and is based on available biochemical evidence at diagnosis.
Standard therapy of phosphate and active vitamin D
Calcitriol doses for adults are prescribed in the range of 0.5 to 0.75 microgram per day with a phosphate dose of 750 to 1,000 mg divided and taken three to four times a day. Phosphate dosage should be increased gradually to avoid side effects such as gastrointestinal problems.
XLH patients have low muscle strength and may experience fatigue, weakness, pain, and enthesopathy (problems in the attachment of ligaments and tendons), all of which can impact movement and reduce quality of life. Physical and occupational therapy can help in improving joint movement and prevent pain while carrying out daily activities. Non-steroidal anti-inflammatory drugs taken orally or injected inside the joints may be recommended for pain relief.
Continued standard therapy with phosphate and vitamin D supplements can promote dental health in people with XLH. Maintaining oral hygiene by daily flossing and occasional fluoride treatment may prevent infections.
Both children and adults with XLH have dental abscesses that can lead to the loss of primary (baby teeth) and permanent teeth.
Therefore, dental visits once every six months can help assess any issues in the teeth and gums, and determine if any corrective measures need to be taken, including sealing gaps in the teeth or supragingival and/or subgingival debridement (removal of plaque and calculus above and below the gums).
Treatment for hearing loss
Hearing loss may be observed in XLH patients from as early as age 11. The standard treatment for hearing loss includes the use of hearing aids, low exposure to noise, and avoiding ototoxic medications, or medications that can damage the ear, such as certain antibiotics and chemotherapy agents.
Crysvita (burosumab), developed by Ultragenyx Pharmaceutical, was recently approved by the U.S. Food and Drug Administration to treat XLH in children 6 months and older. Crysvita was also granted conditional marketing authorization by the European Medicines Agency for children with XLH who are 1 or older.
Crysvita is an antibody that works by binding to the excess FGF23 protein responsible for the increased excretion of phosphate by the kidneys. By binding to FGF23, Crysvita helps with the reabsorption of phosphate by the kidneys and promotes bone growth by increasing the availability of phosphate in the blood.
The treatment is administered as an injection at a starting dose of 0.4 mg per kg every two weeks in children and at a dose of 1 mg per kg every four weeks in adults until serum phosphate levels are within the normal range. The dosing can be restarted at half the previous dose once phosphate levels go below the normal range again.
Apart from standard therapy and Crysvita, several new treatment options for XLH are under development. These are in early stages of development and only being tested in animal models at the moment.
Sclerostin is a protein produced by the SOST gene in bone cells to inhibit excessive bone growth. The levels of this protein are elevated in XLH patients. Researchers have found that targeting sclerostin using an antibody improved bone health in mouse models of XLH, although it did not seem to alter bone length or body weight.
FGF23 c-tail Fc
FGF23 functions by binding the FGF receptors found on the surface of cells. As part of the mechanism that regulates FGF23 signaling, the protein gets cleaved into two fragments called the C-terminal (c-tail) and N-terminal fragments. The c-tail of FGF23 can still bind to FGF receptors but cannot carry out normal function. This c-tail survives only for a short time before being degraded after which more full-length FGF23 can bind to the receptor and resume signaling, leading to the kidneys excreting phosphate in the urine.
Researchers have synthesized an FGF23 c-tail fusion protein that can be retained in the body for a longer duration without being degraded, therefore inhibiting FGF23 signaling for longer. The administration of this FGF23 c-tail fusion protein in mouse models of XLH for over seven weeks showed improvements in bone formation and elevated levels of phosphate in the blood.
NVP-BGJ398 is a molecule that blocks one of the receptors for the FGF23 protein called FGFR23. A preclinical study in mouse models of XLH showed that long-term NVP-BGJ398 treatment prevents FGF23 from binding to this receptor and carrying out its function. This increases blood phosphate and calcium levels, and enhances bone mineralization and growth.
Last updated: Dec. 9, 2019
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