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The Role of the Pharmacist in Managing Patients With X-Linked Hypophosphatemia

INTRODUCTION

Disorders of calcium and phosphorus are encountered in a wide variety of clinical situations across the lifespan. One of these, hypophosphatemia, is observed in 2% to 5% of hospitalized patients and is very common among those with alcohol use disorders.1

A rare genetic condition, X-linked hypophosphatemia (XLH), is considered the prototypic disorder of renal phosphate wasting. In patients with XLH the body’s stores are not conserved by the kidneys in patients with this disorder. Traditionally managed with vitamin D and supplements of calcium and phosphate, research into the pathophysiologic causes of XLH is yielding more specific treatments that promise to improve bone physiology and prevent sequelae in those with this condition.2

In this program, the underlying functions of phosphate, genetic causes and pathophysiology of XLH, presentation and symptoms of XLH, and current and emerging approaches to clinical management of XLH are reviewed.

CALCIUM, PHOSPHORUS, AND VITAMIN D PHYSIOLOGY

In the human body, calcium and phosphorus homeostasis is affected by many different hormonal, nutritional, and physiologic factors that regulate intestinal absorption, influx and efflux from bone, and kidney excretion and reabsorption. While a common constituent of the body and the major intracellular anion, phosphorus is also covalently bound in organic phosphate esters in genetic material and metabolic enzymes. A small amount of intracellular inorganic phosphate is involved in a critical function throughout the body — regeneration of the storage molecule for energy, adenosine triphosphate (ATP).3,4

The limited amount of inorganic phosphate available in the extracellular space is also important in a wide variety of normal body functions. Extracellular inorganic phosphate (which is measured when serum phosphorus levels are assayed) is the primary determinant of intracellular phosphate; it is involved in metabolic regulation, hydrogen ion shifts, and balance among vitamin D, serum calcium, and levels of the hormones calcitonin, cortisol, and parathyroid hormone. As depicted in Figure 1, serum phosphorus levels can affect and be affected by bone, kidney, and intestine activity.2,4

Figure 1. Interplay among intracellular and extracellular phosphorus stores of the body.
figure 1

Phosphorus is consumed by most people as part of the normal diet of dairy products, meat, and vegetables. Serum phosphorus concentrations can vary by 2 mg/dL throughout the day based on carbohydrate intake, insulin secretion, and diurnal variation. The traditional model of gastrointestinal absorption of phosphorus has emphasized the actions of vitamin D and parathyroid hormone (PTH) for increases in mineral absorption, but passive absorption also occurs.3,5

Phosphorus and phosphate are excreted renally. Following glomerular filtration, 85% to 90% of the ions are normally reabsorbed in the proximal renal tubule by passive transport coupled to the positive sodium ion. Reabsorption is inhibited by PTH and the active form of vitamin D3, 1,25-dihydroxyvitamin D3 (calcitriol); growth hormone, insulin, and insulin-like growth factor 1 increase phosphate reabsorption in the renal tubule. As shown in Figure 2, phosphate transport is regulated by fibroblast growth factor 23 (FGF23); its action depends on a cofactor, transmembrane protein klotho.3,4,6


figure 2
Figure 2. Hormonal and organ influences on phosphate metabolism and defects present in X-linked hypophosphatemia.
Source: Adapted from figure online at http://www.ultragenyx.com/pipeline/krn23-xlh.

HYPOPHOSPHATEMIA

Normal serum phosphorus levels vary according to age. Hypophosphatemia is defined as serum phosphorus concentrations less than 4 mg/dL in children younger than 12; the normal range gradually decreases during adolescence, and the lower end of the normal range in adults is 2.5 mg/dL. The condition is generally asymptomatic until levels reach about 1 mg/dL in adults. Hypophosphatemia can be acute or chronic. When hypophosphatemia is severe, symptoms result from reduced levels of 2,3-diphosphoglycerate in erythrocytes and intracellular ATP levels in virtually all organ systems. The neurologic system is particularly affected, with symptoms of irritability, apprehension, weakness, numbness, paresthesia, and confusion. If not corrected, severe hypophosphatemia can lead to seizures or coma. Given the role of phosphates in bone modeling, osteomalacia and osteopenia are other potential outcomes of deficiency states.4

X-linked hypophosphatemia

XLH is a rare genetic disorder with an estimated incidence of 1 in every 20,000 live births. It has been referred to as vitamin D–resistant rickets in the past. The X-linked dominant mutation occurs in the phosphate regulating endopeptidase homolog, X-linked (PHEX) gene (Xp22.1). It most often presents in children between 6 months and 2 years of age as lower-extremity bowing, short stature, and over time, joint pain and impaired mobility. Because the mutation is dominant (one mutant gene is sufficient to produce the condition), it can occur in females as well as males. Girls born to a father with the condition are certain to have XLH, since the hemizygous father would by definition transmit a defective, dominant gene.7

As a genetic disorder, XLH is sometimes diagnosed before phenotypic expression through specialized testing in individuals who have family members with the disease. Children can also present initially with dental abscesses. Since these are not caused by dental caries, the teeth may have a normal external appearance. In adults with the disease, hearing impairment and arthritis are common as a result of bone abnormalities.2,8,9

PATHOPHYSIOLOGY

In XLH, loss-of-function mutations on the gene that codes for PHEX results in overproduction of FGF23 by the osteocyte/osteoblast. This peptide hormone regulates circulating phosphate levels by reducing renal tubular phosphate reabsorption and inhibiting renal vitamin D production. Elevated FGF23 results in excess phosphate excretion from the kidney as well as decreased synthesis of 1,25-dihydroxyvitamin D3, which reduces active phosphate absorption in the gastrointestinal tract (Figure 2).9

Conditions that may acutely exacerbate the phosphate wasting seen in patients with XLH include prematurity, malignancy, diseases of organs associated with vitamin D and calcium metabolism such as kidney disease or liver and biliary tract disease, and rarely malabsorption syndromes in conditions such as celiac disease or cystic fibrosis.10 Medications such as loop diuretics, corticosteroids, anticonvulsants (phenytoin), and antacids that contain aluminum (due to the binding of aluminum to phosphates) may also exacerbate XLH signs and symptoms.

Without effective treatment, chronic hypophosphatemia in patients with XLH can lead to rickets and osteomalacia, stunted growth, persistent short stature (adult height of 4 feet or less), lower-limb deformity, pain, and physical dysfunction that can limit daily activities. Patients sometimes need corrective surgery for severe bowing or tibial torsion unlikely to be corrected by medical management. To prevent problems in the mouth, patients need to adhere to a rigorous oral hygiene regimen and regular schedule of professional check-ups.2,7,9

Case study 1: Pediatrics XLH presentation

MJ is a 19-month-old, 10.7-kg female toddler, coming in for her 18-month immunizations at her pediatrician’s office. Her mother complains that MJ has not wanted or tried to stand or walk unlike her two older brothers, and when she does try, she falls over immediately, not able to stand for more than a few seconds. She also notes that MJ’s legs seem to bend and arch out at the knees. MJ was born full term and delivered vaginally, without any medical concerns otherwise. Her diet is normal for her age with formula and solid foods. Her vaccinations are up to date, including influenza last year. All other developmental milestones are within normal range including speech, vision, hearing, and cognition. MJ’s weight, height, and head circumference measured at the 30th, 5th, and 30th percentiles, respectively.

Musculoskeletal examination is notable for bowing of the legs, and X-ray imaging shows the bone structure depicted in Figure 3. Pertinent laboratory findings include serum calcium within normal limits, serum phosphorus 2.8 mg/dL (reference range provided by the laboratory, 3.8–6.5 mg/dL), elevated serum alkaline phosphatase (ALP), and decreased tubular reabsorption of phosphate (TRP) corrected for glomerular filtration rate (TRP/GFR) of 2.0 mg/dL (reference range 2.9–6.5 mg/dL).


figure 3
Figure 3. X-ray image of legs of young child with nutritional rickets
Image source: Open access. U.S. National Library of Medicine. 2010
(https://openi.nlm.nih.gov/detailedresult.php?img=PMC3005686_JCRPE-2-137-g6&req=4)

Clinical Presentation

Rickets, osteomalacia, and growth retardation occur as a result of XLH. XLH is the most common genetic cause of rickets and osteomalacia. The most prominent clinical feature of XLH is bowing deformities of the legs (Figure 4); however, the symptoms of XLH vary widely depending on the severity of the condition. Some people may present with bone-related symptoms such as bone pain and joint pain, while others may present only with hypophosphatemia.11 Because XLH is a rare disease and has a genetic etiology, it may not be diagnosed or suspected until other causes of hypophosphatemia (e.g., vitamin-dependent hypophosphatemia) are ruled out.

Typical symptoms of XLH include slowed growth rate in the first year of life, beginning to walk late or not walking beyond the reasonable age, bone pain, unstable gait, joint pain caused by calcification of tendons and ligaments (enthesopathy), stress fractures, muscle pain and weakness, dental abscesses and pain, abnormal dental development, and rickets despite supplemental treatment with vitamin D.2,11

Some patients may also present with pain flaring of wrists or ribs at the diaphragm, fractures, skull deformity, osteopenia, or scoliosis.10

Children with XLH typically present with bowed legs, medial tibial torsion (widened legs arching out on the knees), and short stature. The structural symptoms are noticeable within the first 1 to 2 years of life when a child starts to walk and bowing of the weight-bearing long bones become apparent. Due to this early-stage presentation of bone-related symptoms, XLH is often misdiagnosed as rickets of vitamin D deficiency.

Dental and periodontal defects are common in patients with XLH. Because of improper development of dentin, enamel, and pulp related to low phosphate levels, dental abscesses can occur due to spontaneous infection of the dental pulp tissue, without any trauma or decay. However, patients’ teeth look normal clinically, making the diagnosis and treatment of the abscesses complicated.12

Craniosynostosis may be present, manifested by signs of elevated intracranial pressure such as headaches, vomiting, papilledema, or bulging of the anterior fontanel.13 In adult patients, case reports of enthesopathy of vertebral ligaments, spinal cord compression and paraplegia, and spinal stenosis reflect the significant joint deformity and impaired mobility that can accompany this condition.11,14

Sensorineural hearing may be affected for some patients, but this typically presents during adulthood in treated patients.11,14 Patients may have mild-to-severe sensorineural hearing loss, which typically affects low and high frequency sounds. Some patients may complain of tinnitus and vertigo associated with low frequency hearing loss.12

Once a patient’s family history is taken (it is important to ask about parents or siblings with short stature and rickets), imaging of the knees needs to be performed to assess the initial bone structure and to rule out other causes for short stature such as skeletal dysplasias.7

To assess the possibility of a diagnosis of XLH, laboratory tests are needed, including serum calcium, phosphorus, PTH, and vitamin D assays. To confirm the diagnosis by demonstrating renal wasting of phosphate, a 2-hour fasting urine specimen with a midpoint blood sample is used to calculate the percentage of TRP and to determine the tubular threshold maximum for phosphate.2


figure 4
Figure 4. Changes in bone structure seen in patients with rickets or osteomalacia
Source: National Library of Medicine (US). Genetics Home Reference [Internet]. Bethesda (MD): The Library; 2018 Jun 12 [cited 2018 Jun 13]. Available from: https://ghr.nlm.nih.gov/condition/hereditary-hypophosphatemicrickets#synonyms.

Case study 2: Adult XLH presentation

BR is a 39-year-old woman who was diagnosed with vitamin D-resistant rickets after multiple attempts to correct the symptoms with vitamin D and phosphate supplements when she was younger. She is complaining of weakness of the lower extremities, pain in her knees and back, and hearing loss in the left ear. She is of short stature (3 feet 10 inches) and her gait is unstable mainly due to pain on walking. Her diet is within normal range and she denies any alcohol, tobacco, or illicit drug use. Her family history is significant for rickets as her father and her sister both were diagnosed with vitamin D-resistant rickets, at the ages of 5 and 2, respectively. She has not been genetically tested for XLH. She has been taking vitamin D and phosphate supplements but admits to not taking them regularly as they do not seem to help her pain.

Laboratory findings are within normal limits for serum calcium, serum phosphorus, PTH, growth hormone, and insulin-like growth factor-1 (IGF-1) concentrations. 25-OH vitamin D3 and 1,25-(OH)2-vitamin D3 levels are slightly below normal. Serum ALP is slightly elevated. TRP/GFR is 1.6 mg/dL (reference range 2.2–3.6 mg/dL).

TREATMENT

Therapeutic goals in patients with XLH vary by age at diagnosis, whether the epiphyseal plate has closed and growth is therefore complete, and the overall severity of the condition. Some patients with XLH are relatively unaffected and do not require treatment. For most of those diagnosed as children, effective therapies are critical in attaining a relatively normal height in adulthood and avoiding complications of the disease. In adults with XLH, treatment is directed at reducing pain symptoms and the extent of osteomalacia.2

The initial treatment for XLH focuses on maintaining adequate levels of phosphate and vitamin D. To achieve this goal, phosphate supplements and high-dose vitamin D have been the mainstay of therapy for XLH. Calcitriol increases calcium and phosphorus absorption and increases mineralization of the bone indirectly via increased calcium absorption in intestinal lumen.10 Treatment is typically initiated upon diagnosis, usually in early childhood, as this has been associated with better outcomes for XLH. Treatment should be continued through adolescence (when growth has stopped) in mild cases or through adulthood in most cases. However, treatment regimens with phosphate supplements are complicated by the need for multiple daily dosing and the use of various formulations. Additionally, these treatments do not address the underlying cause of reduced phosphate reabsorption, and their use is associated with treatment-limiting adverse effects such as hypercalcemia, elevated PTH, and nephrocalcinosis.7

Maintenance treatment has been shown to slow progression of bowing, promote growth, progressively correct leg deformities, facilitate tooth mineralization, and reduce the need for corrective surgery.7,12 It is important to treat patients with both phosphate and calcitriol because treatment with phosphate alone increases the risk for hyperparathyroidism. However, normalization of the serum phosphorus concentration is not a therapeutic goal for XLH because it frequently indicates overtreatment and increases the risk for treatment-related complications.11

A new monoclonal antibody, burosumab, targets elevated levels FGF23 and was recently approved for treatment of XLH of adult and pediatric patients 1 year of age or older. Clinical trials have demonstrated efficacy and safety in adults and children without complications of phosphate therapy.9

Children

Medical therapy

The goal of treatment is to decrease bone pain (response expected within a few weeks), normalize the serum ALP level in 6–12 months, increase in growth velocity in about 1 year, and straighten the legs in 3–4 years (1-cm decrease in intercondylian distance [between the medial and lateral condyle at the knee] or in intermalleolar distance [between the two malleoli at the two ankles], checked every 6 months).12 The treatment focuses on maintaining adequate levels of phosphate and vitamin D through supplementation with oral phosphate administered 3 to 5 times daily and high-dose calcitriol.

Oral phosphate salts: The dose for phosphate supplementation varies depending on the severity of the disease and developmental stage of the patient. In infants, the dose is 55–70 mg/kg per day divided in 3 to 5 doses. The starting dose for infants and children is typically 40 mg of elemental phosphorus/kg/day; in addition to dosing during the child’s waking hours, a nighttime dose is recommended to achieve satisfactory results.16 If there is no improvement in the growth within the first year of therapy, the dose can be titrated upward based on age, weight, and clinical condition. For adolescents in puberty, the dose is 35–50 mg/kg per day divided in 3 doses per day.2,12

Vitamin D: Calcitriol is the synthetic analog of the active form of vitamin D, 1,25-dihydroxyvitamin D3. The dose is 20–30 ng/kg/day administered in 2 to 3 divided doses to 50–70 ng/kg/day up to a maximum dose of 3 mcg daily with the phosphate.11 While effective in increasing the absorption of calcium and phosphorus, the use of calcitriol does not correct renal phosphate wasting in patients with XLH.15

Growth hormone (GH): GH has been used as adjunctive therapy for XLH in children in an effort to increase the growth rate. However, reports of the long-term outcome of using GH have not been consistent and include cases of increased serum ALP activity and worsening of leg deformities.2 There is no adequately controlled evidence to support its use to improve adult height in a typical population with XLH. Other limitations of GH are its cost and side effects.

Surgery

Corrective osteotomies are not routinely performed in children under 6 years of age because medical therapy typically manages bone deformities in this early developmental age group.2 For children whose diagnosis is delayed or whose initial treatment is not successful, osteotomy can be considered to align severely distorted legs. In prepubertal children who have not yet completed their full growth velocity, surgical therapy can be considered using the least invasive option. However, it is associated with potential for prematurely stopping growth.2,11 Newer and less invasive approaches include epiphysiodesis, which induces corrective differential growth of the growth plate.2

Dental care

Rigorous dental hygiene is a mainstay of management, including brushing 2 to 3 times daily and having regular dental hygienist visits. Sealant application to the enamel of the teeth may be performed if deemed necessary. Periodic dental procedures may also be necessary for spontaneous abscesses that may occur in children.

Other interventions

Craniosynostosis (abnormal fusion of the skull) secondary to hypophosphatemic rickets is the most common metabolic cause of congenital craniosynostosis. It can present with increased intracranial pressure, headache, or papilledema. When craniosynostosis is suspected, the patient should be screened and referred to a craniofacial specialist for further evaluation.13

Adults

Medical therapy

Patients who initiated therapy at the time of a pediatric diagnosis of XLH often need to continue treatment in adulthood. Patients sometimes exhibit a lack of adherence to therapy in adulthood because the effects of XLH are not as prominent in adulthood as they were in developmental stages. As such, adult patients may not realize the therapeutic benefits of treatment.12 However, the pathophysiology of phosphate wasting persists chronically in their lifetime, and patients can still benefit from treatment. In contrast, asymptomatic patients may not benefit from continued therapy, but may experience complications from the therapy. Thus, in adulthood, treatment should be preferentially considered for patients with symptoms.2,12,16

As in children, the first-line agents for XLH in adults are phosphate supplements and calcitriol.2 The goal of treatment should focus on resolving symptoms such as pain, decreasing the extent of osteomalacia, and improving compromised function and mobility.2,16 Of note, enthesopathy leading to spinal cord compression and pain (e.g., paraspinal enthesopathy and spinal ligament calcification) does not improve with treatment. Treatment may be stopped with resolution of the symptoms and restarted if symptoms recur. Since symptom resolution is the therapeutic goal for adult patients, treatment should be discontinued if symptoms do not improve within 1 year.2

As discussed further in the Newer Treatments section, adult patients have benefited from therapy with burosumab. Its place in therapy in adults with XLH who fail phosphate/calcitriol treatment is not yet clear.

Calcitriol: When treatment is being started or restarted, calcitriol is given about 1 week before phosphate supplementation begins. This decreases the risk of exacerbating pre-existing secondary hyperparathyroidism, or inducing the condition when calcitriol increases the serum concentration of phosphate while causing a further depletion of serum calcium (see Complications of treatment).

During this initial week before phosphate therapy, calcitriol is given at a dose of 0.5–0.75 mcg/day in 2 divided doses for patients with normal calcium levels and normal or only mildly elevated serum PTH.2

Oral phosphate salts: For patients with normal calcium levels and normal or mildly elevated serum PTH, daily elemental phosphorus 250 mg should be started after 1 week of treatment with calcitriol. The dose should be titrated every 4 days to 750–1,000 mg of elemental phosphorus.2

Cinacalcet: In patients with hyperparathyroidism (i.e., overactive parathyroid gland in response to low serum calcium level), particularly those with rising serum PTH and ALP levels, the calcimimetic agent cinacalcet is used to normalize the serum PTH level. The initial dose is 30 mg at bedtime with increases to a maximum dose of 60 mg at bedtime. However, outcomes have varied; some patients have had refractory hyperparathyroidism.2

Pregnant women: There are currently no evidence-based recommendations on the use of phosphate and calcitriol in pregnant women with XLH. However, if a woman with XLH is on an active maintenance therapy at the time of conception, she should be continued on treatment through the pregnancy with careful monitoring of urinary calcium-to-creatinine ratios to monitor hypercalciuria for any needed changes to the therapy.11,16

Surgery

Some patients continue to experience persistent lower-limb bowing and torsions despite medical treatment and may require surgical treatment. In older children of postpubertal age or adults, surgical procedures may include joint replacement surgery, especially of the knee or hip. A total hip and knee arthroplasty may be required for some patients because of degenerative joint disease and enthesopathy. Patients should begin phosphate and calcitriol supplementation 3 to 6 months before the surgical procedure and continue it for 6 to 9 months after.2

Dental care

Patients with XLH are susceptible to recurrent dental diseases and abscesses; these can result in numerous root canals and tooth extractions, leading to premature loss of permanent teeth. Consistent and thorough oral hygiene with flossing and regular dental care including fluoride treatments is necessary to prevent dental problems. Pit and fissure sealants have been recommended without a good amount of evidence, and no specific therapy has been demonstrated to prevent dental complications.2,12

Sensorineural hearing

Patients with complaints of hearing loss, tinnitus, or vertigo should be referred to a specialist for hearing tests as well as for management options. These may include hearing aid, vibrotactile devices, and cochlear implantation.11

Complications of treatment

The major complications from long-term treatment with phosphate and calcitriol supplementation include gastrointestinal side effects and risk of metabolic and endocrine abnormalities such as hypercalcemia, hypercalciuria, nephrolithiasis, nephrocalcinosis, hyperparathyroidism, and possibly chronic kidney disease.2 Among these, the two most important complications of XLH are nephrocalcinosis and hyperparathyroidism.16

When phosphate is used unopposed or if the patient’s serum concentration is relatively high, it can increase the risk for hyperparathyroidism. Conversely, calcitriol can increase the risk for hypercalcemia, hypercalciuria (urinary calcium concentration >4 mg/kg/day or calcium/creatinine ratio >0.7 in the first year of life or above 0.3 after 1 year), and nephrocalcinosis if used unopposed or the patient’s serum concentration is high.2,11,17

Hyperparathyroidism may occur at any time in the course of XLH, primarily because of PTH stimulation from high doses of phosphorus (>50 mg/kg/day). This secondary hyperparathyroidism, if it persists for a long period of time, can damage normal parathyroid function and potentially result in tertiary hyperparathyroidism.17 Tertiary hyperparathyroidism is not very common but is a significant health risk for intense bone resorption, nephrocalcinosis, and renal insufficiency. Contributory factors to the progression of tertiary hyperparathyroidism include early age of initial treatment, duration of treatment, high doses of elemental phosphorus, and very high PTH levels (~400 pg/mL).17

Nephrocalcinosis is diagnosed based on renal ultrasonography and is present in up to 80% of patients with XLH.16 Nephrocalcinosis can develop from an excessive calcitriol dose or from nonadherence with oral phosphate supplementation. Thus, careful surveillance of serum and urine calcium is necessary to minimize nephrocalcinosis, and the dose of calcitriol should be reduced when hypercalcemia or hypercalciuria occur.17 Alternatively, administration of thiazide diuretics with or without amiloride can arrest the progression of nephrocalcinosis.16

Monitoring and dose adjustments

For patients on phosphate and calcitriol therapy, the following monitoring is recommended2,11,17:

  • Quarterly monitoring of serum concentrations of phosphate, calcium, creatinine, ALP, and intact PTH. Doses of phosphate and calcitriol should be adjusted based on (1) evidence of therapeutic success including reduction in serum ALP activity, changes in musculoskeletal examination, improvement in radiographic rachitic changes, and improved growth velocity; and (2) evidence of therapeutic complications including hyperparathyroidism, hypercalciuria, and nephrocalcinosis. For adults whose conditions are stable during long periods of treatment, monitoring can be done every 6 to 9 months.
    • If phosphorus supplementation causes diarrhea that is not tolerable, the dose of phosphorus should be decreased by 250 to 500 mg and then gradually titrated in steps of 125 mg. ALP is useful in assessing skeletal healing and should decrease with treatment. If slow growth and elevated ALP persist, the phosphorus dose might not be adequate or an issue of nonadherence may be present.
    • Normophosphatemia may indicate overtreatment in some patients and may result in secondary hyperparathyroidism.
    • Hypercalcemia or hypercalciuria may indicate a need to decrease the calcitriol dose.
    • PTH levels are measured to assess hyperparathyroidism secondary to treatment. PTH levels should decrease if the calcitriol dose is increased or phosphate dose is decreased.
    • Alterations in biochemical values are surrogate endpoints and may not predict skeletal response.
  • Quarterly monitoring of urinary calcium, phosphate, and creatinine for evidence of hyperparathyroidism, increased renal phosphate or calcium excretion, and signs of chronic kidney disease.
  • Annual X-ray imaging of the lower extremities to assess skeletal response to treatment
    • In children, decreased bowing and increased bone growth should be noted.
  • Semiannual or annual renal ultrasound to assess for nephrocalcinosis
  • Dental follow-up twice a year at minimum
  • Patient counseling to avoid medications that may exacerbate or worsen rickets (e.g., antacids)

NEWER TREATMENTS

After many years of treatment of XLH with phosphate and calcitriol, novel approaches to treating XLH have been developed within the past several years and some are currently in clinical trials. At the time this program was prepared (summer 2018), the Clinicaltrials.gov registry listed 27 active, completed, or future studies on XLH in the United States and abroad, including 19 that focused on pediatric patients. A majority of these approaches target the underlying pathophysiology with FGF23 antibodies to neutralize the effects of the increased FGF23 in XLH. Other approaches involving the FGF23 antibodies include inhibiting downstream FGF23 signaling or competing with FGF23 receptors.12

One of the most actively studied monoclonal FGF23 antibodies is KRN23 (burosumab), a recombinant agent that targets FGF23. Currently, 13 clinical trials are registered in Japan, South Korea, and the United States. Clinical trials investigating burosumab began in 2008, and the agent has been approved for use in both pediatric and adult patients in the European Union and the United States, where it was designated an orphan drug in 2014 and 2009, respectively. Three phase 2 and three phase 3 clinical trials have been completed to date, and two phase 2 trials are ongoing for treatment of patients with tumor-induced osteomalacia and epidermal nevus syndrome.

The relative place in therapy of this new drug is not yet clear. Since it is a more specific treatment for the underlying defect, burosumab could emerge as a preferred agent as clinical experience accumulates for its use in pediatric and adult patients with XLH. An important question to be addressed is whether early treatment can change the clinical course of this lifelong condition.

Resources for Pharmacists: Pharmacists should be aware of and if appropriate, counsel patients and caregivers that this product has a patient assistance program to assist with insurance coverage and financial support of patients with XLH.

Evidence to date

Burosumab-twza (Crysvita) is a fully human recombinant immunoglobulin G1 monoclonal antibody that targets FGF23. It is approved in the United States for treatment of XLH in adults and children 1 year of age or older. It binds to and inhibits the biological activity of FGF23, thereby restoring renal phosphate reabsorption and increasing serum concentration of 1,25-dihydroxyvitamin D3. Burosumab should not be used (1) in conjunction with oral phosphate and vitamin D supplementation, (2) if serum phosphorus is within or above the normal range for age, or (3) in patients with severe renal impairment or end-stage renal disease.18

Children

Two phase 2 clinical trials investigated the efficacy and safety of burosumab in pediatric patients.9,18 In a randomized, open-label, dose-defining phase 2 trial, 52 prepubescent XLH patients of 5–12 years of age received either burosumab or placebo subcutaneously every 2 or 4 weeks up to a maximum dose of 2 mg/kg for at least 64 weeks. The mean serum phosphorus level significantly increased from 2.4 ± 0.4 mg/dL to 3.3 ± 0.4 and 3.4 ± 0.45 mg/dL at week 40 and week 64, respectively. The mean TRP/GFR increased significantly from 2.2 ± 0.49 mg/dL to 3.3 ± 0.6 and 3.4 ± 0.53 mg/dL at week 40 and week 64, respectively. The mean serum ALP significantly decreased from 462 ± 110 U/L to 354 ± 73 U/L at week 64 (23% decrease). Radiographic evaluation revealed significant improvements in mean Rickets Severity Score (RSS) and Radiographic Global Impression of Change (RGI-C); lower RSS indicates improvements in rickets and a change of RGI-C score of +2.0 reflects bone healing. Of 26 patients receiving burosumab every 2 weeks, 18 achieved an RGI-C score of +2.0 or more at week 40 and maintained the scores above 2.0 at week 64. The mean height Z score improved from –1.72 ± 1.03 at baseline to –1.54 ± 1.13 at week 64. Adverse effects included injection site reaction, headache, cough, nasopharyngitis, and pain in an arm or leg. One patient was hospitalized for fever and myalgia, which were moderate in severity and possibly related to burosumab, one patient had severe rash, and one had a tooth abscess.9

The second study was an open-label, 64-week trial of 13 children ages 1–4 years. All of the children received burosumab at a dose of 0.8 mg/kg every 2 weeks titrated of up to 1.2 mg/kg based on serum phosphorus measurements for at least 40 weeks of therapy. The mean serum phosphorus level significantly increased from 2.5 ± 0.28 mg/dL to 3.5 ± 0.49 at week 40. The mean serum ALP concentration decreased from 549 ± 194 U/L to 335 ± 88 U/L at week 40 (36% decrease). Radiographic evaluation revealed significant improvements in mean RSS (from 2.9 to 1.2) and mean RGI-C (+2.3 ± 0.08). All 13 patients achieved an RGI-C score of +2.0 or more. Adverse effects occurring in more than 3 participants in this small trial were pyrexia and vomiting.18

Adults

In a dose-escalation, dose-extension, open-label study of 28 adult patients with XLH, patients were given increasing doses of burosumab every 4 weeks for a total of 4 doses and continued to receive phosphate-titrated doses once monthly for 12 months. Most patients had relatively stable doses after the eighth dose of burosumab; 80% of them were on either 0.6 or 1 mg/kg. The main study outcomes were serum phosphorus level and safety. From a total of 28 patients with a mean age of 41.9 years (range, 19 to 66), 26 received four doses and 19 received all 16 doses over the study. During dose escalation, TRP/GFR, serum phosphorus, and 1,25-dihydroxyvitamin D3 levels increased, peaking at 7 days for TRP/GFR and serum phosphorus, and at 3–7 days for 1,25-dihydroxyvitamin D3.19

After each of four escalating doses, peak serum phosphorus levels were between 2.5 and 4.5 mg/dL in 14.8%, 37.0%, 74.1%, and 88.5% of participants, respectively. During the 12-month extension, peak serum phosphorus was in the normal range for 57.9%–85.0% of participants, and 25% maintained trough serum phosphorus levels within the normal range. Mean serum and urinary calcium remained within normal limits. Transient hypercalcemia (calcium >10.5 mg/dL) occurred in 2 patients and hypercalciuria occurred in 5 patients. The urinary phosphate level varied widely among the patients. Adverse events included arthralgia, nasopharyngitis, back pain, extremity pain, diarrhea, sinusitis, upper respiratory infection, dizziness, headache, injection site reaction, and restless leg syndrome.19

In a randomized, double-blind, placebo-controlled study of 134 adults with XLH, patients received burosumab 1 mg/kg every 4 weeks for 24 weeks.18 All patients had skeletal pain associated with XLH/osteomalacia at baseline, the mean age of patients was 40 years (range 19 to 66 years), and 35% of participants were men. Oral phosphate and calcitriol treatment was not allowed during the study. Compared with placebo group, significantly more patients from the burosumab group achieved serum phosphorus levels above the lower limit of normal (8% vs. 94%). The mean TRP/GFR improved significantly in the burosumab group compared with placebo at week (from 1.68 vs. 1.60 to 2.21 vs. 1.73, respectively). Radiographic evaluation of osteomalacia and active fracture/pseudofracture sites revealed that burosumab group demonstrated a higher rate of complete healing vs. placebo group at week 24. Additionally, a total of 6 new fractures or pseudofractures appeared in 68 patients with burosumab compared with 8 in 66 patients in the placebo group. While burosumab therapy was associated with a significant improvement in stiffness compared with placebo at 24 weeks, there was no significant difference in pain between the two groups.20

A 48-week, open-label, single-arm study in 14 patients with XLH assessed the effects of burosumab on improvement of osteomalacia. Patients received 1 mg/kg injection of burosumab every 4 weeks and other treatments were not permitted during the study. At baseline, the mean age of patients was 40 years (range 25 to 52 years) and 43% were men. After 48 weeks of treatment, osteomalacia was improved in 10 patients, with a decrease of 57% in osteoid volume/bone volume. Osteroid thickness declined in 11 patients from a mean of 17 ± 4.1 micrometers to 12 ± 3.1 micrometers (–33% change). Mineralization lag time also declined in 6 patients from a mean of 594 ± 675 days to 156 ± 77 days (– 74%).18

Dosage and adverse events

For children, the starting dose of burosumab is 0.8 mg/kg rounded to the nearest 10 mg, administered subcutaneously every 2 weeks. The minimum starting dose is 10 mg up to a maximum dose of 90 mg. Doses may be titrated based on periodic monitoring up to about 2 mg/kg or the maximum dose to achieve normal serum phosphorus level. For adults, the dose is 1 mg/kg rounded to the nearest 10 mg, administered subcutaneously every 4 weeks.18

About 25% of pediatric patients experienced adverse effects of headache, injection site reaction, vomiting, pyrexia, pain in extremity, or decreased vitamin D levels. About 5% of adult patients reported back pain, headache, tooth infection, restless leg syndrome, decreased vitamin D level, dizziness, constipation, and increased phosphorus levels.18

Case studies 1 and 2 (continued)

Case 1. MJ can begin therapy with oral phosphate salts and calcitriol to increase the serum phosphorus level and decrease ALP and bone damage. With a weight of 10.7 kg, she can be prescribed 40 mg of elemental phosphorus per kg per day in 4 divided doses and given with calcitriol 20 ng/kg twice daily. On this regimen, monitoring is needed as follows:

  • Serum concentrations of phosphorus, calcium, creatinine, ALP, and intact PTH should be measured after 4–6 weeks of therapy to assess and adjust the doses if necessary. Hypercalcemia or hypercalciuria may be a sign to decrease the calcitriol dose. PTH levels are measured to assess hyperparathyroidism secondary to treatment and should decrease if the calcitriol dose is increased or phosphate dose is decreased.
  • Once stabilized, therapy can be monitored quarterly monitoring based on urinary calcium, phosphate, and creatinine for evidence of hyperparathyroidism and increased renal phosphate or calcium excretion.
  • Annual X-ray imaging of the lower extremity to assess skeletal response to treatment decreasing bowing should be noted.
  • Monitor growth and height velocity.
  • Semiannual or annual renal ultrasound should be conducted to check for nephrocalcinosis.
  • Dental examinations are recommended twice a year at a minimum.

If no improvement is seen with the replacement therapy or if it is not tolerated, MJ can be considered for treatment with burosumab, at an initial dose of 10 mg administered subcutaneously every 2 weeks (0.8 mg/kg, rounded to the nearest 10 mg). Supplemental vitamin D and phosphorus products should be discontinued during burosumab therapy. The burosumab dose can be increased up to about 2 mg/kg to the maximum dose to achieve an adequate serum phosphorus level based on monitoring every 4 to 6 weeks during titration. Once stable, MJ should be monitored quarterly for serum levels of phosphate, calcium, creatinine, ALP, and intact PTH as well as radiographic evaluation to assess response to the treatment.

Case 2. Given BR’s family history and unsuccessful vitamin D supplementation therapy, XLH is suspected. While testing may be necessary for infants and children to begin early treatment for optimal outcomes, it may not be necessary for adult patients who are stable with corrective therapy. However, confirmatory tests, if indicated for XLH-specific treatment, can be done via molecular genetic testing to determine if the PHEX variant is present.

BR should stay on the supplemental therapy with oral phosphorus and calcitriol to maintain homeostasis, unless otherwise determined based on laboratory findings. Since she is normocalcemic and her PTH is within normal limits, she can continue on calcitriol 0.5–0.75 mcg/day administered in two divided doses and 250 mg/day of elemental phosphorus after 1 week of calcitriol treatment. Serum concentrations of phosphate, calcium, creatinine, ALP, and intact PTH should be measured quarterly and the dose adjusted as needed. Other monitoring includes semiannual or annual renal ultrasound examination to check for nephrocalcinosis.

If no improvement is seen with the replacement therapy or if it is not tolerated, BR can be considered for treatment with burosumab, at an initial dose of 1 mg/kg rounded to the nearest 10 mg, administered subcutaneously every 4 weeks. Supplemental vitamin D and phosphorus products should be discontinued during burosumab therapy.

She may also need to be referred to an orthopedic specialist for further consultation to determine if her joint and bone conditions are worsening and assess causes of her back pain as well as to an otolaryngologist for her hearing problem.

CONCLUSION

Medication regimens used to manage XLH are complex but can play an important role in the lives of patients. Those on standard therapies need assistance with organizing multiple daily doses and maintaining a positive attitude about the disease and its characteristic aches and pains. Newer therapies are injectable agents given every 2 or 4 weeks, presenting a new set of challenges to patients and reinforcing the need for medication therapy monitoring and management.

Resources for Pharmacists: Information about XLH for patients and health professionals is available online at the XLH Network and XLH Link.

References

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