The pediatric XLH clinic nurse’s communication challenge
X-linked hypophosphatemia is the most common inherited phosphate-wasting disorder in the United States, affecting approximately 1 in 20,000 people. It is caused by loss-of-function mutations in the PHEX gene on the X chromosome. PHEX encodes an endopeptidase expressed in osteocytes — the mature bone cells embedded within the mineralized bone matrix — that plays a critical role in regulating FGF23, the phosphatonin hormone that signals the kidney to excrete phosphate. When PHEX is lost, osteocytes produce excess intact FGF23, which chronically suppresses renal phosphate reabsorption and inappropriately reduces calcitriol synthesis, producing the combination of hypophosphatemia and inadequate active vitamin D that drives rickets, impaired linear growth, wrist and ankle widening, leg bowing, bone pain, and dental abscesses.
The communication challenge in the pediatric XLH clinic is not complexity alone — it is a conceptual mismatch between what families know about bone disease and what XLH actually is. Most Spanish-speaking families who receive a pediatric rickets diagnosis bring a model inherited from their communities: raquitismo is caused by insufficient vitamin D, insufficient calcium, or insufficient sun exposure. It is a deficiency disease. Deficiency diseases are corrected by replacing the missing substance, and when the substance is replaced and the bones heal, the treatment can stop. This model accurately describes nutritional vitamin D deficiency rickets, which remains common in many Latin American communities. It is a poor fit for XLH, and when families apply it, they produce three distinct adherence errors that are the most common reasons for preventable disease progression, iatrogenic nephrocalcinosis, and lost peak bone mineral accrual in the pediatric XLH clinic.
The first error is stopping calcitriol and phosphate when symptoms resolve — applying the “deficiency corrected, treatment complete” model to a condition caused by a genetic mutation that does not correct. The second error is substituting calcium supplements for prescribed calcitriol and phosphate — applying the calcium-deficiency model of rickets to a phosphate-deficiency disease with normal serum calcium, producing nephrocalcinosis by loading the kidney with calcium while phosphaturia continues. The third error is stopping biological therapy when imaging shows apparent disease resolution — misinterpreting the pharmacodynamic marker of therapeutic success (normal growth plates on burosumab) as evidence of genetic remission that does not exist.
Three conversations from the pediatric XLH clinic:
Scenario 1: Marco Ibáñez-Torres — 7 years old, Houston, Texas
Marco Ibáñez-Torres had been born in Houston to parents who had emigrated from the state of Jalisco five years before his birth. His father, Ernesto Ibáñez-Espinoza, was a licensed plumber who had built a stable life in the city’s construction sector. His mother had no known family history of bone disease. Marco had been a healthy infant until his pediatrician noticed genu varum — bilateral bowing of the legs — at the 15-month well-child visit. The degree of bowing was greater than expected for normal physiological genu varum of early childhood, and the bowing was accompanied by widening of the wrists visible on physical examination. His pediatrician ordered laboratory evaluation and a wrist X-ray. The results were striking: serum phosphate 1.8 mg/dL (reference range 3.5–6.5 mg/dL for his age), calcitriol (1,25-dihydroxyvitamin D3) 16 pg/mL (inappropriately low despite hypophosphatemia, which should stimulate calcitriol synthesis), 25-hydroxyvitamin D 31 ng/mL (normal), calcium 9.8 mg/dL (normal), PTH 38 pg/mL (normal), alkaline phosphatase 890 IU/L (markedly elevated, reflecting increased osteoblast activity in an unsuccessfully mineralizing skeleton). The tubular maximum phosphate reabsorption per GFR (TmP/GFR) was 1.1 mg/dL — markedly below the normal lower limit of approximately 3.5 mg/dL, confirming renal phosphate wasting. The wrist X-ray showed classic rachitic changes: widened, frayed, cupped metaphyses bilaterally.
Marco was referred to the pediatric metabolic bone disease clinic at Texas Children’s Hospital. Genetic testing confirmed a hemizygous PHEX mutation: c.1645C>T, producing p.Arg549*, a premature stop codon that eliminates the endopeptidase catalytic domain entirely. His mother was tested and found to be heterozygous for the same mutation; she had mild short stature (height 153 cm) and a history of recurrent dental abscesses throughout her twenties that she had attributed to poor dental care, which were now recognized as the dental manifestation of her undiagnosed XLH. The diagnosis was X-linked hypophosphatemia.
Marco was started on calcitriol 15 nanograms per kilogram per day divided into two doses and neutral phosphate solution 30 milligrams per kilogram per day divided into four doses given with meals and snacks. The clinic nurse, Rosa Herrera-Espinoza, spent forty minutes with Ernesto and Marco’s mother at the first education visit. She explained the medication schedule, the monitoring plan (serum phosphate, calcitriol, calcium, PTH, urine calcium-to-creatinine ratio every three months; renal ultrasound every six months; wrist X-ray every six months), and the expectation of gradual improvement over one to two years. She emphasized that the treatment was for long-term management, not for short-term relief.
Over the next two years, Marco responded well to treatment. His serum phosphate rose to 2.8 mg/dL — not fully normalized, because the FGF23 excess continued to produce some ongoing phosphaturia, but substantially improved from 1.8 mg/dL. His alkaline phosphatase fell to 420 IU/L. The Thacher rickets severity score on wrist and knee X-rays improved from 3.0 at diagnosis to 1.0 at age three. His leg bowing was visibly reduced, though not completely corrected. His bone pain, which Ernesto had described as Marco crying when he stood up from naps and refusing to walk on harder floors, resolved completely by six months after starting treatment. By age four, Marco was running with his classmates at preschool, playing soccer in the backyard, and showing none of the acute distress that had accompanied his early steps.
Ernesto watched Marco’s transformation and made the inference that any thoughtful parent would make: the treatment had worked. Marco was well. The medications — which required refrigeration, careful timing with meals, and four daily phosphate doses that Marco increasingly resisted — had done their job. At age five and a half, after a week of particular difficulty getting Marco to take the phosphate doses in the afternoon, Ernesto decided to trial stopping the medications to see if Marco remained well. He planned to restart them if problems appeared. He did not call the clinic. He expected the bone clinic’s six-month follow-up to confirm that Marco no longer needed treatment.
The six-month follow-up was the next clinic appointment. Ernesto did not mention that he had stopped the medications fourteen months earlier. He mentioned it only when Rosa asked to review the current medication bottles for adherence assessment, and Ernesto acknowledged that the bottles had been returned to the pharmacy, unopened, eight months ago. The lab results from that visit told the story: serum phosphate 1.7 mg/dL. Alkaline phosphatase 680 IU/L. Wrist and knee X-rays: Thacher rickets severity score 2.3 — worse than the prior visit score of 1.0, and approaching the score at initial diagnosis. Bilateral wrist widening had recurred. Marco had not complained of bone pain, and Ernesto had interpreted the absence of pain as confirmation that stopping the medications had been safe.
Rosa Garcia-Espinoza sat down with Ernesto and explained what had happened, beginning with the genetic architecture of XLH. She drew a diagram of a bone cell — an osteocyte — embedded in the mineralized bone matrix, surrounded by the canalicular network through which it communicates with the bone surface. She explained that PHEX is a gene expressed in these osteocytes and that it regulates FGF23, a hormone the osteocyte produces and secretes into the bloodstream. In a person without XLH, PHEX function keeps FGF23 at appropriate levels. When PHEX is mutated and non-functional — as in Marco’s hemizygous PHEX c.1645C>T, which produces a truncated protein lacking the catalytic domain entirely — the osteocyte cannot regulate its FGF23 production properly. It produces too much intact FGF23.
FGF23, she continued, travels through the bloodstream to the kidney, where it binds a receptor complex on the apical surface of proximal tubule cells. The receptor complex is FGFR1c in association with the transmembrane protein Klotho. When FGF23 activates this FGFR1c-Klotho complex, the signal inside the proximal tubule cell downregulates two sodium-phosphate cotransporters — NaPi-IIa and NaPi-IIc — that are responsible for reabsorbing filtered phosphate from the tubular lumen back into the bloodstream. When these transporters are downregulated, phosphate that the glomerulus has filtered from the blood passes into the urine rather than being recovered. This is phosphaturia — renal phosphate wasting. In a healthy kidney, approximately 85 percent of filtered phosphate is reabsorbed; in Marco’s kidney, FGF23 excess reduces reabsorption substantially, driving serum phosphate to 1.7–1.8 mg/dL chronically.
FGF23 also, she explained, inhibits the renal enzyme 1-alpha hydroxylase — the enzyme that converts 25-hydroxyvitamin D to calcitriol, the active form. This is why Marco’s calcitriol was 16 pg/mL at diagnosis despite normal vitamin D stores: his osteocytes were telling his kidney to suppress calcitriol synthesis at the same time they were telling it to waste phosphate. This dual suppression — phosphaturia plus calcitriol suppression — is what makes XLH harder to correct than nutritional rickets, where supplementing vitamin D restores both calcitriol and intestinal phosphate absorption. In XLH, the kidney actively resists the body’s attempts to maintain phosphate homeostasis because of the FGF23 signal it receives continuously from every osteocyte in the skeleton.
Now Rosa came to the key point. She placed her hand on the diagram and said: this mutation — the c.1645C>T in Marco’s PHEX gene — is in every osteocyte in Marco’s body. It was there when Marco was born. It will be there for the rest of Marco’s life. There is no treatment today that corrects this genetic mutation. Every new osteocyte that forms as Marco’s bones remodel and grow has the same mutation. Every one of those osteocytes produces excess FGF23. The FGF23 excess does not diminish when the medication is working — it is being overcome by the medication. When Marco’s bone pain went away two years ago, that was the calcitriol providing enough active vitamin D to improve intestinal phosphate absorption and the phosphate supplements replacing enough of the wasted phosphate to support bone mineralization well enough to stop the periosteal microfractures that cause the pain. The mutation did not change. The FGF23 production did not decrease. The phosphaturia did not resolve. The medication was overriding the disease, not curing it.
When Ernesto stopped the medications eighteen months ago, the phosphaturia continued at full force, because the FGF23 excess continued, because the PHEX mutation continued. Serum phosphate fell from 2.8 back toward 1.7–1.8. The growth plates of Marco’s wrists and knees, still actively growing at age five and six, were again insufficiently mineralized. The growth plate changes on today’s X-ray were the evidence. Marco had not had bone pain because the rickets severity, while worsening on imaging, had not yet returned to the level that was producing symptomatic microfractures. But the X-ray could not lie: the Thacher score had more than doubled from 1.0 to 2.3. Fourteen months of preventable disease progression had occurred because of a reasonable but incorrect inference.
Rosa gave Ernesto a frame he used for his own work: “Es como el agua filtrada. La bomba de filtro saca el contaminante del agua mientras está funcionando. Si apagas la bomba porque el agua se ve limpia, el contaminante vuelve — no porque haya llegado de afuera, sino porque estaba ahí todo el tiempo y el filtro era lo que lo estaba quitando. La XLH de Marco es igual: el medicamento es el filtro. La mutación es la fuente del problema que nunca desaparece. Cuando paramos el filtro, el problema regresa de inmediato.” (It is like filtered water. The filter pump removes the contaminant from the water while it is running. If you turn off the pump because the water looks clean, the contaminant returns — not because it came from outside, but because it was there all along and the filter was what was removing it. Marco’s XLH is the same: the medication is the filter. The mutation is the source of the problem that never goes away. When we stop the filter, the problem returns immediately.) Ernesto understood. He had not known. He did now. Marco’s calcitriol and phosphate were restarted at the same doses.
Scenario 2: Daniela Vásquez-Morales — 5 years old, San Antonio, Texas
Daniela Vásquez-Morales had been diagnosed with XLH at age three after her mother, Sonia Vásquez-Torres, noticed that Daniela’s legs were bowing inward when she walked and that she waddled in a way that Daniela’s pediatrician described as “not typical for a toddler at this age.” Laboratory workup confirmed the diagnosis: serum phosphate 2.0 mg/dL, calcitriol 19 pg/mL, calcium 10.1 mg/dL (normal), PTH 32 pg/mL (normal), TmP/GFR 1.3 mg/dL. PHEX sequencing found a splice-site mutation at intron 9 (c.1215+1G>A). The mutation had been inherited from Sonia, who was heterozygous and had been evaluated for the first time at age thirty-four; her manifestations were limited to short stature (154 cm) and two prior dental abscesses attributed to “bad teeth,” both of which now had an explanation. Daniela’s XLH was more severe than her mother’s, as is common in females with unfavorable X-inactivation patterns.
Daniela was started on calcitriol and phosphate supplementation at the UT Health San Antonio pediatric metabolic bone disease clinic. The clinic nurse, Elena Fuentes-Cisneros, conducted the initial education session and provided Sonia with written instructions in Spanish, including the four-times-daily phosphate dosing schedule, the importance of giving calcitriol with food, the monitoring plan, and a detailed explanation of why the treatment was long-term management of a genetic condition, not short-term treatment of a correctable deficiency.
Sonia received this education attentively, but she brought to the appointment a framework for bone disease that she had developed over many years watching her mother-in-law manage osteoporosis in Mexico and her own mother manage a neighbor’s child with rickets when she was a child in Oaxaca. Her model of rickets was: bone disease caused by insufficient calcium and vitamin D, treated with vitamin D and calcium until the bones healed. Calcitriol — the active form of vitamin D — was in her mental model the key vitamin D for bone health. She associated “active vitamin D for bone health” with “calcium deficiency needs calcium.” The prescription phosphate supplements were expensive and required authorization from the insurance company every ninety days, which twice resulted in brief gaps in supply. When Daniela was four years old, Sonia read an article in a Spanish-language health magazine about bone health in children that emphasized calcium and vitamin D for strong bones. She researched calcitriol and found that it was used for “bone disease and calcium deficiency.” She concluded that the most direct treatment was calcium. She purchased calcium carbonate 500 mg chewable tablets at the pharmacy, giving Daniela one tablet twice daily. She did not restart the prescription calcitriol or phosphate when the last prescription ran out three months later, concluding that the over-the-counter calcium was providing equivalent or better bone nutrition.
At the six-month follow-up visit, Elena Fuentes-Cisneros noticed that Daniela’s laboratory results were unusual. Serum phosphate was still 2.0 mg/dL — no improvement from her last on-treatment value, but also not worse. Serum calcium was 10.6 mg/dL — at the upper end of normal. PTH was 14 pg/mL — low normal, suppressed. The urine calcium-to-creatinine ratio was 0.38 (elevated; normal <0.25 in this age group). The finding that required immediate discussion: the renal ultrasound, performed as part of routine XLH monitoring, showed bilateral medullary nephrocalcinosis — echogenic deposits in the renal medullary pyramids bilaterally, consistent with calcium phosphate crystal deposition in the collecting tubule epithelium and medullary interstitium. When Elena asked Sonia to describe the current medication regimen, Sonia produced the calcium carbonate bottle from her bag and explained her reasoning.
Elena understood immediately what had happened. She began the explanation with the distinction that mattered most: the difference between the two types of rickets.
Nutritional rickets — raquitismo nutricional, the disease Sonia associated with the word raquitismo — begins with vitamin D deficiency. Without adequate vitamin D, the intestine cannot absorb calcium or phosphate properly from food. Serum calcium falls. The parathyroid glands detect the low serum calcium and secrete PTH to compensate: PTH mobilizes calcium from bone, stimulates the kidney to retain calcium in the urine, and stimulates 1-alpha hydroxylase to make more calcitriol from available vitamin D stores. This secondary hyperparathyroidism with low serum calcium is the signature of nutritional rickets. The bones soften because both calcium and phosphate are insufficient. Treatment: give vitamin D to restore intestinal calcium and phosphate absorption, and give calcium to replenish the calcium deficit that the years of inadequate absorption have produced. The disease is a deficiency disease — the substance causing the deficiency (vitamin D) is corrected, the downstream deficiencies (low calcium, low phosphate) are corrected, the bones remineralize, the disease resolves.
Daniela’s XLH, Elena continued, had a different mechanism at every step. Daniela’s serum calcium had been 10.1 mg/dL at diagnosis — completely normal. Her PTH had been 32 pg/mL — normal. Her 25-hydroxyvitamin D had been 34 ng/mL — normal. The parathyroid gland had not needed to compensate for any calcium deficiency, because there was no calcium deficiency. The bone disease was caused exclusively by phosphate insufficiency, and that phosphate insufficiency was caused exclusively by the kidneys wasting phosphate in the urine because of the FGF23 excess from the PHEX mutation. Sonia’s daughter did not lack calcium. She lacked phosphate, and she lacked it for a genetic reason that produced it continuously and unconditionally.
Calcitriol in XLH, Elena explained, was not given because Daniela lacked calcium or vitamin D. It was given for two XLH-specific reasons. First, FGF23 suppresses the kidney’s 1-alpha hydroxylase enzyme, so calcitriol synthesis is inappropriately low for the degree of hypophosphatemia; directly supplementing calcitriol bypasses this block and ensures Daniela has adequate active vitamin D to support bone mineralization. Second, calcitriol upregulates NaPi-IIb — a sodium-phosphate cotransporter in the intestinal brush border — increasing intestinal phosphate absorption. By improving intestinal phosphate uptake, calcitriol partially compensates for the phosphate the kidneys are wasting. The phosphate supplements directly replace the phosphate the kidneys cannot retain. Together, the two medications work to raise serum phosphate toward the range needed for growth plate mineralization. Neither medication addresses the PHEX mutation or the FGF23 excess. They are managing the downstream consequences of the genetic defect, and they are doing so specifically for phosphate, not for calcium.
When Sonia gave Daniela calcium carbonate twice daily instead, Elena continued, several things happened in sequence. Daniela’s calcium intake increased substantially beyond her need. Her serum calcium rose to 10.6 mg/dL. Her parathyroid gland detected the elevated serum calcium and appropriately suppressed PTH, bringing it from 32 to 14 pg/mL. PTH is one of the stimuli for renal 1-alpha hydroxylase activity — it promotes calcitriol synthesis. With PTH now further suppressed, the endogenous calcitriol synthesis — already being suppressed by FGF23 — was reduced further by the removal of the PTH stimulus. Intestinal phosphate absorption, which calcitriol supports, decreased. The serum phosphate, receiving no benefit from calcitriol and no direct phosphate supplementation, remained at 2.0 mg/dL.
Meanwhile, the elevated calcium load was being filtered by Daniela’s kidneys. Urinary calcium excretion rose, producing the elevated urine calcium-to-creatinine ratio of 0.38. In the collecting tubule, Daniela’s urine contained high calcium and low phosphate simultaneously — the low phosphate because FGF23-driven phosphaturia was continuing unopposed without phosphate supplementation. In the alkaline environment of the medullary collecting duct, the ion activity product of calcium and phosphate can reach the solubility threshold for calcium phosphate. When it does, calcium phosphate precipitates in the tubular epithelium and medullary interstitium. Over months, these deposits accumulate. This was the medullary nephrocalcinosis visible on ultrasound: echogenic deposits in the medullary pyramids bilaterally, caused by three months of high-calcium supplementation to a child whose kidneys were simultaneously wasting phosphate and receiving an excess calcium load.
Elena used a clear metaphor: “Es como si un tuño de agua tuviera un agujero por donde sale el agua, y en vez de tapar el agujero, usted estuviera echando más agua por el otro lado. El agua que echa se va igual por el agujero, y el exceso que no cabe crea pétrea dentro del tuño. La XLH tiene un agujero de fósforo en los riñones. El tratamiento es tapar el agujero con el fosfato y el calcitriol que ayuda a absorber más fósforo del intestino. El calcio extra no tapa el agujero de fósforo — entra por un lado y sale por el otro, y el exceso en el riñón puede formar cálculos.” (It is like a water pipe that has a hole through which water escapes, and instead of plugging the hole, you are pouring more water in from the other side. The water you pour escapes through the same hole, and the excess that does not fit creates deposits inside the pipe. XLH has a phosphate hole in the kidneys. The treatment is to plug the hole with phosphate and with calcitriol that helps absorb more phosphate from the intestine. Extra calcium does not plug the phosphate hole — it comes in one side and goes out the other, and the excess in the kidney can form stones.)
Sonia’s face showed the recognition that comes when a model that seemed reasonable is shown to be wrong. She had not known that Daniela’s rickets was phosphate-deficiency rickets. She had not known that Daniela’s calcium was normal. She had not known that calcium supplements could cause kidney damage in a child whose kidneys were already wasting phosphate. The nephrocalcinosis was still early and likely to be stable or improve with proper treatment restored. Calcitriol and phosphate were restarted. Calcium carbonate was stopped. Renal ultrasound follow-up was scheduled at three months.
Scenario 3: Alejandro García-Cruz — 9 years old, Dallas, Texas
Alejandro García-Cruz had been one of the most severely affected XLH patients followed at the Children’s Medical Center Dallas pediatric endocrinology and metabolic bone disease program. He had been diagnosed at 18 months with a PHEX mutation c.877G>A causing p.Asp293Asn — a missense variant in the zinc-binding catalytic domain of the PHEX protein that abrogates enzymatic function — and had been started immediately on calcitriol and phosphate supplementation. Despite good compliance with the conventional regimen through age four, his rickets severity remained substantial: wrist and knee X-rays at age four showed a Thacher rickets severity score of 3.5 (moderate to severe), bilateral leg bowing was visible and worsening, and his growth velocity had fallen to the 5th percentile for age despite the standard doses of calcitriol and phosphate. Laboratory values on therapy showed serum phosphate of 2.2 mg/dL — better than untreated but still significantly below normal — and TmP/GFR of 1.6 mg/dL, indicating persistent renal phosphate wasting.
His care team discussed the options and recommended transitioning to burosumab, the anti-FGF23 monoclonal antibody approved by the FDA in 2018 for XLH in pediatric patients. Alejandro’s mother, Gabriela García-Torres — a bilingual school secretary at an elementary school in the Dallas Independent School District — was thoughtful and engaged in Alejandro’s care. She had managed the complicated conventional regimen diligently for three years. She consented to burosumab after a thorough informed consent discussion that included the mechanism of action, the injection schedule (subcutaneous every two weeks), the monitoring plan, the cost (approximately $20,000 per month, covered by insurance with prior authorization), and the expected response timeline.
Alejandro’s response to burosumab was dramatic. Within three months of starting: serum phosphate 3.4 mg/dL (approaching normal for the first time in his life). TmP/GFR 3.8 mg/dL (normalized, indicating burosumab had successfully inhibited FGF23-driven proximal tubule phosphate wasting). Calcitriol 48 pg/mL (appropriate now that FGF23 inhibition removed the 1-alpha hydroxylase suppression). Alkaline phosphatase 380 IU/L, declining. At one year: serum phosphate 3.8 mg/dL. TmP/GFR 4.2 mg/dL. Thacher rickets severity score 0.8 — from 3.5 at treatment start, a near-complete radiographic resolution of rickets. Alejandro’s leg bowing was visually corrected: he walked normally, ran normally, kept up with his fourth-grade class in physical education. Gabriela had photographed his legs at treatment start and at one year. She showed the before and after images to everyone who asked about his treatment, because the visible difference was remarkable — from measurably bowed legs to straight ones, in twelve months.
At the October 2026 follow-up visit, Gabriela presented the radiology report from the bilateral knee X-rays taken two weeks earlier. The report read: “Growth plates appear within normal limits for stated age. No significant rickets changes observed. Bilateral lower extremity alignment within normal range.” Gabriela had read the report carefully. She had also received the prior authorization renewal paperwork for burosumab for the coming year, which required a full business day of phone calls and documentation to complete. The cost of the medication, while covered by insurance, required annual reauthorization that she found exhausting. She looked at Alejandro’s straight legs, looked at the X-ray report, and made the assessment that any reasonable parent would make: the bones are normal. The treatment has worked. Perhaps it is time to stop.
She did not stop at that visit. She discussed it with the care team, who referred her to the metabolic bone clinic nurse, Carmen Vásquez-Morales, for an education session. Gabriela presented her reasoning clearly: the X-ray says normal. The legs are straight. Alejandro has no pain. The medication is twenty thousand dollars a month and requires prior authorization every year. What is the evidence that continuing is necessary when the disease appears to be resolved?
Carmen acknowledged the reasoning and its internal consistency. She then explained burosumab’s mechanism in terms she had found resonated with families who had asked this question before.
Burosumab is a monoclonal antibody — a molecule designed in the laboratory to bind specifically to one target. Its target is FGF23, the hormone that Alejandro’s osteocytes produce in excess because of the PHEX mutation. Burosumab binds to FGF23 at its N-terminal domain — the region of the FGF23 molecule that interacts with the FGFR1c receptor. When burosumab is bound to FGF23, FGF23 cannot activate FGFR1c-Klotho. The kidneys do not receive the signal to downregulate NaPi-IIa and NaPi-IIc. The cotransporters remain expressed at normal levels. Phosphate is reabsorbed normally. Serum phosphate normalizes. Growth plate mineralization proceeds. Legs straighten. X-ray shows normal growth plates.
All of this — the normal serum phosphate, the normal X-ray, the straight legs — is the burosumab working. It is not the PHEX mutation resolving. The PHEX mutation is in every osteocyte in Alejandro’s body. It was there at birth. It will be there when Alejandro is forty. Every new osteocyte that forms as Alejandro’s bones remodel — osteoblasts that differentiate into osteocytes as new bone matrix is produced — has the same PHEX c.877G>A mutation. Every osteocyte produces excess FGF23. The FGF23 production has not diminished because of the burosumab; it is being continuously produced. What burosumab is doing is binding that FGF23 in the circulation before it can reach the kidney. As long as burosumab plasma concentration is above the level needed to bind the circulating FGF23, the kidney does not see it. The kidney functions normally. The bones mineralize normally. The moment burosumab plasma concentration falls below that threshold, free FGF23 reaches the kidney and the phosphaturia resumes.
Carmen explained the pharmacokinetics. Burosumab’s plasma half-life is approximately 21 days. With injections every two weeks, the maintenance dose replenishes the antibody faster than it is cleared, keeping plasma concentrations consistently above the therapeutic threshold. When injections stop, no new antibody is added. The existing antibody in Alejandro’s bloodstream is cleared at the rate determined by its half-life: approximately half is gone at three weeks, three-quarters at six weeks, seven-eighths at nine weeks. As the antibody concentration falls, free FGF23 — still being produced continuously by osteocytes — accumulates in the circulation. When free FGF23 reaches sufficient concentration to activate FGFR1c-Klotho, NaPi-IIa and NaPi-IIc begin to be downregulated. Phosphate reabsorption falls. Serum phosphate begins to drop, typically detectable at four to six weeks after the last injection.
Carmen had specific data for Alejandro’s situation. To demonstrate what would happen if burosumab were stopped, the team had checked his serum phosphate and TmP/GFR six weeks after a prior missed injection period when prior authorization had lapsed for three weeks. At that six-week post-authorization-lapse check: serum phosphate 2.3 mg/dL. TmP/GFR 1.9 mg/dL. In six weeks, his serum phosphate had fallen from 3.8 toward the 2.3 range. Not to his pre-treatment baseline of 2.2 — but measurably declining toward it. Three weeks of prior authorization lapse had been enough to allow FGF23 to reassert its effect on the proximal tubule.
The additional issue, Carmen continued, was the growth window. Alejandro was nine years old. He had roughly five to seven more years of active skeletal growth before his growth plates closed and his long bone longitudinal growth ended. The bone mineral accumulated during this window contributed substantially to his lifetime peak bone mass — the maximum bone density and bone strength he would achieve, typically in the late teens to early twenties. XLH patients who had inadequate phosphate control during childhood and adolescence consistently showed lower peak bone mass in adulthood, higher rates of stress fractures, earlier onset of enthesopathy (calcification of tendons and ligaments that produces joint pain and stiffness in adulthood), and more severe osteomalacia in adult bone biopsies compared to patients with sustained phosphate normalization throughout childhood. Stopping burosumab at age nine because the current X-ray looked normal would sacrifice the six remaining years of the peak bone mineral accrual window that were the point of starting burosumab in the first place.
Gabriela listened carefully. She asked the question Carmen had been asked before: “If I stop and the labs start to decline, can I just restart?” Carmen’s answer was honest. Yes, burosumab can be restarted. But every month of subtherapeutic serum phosphate during Alejandro’s childhood growth is a month of inadequate mineralization at the growth plate that cannot be recaptured. The prior authorization process typically takes three to four weeks. During that period, and during the weeks it takes for burosumab plasma concentration to rebuild after restart, Alejandro’s growth plates are not mineralizing optimally. The strategy of stopping and restarting in response to lab decline also meant monitoring labs every six weeks to detect the decline — additional blood draws, additional clinical burden. The administrative burden of annual prior authorization, while genuinely frustrating, was the mechanism that kept Alejandro’s growth plates normal on X-ray and his legs straight.
Gabriela asked Carmen to write out the explanation she had just given in a way she could share with her husband, who had not been at the visit. Carmen wrote two paragraphs in Spanish and gave her the paper. “La radiografía normal,” the note began, “es la prueba de que el burosumab está funcionando. No es la prueba de que la XLH de Alejandro se curó. Cuando paramos el burosumab, el FGF23 que el medicamento estaba atrapando queda libre en la sangre de Alejandro en dos a cuatro semanas — porque los huesos de Alejandro nunca dejaron de producirlo. Para cuando la próxima radiografía empiece a mostrar cambios, los huesos ya llevan meses deteróndose por dentro.” (The normal X-ray is proof that burosumab is working. It is not proof that Alejandro’s XLH was cured. When we stop burosumab, the FGF23 that the medication was trapping becomes free in Alejandro’s blood within two to four weeks — because Alejandro’s bones never stopped producing it. By the time the next X-ray starts to show changes, the bones have already been deteriorating for months from the inside.) Gabriela folded the paper and placed it in her wallet next to Alejandro’s insurance card. She completed the prior authorization paperwork the following Tuesday.
Key Spanish phrases for the pediatric XLH clinic
For the conversation about permanent genetic disease requiring lifelong treatment: “La XLH es causada por una mutación genética permanente — no por una deficiencia que se puede corregir. El medicamento controla los efectos de la mutación, pero no la cura. Parar el medicamento cuando los síntomas mejoran es como apagar el filtro de agua porque el agua se ve limpia — el contaminante estaba ahí todo el tiempo y el filtro era lo que lo estaba quitando.” (XLH is caused by a permanent genetic mutation — not by a deficiency that can be corrected. The medication controls the effects of the mutation but does not cure it. Stopping the medication when symptoms improve is like turning off the water filter because the water looks clean — the contaminant was there all along and the filter was what was removing it.)
For the conversation about phosphate supplements four times daily: “El fosfato se da cuatro veces al día porque los riñones lo botan en horas — no porque sea una vitamina que se acumula. Si se da dos veces al día, hay muchas horas en que el fósforo en la sangre está muy bajo y los huesos no pueden mineralizarse bien.” (Phosphate is given four times a day because the kidneys waste it within hours — not because it is a vitamin that accumulates. If given twice a day, there are many hours when phosphorus in the blood is very low and the bones cannot mineralize well.)
For the conversation distinguishing XLH from nutritional rickets: “El raquitismo de Daniela no es por falta de calcio ni de vitamina D — el calcio de Daniela está normal. Es por falta de fósforo que los riñones botan en la orina. El calcio extra no arregla el fósforo y puede formar cálculos en los riñones.” (Daniela’s rickets is not from lack of calcium or vitamin D — Daniela’s calcium is normal. It is from lack of phosphorus that the kidneys waste in the urine. Extra calcium does not fix the phosphorus and can form stones in the kidneys.)
For the conversation about burosumab continuation after X-ray normalization: “La radiografía normal es la prueba de que el burosumab está funcionando — no de que la XLH se curó. La mutación de Alejandro sigue ahí y sigue produciendo el problema. El medicamento atrapa ese problema en la sangre antes de que llegue a los riñones. Cuando paramos, en dos a cuatro semanas el problema llega a los riñones de nuevo.” (The normal X-ray is proof that burosumab is working — not that XLH was cured. Alejandro’s mutation is still there and still producing the problem. The medication traps that problem in the blood before it reaches the kidneys. When we stop, within two to four weeks the problem reaches the kidneys again.)
For nephrocalcinosis monitoring education: “Como parte del seguimiento de la XLH, hacemos ultrasonido de los riñones cada seis meses para ver si hay pequeños depósitos de calcio en los riñones. Esto puede pasarle a algunos niños con XLH incluso con el tratamiento correcto. Es por eso que también revisamos la orina regularmente — si hay demasiado calcio en la orina, ajustamos el calcitriol para proteger los riñones.” (As part of XLH follow-up, we do a kidney ultrasound every six months to check for small calcium deposits in the kidneys. This can happen in some children with XLH even with correct treatment. That is why we also regularly check the urine — if there is too much calcium in the urine, we adjust the calcitriol to protect the kidneys.)