Burosumab treatment for fibroblast growth factor-23-associated hypophosphatemia in an adult patient with severe fibrous dysplasia in McCune–Albright syndrome: case report and review of the literature

Abstract

McCune–Albright syndrome (MAS) is a rare mosaic genetic disorder caused by a mutation in the GNAS gene and typically presents with a triad of symptoms: fibrous dysplasia of bones, café-au-lait macules, and precocious puberty. The GNAS mutation leads to overproduction of fibroblast growth factor-23 (FGF23), which may result in hypophosphatemia. Burosumab, a monoclonal antibody against FGF23, is approved for the treatment X-linked hypophosphatemia and tumor-induced osteomalacia. There are currently no data on its efficacy and safety in fibrous dysplasia/MAS patients. A 27-yr-old male with MAS was under the care of the Endocrinology Department for persistent hypophosphatemia and skeletal complications despite treatment with oral phosphate supplements and calcitriol. He started treatment with burosumab (1 mg/kg s.c. every 4 wk) and achieved normalization of calcium–phosphate metabolism (phosphate 0.83 mmol/L vs 0.38 mmol/L; PTH 70.4 pg/mL vs 177 pg/mL) and significant reduction in alkaline phosphatase activity (ALP 620 IU/L vs 1182 IU/L) and bone fraction of alkaline phosphatase activity (BALP 327 IU/L vs 603 IU/L). No further fractures were observed during 24 mo of treatment. The patient reported a reduction in bone pain and improved well-being. No adverse effects were reported during treatment. This is the first reported case of burosumab treatment in an adult patient with fibrous dysplasia/MAS. The therapy had positive effects on the patient’s well-being, calcium–phosphate balance, and bone markers. However, longer follow-up and further safety studies are needed before routine use in adult fibrous dysplasia/MAS patients.

Introduction

McCune–Albright syndrome (MAS) is a rare mosaic genetic disorder affecting 1/100 000 to 1/1 000 000 of the global population.¹ It is caused by a somatic gain-of-function mutation in the GNAS gene, located on chromosome 20q13.3, resulting in mosaic activation of the G protein alpha subunit.² The disorder, as first described in 1936, presents with a triad of symptoms: fibrous dysplasia of bones, café-au-lait macules, and precocious puberty.³ Adding to this triad are multiple endocrinopathies characterized by hyperactivity.⁴ Since the mutation occurs post-zygotically, MAS typically follows a mosaic pattern, meaning different tissues may be affected to varying degrees. It also means that different patients can have widely varying phenotypes based on which tissues and organs are affected by the GNAS mutation. The spectrum of clinical manifestations can range from mild, localized symptoms to severe, multi-organ involvement.

In fibrous dysplasia, the GNAS mutation leads to the overproduction of fibroblast growth factor-23 (FGF23), causing hypophosphatemia, which contributes further to bone abnormalities. The degree of FGF23 overproduction is correlated with the burden of affected bone. The ensuing hypophosphatemia, due to renal phosphate wasting, can result in fragility fractures, pain, increased propensity for skeletal deformities, and muscle weakness.

Burosumab, a monoclonal antibody that targets FGF23, has been used primarily as a therapy for X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO).⁵

To date, only 4 cases of children with MAS have been reported to have been treated with burosumab.^6–9 A phase 2 clinical trial of burosumab treatment in fibrous dysplasia is currently underway (NCT05509595). We present the first case of an adult male with MAS who was treated with burosumab, leading to normophosphatemia and clinical improvement safely over a 2-yr period.

Case presentation

A 27-yr-old male with MAS, characterized by growth hormone (GH) excess and hypophosphatemia was treated with oral phosphate and calcitriol without success. He suffered multiple fractures and experienced muscle weakness and pain. The diagnosis of MAS was established at the age of 6 yr due to fibrous dysplasia manifesting as increased head circumference, deformities of the lower limbs, scoliosis, and café-au-lait spots. Hypophosphatemia was first diagnosed at the age of 8 yr and oral phosphate supplementation was introduced a year later. The patient’s medical history included precocious puberty at the age of 8 yr, which resulted in short stature. Bilateral calcium oxalate nephrolithiasis and nephrocalcinosis were experienced at the age of 9 yr. Fibrous dysplasia resulted in skeletal deformities and multiple fragility fractures of the lower and upper extremities requiring surgical correction (Figure 1A-G). Scoliosis required surgical correction. Muscle weakness and bone pain combined for poor quality of life. Low BMD, multiple fractures, and skeletal pain led to treatment with bisphosphonates, first alendronate and then zoledronic acid at the age of 22. One year later, he was treated with denosumab 60 mg s.c. every 6 mo. The antiresorptive therapies did not ameliorate the bone pain, and he experienced further pathological fractures of both humeri. Also at age 22, GH excess was diagnosed based on elevated fasting serum GH = 11.8 μg/L and insulin-like growth factor 1 (IGF-1) level = 356 μg/L (upper limit of normal, ULN = 304 μg/L) and lack of GH suppression on oral glucose tolerance test (OGTT) with nadir GH = 7.9 μg/L. He did not have classic acromegalic features. The patient had also mild hyperprolactinemia (PRL = 18 μg/L). MRI revealed no pituitary lesions, but showed massive thickening of the bones of the skull vault and base with involvement of the paranasal sinuses and temporal pyramids (Figure 1F). Considering the overall clinical picture, which included craniofacial expansion of fibrous dysplasia (Figure 1A) and autonomous GH secretion, the patient was started on a first-generation somatostatin receptor ligand (SRL), lanreotide autogel, at a dose of 120 mg every 4 wk) was started. After 6 mo, GH and IGF-1 levels remained elevated. He was transitioned from the first generation SRL to pasireotide 40 mg every 4 wk i.m. Serum GH concentration fell to 3.8 μg/L, and the serum IGF-1 level normalized (IGF-1 = 259 μg/L) after 3 mo. Pasireotide treatment was continued. However, the patient did not observe any reduction in bone pain and or an increase in muscle strength. The patient was also on L-thyroxine replacement for the primary hypothyroidism. Ultrasound revealed a nodular goiter. He had positive family history for Hashimoto’s disease.

Figure 1.

(A) A 27-yr-old male with McCune–Albright syndrome presenting with increased head circumference, craniofacial fibrous dysplasia, and café-au-lait spot on his left cheek. (B) X-ray of both forearm bones and all metacarpal bones—deformed shafts and epiphysis, numerous cystic changes in the distal parts of the shafts of the forearm bones, in the wrist and metacarpal bones. (C) Chest X-ray: significant deformation and asymmetry resulting from significant right-sided scoliosis of the thoracic spine stabilized with 2 rods, screws, and metal loops. Significant deformation of all ribs with segmentally changed bone structure. Significant deformation and bone remodeling in the proximal humerus, clavicles widened with altered bone structure. (D) Chest CT: deformation and asymmetry of the chest with severe thoracic spine scoliosis and deformed and widened ribs bilaterally. Mediastinum rotated and displaced. The lung parenchyma in the paravertebral parts with segmentally worse aeration, due to compression. (E) Severe skeletal deformities, right-sided scoliosis, scars from surgical corrections, café-au-lait macules on patient’s back. (F) Head MRI—T1-weighted gadolinium enhanced scan: severe fibrous dysplasia of the bones of skull vault and base and moderately heterogeneously enhanced pituitary gland (12 × 20 × 3 mm) located in a shallowed wide Sella, without focal lesions with medially positioned pituitary stalk. (G) Pelvic X-ray: significant deformation of the lumbar-sacral spine with 2 metal rods and double screws, pelvis and proximal sections of both femurs with metal stabilization of both hip joints. Abnormal bone structure in the heads of both femurs and in the distended and deformed trochanters and proximal parts of the shafts.

No signs of gynecomastia or proliferative changes in the testes (volume of left testicle 15.3 mL, right testicle 15.6 mL) were found on ultrasound examination. The bilateral nephrolithiasis and nephrocalcinosis required lithotrypsy, but normal renal function was maintained. In addition, an abdominal MRI detected dilatation of secondary pancreatic ducts and intraductal papillary mucinous neoplasms scattered throughout the pancreatic parenchyma, with the biggest lesion in the body of the pancreas measuring 24 × 14 mm. These lesions did not progress over several years. The patient denied any gastrointestinal discomfort.

Physical examination revealed short stature (height 158 cm), increased head circumference, multiple bone deformities, scoliosis, low muscle mass, scars from previous orthopedic surgery, and café-au-lait skin hyperpigmentation with the Maine coastline shape (Figure 1A and G). The patient ambulated with the assistance of crutches.

Hypophosphatemia was presented from the time of diagnosis at the age of 8 yr. Neither spontaneous resolution of hypophosphatemia with age nor regression of hypophosphatemia with oral phosphate supplementation and active vitamin D metabolites was observed. The patient reported occasional gastrointestinal symptoms associated with oral phosphate therapy. Over the years, biochemical control of calcium and phosphate metabolism was not achieved despite conventional treatment of hypophosphatemia. As a results, subsequent multiple fractures occurred. In addition, the patient reported persistent bone pain and decreased exercise tolerance.

Due to concerns about the potential impact of FGF23-associated (serum FGF23 = 495 kRU/L, normal range: 26-110 kRU/L) persistent hypophosphatemia (serum phosphate level 0.67 mmol/L, normal range: 0.81-1.45 mmol/L) on osteomalacia, as well as nephrolithiasis and potential hyperparathyroidism, a trial of burosumab (1 mg/kg body weight s.c. every 4 wk) was started. The patient had stopped taking oral phosphates and calcitriol 12 d prior to the first administration of burosumab. After stopping oral medication, the patient’s phosphate concentration fell to 0.38 mmol/L, and they reported an increase in bone and joint pain. Normalization of serum phosphate was achieved just after the first burosumab administration (serum phosphate 0.82 mmol/L vs 0.38 mmol/L) and a normal phosphate concentration was maintained during the 24-mo period of therapy (Figure 2). We also observed normalization of serum parathormone (PTH) (70.4 pg/mL vs 177 pg/mL), a substantial reduction in total alkaline phosphatase activity (ALP) (620 IU/L vs 1182 IU/L) and bone fraction of alkaline phosphatase (BALP) (327 IU/L vs 603 IU/L) (Figure 2). When the interval between drug injections was extended, a decrease in phosphate concentrations below the lower limit of normal was observed. Two weeks after burosumab administration, serum phosphate was in the upper limit of normal and an increase in 1,25(OH)₂D₃ was also noted (Figure 3). No additional calcium supplementation was needed for the patient, but an increase of vitamin D dose from 2000 to 4000 IU/d was required. During the 24-mo treatment period with burosumab, the patient reported improved general well-being, reduced bone pain as evidenced by an improvement in the Visual Analog Scale score from 7 to 4, and no new fractures. An increase in muscle strength was measured by grip strength dynamometer (Charder MG4800): the mean from three trials increasing from 37.8 kg in right hand and 37.5 kg in left hand to 42.2 kg and 41.1 kg, respectively. We also observed an increase in total BMD from 1.239 to 1.315 g/cm². No adverse effects, such as hyperphosphatemia or injection-site reactions, were reported during the 2-yr treatment period.

Figure 2.

Phosphate and parathormone concentrations and alkaline phosphatase activity before and after burosumab treatment for 2 yr.

Figure 3.

Phosphate and 1,25(OH)₂D₃ increase in concentration to the upper limit of normal 2 wk after each burosumab administration at a dose 1 mg/kg s.c. and decrease to the lower limit of normal 4 wk after injection.

Discussion

McCune–Albright syndrome remains a challenge for clinicians due, in part, to its variable diverse presentations. Pathogenic mutations in the GNAS gene result in loss of α-subunit GTPase activity, leading to inappropriate production of cAMP. The majority of mutations (>95%) occur at positions R201H and R201C.² McCune–Albright syndrome is a mosaic disease; it is not inherited; no genetic or environmental risk factors have been described.³ The extent and location of the tissue carrying the mutation determines the phenotype of MAS.

The diagnosis of MAS is often made on the basis of the clinical presentation, which includes fibrous dysplasia, café-au-lait skin pigmentation, precocious puberty, thyroid abnormalities, GH excess, and/or neonatal hypercortisolism.³ The diagnosis based on clinical presentation was established in our case at the age of 6 yr.

The most common manifestations of MAS include fibrous dysplasia. The presentation of patients with fibrous dysplasia/MAS is variable. It may involve a single site or multiple sites, and may result in additional skeletal manifestations such as fractures and deformities, including the skull.¹⁰ Undiagnosed excessive GH secretion in MAS additionally exacerbates fibrous dysplasia, especially in the craniofacial area, which can lead to macrocephaly, visual disturbances, and even vision and hearing loss.¹¹ Skeletal deformities and premature puberty can cause the lack of characteristic high growth despite GH excess. In our case, GH excess was diagnosed based on the lack of GH suppression on OGTT and elevated IGF-1 concentrations only at the age of 22. We may suspect that GH excess may have been present before, as the patient had macrocephaly and severe craniofacial fibrous dysplasia.

Fibroblast growth factor-23 is a hormone secreted by osteoblasts/osteocytes that regulates phosphate and vitamin D levels. There are active (intact, iFGF23) and inactive (C-terminal, cFGF23) forms.¹² One of the sites of action of FGF23 is proximal tubule cells, reducing renal inorganic phosphate reabsorption, which affects the regulation of blood phosphate levels by reducing the expression of phosphate transporter genes.¹³ By inhibiting the expression of renal proximal tubule hydroxylase 1-α, FGF23 also reduces levels of active vitamin D and the extent of intestinal phosphate absorption.¹³ Elevated levels of FGF23 are found in the phosphate wasting disorders, such as XLH,¹⁴ TIO,¹⁴ autosomal dominant and autosomal recessive hypophosphatemic rickets,¹⁵ and fibrous dysplasia.¹⁴

In fibrous dysplasia, the extent of FGF23 overproduction correlates with the severity of disease, with overt hypophosphatemia occurring only in patients with widespread skeletal involvement, leading to frequent fractures, pain, a higher risk of deformities, and muscle weakness. Our patient, with elevated levels of serum FGF23, had extensive fibrous dysplasia since early childhood resulting in bone deformities, increased head circumference, scoliosis, and multiple fractures of long bones requiring surgical intervention.

Conventional treatment of hypophosphatemia in fibrous dysplasia is based on therapeutic experience with XLH that consists of multiple daily doses of oral phosphate formulations and calcitriol. Despite this approach, some patients continue to experience pain and fractures that interfere with their daily functioning. This is similar to the patient in this report, who still experienced new fractures, pain, and hypophosphatemia. This conventional therapy does not target deficiencies in renal phosphate reabsorption and 1,25(OH)₂D₃ production.¹⁶ Side effects of oral phosphate supplements, such as gastrointestinal disorders, nephrocalcinosis, and hyperparathyroidism, further reduce compliance.³

Treatment of patients with fibrous dysplasia/MAS focuses on improving quality of life, reducing pain, and improving function by preventing bone fractures and deformities. Pharmacological treatment includes bisphosphonates or denosumab. However, experience with these approaches is limited. Nonpharmacological interventions include physiotherapy and orthopedic surgery.

Among the intravenous bisphosphonates, zoledronic acid, and pamidronate acid seem to be effective, increasing BMD and reducing bone resorption markers. Alendronate does not reduce bone pain, so it is not recommended in patients with fibrous dysplasia.¹⁷ Similar to published reports, our patient did not experience any subjective benefits with bisphosphonates. Denosumab is a human monoclonal antibody that blocks the activity of the RANKL. It reduces the activity of osteoclasts while allowing bone formation to proceed. However, a side effect of denosumab use in fibrous dysplasia/MAS patients may be hypocalcemia due to increased bone turnover and calcium demands, particularly in young patients and those with severe disease.¹⁸ Moreover, after discontinuation of denosumab, rebound of bone turnover markers and hypercalcemia is observed, particularly in those with a high disease burden.¹⁹ In our case, denosumab did not relieve bone pain, and new arm fractures occurred during the treatment. However, the dose used in our case was low, ie, 60 mg every 6 mo, compared to moderate or high regimens (120 mg every 4 wk) that are often used in fibrous dysplasia/MAS.

Burosumab is a human recombinant IgG1 monoclonal antibody that targets FGF23. By binding to FGF23, it inhibits its activity, resulting in increased renal tubular phosphate reabsorption and serum phosphate levels. It is indicated for the treatment of hypophosphatemic rickets caused by overproduction of FGF23 (XLH, TIO). Given the limitations of conventional therapy (gastroenterological complaints, nephrocalcinosis, etc.) in fibrous dysplasia/MAS, burosumab seems to be a logical next therapeutic step. To date, there is no evidence on the efficacy and safety of burosumab treatment in adults with fibrous dysplasia/MAS. This is, thus, the first report.

Considering the results of clinical trials, the dosage of burosumab in adults is 1 mg/kg every 4 wk, which was used in our patient.²⁰ The half-life of burosumab is estimated to be 13-19 d, while phosphate levels in adults remained within normal limits above the minimum level for up to 4 wk after subcutaneous injection of the drug.²¹ This was also observed in our reported case. When injections were given every 4 wk, the patient remained normophosphatemic but when the treatment interval was extended to 5 wk, phosphate levels decreased. The phosphate concentration 2 wk after burosumab injection was in the upper limit of normal range, and 4 wk after the injection, it was in the lower reference range. The phosphate levels remained normal during the 2 yr of therapy. Most important, during the 2-yr follow-up with burosumab, there were no new fractures, and the patient reported reduction in bone pain as evidenced by an improvement in the Visual Analog Scale score and increase in muscle strength.

To the best of our knowledge, only 4 cases of burosumab treatment in pediatric patients with MAS have been described to date.^6–9 In all cases, conventional therapy was suboptimal and the patients continued to have hypophosphatemia and pain. Gladding et al., Apperley et al., and Barbato et al. described 7-, 5-, and 9-yr-old boys with MAS who required subcutaneous burosumab therapy every 2 wk at starting doses of 1.1, 0.5, and 0.4 mg/kg, respectively.^6,7,9 Sawamura et al. described a 11-yr-old girl who received burosumab injections at a dose of 0.8 mg/kg, also every 2 wk.⁸ All the pediatric patients reported reduced pain and improvements in strength and stamina. The same effect was observed also in our patient just after the first month of burosumab therapy at a dose of 1 mg/kg every 4 wk. In all described pediatric cases and in our case, calcium–phosphate balance was achieved: normophosphatemia and PTH levels. Biochemical studies indicated a significant reduction in alkaline phosphatase activity in all pediatric cases as well in our patient.^6–9 Sawamura et al. also noted radiographic improvement in BMD with burosumab treatment. We have also observed a slight increase in total BMD after 2 yr of therapy. We also noted an increase in muscle strength as measured by a hand dynamometer. The interval between injections to maintain biochemical normalization was not 2 wk as in the pediatric population, but 4 wk. In the 4 children described in the literature,^6–9 no adverse effects were noted. Similarly, in our case, no adverse events occurred during 24 mo of follow-up. What is most important, no new fractures were observed in our case. Further studies are needed on the effects of burosumab on actual fibrous dysplasia tissue, stem cell proliferation, fibrous dysplasia lesion activity, or lesion mineralization. Given the relatively high cost of treatment with burosumab, it is worth noting that the dose in adult patient is lower and intervals longer than in pediatric patients.

Conclusions

Fibroblast growth factor-23-related hypophosphatemia is one of the major clinical issues in MAS, correlated with fibrous dysplasia burden, which has a significant, adverse effect on quality of life. Conventional treatment with oral phosphate supplements and calcitriol is often suboptimal. This is the first reported case of burosumab treatment in an adult patient with FGF23-related hypophosphatemia in MAS. In this case, positive effects of the therapy were observed, both in terms of the patient’s reported well-being and in terms of calcium–phosphate balance and bone markers. A longer follow-up in a larger group of adult patients with MAS is now reasonable. This subsequent study should include both efficacy and safety parameters.

Author contributions

Maria Stelmachowska-Banaś (Conceptualization, Investigation, Writing—original draft, Writing review & editing, Supervision), Karolina Cylke-Falkowska (Investigation, Writing—original draft, Writing—review & editing), Wojciech Zgliczynski (Supervision), John P. Bilezikian (Writing—review & editing, Supervision), and Waldemar Misiorowski (Writing—review & editing, Supervision)

All authors have read and agreed to the final version of the manuscript.

Funding

No public or commercial funding.

Conflicts of interest

All authors declare that they have no conflict of interest.

Data availability

The data on which this article is based on can be found in the article and its figures. For further information, please contact the authors.

Patient consent

The patient has given written informed consent for the use of medical information and photographs for the publication of the article.