Case presentation

A 62-year-old woman was referred to our hospital in January 2022, with a two-year history of progressive generalized bone pain and proximal muscle weakness. Her symptoms began in 2020 with pain involving the lower limbs and pelvis. In 2021, she sustained an incomplete pelvic fracture and a left femoral metaphyseal fracture after a low-energy fall, both managed conservatively. She developed worsening pain, fatigue, and progressive muscle weakness, leading to severe functional impairment and loss of independent ambulation. During the course of her illness, the patient was initially misdiagnosed with osteoarthritis and received ineffective treatment with glucosamine and bilateral knee viscosupplementation. A subsequent diagnosis of osteoporosis prompted referral to the Rheumatology Department in February 2022. Physical examination revealed diffuse tenderness over the pelvis and lower limbs and symmetric pelvic girdle weakness. No palpable masses were identified. Dual-energy X-ray absorptiometry showed osteoporosis (total femur T-score, -3.2), and laboratory evaluation demonstrated severe hypophosphatemia, prompting referral to the Nephrology Department. Biochemical evaluation demonstrated renal phosphate wasting, evidenced by an inappropriately elevated fractional excretion of phosphate (FeP), together with hypophosphatemia, reduced 1,25-dihydroxyvitamin D levels, elevated parathyroid hormone and alkaline phosphatase concentrations, and increased serum FGF-23 levels (Table 1).

 | Initial result (before surgery) | Six weeks post burosumab initiation (20mg SC) | Reference range
Phosphorus (mg/dL) | 1.5 | 3.8 | 2.5-4.9
FeP (%) | 18.99 | 11 | <5-20%
Calcium (mg/dL) | 8.7 | 8.9 | 8.5-10.2
1,25 dihydroxyvitamin D (pg/mL) | <2.6 | 26 | 19.6-54.3
PTH (pg/mL) | 101 | 43 | 15-65
ALP (U/L) | 459 | 95 | 35-105
Creatinine (mg/dL) | 1.1 | 0.9 | 0.6-1.3
FGF-23 (UA/mL) | 348 | 85 | <180

Genetic testing targeting the ADCY10, AGXT, AP2S1, CLCN5, CLDN16, CLDN19, CYP24A1, DMP1, ENPP1, FAM20A, FAM20C, FGF23, GNA11, GHRPR, HNF4A, HOGA1, HPRT1, KCNJ1, OCRL, PHEX, SGK3, SLC12A1, SLC22A12, SLC26A1, SLC2A9, SLC34A1, SLC34A3, SLC3A1, SLC4A1, SLC7A9, and SLC9A3RA genes identified no pathogenic variants, making a hereditary hypophosphatemic disorder less likely. TIO was therefore suspected, and oral phosphate and calcitriol were initiated while tumor localization was pursued.

Transiliac bone biopsy demonstrated increased osteoid volume in cortical bone with preserved cortical thickness and porosity. Trabecular bone showed features of osteomalacia with impaired mineralization (Figure 1). A 68Ga-DOTATATE PET/CT scan performed in November 2022 demonstrated somatostatin receptor expression in a soft-tissue lesion involving the right aspect of the C7 vertebra. Cervical magnetic resonance imaging (MRI) confirmed an infiltrative lesion at the C7 vertebra with osseous destruction and extension into the epidural and paravertebral spaces, as well as into the C7-T1 neural foramen (Figure 2).

Figure 1: Bone biopsy revealing osteomalaciaVon kossa staining, demonstrates increased osteoid (arrows). Original magnification x100

Figure 2: Cervical MRI demonstrating the localization of the FGF23-producing tumor at the C7 vertebral levelMRI: magnetic resonance imaging; FGF23: FGF-23: fibroblast growth factor 23Infiltrative lesion at the C7 vertebra with osseous destruction. The orange and green asterisks delineate the tumor margins, while the red circles indicate the tumor dimensions on different imaging planes

In March 2023, the patient underwent C7 laminectomy and pediculectomy with en bloc resection of the infiltrative lesion. The C6-C8 nerve roots were infiltrated by the tumor and required resection. Histopathological examination was inconclusive. Oral phosphate and calcitriol were discontinued three weeks after surgery. Serum phosphate normalized to 3.5 mg/dL, the FeP decreased to 9.44%, and the patient regained independent ambulation. At follow-up, serum phosphate remained within the low-normal range (2.5-2.7 mg/dL); however, FeP progressively increased from 16% to 21% (Figure 3), preceding symptomatic relapse.

Figure 3: Fractional excretion of phosphate over timeThe horizontal shaded band indicates the expected fractional excretion of phosphate in the setting of hypophosphatemia (<20%). Values obtained during oral phosphate supplementation are artificially elevated and are indicated by the vertical shaded region

In April 2024, recurrent bone pain and muscle weakness were accompanied by hypophosphatemia (2.2 mg/dL) and an increased FeP (27.8%). Repeat 68Ga-DOTATATE PET/CT demonstrated a new focus of somatostatin receptor uptake in the right parietal calvarium, whereas spinal magnetic resonance imaging showed no residual or recurrent cervical disease. As the calvarial lesion was not amenable to surgery or radiotherapy, burosumab, a human monoclonal antibody that inhibits FGF-23, was initiated at 40 mg every four weeks (0.51 mg/kg) in May 2024.

Biochemical parameters, including serum phosphate, calcium, PTH, 1,25-dihydroxyvitamin D, renal function, and FeP, were monitored every two weeks during the first six months of treatment and monthly thereafter. The patient was also monitored for treatment-related adverse events, including injection-site reactions and hypersensitivity, none of which occurred.

Following transient hyperphosphatemia, the dose was reduced to 20 mg and subsequently to 10 mg every four weeks (Figure 4). Thereafter, the patient remained normophosphatemic and asymptomatic. FeP significantly declined after surgery and following burosumab initiation (Figure 3). The patient has since remained normophosphatemic and asymptomatic on the 10 mg regimen. After 25 months of treatment, serum phosphate was 3.7 mg/dL, and the patient remained independently ambulatory without requiring analgesics. Serial 68Ga-DOTATATE PET/CT scans demonstrated stable uptake in the right parietal calvarial lesion, with no evidence of disease progression.

Figure 4: Serum phosphate concentrations throughout the different treatment phases, with corresponding burosumab dosesThe horizontal shaded area indicates the reference range (2.5-4.5 mg/dL), and the vertical shaded region denotes the period during which the patient received oral phosphate supplementation and calcitriol