Fibrous dysplasia (FD) is a congenital disease caused by somatic mutations in the GNAS gene, which encodes G-protein α-subunit (Gαs) in the osteoblastic cell lineage. The underlying molecular mechanism of the disease is hyperactivation of adenyl cyclase in vivo and subsequent excessive production of cAMP, disrupting normal osteoblast differentiation and osteoclast function (1, 2). Patients with FD commonly experience bone pain, deformities, and fractures due to elevated bone turnover and impaired bone microstructure. FD sometimes manifested as a component of McCune-Albright Syndrome (MAS), alongside characteristic café-au-lait skin macules and hyperfunctioning endocrinopathies, including precocious puberty, hyperthyroidism, and acromegaly. Both FD and MAS are associated with severely reduced quality of life, underscoring the need for effective medical management. The prevalence of FD/MAS was estimated at 61.0 per 1,000,000 individuals in Denmark in 2018 (3). In developing countries, the true prevalence may be underestimated due to higher birth rates and limited availability of prenatal diagnostic methods. These factors emphasize the unmet need for optimized therapeutic and follow-up strategies for patients with FD/MAS.

In pediatric patients, the need for effective therapeutic strategies is particularly critical. FD/MAS often manifests during childhood and progresses actively throughout adolescence, leading to the expansion of skeletal lesions and worsening bone pain. These clinical observations underscore the importance of early and proactive management during the pediatric stage. However, there remains a lack of systematic studies evaluating the safety and efficacy of available treatments in this population.

Bisphosphonates have been used for several decades as the standard treatment for FD/MAS, and have demonstrated efficacy in alleviating bone pain in a significant proportion of patients (4–6). However, as anti-resorptive agents that primarily inhibit osteoclast attachment and activity on the bone surface, bisphosphonates are mechanistically limited in their capacity to reduce FD lesions. Data indicate that bisphosphonates have limited efficacy in reducing skeletal burden and, more specifically, demonstrate no benefit in controlling craniofacial lesions, as shown in a large cohort of 31 patients with craniofacial FD treated with bisphosphonates (7). Particularly in pediatric patients with craniofacial involvement, given the rapid skeletal growth and modeling drift, static anatomical lesions can rapidly progress to cause deformity and subsequent complications, including neural compression and impaired somatic growth; therefore, effective lesion control is urgently needed to prevent disease progression. In this context, bisphosphonate therapy often falls short of achieving adequate therapeutic efficacy. Although zoledronate and pamidronate have demonstrated substantial efficacy in alleviating FD-related bone pain, often resulting in near-complete pain resolution (1), Florenzano et al. reported in a 2019 study that one year of zoledronate treatment did not result in a reduction in SBS, with a mean increase of 3.1 observed among patients younger than 15 years. BTMs demonstrated heterogeneous responses during treatment. ALP levels did not differ from those in untreated pediatric patients, whereas β-CTX and P1NP decreased by only approximately 18% on average (8, 9).

More recently, denosumab has shown promising therapeutic effects in patients with FD/MAS, especially in those who were refractory to bisphosphonate therapy (10, 11). Several case reports have described reductions in skeletal disease burden following denosumab treatment, including suppressed bone turnover, reduced lesion activity on bone scintigraphy, and even diminished lesion. These findings support the potential role of denosumab as a preferable treatment option for FD/MAS (12, 13). Based on these reports and available clinical data in adult patients, we hypothesized that denosumab might confer superior efficacy compared with conventional bisphosphonate therapy in pediatric patients with FD/MAS, and we designed this study to test this hypothesis. Meanwhile, given the frequent reports of post-injection hypocalcemia and rebound hypercalcemia during drug cessation or dose adjustment, the safety profile of denosumab represents another critical endpoint requiring careful evaluation, especially in pediatric patients.

In our study, we recruited 5 FD/MAS patients under the age of 18 and treated them with a standard denosumab regimen. We aimed to evaluate the drug’s efficacy in early disease control, focusing on outcomes such as bone pain relief, suppression of bone turnover, and reduction in lesion size and radioactivity uptake. Importantly, we designed strict monitoring of adverse events during and after follow-up, to ensure the safety of treatment in this special pediatric population, and provided inferable instructions for their prevention and management.

This study represents the first clinical investigation to evaluate the efficacy and safety of denosumab in pediatric patients with FD/MAS. Notably, all enrolled patients presented with polyostotic lesions involving the skull, highlighting the clinical significance of this research in managing early-stage, high-burden FD/MAS in children. The findings demonstrated that denosumab effectively suppressed disease activity, as evidenced by substantial reductions in serum ALP levels and attenuation of lesion size and radiotracer uptake, in parallel with decreases in β-CTX and P1NP levels. Meanwhile, all patients demonstrated increases in BMD during follow-up, as confirmed by DXA assessments performed at baseline and at the end of the follow-up period. These findings indicate that denosumab therapy did not impair calcium deposition or BMD accrual at the femoral neck, lumbar spine and total hip. The assessed sites were free of FD involvement and were therefore excluded from lesion-specific analysis. These results provide valuable insight into potential therapeutic strategies for pediatric FD/MAS patients, a population often characterized by poor prognosis due to high bone turnover, craniofacial involvement, and multiple endocrinopathies associated with MAS.

Historically, bisphosphonates including alendronate, pamidronate and zoledronate have served as the cornerstone of FD/MAS treatment for several decades. These agents have demonstrated efficacy in preserving BMD and reducing BTMs (6). In particular, intravenous administration of pamidronate and zoledronate has been shown to significantly alleviate FD-associated bone pain, emphasizing their utility in pain management (16, 17). However, multiple studies have reported limitations of bisphosphonates, especially in patients with markedly elevated bone turnover, extensive skeletal involvement, and craniofacial lesions (18, 19). This clinical profile is common among pediatric FD/MAS patients, underscoring the pressing need for individualized treatment strategies and age-specific clinical guidelines.

The findings of our study confirm the efficacy of denosumab in the pediatric population, particularly in reducing lesion-specific bone turnover activity and overall skeletal burden. Previous research has identified a positive correlation between RANKL expression and skeletal burden in FD/MAS patients (20). Denosumab, as a humanized monoclonal antibody targeting RANKL, has already demonstrated efficacy in reducing skeletal burden in adult FD patients (12, 13). Combined with our results, these data provide a refreshed general view that denosumab is effective across pediatric and adult age groups. Collectively, this evidence supports denosumab as a promising therapeutic alternative for managing FD in FD/MAS patients. Notably, for pediatric FD/MAS patients who often present with higher disease activity and reduced responsiveness to conventional treatments, denosumab may offer a more effective option when administered under careful clinical supervision.

In our study, denosumab demonstrated remarkable efficacy in controlling FD-associated bone pain, suppressing bone turnover, and reducing SBS in pediatric patients. Among the 3 patients who reported baseline bone pain, all experienced substantial relief, with no recurrence during the follow-up period. Serum ALP levels were reduced to 39 ± 9% of baseline, with 4 of 5 patients achieving values below the upper limit of normal. Based on our center’s experience with bisphosphonate therapy in FD/MAS (4), which typically results in a mean reduction to approximately 69% of baseline, denosumab appeared to demonstrate greater efficacy in suppressing this bone turnover marker. Given that ALP serves as a key marker of overall bone turnover, this reduction suggests effective and sustained suppression of FD-lesion activity. This interpretation is further supported by the marked decreases in serum β-CTX and P1NP levels observed across all patients.

Reduction in lesion radioactivity uptake was also observed in patients during follow-up. One patient demonstrated a decrease in the size of the skull base lesion and near-complete resolution of the FD lesion in the left femur, resulting in a reduction of the SBS score from 18.51 to 10.64. Other patients exhibited varying degrees of decreased radioactivity uptake, although no significant changes in lesion size were noted. These findings may suggest a partial alleviation of disease burden, albeit insufficient to produce a significant reduction in SBS score (12). Similar lesion regression has been reported in other clinical trials investigating denosumab, though with differences in dosage and administration schedules. Notably, most cases documenting lesion regression involved higher denosumab doses (120 mg every three months or at shorter intervals) compared to the 60 mg every 3 months regimen used in our study, implying that higher doses may be more effective in managing FD (12).

Despite the notable therapeutic benefits, adverse events, particularly hypercalcemia were observed, consistent with existing literature. Common adverse effects associated with denosumab include hypocalcemia, osteonecrosis of the jaw, hypercalcemia following drug cessation, rash, and dizziness, with hypercalcemia representing one of the most severe complications (12, 21). The safety of denosumab in pediatric patients with FD/MAS was first noted by Collins et al. in a 2012, who reported severe rebound hypercalcemia following drug cessation in a 9-year-old boy (14). Case reports remain scarce. Although reports on the use of denosumab in pediatric patients with FD/MAS are limited, its safety profile has been more extensively characterized in pediatric patients with osteogenesis imperfecta (22). In this population, hypercalcemia has been commonly reported, with approximately 14.3% of patients progressing to hypercalcemic crisis, which is informative for interpreting the safety concerns in our study. The hypercalcemia observed upon denosumab discontinuation may be explained by rebound osteoclastogenesis mediated by osteomorphs (23), or by rapid resorption of the excessive bone tissue formed during treatment. Patients P2 and P3 experienced hypocalcemia prior to the onset of hypercalcemia, indicating an initially adequate osteoclastic suppression by denosumab, followed by an exaggerated rebound in bone resorption when timely follow-up was lacking. The risk of hypercalcemia may be exacerbated by factors such as prolonged drug withdrawal, hypervitaminosis D, immobilization, excessive calcium intake, or hyperthyroidism (21, 24–26), particularly given that all patients received calcium and vitamin D supplementation following denosumab administration. In these 2 cases, hypercalcemia was precipitated by unsupervised calcium supplementation and a lack of adherence to safety monitoring protocols, causing nausea and vomiting, which contributed to dehydration and clinical deterioration, ultimately culminating in a hypercalcemic crisis. This underscores the critical need for strict patient education and rigorous monitoring strategies to ensure patient safety, rather than solely attributing the events to drug mechanisms. These findings underscore the need for strict safety monitoring during denosumab therapy and emphasize the importance of patient adherence to treatment protocols. When follow-up procedures and safety monitoring are rigorously observed, the risk of adverse events during denosumab treatment can be effectively controlled.

Based on our center’s experience in treating FD/MAS, hypercalcemia is the most common adverse event observed during denosumab cessation or interval adjustments. This complication is particularly frequent and severe in pediatric patients due to their relatively high bone metabolic activity. Conventional management strategies for cessation-related hypercalcemia include hydration, administration of calcitonin, and corticosteroid therapy (27). However, a standardized approach for long-term prevention has not yet been established due to insufficient data. Common preventive strategies involve close monitoring of serum calcium, phosphate, and BTMs, along with the use of sequential bisphosphonate therapy following denosumab discontinuation (27, 28). The rationale for sequential bisphosphonate use is to transition from denosumab to a less potent anti-resorptive agent, thereby mitigating the abrupt rebound of bone resorption. In clinical practice, zoledronate is commonly used at a dose of 0.025mg/kg every 3 months, with the first dose given 3 months after denosumab cessation (29). Monthly monitoring of serum markers is recommended for the first 3 months following denosumab cessation or interval adjustment to allow early detection of rebound hypercalcemia. For patients whose serum calcium exceeds the upper limit of normal, an immediate dose of zoledronate 0.025mg/kg is advised. If hypercalcemia persists, administration of denosumab at 0.25mg/kg may be considered (27).

Moreover, recent studies have shown that denosumab administered at a dose of 120mg every 4 weeks can effectively control disease activity in patients with FD/MAS without a high incidence of severe adverse events, although cases of rebound hypercalcemia following treatment discontinuation have been reported (12). We hypothesize that optimization of denosumab dosing strategies and administration intervals may mitigate adverse effects while maximizing therapeutic efficacy; therefore, future prospective studies are warranted to establish safer and more effective treatment protocols for this unique pediatric patient population.

The findings of our study highlight the efficacy of denosumab in treating pediatric FD/MAS patients. Denosumab demonstrated significant benefits in alleviating FD-associated bone pain, reducing bone turnover, and controlling lesion activity.

Nonetheless, safety considerations must remain a central focus during denosumab therapy, particularly in relation to MAS manifestations, baseline BTMs levels, treatment regimens, and patient adherence. These factors may influence both the risk of severe adverse events and overall treatment effectiveness. Therefore, comprehensive pre-treatment evaluation and close monitoring throughout the treatment course are essential to ensure patient safety. The risk of adverse events during denosumab treatment can be effectively controlled when sticking to strict follow-up procedures and safety monitoring.