Abstract
Background
Fibrous dysplasia (FD) is a rare bone disorder often presenting in children with bone pain, pathological fractures, and deformities. Bisphosphonates, as anti-resorptive agents, are increasingly used in pediatric FD to reduce symptoms and improve skeletal health. However, their efficacy and safety in this population remain incompletely defined.
Methods
This systematic review was conducted according to PRISMA guidelines after registration on PROSPERO with ID: CRD420251102346. A comprehensive search of PubMed, Embase, Cochrane Library, and LILACS databases was performed up to June 25, 2025, using keywords ((FIBROUS DYSPLASIA) AND ((PAEDIATRIC) OR (CHILDREN)) AND (BISPHOSPHONATE)). Studies were included if they involved original clinical data, reported on bisphosphonate therapy in children (mean age <16 years), and were published in English. Data were extracted on demographics, clinical features, treatment regimen, biochemical outcomes, pain scores, complications, and radiological response.
Results
A total of seven studies comprising 92 pediatric patients were included. Pamidronate was the most commonly used bisphosphonate, followed by zoledronic acid. All studies reported significant reduction in bone pain, and several noted decreased fracture frequency. Biochemical improvements, especially reductions in alkaline phosphatase, were consistently observed. However, radiological improvement and correction of skeletal deformities were limited. Bisphosphonate therapy was generally well-tolerated, with transient fever, mild infusion-related bone pain, and asymptomatic hypocalcemia being the most common adverse effects.
Conclusion
Bisphosphonates are effective in improving clinical symptoms and biochemical markers in children with fibrous dysplasia but have limited impact on structural deformities. They demonstrate a favorable short-term safety profile.
Keywords: Pediatric, Fibrous dysplasia, Bisphosphonates, Pamidronate, Zoledronic acid
1. Introduction
Fibrous dysplasia (FD) is a rare, non-inherited bone disorder characterized by the replacement of normal bone with fibro-osseous tissue, leading to structural weakness, deformities, pain, and pathological fractures.1 It may occur in a monostotic or polyostotic form and is frequently associated with endocrine abnormalities in the setting of McCune-Albright syndrome (MAS).2 The pediatric population is particularly vulnerable, as disease onset during skeletal growth can result in progressive deformity and functional impairment.3
Currently, no curative treatment exists for fibrous dysplasia. Management strategies focus on symptom control, prevention of complications, and maintenance of function.4 Bisphosphonates; potent inhibitors of osteoclastic bone resorption; have been increasingly utilized in the treatment of FD due to their potential to reduce bone pain, stabilize lesions, and decrease fracture risk.5,6 While these agents have shown promise in adult populations, their role in pediatric cases remains less clearly defined due to concerns related to long-term safety, skeletal growth, and variable clinical outcomes.7
This systematic review aims to critically evaluate the existing evidence regarding the efficacy, safety, and clinical outcomes of bisphosphonate therapy in children with fibrous dysplasia. By synthesizing data from available studies, we seek to provide an evidence-based perspective on the therapeutic value and limitations of bisphosphonates in this unique patient group.
2. Methods
2.1. Search strategy
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines after registration on PROSPERO with ID: CRD420251102346. A comprehensive electronic literature search was performed up to June 25, 2025, across PubMed, Cochrane Library, and LILACS databases and Embase on August 03, 2025. The search strategy used a combination of MeSH terms and keywords relevant to the study population: ((FIBROUS DYSPLASIA) AND ((PAEDIATRIC) OR (CHILDREN)) AND (BISPHOSPHONATE)), Boolean operators and various keyword combinations were applied to ensure search sensitivity. Additionally, references of all included articles were manually screened for eligible studies, and the “related articles” feature in databases was also used to identify further relevant publications. Initial screening of titles and abstracts was conducted by one reviewer (AR), and duplicates were removed. Potentially eligible full-text articles were retrieved for detailed review.
2.2. Eligibility criteria
Studies were considered eligible for inclusion if they met the following criteria: they were original research articles, included patients with a diagnosis of fibrous dysplasia, involved treatment with bisphosphonates, reported a mean age of participants under 16 years, and were published in the English language. Studies were excluded if they were case reports, case series with fewer than three patients, letters to the editor, review articles, cadaveric or animal studies, or if the mean patient age exceeded 16 years. The final inclusion of studies was determined independently by two reviewers (AR and BBN) as in Fig. 1.
Fig. 1.
PRISMA flow diagram.
2.3. Data extraction
Data extraction was carried out independently by two investigators (AR and BBN), who recorded all relevant information into a structured spreadsheet (Microsoft Excel, USA). A reviewer (BBN) repeated the data extraction process independently to ensure consistency and accuracy. Extracted data included details of the study design, level of evidence, patient demographics, predominant presenting symptoms, associated systemic features, treatment regimen, type and dosage of bisphosphonate used, and route of administration. Furthermore, biochemical parameters such as serum calcium, serum phosphorus, and alkaline phosphatase levels were recorded when available, along with pain scores, reported complications, and final clinical or radiological outcomes (Table 1, Table 2).
Table 1.
Study characteristics.
| Study (Author, Year) | Country | Design | Sample Size | Mean Age (Years) | Gender (M/F) | Type of FD | Follow-up Duration |
|---|---|---|---|---|---|---|---|
| Lala et al., 2000 | Italy | Case series | 9 | 9.6 | 2/7 | Not specified | 12 months |
| Zacharin et al., 2000 | Australia | Prospective case series | 9 | 14.4 | 6/3 | Polyostotic, MAS | 24 months |
| Plotkin et al., 2003 | Canada | Case series | 18 | 9.8 | 10/8 | Mixed, some MAS | 72 months |
| Kos et al., 2004 | Poland | Pilot prospective study | 6 | 14.5 | 2/4 | Not specified | 19 months |
| Lala et al., 2006 | Italy | Case series | 14 | 11.4 | 4/10 | Polyostotic, MAS/variant | 63 months |
| Thomsen et al., 2014 | Denmark | Case series | 26 | 16.0 | 10/16 | Not specified | 48 months |
| Tripathy et al., 2020 | India | Retrospective | 10 | 9.1 | 4/6 | 8 polyostotic, 2 mono | 32.6 months |
Table 2.
Intervention and outcomes.
| Study | Bisphosphonate Used | Dose & Regimen | Primary Indication | Fracture Healing | Biochemical Improvement (ALP) | Radiological Changes | Adverse Effects |
|---|---|---|---|---|---|---|---|
| Lala et al., 2000 | Pamidronate | 0.5–1 mg/kg/day IV, repeated 2–5 cycles | Pain, fractures | Yes (16 fractures) | Normalized after 2–4 cycles | Increased bone density, no healing on X-ray | Transient bone pain, fever, hypocalcemia |
| Zacharin et al., 2000 | Pamidronate | 1 mg/kg/day IV × 3 days, every 6 months × 2 yrs | Pain, MAS | Not reported | ↓ ALP from 818 to 654 | Not significant | Mild acute reaction on first dose |
| Plotkin et al., 2003 | Pamidronate ± Alendronate | 0.5 mg/kg D1, 1 mg/kg D2–3, q4mo | Pain | 11 fractures treated | Persistently ↓ ALP | Continued lesion in some | Flu-like symptoms, asymptomatic hypocalcemia |
| Kos et al., 2004 | Pamidronate | 1 mg/kg × 3 days q4–6mo | Pain, facial growth | Not specified | Normal biochemical parameters | Hearing improvement | Fever |
| Lala et al., 2006 | Pamidronate | 0.5–1 mg/kg/day × 3 days, variable interval | Pain, fractures | Fractures ↓ (21 → 4/yr) | ALP ↓ (1745 → 1018 U/L) | Cortical thickening in 5 cases | Hyperpyrexia, bone pain, hypocalcemia |
| Thomsen et al., 2014 | Zoledronic acid | Not specified | Pain | Not specified | ALP ↓ from 10 → 5 | Ambiguous effect | Not specified |
| Tripathy et al., 2020 | Zoledronic acid | 0.1 mg/kg IV q4–6mo | Pain | Union in 2.1 ± 0.6 mo | ALP ↓ (895 → 544 U/L) | No deformity correction | Fever, myalgia, hypocalcemia (1 case) |
Risk of bias was assessed using the Newcastle–Ottawa Scale (NOS) adapted for non-randomized studies. The NOS evaluates studies on three domains: selection, comparability, and outcome (total score: 0–9). Studies scored between 4 and 7, indicating overall moderate risk of bias (Table 3).
Table 3.
Risk of bias using the Newcastle–Ottawa Scale (NOS).
| Study | Selection (0–4) | Comparability (0–2) | Outcome (0–3) | Total Score (0–9) | Risk of Bias |
|---|---|---|---|---|---|
| Lala et al., 2000 | ★★★ | ★ | ★★ | 6 | Moderate |
| Zacharin et al., 2000 | ★★ | ★ | ★ | 4 | Moderate–High |
| Plotkin et al., 2003 | ★★★ | ★ | ★★ | 6 | Moderate |
| Kos et al., 2004 | ★★ | ★ | ★ | 4 | Moderate–High |
| Lala et al., 2006 | ★★★ | ★ | ★★ | 6 | Moderate |
| Thomsen et al., 2014 | ★★ | ★ | ★ | 4 | Moderate–High |
| Tripathy et al., 2020 | ★★★ | ★★ | ★★ | 7 | Low–Moderate |
Note: Assessed as Low (7–9), Moderate (5–6), or High (≤4) risk of bias.
2.4. Statistical analysis
Data collected on MS Excel 2013 and analyzed on same. Descriptive statistical analysis was carried out for both categorical and continuous variables. Categorical data were summarized as absolute numbers and percentages, whereas continuous variables were reported as means with standard deviations. Given the variability in study design and outcome measures, a quantitative meta-analysis was not performed, and results were instead synthesized descriptively.
3. Result
A total of seven studies involving 92 pediatric patients with fibrous dysplasia (FD) were included in this review.8, 9, 10, 11, 12, 13, 14 The age at treatment initiation ranged from 9.1 to 16 years. The studies included four case series,8,10,12,13 two prospective studies,11,14 and a retrospective case series.9 Across all studies, the predominant symptom leading to treatment was bone pain, followed by pathological fractures and various endocrinopathies.
3.1. Clinical features and comorbidities
Lala et al. (2000) described 9 pediatric patients with precocious puberty, skin dysplasia, and Cushing syndrome, with 4 of them having sustained 16 fractures prior to therapy.12 Zacharin et al. (2000) studied 9 male patients with polyostotic FD and café-au-lait spots, most of whom had MAS.11 Plotkin et al. (2003) reported that all 18 patients presented with bone pain, and 7 had hypophosphatemia; 6 of the 18 had MAS or precocious puberty.10 Kos et al. (2004) included 6 patients with craniofacial deformities, tumor-like growth, and facial sensory impairments.14 Lala et al. (2006) analyzed 14 patients, 10 of whom had sustained multiple fractures, with associated findings including Cushing syndrome, hyperthyroidism, and testicular microlithiasis.8 Thomsen et al. (2014) studied 26 patients with deformities including craniofacial changes, neurological impairments, and exophthalmos.9 Tripathy et al. (2020) included 10 patients with café-au-lait spots, precocious puberty, and recurrent fractures.13 (Table 1).
3.2. Bisphosphonate treatment regimens
All patients were treated with intravenous bisphosphonates. Pamidronate was the most frequently used agent, administered in five studies.8,10, 11, 12,14 Dosing commonly involved 0.5–1 mg/kg/day for 2–3 days, repeated every 4–6 months. Zoledronic acid was used in two studies,9,13 with dosing in Tripathy et al. being 0.1 mg/kg IV infusion, administered up to 5 times per patient.13 Calcium and vitamin D supplementation were used in several protocols.10 Pamidronate was the most frequently used agent across studies, typically administered every 4–6 months, whereas zoledronic acid was used less frequently but at higher potency (Table 2).
3.3. Biochemical outcomes
Where reported, bisphosphonate therapy led to reductions in alkaline phosphatase (ALP) levels, indicating decreased bone turnover. Lala et al. (2006) reported a decline in ALP from 1745 U/L to 1018.5 U/L,8 while Tripathy et al. (2020) noted a reduction from 895.75 ± 79.64 to 544.12 ± 47.35 U/L.13 Zacharin et al. (2000) documented a drop from 818.5 ± 181.7 to 654 ± 171 U/L at 24 months.11 Plotkin et al. (2003) reported persistently low ALP and phosphate levels post-treatment.10 In Kos et al. (2004), all biochemical parameters remained within normal ranges throughout therapy.14
3.4. Pain and fracture outcomes
All studies consistently reported substantial pain reduction following treatment.8, 9, 10, 11, 12, 13, 14 Thomsen et al. (2014) recorded a VAS score drop from 10 to 5.9 Lala et al. (2006) found that although 8 of 14 patients had pain at baseline, none reported pain at the end of follow-up.8 Plotkin et al. (2003) observed improved stamina and bone pain relief.10 Zacharin et al. (2000) and Lala et al. (2000) also documented significant pain control.11,12
Fracture-related outcomes were favorable in most studies. Lala et al. (2006) noted a reduction in fracture rate from 21 per year to 4 per year.8 Tripathy et al. (2020) observed fracture union in 2.1 ± 0.6 months, although pre-existing deformities did not resolve.13
3.5. Radiological and functional outcomes
Radiological changes included cortical thickening, increased lesion density, or stabilization of lesion margins, primarily assessed via plain radiographs. Radiographic improvement varied. Lala et al. (2006) observed cortical thickening in 5 of 14 patients,8 while Lala et al. (2000) noted increased bone density in lesional and extralesional areas.12 However, none of the studies; including those by Tripathy et al. (2020) and Plotkin et al. (2003); reported meaningful correction of skeletal deformities, craniofacial anomalies, or neurologic impairments.
3.6. Adverse events
Bisphosphonates were generally well tolerated. The most commonly reported side effects were transient fever, flu-like symptoms, infusion-related bone pain, and mild hypocalcemia. Lala et al. (2000, 2006) and Plotkin et al. (2003) observed transient symptomatic hypocalcemia in some patients, managed conservatively.8,10,12 Tripathy et al. (2020) reported fever and myalgia in all patients within 2–3 days post-infusion, and one case of symptomatic hypocalcemia.13 Kos et al. (2004) noted mild fever, and Zacharin et al. (2000) documented only mild acute phase reactions on first exposure.11,14
4. Discussion
This systematic review evaluated seven studies comprising a total of 92 pediatric patients with FD treated with intravenous bisphosphonates. The predominant clinical indications were persistent bone pain, pathological fractures, and deformities, frequently occurring in the context of McCune-Albright syndrome. Pamidronate was the most widely used bisphosphonate, followed by zoledronic acid. Across all studies, bisphosphonate therapy led to marked reductions in pain and improvements in serum biochemical markers, particularly alkaline phosphatase, indicative of decreased bone turnover. Some studies reported a reduction in fracture incidence and accelerated fracture healing. However, radiological outcomes remained suboptimal, with no consistent evidence of reversal in bone deformities or structural abnormalities. Treatment was well tolerated with minimal and transient adverse effects, including infusion-related symptoms and asymptomatic hypocalcemia.
4.1. Mechanism of action in pediatric bone
FD in pediatric patients presents a unique clinical challenge due to its chronic, progressive nature, its association with endocrinopathies such as MAS, and its impact on quality of life through persistent bone pain, fractures, and deformities.15 The pathophysiology of FD, involving abnormal bone resorption and replacement with fibrous tissue, makes it a plausible target for anti-resorptive therapies such as bisphosphonates.16
Bisphosphonates, particularly nitrogen-containing compounds like pamidronate and zoledronic acid, act by inhibiting farnesyl pyrophosphate synthase within the mevalonate pathway, thereby suppressing osteoclast activity and inducing apoptosis of bone-resorbing cells. In the context of FD, where bone remodeling is aberrant and favoring fibrous tissue proliferation, suppression of osteoclast-mediated resorption may theoretically stabilize lesions and reduce associated bone pain.16 However, pediatric bone is a dynamic, actively remodeling tissue undergoing growth and modeling processes. This physiologic remodeling is essential for longitudinal growth and architectural refinement. Bisphosphonates, by broadly reducing turnover, may inadvertently impair normal modeling, particularly in growing bones. Moreover, bisphosphonates do not reverse the underlying mutation in the GNAS gene nor directly target the fibrous stroma, explaining their limited efficacy in structural reconstitution of FD lesions.15
4.2. Variability in dosing and treatment protocols
A notable limitation across studies was the inconsistency in dosing regimens, drug choice, and treatment intervals. Pamidronate protocols ranged from 0.5 to 1 mg/kg/day for 2–3 days every 3–6 months, whereas zoledronic acid was typically administered at 0.05–0.1 mg/kg less frequently.9,13 Adjuncts like calcium and vitamin D were inconsistently described. The absence of standardized protocols reflects both a lack of consensus in pediatric FD management and the individualized nature of treatment based on disease severity and comorbidities. This heterogeneity poses challenges to comparison, synthesis, and meta-analysis, and limits the ability to define evidence-based therapeutic benchmarks.
Across the included studies, pamidronate was the most commonly administered bisphosphonate, with variable dosing regimens. Zoledronic acid, a more potent bisphosphonate, was used in more recent studies (Thomsen et al., 2014; Tripathy et al., 2020).9,13
4.3. Efficacy of bisphosphonates
Pain reduction was the most consistently observed benefit across all studies. Pain in FD arises due to micro-fractures, mechanical instability, and abnormal intramedullary pressure. Bisphosphonates alleviate these symptoms likely through stabilization of microarchitecture and reduction in metabolic activity. The VAS scores dropped significantly post-treatment in studies by Lala et al. (2006) observed complete resolution of pain in 14 children who previously experienced frequent episodes of bone discomfort,8 while Thomsen et al. (2014) noted a significant drop in VAS scores following zoledronate treatment.9 These findings support bisphosphonates as effective analgesic agents in FD, possibly through their anti-inflammatory and anti-resorptive actions.
Fracture outcomes were also favorable; the fracture rate dropped significantly in some studies, and healing time was shorter in treated children. Lala et al. (2006) reported a dramatic decrease from 21 to 4 fractures per year following pamidronate therapy,8 while Tripathy et al. (2020) documented fracture healing within 2.1 ± 0.6 months in patients treated with zoledronic acid.13 Despite this positive impact on fracture healing and frequency, none of the studies showed consistent reversal of deformities or correction of skeletal malalignment, highlighting a major limitation of bisphosphonate therapy in altering structural bone changes once they are established.
These improvements in pain and fracture outcomes are complemented by reductions in ALP, a marker of osteoblastic activity and disease burden, suggesting effective biochemical control of disease activity. Biochemical improvement, primarily indicated by reductions in ALP, was consistently seen across studies that reported these values. Lala et al. (2006), Tripathy et al. (2020), and Zacharin et al. (2000) all demonstrated significant post-treatment declines in ALP, reflecting decreased osteoclastic activity and bone turnover.8,11,13 However, changes in calcium and phosphorus levels were less consistently reported, though transient asymptomatic hypocalcemia was a frequent side effect, as noted by Plotkin et al. (2003) and Lala et al. (2000, 2006).8,10,12
Radiological outcomes were mixed. Some studies reported radiographic stabilization or increased cortical thickening (Lala et al., 2006; Lala et al., 2000),8,12 but others, such as Plotkin et al. (2003), found no visible radiological healing despite symptomatic improvement.10 This suggests that while bisphosphonates may alleviate symptoms and reduce metabolic activity, they may not fully reverse the anatomical manifestations of the disease.
4.4. Safety and adverse effects
The safety profile of bisphosphonates in the included pediatric studies was reassuring.17 Acute adverse effects were limited to flu-like symptoms, mild bone pain, and transient hypocalcemia; all self-limited and managed conservatively.18 These findings are consistent with broader pediatric osteoporosis literature, including studies on osteogenesis imperfecta and juvenile osteoporosis, where bisphosphonates have shown excellent tolerability over multi-year use. Long-term safety, especially concerning growth plate dynamics, dental health, and potential oversuppression of bone turnover, remains insufficiently explored. While none of the studies reported growth arrest, this outcome should be actively monitored in future long-term cohorts. In our included study, no severe or long-term adverse events were observed in any of the included studies, supporting the tolerability of these drugs in a pediatric population.8, 9, 10, 11, 12, 13, 14
Long-term bisphosphonate use in children has raised concerns regarding metaphyseal sclerotic bands, delayed bone remodeling, and potential growth plate effects. While these were not reported in the included studies, data from pediatric osteoporosis cohorts suggest that these radiographic changes are typically benign and do not impair growth. Nonetheless, continuous monitoring is advised in children receiving prolonged treatment.
4.5. Limitation
Most included studies were observational case series or retrospective reviews, with inherent risk of bias and limited external validity. Sample sizes were small, and many lacked comparator arms. Moreover, outcome measures were variable, with some studies reporting only subjective endpoints and few including objective metrics. Follow-up durations were also inconsistent, with a paucity of data on long-term outcomes such as recurrence, progression, or skeletal maturity endpoints. Additionally, radiological assessments were often qualitative or semi-quantitative, limiting evaluation of anatomical outcomes.
Most studies had moderate methodological quality. Lack of comparator groups, small sample sizes, and heterogeneity in outcome measures were common, contributing to a moderate risk of bias in five studies. Only one study (Tripathy et al., 2020) achieved a score of 7, reflecting clearer methodological rigor.13
While we conducted a comprehensive search across PubMed, Cochrane Library, LILACS, and Embase, we acknowledge other database were not included due to resource constraints. Our restriction to English-language publications may have excluded relevant studies in other languages. Finally, given the clinical and methodological heterogeneity across included studies, we were unable to perform a quantitative meta-analysis, relying instead on descriptive synthesis.
4.6. Clinical and therapeutic implications
Despite these limitations, this review offers important insights for clinical practice. Bisphosphonates are a valuable option for symptomatic control in pediatric FD, offering pain relief, biochemical stabilization, and possibly reduced fracture burden. They should be considered early in the disease course, especially for children with polyostotic involvement or MAS, before structural damage becomes irreversible. However, they should not be expected to reverse deformities or eliminate the need for surgical intervention when indicated. Multidisciplinary management involving endocrinology, orthopedics, and rehabilitation remains key to optimizing outcomes.
4.7. Recommendations for future research
Future investigations should aim to establish standardized treatment protocols through prospective multicenter trials. Randomized controlled trials comparing different bisphosphonate agents or dosing strategies are essential. Studies evaluating the impact of bisphosphonate therapy on growth, final height, and bone quality are especially important in the pediatric population. Development of composite outcome scores—including pain, function, radiologic findings, and quality of life—could enhance longitudinal assessment. Additionally, research exploring novel therapies such as denosumab, anti-RANKL monoclonal antibodies, or gene-targeted treatments for GNAS mutations may provide new avenues for disease modification beyond symptomatic control.
5. Conclusion
Bisphosphonate therapy, particularly with pamidronate and zoledronic acid, appears to be an effective and well-tolerated treatment option for managing bone pain and reducing fracture risk in pediatric patients with fibrous dysplasia. The treatment is associated with a measurable decrease in bone turnover markers such as alkaline phosphatase and has demonstrated favorable short-term clinical outcomes. However, current evidence suggests that bisphosphonates do not reverse pre-existing skeletal deformities or consistently improve radiological features and long-term disease modification remains limited.
Consent to participation
Not Applicable.
Author's contribution
A. R. - Planning of study, writing and revising the manuscript.
B. B. N. – Data Management and revising the manuscript.
Ethical review committee statement
Not Applicable.
Financial support and sponsorship
This research received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Acknowledgement
None.
Footnotes
This article is part of a special issue entitled: Pediatric orthopedics published in Journal of Clinical Orthopaedics and Trauma.
Contributor Information
Anil Regmi, Email: regmiaanil@gmail.com.
Bishwa Bandhu Niraula, Email: bishwa8bangladesh@gmail.com.
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