Denosumab Reduces Lesional Fluoride Skeletal Burden on Na[18F]F PET-CT in Patients With Fibrous Dysplasia/McCune–Albright Syndrome

Abstract

Context The correlation between Fibrous Dysplasia/McCune-Albright syndrome (FD/MAS) skeletal disease burden on Na[18F]F-PET-CT and serum bone turnover markers (BTMs) was recently described. The effect of treatment on lesional fluoride burden in FD/MAS is unknown. Objective To investigate treatment response measurements in FD/MAS patients who underwent Na[18F]F-PET-CT and treatment with antiresorptives. Design Observational case series. Setting Academic center of expertise for rare bone diseases. Patients 15 consecutive patients with FD/MAS with baseline and follow-up Na[18F]F-PET-CT-parameters of healthy bone and FD lesions, BTMs and pain scores at start of denosumab (n=8) and non-denosumab patients (n=7). Main outcome(s) On Na[18F]F-PET-CT the Volumetric measures of FD-burden (FTV) and ‘Fraction affected skeleton’ (FAS), represented the portion of the skeleton affected. This was correlated with BTMs and pain. Results Disease activity decreased significantly, with FTV 361cm 3 to 97cm 3, p=0.018 in denosumab-treated patients, not in non-denosumab patients (p=0.249). Serum P1NP and Alkaline Phosphatase (ALP) decreased significantly: 82ng/mL vs 55ng/mL, p=0.023 and 119 IU/L vs 84 IU/L, p=0.020, respectively. In denosumab-treated patients pain scores improved leading to pain medication reduction. This correlated with lesional uptake whilst healthy bone activity did not change. BTMs and FTV correlated positively, P1NP r=0.730; p<0.001 and ALP r=0.406; p=0.006, as dis change in BTMs and FTV: P1NP (p=0.032) and ALP (p=0.024). FAS strongly correlated with treatment-induced decrease in ALP (p=0.027) and P1NP (p=0.009). Conclusion Na[18F]F-PET-CT captured treatment-induced lesional changes which correlated with BTMs and pain reduction. Therefore Na[18F]F-PET-CT can be used as an objective local parameter of response to denosumab treatment in FD/MAS.

18F-Sodium Fluoride PET as a Diagnostic Modality for Metabolic, Autoimmune, and Osteogenic Bone Disorders: Cellular Mechanisms and Clinical Applications

“…Similarly, osteoclasts can promote osteoblasts and bone formation by releasing transforming growth factor beta (TGF-β) and insulin-like growth factor 1 (IGF-1) from the bone matrix [ 26 , 27 ]. Anti-resorptive therapies, such as denosumab, can obstruct the osteoclast–osteoblast communication by preventing RANKL from binding to receptor activator of nuclear factor-κ B (RANK) on the osteoclast surface, inhibit osteoclast formation, and decrease osteoclast-derived coupling factors that stimulate bone formation by osteoblasts, which can all be detected and monitored using 18 F-NaF-PET [ 28 , 29 ].…”

“…It would be interesting to observe the effect of other therapeutic anti-resorptive agents, such as denosumab, on the 18 F-NaF uptake of osteoporotic patients. It has been shown that denosumab treatment in patients with fibrous dysplasia/McCune–Albright syndrome, a rare condition in which fibrous tissues replace the bone, decreases the disease burden measured by 18 F-NaF-PET/CT, as well as serum procollagen-1 N-terminal peptide (P1NP) and alkaline phosphatase levels [ 29 ].…”

Successful treatment with denosumab for pelvic fibrous dysplasia

“…Several recent reports have shown that patients with refractory FD benefit from denosumab treatment with different schedules and doses (Table 1). [7][8][9][10][11][12]17,18] Majoor et al suggested that a treatment regimen of 60 mg every 6 months was insufficient to achieve a sustained reduction of bone turnover markers in patients with FD, and all patients were eventually treated with 60 mg of denosumab every 3 months. [9] Favorable clinical responses to treatment with denosumab in these reports and our case support further investigation regarding the potential use of denosumab in patients with refractory FD.…”

“…Although the use of denosumab in FD is currently off-label, the information in this report supports the consideration of denosumab in the treatment algorithm for patients with FD unsuitable for surgical treatment. PFD (21) MAS ( 9) MFD ( 7 van der Bruggen, 2021 [18]…”

Safety of therapy with and withdrawal from denosumab in fibrous dysplasia and McCune-Albright syndrome: an observational study

“…( 25 , 26 ) In an FD/MAS mouse model, Dmab halted the progression of lesions, induced the formation of mineralized bone within lesions, and prevented the development of new FD lesions. ( 27 ) In humans successful treatment has been observed in BP refractory patients, leading to diminished growth rate ( 28 , 29 ) or even regression of lesions, ( 30 , 31 ) to pain reduction and to decreased bone turnover. ( 32 , 33 , 34 , 35 ) Nevertheless, data on the safety of long‐term Dmab use and especially on Dmab withdrawal in FD/MAS have not been reported.…”