Interaction of adipose, muscle, and bone tissues in X-linked hypophosphatemic rickets (XLH)

• Ano de defesa: 2025
• Autor(a) principal: Silva, Maisa Monseff Rodrigues da
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: eng
• Instituição de defesa: Biblioteca Digitais de Teses e Dissertações da USP
• Palavras-chave em Português: PHEX; Adipose tissue; Espectroscopia muscular; Fósforo; Muscle spectroscopy; Muscle tissue; Phosphorus; Tecido adiposo; Tecido muscular; XLH
• Link de acesso: https://www.teses.usp.br/teses/disponiveis/17/17138/tde-26052025-094453/

X-linked hypophosphatemic rickets (XLH; OMIM#307800), although a rare disease, is the most common form of genetic rickets. It results from an inactivating mutation in the PHEX gene that is associated with an increase in the circulating rate of FGF23 and, consequently, with phosphaturia and hypophosphatemia. Several aspects remain to be elucidated, including the relationship between metabolic changes in muscle and adipose tissues and bone disease in XLH. In this cross-sectional study, we used a convenience sample selected from the osteometabolism outpatient clinic of HCFMRP-USP to evaluate the relationship between metabolic alterations in muscle tissue and bone marrow adipose tissue and XLH bone disease. The study included 11 patients with XLH (8W and 3M) and 22 individuals in the control group (16W and 6M). Nuclear magnetic resonance spectroscopy (NMR) technique was used to evaluate the use of muscle phosphorus (Pi) and hydrogen (H) spectroscopy, respectively, and the quantitative and qualitative estimation of bone marrow adipose tissue. It was also our aim to evaluate the relationship between muscle cytokines and insulin resistance with bone changes in XLH. The bone phenotype was evaluated by bone densitometry and trabecular bone score (TBS). Bone densitometry was also used to assess body composition. Given that XLH is a rare disease, the groups were matched in a 2:1 ratio (control to XLH) matched by sex (C=16W, XLH=8W; C=6M, XLH=3M) and age (C=30, IQR 24-33; XLH=31, IQR 23-34 years; p=0.955). Individuals in the XLH group presented higher BMI (C=22.5, IQR 21.0-23.8; XLH=26.3, IQR 22.4-31.1 kg/m², p=0.014) and a higher fat mass index (C=6.83, IQR 5.22- 7.88; XLH=9.79, IQR 6.72-14.65 kg/m², p=0.011), without significant differences in total fat percentage or lean mass. XLH patients also presented higher FGF 23 values (C=42.7, IQR 34.92-46.85; XLH=51.1, IQR 46.5-79.6 pg/mL p=0.002), and lower phosphorus values (C=3.96, IQR 3.86-4.84; XLH=2.02, IQR 1.89-2.31mg/dL, p<0.0001). Bone analysis revealed an increase in lumbar spine density as measured by areal densitometry (C=1.155, IQR 1.074- 1.271; XLH=1,492, IQR 1,359-1,628 g/cm², p=0.0003). After adjusting for patient height, estimated volumetric bone densitometry results were sustained (C=0.161, IQR 0.146-0.172; XLH=0.212, IQR 0.188-0.234 g/cm³, p<0.001). XLH patients also had a higher TBS than the control group (C=1.425, IQR 1.377-1.476; XLH=1.652, IQR 1.557-1.728 AU, p<0.001). On the other hand, the control group exhibited significantly higher bone mass at the 1/3 radius when measured by densitometry. There was no difference in bone mass in other sites (total hip and femoral neck). There was no difference in tibial bone marrow adiposity between the groups (C=92, IQR 84.5-94.2; XLH=91.10, IQR 88.5-92.7%, p=0.77), nor of its saturated and unsaturated fractions. When analyzing the intramuscular lipids of the soleus muscle with hydrogen spectroscopy by MRS, a higher concentration of extramyocellular lipids (EMCL) was observed in the XLH group (C=1387, IQR 1017-1790; XLH=2337, IQR 1655-5698AU, p=0.03), with no significant difference in intramyocellular lipids. Insulin resistance parameters were normal and showed no significant difference between the groups, as calculated by HOMA-IR (C=1.48, IQR 1.00-2.15; XLH=1.77, IQR 1.22-3.99 AU, p=0.281) and Triglycerides Index (TyG) (C=7.94, IQR 7.8-8.4; XLH=8.48, IQR 7.65-8.87 AU, p=0.264). Phosphorus spectroscopy was performed on the soleus muscle before and after exercise. The control group displayed higher phosphocreatine levels at rest (C=0.0213, IQR 0.0181-0.0248; XLH=0.0153, IQR 0.0090-0.0193 AU, p=0.021), but there was no difference in the other parameters (ATP levels, pH, Mg, and Pi), neither at rest nor after exercise. The present study suggests that overweight and obesity are frequent among XLH subjects; despite this, they show a healthy fat distribution profile and normal insulin resistance parameters. Curiously, not only BMD but also TBS are increased in lumbar spine of XLH. BMD in 1/3 radius was lower in XLH suggesting an impairment in cortical bone. The slight abnormalities found in the bone phenotype are compatible with a history of no fragility fracture. The present study encourages further studies to evaluate the meaning of lower muscle levels of phosphocreatine in XLH and its consequence for bone strength.