Identification of bone metabolism disorders in patients with Alström and Bardet-Biedl syndromes based on markers of bone turnover and mandibular atrophy

Abstract

Objectives: Causative variants in genes responsible for Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) cause damage to primary cilia associated with correct functioning of cell signaling pathways in many tissues. Despite differences in genetic background, both syndromes affect multiple organs and numerous clinical manifestations are common including obesity, retinal degeneration, insulin resistance, type 2 diabetes and many others. The aim of the study was to evaluate bone metabolism abnormalities and their relation to metabolic disorders based on bone turnover markers and presence of mandibular atrophy in patients with ALMS and BBS syndromes.

Material and methods: In 18 patients (11 with ALMS and 7 with BBS aged 5-29) and in 42 age-matched (p < 0.05) healthy subjects, the following markers of bone turnover were assessed: serum osteocalcin (OC), osteoprotegerin (OPG), s-RANKL and urinary deoxypyridinoline - DPD. In addition, a severity of alveolar atrophy using dental panoramic radiograms was evaluated.

Results: Lower serum OC (p = 0.0004) and urinary DPD levels (p = 0.0056) were observed in the study group compared to controls. In ALMS and BBS patients, serum OC and urinary DPD values negatively correlated with the HOMA-IR index, while a positive correlation between the OC and 25-OHD levels and a negative correlation between s-RANKL and fasting glucose concentrations were found. A significant difference in the incidence of low-grade mandibular atrophy between patients with ALMS and BBS and controls (p < 0.0001) was observed.

Conclusions: The identification of bone metabolism disorders in patients with ALMS and BBS syndromes indicates the necessity to provide them with appropriate diagnosis and treatment of these abnormalities.

Keywords: 25-OHD, 25-hydroxyvitamin D; ALMS; ALMS, Alström syndrome; AP, alkaline phosphatase; AST, aspartate transaminase; Alveolar atrophy; BBS; BBS, Bardet-Biedl syndrome; BMD, bone mineral density; BMI SDS, body mass index standard deviation score; BMI, body mass index; Bone turnover markers; Ciliopathy; DM, diabetes mellitus; DPD, urinary deoxypyridinoline; DXA, dual energy X-ray absorptiometry; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance assessment; IQR, interquartile range; LDL, low-density lipoprotein; LMS, least mean squares; MCW, mandibular cortical width; MIC, mandibular inferior cortex; Me, median; OC, serum osteocalcin; OPG, osteoprotegerin; PTH, parathyroid hormone; T2DM, type 2 diabetes mellitus; s-RANKL, soluble Receptor Activator of Nuclear factor κB Ligand.

Fig. 1

Panoramic dental radiograph of the mandibular bone with assessment of the IC/IM resorption index and MCW index. IC - the distance from the lower edge of the mandible to the upper border of the alveolar part, assessed in the line of the chin opening; IM - the distance from the lower edge of the mandible to the lower edge of the chin opening; MCW - mandibular cortical width.

Fig. 2

Correlations between metabolism turnover markers and laboratory test results in the study group: a. HOMA-IR vs. osteocalcin (R = -0.7785; p = 0.0004); b. HOMA-IR vs. DPD (R = -0.5221; p = 0.0316); c. 25-OHD vs. osteocalcin (R = 0.5773; p = 0.0242); d. fasting glucose level vs. sRANKL (R = -0.5537; p = 0.0211). s-RANKL - soluble Receptor Activator of Nuclear factor κB Ligand; DPD - urine concentration of pyridinoline; 25-OHD - 25-hydroxyvitamin D; HOMA-IR - homeostatic model of insulin resistance assessment.