Bone Mineral Density in Congenital Generalized Lipodystrophy: The Role of Bone Marrow Tissue, Adipokines, and Insulin Resistance

Abstract

Congenital Generalized Lipodystrophy (CGL) is a rare syndrome characterized by the almost total absence of subcutaneous adipose tissue due to the inability of storing lipid in adipocytes. Patients present generalized lack of subcutaneous fat and normal to low weight. They evolve with severe metabolic disorders, non-alcoholic fatty liver disease, early cardiac abnormalities, and infectious complications. Although low body weight is a known risk factor for osteoporosis, it has been reported that type 1 and 2 CGL have a tendency of high bone mineral density (BMD). In this review, we discuss the role of bone marrow tissue, adipokines, and insulin resistance in the setting of the normal to high BMD of CGL patients. Data bases from Pubmed and LILACS were searched, and 113 articles published until 10 April 2021 were obtained. Of these, 76 were excluded for not covering the review topic. A manual search for additional literature was performed using the bibliographies of the studies located. The elucidation of the mechanisms responsible for the increase in BMD in this unique model of insulin resistance may contribute to the understanding of the interrelationships between bone, muscle, and adipose tissue in a pathophysiological and therapeutic perspective.

Skeletal alterations in lipodystrophy

“…Also, later in life, during adolescence, the young patient showed osteolytic lesions which appeared and propagated mainly in the long bones, suggesting that these lesions might be an early sign of lipodystrophy. The presence and progression of bone alterations in CGL has also been described in another interesting study that reviewed 24 cases of genetic CGL; on the basis of all these reports, frequent and peculiar imaging features of skeletal abnormalities, described in generalized lipodystrophic syndromes, are osteosclerosis [20] , lytic lesions, and/or pseudo-osteopoikilosis, often associated with transformation of the bone marrow as also described in a recent review of the literature [19] .…”

“…Since the first description, by Bandeira et al, of altered bone density [18] in subjects affected by Berardinelli-Seip syndrome, more recent reports have shown that children affected by this syndrome grow rapidly and also have advanced bone age [19] . Moreover, several mutations have been described in different genes which might also lead to alterations in several different tissues, including the skeleton.…”

Heterogeneity and high prevalence of bone manifestations, and bone mineral density in congenital generalized lipodystrophy subtypes 1 and 2

“…Low levels of leptin and adiponectin, as well as hyperinsulinemia have already been implicated in the role of increased bone mass in CGL1 and CGL2 ( 14 , 32 ). However, insulin resistance is also present in CGL3 and CGL4 without elevated BMD, and studies with adipokines are still controversial.…”

Impact of metabolic syndrome on bone mineral density in men over 50 and postmenopausal women according to U.S. survey results

“…Additionally, the study by Jiang et al provided substantial evidence of a consistent relationship between low levels of HDL-C and an increase in BMD in the context of MetS while also indicating that elevated triglyceride levels positively correlate with BMD 50 . Reports have suggested that individuals with insulin resistance and elevated insulin levels due to MetS might experience an increase in BMD 51 . Animal experiments further corroborated these findings, demonstrating that insulin could enhance BMD by facilitating osteocalcin signaling, aligning with our study's conclusions 52 .…”