Early-Onset Osteoporosis: Rare Monogenic Forms Elucidate the Complexity of Disease Pathogenesis Beyond Type I Collagen

Abstract

Early-onset osteoporosis (EOOP), characterized by low bone mineral density (BMD) and fractures, affects children, premenopausal women and men aged <50 years. EOOP may be secondary to a chronic illness, long-term medication, nutritional deficiencies, etc. If no such cause is identified, EOOP is regarded primary and may then be related to rare variants in genes playing a pivotal role in bone homeostasis. If the cause remains unknown, EOOP is considered idiopathic. The scope of this review is to guide through clinical and genetic diagnostics of EOOP, summarize the present knowledge on rare monogenic forms of EOOP, and describe how analysis of bone biopsy samples can lead to a better understanding of the disease pathogenesis. The diagnostic pathway of EOOP is often complicated and extensive assessments may be needed to reliably exclude secondary causes. Due to the genetic heterogeneity and overlapping features in the various genetic forms of EOOP and other bone fragility disorders, the genetic diagnosis usually requires the use of next-generation sequencing to investigate several genes simultaneously. Recent discoveries have elucidated the complexity of disease pathogenesis both regarding genetic architecture and bone tissue-level pathology. Two rare monogenic forms of EOOP are due to defects in genes partaking in the canonical WNT pathway: LRP5 and WNT1. Variants in the genes encoding plastin-3 (PLS3) and sphingomyelin synthase 2 (SGMS2) have also been found in children and young adults with skeletal fragility. The molecular mechanisms leading from gene defects to clinical manifestations are often not fully understood. Detailed analysis of patient-derived transiliac bone biopsies gives valuable information to understand disease pathogenesis, distinguishes EOOP from other bone fragility disorders, and guides in patient management, but is not widely available in clinical settings. Despite the great advances in this field, EOOP remains an insufficiently explored entity and further research is needed to optimize diagnostic and therapeutic approaches.

A Novel RUNX1 Genetic Variant Identified in a Young Male with Severe Osteoporosis

“…Given the often ubiquitous and transcriptional nature of the affected genes, extraskeletal manifestations affecting other organ systems have been described. (4) In our patient, it is possible that his hematological and nephrological conditions are related to the known RUNX1 variant. Interestingly, a novel Mendelian randomization study provided evidence that the hematopoietic system may regulate the skeletal system in humans, with red and white blood cell traits observed to have positive and inverse causal effects on BMD, respectively.…”

Lipocalin-2 is associated with FGF23 in WNT1 and PLS3 osteoporosis

“…WNT1 and PLS3 are two crucial factors regulating bone metabolism and abnormalities in their signaling have been linked to severe early-onset osteoporosis ( 20 ). The pathway for WNT1 is quite well known: WNT1 signals through the canonical WNT/beta-catenin pathway by binding to a transmembrane dual co-receptor consisting of LRP5/LRP6 and seven transmembrane G-protein Frizzled (FZD), initiating an intracellular cascade resulting in increased bone formation and decreased bone resorption.…”

A practical guide to the diagnosis and management of osteoporosis in childhood and adolescence

“…Advances in our understanding of the genetic basis of congenital bone fragility have been among the most important discoveries in the pediatric osteology field since the turn of the century, with numerous reviews describing what now approaches nearly two dozen monogenic causes of primary, juvenile-onset, monogenic osteoporosis ( 22 , 31 – 34 ). In children with a significant fracture history but a negative work-up for an acute or chronic illness, the hunt for a genetic cause of osteoporosis is reasonable (even in the absence of hallmark signs such as blue sclerae or dentinogenesis imperfecta, which are not always present in primary osteoporosis).…”