What genes are associated with premature osteoporosis in individuals under 50?

Genes Associated with Premature Osteoporosis

When evaluating premature osteoporosis (occurring before age 50), specific monogenic causes should be investigated after excluding secondary factors, with the most common genetic culprits being COL1A1/COL1A2 (type I collagen defects), followed by LRP5, WNT1, PLS3, and SGMS2 mutations. 1, 2

Primary Monogenic Causes

Type I Collagen Gene Defects (Most Common)

• COL1A1 and COL1A2 are the most frequent genetic causes of early-onset osteoporosis, affecting type I collagen biosynthesis 1, 2
• These defects represent the commonest contributors to primary osteoporosis in young individuals 2

WNT Signaling Pathway Genes

• LRP5 (low-density lipoprotein receptor-related protein 5): Loss-of-function variants lead to early-onset osteoporosis 1, 2
• WNT1: Loss-of-function variants in this key regulatory protein of canonical WNT signaling cause early-onset osteoporosis 1, 2
• Both genes are critical for bone formation and maintenance 1

X-Linked Osteoporosis

• PLS3 (plastin-3): Mutations in this actin-binding protein gene cause X-chromosomal osteoporosis that especially affects males 1, 2
• This represents a distinct inheritance pattern compared to autosomal forms 1

Sphingolipid Metabolism

• SGMS2 (sphingomyelin synthase 2): Recently discovered mutations disturb sphingolipid metabolism and signal transduction, underscoring the complexity of molecular pathology in monogenic early-onset osteoporosis 1, 2
• This gene is critical for signal transduction affecting sphingomyelin metabolism 2

Clinical Approach to Genetic Testing

When to Consider Genetic Evaluation

• Fragility fractures occurring in childhood or young adulthood without evident secondary cause warrant investigation for monogenic bone disease 1
• Genetic testing should be considered only after thorough diagnostic workup excludes secondary factors and comorbidities 2
• Secondary causes can be found in up to 90% of cases, making their exclusion critical before pursuing genetic testing 1

Diagnostic Criteria for Young Patients

• Children and adolescents (<20 years): Z-score ≤ -2.0 plus fragility fractures or underlying chronic disease 1, 2
• Young adults (20-50 years): Z-score ≤ -2.0 or T-score ≤ -2.5 plus clinically significant fracture history 1, 2
• Low-energy vertebral compression fractures alone establish the diagnosis even without osteoporosis by BMD criteria 2

Important Clinical Caveats

Limitations of Current Knowledge

• Despite these genetic discoveries, the molecular mechanisms in early-onset osteoporosis remain largely unknown 2
• If no causal gene is identified after comprehensive testing, the condition is deemed idiopathic osteoporosis 2
• Peak bone mass is genetically determined but can also be affected by lifestyle factors, making pure genetic attribution complex 3

Avoid Common Pitfalls

• Do not pursue genetic testing before excluding secondary causes: Hypogonadism, glucocorticoid use, malabsorption, endocrine disorders, and medications account for the vast majority of cases 3, 1
• Do not diagnose osteoporosis in young adults based solely on BMD: The diagnosis requires both low BMD and fragility fractures or underlying disease 4, 1
• Do not overlook environmental factors: Puberty constitutes a vulnerable period where lifestyle factors significantly impact bone acquisition 3