Musculoskeletal Aging

Musculoskeletal aging refers to progressive changes in bones, muscles, joints, and connective tissues that affect strength, balance, and mobility.

Biomarkers are measurable indicators of biological processes that reflect aging-related degeneration in bone, muscle, cartilage, and connective tissue. They can support early detection, monitor disease progression, and evaluate treatment responses.

Azad et al. synthesized current knowledge on the biologic mechanisms underlying musculoskeletal aging, focusing on the implications for the aging spine. The complexity of the aging process, characterized by a convoluted interplay between genetic, environmental, and lifestyle factors, necessitates a comprehensive understanding of the biologic processes and reliable methods of surveying biologic states to inform effective diagnostic, predictive, and prognostic strategies. Biomarkers emerge as invaluable tools in this domain, offering insights into the early detection, risk assessment, and targeted intervention for age-related musculoskeletal decline. A review highlights various biomarker types including diagnostic, predictive, and prognostic, and explores their distinct roles in enhancing our understanding of musculoskeletal aging. Navigating the interconnected landscape of cellular senescence, sarcopenia, osteoporosis, and frailty, this review underscores the critical importance of developing personalized care approaches for the aging population. By identifying and integrating functional biomarkers, researchers and clinicians can elucidate the underlying mechanisms and devise tailored strategies to alleviate the musculoskeletal decline associated with the aging process. They envision an “active surveillance” future where biomarkers of musculoskeletal aging are integrated into clinical practice, empowering clinicians to make proactive, data-driven decisions that improve Spine Health in Older Adults ¹⁾.

Bone Formation:

Osteocalcin (OCN)
Bone-specific alkaline phosphatase (BSAP)
Procollagen type I N-terminal propeptide (P1NP)

Bone Resorption:

C-terminal telopeptide of type I collagen (CTX-I)
N-terminal telopeptide of type I collagen (NTX-I)
Tartrate-resistant acid phosphatase 5b (TRACP-5b)

Mineral Metabolism:

Calcium, Phosphate
25(OH) Vitamin D
Parathyroid hormone (PTH)
Fibroblast growth factor 23 (FGF-23)

Muscle Atrophy / Sarcopenia:

Creatinine (serum and urinary)
C-terminal Agrin Fragment (CAF)
GDF-15 (Growth Differentiation Factor-15)
Myostatin (negative regulator of muscle growth)
Follistatin (inhibitor of myostatin)

Inflammation / Catabolism:

C-reactive protein (CRP)
Interleukin-6 (IL-6)
Tumor necrosis factor alpha (TNF-α)

Muscle Mass and Function (Imaging-based):

Appendicular lean mass index (ALMI via DXA)
Muscle cross-sectional area (MRI or CT)
Handgrip strength, gait speed, SPPB score

Cartilage Turnover:

Cartilage oligomeric matrix protein (COMP)
C2M (MMP-derived degradation product of type II collagen)
CTX-II (C-terminal telopeptide of type II collagen)
PIIANP (Procollagen type II N-terminal propeptide)

ECM and Matrix Remodeling:

Matrix metalloproteinases (MMP-3, MMP-9)
Tissue inhibitors of MMPs (TIMPs)
Advanced glycation end-products (AGEs) and Pentosidine

DNA methylation clocks (e.g. Horvath clock)
Telomere length
Circulating microRNAs (e.g., miR-21, miR-206)
Senescence-associated secretory phenotype (SASP factors)

Early detection of osteosarcopenia and frailty.
Monitoring response to exercise or pharmacologic interventions.
Risk stratification for falls, fractures, or immobility.
Translational research for aging interventions and longevity.

Bone loss begins around age 30, accelerates after menopause.
Osteopenia / Osteoporosis due to reduced bone mineral density (BMD).
Increased bone porosity and altered collagen cross-linking.
Common fractures: hip, vertebral, wrist.

Sarcopenia: age-related loss of muscle mass, strength, and function.
Atrophy of type II fibers (fast-twitch) more than type I.
Mitochondrial dysfunction and reduced regenerative capacity.
Consequences: decreased strength, slower gait, falls.

Cartilage degeneration, leading to osteoarthritis.
Synovial fluid changes: reduced viscosity and joint lubrication.
Stiffening of ligaments and tendons due to collagen cross-linking.
Joint stiffness, especially in knees and hips.

“Inflammaging”: chronic low-grade inflammation contributes to degeneration.
Oxidative stress: damages proteins, DNA, and lipids.
Reduced anabolic signaling: IGF-1, mTOR, growth hormone.
Stem cell exhaustion: reduced repair capacity (e.g., satellite cells).

↑ Risk of falls, fractures, and immobility.
Contributes to frailty, loss of independence, and poor prognosis.
May overlap with osteosarcopenia, cachexia, or geriatric syndromes.

Resistance training: most effective intervention against sarcopenia.
Calcium + Vitamin D supplementation for bone health.
Protein intake: ≥ 1.2 g/kg/day recommended in older adults.
Pharmacologic options: bisphosphonates, denosumab, SERMs.
Fall prevention: balance training, home safety adaptations.

¹⁾

Azad TD, Li MW, Ping-Yeh C, Jones KE, Lord EL, Molina CA, Walker CT, Osorio JA, Pizones J, Theologis A, van Hooff M, Yagi M, Kelly MP, de Kleuver M, Hu SS, Shah SA, Pellisé F, Walston JD, Eastlack RK, Ames CP; Scoliosis Research Society Adult Spinal Deformity Task Force on Senescence. Musculoskeletal biomarkers in health and disease: implications for the aging spine-a review for spinal surgeons by the SRS adult spinal deformity task force on senescence. Spine Deform. 2025 Jun 4. doi: 10.1007/s43390-025-01124-w. Epub ahead of print. PMID: 40465097.