Procollagen type I N-terminal propeptide (PINP) and C-terminal propeptide (PICP) are enzymatically cleaved fragments derived from the C-terminal domain of type I collagen during osteoblast-mediated biosynthesis. These peptides serve as specific biomarkers of bone formation, reflecting collagen I synthesis rates and osteoblast activity (3). Because PINP resistant to freeze-thaw cycles, it is easier and more economical to measure than PICP, it is more widely used in clinical practice (20, 21). The Bone Marker Criteria Working Group of the Osteoporosis Foundation and the International Federation of Clinical Chemistry and Laboratory Medicine have recommended the use of serum PINP as a reference marker for evaluating bone formation (17, 22). Significant differences in PINP between age and sex have been observed in many studies. Serum concentrations of PINP peak during infancy, decline intermittently through childhood, and diverge markedly during puberty. Adolescent males exhibit sustained PINP elevation correlating with delayed peak height velocity, whereas females demonstrate progressive declines post-menarche. These patterns mirror sex-dimorphic endocrine regulation of skeletal maturation and growth plate dynamics (23, 24).

Bone-specific alkaline phosphatase (BALP), a tissue-specific isoform of alkaline phosphatase (ALP), is exclusively synthesized by osteoblasts and serves as a specific biomarker of osteoblast activity. While total ALP exhibits limited diagnostic specificity due to its expression in hepatobiliary and intestinal tissues, BALP demonstrates superior specificity for skeletal pathology in pediatric populations, particularly given the low incidence of hepatic comorbidities in children (25, 26). Notably, BALP quantification is minimally confounded by renal dysfunction, establishing its utility as the preferred biomarker for bone metabolism assessment in hemodialysis patients (27). During growth periods, BALP and PINP exhibit parallel trajectories, peaking during early-to-mid puberty with strong correlations to height velocity. Sexual dimorphism is evident: adolescent males display higher peak BALP and PINP concentrations occurring later than females, reflecting androgen-driven growth plate maturation (18, 28, 29).

OC (osteocalcin), a 49-amino acid γ-carboxyglutamic acid-containing protein secreted by osteoblasts, regulates calcium deposition and hydroxyapatite crystallization within the bone matrix (3). OC increases with age, peaking at 11–13 years of age in boys and 9–12 years of age in girls. Unlike BALP and PINP, the pubertal peak of OC may be lower in boys than in girls (17). Unlike PINP and BALP which reflect collagen synthesis and mineralization phases respectively, OC demonstrates dual functionality: while classically categorized as a formation marker, emerging evidence implicates OC in coupled bone turnover through paracrine modulation of osteoblast-osteoclast cross-talk (30, 31). Controversy persists regarding OC’s primary role, with some studies proposing its classification as a turnover biomarker given its homeostatic regulation of formation-resorption equilibrium independent of mineralization (17, 32). Methodologically, OC exhibits pronounced diurnal variation, with the highest concentration in the morning, necessitating standardized morning phlebotomy to ensure analytical reliability (17, 33).

N-terminal telopeptide (NTX) and C-terminal telopeptide (CTX) of type I collagen are osteoclast-derived proteolytic fragments released during collagen I degradation—the primary collagenous component of bone matrix. These telopeptides serve as specific biomarkers for quantifying bone resorption rates and metabolic turnover (34). While NTX is predominantly urinary-excreted, CTX exists in both serum and urine. Due to its ease of measurement, CTX is commonly measured in clinical settings. By specifically targeting β-isomerized aspartic acid residues within the C-terminal telopeptide region of type I collagen, β-CTX immunoassays have emerged as the gold-standard clinical methodology due to their enhanced epitope specificity and consistently superior analytical performance demonstrated in cross-laboratory validation studies (3, 34). CTX expression is relatively stable and slightly increased in childhood, peaks in early adolescence, and subsequently decreases (35, 36). serum β-CTX levels exhibit gradual prepubertal increases in both sexes, followed by sexual dimorphism during puberty. Females show stabilization post-menarche correlating with earlier growth plate closure, whereas males maintain ascending β-CTX levels until late puberty, reflecting prolonged endochondral ossification (34, 36). Studies have shown that CTX is more susceptible to diet, circadian patterns and renal function than PINP. Data suggest that CTX levels are inaccurately increased in patients with significant renal impairment and may be five times higher in hemodialysis patients. Standardized morning fasting sampling is therefore recommended to minimize pre-analytical variability (14, 37).

Tartrate-resistant acid phosphatase (TRAP), a lysosomal enzyme secreted by osteoclasts and monocyte-macrophage lineage cells, exists as two isoforms: TRAP-5a and TRAP-5b. TRAP-5b, being osteoclast-specific, serves as a robust biomarker for quantifying osteoclast numbers and bone resorption activity (38). TRAP-5b exhibits childhood-specific patterns, with a maximum value at birth followed by an accelerated and sustained decline during puberty (18). Unlike CTX, TRAP-5b directly correlates with osteoclast population size and is less affected by renal function, so TRAP-5b can be used to measure bone resorption in patients with impaired renal function (14, 39).

Osteoporosis was previously recognized as a disease of old age, but is now of great concern in children and adolescents. The major determinant of lifetime risk for osteoporosis is the magnitude of peak bone mass attained in early adulthood, suggesting that bone health in childhood has a significant impact on lifetime risk for osteoporosis and osteoporotic fractures (35, 47). Osteoporosis in children is usually categorized into hereditary primary osteoporosis and secondary osteoporosis caused by systemic disease or drug use. The most common form of primary childhood osteoporosis is impaired osteogenesis, which is primarily associated with mutations in genes involved in the synthesis or post-transcriptional modification of type I collagen (48, 49). The International Society for Clinical Densitometry (ISCD) diagnostic criteria (2013 revision) mandate: (1) ≥1 vertebral compression fracture(s) without underlying focal pathology or high-impact trauma, or (2) low bone mineral density (BMD; Z-score <−2.0) plus significant fracture history (≥2 long bone fractures before age 10 or ≥3 before age 18) (48, 49).

Although not included in osteoporosis diagnostic criteria, BTMs are clinically essential for monitoring treatment response. BTMs are pivotal for monitoring antiresorptive therapy response, with bisphosphonate treatment typically reducing β-CTX by 50-80% within 2 months and PINP by 40-60% within 6 months (14). Multiple international guidelines recognize bone turnover markers (BTMs) as tools for initial osteoporosis assessment and treatment monitoring ( Table 1 ). Their superior clinical responsiveness supports therapeutic decision-making. Consequently, the International Osteoporosis Foundation (IOF) and European Calcified Tissue Society (ECTS) recommend BTMs to detect suboptimal treatment adherence (45). International consensus further endorses BTM evaluation of bone remodeling status before initiating anti-osteoporosis therapy, facilitating early assessment of treatment adherence and responsiveness within months of commencement, thereby guiding ongoing therapeutic decisions (46). Specifically, IOF/ECTS advise baseline PINP or β-CTX measurement prior to oral bisphosphonate initiation, with reassessment at 3 months verifying reductions exceeding the least significant change (LSC) (50). Clinically, Denosumab is often used to treat osteoporosis, with transition to bisphosphonate therapy at the end of denosumab treatment. Within days of denosumab treatment, CTX decreases to near undetectable levels and PINP reaches its lowest value within 3–6 months. Without timely transition to bisphosphonate therapy after the final denosumab injection, BTMs rise rapidly, which may be associated with rebound compression fractures. The Endocrine Society therefore recommends the use of BTMs to guide the transition to denosumab therapy. And there are data from studies suggesting that patients who receive PINP monitoring are more likely to start oral bisphosphonate therapy after ending denosumab therapy (14, 51). However, additional studies are needed to validate the clinical usefulness of BTMs, establish standardized reference ranges, and determine the optimal timing and frequency of monitoring.

Rickets, a metabolic bone disorder predominantly affecting children and adolescents, arises from vitamin D deficiency or aberrant vitamin D metabolism. Insufficient vitamin D impairs intestinal calcium and phosphate absorption, leading to hypocalcemia and hypophosphatemia that disrupt normal bone mineralization45. In hypophosphatemic rickets, bone formation markers such as OC and ALP may be elevated showing an increase in bone formation stimulation, while a decrease in ALP activity is a good indicator of treatment efficacy. Conversely, bone resorption markers such as NTX may be elevated, reflecting accelerated bone resorption and the extent of bone destruction (52, 53). These dynamic BTM profiles enable quantitative assessment of disease severity and treatment efficacy in rickets management.

Primary hyperparathyroidism (PHPT) characterized by autonomous overproduction of parathyroid hormone (PTH) from one or more parathyroid glands. Studies have shown that serum markers of bone formation, such as BALP, are often elevated in patients with PHPT, whereas bone resorption markers may not be significantly increased. Early biochemical intervention is critical to mitigate progressive bone loss and osteoporosis risk. Serial BTM monitoring, combined with DXA and BMD assessment, facilitates personalized management to prevent fragility fractures (54, 55). Parathyroidectomy (PTX) normalizes BTMs, with β-CTX restoration to physiological levels indicating successful resolution of PTH-driven bone resorption (55).

PHPT associated with multiple parathyroid gland hyperplasia and/or adenomas (syndromic type) is a multiple endocrine tumor type 1 (MEN 1), the most common endocrinopathy, which is an inherited disorder. Elevated PTH begins in late childhood, adolescence, or early adulthood and may negatively affect the normal acquisition of peak bone mass. It was found that in untreated patients with MEN1-associated PHPT, serum bone alkaline phosphatase (BALP) levels were significantly elevated, showing higher osteoblastic activity. In contrast, in patients with sporadic PHPT, BALP levels were within the normal range. In addition, it was observed that serum PTH, calcium ion, total calcium and BALP levels were significantly reduced in patients with MEN1-associated PHPT and sporadic PHPT after PTX. This suggests that PTX restores normal levels of serum BTMs and reduces bone resorption activity (56). Thus, integrative BTM and BMD evaluation optimizes therapeutic decision-making in PHPT management.

Juvenile idiopathic arthritis (JIA) is a disease associated with imbalances in bone metabolism. Studies demonstrate that BTMs correlate with disease activity and therapeutic response in JIA, BALP levels reflect inflammatory osteoblast activation (57), while increased β-CTX concentrations are associated with adiposity and hyperleptinemia (58, 59). Concomitant reductions in BMD further underscore the elevated osteoporosis and fracture risk in this population (57).

Current data suggest that JIA-associated bone loss arises from a resorption-formation imbalance, driven by chronic inflammation and metabolic disturbances. While BTM profiling provides actionable insights into skeletal health and treatment efficacy, the precise mechanisms linking JIA pathophysiology to bone remodeling remain incompletely elucidated. Targeted interventions to preserve bone mass in JIA, particularly those addressing inflammatory and leptin-mediated pathways, require further translational and clinical validation.

Pediatric obesity is associated with suppressed bone turnover, particularly in females, as evidenced by reduced OC, NTX, and OC/NTX ratios. This hypometabolic state may arise from dual mechanisms: (1) impaired osteoblast differentiation or activity due to adipocyte-dominated marrow microenvironmental remodeling; and (2) chronic low-grade inflammation with elevated TNF-α, IL-6 inhibiting Wnt/β-catenin signaling pathways critical for osteogenesis (36). The adipokine imbalance characteristic of obesity, notably hyperleptinemia, further exacerbates skeletal metabolism dysregulation through central nervous system-mediated suppression of bone formation (60).Although these mechanisms collectively suggest reduced bone strength and compromised peak bone mass accrual in obese adolescents, causal relationships remain contentious. Prospective cohort studies are needed to clarify whether obesity-induced bone turnover suppression independently predicts long-term fracture risk or merely associates with established osteoporosis risk factors.

Type 1 diabetes mellitus (T1DM) exerts deleterious effects on pediatric bone health through multifactorial pathways. Chronic hyperglycemia disrupts calcium-vitamin D homeostasis, induces advanced glycation end-product (AGE) accumulation in bone collagen, promotes marrow adiposity via osteoblast-adipocyte transdifferentiation, and exacerbates oxidative stress—collectively impairing osteoblastogenesis while enhancing osteoclastic activity (61). Evidence indicates that T1DM children exhibit suppressed bone remodeling, characterized by reduced bone formation markers (e.g., PINP) and elevated resorption markers (e.g., β-CTX), predisposing them to low BMD and fragility fractures (61, 62).

While optimized glycemic control may attenuate these metabolic perturbations, the precise molecular mechanisms underlying diabetic osteopathy, particularly AGE-RAGE axis activation and Wnt/β-catenin pathway inhibition, require further elucidation. Targeted therapeutic strategies combining glycemia management with bone anabolic agents represent a promising avenue for mitigating skeletal complications in pediatric T1DM.