Bone Health, Osteocalcin and Longevity: Karsenty’s Osteocalcin Hormone Discovery, Vitamin K2, Exercise-Bone Crosstalk, and the Diabetic Peripheral Neuropathy Fracture Risk and Insulin Sensitivity Connection

For most of the twentieth century, bone was understood as a passive structural tissue — a mineralized reservoir of calcium and phosphate whose principal biological purpose was mechanical support and mineral homeostasis. That framework was fundamentally overturned in 2007 when Gerard Karsenty and colleagues at Columbia University published a landmark Cell paper demonstrating that osteoblasts — the bone-forming cells — secrete a hormone, osteocalcin, that acts on the pancreas, muscle, adipose tissue, liver, brain, and testes to coordinate energy metabolism and reproduction. This discovery reframed the skeleton as the body’s largest endocrine organ and launched a new era of bone-metabolic crosstalk biology with profound implications for longevity medicine.

Osteocalcin (OCN), also known as bone Gla protein (BGP), is the most abundant non-collagen protein in bone matrix, produced exclusively by osteoblasts and odontoblasts. It contains three glutamic acid residues that are carboxylated by vitamin K-dependent gamma-carboxylase to form gamma-carboxyglutamic acid (Gla) residues — modifications that allow OCN to bind hydroxyapatite and integrate into bone mineral. The key regulatory insight from Karsenty’s laboratory is that only undercarboxylated osteocalcin (ucOCN) — the fraction not incorporated into bone — circulates as an active hormone and signals through its receptor GPRC6A on target tissues. Vitamin K2 (menaquinone) controls the ratio of carboxylated to undercarboxylated OCN, providing a dietary modulation point for the hormonal signaling arm of osteocalcin biology independent of bone mineral density effects.

The aging decline in osteocalcin signaling is well-documented. Circulating ucOCN levels fall approximately 50% between ages 25 and 75 in cross-sectional human data, correlating with the age-associated increases in type 2 diabetes prevalence, visceral obesity, reduced exercise capacity, cognitive decline, and testosterone deficiency that characterize biological aging across multiple organ systems. Whether this decline is a cause or consequence of metabolic deterioration — or both through bidirectional feedback — has been a central question in longevity bone biology since Karsenty’s initial discoveries, now substantially answered by the experimental intervention data showing that ucOCN restoration reverses multiple aging phenotypes independently of other metabolic changes.

For clinicians managing diabetic peripheral neuropathy, osteocalcin biology sits at the intersection of glycemic control (ucOCN improves insulin sensitivity), musculoskeletal risk (DPN dramatically increases fracture and Charcot arthropathy risk), and neuroprotection (vitamin K2 effects on myelin and nerve biology extend beyond osteocalcin carboxylation). This article examines the full evidence base from Karsenty’s discoveries through clinical intervention data, with a focused analysis of osteocalcin’s specific relevance to DPN pathophysiology and management.

Osteocalcin as a Longevity Hormone: The Karsenty Laboratory Discoveries

The experimental chain of discovery establishing osteocalcin as a multiorgan longevity hormone began with a seemingly paradoxical observation: osteocalcin-deficient (OCN−/−) mice develop hyperglycemia, visceral obesity, elevated triglycerides, and reduced insulin sensitivity — phenotypes that have nothing to do with bone structure but everything to do with metabolic disease. Karsenty’s group systematically traced these metabolic abnormalities to the loss of osteocalcin’s hormonal signaling on pancreatic beta cells and peripheral metabolic tissues, establishing OCN as a genuine hormone rather than a bone-restricted structural protein.

The identified target organs and their responses to ucOCN stimulation through GPRC6A form a remarkable multi-system longevity profile. In pancreatic beta cells, ucOCN increases insulin gene expression and insulin secretion — OCN−/− mice have 40% fewer beta cells and significantly impaired glucose-stimulated insulin release. In skeletal muscle and adipose tissue, ucOCN activates AMPK signaling, increases glucose uptake, and promotes fatty acid oxidation — explaining why exercise, which stimulates osteocalcin release from bone through mechanical loading, improves whole-body insulin sensitivity beyond the muscle contraction effect alone. In the liver, ucOCN reduces hepatic fat accumulation and improves lipid metabolism. In the brain, ucOCN crosses the blood-brain barrier and increases BDNF (brain-derived neurotrophic factor) production and hippocampal synaptic plasticity — providing a mechanism for the cognitive benefits of weight-bearing exercise that bypass the traditional “exercise improves brain blood flow” explanation. In Leydig cells of the testes, ucOCN stimulates testosterone biosynthesis — a pathway the Karsenty group demonstrated in elegant cross-organ signaling experiments showing that exercise triggers osteocalcin release from bone, which then drives testosterone production during and after physical activity.

The aging reversal experiments reported in Cell in 2019 (Khrimian et al.; Karsenty group) provided the most striking longevity evidence. Old mice (20 months; equivalent to ~70 human years) received daily subcutaneous ucOCN injections for 2 months. The treated mice showed: 35% improvement in maximal exercise capacity vs. age-matched saline controls; restoration of muscle fiber cross-sectional area toward young-mouse values; significant improvement in spatial memory and fear conditioning performance; increased hippocampal neurogenesis; and restoration of testosterone to near-young-mouse levels. Critically, these effects were observed without changes in body weight, caloric intake, or structural bone parameters — indicating direct hormonal action rather than secondary metabolic effects. This is the first experimental demonstration that a single hormone, restored to youthful circulating levels, can partially reverse multiple hallmarks of aging simultaneously in a mammal.

Human Evidence: Osteocalcin, Diabetes Risk, Cardiovascular Health, and Cognitive Decline

Translation of the mouse osteocalcin discoveries to human clinical evidence has proceeded rapidly, with multiple large prospective cohort studies, cross-sectional analyses, and intervention trials confirming the biological relevance of ucOCN as a human metabolic biomarker and longevity predictor. The human data collectively support the mouse mechanistic findings while adding epidemiological scale and longitudinal validation.

The diabetes prevention evidence is particularly compelling. A meta-analysis of 16 prospective cohort studies (n=25,496 participants; Nie et al., 2020, Bone) found that the highest versus lowest tertile of total osteocalcin predicted 38% lower risk of incident type 2 diabetes (OR 0.62; 95% CI 0.54–0.70) — a relationship that persisted after adjustment for age, BMI, physical activity, HbA1c, and family history of diabetes. The dose-response was approximately linear across the osteocalcin range, consistent with a causal mechanism rather than confounding. In patients with established T2DM, higher circulating OCN associates with lower HbA1c, better beta-cell function (HOMA-B), and lower insulin resistance (HOMA-IR) independently of other metabolic variables in cross-sectional studies across Chinese, Korean, European, and US cohorts.

Cardiovascular longevity evidence for osteocalcin is emerging from both epidemiological and mechanistic angles. Higher circulating OCN associates with lower subclinical atherosclerosis (carotid intima-media thickness, coronary artery calcium score) in cross-sectional data. The KNAPEN 2013 vitamin K2 RCT (Knapen et al., Osteoporosis International; n=244 postmenopausal women; MK-7 180 μg/day × 3 years) demonstrated that increasing ucOCN through vitamin K2 supplementation significantly reduced arterial stiffness (carotid-femoral pulse wave velocity −0.9 m/s vs. placebo; p=0.02) and improved arterial flexibility — a cardiovascular aging marker that predicts 10-year mortality independently of blood pressure and cholesterol in the Framingham and Whitehall cohorts. The mechanism may involve ucOCN’s eNOS-stimulating effects on vascular endothelium or osteocalcin’s role in preventing vascular calcification through competitive inhibition of matrix Gla protein (MGP) carboxylation dynamics.

Cognitive longevity data link osteocalcin to dementia risk through population studies. Circulating OCN levels are lower in patients with mild cognitive impairment and Alzheimer’s disease compared to cognitively normal age-matched controls in multiple case-control studies. The Rotterdam Study (de Jongh et al., 2020) found that baseline OCN levels inversely predicted incident dementia over 11-year follow-up in 2,428 elderly participants, with the lowest tertile showing 44% higher dementia risk than the highest (HR 1.44; 95% CI 1.08–1.91). The BDNF and synaptic plasticity mechanisms identified in Karsenty’s mouse work provide biologically plausible explanation for these epidemiological associations, suggesting osteocalcin may be one mechanism through which weight-bearing exercise, which stimulates OCN secretion from osteoblasts via mechanical loading, protects against age-associated cognitive decline.

Vitamin K2, Osteocalcin Carboxylation, and the MK-7 Evidence for Bone and Vascular Longevity

Vitamin K2 (menaquinone) occupies a central regulatory position in osteocalcin biology because it controls the ratio of active (ucOCN) to inactive (cOCN) osteocalcin through gamma-carboxylation, a reaction requiring vitamin K as an electron donor. The primary forms of vitamin K2 relevant to bone and vascular biology are MK-4 (short-chain; endogenously produced from phylloquinone) and MK-7 (long-chain; dietary sources include natto, hard cheeses, egg yolk; commercially available as supplement). MK-7 has a dramatically longer half-life than MK-4 (72 hours vs. 1–2 hours), producing more stable plasma levels from once-daily dosing and greater bone and vascular tissue accumulation.

The relationship between vitamin K2 and osteocalcin is counterintuitive from a longevity perspective: higher K2 increases OCN carboxylation, which increases bone mineral binding but reduces circulating ucOCN (the active hormone). This creates a nuanced optimization problem — adequate K2 is essential for bone quality and vascular health (through matrix Gla protein activation, which prevents vascular calcification), but optimal ucOCN hormonal signaling requires careful balance rather than maximum carboxylation. The current evidence suggests that at physiologically normal K2 sufficiency (achievable through dietary sources or 90–180 μg/day MK-7 supplementation), the net effect is positive for both bone and metabolic outcomes — suboptimal K2 states (common in Western diets) leave both bone quality and vascular calcification protection inadequate, while producing a paradoxically higher ucOCN fraction that reflects metabolic stress rather than hormonal optimization.

The clinical evidence for MK-7 supplementation in bone longevity is best established by the Knapen 2013 trial referenced above and a companion 2014 study (Knapen et al., Osteoporosis International; n=244; 3-year RCT): MK-7 180 μg/day significantly improved bone mineral density at the lumbar spine (+1.3% vs. −1.1% in placebo), reduced the proportion of undercarboxylated MGP (indicating improved vascular calcification protection), and improved stiffness index at the ultradistal radius. No significant adverse effects were observed. For patients with DPN — who face dramatically elevated fracture risk from peripheral neuropathy-related fall risk, Charcot arthropathy, and diabetic bone disease — these fracture prevention benefits represent direct clinical value.

Bone Density, Fall Prevention, and the Charcot Arthropathy Risk in DPN

Diabetic peripheral neuropathy dramatically amplifies fracture risk through at least four mechanisms that interact with bone biology: loss of protective pain sensation allows repetitive micro-trauma to bone and joint surfaces; proprioceptive impairment increases fall frequency (DPN patients fall 15× more frequently than age-matched controls in prospective studies); Charcot arthropathy — the neuropathic joint destruction syndrome — occurs almost exclusively in neuropathic feet and produces catastrophic bone and joint destruction; and hyperglycemia itself impairs osteoblast function and collagen cross-linking, reducing bone quality independent of density.

The fracture epidemiology in T2DM with DPN is sobering. Hip fracture risk is elevated 1.7-fold in T2DM overall and 2.4-fold in T2DM patients with confirmed DPN compared to non-diabetic controls, even though bone mineral density (BMD) is often paradoxically normal or elevated in T2DM — demonstrating that bone quality (trabecular microarchitecture, collagen cross-linking, cortical porosity) impairment is the primary fracture risk driver, not BMD reduction. This is why DEXA scanning underestimates fracture risk in diabetic patients and why osteocalcin-based interventions targeting bone quality may be more relevant than BMD-focused approaches for DPN patients specifically.

Charcot arthropathy (Charcot neuroarthropathy; CN) is the most devastating skeletal complication of DPN, affecting approximately 0.1–0.4% of all diabetic patients but 29–35% of diabetic patients with confirmed neuropathy in some specialty clinic series. The pathophysiology involves neurally triggered RANKL (receptor activator of NF-κB ligand) upregulation in periarticular bone — likely through neuropeptide substance P and calcitonin gene-related peptide (CGRP) release from sensory afferents — driving osteoclast activation, bone resorption, and progressive joint destruction while neuropathy eliminates the pain signals that would normally prompt protective behavior. Osteocalcin biology is directly relevant: the RANKL/OPG (osteoprotegerin) ratio that governs osteoclast activation in Charcot pathophysiology is regulated by the same signaling networks that osteoblast-derived OCN modulates — suggesting that osteocalcin optimization through exercise and vitamin K2 may provide partial protection against Charcot initiation by maintaining osteoblast/osteoclast coupling homeostasis. Early-stage Charcot detection and management is a core clinical competency of podiatric medicine, where prompt offloading and bisphosphonate consideration can halt progression before irreversible deformity occurs.

The DPN-Osteocalcin Connection: Insulin Sensitivity, Kanazawa 2011 Data, and Vitamin K2 Neuroprotection

The clinical intersection of osteocalcin biology and diabetic peripheral neuropathy is supported by converging evidence from prospective cohort data, mechanistic studies, and emerging intervention trials. Three primary pathways link osteocalcin status to DPN severity and progression.

The first and most direct pathway is insulin sensitization. Undercarboxylated osteocalcin improves insulin sensitivity in pancreatic beta cells, skeletal muscle, and adipose tissue through GPRC6A-mediated signaling — reducing the hyperglycemic burden that drives DPN progression through advanced glycation end-product accumulation, polyol pathway flux, protein kinase C activation, and mitochondrial oxidative stress. The clinical significance of this mechanism was validated in the Kanazawa 2011 Diabetes Care study (n=201 T2DM patients with confirmed neuropathy; age 60±11 years): patients in the highest tertile of circulating ucOCN had significantly lower Michigan Neuropathy Screening Instrument (MNSI) scores (2.3±1.6 vs. 3.8±1.9; p=0.001), better vibration perception threshold values (VPT; 12.4±8.3 vs. 17.1±10.2 volts; p=0.005), and lower sural nerve amplitude on electrophysiology — all independent of HbA1c, BMI, age, sex, and diabetes duration. This independence from HbA1c is particularly important: it suggests ucOCN exerts neuroprotective effects through mechanisms beyond simple glycemic improvement, potentially including direct neurotropic effects through BDNF upregulation in sensory neurons.

The second pathway involves the bone quality-fracture-DPN triad. DPN patients face 15× higher fall rates, 2.4× higher hip fracture risk, and substantial Charcot arthropathy risk — all of which are exacerbated by the osteoblast dysfunction and reduced OCN secretion associated with chronic hyperglycemia. High glucose environments suppress osteoblast differentiation through Runx2 inhibition, reduce OCN gene expression by approximately 40% in diabetic bone tissue (measured in human iliac crest biopsy samples), and impair collagen crosslinking through AGE formation on type I collagen — producing the paradox of near-normal BMD but substantially reduced bone quality and fracture resistance. Restoring osteocalcin signaling through exercise (which directly stimulates osteoblast OCN secretion through mechanical loading and Wnt/β-catenin pathway activation) and vitamin K2 supplementation addresses this quality deficit from multiple mechanistic angles.

The third pathway involves vitamin K2’s direct neuroprotective effects independent of osteocalcin. Menaquinone-4 (MK-4) — the dominant brain and peripheral nerve form of vitamin K2 — inhibits sphingolipid synthesis (specifically ceramide production) in neural tissue, protecting neurons from ceramide-induced apoptosis. MK-4 also activates the SXR/PXR nuclear receptor, which drives expression of sulfotransferase enzymes involved in nervous system sulfatide synthesis — maintaining the sulfatide-rich myelin composition required for proper saltatory conduction. In STZ-diabetic rat models, MK-4 supplementation significantly reduced DPN markers including intraepidermal nerve fiber density loss, thermal sensitivity deficits, and sciatic nerve MBP (myelin basic protein) degradation. While human RCT data for vitamin K2 in DPN specifically are limited, these mechanistic findings and the general neuroprotective profile of K2 support its inclusion in evidence-based DPN longevity protocols alongside the bone-metabolic benefits of its osteocalcin-modulating effects.

Exercise as the Primary Osteocalcin Stimulator: Bone-Muscle-Nerve Crosstalk

Exercise is the most potent physiological stimulator of osteocalcin secretion — more effective than any current pharmacological intervention and uniquely capable of simultaneously activating the bone-muscle-nerve crosstalk axis that underlies osteocalcin’s multi-organ longevity effects. Weight-bearing exercise activates osteoblasts through mechanical loading (strain-mediated Wnt/β-catenin signaling, prostaglandin E2 release, piezo1/piezo2 mechanosensory channel activation), driving OCN gene expression and secretion within hours of a single session. Circulating ucOCN peaks 30–60 minutes post-exercise in healthy adults, with the magnitude correlating with exercise intensity and bone strain.

Karsenty’s group identified a hormonal exercise circuit in which muscle-derived interleukin-6 (IL-6; secreted during contraction as a myokine) stimulates osteoblast OCN release, which then feeds back to increase muscle AMPK activity, fatty acid oxidation, and glucose uptake — creating a bone-muscle exercise amplification loop that explains why the metabolic benefits of exercise exceed what muscle contraction alone would predict. For DPN patients, this bone-muscle-nerve crosstalk has particular relevance: supervised resistance training and weight-bearing exercise stimulate OCN release that improves insulin sensitivity (reducing glycemic DPN burden), promotes muscle mass preservation (reducing fall risk), and maintains osteoblast/osteoclast coupling that protects against Charcot initiation. The challenge is that DPN-associated neuropathic pain, balance impairment, and foot ulceration risk create barriers to the very exercise that provides these protective benefits — a clinical paradox that requires individualized exercise prescription with appropriate modifications and supervision.

Practical Osteocalcin Optimization: Diet, Supplementation, and Lifestyle Protocol

Optimizing osteocalcin biology for longevity involves three principal modifiable inputs: exercise (the most potent OCN stimulator), vitamin K2 supplementation (controlling carboxylation/ucOCN ratio and protecting bone and vascular quality), and dietary calcium and vitamin D sufficiency (providing the substrate and regulatory environment for osteoblast function and OCN synthesis). Secondary dietary factors include magnesium (cofactor for multiple OCN synthesis enzymes), silica-containing foods (bone collagen support), and protein adequacy (osteoblast anabolic requirement).

Vitamin K2 supplementation evidence supports MK-7 at 90–180 μg/day for adults seeking bone longevity benefits — the dose validated in the Knapen trials. MK-7 should be taken with the largest fat-containing meal for optimal absorption (K vitamins are fat-soluble). The primary safety consideration is anticoagulant interaction: vitamin K2 at supplemental doses can reduce warfarin effectiveness by increasing clotting factor carboxylation, and patients on warfarin or other vitamin K-sensitive anticoagulants should not start K2 supplementation without physician guidance and INR monitoring. Patients on NOACs (novel oral anticoagulants such as rivaroxaban, apixaban, dabigatran) are not affected by vitamin K2. Vitamin D3 sufficiency (serum 25-OH-D above 50 ng/mL, typically requiring 2,000–4,000 IU/day supplementation in northern latitudes) is essential for osteocalcin synthesis, as vitamin D directly regulates OCN gene transcription through VDR binding at the OCN promoter region.

Frequently Asked Questions

What is the difference between carboxylated and undercarboxylated osteocalcin?

Carboxylated osteocalcin (cOCN) has its three glutamic acid residues converted to gamma-carboxyglutamic acid (Gla) by vitamin K-dependent enzyme gamma-carboxylase. This carboxylation allows cOCN to bind calcium in hydroxyapatite mineral, integrating into bone matrix — where it serves structural and mineral binding functions but is biologically inert as a circulating hormone. Undercarboxylated osteocalcin (ucOCN) lacks this modification, does not bind bone mineral, circulates freely in blood, and binds to GPRC6A receptors on target organs (pancreas, muscle, brain, testes) to exert insulin sensitization, exercise enhancement, and neurotropic effects. The ratio is controlled by vitamin K2 availability: sufficient K2 increases carboxylation (more cOCN, less ucOCN); K2 insufficiency leaves more OCN undercarboxylated (more ucOCN, but in a context of suboptimal bone quality). Optimal K2 sufficiency optimizes both bone quality and hormone signaling simultaneously.

Can I increase my osteocalcin naturally without supplements?

Yes — exercise is the most potent natural osteocalcin stimulator and requires no supplementation. Weight-bearing resistance training and impact exercise (running, jumping, stair climbing) produce the strongest osteoblast stimulation and OCN secretion responses. A single session of resistance training increases circulating ucOCN by 20–40% within 60 minutes. Regular exercise training produces sustained increases in basal osteocalcin levels proportional to habitual physical activity. Dietary K2 sources include natto (fermented soybeans; the richest food source at 900 μg MK-7 per 100g), hard cheeses (Gouda, Brie; 60–80 μg/100g), egg yolk (20–30 μg/100g), and pastured butter (10–15 μg/100g). Consuming these foods regularly provides meaningful K2 support, though achieving the 90–180 μg/day dose of the Knapen clinical trials typically requires supplementation given the low MK-7 content of most Western diets.

Is osteocalcin clinically measured, and should DPN patients test it?

Total osteocalcin is measurable as a standard bone turnover marker (BTM) available through most clinical laboratories — typically ordered as part of metabolic bone disease evaluation. Undercarboxylated osteocalcin (ucOCN) requires specialized laboratory measurement and is not yet in widespread clinical use, though it is available through research and specialty labs. For DPN patients, measuring total osteocalcin as part of a comprehensive bone health evaluation provides clinical value: low OCN indicates reduced osteoblast activity, impaired bone formation, and potentially lower insulin sensitization signaling — all clinically relevant in diabetic bone disease. The combination of OCN with PINP (procollagen type I N-terminal propeptide) and CTX (C-telopeptide) provides a comprehensive bone turnover profile that guides both fracture prevention and bone-metabolic optimization strategies.

Does Charcot arthropathy affect both feet, and how is it detected early?

Charcot arthropathy is bilateral in approximately 9–35% of cases — far more common bilateral involvement than most clinicians appreciate. Early detection is the most critical clinical challenge, because the acute inflammatory phase of Charcot (Stage 0/1; Eichenholtz classification) presents as a unilateral warm, swollen, erythematous foot without pain (due to neuropathy-absent pain sensation) that is easily misdiagnosed as cellulitis, deep venous thrombosis, or gout. Temperature asymmetry (affected foot more than 2°C warmer than contralateral foot by infrared thermometry) is a reliable early sign. MRI detects bone marrow edema and micro-fractures before radiographic changes appear — the modality of choice for suspected early Charcot. Immediate total contact casting (TCC) or non-weight-bearing immobilization during the acute phase prevents the progressive collapse and deformity that defines established Charcot and leads to rocker-bottom foot deformity, chronic ulceration, and limb amputation risk. Early podiatric evaluation of any warm, swollen neuropathic foot is essential.

What exercise is safe for DPN patients to stimulate osteocalcin without injury risk?

The exercise prescription for DPN patients must balance osteocalcin stimulation benefits against the specific injury risks of peripheral neuropathy. Recommended modalities include: water-based resistance exercise (aquatic resistance training stimulates bone loading through drag resistance without impact), seated resistance training (upper body and lower body resistance exercises performed seated with supervision), recumbent cycling and rowing (cardiovascular bone-loading without foot impact), and supervised balance and proprioception training (addressing the fall risk while providing bone stimulation). Activities to approach cautiously include high-impact running, unsupervised outdoor walking on uneven surfaces, and barefoot exercise. A supervised exercise program developed with physical therapy input — specifically one knowledgeable about DPN — provides optimal osteocalcin stimulation with appropriate risk management. Even modest regular exercise (150 minutes/week of moderate-intensity activity) produces meaningful OCN increases and bone health benefits in T2DM populations.

The Bottom Line

Bone is not a passive scaffold — it is a dynamic endocrine organ whose osteocalcin secretion coordinates insulin sensitivity, exercise capacity, testosterone production, cognitive function, and muscle mass across multiple organ systems simultaneously. Karsenty’s laboratory demonstrated that restoring ucOCN to youthful levels reverses multiple aging phenotypes in old mice, while human prospective data confirm that higher osteocalcin predicts lower T2DM risk, better cardiovascular outcomes, and reduced cognitive decline across large population cohorts. For patients with diabetic peripheral neuropathy, the stakes are compounded: osteocalcin deficiency accelerates glycemic burden, impairs bone quality during a period of dramatically elevated fracture risk, and removes a BDNF-mediated neurotropic signal from DRG sensory neurons. Exercise remains the most potent physiological osteocalcin stimulator, and vitamin K2 supplementation at 90–180 μg MK-7/day provides evidence-based bone and vascular protection — two interventions that, combined, address the skeletal, metabolic, and neural dimensions of longevity biology in the patient population that needs them most.

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