Hypothesis

Age-related decline in vitamin K status reduces osteocalcin carboxylation, increasing circulating undercarboxylated osteocalcin (ucOC). We propose that ucOC, unlike its carboxylated form, binds weakly to hydroxyapatite (HA) surfaces and displaces tightly bound water molecules that normally stabilize nanocrystal surfaces. This loss of interfacial water lowers the energetic barrier for HA crystal fusion, promoting enlargements from ~9 nm to >18 nm. Larger crystals then further reduce matrix‑bound water, creating a feed‑forward loop that exacerbates osteocyte mechanosensory dysfunction.

Mechanistic Model

1. Carboxylated osteocalcin (cOC) possesses a high affinity for HA due to its γ‑carboxyglutamic acid residues, which chelate calcium ions and organize a hydration layer at the crystal interface.[4]
2. ucOC lacks these carboxyl groups, resulting in weaker electrostatic interactions and a reduced capacity to retain interfacial water.
3. With aging, falling vitamin K levels shift the OC pool toward ucOC, decreasing surface‑bound water density.
4. Reduced water lubrication increases surface energy, facilitating Ostwald ripening‑like coalescence of HA nanocrystals under physiological supersaturation.[1]
5. Enlarged crystals diminish bound water, raise brittleness, and impair osteocyte detection of fluid shear stress, blunting adaptive bone formation.

Testable Predictions

• Prediction 1: In older adults, serum ucOC levels will inversely correlate with the amount of matrix‑bound water measured by low‑field nuclear magnetic resonance relaxometry, independent of BMD.
• Prediction 2: Experimental addition of recombinant ucOC to cultured osteocyte‑like cells will decrease HA nanocrystal size in vitro‑induced mineralization assays, whereas cOC will prevent growth.
• Prediction 3: A 12‑month randomized controlled trial of vitamin K2 (MK‑7) supplementation (450 µg/day) in participants >65 years will decrease serum ucOC, increase the carboxylated OC fraction, and lead to a measurable reduction in HA crystallite size (assessed by synchrotron X‑ray diffraction of tibia biopsies) concomitant with improved ultrasonic velocity.
• Prediction 4: Genetic knockdown of osteocalcin in mice fed a vitamin K–sufficient diet will still show enlarged HA crystals if ucOC is overexpressed, demonstrating that ucOC’s effect is independent of total OC levels.

Falsifiability

If vitamin K supplementation fails to lower ucOC or does not alter HA crystallite size despite raising cOC, the proposed causal link between ucOC‑mediated water loss and crystal growth would be refuted. Similarly, if ucOC addition does not affect interfacial water or crystal growth in vitro, the mechanistic core of the hypothesis is invalidated.

References

[1] https://pubmed.ncbi.nlm.nih.gov/40794153/ [2] https://pubmed.ncbi.nlm.nih.gov/9504950/ [3] https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00757/full [4] https://pubmed.ncbi.nlm.nih.gov/19776145/