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Salivary Bioscience Bulletin

New Development – Osteocalcin Can Be Measured In Saliva

Drop Date: December 2019

In This Drop: New Development – Osteocalcin Can Be Measured In Saliva

In a seminal study published in Cell Metabolism in the fall of 2019, Berger et al., concluded that “a bone-derived signal is necessary to develop an acute stress response (ASR).” Surprisingly, a quick literature review reveals that Osteocalcin is rarely even mentioned in the history of research on stress in humans. This begs the question: Is it possible that this overlooked skeletal hormone could inform our understanding of human stress reactivity and regulation?

Osteocalcin in Saliva

A substantial amount of scientific literature describes Osteocalcin as a hormone derived from bone, and the mechanisms that link its levels directly to the activity of the parasympathetic branch of the autonomic nervous system (ANS), as well as aspects of metabolism, exercise capacity, brain development, aging, and male fertility. In the past few weeks, Salimetrics released a validated Salivary Osteocalcin Assay and preliminary observations suggest a modest-to-strong serum-saliva association. These conceptual and methodological advances have the potential to break new ground, and in the interest of enabling our understanding to continue to advance to new limits, Salimetrics is allowing access to our early stage methods such that the Salivary Bioscience scientific community can leverage this know-how.

Below, we briefly review some key Osteocalcin findings and its correlates and concomitants as entry points for interested readers. For a more detailed overview, we suggest reading Moser and van der Eerdan (2018) Osteocalcin—A Versatile Bone-Derived Hormone, published in Frontiers in Endocrinology.

The Autonomic Nervous System

Contemporary theorists propose that a surge in osteocalcin levels is necessary to initiate the stress-response in the detailed study, Mediation of the Acute Stress Response by the Skeleton (Berger et al., 2019). A key assumption is that the skeleton evolved as a protective system in order to prepare boney vertebrates from danger. After sensing fear, it is hypothesized that bone rapidly (within minutes) releases massive amounts of osteocalcin which directly effects the parasympathetic brake on the ANS as a critical precursor to prepare for the fight or flight response. In multiple case controlled experimental studies, Berger’s team exposed mice and rats to various stressors followed by testing circulating bioactive osteocalcin in serum. They also exposed humans to the TSST and subsequently tested serum osteocalcin levels as well. The findings are remarkably consistent across studies– under stress-induced conditions, the bioactive osteocalcin levels rapidly increased. Further experiments in this same study followed the osteocalcin release pathway and timing necessary to mount the Acute Stress Response (ASR).

Neurobiology of Learning and Memory

Further exploration of the Osteocalcin knock-out mice by Oury F., et al., discovered evidence that osteocalcin crosses the blood-brain barrier and binds to cerebral neurons. Subsequent experiments explored Osteocalcin’s effects on depression, anxiety, learning, and memory, suggesting additional biological functions beyond bone and metabolic functions. Evidence promoting increased depression, anxiety, decreased learning, and memory capacity was revealed between Osteocalcin deficient mice and their wild-type counterparts. Administration of Osteocalcin by intracerebro-ventricular (ICV) infusions remediated the learning and memory deficit – possibly by preventing neuronal apoptosis in the hippocampus. Further, fetal brain development was impaired in osteocalcin deficient mice resulting in mild to severe cognitive impairment. In humans, research by Puig J., et al., also showed deleterious cognitive performance indicators correlated with lower osteocalcin levels in obese subjects. This research may also carry significance in cognitive decline due to aging, since osteocalcin synthesis and/or activation also decreases with age. One such study by Khrimian L., et al., indicated that exogenous osteocalcin can improve hippocampal-dependent memory in mice and identify molecular tools to harness this pathway for therapeutic purposes.

Obesity and Metabolism

Osteocalcin regulates glucose metabolism, and several studies have linked Osteocalcin regulation to effects on insulin sensitivity and obesity. The first evidence of this relationship was generated using Osteocalcin deficient mice, which developed an atypical storage of visceral fat (Ducy, et al). Later, experiments by Lee NK., et al., revealed further evidence that bone may actively promote regulation of energy homeostasis. It was noted in this study that Osteocalcin knock-out mice were glucose intolerant and maintained decreased insulin secretion, insulin resistance, and β-cell proliferation while exhibiting increased adiposity and serum triglyceride levels. Fulzele K., et al., also reported that mice lacking insulin receptor signaling in osteoblasts show increased adiposity and hyperglycemia in addition to severe glucose intolerance and insulin resistance. Based on this evidence, Ferron M., et al., performed a study supplying daily intermittent injections of osteocalcin to mice consuming a high-fat-diet, which partially restored insulin sensitivity and glucose tolerance, as well as displaying additional functional benefits. Results suggest a strong improvement in glucose regulation and increased type 2 diabetes resistance. Huang L., et al., also mirrored these findings in Osteocalcin treated rats while Fernandez-Real JM., et al., reproduced similar associations in humans performing resistance training.

Sports Performance

With strong links to glucose metabolism, researchers have naturally been drawn to Osteocalcin’s role in Sports Performance with interesting results. Specifically, researchers investigated the adaption of Osteocalcin levels to provide optimal performance in humans and rodents. Research by Lin X., et al., and Mera P., et al., shows that undercarboxylated osteocalcin improved muscle glucose uptake in rodent models. In humans, research by Levinger I., et al., Kim YS., and Ahn N., et al., identified that undercarboxylated osteocalcin also supports musculoskeletal interactions, specifically noting that increases in osteocalcin levels improved performance, fitness, and even CRP levels. Many studies also found improved insulin sensitivity were highly correlated with increased in osteocalcin levels.

Salivary Osteocalcin and Your Research Program

Is it possible that the inclusion of salivary osteocalcin in your studies of human health and development would advance your research program? Based on our review of the current literature, we believe it’s very likely. However, much more research needs to be done to make this a certainty. Salimetrics capability of measuring osteocalcin using a minimally invasive specimen opens this window of research opportunity wide. We encourage those interested to review these exciting findings, revisit the core scientific assumptions, consider the utility of this interesting bone derived hormone in their research, and connect with our scientific team for the latest updates and findings related to the integration of salivary osteocalcin in studies of human development, stress, health, performance, and well-being.

Salimetrics is here and ready to support your next research discovery – simply Contact Us to get started.


  1. Moser, Sarah C, J. Van der Eerden. (2018) Osteocalcin- A Versatile Bone-Derived Hormone. Front Endocrinol( Lausanne). 9: 794.
  2. Berger JM, Singh P, Khrimian, Morgan DA, Chowdhury S, Arteaga-Solis, Horvath TL, et al. (2019). Mediation of The Acute Stress Response by the Skeleton. Cell Metab. 30( 5):890-902.
  3. Oury F, Khrimian L, Denny CA, Gardin A, Chamouni A, Goeden N, et al. (2013). Maternal and offspring pools of osteocalcin influence brain development and functions. Cell. 155(1):228-41.
  4. Puig J, Blasco G, Daunis -i- Estadella J, Moreno M, Molina X, Alberich-Bayarri A, Xifra G,et al. (2016). Lower serum osteocalcin concentrations are associated with brain microstructural changes and worse cognitive performance. Clin Endocrinol. 84(5):756-63.
  5. Khrimian L, Obri A, Ramos-Brossier M, Rousseaud A, Moriceau S, Nicot AS, et al. (2017). Gpr158 mediates osteocalcin’s regulation of cognition. J Exp Med. 214(10):2859-2873.
  6. Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, et al. (1996). Increased bone formation in osteocalcin-deficient mice. Nature. 382(6590):448-52.
  7. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD,Confavreux C, et al. (2007). Endocrine regulation of energy metabolism by the skeleton. Cell. 130(3):456-69.
  8. Fulzele K, Riddle RC, DiGirolamo DJ, Cao X, Wan C, Chen D, et al. (2010). Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell. 142(2):309-19.
  9. Ferron M, McKee Md, Levine RL, Ducy P, Karsenty G, et al. (2012). Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. Bone. 50(2):568-75.
  10. Huang L, Yang L, Luo L, Wu P, Yan S. (2017). Osteocalcin Improves Metabolic Profiles, Body Composition and Arterial Stiffening in an Induced Diabetic Rat Model. Exp Clin Endocrinol Diabetes. 125(4):234-240.
  11. Fernandez-Real JM, Izguierdo M, Ortega F, Gorostiaga E, Gomez- Ambosi J, Moreno-Navarrete JM, et al. (2009). The relationship of serum osteocalcin concentration to insulin secretion, sensitivity, and disposal with hypocaloric diet and resistance training. 2009. J Clin Endocrinol Metab. 94(1):237-45
  12. Lin X, Parker L, Mclennan E, Zhang X, Hayes A, McConell G, et al. (2017). Recombinant Uncarboxylated Osteocalcin Per Se Enhances Mouse Skeletal Muscle Glucose Uptake in both Extensor Digitorum Longus and Soleus Muscles. Front Endocrinal. 8:330.
  13. Mera P, LaueK, Ferron M, Confavreux C, Wei J, Galan-Diez M, et al. (2016). Osteocalcin Signaling in Myofibers Is Necessary and Sufficient for Optimum Adaptation to Exercise. Cell Metab. 23(6):1078-1092.
  14. Levinger l, Scott D, Nicholson GC, Stuart Al, Dugue G, McCorguodale T, et al. (2014). Undercarboxylated osteocalcin, muscle strength and indices of bone health in older women. Bone. 64:8-12.
  15. Kim YS, Nam JS, Yeo DW, Kim KR, Suh SH, Ahn CW, (2015). The effects of aerobic training on serum osteocalcin, adipocytokines and insulin resistance on obese young males. ClinEndocrinol. 82(5):686-94.
  16. Ahn N,Kim K. (2016). Effects of 12- week exercise training on osteocalcin, high-sensitivity C-reactive protein concentrations, and insulin resistance in elderly females with osteoporosis. J Phys Ther Sci. (8):2227-31.

*Note: Salimetrics provides this information for research use only (RUO). Information is not provided to promote off-label use of medical devices. Please consult the full-text article.

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