New Study Finds NMN Supports Bone Strength

Bone loss affects 1 in 3 women and 1 in 5 men over age 50 worldwide. As this disease is so prevalent, many researchers are hoping to discover non-pharmaceutical options for its treatment. 

Although age and sex are leading risk factors for bone loss, there is another cause: long-term glucocorticoid use. Over the past 20 years, prescriptions for this steroid have increased by 34%. Although these medications can be beneficial, they also have the damaging side effect of inhibiting bone growth. 

Glucocorticoid-induced bone loss is the most common secondary cause of this condition, leading to significant rises in morbidity, fractures, falls, and frailty. An increase in fracture risk is seen with as little as 3 to 6 months of glucocorticoid treatment. As millions of people need to take these medications, researchers have been searching for ways to mitigate this bone loss — and the answer might be NMN. 

In this article, learn more about a recent study that used NMN to attenuate glucocorticoid-induced bone loss, the basics of NMN and glucocorticoids, and the implications of this research on human health. 

What is NMN? A Recap 

Nicotinamide mononucleotide, also known as NMN, is one of the precursors to NAD+, a crucial coenzyme for cell function, energy production, and healthy aging.

With advancing age, NAD+ levels tend to decline, accelerating chronic disease development and premature aging. Maintaining elevated levels of NAD+ is linked to healthier cells and an increase in both lifespan and healthspan — the years lived healthfully and disease-free. NMN is also linked to weight management, healthy cardiovascular and metabolic markers, cognitive function, and reproductive health. 

Glucocorticoids: A double-edged sword

Synthetic glucocorticoids are a family of drugs that mimic the actions of the naturally occurring glucocorticoids found in the body. Their primary function is to reduce inflammation and suppress the immune system. These drugs work by inhibiting pro-inflammatory pathways of cytokines and chemokines while boosting anti-inflammatory molecules. 

Long-term use of these drugs is used to treat various diseases. While the anti-inflammatory function of glucocorticoids is beneficial, these drugs do have long-term side effects. Glucocorticoid use is linked to an increased risk of bone loss, metabolic dysfunction, heart conditions, delayed wound healing, and increased susceptibility to infections. 

In this study, researchers focused on the bone-degrading effects of glucocorticoids and how NMN may be able to help this process. 

Filling in the holes: NMN battles brittle bones

Published in Molecular Medicine Reports in July 2020, Huang and colleagues aimed to determine if NMN could be used therapeutically for glucocorticoid-induced bone loss. The researchers used a culture of mesenchymal stromal cells (MSCs) to measure NMN’s effects on bone health. MSCs are a type of self-renewing and pluripotent stem cell, meaning they can develop into several different cell types. 

Like NAD+ levels, the quantity and function of MSCs decline with age, leading to impaired tissue regeneration and accelerated aging. Specifically, the researchers used bone MSCs (BSMCs), to which they added dexamethasone, a glucocorticoid. This drug inhibited osteogenesis — the formation of new bone. 

As expected, the glucocorticoid-treated cells had suppressed osteogenesis and function of osteoblasts — cells that form new bone. These cells also had decreased levels of the bone-boosting osteogenic markers. This indicates that glucocorticoids inhibit BMSCs from developing into bone-forming osteoblasts. 

From there, the team treated the cells with NMN to see if the compound could help fight back on this steroid-induced bone loss. After the BSMCs were treated with NMN, the cells had enhanced activity of the osteogenic markers that were reduced after steroid treatment. Not only that, NMN increased bone mineralization — when osteoblasts deposit minerals on the bone matrix for the development of bone.

These results indicate that NMN may be able to attenuate the decrease in osteogenic markers that occurs after long-term use of glucocorticoids, potentially reducing bone loss or bone fracture risk.

Sirtuins and NMN: A dynamic duo

Sirtuins are a family of seven proteins that play a crucial role in health and longevity. When the expression of these so-called “longevity genes” decreases, cellular aging and chronic disease can develop. Sirtuins are dependent on NAD+, so NMN can boost the activity of sirtuins by increasing NAD+ levels. 

One of the sirtuins, SIRT1, is thought to be especially involved in bone health and metabolism. Research has shown that increased expression of SIRT1 is linked to protection against bone loss in mice. 

In this study, glucocorticoids reduced SIRT1 activity in BSMCs, while the subsequent NMN treatment restored SIRT1 levels. Also, expression of the protein PGC-1α, which is downstream of SIRT1 and is involved in energy metabolism, was increased following NMN treatment. By enabling the expression of SIRT1 and PGC-1α, NMN encourages osteogenesis and reverses the glucocorticoid-induced inhibition of bone growth that can lead to bone loss.

To further elucidate how SIRT1 affects the bones, the researchers experimented with inhibiting the protein in BSMCs. In these cells without SIRT1 activity, the bone-protecting effects of NMN were reversed after exposure to glucocorticoids. These sirtuin-lacking BSMCs showed reduced levels of the osteogenic markers that had been increased with NMN treatment. 

These results indicate that NMN on its own — without adequate SIRT1 activity — is not enough to protect the bones from glucocorticoid-induced bone loss; a combination of the anti-aging and bone-boosting duo is needed. 

Key takeaway: What does this research mean? 

• Long-term use of the steroid drugs known as glucocorticoids can lead to bone loss due to reduced activity of bone-boosting osteogenic markers. 
• In this study, cells treated with NMN after steroid exposure had improved osteogenic markers and increased activity of the sirtuin SIRT1, which is involved in bone metabolism.
• These results indicate that NMN may be a useful therapeutic target to protect against bone loss in people taking these medications. 
• However, more research is needed in humans, as this study only assessed NMN’s effects in a cell culture model. 

References: 

Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol. 2011;335(1):2-13. doi:10.1016/j.mce.2010.04.005

Fardet L, Petersen I, Nazareth I. Prevalence of long-term oral glucocorticoid prescriptions in the UK over the past 20 years. Rheumatology (Oxford). 2011;50(11):1982-1990. doi:10.1093/rheumatology/ker017

Huang RX, Tao J. Nicotinamide mononucleotide attenuates glucocorticoid‑induced osteogenic inhibition by regulating the SIRT1/PGC‑1α signaling pathway. Mol Med Rep. 2020;22(1):145-154. doi:10.3892/mmr.2020.11116

Irie J, Inagaki E, Fujita M, et al. Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocr J. 2020;67(2):153-160. doi:10.1507/endocrj.EJ19-0313

Sun W, Qiao W, Zhou B, et al. Overexpression of Sirt1 in mesenchymal stem cells protects against bone loss in mice by FOXO3a deacetylation and oxidative stress inhibition. Metabolism. 2018;88:61-71. doi:10.1016/j.metabol.2018.06.006