Relief for Lower Back Pain May Be On the Way for Millions

(Posted on Monday, December 18, 2023)

This article is part of a broad series on recent advances in the science and medicine of longevity and aging. The series covers a range of topics, including musculoskeletal health. Expect more articles on bone and muscle regeneration to follow.

New findings by scientists at the Johns Hopkins University School of Medicine suggest low back pain may become a thing of the past. The research, published as a preprint in the journal eLife, has pinpointed senescent cells, or “sleeping” cells, as key culprits in back pain. These cells cause the bones of the spine to become porous, allowing nerve fibers to fill the empty spaces. When the nerve fibers get irritated or “pinched”, backache ensues. 

Old Age and Back Pain: Two Peas in a Pod

You know the feeling: you bend over to tie your shoes or put on a sock, when suddenly, ZAP, you feel a sharp jolt in your lower back. If you’ve been spared this pain, then you’re one of the lucky few. At least, for now — statistics suggest that eight in 10 people will experience lower back pain at one point in their lives. 

Although low back pain can happen at any age, it is especially prevalent in older adults. Indeed, musculoskeletal pain affects a considerable percentage of older adults, estimated between 65 to 85%, with back pain accounting for around 36 to 70% of such issues. And even though it was previously thought that back pain reaches its climax around the age of 60 before tapering off again, more recent studies indicate that pain remains common well into later years. In fact, people over the age of 80 are three times more likely to experience severe low back pain than middle-aged adults between the ages of 50 and 59. 

Once back pain sets in, inactivity often follows; since movement hurts, individuals suffering from back pain will frequently cut back on exercise. This can have the knock-on effect of restricting participation in various activities and gatherings, both of which significantly reduce quality of life. 

Despite the prevalence of the issue, the causes of low back pain at the cellular level remain poorly understood. Unsurprisingly, therapeutic interventions have seen mixed results. Especially for those suffering from non-specific low back pain —cases in which there is no clear cause— relief is often short-term, with treatment producing only small changes. 

Enter the Suspect: “Sleeping” Osteoclasts

Think of senescent cells as retired cells in our body that have stopped dividing and working. This usually stops damaged cells from becoming cancer, which is good. However, as we age, these retired cells accumulate and start causing trouble. They release inflammatory molecules that can go on to harm nearby cells and cause other tissues to become inflamed, which can lead to various health problems linked to aging. Cell senescence has been linked to a number of musculoskeletal diseases, including osteoporosis and osteoarthritis.

In previous work, the same laboratory discovered that a particular cell type, called osteoclasts, plays an important role in the formation of pores in the endplates of our vertebrae. Under normal conditions, osteoclasts are in charge of breaking down bone tissue to help with the routine maintenance, remodeling, and repair of our bones. But in certain situations, the osteoclasts ended up misbehaving, leading to excessive pore formation in the endplates of the spine. These endplates sit between the bones of our spine —the vertebrae— and the gell-filled discs that protect and cushion those bones. Here, they act as a buffer between the hard surfaces of the vertebrae and the flexible discs. Endplates also serve as a bridge, allowing nutrients and blood to reach the discs, which do not have a dedicated blood supply of their own. To achieve this, they need to be strong enough to not crack under pressure but porous enough to allow blood and nutrients to move through them — a tricky balancing act. 

The empty space left by all the pores creates an enticing “nook” for new nerves, which set up camp. But once established, the new nerves are prone to becoming irritated and begin firing off pain signals, leading to persistent low back issues. Exactly why osteoclasts began misbehaving and inducing excessive porosity remained unknown, but the researchers suspected cell senescence played a role. 

Treatment on the Horizon?

To test their hunch, the scientists turned to mice suffering from spine hypersensitivity caused either by old age or lumbar spine instability. Next, they analyzed the endplates in these mice to check whether there were any senescent osteoclasts present in the pores. In both cases, biomarkers suggested the presence of osteoclasts and senescent cells. And the stronger the biomarkers, the more porous the endplates and the more sensitive the spine.

Having narrowed down the likely culprit, the researchers sought to target and remove the senescent osteoclasts. They administered an experimental drug called Navitoclax for a total of four weeks. This drug is traditionally used as an anti-cancer drug, but has been found to also effectively single out and destroy senescent cells in mouse models. 

Navitoclax works against senescent cells because it mimics a protein, called BH3, that helps regulate controlled cell death, or apoptosis. Compared to normal cells, senescent cells have altered survival pathways and they often rely on proteins that prevent apoptosis, particularly Bcl-2 (B-cell lymphoma 2) and Bcl-xL (B-cell lymphoma-extra large), to evade the programmed cell death that would otherwise eliminate them. Navitoclax, by mimicking BH3, blocks these anti-apoptotic proteins, thereby inducing programmed cell death in senescent cells that rely on these proteins for survival.  

Treatment with Navitoclax led to a noticeable reduction in senescent osteoclasts in the endplates of the spine — the endplates were less porous and there were fewer signs of degeneration. The decrease in senescent cells and porosity also meant that the mice treated with the drug had fewer new nerves or new blood vessels in their endplates. These structural changes were mirrored by increased activity in treated mice as well as a reduction in pain, as measured by various laboratory tests. 

No such positive changes to the structure of the endplates could be seen in mice that received a placebo, nor were there any changes in their activity levels.

Takeaways

Back pain is a serious condition that can significantly worsen quality of life. Unfortunately, as we age, more of us will begin to experience back issues. In this latest study, researchers clearly implicate senescent osteoclasts in the endplates of the spine with an increase in pores, leading to the formation of new hypersensitive nerves. These easily become irritated, causing pain. By eliminating the senescent osteoclasts with Navitoclax, the researchers were able to regenerate the endplates and reduce back pain in mice. These early results are promising and pave the way for further research.

This article was originally published on Forbes and can be read online here.