Researchers at the Johns Hopkins University School of Medicine have identified a biological mechanism of excess nerve growth in aging spines that could provide a way to treat lower back pain in the elderly. The study, published the journal Bone Research, suggests that lower back pain linked to aging may be caused not only by spinal degeneration, but also from misdirected nerve signals that can potentially be reversed. The team showed how treating this condition with parathyroid hormone (PTH) reduced pain-related behaviors in mouse models of spinal degeneration by rewiring how pain-sensing nerves interact with deteriorating spinal bone.
“During spinal degeneration, pain-sensing nerves grow into regions where they normally do not exist. Our findings show that parathyroid hormone can reverse this process by activating natural signals that push these nerves away,” said the study’s senior author Janet L. Crane, MD, a researcher in the Center for Musculoskeletal Research in the department of orthopedic surgery at Johns Hopkins.
Lower back pain is one of the most common medical conditions worldwide. Treating it is sometimes difficult as most cases are nonspecific because no single anatomical cause can be identified. Ongoing research has increasingly implicated the thin area between the intervertebral disc and vertebral body called the vertebral endplate as a contributor to lower back pain. As described by the researchers, in an aging spine these endplates expand, become porous and sclerotic, and develop abnormal sensory innervation.
For their work, the Johns Hopkins team sought to understand in more detail how these physiological changes drive pain and whether there could be methods to modify them. Their focus was on PTH, which regulates calcium balance and bone remodeling and is already used synthetically to treat osteoporosis. Earlier animal studies from the Johns Hopkins researchers and others suggested that PTH could reduce skeletal pain, but they didn’t understand enough about its activity to know how to effectively alter its effects.
To explore this, the researchers used three mouse models that each with different drivers of spinal degeneration: natural aging, surgically induced lumbar spine instability, and one that develops early intervertebral disc degeneration. The mouse models received daily injections of PTH for periods ranging from two weeks to two months, while control animals received inactive solutions. Using imaging, the team then assessed spinal structure, measured pain-related behaviors such as sensitivity to pressure and heat, and analyzed nerve growth within spinal tissues.
Across all three models, PTH treatment reduced pain behaviors and improved spinal bone structure. They showed that the vertebral endplates became less porous, and mice showed improved tolerance to mechanical and thermal stimuli. At the same time, the density of pain-sensing nerve fibers within the vertebral body and endplate decreased.
These observations led the investigators to discover what activity was occurring at the molecular level that resulted in these changes. They found that the PTH stimulated bone formation osteoblasts to produce a protein that is known to inhibit the growth of nerve fibers called Slit3, with further lab work confirming that Slit3 directly inhibited nerve outgrowth. When the researchers genetically deleted Slit3 or the PTH receptor in osteoblast-lineage cells, PTH no longer reduced abnormal nerve invasion or improved pain behaviors. “Altogether, PTH stimulated osteoblast production of Slit3, decreased aberrant sensory nerve innervation, and provided symptomatic relief of (lower back pain) associated with mouse spinal degeneration,” the researchers wrote.
This work builds on earlier research showing lower back pain is linked to uncoupled bone remodeling in aging spines. Previously this research group had shown that osteoclasts, which break down bone, secrete Netrin-1, a factor that attracts sensory nerves into degenerated endplates. The acidic environments created by the osteoclasts were shown to promote nerve ingrowth and pain and the current study pinpointed Slit3, produced in response to PTH, as a counterbalance to this process capable of repelling nociceptive fibers.
The researchers said this may help explain why some patients treated with PTH analogs in clinical studies for osteoporosis report improvements in back pain, even though pain was not the primary endpoint of those trials. “Our study suggests that PTH treatment of LBP during spinal degeneration may reduce aberrant innervation, laying the foundation for future clinical trials exploring the efficacy of PTH as a disease-modifying and pain-relief treatment for spinal degeneration,” Crane said.
Next steps will be to find how these mechanisms translate to humans and whether patients with specific endplate changes are more likely to benefit. The team also plans to further investigate how Slit3 influences bone vasculature and neural signaling in different regions of the spine, and how genetic background may shape nerve–bone interactions during degeneration.
