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US-20260124450-A1 - METHODS FOR TREATING BONE EROSION

US20260124450A1US 20260124450 A1US20260124450 A1US 20260124450A1US-20260124450-A1

Abstract

Methods and apparatuses (e.g., devices and systems) for nerve stimulation to treat bone erosion, including in patients for having an inflammatory and/or autoimmune conditions, such as, but not limited to, rheumatoid arthritis (RA). In some cases, these methods may reduce or prevent bone erosion by applying electrical stimulation of the nerve (e.g., vagus nerve) in a patient that is desensitized to electrical nerve simulation to suppress inflammation (e.g., by decreasing cytokines such as RANK-L). In some cases this may include applying electrical energy in a manner that would desensitize the suppression of anti-inflammatory cytokines while reducing or preventing bone erosion. Alternatively or additionally, these methods may include applying electrical energy to a subject that is already desensitized to the electrical modulation of cytokines (e.g., RANKL) by nerve stimulation.

Inventors

  • Jacob A. Levine
  • David Chernoff
  • Murthy V. Simhambhatla
  • Amy DEROSIER

Assignees

  • SETPOINT MEDICAL CORPORATION

Dates

Publication Date
20260507
Application Date
20251103

Claims (20)

  1. 1 . A method of reducing bone erosion in a patient that is desensitized to nerve stimulation to reduce a cytokine level, or that has failed to respond to nerve stimulation to reduce a cytokine level, the method comprising: applying electrical stimulation to a nerve to reduce bone erosion, wherein the electrical stimulation is applied as a plurality of doses comprising a series of pulses of between 1 μA to 5 mA at a frequency of between 0.1 Hz and 5 kHz, wherein each dose is between 1 second and 20 minutes in duration.
  2. 2 . The method of claim 1 , wherein applying electrical nerve stimulation comprises the electrical nerve stimulation from an implanted nerve stimulator.
  3. 3 . The method of claim 1 , wherein the nerve is the patient's vagus nerve.
  4. 4 . The method of claim 1 , wherein applying electrical nerve stimulation comprises applying a plurality of doses within a 12 hour period.
  5. 5 . The method of claim 1 , wherein applying electrical nerve stimulation comprises applying the nerve stimulation after applying nerve stimulation to treat inflammation to the same nerve.
  6. 6 . The method of claim 1 , wherein the series of pulses is between 1 μA to 1 mA.
  7. 7 . The method of claim 1 , wherein the series of pulses has a frequency of between 0.1 Hz and 50 Hz.
  8. 8 . The method of claim 1 , wherein each dose is between 1 second and 2 minutes in duration.
  9. 9 . A method of reducing bone erosion in a patient that is desensitized to nerve stimulation to reduce inflammation, or that has failed to respond to nerve stimulation to reduce inflammation, the method comprising: administering a nerve stimulation using an implanted nerve stimulator, wherein the nerve stimulator is configured to treat inflammation by the application of a first set of stimulation parameters that have become ineffective or less effective to treat inflammation, further comprising applying nerve stimulation to the patient to treat bone erosion at these the first set of stimulation parameters or at a second set of stimulation parameters that are different from the first set of stimulation parameters.
  10. 10 . A method of treating bone erosion in a patient, the method comprising: identifying that the patient has failed to respond to the application of electrical energy to a nerve of an anti-inflammatory pathway in the patient to reduce inflammation; and administering electrical energy to the nerve to treat bone erosion.
  11. 11 . The method of claim 10 , wherein administering electrical energy to the nerve to treat bone erosion comprises applying the same intensity of electrical energy to the nerve as was applied to reduce inflammation.
  12. 12 . The method of claim 10 , wherein administering electrical energy to the nerve to treat bone erosion comprises applying an intensity of electrical energy to the nerve that is less than that applied to reduce inflammation.
  13. 13 . The method of claim 10 , wherein administering electrical energy to the nerve to treat bone erosion comprises reducing off time between doses as compared to the application of electrical energy to a nerve of the anti-inflammatory pathway.
  14. 14 . The method of claim 10 , wherein the anti-inflammatory pathway in the patient comprises the patient's vagus nerve.
  15. 15 . The method of claim 10 , wherein the anti-inflammatory pathway in the patient comprises one or more nerve targets comprises one or more of: a cranial nerve, a peripheral nerve, a spinal nerve, or a nerve ending within an organ.
  16. 16 . The method of claim 10 , wherein the method further comprises administering a drug agent to treat inflammation.
  17. 17 . The method of claim 16 , wherein the drug agent comprises a TNF-alpha inhibitor comprising one or more of: etanercept, adalimumab, certolizumab pegol, infliximab, golimumab, and biosimilars thereof.
  18. 18 . The method of claim 10 , wherein the patient has an immune or inflammatory disorder.
  19. 19 . The method of claim 18 , wherein the immune or inflammatory disorder is one of: rheumatoid arthritis and psoriatic arthritis.
  20. 20 . The method of claim 10 , wherein applying electrical energy comprises applying electrical energy from an implanted device.

Description

CROSS REFERENCE TO RELATED APPLICATION This patent application claims priority to U.S. Patent Application No. 63/715,497, filed on Nov. 1, 2024, titled “METHODS FOR TREATING BONE EROSION,” and herein incorporated by reference in its entirety. INCORPORATION BY REFERENCE All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. FIELD The disclosure relates generally to apparatuses (e.g., systems and devices) and methods of nerve stimulation to reduce bone erosion in patients regardless of treatment type, even in patients for which inflammatory therapies have failed. BACKGROUND Bone erosion is a significant complication in the treatment and progression of osteoarthritis (OA), a degenerative joint disease marked by the breakdown of cartilage, joint inflammation, and the degradation of bone. It is currently believed that inflammatory processes, biomechanical stress, and metabolic changes all exacerbate bone erosion and complicate treatment. For example, in OA, inflammation is often localized in the synovium (the membrane that lines the joint) and produces pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α). Current and proposed treatments for bone erosion typically modulate cytokines either directly or by treating synovitis, as it is believed that cytokines activate enzymes that break down cartilage and bone, leading to erosive damage, and that persistent inflammation accelerates bone loss by stimulating osteoclasts (bone-resorbing cells). However, treatment of synovitis and/or modulation of cytokine activity using anti-inflammatory drugs, including NSAIDs, may help reduce pain and inflammation but may not directly halt and may actually exacerbate bone erosion. Previous work by the same inventors, including U.S. Pat. No. 10,449,358 (“the '358 patent”), taught that electrical stimulation of the vagus nerve with particular electrical stimulation parameters, in particular, extremely low duty cycle stimulation that was limited to a single session of less than about two minutes of stimulation every 12-48 hours at between 0.1 mA and 10 mA in amplitude would specifically reduce RANKL levels, increase OPG levels (improving the OPG/RANK ratio) specifically to inhibit osteoclast activity and bone resorption. Outside of these parameters, and in particular at higher duty cycle stimulation levels, the '358 patent taught that electrical stimulation would result in overstimulation of the vagus nerve and desensitization that would inhibit the reduction of bone erosion. Although cytokines and other signaling molecules involved in osteoarthritis (OA) stimulate osteoclasts and modulate bone erosion, modulation of cytokines, including RANKL, to treat bone erosion may be an indirect treatment and may be challenging to titrate and may result in undesirable side effects. What is needed are direct and effective treatments for bone erosion to provide treatments. SUMMARY OF THE DISCLOSURE The present invention relates to methods and apparatuses (systems and devices) for treating bone erosion by neurostimulation even in cases where neurostimulation is contraindicated or discontinued for some reason. In particular, the methods and apparatuses described herein may treat bone erosion by the application of electrical energy to a vagus nerve, a trigeminal nerve, a glossopharyngeal nerve, an optic nerve, and/or a facial nerve to reduce, eliminate or reverse bone erosion using simulation parameters that specifically reduce bone erosion independently of treating synovitis. For example, the methods and apparatuses described herein may apply electrical stimulation at levels previously believed to result in desensitization of the effect on cytokines, such as applying multiple session of electrical stimulation within a twelve hour period. The methods and apparatuses described herein may be particularly effective at significantly reducing or preventing bone erosion which may be independent of the treatment of synovitis. This is significant because most approved drugs, and prior electrical treatments, to reduce bone erosion (particularly in osteoarthritis) treat bone erosion by reducing inflammatory synovitis which then indirectly reduces bone erosions. The ability to specifically treat bone erosion more directly, rather than indirectly through treatment of synovitis, has many benefits. For example, these methods (and apparatuses for preforming them) may be used in patients that are experiencing undesirable bone erosion that is not necessarily due to inflammation and/or a change in RANKL (or OPG), such as a non-RANKL modulating bone erosion disorder. Further, these methods and apparatuses may specifically treat bone erosion using techniques that would be ineffective (or significantly less e