Bisphosphonate treatment can reverse hearing loss

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Preliminary findings from Harvard Medical School researchers at Massachusetts Eye and Ear may pave the way for trials to test bone density medications for hearing loss.

Hearing loss caused by damaged nerves, whether from sound exposure or aging, is irreversible.

There are currently no medications approved by the Food and Drug Administration (FDA) to treat and reverse the most common type of hearing loss, called sensorineural hearing loss (SNHL).

But a new animal study hopes to pave the way for future trials to see whether this type of treatment can be used in people.

New research led by Konstantina Stankovic, HMS associate professor of otolaryngology head and neck surgery at Mass. Eye and Ear, and Albert Edge, the Eaton-Peabody Professor of Otolaryngology Head and Neck Surgery at Mass.

Eye and Ear, have found medications called bisphosphonates, which are commonly used to prevent bone density loss, were able to regrow damaged nerve connections in the inner ear in mice with SNHL.

While the findings require further studying in animal models, the research team hopes it could be a promising target for conducting clinical trials in people with SNHL.

The discoveries were published July 14 in Frontiers in Molecular Neuroscience.

“This is a significant finding because it opens the possibility for repurposing bisphosphonates, which typically treat severe osteoporosis and metastatic bone disease, for the treatment of sensorineural hearing loss,” said Stankovic, director of the Division of Otology and Neurotology at Mass. Eye and Ear.

“We hope the promising results from this pilot study can lead to clinical trials within the next several years.”

Damaged nerves

Disabling hearing loss affects 466 million people worldwide and 56 million in the United States – numbers that are expected to more than double over the next two decades.

Hearing loss can take a toll on health and well-being, and untreated hearing loss costs more than $750 billion in health care spending each year worldwide, due to more hospital stays and greater need for emergency rooms and clinical visits.

For typical hearing, sound waves travel through the ear canal before reaching the eardrum and the tiny bones of the middle ear. They are then converted into electrical signals in the inner ear and transmitted to the brain via the auditory nerve.

One type of hearing loss, called conductive hearing loss, occurs when sound transmission from the ear canal to the inner ear is impaired (such as by a middle ear infection, fluid, or impaired vibration of middle ear bones), leading to a reduction in sound levels reaching the inner ear and an inability to hear soft sounds.

Sensorineural hearing loss, on the other hand, occurs in the inner ear. The most common causes of hearing loss are noise exposure and aging, which results in loss of connections, called synapses, between nerve cells and sensory hair cells found in the inner ear. This type of SNHL is referred to as cochlear synaptopathy.

Research hopes

Previous research from Stankovic’s lab looked to identify potential pathways to treat SNHL. Their analyses found that osteoprotegerin, a substance typically secreted by bone cells to inhibit bone remodeling, is highly produced by cochlear neurons and promotes their survival.

In previous studies, doctors have observed that people with SNHL due to severe otosclerosis who take bisphosphonates have the ability to significantly improve their hearing loss and understand speech.

Word recognition is a sensitive measure of cochlear nerve function. That revelation, along with the previous results from the influence of the drug on the rapid increase and survival of cochlear stem cells, prompted the researchers’ new study to determine the effects of bisphosphonates on cochlear synaptopathy.

The scientists administered bisphosphonates to mice 24 hours after noise exposure. They found that the medication had a dramatic effect at regenerating the synapses between inner hair cells and spiral ganglion neurons found in the ear, and restoring cochlear function.

The team further suggested that their finding provides possible mechanisms that could explain why some patients in the clinic have improved their ability to recognize speech after bisphosphonate treatment. They also suggest that bisphosphonates are worth considering to reverse the loss of nerve connections for the treatment of human SNHL.

Stankovic cautioned that the research is still in its early phases. More research is needed, in animals and then in clinical safety and efficacy trials, before this could be a recommended treatment.

“It is our hope that, with further study, we can offer patients who have currently irreversible hearing damage a medication that might stall or reverse their hearing loss,” she said.


Bisphosphonates define a class of drugs that are widely indicated since the 1990s to treat osteoporosis both in men and women. Their effectiveness in treating osteoporosis and other conditions is related to their ability to inhibit bone resorption.[1][2][3]

FDA-approved indications for bisphosphonates include treatment of osteoporosis in postmenopausal women, osteoporosis in men, glucocorticoid-induced osteoporosis, hypercalcemia of malignancy, Paget disease of the bone, and malignancies with metastasis to the bone.

Non-FDA-approved indications include the treatment of osteogenesis imperfecta in children as well as adults and the prevention of glucocorticoid-induced osteoporosis.

Mechanism of Action
Bisphosphonates have a structure similar to native pyrophosphate and divide into two groups: nitrogen-containing and non-nitrogen containing bisphosphonates.

Nitrogen-containing bisphosphonates include alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid.

Non-nitrogen containing bisphosphonates include etidronate, clodronate, and tiludronate. All bisphosphonates inhibit bone resorption by attaching to hydroxyapatite binding sites on the bone, particularly in areas with active resorption.

As osteoclasts resorb bone, the bisphosphonate embedded in the bone is released and impairs the osteoclast’s ability to continue bone resorption.[2][4][5]

Nitrogen-containing bisphosphonates work by inhibiting farnesyl pyrophosphate synthase, which is important in promoting attachment of the osteoclast to the bone. As a result, the osteoclast detaches from the bone surface, thus inhibiting bone resorption.

Non-nitrogen containing bisphosphonates, on the other hand, are metabolized within the cell to substrates that replace the terminal pyrophosphate moiety of adenosine triphosphate, forming a nonfunctional molecule which competes with adenosine triphosphate in the energy metabolism of the cell.

This situation initiates osteoclast apoptosis, which in turn leads to an overall decrease in the bone breakdown.

Nitrogen-containing bisphosphonates are much more potent antiresorptive agents than the non-nitrogen-containing bisphosphonates. Also, non-nitrogen containing bisphosphonates are found to have a high potential to inhibit bone mineralization and can cause osteomalacia. For this reason, they are no longer in broad-based use.

EFFICACY OF BISPHOSPHONATES

All bisphosphonates improve bone mineral density in postmenopausal women with osteoporosis. Alendronate, risedronate, and zoledronic acid decrease the risk of spine, hips as well as other nonvertebral fractures. Ibandronate has not consistently shown to reduce the risk of hip fractures.

Alendronate: Reduces vertebral fracture risk by about 50%, hip fractures, and other nonvertebral fractures by about 30%.[6][7]

Risedronate: Reduces vertebral and nonvertebral fractures by about 40%.[8]

Zoledronic acid: Reduces vertebral fracture risk by about 70%, hip fractures, and other nonvertebral fractures by about 35%.[9][10]

Ibandronate: Reduces vertebral fractures by about 50%. No reduction in risk of nonvertebral fractures.[11]

References

1.Otto S, Pautke C, Van den Wyngaert T, Niepel D, Schiødt M. Medication-related osteonecrosis of the jaw: Prevention, diagnosis and management in patients with cancer and bone metastases. Cancer Treat. Rev. 2018 Sep;69:177-187. [PubMed]

2.Farrell KB, Karpeisky A, Thamm DH, Zinnen S. Bisphosphonate conjugation for bone specific drug targeting. Bone Rep. 2018 Dec;9:47-60. [PMC free article] [PubMed]

3.Miller K, Steger GG, Niepel D, Lüftner D. Harnessing the potential of therapeutic agents to safeguard bone health in prostate cancer. Prostate Cancer Prostatic Dis. 2018 Nov;21(4):461-472. [PMC free article] [PubMed]

4.Frediani B, Giusti A, Bianchi G, Dalle Carbonare L, Malavolta N, Cantarini L, Saviola G, Molfetta L. Clodronate in the management of different musculoskeletal conditions. Minerva Med. 2018 Aug;109(4):300-325. [PubMed]

5.Bernardi S, Di Girolamo M, Necozione S, Continenza MA, Cutilli T. Antiresorptive drug-related osteonecrosis of the jaws, literature review and 5 years of experience. Musculoskelet Surg. 2019 Apr;103(1):47-53. [PubMed]

6.Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998 Dec 23-30;280(24):2077-82. [PubMed]

7.Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996 Dec 07;348(9041):1535-41. [PubMed]

8.Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999 Oct 13;282(14):1344-52. [PubMed]

9.Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR., HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N. Engl. J. Med. 2007 May 03;356(18):1809-22. [PubMed]

10.Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S., HORIZON Recurrent Fracture Trial. Zoledronic acid and clinical fractures and mortality after hip fracture. N. Engl. J. Med. 2007 Nov 01;357(18):1799-809. [PMC free article] [PubMed]

11.Chesnut CH, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A, Felsenberg D, Huss H, Gilbride J, Schimmer RC, Delmas PD., Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE). Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J. Bone Miner. Res. 2004 Aug;19(8):1241-9. [PubMed]


More information: Richard Seist et al. Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate, Frontiers in Molecular Neuroscience (2020). DOI: 10.3389/fnmol.2020.00087

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