Bisphosphonates for Hearing Loss

Overseen By Su Htwe

Age: Any Age

Sex: Any

Trial Phase: Phase 4

Sponsor: Hospital for Special Surgery, New York

Must be taking: Bisphosphonates

Disqualifiers: Family history hearing-loss, Pregnancy

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 63 months

100 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are a child currently receiving bisphosphonate treatment, you will continue with it as part of the study.

What data supports the effectiveness of the drug Risedronate Oral Tablet for hearing loss?

Research suggests that bisphosphonates, like Risedronate, may help with hearing loss related to otosclerosis (a bone condition in the ear) by improving hearing outcomes without causing harm to the ear. ^{1 2 3 4 5}

How is the drug Risedronate unique for treating hearing loss?

Risedronate is unique for treating hearing loss because it is a bisphosphonate, typically used for bone conditions like osteoporosis, and works by inhibiting bone resorption (breakdown). This is different from other hearing loss treatments, which usually do not involve bone-targeting drugs. ^{6 7 8 9 10}

What is the purpose of this trial?

Osteogenesis Imperfecta-related hearing loss usually occurs in individuals with mild (type I) OI and is much earlier in onset than age-related hearing loss, with the majority of individuals experiencing some minor hearing loss in their 20s. Bisphosphonates have been successfully used to treat otosclerosis, a common cause of hearing loss similar to OI-related hearing loss. As many individuals with OI-related hearing loss also present with otosclerosis and because of their mechanistic similarities, the investigators propose studying the effects of bisphosphonate treatment on individuals diagnosed with both OI type I and hearing loss, thereby determining its effectiveness as a potential treatment for hearing loss. The investigators will enroll 50 individuals diagnosed with type I OI and age 18-100. 25 adults will be enrolled into the treatment arm and receive bisphosphonate treatment (must have at least mild hearing loss), while 25 adults will be enrolled into the control arm. The investigators will enroll 25 children (6-17 years of age) diagnosed with OI who are currently receiving bisphosphonate treatment as part of their care for orthopedic symptoms. The investigators will also observe 25 children (6-17 years of age) diagnosed with OI who are NOT currently receiving bisphosphonate treatment. The study duration is 63 months (approximately 5 years). Enrollment is anticipated to begin in November 2019.

Research Team

Cathleen Raggio, MD

Principal Investigator

Hospital for Special Surgery, New York

Eligibility Criteria

This trial is for individuals with type I Osteogenesis Imperfecta (OI) and hearing loss. Adults aged 18+ with mild hearing loss and children aged 6-17, whether currently on bisphosphonates or not, can join. Participants must have a Vitamin D level >30. Those with family history of non-OI related hearing loss or pregnant individuals cannot participate.

Inclusion Criteria

My child is between 6 and 17 years old.

I am between 6 and 17 years old.

I have been diagnosed with mild hearing loss.

Exclusion Criteria

My family has a history of hearing loss not due to OI or work.

ALL ARMS: Pregnancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Adults with type 1 OI receive Risedronate treatment; children observed for changes in hearing, quality of life, and bone density

63 months

Yearly visits for assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• Risedronate Oral Tablet

Trial Overview The study tests the effects of Risedronate Oral Tablet, a bisphosphonate, on OI-related hearing loss in adults and observes its use in children already receiving it for orthopedic symptoms. It's a comparison between treated adults/children and untreated controls over approximately 5 years.

Participant Groups

Group I: Adult Treatment Arm Experimental Treatment 1 Intervention

Intervention treatment arm. Adults (18+ years) with type 1 OI. Must have at least mild hearing loss. Will receive Risedronate (35mg, 0-2x/week as clinically indicated) for duration of study. Changes in hearing, quality of life, and bone density will be monitored.

Group II: Adult Control Arm Active Control 1 Intervention

Observational arm. Adults (18+ years) with type 1 OI. Changes in hearing, quality of life, and bone density will be monitored.

Group III: Child (Control Arm) Active Control 1 Intervention

Observational arm. Children (6-17 years) with any type of OI who are not receiving bisphosphonate treatment. Changes in hearing, quality of life, and bone density will be observed for the duration of the study.

Group IV: Child (Bisphosphonate Arm) Active Control 1 Intervention

Observational (no investigational intervention) arm. Children (6-17 years) with any type of OI who are already receiving bisphosphonate treatment as standard of care treatment for orthopedic symptoms. Changes in hearing, quality of life, and bone density will be observed for the duration of the study.

Who Is Running the Clinical Trial?

Hospital for Special Surgery, New York

Lead Sponsor

Trials

257

Recruited

61,800+

Northwell Health

Collaborator

Trials

481

Recruited

470,000+

East River Medical Imaging

Collaborator

Trials

1

Recruited

100+

The New York Community Trust

Collaborator

Trials

7

Recruited

1,200+

Findings from Research

The study confirms that osteonecrosis of the auditory canal, a rare condition, can occur in patients taking bisphosphonates, a class of drugs commonly used to treat osteoporosis and other bone diseases.

This finding is supported by reports found in databases of adverse drug reactions, highlighting the need for awareness among healthcare providers regarding this potential side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bisphosphonate-associated osteonecrosis of the auditory canal. Kharazmi, M., Hallberg, P., Persson, U., et al.[2013]

In a retrospective study of 10 patients with otosclerosis-related sensorineural hearing loss, treatment with third-generation bisphosphonates (risedronate or zoledronate) resulted in stabilization of hearing loss over an average follow-up of 13 months, with no major complications reported.

Out of the 19 ears treated, 2 patients showed actual improvement in hearing, indicating that these bisphosphonates may not only halt progression but could also enhance hearing outcomes in some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Third-generation bisphosphonates for treatment of sensorineural hearing loss in otosclerosis. Quesnel, AM., Seton, M., Merchant, SN., et al.[2021]

Long-term use of bisphosphonates for osteoporosis treatment is linked to a small but significant increase in the risk of cholesteatoma in the external auditory canal, particularly with higher doses and longer treatment durations, based on a study of 131,794 patients in Denmark.

Despite the increased risk of cholesteatoma, the overall incidence remains low, with no cases of bone destruction observed during the 7-year study period, indicating that while there are risks, they are relatively rare.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

External auditory canal and middle ear cholesteatoma and osteonecrosis in bisphosphonate-treated osteoporosis patients: a Danish national register-based cohort study and literature review. Thorsteinsson, AL., Vestergaard, P., Eiken, P.[2021]

External auditory canal osteonecrosis is a rare but serious complication associated with antiresorptive medications like denosumab and bisphosphonates, as demonstrated in two case studies involving patients with postmenopausal osteoporosis.

Both patients showed exposed bone in the external auditory canal but had stable conditions after stopping the medication and receiving conservative management, highlighting the importance of early diagnosis and ENT referral when symptoms arise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two Cases of External Auditory Canal Osteonecrosis in Patients on Antiresorptive Therapy for Osteoporosis. Kumar, S., Diamond, T., Walton, J.[2023]

Local delivery of bisphosphonates, specifically through methods like placing alginate beads on the round window membrane or using microfluidic pump infusion, significantly improves drug localization and concentration in the cochlea compared to systemic delivery.

The study found no significant ototoxicity associated with either local or systemic delivery of the bisphosphonate 6-FAM-ZOL, suggesting that this treatment approach could be safe for patients with cochlear otosclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-Ototoxic Local Delivery of Bisphosphonate to the Mammalian Cochlea. Kang, WS., Sun, S., Nguyen, K., et al.[2018]

In a study involving 30 participants (15 with gastro-oesophageal reflux disease and 15 healthy controls), risedronate tablets showed similar rapid oesophageal transit, disintegration, and gastric emptying times in both groups, indicating that the medication is safe for use even in patients with GERD.

The design of the risedronate tablet, including its oval shape and film-coating, helps to promote quick movement through the oesophagus and reduces the risk of prolonged contact, which is beneficial for patients at risk of oesophageal irritation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oesophageal transit, disintegration and gastric emptying of a film-coated risedronate placebo tablet in gastro-oesophageal reflux disease and normal control subjects. Perkins, AC., Wilson, CG., Frier, M., et al.[2019]

In a study involving 80 healthy, postmenopausal women, risedronate (5 mg) did not cause any oesophageal or gastroduodenal ulcers, indicating its safety for upper gastrointestinal health.

In contrast, the aspirin group experienced significant gastrointestinal injuries, including gastric ulcers and erosions, highlighting risedronate's favorable gastrointestinal profile compared to aspirin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo-controlled, randomized, evaluator-blinded endoscopy study of risedronate vs. aspirin in healthy postmenopausal women. Lanza, FL., Rack, MF., Li, Z., et al.[2019]

In a study involving 25 elderly volunteers, the new film-coated tablet formulation of risedronate showed significantly faster esophageal transit compared to the original gelatin capsule, with mean transit times of 3.3 seconds for tablets versus 23.8 seconds for capsules.

The film-coated tablets eliminated delays in esophageal transit seen in 28% of participants with the capsule formulation, indicating a safer and more effective option for patients, especially those with swallowing difficulties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Esophageal transit of risedronate cellulose-coated tablet and gelatin capsule formulations. Perkins, AC., Wilson, CG., Frier, M., et al.[2019]

Risedronate, an oral bisphosphonate, effectively inhibits bone resorption and improves bone health, showing significant pain reduction and decreased alkaline phosphatase levels in patients with Paget's disease after just 3 months of treatment at 30 mg/day.

In postmenopausal women, risedronate at doses of 5 mg/day for up to 2 years increased bone mass, and 2.5 mg/day helped prevent bone loss during glucocorticoid treatment, with a safety profile similar to placebo regarding gastrointestinal and other adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risedronate. Goa, KL., Balfour, JA.[2018]

Bisphosphonates, while effective in inhibiting bone resorption, can lead to painful bone exposures in the jaws, with a significant incidence observed in patients treated for multiple myeloma and metastatic cancers, particularly with Zometa and Aredia.

Pre-therapy dental care is crucial in reducing the incidence of bisphosphonate-related jaw complications, and for those affected, a treatment regimen of antibiotics and antiseptic mouthwash is highly effective in managing pain, achieving a 90.1% success rate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. Marx, RE., Sawatari, Y., Fortin, M., et al.[2022]

References

1. Scotland pubmed.ncbi.nlm.nih.gov

Bisphosphonate-associated osteonecrosis of the auditory canal. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

Third-generation bisphosphonates for treatment of sensorineural hearing loss in otosclerosis. [2021]

3. England pubmed.ncbi.nlm.nih.gov

External auditory canal and middle ear cholesteatoma and osteonecrosis in bisphosphonate-treated osteoporosis patients: a Danish national register-based cohort study and literature review. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Two Cases of External Auditory Canal Osteonecrosis in Patients on Antiresorptive Therapy for Osteoporosis. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Non-Ototoxic Local Delivery of Bisphosphonate to the Mammalian Cochlea. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Oesophageal transit, disintegration and gastric emptying of a film-coated risedronate placebo tablet in gastro-oesophageal reflux disease and normal control subjects. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Placebo-controlled, randomized, evaluator-blinded endoscopy study of risedronate vs. aspirin in healthy postmenopausal women. [2019]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Esophageal transit of risedronate cellulose-coated tablet and gelatin capsule formulations. [2019]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Risedronate. [2018]

10. United States pubmed.ncbi.nlm.nih.gov

Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. [2022]