Introduction
Otosclerosis is an osseous dysplasia of the otic capsule characterised by enzyme-mediated bone resorption and bone formation. The term otospongiosis more accurately describes the lesions seen, but the original term (otosclerosis) remains in more common use. The usual site of activity, anteriorly in the oval widow of the vestibule, causes stapedial fixation resulting in conductive hearing loss. Less commonly, otospongiotic foci occur in other areas of the otic capsule, leading to sensorineural hearing loss.
Forty-six years ago, it was suggested that sodium fluoride might have a beneficial effect on the progression of otosclerosis.Reference Shambaugh and Scott1 Since then, Causse et al. have shown that sodium fluoride reduces enzyme levels in the perilymph of patients with otosclerosis and inhibits trypsin.Reference Causse, Uriel, Berges, Shambaugh, Bretlau and Causse2 Linthicum et al. found reduced strontium uptake around the oval window after patients received sodium fluoride, suggesting a halt in the otosclerotic process.Reference Linthicum, House and Althaus3 Bretlau et al. reported a significantly higher calcium/phosphate ratio in sodium fluoride treated cases of otospongiotic stapes, indicating increased mineralisation and stabilisation of otospongiotic lesions.Reference Bretlau, Hansen, Causse and Causse4
A number of case–control studies and one randomised, controlled trial have shown the benefits of sodium fluoride. Derks et al. retrospectively studied 17 right ears of patients with cochlear otosclerosis who received fluoride tablets for one to five years, and 22 right ears of patients with cochlear otosclerosis not receiving medical treatment.Reference Derks, De Groot, Raymakers and Veldman5 They found minimal deterioration in hearing in the treated group, but a mean 9.5 dB (range 0 to 36.7 dB) deterioration in sensorineural hearing in the untreated group (p < 0.001). The mean follow up of those receiving fluoride was 3.2 years, compared with 4.6 years for control group patients.
Colletti and Fiorino used the on-off stapedial reflex to select 128 relatives of patients with otosclerosis who themselves had subclinical otosclerosis (with audiometric thresholds of >20 dB and an air–bone gap of <10 dB).Reference Colletti and Fiorino6 They conducted a prospective, age-matched, controlled study with five years' follow up. The 63 subjects receiving sodium fluoride, calcium and vitamin D for two years had significantly less hearing loss at two and five years, compared with 65 subjects in the untreated group. In addition, 19.7 per cent of the control group developed hearing loss after five years, compared with 8.5 per cent of the group receiving sodium fluoride for the first two years.
Forquer et al. retrospectively assessed 192 patients.Reference Forquer, Linthicum and Bennett7 They reviewed the records of patients with audiometric data showing progressive hearing loss over two years, who were then treated for six to 12 months with 25 mg sodium fluoride and calcium daily and followed up for a further five years. Ninety-eight patients had stapedial otosclerosis, and in 35 per cent progression ceased following sodium fluoride and calcium treatment. In 11 per cent, progression slowed to half the rate of loss, on average, and in 54 per cent treatment did not affect the rate of loss. Ninety-four patients had cochlear otosclerosis; in 32 per cent progression ceased after treatment with sodium fluoride and calcium, in 31 per cent progression slowed to an average of 60 per cent of the previous rate of loss, and in 37 per cent treatment did not affect the rate of loss. In the 202 control patients matched for diagnosis, hearing change showed no tendency to stabilise.
Bretlau et al. conducted a double-blind, placebo-controlled trial of 40 mg sodium fluoride daily in patients with a clinical diagnosis of otosclerosis. After at least two years' follow up, significantly more of the control group had suffered a hearing deterioration of >10 dB, compared with the patients receiving fluoride.Reference Bretlau, Causse, Causse, Hansen, Johnsen and Salomon8 In the control group of 52 patients, 25 per cent suffered hearing deterioration of >10 dB, compared with only 7 per cent of the 43 patients in the treatment group.
Materials and methods
A Medline and PubMed search was conducted using the following search strategy: (‘otosclerosis’[MeSH Terms] or ‘otosclerosis’[All Fields]) and (‘fluorides’[MeSH Terms] or ‘fluorides’[All Fields] or ‘fluoride’[All Fields]). Abstracts were reviewed independently by two authors, and the full text was acquired for relevant articles.
Discussion
In 1992, Browning and Gatehouse estimated the UK prevalence of otosclerosis to be 2 per cent.Reference Browning and Gatehouse9 This prevalence is thought to be dropping, possibly as a result of measles vaccination. However, otosclerosis remains a fairly common cause of hearing loss. If effective, sodium fluoride would therefore prevent a significant amount of disability.
A 2.2 mg sodium fluoride tablet costs less than a penny. There is therefore no financial drive for manufacturers to investigate the effectiveness of sodium fluoride. A follow up period of at least two years is likely to be required to show an effect, so there is no incentive for quick publication. These factors make it less likely that any higher quality evidence for the effectiveness of sodium fluoride will become available. Clinicians must therefore make a judgement based on current research.
Diagnosis
Otosclerosis is diagnosed largely on clinical grounds. Suspicion is raised by a conductive hearing loss seen in conjunction with a type A tympanogram, Carhart's notch and absent stapedial reflexes. The ipsilateral stapedial reflex is often absent in the presence of a conductive hearing loss of any cause; however, absence of a contralateral reflex when the sound stimulus is to a normal opposite ear is highly suggestive of stapedial otosclerosis. Van Wagoner and Campbell described a negative on-off (biphasic) type of acoustic reflex which is seen in early otosclerosis.Reference Van Wagoner and Campbell10 This abnormal acoustic reflex response may be seen at the onset of the contralateral stimulus and again when the sound is turned off. This method of early diagnosis makes possible the option of treatment with sodium fluoride in order to prevent disease progression.
Pure cochlear otosclerosis should be suspected in patients with slowly progressive sensorineural hearing loss who have a family history of otosclerosis. The audiometric hearing loss pattern tends to be of a flat or ‘cookie bite’ type, and an on-off type stapedial reflex may be present.Reference Shambaugh11
Computed tomography (CT) scanning can assist in the diagnosis of otosclerosis. Naumann et al. assessed the accuracy of a 0.5 mm cubical scan technique for the identification of otospongiotic foci.Reference Naumann, Porcellini and Fisch12 Otosclerotic foci were seen in 74 per cent of cases of clinically suspected otosclerosis. The size of the fenestral focus correlated with the size of the air–bone gap, but the extent of otosclerotic cochlear involvement did not correlate with bone conduction thresholds. Derks et al. found that CT scanning could not reliably be used to demonstrate the efficacy of sodium fluoride treatment of otosclerosis, implying that scanning is not of value in deciding when to cease fluoride treatment.Reference Derks, De Groot, Raymakers and Veldman5
When to use sodium fluoride?
Sodium fluoride has been found to help prevent both conductive and sensorineural hearing loss in patients with otosclerosis. Derks et al. found fluoride treatment more effective if the initial sensorineural hearing loss was less than 50 dB.Reference Derks, De Groot, Raymakers and Veldman5 This suggests that it may be worth considering fluoride treatment earlier rather than later. Causse and Causse, being enthusiastic proponents of preventative treatment, have proposed a strategy of treatment of very early otosclerosis, with detection by screening families of patients with otosclerosis, or even all schoolchildren, to detect the on-off stapedial reflex.Reference Causse and Causse13
Otosclerosis should also be considered in patients with vestibular symptoms. Freeman found vestibular dysfunction in 165 (37 per cent) of 438 patients with cochlear otospongiosis.Reference Freeman14 Fifty-one of these received sodium fluoride, calcium and vitamin D, and 46 reported complete or partial relief of vestibular dysfunction symptoms.
What dose?
There have been no studies comparing the effectiveness of different doses of sodium fluoride, and little explanation in the studies that have been published as to their rationale of dosage choice.
Causse and Causse found that a low dose of 1.5–10 mg can be effective in preventing disease progression at an early stage.Reference Causse and Causse13 Similarly, Colletti and Fiorino found a 6–16 mg dose (related to age) to be effective in preventing hearing loss in cases of early otosclerosis.Reference Colletti and Fiorino6
Ten per cent of UK drinking water is fluoridated at a level of 1 mg/l.15 Drinking 2 litres of tap water a day would therefore result in a daily dose of 2 mg of fluoride. Vartiainen and Vartiainen conducted a study of patients with surgically proven otosclerosis followed up for more than five years, and found that air and bone conduction thresholds in the unoperated ear of patients drinking fluoridated tap water were significantly better than the same thresholds in patients drinking fluoride-poor water.Reference Vartiainen and Vartiainen16
Bretlau et al. conducted a double-blind, placebo-controlled study using higher doses, giving 20 mg sodium fluoride twice daily along with 500 mg calcium gluconate and 400 units of vitamin D.Reference Bretlau, Causse, Causse, Hansen, Johnsen and Salomon8 They referred to a personal communication of evidence that smaller doses of sodium fluoride (i.e. 9 mg daily) favoured primarily bone formation and mineralisation. On the other hand, larger doses of sodium fluoride (25–60 mg) mainly act by slowing down resorption. Derks et al. used even higher doses in their case–control series, giving 75 mg sodium fluoride or sonofluorophosphate daily.Reference Derks, De Groot, Raymakers and Veldman5
Low dose sodium fluoride has few side effects. The main side effect is that, in growing teeth, sodium fluoride can over time cause dental fluorosis (i.e. white or brown discolouration of teeth), and should therefore be avoided or used with caution in children under six years of age.
Higher dose sodium fluoride can occasionally cause gastrointestinal upset, with a burning sensation of the mouth, sore tongue, hyper-salivation, vomiting, diarrhoea and abdominal pain. Das et al. found atrophic gastritis on gastric antral biopsy in all 10 patients taking 30 mg sodium fluoride daily, but in only one of 10 matched controls.Reference Das, Susheela, Gupta, Dasarathy and Tandon17 However, in their randomised, controlled trial, Bretlau et al. gave patients 20 mg enteric-coated sodium fluoride twice daily with calcium carbonate and vitamin D, and found no difference in side effects between treatment and placebo groups.Reference Bretlau, Causse, Causse, Hansen, Johnsen and Salomon8
Sodium fluoride taken orally is mainly absorbed within the stomach by passive diffusion. It forms an acid in water, and this is thought to be responsible for the associated gastritis. Unfortunately, Deka et al. found that enteric-coated forms of sodium fluoride had much lower and more widely varying degrees of absorption.Reference Deka, Kacker and Shambaugh18 However, they also found that taking 1 g of calcium carbonate at the same time as sodium fluoride only slightly reduced absorption and resulted in a smaller variation in absorption between individuals. They postulated that calcium carbonate reduced the gastric irritation caused by sodium fluoride.
Animal studies (in rats, mice and rabbits) have shown that fluoride is not a teratogen, and epidemiological studies conducted in areas with high levels of naturally fluoridated water have shown no increase in birth defects. There is however a potential risk that heavy exposure to fluoride in utero may result in skeletal fluorosis, which would become evident in childhood. The decision to use sodium fluoride in pregnancy would have to weigh this potential risk against any benefit in halting the rapid progression of otosclerosis which can occur during pregnancy.
How long for?
No trial has set out to determine how long treatment with sodium fluoride should continue. Most studies have continued such treatment without a definite end-point. It may be that once sodium fluoride has induced mineralisation the benefit remains, but it is also possible that continued sodium fluoride is required to prevent resorption. Derks et al. commented that, in their retrospective case–control study, the six patients who discontinued fluoride therapy had minimal hearing deterioration at further follow up between two and seven years after discontinuation.Reference Derks, De Groot, Raymakers and Veldman5 These patients had been treated with fluoride for between 2.3 and 4.6 years before stopping treatment.
Conclusions
The literature suggests that sodium fluoride, possibly in combination with calcium carbonate, can reduce the rate of deterioration of both conductive and sensorineural hearing loss in patients with otosclerosis. Treatment with sodium fluoride at lower doses appears to be effective at halting progression in the early stages of the disease. Thus far, studies have investigated the use of higher doses to halt later progress of the disease. Current research does not provide clear evidence on how long sodium fluoride treatment should be continued.
