SERUM 25-HYDROXY VITAMIN D AND BONE MINERAL DENSITY IN MULTIPLE CANAL INVOLVEMENT OF BENIGN PAROXYSMAL POSITIONAL VERTIGO

Abstract

Background and Objective

Benign paroxysmal positional vertigo (BPPV) has been associated with low serum 25-hydroxyvitamin D levels and reduced bone mineral density (BMD), but it remains unclear whether these factors contribute to involvement of multiple semicircular canals. This study aimed to evaluate whether decreased BMD or vitamin D concentrations are associated with multi-canal BPPV.

Methods

In this single-center retrospective study, 102 consecutive patients with idiopathic BPPV confirmed by video-oculography (VOG) were analyzed. All patients had serum 25-hydroxyvitamin D measurements and BMD T-scores assessed.

Results

Among 102 patients (29 men, 73 women; mean age 62.3 ± 14.5 years), 70 had single-canal BPPV and 32 had multi-canal involvement. Mean vitamin D concentrations did not differ significantly between single-canal (24.52 ± 13.9 ng/mL) and multi-canal groups (19.55 ± 11.5 ng/mL; p = 0.0821). BMD T-scores were likewise similar (-1.93 ± 1.23 vs. -1.85 ± 1.34; p = 0.7639). Logistic regression showed that vitamin D insufficiency, vitamin D deficiency, osteopenia, and osteoporosis were not independent predictors of multi-canal BPPV.

Conclusion

Low serum vitamin D levels and reduced BMD T-scores were not independently associated with multi-canal involvement in BPPV as confirmed by VOG diagnostics.

Introduction

The pathophysiology of BPPV involves otoconia that break free from the otolithic membrane and become entrapped within the semicircular canal, a condition referred to as canalolithiasis (1), or adhered to the cupula of the semicircular canal, known as cupulolithiasis (2). The calcium-based otoconia crystal moves freely within the endolymph of the semicircular canal, causing positional vertigo by head movements (canalolithiasis) (1).

The most common causes identified for BPPV are head trauma, viral neurolabyrinthitis, and idiopathic causes (3). Vitamin D deficiency and impaired calcium metabolism associated with osteoporosis have also been identified in the occurrence and recurrence of BPPV (4). Although it has a benign and self-limiting nature, annual recurrences of BPPV have been suggested in approximately 15% of the patients (5). There is no established way to prevent its recurrence, however, recent investigations have found a connection between disrupted calcium metabolism and the development of BPPV (6). Patients with BPPV exhibited lower T-scores compared to controls, and the presence of osteopenia or osteoporosis was linked to an increased likelihood of idiopathic BPPV (7). Low circulating vitamin D levels, whether insufficient or deficient, correlate with BPPV occurrence (8), and nutritional support with calcium carbonate and vitamin D has been demonstrated to lower the annual relapse rate of BPPV in participants exhibiting suboptimal serum vitamin D concentrations (4, 6). However, neither serum vitamin D concentration nor BMD T-score appears to be a distinguishing factor among the different subtypes of BPPV (9).

Multiple canal involvement is not common in BPPV. The prevalence of BPPV involving multiple canals ranged from 5% by positioning maneuvers (10). to 21.2% by video-oculography (VOG) (11) in previous reports. A history of trauma was linked to a higher likelihood of multiple-canal BPPV (12). However, not many other risk factors have been identified. Of interest, whether low T-scores of and low blood vitamin D levels increase the multiple canal involvement of BPPV remains unexplored. This study investigated whether low T-scores of BMD and low blood vitamin D concentrations were related to the occurrence of the multiple canal involvement of BPPV. Nystagmus in all patients was quantified using VOG and the number of canals involved was confirmed by VOG for diagnostic accuracy.

Methods

Patients

A total of 102 consecutive idiopathic BPPV patients who underwent video-oculography, bone densitometry and serum vitamin D levels were enrolled for this study from January 2017 until June 2020 at the dizziness clinic at a university-affiliated tertiary hospital. The data were retrospectively reviewed. All patients who presented with positional vertigo were evaluated by the criteria established by The Bárány Society’s Committee on Vestibular Disorder Classification (13). Positional nystagmus was assessed by ictal video-oculography (VOG) (Micromedical Technologies, USA). The number of canal involvement was confirmed by ictal VOG. Patients diagnosed with single-canal and multiple-canal BPPV by ictal VOG were included in this study. Individuals with comorbid labyrinthine conditions—such as vestibular neuritis, labyrinthitis, sudden sensorineural hearing loss, or Meniere’s disease —as well as those with CNS conditions or previous head injury, were excluded from analysis. Informed consent was waived with approval from the institutional ethics board (reference number; VC21RISI0077) due to the retrospective format of the study and the analysis using de-identified clinical data.

Bone densitometry and serum vitamin D levels

Bone mineral density (BMD, g/cm²) was assessed in the L1–L4 region of the lumbar spine and the femur employing dual-energy X-ray absorptiometry (DXA) performed with the Lunar Prodigy Advance Scans (GE Healthcare, USA). Based on criteria established by the World Health Organization, osteoporosis is characterized by a bone mineral density (BMD) T-score of ≤ -2.5 compared to the average young adult reference value. A T-score between -2.5 and -1.0 is defined as osteopenia, while a T-score of ≥ -1.0 is classified as within the normal range. T-scores were measured at both the lumbar spine and femur, and the lower of the two values was used for classification and statistical modeling. These classification were applied according to the lowest measured T-score in individuals aged 50 years and older (14). The age threshold of 50 years was selected in accordance with prior research indicating that the average menopausal onset age among women in Korea is 50.2 ± 3.7 years (15). Levels of serum 25-hydroxyvitamin D were determined through a chemiluminescent immunoassay method (ARCHITECT i2000, Abbott Laboratories, Abbott Park, USA). Serum 25-hydroxyvitamin D concentrations were classified as deficient (≤ 20 ng/mL), insufficient (> 20 to < 30 ng/mL), or normal (≥ 30 ng/mL), in accordance with established criteria (16- 18). Patients were grouped accordingly based on their measured vitamin D concentrations.

Statistics

Independent t-tests were applied to continuous variables, whereas categorical variables were examined using chi-square or Fisher’s exact tests. A p-value below 0.05 was considered indicative of significant group differences. Multivariable logistic regression models were fitted to examine the significant predictors for multiple-canal BPPV. In the logistic model, the multiple canal BPPV was considered as an event category, and each model was controlled for covariates, including sex, age, vitamin D insufficiency/deficiency, osteopenia, and osteoporosis. Either vitamin D insufficiency or vitamin D deficiency, and either osteopenia or osteoporosis were considered as separate covariates in model 1, while they were combined in model 2. Data are expressed as means with corresponding standard deviations (mean ± SD). Data were analyzed with SAS version 9.4 (SAS Institute, Cary, NC, USA).

Results

Patient characteristics

Table 1 provides a summary of the patients' clinical characteristics. A total of 102 patients presented with positional vertigo. Of the total cohort, 70 patients were identified with single-canal involvement, while 32 patients presented with multiple-canal involvement. In multiple-canal BPPV, only two patients were determined to have triple-canal BPPV during the research period (data not shown). There were 48 women and 22 men with single-canal BPPV (female-to-male ratio, 2.18: 1) and 25 women and 7 men with multiple-canal BPPV (female-to-male ratio, 3.57: 1). Both single and multiple-canal BPPV were more frequent in females. However, the proportion of female patients was not significantly different across the two BPPV subtype groups (p = 0.3553). The patient ages were distributed from 18 to 87 years (mean age ± SD, 63.53 ± 13.6 years in single-canal BPPV vs. 59.50 ± 16.2 years in multiple-canal BPPV) and the mean age was comparable in single- versus multiple-canal BPPV (p = 0.1952).

Table 1.

Characteristics of patients

	Single-canal BPPV	Multiple-canal BPPV	p-value
Total number	70	32
Sex, female (%)	48(68.6%)	25(78.1%)	0.3553
Age (years, mean ± SD)	63.53±13.6	59.50±16.2	0.1952
25-hydroxyvitamin D (ng/ml, mean ± SD)	24.52±13.9	19.55±11.5	0.0821
BMD T-score (mean ± SD)	-1.93±1.23	-1.85±1.34	0.7639
25-hydroxyvitamin D status			0.2219
Normal (%)	21 (30.4%)	5(15.6%)
Vitamin D insufficiency (%)	18 (26.1%)	8 (25%)
Vitamin D deficiency (%)	30 (43.5%)	19 (59.4%)
Bone mineral density			0.3003
Normal (%)	8 (13.6%)	4 (16.7%)
Osteopenia (%)	33 (55.9%)	9 (37.5%)
Osteoporosis (%)	18 (30.5%)	11 (45.8%)

Analysis was performed using independent t-test for continuous variables and χ² test or Fisher’s exact test for categorical variables. Abbreviations; BMD=Bone Mineral Density; SD=standard deviation.

Classification of canal involvement

The various canal subtypes of BPPV are presented in Figure 1. In single canal BPPV, the posterior semicircular canal (PSCC), canalolithiasis (49%) was the most common type of canal involvement. The proportion of the total horizontal semicircular canal (HSCC) involvement (50%) was the same to total PSCC involvement (50%); however, cupulolithiasis (26%) and canalolithiasis (24%) occurred at a similar proportion in HSCC BPPV (Fig. 1A). In multiple canal BPPV, PSCC and HSCC co-involvement was most common, and the following was bilateral PSCC and PSCC co-involvement (25%) (Fig. 1B).

Figure 1.

Specification of canal involvement in single- and multi- canal BPPV. A. In BPPV confined to a single canal, the PSCC, canalolithiasis (49%) was the most common type of canal involvement. The proportion of the total HSCC involvement (49%) was similar to total PSCC involvement (50%); however, cupulolithiasis (26%) and canalolithiasis (23%) occurred at a similar proportion in HSCC BPPV. B. In multiple canal BPPV, PSCC and HSCC (PH, 60%) co-involvement was most common, and the following was bilateral PSCC and PSCC co-involvement (25%). Abbreviation; PSCC=posterior semicircular canal; ASCC=anterior semicircular canal; HSCC=horizontal semicircular canal; PP=PSCC+PSCC; PH=PSCC+HSCC; HH=HSCC+HSCC; PA=PSCC+ASCC; PHA=PSCC+HSCC+ASCC; PHP=PSCC+HSCC+ PSCC.

Vitamin D insufficiency/deficiency and multiple-canal BPPV

The concentrations of blood vitamin D are summarized in Table 1. The mean serum vitamin D concentration was 24.52 ± 13.9 ng/mL in individuals with single-canal BPPV and 19.55 ± 11.5 ng/mL in those with multiple-canal BPPV. Although the level seemed to be lower in participants with multiple-canal involvement, differences were not statistically significant (p = 0.0821) (Table 1). In single-canal BPPV, mean vitamin D ± SD concentration was not significantly different between the canal types (PSCC=22.8 ± 13.3, HSCC=24.1 ± 13.4, p=0.1506) (data not shown). There were two cases of triple-canal BPPV, with a mean serum vitamin level of 26.68 ± 24.4 (mean ± SD) (data not shown). The proportion of individuals with insufficient or deficient vitamin D concentrations showed no significant difference across single- and multi-canal BPPV patients (p = 0.2219) (Table 1).

Osteopenia/osteoporosis and multiple-canal BPPV

Table 1 summarizes the BMD T-scores for each group. The average T-score was -1.93 ± 1.23 in the single-canal BPPV patients and -1.85 ± 1.34 in the multiple-canal BPPV patients, with no statistical significance between the two (p = 0.7639) (Table 1). In single-canal BPPV, mean T-score ± SD level was not significantly different between the canal types (PSCC=-1.94 ± 1.28, HSCC=-1.97 ± 1.28, p=0.4235) (data not shown). There were two cases of triple-canal BPPV, with mean T-scores ± SD of -2.05 ± 0.92 (data not shown). Analysis revealed that the presence of osteopenia or osteoporosis was comparable, showing no significant difference between patients diagnosed with single-canal BPPV and those with multiple-canal involvement (p = 0.3003) (Table 1).

Multivariable logistic regression analysis

To evaluate potential predictors of multiple-canal BPPV, a multivariable logistic regression analysis was performed (Table 2), controlling for age, sex, insufficient or deficient vitamin D, along with the existence of osteopenia or osteoporosis. The multivariate logistic regression demonstrated that neither vitamin D insufficiency (OR= 1.518, 95%CI: 0.325 – 7.091) nor deficiency (OR = 2.526, 95%CI: 0.645 – 9.889) was an independent predictor of multiple canal involvement in BPPV patients. Osteoporosis (OR = 1.163, 95%CI: 0.231 – 5.861) and osteopenia (OR = 0.604, 95%CI: 0.131 – 2.783) were also not significant predictors between single and multiple-canal BPPV (Table 2).

Table 2.

Independent predictors of multiple BPPV in multivariable logistic regression analysis

Variables	Adjusted odds ratio	95% Confidence interval		p-value
Model 1
Sex (female)	1.39	0.443	4.363	0.573
Age (unit=1)	1.004	0.948	1.064	0.8793
Vitamin D insufficiency	1.518	0.325	7.091	0.5954
Vitamin D deficiency	2.526	0.645	9.889	0.1834
Osteopenia	0.604	0.131	2.783	0.5174
Osteoporosis	1.163	0.231	5.861	0.8551
Model 2
Sex (female)	1.549	0.521	4.608	0.4316
Age (unit=1)	1.006	0.951	1.064	0.8402
Vitamin D insufficiency/deficiency	2.219	0.621	7.926	0.2199
Osteopenia/osteoporosis	0.839	0.198	3.561	0.8117

Discussion

Recent research has consistently identified a relationship connecting vitamin D insufficiency or deficiency with BPPV, together with a correlation of osteopenia or osteoporosis to this condition. Osteoporosis and vitamin D deficiency are now commonly recognized as factors linked to the onset and repeated episodes of BPPV (4, 6, 9). However, the relationship between low T-scores of BMD and low blood vitamin D concentrations and the subtypes of BPPV was controversial in recent research reports (9, 19, 20). Marslovara et al. reported that serum vitamin D concentrations tended to be lower in individuals with posterior canal BPPV and canalolithiasis relative to those with cupulolithiasis (19). Furthermore, Nakada et al. observed that individuals experiencing horizontal canal canalolithiasis presented with decreased serum vitamin D concentrations in comparison with patients having cupulolithiasis (20). Han et al. reported no notable differences in blood vitamin D concentrations or BMD T-scores among individuals with different subtypes of idiopathic BPPV. Additionally, the prevalence of vitamin D deficiency/insufficiency and osteoporosis/osteopenia did not differ significantly between subtypes (9). These results are consistent with our findings, which revealed no notable differences in mean serum vitamin D concentrations or BMD T-scores between PSCC and HSCC subtypes among individuals with single-canal BPPV.

In this study, Vitamin D insufficiency/deficiency did not emerge as significant risk factors for BPPV involving multiple canals when evaluated relative to cases with single-canal BPPV. Likewise, osteopenia and osteoporosis were not independent risks for the development of multiple-canal BPPV. Subgroup analysis revealed no notable difference in the proportion of vitamin D insufficiency/deficiency or osteopenia/osteoporosis between the multiple-canal and single-canal BPPV groups. Meanwhile, the most frequently involved canal types were PSCC or HSCC in both single and multiple canal BPPV.

Otoconia are micron-sized nanostructures composed primarily of calcite crystals (>90%) and an organic matrix rich in glycoproteins (<10%) (21). They exhibit dynamic calcium metabolism, with calcium uptake occurring on a timescale similar to that of bone, though to a lesser extent. Notably, saccular otoconia demonstrate greater calcium uptake compared to utricular otoconia (22). Several calcium-regulating components, including epithelial calcium channels ECaC1 (TRPV5, CaT2) and ECaC2 (TRPV6, CaT1), plasma membrane Ca²⁺-ATPases (PMCA3, PMCA1 and PMCA4), Na⁺/Ca²⁺ exchangers (NCX2, NCX1 and NCX3), and calbindin isoforms (D28k and D9k) are expressed in the semicircular canals and cochlear structures (23). The semicircular canal duct also expresses the vitamin D receptor, and the active form of vitamin D, 1,25-dihydroxyvitamin D3, enhances epithelial expression of Ca²⁺ channels, including calbindin isoforms (D28k and D9k) and ECaC1 (23). These findings support a potential mechanism in the relationship of vitamin D deficiency and osteoporosis with the development of BPPV, as well as the possible protective role of vitamin D plus calcium carbonate supplementation on yearly BPPV recurrence. However, our results support that the involvement of multiple canals in BPPV might be from a mechanism independent of vitamin D deficiency or osteoporosis. Factors such as the amount of detached otolith, the type or the specific location of the affected semicircular canal itself could play a more decisive role in determining whether BPPV involves a single or multiple canals.

Although all patients in this study were assessed with VOG objectively by analyzing the nystagmus patterns of BPPV, thus providing high accuracy and consistency in the diagnosis of single and multiple canal involvement, limitations exist within this study. First of all, this study was designed as a retrospective investigation limited to one hospital setting, which may have resulted in selection bias. Consequently, the temporal correlation in relation to calcium supplementation and vitamin D and recurrent episodes of multiple-canal BPPV could not be assessed. The relatively small sample size could be another limitation of our study. In this context, the small number of multi-canal BPPV cases observed likely reflects the true rarity of this entity. However, in clinical practice, multi-canal involvement may also be influenced by disease chronicity and mechanical factors, including repeated or non-optimized repositioning maneuvers, as well as unsupervised self-treatment such as Brandt–Daroff exercises, which may contribute to secondary canal involvement and should be considered when interpreting the prevalence of multi-canal BPPV. In addition, parathyroid hormone (PTH) levels and thyroid function tests were not included in routine patient screening and were performed only when osteoporosis was confirmed after the diagnosis of BPPV. As a result, the number of patients with parathyroid or thyroid abnormalities was insufficient for inclusion in the statistical model. Although vitamin D and calcium supplementation, as well as bisphosphonate use, were considered for osteoporosis management, the sample sizes were insufficient to validate these factors as independent variables in this retrospective study. Furthermore, detailed information on symptom duration, recurrence history, prior canalith repositioning maneuvers, and vestibulosuppressive medication use was not consistently available, limiting further analysis of factors associated with multi-canal BPPV. Nevertheless, prolonged use of vestibulosuppressive agents before diagnosis may delay appropriate management and potentially contribute to more complex BPPV presentations, warranting further investigation in future prospective studies.

In conclusion, taken together, the present study suggests that individuals diagnosed with either single- or multi-canal BPPV exhibited osteopenia or osteoporosis and vitamin D insufficiency or deficiency, with the horizontal (HSCC) and posterior (PSCC) semicircular canals being the most frequently involved canal types. However, neither low serum vitamin D levels nor reduced BMD T-scores were independently predictors of multi-canal involvement in BPPV. Factors such as the amount of detached otolith, type or position of the involved semicircular canal per se may be more crucial in determining single or multiple canal BPPV.

Conflict of interest

The authors declare that they have no conflict of interest.