Intranasal Vitamin B12 Is Promising Therapy For The Geriatric Population
Overview
Vitamin B12 deficiency is prevalent among the elderly. Traditional treatment through intramuscular injections has notable drawbacks, prompting the exploration of safer and more convenient methods such as intranasal administration. This study evaluates the effects of two intranasal vitamin B12 dosing regimens in elderly patients with vitamin B12 deficiency.
Sixty patients aged 65 and older were randomly assigned to either a loading dose regimen (daily administration for 14 days followed by weekly doses) or a regimen without a loading dose (administration every 3 days) over 90 days. Each dose provided 1000 µg of cobalamin. Serum levels of total vitamin B12, holotranscobalamin (holoTC), methylmalonic acid (MMA), and total homocysteine (tHcy) were measured on days 0, 7, 14, 30, 60, and 90.
Both regimens led to a rapid rise in vitamin B12 and holoTC concentrations, and a normalization of elevated MMA and tHcy levels. The loading dose regimen achieved the quickest and highest increase, reaching a median vitamin B12 concentration of 1090 pmol/L (reference range 350-650 pmol/L) after 14 days. However, following weekly administration, B12 levels declined to a median of 530 pmol/L after 90 days. In contrast, the no loading dose regimen resulted in a gradual increase, reaching a median vitamin B12 concentration of 717 pmol/L after 90 days.
Intranasal vitamin B12 administration is an effective and appropriate method for restoring and maintaining adequate vitamin B12 levels in elderly patients.
Introduction
Vitamin B12 (cobalamin) deficiency is prevalent in the elderly, with estimates indicating that approximately 20% of individuals aged 60 and over, and 23-35% of those aged 80 and above, are affected. This deficiency arises from impaired absorption of food-bound vitamin B12, reduced dietary intake, and the use of certain medications. The absorption process involves a complex mechanism requiring an acidic stomach environment, pepsin, and intrinsic factor, which facilitates the absorption of vitamin B12 in the intestines. This vitamin is then bound to transcobalamin II and transported to the liver and other tissues, where it acts as a coenzyme for crucial biochemical reactions necessary for blood formation and proper brain and nervous system functioning. Consequently, a deficiency in vitamin B12 can lead to anemia and neurological issues such as muscle weakness, cognitive decline, depression, fatigue, neuropathy, and stroke.
Vitamin B12 deficiency can develop over 3-4 years due to substantial liver stores of cobalamin. Before manifesting classic symptoms like pernicious anemia, patients may experience a stage of inadequacy characterized by abnormal levels of biomarkers related to vitamin B12 deficiency, such as holotranscobalamin, methylmalonic acid, and homocysteine. This subclinical deficiency phase is associated with low or marginal vitamin B12 concentrations.
The standard treatment for vitamin B12 deficiency involves administering cobalamin (either hydroxo- or cyanocobalamin) via intramuscular injection. However, these injections can be painful and may cause adverse events such as infections and bruises, making self-administration challenging for elderly patients. Consequently, safer and more convenient administration methods, such as oral and intranasal routes, have been explored. Studies have demonstrated that daily oral administration of crystalline cyanocobalamin effectively normalizes serum cobalamin levels in deficient patients, although it is unsuitable for rapid supplementation in cases of severe deficiency due to the limited passive absorption. In intranasal vitamin administration, rapid and reproducible absorption of hydroxocobalamin and cyanocobalamin have been observed.
Previous research comparing intranasal cyanocobalamin to intramuscular hydroxocobalamin in cobalamin-deficient elderly individuals showed a swift increase in serum cobalamin levels following intranasal administration. However, it did not provide comprehensive insights into the pharmacokinetics and effects on vitamin B12 and related biomarkers after repeated intranasal administration.
Typically, intramuscular treatment for dietary vitamin B12 deficiency begins with a loading dose followed by maintenance therapy, contrasting with the steady daily doses used in oral treatment due to limited passive absorption. It remains unclear whether a loading dose is necessary for rapid treatment of vitamin B12 deficiency via intranasal administration. Therefore, this study aimed to compare two intranasal vitamin B12 dosage regimens (with and without loading dose) in elderly patients deficient in vitamin B12, focusing on vitamin B12 levels and three biomarkers indicative of deficiency: holotranscobalamin, methylmalonic acid, and total homocysteine. Additionally, the study explored the effects of these regimens on cognition and depression.
Methods
Inclusion Criteria
– Patients aged 65 years or older visiting the geriatric outpatient clinic or admitted to the geriatric ward at Spaarne Gasthuis, Haarlem and Hoofddorp, Netherlands.
– Documented total vitamin B12 levels less than 250 pmol/L within the past three months.
– Presence of hyperhomocysteinemia (>15 μmol/L) or at least two symptoms potentially indicative of cobalamin deficiency, such as:
– Hemoglobin (Hb) below reference value.
– Red blood cell count below reference value.
– Fatigue.
– Memory impairment.
– Irritability.
– Personality changes.
– Muscle weakness.
– Depression.
– Poor appetite.
– Weight loss.
Exclusion Criteria
– Inability to give informed consent or comprehend study information.
– Mini-Mental State Examination (MMSE) score ≤19.
– Inability to self-administer the intranasal spray, except with assistance from a spouse or home care nurse.
– Concurrent use of other nasally administered medications.
– Chronic rhinitis.
– Use of vitamin B12-containing dietary supplements.
– Severe renal impairment (glomerular filtration rate [GFR] < 20 mL/min).
– Ethical or medical concerns determined by the investigators.
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Analysis
Statistical analysis was conducted using IBM SPSS Statistics software version 28.0.1.0 for Mac. Graphs were generated with GraphPad Prism version 9.5.0 for MacOS. The Kolmogorov-Smirnov test assessed the normality of data distribution. For normally distributed continuous variables, differences were evaluated using an independent samples t-test. The Mann-Whitney U test was employed for variables not following a normal distribution. For these non-normally distributed variables, the median and the interquartile ranges (25th and 75th percentiles) were calculated to summarize the data.
Results
Over the study period, 100 patients were initially enrolled. However, 24 patients did not complete the 90-day period due to various reasons: two patients started other intranasal medications, five voluntarily withdrew, nine were excluded by researchers for non-compliance, seven were lost to follow-up, and one patient died. Ultimately, 76 patients completed the study, but 16 were excluded from the final analysis due to missing or mishandled samples.
The median changes in total vitamin B12 and holotranscobalamin (holoTC) concentrations over time. In the loading dose group, daily intranasal cobalamin administration led to a rapid rise in total serum vitamin B12 levels, increasing from a median of 230 to 1090 pmol/L within two weeks. This was followed by a decline to a median of 530 pmol/L after transitioning to weekly administration at 90 days. Conversely, the no loading dose regimen resulted in a steady increase in vitamin B12 levels from 224 to 717 pmol/L over 90 days. Significant differences (P < 0.001) in median vitamin B12 levels between the regimens were observed at days seven and 14, but not at day 90. HoloTC concentrations followed a similar trend, with the loading dose regimen reaching a median of 300 pmol/L initially, then decreasing to 184 pmol/L at 90 days. The no loading dose group showed a steady increase to 260 pmol/L at 90 days.
The changes in median methylmalonic acid (MMA) and total homocysteine (tHcy) levels over time are shown. Both biomarkers exhibited similar patterns across dosage regimens, with reductions in the first 30 days of supplementation, maintaining these lower levels until study completion. MMA levels dropped from 0.27 μmol/L in the loading dose group and 0.30 μmol/L in the no loading dose group to approximately 0.20 μmol/L at days 30 and 90. tHcy concentrations decreased from 19 μmol/L and 18 μmol/L in the respective groups to around 15 μmol/L at days 30 and 90.
Cognitive function, assessed by the MMSE and clock test, and mood, measured by the GDS-15, were evaluated at baseline and study end. Due to various reasons, not all patients completed these assessments. In 39 patients (19 in the loading dose group and 20 in the no loading dose group), MMSE scores were similar at baseline (27 vs. 28) and remained unchanged at the study’s end (both 27). The clock test, performed in 26 patients, showed no differences between treatment groups.
The GDS-15 was completed by 34 patients (17 per group), with median scores initially at 2.0 in the loading dose group and 3.5 in the no loading dose group, which adjusted to 2.5 and 2.0 respectively after 90 days. Initially, three patients in the loading dose group and seven in the no loading dose group had GDS scores ≥5, decreasing to two patients in each group by study end.
During the study, one patient died and another was hospitalized, but these events were not considered related to study participation. Adverse events were reported in 10 patients, with six from the loading dose group and four from the no loading dose group. Reported adverse events included rash, headache, nosebleed, fatigue, colds, and stomach flu.
Conclusion
Intranasal vitamin B12 administration is an effective and appropriate method for restoring and maintaining adequate vitamin B12 levels in elderly patients with a deficiency. The study found no significant differences between the two treatment regimens. A regimen combining a loading dose and no loading dose, involving administration every three days for two weeks followed by weekly doses, appears to be the optimal approach for treating vitamin B12 deficiency in elderly patients.
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