AMER ICA N JOURNAL OF OT OLARYNGOLOGY –H EA D A N D N EC K ME D I CIN E AN D SUR G E RY 3 5 ( 2 01 4 ) 8 5 –8 8
Available online at www.sciencedirect.com
ScienceDirect www.elsevier.com/locate/amjoto
Vitamin D deficiency: A simple algorithm employing weekly administration of 50,000 IU of vitamin D☆,☆☆ Laura Middleton, BA a , Brendan C. Stack Jr., MD b, c,⁎, Ann T. Riggs, MD a , Donald L. Bodenner, MD, PhD a, c a b c
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA UAMS Thyroid Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA
ARTI CLE I NFO
A BS TRACT
Article history:
Objective: Vitamin D deficiency affects parathyroid hormone levels and is endemic in the
Received 19 September 2013
American population due to diet and lifestyle. The aim of this study was to evaluate a treatment algorithm using weekly doses of 50,000 IU of Vitamin D2 for thyroid and parathyroid surgery patients. Study Design: Prospective, non-randomized. Setting: University health sciences center. Subjects and Methods: Patients at a thyroid center being treated for benign and malignant thyroid diseases or parathyroid disease. Subjects with total vitamin D levels less than 30 ng/ dl were prospectively treated with weekly doses of 50,000 IU of vitamin D2 (D2) for durations dependent upon initial vitamin D (25-hydroxyvitamin D) levels. Vitamin D levels were measured after the treatment intervals and change in levels from baseline was determined. Results: Subjects receiving 8 weeks of therapy demonstrated an average increase in vitamin D level of 13.4 ng/ml, 10 weeks of therapy showed an increase of 16.35 ng/ml, and 12 weeks showed an average increase of 21.6 ng/ml. The treatment groups had success rates of 82%, 75%, and 71% after 8, 10, and 12 weeks of therapy respectively. When only compliant patients were evaluated (defined as greater than 3-ng/ml increase after therapy), the success rates after 8, 10, and 12 weeks increased to 95%, 79%, and 71% respectively. Conclusions: A simple algorithm using 50,000 IU of vitamin D2 corrects its deficiency in the majority of subjects treated. This is a simple method of treatment for thyroid and parathyroid patients who are vitamin D deficient. Thyroid and parathyroid conditions are frequently treated by otolaryngologists and vitamin D deficiency can complicate their diagnosis and/or management. © 2014 Elsevier Inc. All rights reserved.
☆
Financial disclosure: (1) This research did not require any departmental or outside funding. (2) None of the authors have financial ties to any companies related to the content of this research. (3) None of the authors have financial disclosures to declare. ☆☆ Conflict of interest: None. ⁎ Corresponding author at: Department of Otolaryngology-HNS, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot# 543, Little Rock, AR 72205, USA. E-mail address: [email protected] (B.C. Stack). 0196-0709/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjoto.2013.12.002
86
1.
AMER ICA N JOURNAL OF OT OLARYNGOLOGY –HE A D A N D N EC K ME D IC IN E AN D S U R G ER Y 3 5 ( 2 01 4 ) 8 5 –8 8
Introduction
There is a marked increase in information and interest concerning the effects of vitamin D as an agent for the possible prevention and/or treatment of many common ailments, in addition to its value in bone health. There is growing clinical evidence that vitamin D may prevent the development of multiple sclerosis, diabetes, rheumatoid arthritis, congestive heart failure, and some anecdotal evidence for preventing schizophrenia and depression [1]. Methods for increasing vitamin D levels have long included food sources, sun exposure, or supplementation. Most individuals will not consume an adequate amount of vitamin D through food sources. This is exacerbated by the current emphasis on protection from exposure to the sun's UV rays. These factors highlight the importance of an efficient method of correcting vitamin D insufficiency by supplementation. Vitamin D supplementation is not a novel idea as health care professionals have been administering oral forms of vitamin D for many years; however no universally accepted treatment guideline has been established that recommends dosage and/ or time period of treatment to reach normal levels. The present study prospectively examined the efficacy of weekly doses of 50,000 IU of vitamin D2 in correcting vitamin D deficiency, with treatment duration dependent upon the initial vitamin D level. The study population consisted of patients presenting to a thyroid and parathyroid surgery center at a university health sciences center with benign and malignant diseases. This experience was gained by treating a population of patients undergoing thyroid and parathyroid surgery and closely monitoring their calcium, parathyroid hormone and 25 OH vitamin D levels. Similar populations may be encountered in selected otolaryngology practices. Using this algorithm, normal vitamin D levels were attained in the majority of study subjects.
2.
Methods
The treatment algorithm was evaluated in the Thyroid Center at the University of Arkansas for Medical Sciences. The subjects were seen primarily for thyroid and parathyroid disorders. The study was approved by the institutional review board at the University of Arkansas for Medical Sciences. Subjects were included in the study if they had no signs, symptoms, or history of malabsorption, were identified as vitamin D deficient (initial 25(OH) D level < 30 ng/ml) and had a post-treatment level drawn within 4 weeks of completing the protocol. The time frames of treatment in our protocol were based upon our previous experience treating vitamin D deficiency. Data collected also included the subject's age, ethnicity, and BMI. Subjects were assigned to treatment groups based on initial 25(OH) D levels. Patients presenting with levels at 1–10 ng/ml were treated with 50,000 IU of D2 orally for 12 weeks, 11–20 ng/ml were treated with 50,000 IU for 10 weeks, and 21–30 ng/ml were treated for 8 weeks. A final total 25(OH) D level greater than 30 ng/ml was considered sufficient, and patients were instructed to continue vitamin D3 therapy of 1000 IU daily in order to remain sufficient.
Subjects were considered non-compliant if there was less than a 3-ng/ml rise in total vitamin D level after the protocol had ended.
3.
Results
Seventy-six subjects were included in the study. Eighty-eight percent were white, 11% were black, and 91% were female. The average age was 61.9 years (± 1.9 years), and average body mass index was 30.0 (±0.9). Forty-nine (64%) subjects were mildly deficient at the initiation of treatment (21–30 ng/ml), 20 (26 %) were deficient (11–20 ng/ml) and only 7 (9%) were severely deficient (1–10 ng/ml). Treatment of all three groups established sufficient 25(OH)D levels in the majority of subjects. As shown in Fig. 1, subjects receiving 8 weeks of therapy demonstrated an average increase of 13.4 ng/ml, 10 weeks of therapy produced an increase of 16.3 ng/ml, and 12 weeks of therapy showed an average increase of 21.6 ng/ml. As shown in Fig. 2, the treatment groups had success rates of 95%, 79%, and 71% at 8, 10, and 12 weeks respectively without inclusion of non-compliant patients and success rates of 82%, 75%, and 71% respectively with the inclusion of non-compliant patients. Non-compliance was uncommon with only 8 patients (10%) demonstrating 25(OH)D levels that either decreased or failed to rise by more than 3 ng/ml above the level drawn at therapy onset. Non-compliance was similar in all groups: 14 %, 5% and 0% in patients mildly deficient, deficient and severally deficient groups respectively. No patients in the study had signs or symptoms that would indicate malabsorption issues.
4.
Discussion
Vitamin D deficiency is a common worldwide problem and the focus of numerous epidemiological studies. An estimated 1 billion people worldwide have been found to have some form
Fig. 1 – Effect of Vitamin D repletion regimen on 25 OH levels. 25-Hydroxyvitamin D levels before and after treatment with 50,000 IU on vitamin D2. Average initial level (black box) and final level (gray box), for three treatment periods of 8, 10, and 12 weeks.
AMER ICA N JOURNAL OF OT OLARYNGOLOGY –H EA D A N D N EC K ME D I CIN E AN D SUR G E RY 3 5 ( 2 01 4 ) 8 5 –8 8
Fig. 2 – Success of vitamin D repletion regimen. Percent of subjects successfully treated with 50,000 IU of vitamin D2. All subjects (gray box) and compliant subjects (black box), with non-compliance defined as an increase of 3 ng/ml or less in vitamin D at the end of the treatment period.
of vitamin D insufficiency [2]. This number includes 40% to 100% of US and European elderly women and men still living in the community [3]. This does not include those living in nursing home facilities where the incidence of vitamin D deficiency is even higher [4]. Also at risk are children and young adults, with 52% of Hispanic/black adolescents and 48% of white pre-adolescent females with levels less than 20 ng/ml [1]. Other factors associated with vitamin D deficiency include older age (> 80 years), higher BMI (>25 kg/m2), use of concomitant medications known to affect vitamin D metabolism, vitamin D supplementation at less than 400 IU daily, poor general health, malabsorption, limitation in daily activities, poor exercise levels, lower education level and annual income, and lower number of weekly servings of vitamin D containing foods [5]. Successful Vitamin D repletion and sustained sufficiency levels have the most pronounced effect on bone metabolism. Examples include a significant increase in bone mineral density at both the lumbar spine and femoral neck regions [6], a 25% reduction of hip and other non-vertebral fractures in elderly individuals [7], and an increase in lean body mass as well as skeletal bone mineral content and/or bone mineral density at several key skeletal sites in premenarchal girls [8]. Recently, correcting vitamin D deficiency has been shown to reduce falls by 70 % [9] to 95% [10] compared with uncorrected individuals. Vitamin D sufficiency is also associated with a significant decrease in the risk of all-cause mortality [11]. With roughly 15% of the world's population reporting vitamin D insufficiency, a proven algorithm for replenishment would be extremely helpful. Several studies have attempted to establish a method to correct Vitamin D insufficiency and have made strides toward reaching an effective method; however, few of these studies have uniformly achieved a minimum level of vitamin D sufficiency (30 ng/ml or 50 nmol/l). Pepper et al. [12] identified 36 discrete prescribing regimes for the treatment of vitamin D deficiency in the literature. Of these regimes, the three most commonly followed were (1) Ergocalciferol (vitamin D2) 50,000 IU once weekly for a duration of 4 weeks, followed by 50,000 IU once monthly for a duration of 5 months; (2) Ergocalciferol 50,000 IU once monthly for a duration of
87
6 months; and (3) Ergocalciferol 50,000 IU three times per week for a duration of 6 weeks. Each of the proposed methods increased 25(OH) D concentrations in the majority of patients, however vitamin D sufficiency was only obtained in 38%, 42%, and 82% respectively across the methods presented. In a meta-analysis of previously conducted randomized clinical trials, Broe et al. [9] compared the effect of four vitamin D doses with placebo on vitamin D status. One hundred twenty-four nursing home residents in a long-term care facility were assigned to one of four vitamin D dosage groups: 200 IU, 400 IU, 600 IU, or 800 IU as compared against a placebo group. Participants were randomly assigned to a treatment group over a 5-month study period with an initial 25(OH) D serum levels taken at study onset and conclusion. The 800-IU supplementation group showed the greatest impact on 25(OH) D levels from a baseline of 21.4 ± 9.2 ng/ml rising to a final serum level of 29.95 ± 5.86 ng/ml. Average follow-up levels for the other trial groups showed still insufficient levels ranging from 22 to 24 ng/ml. Participants in this study were also allowed to continue any multivitamin supplementation during the course of the study, which may have increased vitamin D intake for all treatment groups. Holick et al. [13] conducted a randomized, placebocontrolled, double-blind study of healthy vitamin D-deficient adults aged 18–84 years who received placebo, 1000 IU vitamin D3, 1000 IU vitamin D2, or 500 IU vitamin D2 plus 500 IU vitamin D3 daily for a period of 11 weeks at the end of the winter season. Adults who received the placebo showed no change in vitamin D levels, while adults who ingested vitamin D2 gradually increased their 25(OH) D levels from 16.9 ± 10.5 ng/ml to 25.8 ± 6.8 ng/ml during the first 6 weeks of the study and remained stable at these levels thereafter. Another alternative for vitamin D replenishment is the administration of yearly dosage with 600,000 IU of vitamin D3. Diamond et al. [6] conducted a prospective open-label study to assess the safety and efficacy of this treatment method in 5 men and 45 women with vitamin D deficiency. Average baseline levels were increased over 350% at 4 and 128% at 12 months without significant toxicity. However, the use of such large doses of ergocalciferol has come under scrutiny after a yearly dose of 500,000 IU was associated with an increase falls and fractures in elderly patients [14]. There is continued debated on what level of vitamin D constitutes deficiency. The Institute of Medicine defined vitamin D levels less than 20 ng/ml as deficient. However, physiologic studies have shown that PTH levels remain elevated with vitamin D levels between 20 and 30 ng/ml, reaching a plateau only when levels are above 30 ng/ml [15]. Therefore, we have included patients with vitamin D levels between 20 and 30 ng/ml in the present study and labeled them insufficient rather than frankly deficient. Vitamin D is a fat-soluble vitamin so overdose and toxicity are theoretic concerns for treatments of deficiency. For this reason, our protocol limits repletion for defined periods of time. We have not had any clinical or measured toxicity using our protocol. There are no existing guidelines that limit populations that should not be replenished based on comorbidities. Less aggressive (smaller doses) of vitamin D repletion than proposed by our protocol has been tried but requires prolonged treatment and may never be successful.
88
AMER ICA N JOURNAL OF OT OLARYNGOLOGY –HE A D A N D N EC K ME D IC IN E AN D S U R G ER Y 3 5 ( 2 01 4 ) 8 5 –8 8
We adopted a simple treatment algorithm for each of the above levels of insufficiency and deficiency based on an 8-, 10-, and 12-week daily supplementation schedule using 50,000 IU of vitamin D followed by a maintenance dose of 1000 IU vitamin D daily. Our results for successful repletion fell into the range of those reported in other studies. This approach is simple, effective, and helpful for otolaryngologists who might encounter vitamin D deficiency in their endocrine surgery cases. The treatment schedule is applied based on 25(OH) D levels at presentation: 1 to 10 ng/ml received 12 doses, 11 to 20 ng/ml received 10 doses and 21 to 30 ng/ml received 8 doses. After treatment was completed the patients were maintained on 1000 IU D3 daily. Despite the recent IOM recommendation that 800 IU of daily vitamin D is sufficient in the elderly [16], the Endocrine Society recently published practice guidelines for the treatment of vitamin D deficiency [17] and suggested that the target vitamin D level should be 30 ng/ml and doses higher than 800 IU daily may be needed to reach this goal. We chose 1000 units daily after subjects were replenished. This maintenance dose is safe as shown by Kimball et al. [18] who demonstrated that 25-hydroxy Vitamin D levels as high as 75 nmol/l at a supplementation rate of 4000–10,000 IU have been shown to be safe as well as increase fracture prevention.
5.
Conclusion
This study proposes that a simple algorithm based on weekly administration of 50,000 IU of vitamin D, for a defined duration, normalizes vitamin D levels in the majority of our subjects studied. We now need to apply it in a randomized prospective method to validate wider applicability.
REFERENCES
[1] Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81. [2] Dawson-Hughes B, Chen P, Krege JH. Response to teriparatide in patients with baseline 25-hydroxyvitamin D insufficiency or sufficiency. J Clin Endocrinol Metab 2007;92:4630–6. [3] Linnebur SA, Vondracek SF, Griend JP, et al. Prevalence of vitamin D insufficiency in elderly ambulatory outpatients in Denver, Colorado. Am J Geriatr Pharmacother 2007;5:1–8. [4] Drinka PJ, Krause PF, Nest LJ, et al. Determinants of vitamin D levels in nursing home residents. J Am Med Dir Assoc 2007;8: 76–9.
[5] Holick MF, Siris ES, Binkley N, et al. Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab 2005;90:3215–24. [6] Diamond TH, Ho KW, Rohl PG, et al. Annual intramuscular injection of a megadose of cholecalciferol for treatment of vitamin D deficiency: efficacy and safety data. [see comment] Med J Aust 2005;183:10–2. [7] Boonen S, Lips P, Bouillon R, et al. Need for additional calcium to reduce the risk of hip fracture with vitamin d supplementation: evidence from a comparative metaanalysis of randomized controlled trials. J Clin Endocrinol Metab 2007;92: 1415–23. [8] Kantorovich V, Gacad MA, Seeger LL, et al. Bone mineral density increases with vitamin D repletion in patients with coexistent vitamin D insufficiency and primary hyperparathyroidism. J Clin Endocrinol Metab 2000; 85:3541–3. [9] Broe KE, Chen TC, Weinberg J, et al. A higher dose of vitamin d reduces the risk of falls in nursing home residents: a randomized, multiple-dose study. J Am Geriatr Soc 2007;55: 234–9. [10] Dawson-Hughes B. Serum 25-hydroxyvitamin D and functional outcomes in the elderly. Am J Clin Nutr 2008;88: 537S–40S. [11] Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 2007;167:1730–7. [12] Pepper KJ, Judd SE, Nanes MS, et al. Evaluation of vitamin D repletion regimens to correct vitamin D status in adults. Endocr Pract 2009;15:95–103. [13] Holick MF, Biancuzzo RM, Chen TC, et al. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab 2008;93:677–81. [14] Sanders KM, Stuart AL, Williamson EJ, et al. Annual highdose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010;303: 1815–22. [15] Dawson-Hughes B, Heaney RP, Holick MF, et al. Estimates of optimal vitamin D status. Osteoporos Int 2005;16:713–6. [16] Boucher BJ. The 2010 recommendations of the American Institute of Medicine for daily intakes of vitamin D. Public Health Nutr 2011;14:740. [17] Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2008;96:1911–30. [18] Kimball SM, Ursell MR, O'Connor P, et al. Safety of vitamin D3 in adults with multiple sclerosis. Am J Clin Nutr 2007;86: 645–51.
Available online at www.sciencedirect.com
ScienceDirect www.elsevier.com/locate/amjoto
Vitamin D deficiency: A simple algorithm employing weekly administration of 50,000 IU of vitamin D☆,☆☆ Laura Middleton, BA a , Brendan C. Stack Jr., MD b, c,⁎, Ann T. Riggs, MD a , Donald L. Bodenner, MD, PhD a, c a b c
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA UAMS Thyroid Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA
ARTI CLE I NFO
A BS TRACT
Article history:
Objective: Vitamin D deficiency affects parathyroid hormone levels and is endemic in the
Received 19 September 2013
American population due to diet and lifestyle. The aim of this study was to evaluate a treatment algorithm using weekly doses of 50,000 IU of Vitamin D2 for thyroid and parathyroid surgery patients. Study Design: Prospective, non-randomized. Setting: University health sciences center. Subjects and Methods: Patients at a thyroid center being treated for benign and malignant thyroid diseases or parathyroid disease. Subjects with total vitamin D levels less than 30 ng/ dl were prospectively treated with weekly doses of 50,000 IU of vitamin D2 (D2) for durations dependent upon initial vitamin D (25-hydroxyvitamin D) levels. Vitamin D levels were measured after the treatment intervals and change in levels from baseline was determined. Results: Subjects receiving 8 weeks of therapy demonstrated an average increase in vitamin D level of 13.4 ng/ml, 10 weeks of therapy showed an increase of 16.35 ng/ml, and 12 weeks showed an average increase of 21.6 ng/ml. The treatment groups had success rates of 82%, 75%, and 71% after 8, 10, and 12 weeks of therapy respectively. When only compliant patients were evaluated (defined as greater than 3-ng/ml increase after therapy), the success rates after 8, 10, and 12 weeks increased to 95%, 79%, and 71% respectively. Conclusions: A simple algorithm using 50,000 IU of vitamin D2 corrects its deficiency in the majority of subjects treated. This is a simple method of treatment for thyroid and parathyroid patients who are vitamin D deficient. Thyroid and parathyroid conditions are frequently treated by otolaryngologists and vitamin D deficiency can complicate their diagnosis and/or management. © 2014 Elsevier Inc. All rights reserved.
☆
Financial disclosure: (1) This research did not require any departmental or outside funding. (2) None of the authors have financial ties to any companies related to the content of this research. (3) None of the authors have financial disclosures to declare. ☆☆ Conflict of interest: None. ⁎ Corresponding author at: Department of Otolaryngology-HNS, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot# 543, Little Rock, AR 72205, USA. E-mail address: [email protected] (B.C. Stack). 0196-0709/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjoto.2013.12.002
86
1.
AMER ICA N JOURNAL OF OT OLARYNGOLOGY –HE A D A N D N EC K ME D IC IN E AN D S U R G ER Y 3 5 ( 2 01 4 ) 8 5 –8 8
Introduction
There is a marked increase in information and interest concerning the effects of vitamin D as an agent for the possible prevention and/or treatment of many common ailments, in addition to its value in bone health. There is growing clinical evidence that vitamin D may prevent the development of multiple sclerosis, diabetes, rheumatoid arthritis, congestive heart failure, and some anecdotal evidence for preventing schizophrenia and depression [1]. Methods for increasing vitamin D levels have long included food sources, sun exposure, or supplementation. Most individuals will not consume an adequate amount of vitamin D through food sources. This is exacerbated by the current emphasis on protection from exposure to the sun's UV rays. These factors highlight the importance of an efficient method of correcting vitamin D insufficiency by supplementation. Vitamin D supplementation is not a novel idea as health care professionals have been administering oral forms of vitamin D for many years; however no universally accepted treatment guideline has been established that recommends dosage and/ or time period of treatment to reach normal levels. The present study prospectively examined the efficacy of weekly doses of 50,000 IU of vitamin D2 in correcting vitamin D deficiency, with treatment duration dependent upon the initial vitamin D level. The study population consisted of patients presenting to a thyroid and parathyroid surgery center at a university health sciences center with benign and malignant diseases. This experience was gained by treating a population of patients undergoing thyroid and parathyroid surgery and closely monitoring their calcium, parathyroid hormone and 25 OH vitamin D levels. Similar populations may be encountered in selected otolaryngology practices. Using this algorithm, normal vitamin D levels were attained in the majority of study subjects.
2.
Methods
The treatment algorithm was evaluated in the Thyroid Center at the University of Arkansas for Medical Sciences. The subjects were seen primarily for thyroid and parathyroid disorders. The study was approved by the institutional review board at the University of Arkansas for Medical Sciences. Subjects were included in the study if they had no signs, symptoms, or history of malabsorption, were identified as vitamin D deficient (initial 25(OH) D level < 30 ng/ml) and had a post-treatment level drawn within 4 weeks of completing the protocol. The time frames of treatment in our protocol were based upon our previous experience treating vitamin D deficiency. Data collected also included the subject's age, ethnicity, and BMI. Subjects were assigned to treatment groups based on initial 25(OH) D levels. Patients presenting with levels at 1–10 ng/ml were treated with 50,000 IU of D2 orally for 12 weeks, 11–20 ng/ml were treated with 50,000 IU for 10 weeks, and 21–30 ng/ml were treated for 8 weeks. A final total 25(OH) D level greater than 30 ng/ml was considered sufficient, and patients were instructed to continue vitamin D3 therapy of 1000 IU daily in order to remain sufficient.
Subjects were considered non-compliant if there was less than a 3-ng/ml rise in total vitamin D level after the protocol had ended.
3.
Results
Seventy-six subjects were included in the study. Eighty-eight percent were white, 11% were black, and 91% were female. The average age was 61.9 years (± 1.9 years), and average body mass index was 30.0 (±0.9). Forty-nine (64%) subjects were mildly deficient at the initiation of treatment (21–30 ng/ml), 20 (26 %) were deficient (11–20 ng/ml) and only 7 (9%) were severely deficient (1–10 ng/ml). Treatment of all three groups established sufficient 25(OH)D levels in the majority of subjects. As shown in Fig. 1, subjects receiving 8 weeks of therapy demonstrated an average increase of 13.4 ng/ml, 10 weeks of therapy produced an increase of 16.3 ng/ml, and 12 weeks of therapy showed an average increase of 21.6 ng/ml. As shown in Fig. 2, the treatment groups had success rates of 95%, 79%, and 71% at 8, 10, and 12 weeks respectively without inclusion of non-compliant patients and success rates of 82%, 75%, and 71% respectively with the inclusion of non-compliant patients. Non-compliance was uncommon with only 8 patients (10%) demonstrating 25(OH)D levels that either decreased or failed to rise by more than 3 ng/ml above the level drawn at therapy onset. Non-compliance was similar in all groups: 14 %, 5% and 0% in patients mildly deficient, deficient and severally deficient groups respectively. No patients in the study had signs or symptoms that would indicate malabsorption issues.
4.
Discussion
Vitamin D deficiency is a common worldwide problem and the focus of numerous epidemiological studies. An estimated 1 billion people worldwide have been found to have some form
Fig. 1 – Effect of Vitamin D repletion regimen on 25 OH levels. 25-Hydroxyvitamin D levels before and after treatment with 50,000 IU on vitamin D2. Average initial level (black box) and final level (gray box), for three treatment periods of 8, 10, and 12 weeks.
AMER ICA N JOURNAL OF OT OLARYNGOLOGY –H EA D A N D N EC K ME D I CIN E AN D SUR G E RY 3 5 ( 2 01 4 ) 8 5 –8 8
Fig. 2 – Success of vitamin D repletion regimen. Percent of subjects successfully treated with 50,000 IU of vitamin D2. All subjects (gray box) and compliant subjects (black box), with non-compliance defined as an increase of 3 ng/ml or less in vitamin D at the end of the treatment period.
of vitamin D insufficiency [2]. This number includes 40% to 100% of US and European elderly women and men still living in the community [3]. This does not include those living in nursing home facilities where the incidence of vitamin D deficiency is even higher [4]. Also at risk are children and young adults, with 52% of Hispanic/black adolescents and 48% of white pre-adolescent females with levels less than 20 ng/ml [1]. Other factors associated with vitamin D deficiency include older age (> 80 years), higher BMI (>25 kg/m2), use of concomitant medications known to affect vitamin D metabolism, vitamin D supplementation at less than 400 IU daily, poor general health, malabsorption, limitation in daily activities, poor exercise levels, lower education level and annual income, and lower number of weekly servings of vitamin D containing foods [5]. Successful Vitamin D repletion and sustained sufficiency levels have the most pronounced effect on bone metabolism. Examples include a significant increase in bone mineral density at both the lumbar spine and femoral neck regions [6], a 25% reduction of hip and other non-vertebral fractures in elderly individuals [7], and an increase in lean body mass as well as skeletal bone mineral content and/or bone mineral density at several key skeletal sites in premenarchal girls [8]. Recently, correcting vitamin D deficiency has been shown to reduce falls by 70 % [9] to 95% [10] compared with uncorrected individuals. Vitamin D sufficiency is also associated with a significant decrease in the risk of all-cause mortality [11]. With roughly 15% of the world's population reporting vitamin D insufficiency, a proven algorithm for replenishment would be extremely helpful. Several studies have attempted to establish a method to correct Vitamin D insufficiency and have made strides toward reaching an effective method; however, few of these studies have uniformly achieved a minimum level of vitamin D sufficiency (30 ng/ml or 50 nmol/l). Pepper et al. [12] identified 36 discrete prescribing regimes for the treatment of vitamin D deficiency in the literature. Of these regimes, the three most commonly followed were (1) Ergocalciferol (vitamin D2) 50,000 IU once weekly for a duration of 4 weeks, followed by 50,000 IU once monthly for a duration of 5 months; (2) Ergocalciferol 50,000 IU once monthly for a duration of
87
6 months; and (3) Ergocalciferol 50,000 IU three times per week for a duration of 6 weeks. Each of the proposed methods increased 25(OH) D concentrations in the majority of patients, however vitamin D sufficiency was only obtained in 38%, 42%, and 82% respectively across the methods presented. In a meta-analysis of previously conducted randomized clinical trials, Broe et al. [9] compared the effect of four vitamin D doses with placebo on vitamin D status. One hundred twenty-four nursing home residents in a long-term care facility were assigned to one of four vitamin D dosage groups: 200 IU, 400 IU, 600 IU, or 800 IU as compared against a placebo group. Participants were randomly assigned to a treatment group over a 5-month study period with an initial 25(OH) D serum levels taken at study onset and conclusion. The 800-IU supplementation group showed the greatest impact on 25(OH) D levels from a baseline of 21.4 ± 9.2 ng/ml rising to a final serum level of 29.95 ± 5.86 ng/ml. Average follow-up levels for the other trial groups showed still insufficient levels ranging from 22 to 24 ng/ml. Participants in this study were also allowed to continue any multivitamin supplementation during the course of the study, which may have increased vitamin D intake for all treatment groups. Holick et al. [13] conducted a randomized, placebocontrolled, double-blind study of healthy vitamin D-deficient adults aged 18–84 years who received placebo, 1000 IU vitamin D3, 1000 IU vitamin D2, or 500 IU vitamin D2 plus 500 IU vitamin D3 daily for a period of 11 weeks at the end of the winter season. Adults who received the placebo showed no change in vitamin D levels, while adults who ingested vitamin D2 gradually increased their 25(OH) D levels from 16.9 ± 10.5 ng/ml to 25.8 ± 6.8 ng/ml during the first 6 weeks of the study and remained stable at these levels thereafter. Another alternative for vitamin D replenishment is the administration of yearly dosage with 600,000 IU of vitamin D3. Diamond et al. [6] conducted a prospective open-label study to assess the safety and efficacy of this treatment method in 5 men and 45 women with vitamin D deficiency. Average baseline levels were increased over 350% at 4 and 128% at 12 months without significant toxicity. However, the use of such large doses of ergocalciferol has come under scrutiny after a yearly dose of 500,000 IU was associated with an increase falls and fractures in elderly patients [14]. There is continued debated on what level of vitamin D constitutes deficiency. The Institute of Medicine defined vitamin D levels less than 20 ng/ml as deficient. However, physiologic studies have shown that PTH levels remain elevated with vitamin D levels between 20 and 30 ng/ml, reaching a plateau only when levels are above 30 ng/ml [15]. Therefore, we have included patients with vitamin D levels between 20 and 30 ng/ml in the present study and labeled them insufficient rather than frankly deficient. Vitamin D is a fat-soluble vitamin so overdose and toxicity are theoretic concerns for treatments of deficiency. For this reason, our protocol limits repletion for defined periods of time. We have not had any clinical or measured toxicity using our protocol. There are no existing guidelines that limit populations that should not be replenished based on comorbidities. Less aggressive (smaller doses) of vitamin D repletion than proposed by our protocol has been tried but requires prolonged treatment and may never be successful.
88
AMER ICA N JOURNAL OF OT OLARYNGOLOGY –HE A D A N D N EC K ME D IC IN E AN D S U R G ER Y 3 5 ( 2 01 4 ) 8 5 –8 8
We adopted a simple treatment algorithm for each of the above levels of insufficiency and deficiency based on an 8-, 10-, and 12-week daily supplementation schedule using 50,000 IU of vitamin D followed by a maintenance dose of 1000 IU vitamin D daily. Our results for successful repletion fell into the range of those reported in other studies. This approach is simple, effective, and helpful for otolaryngologists who might encounter vitamin D deficiency in their endocrine surgery cases. The treatment schedule is applied based on 25(OH) D levels at presentation: 1 to 10 ng/ml received 12 doses, 11 to 20 ng/ml received 10 doses and 21 to 30 ng/ml received 8 doses. After treatment was completed the patients were maintained on 1000 IU D3 daily. Despite the recent IOM recommendation that 800 IU of daily vitamin D is sufficient in the elderly [16], the Endocrine Society recently published practice guidelines for the treatment of vitamin D deficiency [17] and suggested that the target vitamin D level should be 30 ng/ml and doses higher than 800 IU daily may be needed to reach this goal. We chose 1000 units daily after subjects were replenished. This maintenance dose is safe as shown by Kimball et al. [18] who demonstrated that 25-hydroxy Vitamin D levels as high as 75 nmol/l at a supplementation rate of 4000–10,000 IU have been shown to be safe as well as increase fracture prevention.
5.
Conclusion
This study proposes that a simple algorithm based on weekly administration of 50,000 IU of vitamin D, for a defined duration, normalizes vitamin D levels in the majority of our subjects studied. We now need to apply it in a randomized prospective method to validate wider applicability.
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