Treatment of hypovitaminosis D is essential for osteoporosis patients, especially those with history of fragility fractures. A study by LeBoff MS et al. [18] showed that vitamin D deficiency was associated with low muscle strength, especially in the lower extremities, which affected patient stability and increased risk of falls. Treatment of hypovitaminosis D alone could reduce the fall rate by 14% [19]. Moreover, a meta-analysis study by Yao P, el al. [20] demonstrated that an increased serum 25(OH)D level of 10 ng/mL was related to 20% lower risk of hip fracture. Given that elderly patients with fragility hip fracture had a high incidence of hypovitaminosis D (ranging from 78.4 to 92%) [6, 21], it is, therefore, important to treat this condition in order to prevent future complication.
The effectiveness of different doses of vitamin D supplementation has been evaluated by previous studies, and benefit of high-dose vitamin D supplementation was shown. For instance, Mak JC et al. [22] retrospectively reviewed 124 patients with fragility hip fracture who had vitamin D deficiency and found that high-dose vitamin D3 supplementation (approximately 4,000 IU per day for 14 days) improved serum 25(OH)D level to a sufficient status in 88.9% of patients; however, only 62.5% of patients who received vitamin D3 1,000 IU per day achieved sufficient vitamin D level. A randomized controlled trial that compared different doses of vitamin D3 also found that a high-dose vitamin D3 of 2,000 IU per day for 12 months was able to restore serum 25(OH)D level to a sufficient level by in 93% of subjects, while only 70% of those who received a low-dose of vitamin D3 (800 IU per day) reached a sufficient vitamin D status [23]. Although, the efficacy of vitamin D2 and vitamin D3 in maintaining serum 25(OH)D was comparable [9], there is limited data available specific to the effectiveness of vitamin D2 supplementation in different doses, especially in fragility hip fracture patients. Woranitat W et al. [24] reported a significant difference in the percentages of postmenopausal women with hypovitaminosis D who achieved sufficient vitamin D level after 12 weeks of supplementation. More than three-quarters (86.4%) of patients who received vitamin D2 supplementation of 40,000 IU per week could reach sufficient vitamin D level, whereas 44.0% and 27.3% of patients who took vitamin D2 of 20,000 IU per week and per 2 weeks, respectively, could achieve sufficient vitamin D level. Another study by Sansanayudh N et al. [17] also reported superior results of high-dose vitamin D2 supplementation of 40,000 IU per week for 8 weeks in metabolic syndrome patients with vitamin D deficiency. Similar to those previous reports, our results showed that more patients in the high-dose vitamin D group achieved sufficient vitamin D status (82.8% and 52.5% in the high- and low-dose vitamin D groups, respectively).
Regarding the potential risks of high-dose vitamin D supplementation, alteration in serum calcium can lead to hypercalcemia. Previous study reported that patients with a serum 25(OH)D level exceeding 150 ng/mL were at risk for developing vitamin D intoxication or severe hypercalcemia [25]. Importantly, none of the patients in our study had serum 25(OH)D above 70 ng/mL. Only 2 patients in the high-dose group and 1 patient in the low-dose group developed mild hypercalcemia, which was transient and asymptomatic in all 3 cases. Therefore, our high-dose vitamin D supplementation protocol is safe and effective for the treatment of hypovitaminosis D in fragility hip fracture patients.
In settings where there is limited access for serum vitamin D measurement, physicians can therefore preliminarily prescribe a high-dose vitamin D2 (60,000 IU per week) for 12 weeks and then switch to a maintenance dose of vitamin D2 (10,000 or 20,000 IU per week). It is important to emphasize that a maintenance dose of vitamin D is required after a period of high-dose vitamin D supplementation to maintain sufficient vitamin D status [10]. Bacon CJ et al. [26] reported the long-term sustainability of serum 25(OH)D level via a maintenance dose of vitamin D3 of 50,000 IU per month following a single bolus dose of vitamin D3 500,000 IU.
There is a trend toward increased serum vitamin D measurement worldwide [27]. This increased number of laboratory tests substantially impact healthcare expenditures [28]. In Australia, the cost of vitamin D measurement increased an average of 59% each year, with a forecasted total cost of vitamin D measurement of A$95.6 million in 2010 [29]. In the United States, there was an 83-fold increase in the reimbursement volume for serum 25(OH)D tests from 2000 to 2010 [30]. Similarly – in the UK, the measurement of serum vitamin D was increased approximately 50-fold from 2005 to 2015 [31]. Since the laboratory cost of vitamin D measurement is quite high, the protocol to check serum vitamin D, both pre- and post-treatment, has burdened many medical centers. At our center, the cost of each serum 25(OH)D test is approximately US$30. With an estimated 42,000 hip fractures in Thailand in 2018 [32], evaluating serum vitamin D before and after supplementation would cost approximately US$2,520,000 per year. Since our preliminary high-dose vitamin D supplementation is effective and safe, this protocol is a cost-effective strategy for treating low vitamin D status in elderly patients with hip fracture without measuring serum vitamin D level.
There were some limitations in this study. First, several confounders, such as dietary vitamin D intake and sunlight exposure, were not evaluated or controlled. However, patients with advancing age, lack of physical activity, various comorbidities, and frailty are likely to reduce their exposure to sunlight [33]. We, therefore, assumed sunlight exposure not to be a major factor for changes in serum 25(OH)D level in this patient population. Second, there was a high drop-out rate in this study as expected, which is common among geriatric patients. Nevertheless, there were no differences in baseline patient demographics and clinical characteristics between patients who withdrew and those who completed the study. Third, there are a number of techniques to measure serum 25(OH)D level, and high performance liquid chromatography (HPLC) is considered a standard method [34]. However, the ECL technique used in our study showed good agreement with HPLC, and has been widely used in many centers [35]. Fourth, the follow-up duration in this study was only 12 weeks in duration, so it is possible that a longer-term analysis may have shown a change in serum vitamin D level after switching patients to a maintenance dose. Last, the average baseline serum 25(OH)D level in this study was not extremely low (baseline mean serum 25(OH)D around 18–20 ng/mL); therefore, our high-dose vitamin D supplementation protocol might achieve lower vitamin D status if patients have an initial 25(OH)D level less than that of our study population.