Expression of both vitamin D receptors and the rate-limiting enzyme for vitamin D synthesis, 1-alpha-hydroxylase, has been reported in most immune cells.¹ The suggestion that vitamin D potentially can have immunomodulatory effects in the body has prompted dedicated research in the last
2 decades exploring vitamin D’s role in the disease process that leads to and perpetuates MS. Several observational studies have shown a higher MS risk in individuals with low serum 25-dihydroxyvitamin D [25(OH)D].²,³ Others, such as Mokry et al, used Mendelian randomization to show that individuals with genetically lower 25(OH)D had a twofold greater odds of MS.⁴ It appears that vitamin D status not only is associated with risk of MS but also plays a role in modulating the degree of disease activity.⁵,⁶,⁷ Other studies have demonstrated an effect of vitamin D supplementation on MS disease activity. A randomized, double-blind, placebo-controlled study conducted in Finland found that vitamin D3 supplementation at 20,000 IU weekly had no adverse effects, but the vitamin D3 (add-on treatment to interferon [IFN]-b) group had a significantly lower number of gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI).⁸ The double-blind, multicenter, 48-week SOLAR (double blind placebo controlled study of high dose cholecalciferol oil add on treatment to subcutaneous interferon beta 1a) study is the largest study to date.⁹ The authors found no statistical significant differences in disease-free activity between the placebo group and the vitamin D group. However, there was a nonsignificant trend toward lower relapse rates in the vitamin D-treated group as well as a statistically significant reduction in new lesions at 48 weeks. Several other randomized controlled studies are currently underway to further elucidate the role of vitamin D in MS.

It is recommended that all patients with MS or MS risk factors be screened for vitamin D deficiency. 25(OH)D should be the assay used to evaluate vitamin D status. Vitamin D deficiency is defined as a 25(OH)D below 20 ng/mL, and vitamin D insufficiency as a 25(OH)D of 21 to 29 ng/mL.¹⁰ Vitamin D comes in multiple forms. Vitamin D2 (ergocalciferol) is the plant form of vitamin D and is primarily manufactured. Vitamin D3 (cholecalciferol) is found in animal-based foods and synthesized in humans in the skin by a photolytic process.¹¹

Foods rich in vitamin D include fatty fish (e.g., salmon, mackerel), cod liver oil, egg yolk, and shiitake mushrooms. Cholecalciferol and ergocalciferol are also available from fortified foods (e.g., milk, cereal, orange juice, and cheeses). In general, diet by itself is often a poor source of vitamin D, providing only 40 to 400 IU per food serving. It is also important to note that sunlight (ultraviolet B) exposure and vitamin D production in the skin is highly variable. Factors such skin pigmentation, age, use of sunscreen, and environmental factors such as winter season, high latitude, pollution, cloud cover, and ozone levels will alter an individual’s vitamin D production through the skin.¹²

Vitamin D supplementation through food and production through sunlight will often be inadequate and unpredictable. Therefore, in the setting of vitamin D deficiency or insufficiency, it is not recommended for individuals to use food or sunlight as their main source of repletion. Vitamin D supplementation can be administered daily, weekly, or monthly. Vitamin D3 (cholecalciferol) is widely preferred over vitamin D2 (ergocalciferol), as it has been proved to be the more potent form of vitamin D in humans.¹³ The Endocrine Society recommends a daily supplement dose of 600 to 800 IU to satisfy the
requirements for optimal bone health, but a higher intake (1500-2000 IU) may be needed to achieve and maintain 25(OH)D levels at 30 ng/mL.¹⁰ Considering current evidence, many clinicians who treat patients with MS may choose to empirically supplement to a higher vitamin D level goal, such as 40 to 60 ng/mL, until more conclusive data are found. To obtain such levels, patients may need to take between 2000 and 5000 IU/d of vitamin D.¹¹

Vitamin D toxicity is a rare event caused by inadvertent or intentional ingestion of excessively high amounts of vitamin D.¹⁰ The Endocrine Practice Guidelines Committee expressed concerns in individuals with 25(OH)D levels of 150 ng/mL or higher, when daily doses of vitamin D exceed 10,000 IU or when high intake of vitamin D is combined with high intake of calcium (>1200 mg daily).¹⁰ Although the study was of limited duration, Kimball et al showed that large doses of vitamin D supplementation ranging from 28,000 to 280,000 IU/wk was well tolerated and had no significant adverse effects such as hypercalcemia or hypercalciuria.¹⁴ Other studies performed in pregnant patients demonstrate safety with giving doses of 50,000 IU weekly for up to 12 weeks or a dose as high as two doses of 300,000 IU intramuscularly.¹⁵ Additionally, there have been several studies conducted specifically in patients with MS that showed safety using doses of vitamin D above 10,000 IU/d.¹⁴,¹⁶,¹⁷ Follow-up in these studies ranged from 12 weeks to 1 year. To date, there is a paucity of evidence supporting the use of higher doses of vitamin D over a prolonged time; therefore, regardless of the dose of supplementation initiated, we recommend that 25(OH)D levels are checked 3 months after initiating supplementation and trended over time to ensure levels are within goal and to adjust vitamin D dose. Caution should be taken in patients with impairment of renal function or other disease states such as sarcoidosis or lymphoma that could compound the effects of vitamin D supplementation and lead to hypercalcemia. Additionally, there is some evidence to suggest that higher doses of vitamin D is associated with an increased risk of falls in the elderly.¹⁸

GCs have a particularly large impact on bone loss and fractures.¹⁹ The highest rate of bone loss occurs within the first 3 to 6 months of GC treatment followed by a slower decline with continued GC use.²⁰ Both high daily and high cumulative GC doses increase the risk of fracture, particularly vertebral fracture, because of the greater effects of GCs on trabecular bone than on cortical bone. However, this effect is largely reversible. Once GC treatment is terminated, bone mineral density increases and fracture risk declines.²⁰

Physicians should take a thorough history evaluating the details of GC use (dose, duration, pattern of use) and assess for risk factors for osteoporosis and fractures (falls, history of fractures, frailty, low body weight, hypogonadism, secondary hyperparathyroidism, thyroid disease, family history of hip fracture, history of alcohol use or smoking). In patients older than 40 years, it is recommended that the FRAX calculator (https://www.sheffield.ac.uk/FRAX/) be used to assess fracture risk if the patient does not have osteoporosis. When GC use is included as a risk factor in FRAX, the risk generated is associated with a prednisone dose of ≤7.5 mg/d; therefore, fracture risk should be increased if patients are on a dose above 7.5 mg/d (15% for major osteoporotic fracture and 20% for hip fracture risk).²¹ Patients treated with long-term or high-dose GC who have concomitant osteoporosis risk factors are the individuals at the highest risk of GC-induced osteoporosis. These patients should undergo bone mineral density testing within 6 months of beginning GC treatment.²²

In addition to causing bone loss and fractures, steroid use puts individuals at risk for avascular bone necrosis (AVN). Steroids are now the second most common cause of AVN after trauma, and the prevalence of AVN varies between 3% and 38%.²³ The pathogenesis of GC-induced AVN is not fully understood, but it has been hypothesized to involve progressive destruction of bone vasculature and death of osteocytes, ultimately leading to alteration of bone architecture.²³ The duration of steroid treatment, the total cumulative dose, and the highest daily dose of steroids have been implicated as important factors in the development of avascular necrosis. AVN is typically characterized by pain that is gradual in onset, worsens with activity, relieved by rest, and radiates from the joint down the affected limb. It is important for clinicians to be mindful of these symptoms in their patients taking steroids, as early diagnosis is crucial to prognosis. Conventional radiography is generally the first-line test, with MRI being the most sensitive modality in diagnosing AVN.²³

The American College of Rheumatology 2017 Guidelines recommend that all patients taking prednisone ≥2.5 mg/d for ≥3 months should have a calcium intake of 1000 to 1200 mg/d and 600 to 800 IU/d of vitamin D
in addition to lifestyle modifications of smoking cessation, limiting alcohol intake, and incorporating resistance exercises into daily routine.²² Those with moderate to high risk of fracture should be treated with oral bisphosphonates (BPs) such as alendronate 70 mg weekly, ibandronate 150 mg monthly, or risedronate 35 mg once weekly. Oral BPs are preferred for safety, cost, as well as the lack of evidence of superior antifracture benefits from other osteoporosis medications. An advantage of oral BPs is that they can be stopped if GCs are discontinued; however, because they are poorly absorbed in the gastrointestinal tract, they should be used with caution in patients with upper gastrointestinal disease because of the potential for worsening of gastrointestinal symptoms. For those who do not tolerate oral BPs because of gastrointestinal side effects, intravenous BPs (zoledronic acid 5 mg intravenously per year) can be used. All BPs are contraindicated in patients with hypocalcemia and renal impairment (creatinine clearance below 30 mL/min) and in those who are pregnant or lactating. Rare but recognized side effects of long-term BP use include osteonecrosis of the jaw and atypical subtrochanteric or diaphyseal femoral fractures. Given these concerns, patients on BPS should discuss the medications with their dentist/oral health care provider. Additionally, the need to continue treatment should be reviewed at regular intervals. After 5 years of oral alendronate, risedronate, or ibandronate or after 3 years of intravenous zoledronic acid, fracture risk should be reassessed and a drug holiday should be strongly considered. Lastly, if oral or intravenous BPs are contraindicated, other options include recombinant parathyroid hormone (teriparatide 20 µg subcutaneous daily) and monoclonal antibody RANK ligand inhibitors (denosumab 60 mg subcutaneous every 6 mo).

Another major complication that comes with GC use for longer durations is the suppression of the HPA axis.²⁴ With exogenous steroid use, the adrenocorticotropic hormone (ACTH)-secreting cells of the pituitary atrophy so that when steroids are withdrawn, the pituitary fails to respond appropriately and low ACTH with subsequently low cortisol levels are observed. The longer an individual takes exogenous steroids, the more likely the adrenal gland itself also atrophies leading to an impairment of the adrenals to respond to ACTH. Depending on the duration and dose of GC use, the degree of HPA axis suppression can vary. In general, patients who are more likely to develop HPA axis suppression
are those who receive high doses (>20-30 mg prednisone or equivalent) of systemic GCs for long periods (>3 wk) and those who appear to have Cushingoid features.²⁵ Individuals with adrenal insufficiency typically exhibit nonspecific symptoms such as fatigue, decreased appetite, and abdominal discomfort; however, when they are exposed to any stressor, these same individuals can become critically ill with nausea, vomiting, orthostatic hypotension, and even hemodynamic instability. The full recovery of the HPA axis varies from 1 week to several months after discontinuation of GCs.²⁶

Before starting any course of GC, clinicians should educate their patients about the risk and symptoms of adrenal insufficiency. It is important for clinicians treating patients with MS to have a high suspicion for adrenal insufficiency particularly in patients after discontinuation of high-dose or long-term treatment of GC or patients with nonspecific symptoms after discontinuing steroids of any dose or duration.

To identify patients with suppressed endogenous cortisol production, the standard high-dose cosyntropin stimulation test should be performed. This test consists of measuring serum cortisol immediately before and 30 and 60 minutes after administration of 250 µg of cosyntropin, a synthetic derivative of ACTH. Normal adrenal function is indicated by a serum cortisol concentration ≥18. Those patients with cortisol concentration ≤18 need to be considered for GC replacement therapy under the guidance of an endocrinologist. The stimulation test should be performed once the patient has stopped taking steroids or is given a physiologic dose of steroids (hydrocortisone 10 mg in the morning and 5 mg in the evening or prednisone 5 mg daily). If a patient continues to take steroids at physiologic dosing, then he or she must not take the steroid on the morning of the stimulation test and instead must wait until completing the stimulation test.