Table 1.

Summary of the Findings of Key Studies

Medication	Outcomes from Key Studies	References
Antidiabetic Medications
Metformin	Users of oral antidiabetics were observed in a cohort study to have on average lower mean 25(OH)D serum concentrations of 7.3 nmol/L compared with diabetics not using these drugs. In two similarly designed studies, with a total of over 11,500 patients, a negative association between vitamin D status and oral antidiabetic use was observed, and a further cross-sectional study identified a specific effect due to metformin only.	[76,78–80]
Thiazolidinediones (TDZs)	The decrease in bone mineral density (BMD) and the increase in risk of fracture in type 2 diabetes (T2D) have been shown to be exacerbated as a result of prescription of TZDs to improve insulin sensitivity. A systematic review and meta-analysis suggests that TZD use may result in bone loss that may be specific and moderate in women. Chronic TZD treatment has been reported to elevate the risk of bone fracture more in those women already at a greater risk for bone loss, osteoporosis, and bone fracture, than in men. T2D patients on antidiabetic therapies are likely to have a reduced intake of nutrients essential for bone health, such as vitamin D, calcium, and magnesium.	[83–85,88–90]
Diuretics
Thiazide Diuretics	Associations with vitamin D levels appear mixed. The combination of supplementation with vitamin D (which enhances absorption of intestinal calcium) and thiazide diuretics (which decrease calcium excretion in the urine) and may theoretically result in hypercalcaemia, or exacerbate it. None of four additional studies reported that thiazide treatment resulted in significant alterations in concentrations of 25(OH)D.	[91–96]
Loop Diuretics	The use of loop diuretics resulted in associations with 25(OH)D being either negative or not present, whilst those with 1,25(OH)2D were similarly mixed. A randomized clinical trial comparing placebo with loop diuretic use showed elevation of both 1,25(OH)2D and serum parathyroid hormone (PTH) levels, together with an increased renal calcium excretion that may induce hyperparathyroidism, which, in turn, increases hydroxylation of 25(OH)D, resulting in increased concentrations of 1,25(OH)2D.	[76,91,97]
Potassium-Sparing Diuretics	van Ortein-Luiten et al highlighted an inverse association between potassium-sparing diuretics and vitamin D in the elderly. Another cross-sectional study in patients of a similar demographic failed to replicate these findings.	[76,80]
Medications Used in Cardiovascular Disease
Calcium Channel Blockers	In a cohort study of elderly individuals, the use of calcium channel blockers (such as verapamil and diltiazem) resulted in a reduction of 7.7 nmol/L in levels of 25(OH)D in serum in contrast to non-use. As verapamil and diltiazem are known to inhibit CYP3A4, the anabolism of 25(OH)D precursors in the skin through exposure to UV radiation may be decreased as a consequence, thus resulting in lower serum 25(OH)D. Drugs, such as nifedipine, which are ligands for the nuclear pregnane X receptor (PXR) can induce an increase in vitamin D catabolism.	[23,75,76,98–101]
Angiotensin-Converting Enzyme (ACE) Inhibitors	ACE inhibitor use in a cohort of elderly patients resulted in a 7.6 nmol/L reduction in 25(OH)D serum levels compared with those not prescribed this type of medication. German and Dutch cross-sectional studies also reported lower levels of 25(OH)D in those using these drugs. A further examination of the cohort in the Dutch study and two quasi-experimental studies showed no relationship. Another study identified higher concentrations in those prescribed quinapril, but reported no change in enalapril users.	[76,102–106]
Statins	Statins exert their cholesterol-lowering effects by inhibiting the hydroxymethylglutaryl-coenzyme A reductase (HMG CoA reductase) enzyme, which is rate limiting in cholesterol synthesis; hence, it is thought that statins could also reduce the synthesis of vitamin D. Since simvastatin, lovastatin, and atorvastatin are primarily metabolized by CYP3A4, competition for this enzyme may present another route for drug–vitamin interactions. CYP2C9 primarily metabolizes rosuvastatin and fluvastatin, whereas pravastatin and pitavastatin interact minimally with hepatic enzymes, instead being degraded in the stomach. Reports from several groups have indicated that atorvastatin administration may increase circulating 25(OH)D concentrations. Two studies investigating the effects of pravastatin therapy on vitamin D status identified no significant differences in 25(OH)D levels. Rosuvastatin has been demonstrated to robustly increase levels of vitamin D. In a prospective cohort study in hyperlipidaemic patients, compared with baseline levels, statistically significant increases were observed in both 25-hydroxyvitamin D and 1,25-hydroxyvitamin D. The same authors later reported that 25-hydroxyvitamin D levels increased with rosuvastatin treatment compared to fluvastatin. Well-designed larger multicentre trials are required to resolve the issue.	[105,108–119,122,123]
Bile Acid Sequestrants	Bile acid sequestrants may also bind with vitamin D, and since its metabolites are also present in bile, an elevated excretion of bile acids may also reduce levels of this and other fat-soluble vitamins. One trial in children with familial hypercholesterolaemia reported a significant decrease in vitamin D status in those taking 8 g colestyramine daily over the period of a year. The reduction in absorption of vitamin D induced by colestyramine can occasionally lead to osteomalacia in patients receiving daily doses of colestyramine of >32 g for prolonged periods of over 2 years. Three other studies on the same class of medications reported the opposite findings.	[116,128–135]
Vitamin K Antagonists	Two cross-sectional studies from the Netherlands indicate that patients prescribed vitamin K antagonists experienced more greatly reduced concentrations of 25(OH)D than non-users. This was confirmed in a cross-sectional study from Germany of 7553 males. Four other studies did not report this effect.	[76,79,80,136–139]
Platelet Aggregation Inhibitors	Two cross-sectional studies failed to report an inverse relationship between the use of platelet aggregation inhibitors and vitamin D status. However, three other studies have found to the contrary.	[76,79,80,140,141]
Heparin	When used for 3 months or more, at a dose of ≥15,000 IU, unfractionated heparin has been demonstrated to be associated with osteoporotic fractures and reduced bone density, and vitamin D metabolism is also negatively affected. Low molecular weight heparins are unlikely to reduce bone density to the same extent as unfractionated heparin, but there is the possibility that these compounds may adversely affect vitamin D metabolism.	[206–214]
Digoxin	In one Dutch cross-sectional study of geriatric patients, a negative, tending towards a statistically significant inverse relationship between digoxin and vitamin D was identified. Statistical significance was not confirmed in other studies.	[76,79,80]
CNS Medications
Benzodiazepines	A lack of a significant effect of benzodiazepines has been reported in three cross-sectional studies. Sohl et al, in a subsequent subgroup analysis of participants in their study, did observe a significant inverse association between this category of drug and vitamin D.	[76,80,142]
Antidepressants	The finding of an inverse relationship between the use of selective serotonin reuptake inhibitors (SSRIs) and 25(OH)D levels was reported in two cross-sectional studies.	[80,142]
Enzyme-Inducing Antiepileptic Drugs (AEDs)	A systematic review suggests that in adult patients treated with AEDs, vitamin D deficiency is commonly observed, with consequently reduced levels and frequency of deficiency differing according to the medication used.	[61]
Newer Antiepileptic Drugs	A large retrospective cohort study of over 15,000 patients reported an elevated risk of bone fracture for gabapentin but none with lamotrigine, levetiracetam, or oxcarbazepine. However, a smaller, similarly retrospective, study of 560 patients concluded that there was no association between newer AEDs and lower BMD. Other studies are conflicting.	[63–70]
Gastrointestinal Medications
Proton Pump Inhibitors (PPIs)	Theoretically, the hypochlorhydria induced by this class of medication could result in malabsorption of calcium, with the suggestion that prolonged exposure to acid suppression might be a clinically relevant consequence contributing to increased osteoporosis risk. Vitamin D and calcium for the elderly where high-dose PPI therapy, especially over a long-term period, is being employed, is recommended.	[144–146]
Histamine H2-Receptor Antagonists	Preclinical studies demonstrate that cimetidine inhibits 25-hydroxylases. A small study of nine patients with cimetidine-treated gastric ulcers identified no significant decrease in 25(OH)D serum concentrations from baseline while patients were receiving the medication; however, levels rose significantly once cimetidine was discontinued. Preclinical models fail to identify the same interaction with ranitidine.	[147–150]
Lipase Inhibitors	Orlistat binds within the gastrointestinal tract to the active sites of pancreatic and gastric lipases and thereby blocks absorption of fats in the diet, thus limiting calorie intake; hence, vitamin D uptake and absorption from the diet and supplements may be inhibited. Three studies reported decreased concentrations of 25(OH)D in those receiving orlistat. However, decreases were similarly reported in the control groups, which may be attributable to a reduction in total fat intake.	[194–198]
Laxatives	A reduction in absorption of vitamin D and calcium from food as a result of high doses and prolonged use of stimulant laxatives can lead to hypocalcaemia and osteomalacia.	[73]
Anti-Inflammatory Medications
Corticosteroids	A commonly observed complication of corticosteroid therapy is osteoporosis, and the impact of this class of medication on vitamin D metabolism as a potential contributory factor has been the subject of a number of studies. The majority identified no significant differences in levels of 25(OH)D in comparison to pretreatment or in controls. Lems et al identified that treatment of healthy controls with low-dose prednisone reduced 25(OH)D levels. Lund et al similarly reported 25(OH)D concentrations to be significantly reduced in a study of patients with rheumatoid arthritis taking low-dose prednisone, but none was considered to be deficient. Two other centres reported a lack of significant differences in pre- versus post-treatment 25(OH)D concentrations with prednisolone. In the USA, those taking prednisolone ≥7.5 mg/day (or corresponding doses of other corticosteroids) for ≥6 months are advised to take a daily vitamin D supplement of 800 IU and to maintain a calcium intake of 1500 mg each day.	[151–163,181]
Inhaled Corticosteroids (ICS)	One study failed to identify any effect of inhaled glucocorticosteroids (ICS) on serum 25(OH)D Sohl et al, in a cohort study, reported a significant negative association with lower 25(OH)D in serum in men treated with this class of medication. One systematic review concluded that ICS use may affect markers of BMD and bone metabolism in asthmatic patients and those with COPD, as well as healthy adults. Another meta-analysis identified a significant relationship between greater doses of ICS and elevated turnover of bone in mild COPD as well as asthmatic patients, but this failed to reach significance at lower doses of ICS. A third meta-analysis reported no difference in BMD between asthma patients receiving long-term ICS treatment and healthy controls. A later systematic review and meta-analysis found no significant associations between BMD and fracture risk in asthmatic children and adults receiving long-term ICS treatment. Meta-analyses assessing the association between fracture risk in COPD patients and long-term ICS use have established a modest but significant, dose-dependent increase. In summary, the effect of long-term ICS use may negatively influence bone metabolism and BMD in certain patients, especially those with COPD.	[76,170,173–176,178–180]
Bronchodilators	In one case–control study, a greater risk of femur and hip fractures was reported for larger doses, but this was attenuated after adjusting for underlying disease and oral glucocorticoid use. This finding is supported by a 2-year randomized trial assessing BMD in patients receiving ICS compared to a non-corticosteroid group taking beta2-agonists.	[182,183]
Hydroxychloroquine	One study assessing the predictors and prevalence of deficiency of vitamin D found it to be common in systemic lupus erythematosus patients. Those prescribed hydroxychloroquine had elevated concentrations of 25(OH)D in comparison with non-users.	[199]
Anti-infectives/Antivirals
Antimicrobials	Six small studies investigated the possibility of an association between the use of rifampicin and/or isoniazidand vitamin D status. Of these, four reported a decrease in 25(OH)D, one identified no change, and one demonstrated an increase. Osteomalacia has been reported after therapy prolonged for >1 year, especially when accompanied by low intake of vitamin D.	[184,185,189–193]
Sulphonamides and Urea Derivatives	A cross-sectional study of 892 community-living outpatients in the Netherlands identified a statistically significant negative effect of these medications on vitamin D status.	[80]
Highly Active Antiretroviral Therapy (HAART)	Of three clinical studies, two reported lower concentrations of 25(OH)D in serum in patients prescribed HAART compared with non-users, but this was only statistically significant in one study. Reduction of plasma levels of vitamin D has been reported within 6 months of initiation of therapy with favirenz-based antiretroviral therapy, but not after longer term use.	[202–205]
Medications Used in Malignancy
Chemotherapeutic Agents	Many of these medications are metabolized by CYP3A4 and hence may interact with vitamin D. These include tamoxifen, docetaxel, paclitaxel, ifosfamide, etoposide, vinblastine, vincristine, cyclophosphamide, imatinib, and irinotecan. The effect of the use of docetaxel and anthracycline-based adjuvant chemotherapy on vitamin D plasma levels was investigated in a longitudinal evaluation of breast cancer patients with an early-stage diagnosis, and it was identified that 30–50% were vitamin D deficient at the initial diagnosis of their breast cancer. Two other studies of the same chemotherapy regimens failed to report a significant change in 25(OH)D concentrations; however, in both, patients received vitamin D supplements. Another study in a similar group of patients found that nearly all patients had insufficiency of vitamin D by the completion of neoadjuvant chemotherapy, accompanied by associated alterations in the calcium/ RANKL/OPG axis, which suggests a disruption of regulatory mechanisms at a functional level. Three other studies assessed vitamin D status during chemotherapy. These studies examined patients diagnosed with colorectal, breast, uterine, and ovarian cancers treated with a variety of chemotherapeutic drugs (5-fluorouracil, cisplatin, capecitabine, epirubicin, oxaliplatin, irinotecan, as well as a number of monoclonal antibodies) and reported a lack of significant changes in concentrations of 25(OH)D during treatment.	[215,216,218–223]
Others
Sunscreens	Reduction of synthesis of vitamin D in the skin, and hence plasma levels, can occur as a result of extensive or frequent use of sunscreens, and there is concern that excessive use or overuse may result in deficiency.	[224–228]