Methotrexate Chemotherapy Causes Growth Impairments, Vitamin D Deficiency, Bone Loss, and Altered Intestinal Metabolism—Effects of Calcitriol Supplementation

Abstract

Vitamin D deficiency or insufficiency is prevalent in childhood cancer patients and survivors after chemotherapy; further studies are needed to investigate the underlying aetiology and effectiveness of vitamin D supplementation in preventing chemotherapy-induced bone loss. This study used a rat model of treatment with antimetabolite methotrexate to investigate whether methotrexate chemotherapy causes vitamin D deficiency and if vitamin D supplementation attenuates the resultant bone loss. Methotrexate treatment (five daily injections) decreased serum vitamin D levels (from 52 to <30 ng/mL), reduced body and bone lengthening and tibial trabecular bone volume, and altered intestinal vitamin D metabolism, which was associated with intestinal mucosal damage known to cause malabsorption of nutrients, including dietary vitamin D and calcium. During the early stage after chemotherapy, mRNA expression increased for vitamin D activation enzyme CYP27B1 and for calcium-binding protein TRPV6 in the intestine. During the intestinal healing stage, expression of vitamin D catabolism enzyme CYP24 increased, and that of TRPV6 was normalised. Furthermore, subcutaneous calcitriol supplementation diminished methotrexate-induced bone loss due to its effect suppressing methotrexate-induced increased bone resorption. Thus, in young rats, methotrexate chemotherapy causes vitamin D deficiency, growth impairments, bone loss, and altered intestinal vitamin D metabolism, which are associated with intestinal damage, and vitamin D supplementation inhibits methotrexate-induced bone loss.

Seasonal and Treatment-Related Variation in 25-Hydroxy Vitamin D Concentration in Patients with Rheumatoid Arthritis

“…Moreover, they found that MTX chemotherapy affected the intestinal expression of enzymes crucial in vitamin D metabolism, resulting in an increased expression of CYP27B1 (responsible for converting 25-OH-D to active form) and then CYP24 (vitamin D catabolism). They also observed intestinal damage induced by MTX treatment, which can negatively influence vitamin D absorption from nutrients [14]. We observed a significantly decreased level of 25-OH-D in the summer group treated with MTX, compared with LEF-treated patients.…”

“…The authors considered such hypotheses as the deterioration of vitamin D3 bioavailability from nutrients, the downregulation of the hepatic hydroxylation of calciferol (due to the drug hepatotoxicity), and the disturbance of vitamin D3 skin synthesis [16]. A recent paper published by Su et al presents some interesting data concerning the effect of MTX chemotherapy on 25-OH-D levels in an animal model [14]. The authors confirmed that MTX treatment led to a significant decrease in 25-OH-D serum concentration.…”

“…Seasonal variations in 25-OH-D concentration are a known factor that can influence clinical manifestations of RA [13]. Methotrexate (MTX), the most common drug used in RA treatment, can also affect the 25-OH-D level by interfering with its metabolic pathways and reducing bioavailability [14]. However, studies assessing MTX's effect on 25-OH-D concentration are limited and recruit different patient populations (oncological or juvenile idiopathic arthritis patients) [15,16].…”

The Role of Intestinal Cytochrome P450s in Vitamin D Metabolism

“…Rifampicin administration to patients with idiopathic infantile hypercalcemia (IIH) due to loss-of-function mutations in CYP24A1 induces CYP3A4 , suggesting an alternative pathway for vitamin D inactivation [ 50 ]. In addition, methotrexate chemotherapy (which is commonly used in childhood oncology) leads to bone loss and decreasing serum 25OHD 3 along with altered intestinal Cyp24a1 [ 51 ]. During drug therapy in clinical practice, multiple drugs are frequently used, and adverse drug interactions can sometimes occur.…”