High incidence of vitamin D deficiency in patients undergoing allogeneic stem cell transplantation

Patients undergoing allogeneic stem cell transplants (SCT) are at increased risk for vitamin D deficiency through prolonged hospitalizations and avoidance of sunlight as well as decreased nutritional status and malabsorption related to an allogeneic SCT. Vitamin D deficiency was shown to be as high as 39% in the pretransplant setting [1] and 90% in the postallogeneic transplant setting [2]. The purpose of this study was to confirm the high incidence of vitamin D deficiency in the pre and postallogeneic transplant setting, the demographic factors associated with vitamin D deficiency, and the correlation between vitamin D deficiency and osteopenia and osteoporosis in patients undergoing allogeneic stem cell transplantation. We found that 70% of patients were vitamin D deficient at day 0 of an allogeneic SCT, and 58% of patients were vitamin D deficient at post-transplant day 100. The incidence of osteopenia and osteoporosis in day 100 of the post-transplant setting was 83% and 22%, respectively, however there was no difference in incidence of osteopenia or osteoporosis in patients who were vitamin D deficient or nondeficient. Our study confirms the high incidence of vitamin D deficiency in patients undergoing allogeneic transplant patients. Vitamin D3 (1,25-dihydroxycholecalciferol) is a steroid hormone that plays a central role in calcium and bone homeostasis as well as various immunologic and antiproliferative functions [3, 4]. Vitamin D deficiency can lead to reduced bone density and pathological fractures [5] and is associated with increased risks of cancer and cardiovascular disease [6, 7]. In addition, allogeneic SCT patients are at especially high risk of developing osteoporosis and fractures through increased exposure to glucocorticoids to prevent or treat graft versus host disease [8]. Patients undergoing allogeneic SCT are known to have an increased incidence of vitamin D deficiency [1, 2]. To confirm the elevated incidence of vitamin D deficiency in patients undergoing allogeneic SCT, we reviewed the vitamin D status in both the pre and postallogeneic SCT setting. Initially, we examined vitamin D levels in 72 consecutive patients at approximately day 100 postallogeneic SCT (Post-transplant cohort). We found that 42 (58%) patients were vitamin D deficient with a median vitamin D level of 17 ng/mL and a range of 6–51 ng/mL. The baseline demographics of these patients are outlined in Supporting Information (Table 1). The average age of patients was 48 years with a range of 19–71. The majority of patients was male (56%), white (81%), and had a myeloid malignancy (43%). When comparing vitamin D deficient and nondeficient cohorts, there were no statistically significant differences in age, gender, race, and disease status. After recognizing the high incidence of vitamin D deficiency in the post-transplant cohort, we then sought to determine the vitamin D status in patients before allogeneic SCT (pretransplant cohort), and we measured day 0 vitamin D levels in 240 consecutive patients undergoing allogeneic SCT. In the pretransplant cohort, 168 (70%) of the patients were vitamin D deficient, with a median vitamin D level of 16 ng/mL and a range of 6–59 ng/mL. The baseline demographics of the pretransplant cohort are listed in Supporting Information (Table 2). The average age of patients was 51 with a range of 10–77 years. The majority of patients (62%) was male, white (80%), and had a myeloid malignancy (74%). Patients under age 50 were more likely to be vitamin D deficient (80% versus 64%, P = 0.01). Nonwhite patients were also more likely to be vitamin D deficient (85% vs. 66%, P = 0.02). Gender or disease status did not correlate with vitamin D deficiency. The high incidence of vitamin D deficiency in both the pre and postallogeneic SCT setting is similar to the incidence of vitamin D deficiency in the general population [9-11] (32–50%), in cancer patients (63–75%) [12], and prior studies involving SCT patients [1, 2]. In our study, pretransplant patient had a higher incidence of vitamin D deficiency in comparison to post-transplant patients (70% vs. 58%), however since these were two separate populations we cannot conclude that post-transplants patients are less likely to be vitamin D deficient. There was no demographic variable that was associated with vitamin D deficiency in both the pre and post-transplant cohorts, so in conclusion, we recommend that all patients undergoing SCT should be tested both before and after allogeneic SCT. To determine the impact of vitamin D deficiency on calcium homeostasis, we measured several laboratory correlates in the post-transplant cohort. Patients who were vitamin D deficient had a significantly lower mean albumin level (3.63 vs. 4.0 g/dL, P = 0.001), lower mean ionized calcium level (1.21 vs. 1.25 mmol/L, P = 0.01), higher intact parathyroid hormone (iPTH) levels (131 vs. 80 pg/mL, P = 0.005), and no statistically significant difference phosphate levels. The decrease in ionized calcium with a compensatory increase in serum PTH levels is an expected finding and further emphasizes that vitamin D deficiency in these patients is not an isolated event but a part of larger systemic process. When comparing vitamin D levels versus each laboratory correlate in a linear fashion, there was a positive correlation between vitamin D levels and albumin (P < 0.001) and ionized calcium (P = 0.02), and negative correlation between vitamin D levels and iPTH levels (P value = 0.03) (Supporting Information; Fig. 1). Interestingly, vitamin D deficiency also correlated with a lower albumin level, potentially signaling that vitamin D deficient patients are also malnourished. In the future we plan to longitudinally assess laboratory values in both the pre and post-transplant setting to determine whether these results hold true. Correlations Between Vitamin D and ionized calcium, parathyroid hormone, and albumin in day +100 SCT patients. Vitamin D was drawn at day +100 after allogeneic stem cell transplant along with other laboratory values. We sought to determine if vitamin D correlated with other laboratory values in a linear fashion using a Pearson correlation coefficient. We found a significant direct relationship between vitamin D and ionized calcium and albumin. We found a significant inverse relationship vitamin D and parathyroid hormone. Post-transplant bone loss due to multiple clinical factors is a well-characterized complication for patients undergoing hematopoietic SCTs [13-15]. Day +100 bone density measurements were available for 46 (64%) of our post-transplant cohort. Of the 46 patients with bone density measurements, 38 (83%) had evidence of osteopenia and 10 (22%) had evidence of osteoporosis. The mean T-score for the right hip, left hip, and spine was −1.30. We did not find any significant differences in the rate of osteopenia or osteoporosis between vitamin D deficient and sufficient patients. This rate of osteopenia and osteoporosis is similar to other reports in patients undergoing allogeneic SCT [14, 16]. While our population had a high incidence of osteopenia and osteoporosis, there was no difference in the rates of osteopenia or osteoporosis in vitamin D deficient and sufficient patients. The most likely explanation for the this finding is that other clinical factors including use of glucocorticoids, heparin, lack of exercise, chronic renal disease, gastrointestinal disease, and chemotherapy outweigh vitamin D's impact on bone loss. However, as vitamin D deficiency can be easily corrected at little cost or risk to the patient, we maintain that vitamin D levels should be checked and corrected when deficiency is present. In conclusion, we confirmed that the incidence of vitamin D deficiency is very high in both the pre (70%) and post (58%) SCT setting, and that the vast majority of patients have decreased bone density (83%) irrespective of their vitamin D levels. Given the increasing epidemiologic and laboratory data implicating the vitamin D axis in inflammation, future studies should be undertaken to assess the impact of vitamin D deficiency on traditional clinical outcomes associated with deficiency (including bone density and fracture rates) as well as immunological endpoints (GVHD and infection incidence). Study population and design. All patient and clinical data was collected under an Institutional Board Review protocol. From October 2005 to October 2006, we collected serum vitamin D levels at approximately day 100 in 72 allogeneic SCT patients treated at MD Anderson Cancer Center (post-transplant cohort). As a part of long term follow up care and study of bone health for patients undergoing allogeneic SCT transplants, we also studied the blood levels of calcium, phosphorous, ionized calcium, and bone density. After finding high incidence of vitamin D deficiency in this cohort of post-transplant allogeneic SCT patients, we studied a second cohort of pretransplant allogeneic SCT patients (Pretransplant cohort) to determine if this high incidence of vitamin D deficiency was present before transplantation or resulted from factors in the first 100 days of transplant including lack of sunlight and decreased nutritional intake and absorption. From September 2006 to September 2007, we measured serum vitamin D levels before initiation of conditioning chemotherapy in 240 consecutive patients undergoing allogeneic transplant. Demographic data were obtained from the departmental database. Patients were divided into groups based into four disease categories: lymphoid malignancies including non-Hodgkin lymphoma, Hodgkin lymphoma, and multiple myeloma; myeloid malignancies including acute myelogenous leukemia, myelodysplastic syndrome, and acute lymphoblastic leukemia; myeloproliferative disorders including essential thrombocytosis and CMML; and an “other” category including aplastic anemia, renal cell carcinoma, and breast cancer. Defining vitamin D deficiency and osteopenia/osteoperosis. While there is no consensus on defining a sufficient level of vitamin D, most clinicians agree that a serum 25-hydoxy vitamin D (calcidiol) of <20 ng/mL as deficient [17, 18]. Vitamin D levels were obtained using a CLIA certified assay. For the purpose of our study, we defined vitamin D deficiency as a calcidiol level of <20 ng/mL and Vitamin D nondeficient as a calcidiol level of ≥20 ng/mL. Osteopenia and osteoporosis were defined according NIH consensus [19]. Osteopenia was defined as having a T score < −1.0 standard deviation, and osteoporosis was defined as having T score < −2.5 standard deviations from normal individuals. Statistical analysis. We analyzed vitamin D deficient and nondeficient patients with respect to basic demographic values such as age, gender, race, and disease status using a Pearson chi squared test or Fisher's exact test. To compare vitamin D levels with respect to lab values, we first compared laboratory values of vitamin D deficient and sufficient patients using an unpaired t-test for data that followed normal distribution. For data that did not follow normal distribution even after logarithmic transformation, the Wilcoxin rank-sum test (Mann-Whitney) was used. We also compared vitamin D levels with albumin, ionized calcium, and parathyroid hormone using a Pearson correlation coefficient. The authors thank the patients, the nurses, and the data managers for making this study possible. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Richard W. Joseph*, Amin Alousi*, Bhavana Konda , Krishna Komanduri , Joyce Neumann*, Cindy Trevino*, Karen Stolar*, Muzaffar Qazilbash*, Chitra Hosing*, Partow Kebriaei*, Daniel R. Couriel*, Richard E. Champlin*, Rima Saliba*, Uday Popat*, * Department of Stem Cell Transplant and Cellular Therapy MD Anderson Cancer Center, Houston, Texas, Department of Internal Medicine, University of Miami Miller School of Medicine Regional Campus, Atlantis, Florida, Department of Medicine, Adult Stem Stem Cell Transplant Program University of Miami Sylvester Cancer Center, Miami, Florida.