Research Article
Vitamin B12 Level Have Prognostic Significance in Multiple Myeloma Patients?
Aysun Şenturk Yikilmaz1, Sema Akıncı2, Kamile Silay1*, Sule Mine Bakanay1, Ismail Bekiroglu1 and Imdat Dilek1
1Department of Internal Medicine and Hematology, YildirimBeyazit University, Ankara
2Department of Internal medicine and Hematology, Atatürk Research and Training Hospital, Ankara
*Corresponding author: Kamile Silay, Department of Internal Medicine and Hematology, YildirimBeyazit University, Ankara
Published: 13 Mar, 2018
Cite this article as: Yikilmaz AŞ, Akıncı S, Silay K, Bakanay
SM, Bekiroglu I, Dilek I. Vitamin B12
Level Have Prognostic Significance in
Multiple Myeloma Patients?. Clin Oncol.
2018; 3: 1434.
Abstract
Aim: The aim is to investigate retrospectively the association between vitamin B12 levels at the time
of diagnosis and the complications including hypercalcemia and fractures in multiple myeloma
patients.
Material and Method: The association between vitamin B12 level at the time of diagnosis and
myeloma complications such as hypercalcemia and bone lesions were analyzed with chi-square in
140 multiple myeloma patients.
Findings: Vitamin B12 deficiency was found in 29 patients (20.7%). While the rate of hypercalcemia
is 37.9% in patients with vitamin B12 deficiency, it is 18.9% in patients without deficiency. The
fracture rate was 44.8% in vitamin B12 deficient group and 23.4% in the other group.
Results: Vitamin B12 deficiency at the time of diagnosis is associated with hypercalcemia and bone
fracture rate (p=0.04, p=0.03).
Discussion: Vitamin B12 level might have prognostic significance since hypercalcemia and fracture
rate is increased in the vitamin B12 deficient group. Further studies with a larger patient group are
needed on this subject.
Keywords: Myeloma; Vitamin B12 deficiency; Myeloma bone disease
Introduction
Multiple myeloma is a neoplasm with bone marrow-derived clonal plasma cell growth.
Uncontrolled proliferation of plasma cells results in an end-organ damage, including an abnormal
increase in the production of monoclonal immunoglobulins (paraproteinemia), lytic lesions in
the bones, anemia, infections, hypercalcemia and renal involvement [1]. Multiple myeloma bone
disease (MBD) can cause lytic lesions classic prevalent disease, osteopenia and especially in a specific
portion of the spine, head, bones or long bones may be in the form of multiple lytic lesions [2]. The
main mechanism of MBD is the increase in osteoclastic activity associated with the suppression of
osteoblastic activity in bones. From the moment of diagnosis, bone pain is a major problem [3].
The primary causes of hypercalcemia in patients with myeloma are tumors associated with bone
destruction. This leads to increased osteoclastic bone resorption caused by potent cytokines secreted
from myeloma cells [4]. Another cause of hypercalcemia is the disruption in the functioning of the
kidneys, impairment of the renal calcium load and increased calcium absorption [5].
There are studies in the literature showing that vitamin B12 deficiency and increased risk of
osteoporosis, hip and spine fractures are linked. In these studies, the relationship between vitamin
b12 deficiency and increased risk of osteoporosis and fracture in the healthy population has been
associated with an increase in osteoclast activity, although not fully clarified [6-12]. In large-scale
LASA studies, it has been shown that deoxypyridinoline linkages (deoxypyridinoline cross-links
(DPD), the bone resorption marker, are increased in women with low vitamin B12 levels [13]. Also,
in a study on a placebo-controlled healthy population, a reduction in fracture risk was associated
with vitamin b12 supplementation [14].
There are reports that vitamin B12 deficiency increases the risk of fracture in healthy subjects,
but a relationship between vitamin B12 deficiency and fracture risk in multiple myeloma cases
has not been shown. The presence of increased osteoclastic activity in the etiology of MBD and
hypercalcemia seen in multiple myeloma is also known. We aimed
to investigate retrospectively the association between vitamin B12
levels at the time of diagnosis and the complications including
hypercalcemia and fractures in multiple myeloma patients.
Table 1
Materials and Methods
Study population
140 multiple myeloma patients presented to hematology
outpatient clinic at Ankara Atatürk Training and Research
Hospital were included. The patient’s charts and medical records
were retrospectively analyzed. The routine anemia work up results
including vitamin B12 levels and calcium levels were noted.
Patients with a vitamin B12 level below 220 pg/mL were
considered to be low during the anemia period. Blood samples for
vitamin B12 were taken from peripheral and sterile conditions,
measured by chemiluminescence method in Roche cobas 6000
hormone autoanalyzer. A serum calcium level > 10 mg/dL at the time
of diagnosis was considered as hypercalcemia. Bone fractures were
demonstrated by magnetic resonance imaging and/or direct X-ray.
Statistical analysis
The cases were divided into 2 groups with low and normal vitamin
B12 levels and statistical evaluation was done. Statistical analyzes
were performed using chi-square test using SPSS version 16.0 (SPSS
Inc., Chicago, IL, USA). A value of less than 0.05 was considered
significant.
Findings
Vitamin B12 levels, calcium values and bone fracture status were
evaluated retrospectively multiple myeloma in our study. Of the cases
80 (57.1%) was male, 60 (42.9%) was female. The mean age was 63.5
(± 11.5). The demographic data of the study group are summarized
in (Table 1).
Results
132 (94.3%) patients have been diagnosed with anemia. Out of 132 cases 29 of them (20.7%) was identified with Vitamin B12 deficiency. While 41.4 percent of patients with vitamin B12 deficiency were female, 58.6 percent was male. Out of the 32 Hypercalcemia cases 11 (34.4%) of them has vitamin B12 deficiency. Hypercalcemia was found 37.9% in vitamin B12 deficiency group while18.9% in vitamin B12 normal group. (p=0.04) The bone fracture rate at diagnosis was 44.8% in the group with vitamin B12 deficiency and 23.4% in the group without vitamin B12 deficiency and this difference was statistically significant. (p=0.03).
Discussion
In our study, we found that vitamin B12 deficiency was found in
20.7% of patients with multiple myelomas at the time of diagnosis
and hypercalcemia and bone fracture frequency has been found
increased in these cases. In a previous study in 32 patients with
multiple myeloma, vitamin B12 deficiency was reported as 28%
and there was no correlation between vitamin B12 deficiency and
demographic features and complications [15]. In our study, the rate of
hypercalcemia was higher in the group with vitamin B12 deficiency.
Hypercalcemia in multiple myeloma is a metabolic disorder resulting
in end-organ damage in the disease. Osteoclastic bone resorption
and renal insufficiency, which are formed through the secretion
of plasma cells, are effective in the formation of hypercalcemia. In
our MM cases, the relationship between vitamin B12 deficiency and
hypercalcemia is difficult to establish because of pathophysiological
causes, as there is insufficient data in the literature. In an experimental
study investigating the effect of vitamin B12 on calciummetabolism,
it has been reported that vitamin B12 is effective at the intra
cellular entry of calcium into rat thymocytes [16]. The decrease
in serum vitamin B12 level can be explained by this relationship
mechanism. There are different publications on vitamin B12 levels
in myeloproliferative diseases in which one or more hematopoietic
series cells have excessive proliferation and vitamin B12 depletion
due to the consumption of this rapid proliferation can be observed
[17]. Various studies have shown changes in serum vitamin B12,
transcobalamin 2 and haptocorrinlevels in lymphoproliferative
diseases involving plasmacell dyscrasias including multiple myelomas
[18-21]. In an in vitro study, myeloma cells were shown to be able to
consume vitamin B12 itself [22]. In a study comparing the vitamin
B12 levels of myeloma bone marrow cells with the healthy control
group, the concentration of vitamin B12 in the plasmacells of the
bone marrow was found to be higher. In addition, compared with
the healthy control group, myeloma patients had increased levels
of transcobalamin 2 mediated vitamin B12 uptake in their bone
marrowcells [23-24]. Thisreduction of vitamin B12 might show the
contribution of plasmacells, but more extensive studies are needed
to show this relation. In our study, we found that bone fracture
frequency was increased in patients with vitamin B12 deficiency.
In the literature, the relationship between vitamin B12 and bone
fracture in multiple myeloma cases has not been shown. Therefore,
we believe that our work is meaningful for this patient population.
Pathologic and osteoporotic bone fractures are frequently observed
in multiplemyeloma [25]. In a metanalysis, the incidence of bone
fracture is very high even before diagnosis and after myeloma
diagnosis, the incidence of fractures, mainly vertebrae and rib, are
increased 9 times [26]. In the general population, there are many
studies that have studied vitamin B12 deficiency and osteoporosis
and bone fracture risk. In a meta-analysis of 27 cross-sectional and
longitudinal studies conducted to observe the relationship between
vitamin B12 and fracture risk, it was observed that every 50 pmol/L
reductions in vitamin B12 increased the fracture risk by 4% [27].
Previous studies have shown that vitamin B12 is associated with
decreased body mass index deficits and fracture risk [28-29]. There
lationship between vitamin B12 deficiency and fracture risk can be
partially explained by epidemiological studies [29]. However, it has
been suggested that osteoclast stimulation is primarily responsible for
the relationship between vitamin B12 deficiency and bone structure
deterioration [30].
As a result; it is known that the cases are at an advanced age, with
a multifactorial fracture risk of disease-induced immobilization, chemotherapy
and steroid use. In our study, vitamin B12 deficiency seems
to be associated with an increased risk of fracture. We think that
vitamin B12 is a clinical prognostic factor in the diagnosis of multiple
myeloma in the presence of known effects of vitamin B12 as well as
increased risk of fracture. There is a need for more extensive work on
this particular subject.
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