Calcif Tissue Int (2012) 90:279–285 DOI 10.1007/s00223-012-9577-6
ORIGINAL RESEARCH
Vitamin D Reduces Musculoskeletal Pain After Infusion of Zoledronic Acid for Postmenopausal Osteoporosis Antonino Catalano • Nancy Morabito • Marco Atteritano • Giorgio Basile • Domenico Cucinotta Antonino Lasco
•
Received: 19 August 2011 / Accepted: 30 January 2012 / Published online: 16 February 2012 Ó Springer Science+Business Media, LLC 2012
Abstract The acute-phase response (APR) is a frequent occurrence after infusion of zoledronic acid and is caused by activation of cd T cells. Vitamin D receptor is expressed in immune cells, and vitamin D has immunomodulatory properties. The aim of this prospective study was to test the effect of vitamin D (cholecalciferol) on the incidence of APR and intensity of pain in women undergoing infusion of zoledronic acid for postmenopausal osteoporosis. 60 women were enrolled and randomized into two groups. At baseline, 30 women received an oral bolus of cholecalciferol (300,000 IU), while another 30 women received placebo. On day 5 both groups were treated with a single infusion of zoledronic acid (5 mg) and received a daily supplementation of calcium (1,000 mg) and vitamin D (800 IU). Patients were clinically evaluated and inflammatory markers were assayed before zoledronic acid administration and every 24 h for the following 2 days. The onset of APR has been defined by the occurrence of fever or at least one of the typical symptoms, such as musculoskeletal pain after zoledronic acid infusion. Intensity of pain was measured by a one-dimensional scale (0 = no pain, 10 = unbearable pain). APR developed in 66.6% of patients, with no significant difference between groups. The vitamin group experienced less musculoskeletal pain [median 1 (0–4) vs. 2 (1–8), P \ 0.05] and exhibited lower inflammatory markers (P \ 0.005 vs. placebo). Our data
The authors have stated that they have no conflict of interest. A. Catalano (&) N. Morabito M. Atteritano G. Basile D. Cucinotta A. Lasco Department of Internal Medicine, University of Messina, Pad. C, 3rd floor, A.O.U. Policlinico ‘‘G. Martino,’’ Via C. Valeria, 98125 Messina, Italy e-mail:
[email protected]
demonstrate that cholecalciferol at a dose of 300,000 IU reduces the intensity of musculoskeletal pain after infusion of zoledronic acid for postmenopausal osteoporosis. Keywords Acute-phase response Zoledronic acid Vitamin D Postmenopausal osteoporosis Flu-like syndrome
Aminobisphosphonates (N-BPs) are widely used drugs for the treatment of osteoporosis and other metabolic bone diseases [1]; N-BPs inhibit bone resorption and reduce the risk of fracture [2]. Among intravenously administered N-BPs, zoledronic acid has recently been approved for the treatment of osteoporosis: it requires a single annual infusion due to its high affinity for hydroxyapatite crystals and power of action. Zoledronic acid significantly reduces the risk of vertebral, hip, and other fractures as demonstrated by the HORIZON-Pivotal Fracture Trial [3]. Unfortunately, administration of zoledronic acid is often followed by an acute-phase response (APR), which is a nonspecific, immune-driven reaction to systemic challenge, clinically manifested as a flu-like syndrome observed also with other N-BPs [4–8]. Some evidence suggests that intravenously administered N-BPs are internalized by monocytes and dendritic cells, resulting in inhibition of farnesyl pyrophosphate (FPP) synthase: it implies an accumulation of intracellular metabolites upstream of FPP synthase in the mevalonate pathway, such as isopentenyl pyrophosphate (IPP) and dimetylallyl pyrophosphate (DMAPP), which are potent agonists of the cd T-cell receptor. These antigens induce the activation of cd T cells and the production of the proinflammatory cytokines involved in the pathogenesis of APR by the same lymphocytes [9–11].
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The study of Reid et al. [12] characterized the APR and determined its frequency and the risk factors for its development after zoledronic acid. A correlation between 25(OH)D levels and the onset of APR has been observed [13, 14]. Since the vitamin D receptor (VDR) has been described in cells of the immune system, some hypotheses about the possible role of cholecalciferol and its active metabolite (calcitriol) on immune modulation have been proposed. In vitro and in vivo studies demonstrate that vitamin D promotes innate immunity and exerts an inhibitory action on the adaptative immune system [15–19]. Interestingly, in vitro, upregulation of VDR expression following the activation of cd T cells caused by IPP has been demonstrated, and it was noted that vitamin D is able to regulate negatively the expansion of cd T cells and their production of IFN-c [20]. The aim of this study was to test the effects of a bolus of vitamin D (cholecalciferol) on the incidence of APR and intensity of musculoskeletal pain in women with postmenopausal osteoporosis undergoing infusion of zoledronic acid (5 mg); the secondary outcome was changes in inflammatory markers. Supplementation with vitamin D is a desirable complement to appropriate treatment of postmenopausal osteoporosis, and a bolus of vitamin D allows a faster and significant rise in plasma levels of 25(OH)D that is useful to obtain extraskeletal effects, which usually require concentrations of vitamin D greater than those seen in the general population [21].
Materials and Methods Sixty postmenopausal women (age 64.2 ± 8.24 years) attending the Centre for Prevention, Diagnosis and Treatment of Osteoporosis in the Department of Internal Medicine of the University of Messina were enrolled in this randomized, double-blinded, placebo-controlled pilot study. They were consecutive osteoporotic patients, with or without prevalent vertebral fractures, or osteopenic patients with at least one mild prevalent vertebral fracture (reduction of 20–25% in the height of a vertebral body), who required i.v. therapy with N-BPs. Following WHO criteria, osteopenia and osteoporosis were diagnosed referring to the T score: bone mineal density (BMD) was measured in all patients by a dual-energy X-ray absorptiometric (DXA) densitometer at the lumbar spine (L1–L4) in AP projection and at the femoral neck. Women who had, at least at one site, a T score between -1 and -2.5 SD were considered osteopenic, and those with values \-2.5 SD were considered osteoporotic. Vertebral fractures were detected at morphometric examination of the dorsal and lumbar spine and classified according to Genant’s classification of
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vertebral fractures [22]. Patients with cancer, autoimmune diseases, immunodeficiency, chronic treatment with corticosteroids, liver or renal failure, or hypo- or hypercalcemia and women previously treated with intravenous N-BPs were excluded from this study. A measurement of serum 25(OH)D, within the month prior to enrollment, had to be available for each patient since these women were previously treated with cholecalciferol (400–800 IU/day). Patients with low or normal values of 25(OH)D were recruited. Previous oral or intramuscular treatment with N-BPs was not an exclusion criterion. Patients were randomized into two groups using a computer-generated randomization schedule in the order in which they were enrolled in the study. At baseline, 30 women received an oral bolus of cholecalciferol (300,000 IU/mL; Abiogen Pharma, Pisa, Italy) (vitamin D group), while another 30 women received placebo (placebo group). On day 5, both groups were treated with zoledronic acid (5 mg) and received 500 mg of calcium carbonate and 400 IU of cholecalciferol twice daily starting from the day of infusion for at least 10 days. On day 5 and then on day 6 and day 7, the following inflammation markers were evaluated by routine procedures: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and a1-acid glycoprotein (AGP). On day 5, calcium and creatinine were measured by routine procedures. Serum 25(OH)D levels (baseline and day-5 measurements) were assayed by HPLC (Bio-Rad, Mu¨nchen, Germany). Zoledronic acid was administered in about 30 min at a constant speed soon after sampling on day 5. Patients were instructed to monitor body temperature (measured at the axilla) every 4 h during the day and to write down values in a diary for 2 days. On day 5 and the following 2 days, women were interviewed by the same physician, to detect symptoms attributable to APR: fever, musculoskeletal (pain, joint swelling), gastrointestinal (abdominal pain, nausea, vomiting, diarrhea), eye inflammation, and other (including fatigue, dizziness, nasopharyngitis, edema) were conventionally five symptom clusters; and the occurrence of any postdose adverse event falling within these clusters during the period of study was defined as constituting an APR [12]. During the observation period, the onset of fever (body temperature [37°C) or musculoskeletal pain or recrudescence of pain, when pain was present before zoledronic acid administration, and every other typical symptom were considered due to APR in each case. Severity of musculoskeletal pain was assessed before zoledronic acid infusion on day 5 and then on day 6 and day 7, and patients were asked to assign a score to their pain on a one-dimensional scale (0 = no pain, 10 = unbearable pain). The study protocol was approved by the ethics committee of our hospital and performed according to the principles of the Declaration of Helsinki; informed consent was obtained in every case.
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Statistical analyses were performed using MedCalc software (version 10.2.0.0; MedCalc Software, Mariakerke, Belgium). Values are expressed as mean ± SD or median (interquartile range). Comparisons between groups were performed by unpaired t test or Mann–Whitney test, and within-group comparisons were determined with a paired t test or Wilcoxon matched rank sum test for paired data as appropriate. The v2 test was performed to calculate differences in the proportion of categorical variables. For all tests, P B 0.05 was considered to indicate statistical significance. All reported P values were two-sided.
subjects (15/30) had normal levels, 43% (13/30) had levels between 21 and 29 ng/mL, and 7% (2/30) had levels \20 ng/mL; in the vitamin D group 57% of subjects (17/ 30) had normal 25(OH)D levels, 40% (12/30) had levels between 21 and 29 ng/mL, and 3% (1/30) had levels \20 ng/mL. On day 5, the vitamin D group showed higher serum levels of the metabolite 25(OH)D than the placebo group, as expected (P \ 0.0001) (Table 1). Two women reached the maximum value of 120 ng/mL in the vitamin D group. After infusion of zoledronic acid, we observed an incidence of 66.6% (40/60) in the development of APR, without
Results The characteristics of patients are shown in Table 1. Patients had already been treated with other drugs for osteoporosis for 10–18 months; the choice of therapy with zoledronic acid was motivated by low adherence to previous treatment (29/60), onset of intestinal disorders (14/ 60), insufficient reduction of bone resorption markers and/ or lack of increase in BMD of previous treatment (9/60), or patient preference to i.v. therapy (8/60). Patients were randomized into two groups as described above. The two groups did not significantly differ in age, body mass index (BMI), and T score. They were also quite homogeneous in previous treatments for osteoporosis (placebo group: 7 strontium ranelate, 7 alendronate, 6 risedronate, 5 ibandronate, 2 neridronate, 3 clodronate; vitamin D group: 7 strontium ranelate, 8 alendronate, 7 risedronate, 5 ibandronate, 3 clodronate). Ten patients in the placebo group and the same number in the vitamin D group were undergoing the first administration of N-BP, having never taken oral or intramuscular N-BPs for osteoporosis. The two groups also did not differ in mean levels of vitamin D at baseline (P = 0.64). In particular, in the placebo group 50% of
Table 1 Main characteristics of patients
Data are expressed as mean ± SD or number of subjects (n) and percentage (%); measurements on day 5 were carried out before the administration of zoledronic acid and after 5 days from placebo or a bolus of vitamin D (300,000 IU) * P \ 0.0001 versus baseline and placebo
Table 2 Incidence of adverse events occurring after infusion of zoledronic acid in both groups Symptoms
Placebo (n = 30)
Vitamin D (n = 30)
P
Musculoskeletal
13
10
0.59
Diffuse pain
11
8
Regional pain Fever
2 8
2 6
0.76
Gastrointestinal
4
2
0.66
Nausea
3
2
Abdominal pain
1
1
Vomiting
1
0
Ocular
0
0
–
General
5
3
0.7
3
1
Dizziness Headache
1
1
Fatigue
2
1
23
17
Acute-phase response
0.17
Adverse events are not mutually exclusive; thus, the total number of subjects who have experienced APR cannot be arrived at by simply summing the individual events
Placebo group (n = 30)
Vitamin D group (n = 30)
Baseline
Baseline
Age (years)
63.8 ± 8.16
BMI (kg/m2)
23.9 ± 2.78
25(OH)D (ng/mL) B20, n (%)
32.6 ± 8.7 2 (7)
21–29, n (%)
13 (43)
C30, n (%)
15 (50)
Day 5
Day 5
64.6 ± 8.5 24.13 ± 3.14 34.7 ± 10.1
31.5 ± 7.9 1 (3)
98.1 ± 13.8*
12 (40) 17 (57)
Creatinine (mg/dL)
0.71 ± 0.43
0.73 ± 0.48
Calcium (mg/dL)
9.32 ± 0.4
9.41 ± 0.34
T score Lumbar spine (SD)
-2.73 ± 0.57
-2.48 ± 0.74
Femoral neck (SD)
-2.22 ± 0.53
-2.03 ± 0.54
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Women not previously treated with N-BPs
APR
APR
Yes
No
Yes
No
Vitamin D
7
6
10
7
Placebo
11*
4
12*
3
* P = 0.27
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17 ± 3.95
Day 6
22.5 ± 6.35** 19 ± 3.92** 15.55 ± 4.51 107.55 ± 13.42**,***
82.8 ± 14.75*,*** 71.3 ± 13.25*
88.45 ± 12.66**
13.45 ± 5.94
*** P \ 0.05 versus day 6
Women previously treated with N-BPs
** P \ 0.05 versus day 5
Treatment received
* P \ 0.005 versus placebo
Table 4 Incidence of APR after zoledronic acid infusion by considering previous use of N-BPs
77.85 ± 16.75
77.5 ± 12.01 2.74 ± 1.73**,***
0.58 ± 0.51*,***
Data are expressed as mean ± SD; measurements on day 5 were carried out before administration of zoledronic acid
two groups.
Table 5 Inflammatory markers at all time points
* P \ 0.01 versus day 5 ** P \ 0.05 versus vitamin D
Day 5 Day 7
Data are expressed as median (interquartile range)
Day 6
0.87 ± 0.88**
1 (0–4)*
0.20 ± 0.08
0.5 (0–1)
0.21 ± 0.13
Vitamin D
0.29 ± 0.27
2 (1–8)*,**
Placebo
0.5 (0–1)
Vitamin D
Placebo
Day 5
Maximum pain score on day 7
Day 6
Pain score on day 5
Day 5
Table 3 Intensity of musculoskeletal pain on day 5, before infusion of zoledronic acid, and within the following 48 h
AGP (normal 50–120 mg/dL)
Day 7
ESR (normal 0–15)
Day 7
significant difference between groups (P = 0.17) (Table 2). Fever was present in 23.3% patients (14/60) in at least one of the measurements. On day 6, three patients in the placebo group showed a body temperature above 38°C; these three patients had taken acetaminophen only once, resulting in a rapid defervescence. The amount of musculoskeletal pain, considering the maximum score reported according to the one-dimensional scale on day 6 and day 7, significantly differed between groups: the vitamin D group felt less pain than the placebo group (P \ 0.05) (Table 3). Pain score on day 5 was not a predictor of the increase in pain. By dividing the 60 patients into groups that had or had not previously taken N-BPs (i.e., alendronate, risedronate, ibandronate, neridronate), significant differences in the incidence of APR and the extent of pain were not observed (P = 0.27) (Table 4). The onset of APR was also not significantly different for age, BMI, creatinine, calcium, and BMD values (P [ 0.05). The inflammatory markers evaluated on day 5 did not significantly differ between groups. In all patients an increase of the inflammatory markers from day 5 to day 6 and day 7 was observed (P \ 0.05) (Table 5). On day 6, AGP significantly differed between groups (P \ 0.05); on day 7, all inflammatory markers significantly differed between the two groups (P \ 0.05). Inflammation markers did not return to pre–zoledonic acid infusion levels on day 7, and the changes in inflammation markers were not related to 25(OH)D levels assayed on day 5 in either of the
16.75 ± 4.68*,**
A. Catalano et al.: Vitamin D and Acute-Phase Response
CRP (normal 0–0. mg/dL)
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Discussion APR is characterized by flu-like symptoms such as fever, myalgia, and osteoarticular pain; it is a frequent event in response to intravenous zoledronic acid. APR is usually short-lived, the median time from onset to resolution being 3 days [12]. Zoledronate-induced APR is related to activation of cd T cells, causing a copious production of inflammatory cytokines as observed in in vitro studies [11]. Non-amino BPs, such as clodronate and etidronate, differently from N-BPs, do not inhibit FPP and have no effects on T cells [23]. The administration of a bolus of cholecalciferol 300,000 IU 5 days before the intravenous administration of zoledronic acid (5 mg) reduced inflammation indices and the amount of musculoskeletal pain; the latter is the most commonly reported APR event and is often experienced as a generalized discomfort. All components of APR have their highest onset rate in the first 2 days from zoledronic acid infusion; thus, observing a different severity of pain score between groups within this period is clinically relevant. The inflammatory response is probably not just delayed but reduced in vitamin D group as we reported a rise in serum markers of inflammation in both groups already on day 6. We used a single high dose of cholecalciferol because it is an inactive precursor of calcitriol and is safe and well tolerated; synthesis of 1a,25-dihydroxyvitamin D3 requires a 25-hydroxylation followed by a 1a-hydroxylation catalyzed by cytochrome P-450 (CYP) enzymes in the liver and kidney, respectively. Renal production of 1,25-dihydroxyvitamin D3 is tightly regulated by plasma parathyroid hormone levels and serum calcium and phosphorus levels [21]. 1a-Hydroxylase (1a-OHase, CYP27B1) is also expressed in immune cells such as monocytes and macrophages in response to activation by IFN-c or Toll-like receptor signaling [24]; hence, conversion of 25(OH)D3 to 1,25(OH)2D3 takes place in monocytes and 1,25(OH)2D3 regulates the expression of vitamin D–responsive genes by binding VDR in an intracrine manner. Cipriani et al. [25] demonstrated that a single oral dose of 600,000 IU of cholecalciferol is able to rapidly enhance 25(OH)D and, in particular, a sharp and significant increase was observed after 3 days. Moreover, the potency and safety of a single, large, oral 300,000 IU dose of cholecalciferol in enhancing serum 25(OH)D levels was previously reported [26]. In our study, patients receiving 300,000 IU of cholecalciferol 5 days before zoledronic acid infusion showed a marked rise of 25(OH)D, which is a reliable indicator of vitamin D status. Notably, the highest value recorded (120 ng/mL) of serum 25(OH)D was below the threshold
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of 400 ng/mL, which has recently been reported to cause no symptoms in sporadic cases of vitamin D intoxication [27]. In the placebo group three cases of fever (T [ 38°C) associated with moderate myalgias and arthralgias that required treatment with acetaminophen were recorded: of them, one patient was treated for the first time with an N-BP (previous treatment: strontium ranelate for 12 months), one was previously treated with risedronate for 14 months, and the other one was treated with alendronate for 10 months. It is notable that no patient in the vitamin D group had to take acetaminophen for fever or severe pain and none discontinued usual daily activity because of APR. Is vitamin D an analgesic or anti-inflammatory agent? The anti-inflammatory action of vitamin D is certainly an expression of a more complex immunomodulatory activity, which is supported by several studies [15–20, 28–30]. In vitro, upregulation of VDR was observed in cd T cells after stimulation by nonpeptidic antigens such as IPP or DMAPP, and downregulation of the expression of IFN-c and TNF-b, related to the action of vitamin D, was also detected [20]. The possible role of vitamin D in controlling markers of inflammation has also been suggested by epidemiological observations demonstrating that CRP and fibrinogen show seasonal fluctuations in their own plasma values, with a maximum value during the winter when there is also a nadir of 25(OH)D due to reduced sun exposure [31–35]. Vitamin D inhibits also the prostaglandin (PG) pathway by inhibiting the expression of COX/PG endoperoxidase synthase-2 (COX-2), the inducible ratelimiting enzyme that catalyzes the conversion of arachidonic acid to PGs and related eicosanoids; stimulates the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the enzyme that catalyzes the conversion of PGs to their corresponding 15-keto derivatives; and decreases the levels of PG receptor (EP and FP) [36]. Although a daily dose of 800–1,000 IU/day of cholecalciferol can be enough to achieve the recommended intake of vitamin D, it is not adequate to quickly obtain an optimal state of repletion of 25(OH)D. A good vitamin D status is desirable to reduce fracture risk in patients with low bone mass and to obtain favorable extraskeletal effects such as effects on immunomodulation. It is suggested that adequate levels of 25(OH)D ([40 ng/mL) should be reached before the infusion of N-BPs [13]. The APR also appeared in subjects with vitamin D levels[40 ng/mL, and we speculate that this may at least partially depend on the polymorphism in the VDR. Our data, also obtained from many patients who had been treated with oral N-BPs, show that previous administration of oral N-BPs in both groups is not a ‘‘protective factor’’ that can prevent the possible occurrence of APR following intravenous administration of
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zoledronic acid, although the APR incidence is less common in subjects who have previously used N-BPs (P = 0.27 vs. bisphosphonate-naive subjects). This observation is in line with data published by Reid and coworkers [12]; however, they observed a statistically significant difference. In conclusion, an oral bolus of 300,000 IU of vitamin D attenuated postdose musculoskeletal pain and determined a lower increase of inflammation markers after zoledronic acid infusion. Other authors have studied the incidence of APR after infusion of zoledronic acid in patients who had never been treated with N-BPs (oral or i.v.) and have observed a correlation with vitamin D levels [13]. Our group observed and reported data of patients previously treated (not intravenously) and not treated with N-BPs. The patients previously treated with oral N-BPs, like naive patients, after infusion of zoledronic acid, suffered APR: this may depend on the different ability to inhibit FPP synthase and on different capacities to stimulate cd T cells between various N-BPs and zoledronic acid; zoledronic acid today is the most potent inhibitor of FPP synthase.
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