Article

A phase 2 trial exploring the effects of high dose (10,000 IU/day) vitamin D(3) in breast patients with bone metastases

Department of Medical Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada.
Cancer (Impact Factor: 4.89). 01/2010; 116(2):284-91. DOI: 10.1002/cncr.24749
Source: PubMed

ABSTRACT

Vitamin D deficiency has potential roles in breast cancer etiology and progression. Vitamin D deficiency has also been associated with increased toxicity from bisphosphonate therapy. The optimal dose of vitamin D supplementation is unknown, but daily sunlight exposure can generate the equivalent of a 10,000-IU oral dose of vitamin D(3). This study therefore aimed to assess the effect of this dose of vitamin D(3) in patients with bone metastases from breast cancer.
Patients with bone metastases treated with bisphosphonates were enrolled into this single-arm phase 2 study. Patients received 10,000 IU of vitamin D(3) and 1000 mg of calcium supplementation each day for 4 months. The effect of this treatment on palliation, bone resorption markers, calcium metabolism, and toxicity were evaluated at baseline and monthly thereafter.
Forty patients were enrolled. No significant changes in bone resorption markers were seen. Despite no change in global pain scales, there was a significant reduction in the number of sites of pain. A small but statistically significant increase in serum calcium was seen, as was a significant decrease in serum parathyroid hormone. Treatment unmasked 2 cases of primary hyperparathyroidism, but was not associated with direct toxicity.
Daily doses of 10,000 IU vitamin D(3) for 4 months appear safe in patients without comorbid conditions causing hypersensitivity to vitamin D. Treatment reduced inappropriately elevated parathyroid hormone levels, presumably caused by long-term bisphosphonate use. There did not appear to be a significant palliative benefit nor any significant change in bone resorption.

Full-text

Available from: Wei Ooi, Oct 06, 2014
A Phase 2 Trial Exploring the Effects of
High-Dose (10,000 IU/Day) Vitamin D
3
in
Breast Cancer Patients With Bone Metastases
Eitan Amir, MB, ChB
1
; Christine E. Simmons, MD
2
; Orit C. Freedman, MD
1
; George Dranitsaris, MPharm
1
;
David E. C. Cole, MD
3
; Reinhold Vieth, MD
4
; Wei S. Ooi, MD
1
; and Mark Clemons, MD
1
BACKGROUND: Vitamin D deficiency has potential roles in breast cancer etiology and progression. Vitamin D defi-
ciency has also been associated with increased toxicity from bisphosphonate therapy. The optimal dose of vitamin D
supplementation is unknown, but daily sunlight exposure can generate the equivalent of a 10,000-IU oral dose of
vitamin D
3
. This study therefore aimed to assess the effect of this dose of vitamin D
3
in patients with bone metasta-
ses from breast cancer. METHODS: Patients with bone metastases treated with bisphosphonates were enrolled into
this single-arm phase 2 study. Patients received 10,000 IU of vitamin D
3
and 1000 mg of calcium supplementation
each day for 4 months. The effect of this treatment on palliation, bone resorption markers, calcium metabolism, and
toxicity were evaluated at baseline and monthly thereafter. RESULTS: Forty patients were enrolled. No significant
changes in bone resorption markers were seen. Despite no change in global pain scales, there was a significant
reduction in the number of sites of pain. A small but statistically significant increase in serum calcium was seen, as
was a significant decrease in serum parathyroid hormone. Treatment unmasked 2 cases of primary hyperparathyroid-
ism, but was not associated with direct toxicity. CONCLUSIONS: Daily doses of 10,000 IU vitamin D
3
for 4 months
appear safe in patients without comorbid conditions causing hypersensitivity to vitamin D. Treatment reduced inap-
propriately elevated parathyroid hormone levels, presumably caused by long-term bisphosphonate use. There did not
appear to be a significant palliative benefit nor any significant change in bone resorption. Cancer 2010;116:284–91.
V
C
2010 American Cancer Society.
KEYWORDS: vitamin D, breast cancer, bone metastasis, bisphosphonates, pain.
The importance of vitamin D in the pathogenesis and progression of breast cancer has been demonstrated by in vitro
studies,
1-3
animal studies,
3,4
and in geographic, epidemiologic studies.
5,6
In addition, in some studies, lower measured lev-
els of vitamin D metabolites (25-hydroxyvitamin D) have been shown to correlate with poor prognosis from breast can-
cer.
7,8
These observations are countered by other evidence, including a recent meta-analysis of vitamin D and breast
cancer risk
9
as well as a large randomized trial of vitamin D supplementation
10
that did not demonstrate a benefit to sup-
plementation with vitamin D. Because of this conflicting evidence, there remains no consensus as to the optimal adminis-
tration of this agent in patients with breast cancer. Because calcium and vitamin D metabolism are especially important in
the context of bone metastases from breast cancer, improving the evidence base on the utility of vitamin D in this setting
could be of significant benefit.
The long-term use of bisphosphonates has been shown to affect calcium metabolism adversely in patients with both
osteoporosis and Paget disease of bone. These effects predominantly include hypocalcemia and resultant secondary hyper-
parathyroidism. Therefore, it has been recommended that clinicians encourage calcium and vitamin D supplements in
DOI: 10.1002/cncr.24749, Received: January 29, 2009; Revised: April 29, 2009; Accepted: May 21, 2009, Published online November 13, 2009 in Wiley
InterScience (www.interscience.wiley.com)
Corresponding author: Mark Clemons, MD, Department of Medical Oncology, The Ottawa Hospital Cancer Centre, (Box 912), 501 Smyth Road, Ottawa ON K1H
8L6, Canada; Fax: (613) 247-3511; mclemons@toh.on.ca
1
Department of Medical Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada;
2
Department of Medical Oncology, Odette Cancer Centre, Toronto, On-
tario, Canada;
3
Department of Biochemistry, Women’s College Hospital, Toronto, Ontario, Canada;
4
Department of Biochemistry, Mount Sinai Hospital, Toronto,
Ontario, Canada
The first 2 authors contributed equally to this article.
We thank Esther Lee for her role as research coordinator for this study.
284 Cancer January 15, 2010
Original Article
Page 1
patients receiving long-term bisphosphonate therapy.
11
In
metastatic disease, there is, to our knowledge, a paucity of
data on the extent of calcium and vitamin D supplementa-
tion, although in many centers such supplementation has
been recommended.
12
Work in the metastatic breast can-
cer setting has shown that supplementation with 400 IU/
day vitamin D
3
(cholecalciferol) does not prevent a dis-
turbance of calcium metabolism. This may be related to
prolonged, high-dose bisphosphonate dosing in these
patients resulting in a relative hyperparathyroidism, simi-
lar to that seen with bisphosphonate use in benign bone
disease. In an exploratory analysis, 46 patients with meta-
static breast cancer who were premedicated with vitamin
D at a dose of 400 IU/day and who were receiving third
generation bisphosphonate therapy were compared with a
matched historical control group with neither breast can-
cer nor bone/mineral disease.
13
In patients with metastatic
breast cancer, unlike in benign bone disease, daily supple-
mentation with 400 IU of vitamin D was not sufficient to
prevent secondary hyperparathyroidism. More striking
was the finding that despite standard vitamin supplemen-
tation, 62% of patients had suboptimal levels of serum 25-
hydroxyvitamin D (<75 nmol/L), and 18% had either
insufficient or grossly deficient levels. Furthermore,
patients with metastatic breast cancer to bone often com-
plain of musculoskeletal pain, and evidence from non-
cancer patients has shown that bone pain can be a
manifestation of hypovitaminosis D
3
.
14
Consequently, it
was hypothesized that a substantively greater supplementa-
tion of vitamin D should be considered,
13
and that it
would be reasonable to expect improvements in palliation
in this setting.
At least 4 studies support the concept that maximal
cutaneous synthesis of vitamin D (ie, full-body, maximal
exposure to sunlight) can be equivalent to an oral vita-
min D
3
intake of 10,000 IU/day.
15-18
Furthermore, a
review of data from vitamin D supplementation studies
reveals a dose-response curve for vitamin D that is rela-
tively linear up to 10,000 IU of vitamin D
3
per day,
suggesting that this dose may be a physiologic upper
limit.
19
The present study aimed to assess the effects of
a high physiological dose of vitamin D (10,000 IU per
day) on both palliation and bone turnover in women
with bone metastases from breast cancer. The effects of
this treatment on pain and bone resorption markers
were measured, as was its ability to ameliorate the sec-
ondary hyperparathyroidism of prolonged high-dose
bisphosphonate therapy given to breast cancer patients
with bone metastases.
MATERIALS AND METHODS
Patients
Women with histologically confirmed metastatic breast
cancer and with radiologic or pathologic evidence of bone
metastases, who were clinically stable (defined as no
change in systemic therapy for at least 1 month before
study entry), had a Karnofsky performance score 60,
and had a life expectancy of 6 months were eligible.
Subjects continued their standard cancer therapies (ie, en-
docrine therapy, chemotherapy, and bisphosphonate).
Exclusion criteria included pre-existing hypercalcemia, a
history of renal stone disease, a known hypersensitivity to
vitamin D, severe renal or hepatic dysfunction (defined as
serological test 2 the upper normal range), and preg-
nancy or lactation. Furthermore, any patients who devel-
oped hyperparathyroidism, hypercalcemia, sustained
hypercalciuria, nephrocalcinosis, or deteriorating renal
function while on study were withdrawn from the trial
and had all vitamin D supplements stopped.
Study Endpoints
The primary objectives of this prospective study were to
assess the palliative benefit of 10,000 IU of vitamin D
3
daily, reflected through validated pain scores and the bone
resorption marker urinary N-telopeptide. Secondary
objectives consisted of the evaluation of metabolic conse-
quences of high-dose vitamin D, including serologic
changes in calcium, vitamin D, and parathyroid hormone
(PTH), as well as toxicity or adverse side effects during
treatment.
Trial Design
A prospective, single-center, single-arm, phase 2 trial eval-
uating changes in palliation and biochemical markers of
bone turnover and metabolism was performed. The local
research ethics board approved the study protocol. After
patients provided written informed consent to participate
in the study, all subjects received oral cholecalciferol (vita-
min D
3
) at a daily dose of 10,000 IU for 4 months, along
with 1000 mg/d elemental calcium. Vitamin D
3
was
administered in liquid form (Ddrops, 1000 IU per oil
drop, Toronto, Canada) to reduce the quantity of tablets
that needed to be ingested.
Most previous studies describing the biochemical
response and safety of high-dose vitamin D were con-
ducted for up to 20 weeks.
15-18
Furthermore, toxicities
have been described at doses of 20,000 IU for 12 weeks
20
;
therefore, a 4-month duration at a dose of 10,000 IU was
conservatively chosen as an optimal balance between
High-Dose Vitamin D and Bone Metastases/Amir et al
Cancer January 15, 2010 285
Page 2
likelihood of response and expected toxicity profile. Self-
reported compliance was assessed at each follow-up visit
by individual investigators. Assessments of palliative and
biochemical response were performed at 0, 1, 2, 3, and 4
months of the study.
Palliative response was assessed using the Brief Pain
Inventory
21
and the Functional Assessment of Cancer
Therapy-Bone Pain,
22,23
both validated questionnaires.
At the study assessment time points, second-pass morning
urine samples were collected, and blood was drawn for
laboratory tests. Urine samples were assayed for calcium
and creatinine by a standard kinetic Jaffe method and for
urinary N-telopeptide with the Osteomark enzyme im-
munoassay kit (Wampole Laboratories, Princeton NJ).
The laboratory reference interval for urinary N-telopep-
tide was 26-124 nmol/mmol creatinine. Serum was tested
for calcium (corrected for albumin), albumin, PTH, 25-
hydroxyvitamin D (measured by radioimmunoassay, Dia-
Sorin, Stillwater, Minn), and creatinine. Samples for
PTH were drawn in the morning to avoid any diurnal var-
iation and analyzed immediately. The laboratory refer-
ence interval for PTH (Roche Diagnostics, Montreal,
Canada) was 1.7 to 7.6 pmol/L. Intra- and interassay coef-
ficients of variation were <3%.
Statistical Analysis
Data were presented descriptively as means, medians, or
proportions. Ordinal logistic regression analysis using a
repeated measures structure was used to compare pain
control over the 4-month period relative to baseline. Gen-
eralized estimating equations were also used in a repeated
measures analysis on a number of pain sites and urinary
N-telopeptide, PTH, and 25-hydroxyvitamin D levels rel-
ative to baseline. An initial assessment of urinary N-telo-
peptide, PTH, and 25-hydroxyvitamin D revealed that
they were skewed by some extreme values. This is a com-
mon occurrence with such markers, and the standard
practice of normalizing the distribution by taking its natu-
ral logarithm was used. The adequacy of the procedure
was verified by inspection of the normal plots and applica-
tion of the Skew test. All of the statistical analyses were
performed using Stata statistical software (release 9.0; Sta-
taCorp, College Station, Tex).
RESULTS
Patient Characteristics
Forty patients gave consent for the study, and 38 patients
completed the study. As shown in Table 1, patients had a
median age of 55 years (range, 32-85 years). All had bone
metastases at baseline, but 12 (30%) also had liver metas-
tases, and 10 (25%) had lung metastases. All 40 (100%)
patients were receiving bisphosphonate treatment at study
entry, and 29 (72.5%) patients were already receiving
standard doses of calcium and vitamin D (400 IU/d).
Patient demographics confirmed that patients had low-
risk bone metastases as evidenced by a below-average his-
tory of prior skeletal-related events (6 patients, 15%) as
well as urinary bone resorption markers in the lowest ter-
tile of the normal range (Table 2). Compliance was com-
plete, with all patients reporting that they ingested the
required doses of both vitamin D
3
and calcium.
Table 1. Patient Demographics
Demographic No.
Age, y
Mean
56.3
Median
55
Range
32-85
Estrogen receptor status
Positive
30 (75%)
Negative
10 (25%)
Sites of metastatic disease
Bone
40 (100%)
Liver
12 (30%)
Lung
10 (25%)
Soft tissue
6 (15%)
Bisphosphonate therapy at baseline
Clodronate
10 (25%)
Ibandronate (oral)
5 (12.5%)
Pamidronate
25 (62.5%)
Duration of bisphosphonate use at baseline, mo
Mean
15.2
Median
10
Range
1-78
Endocrine therapy administration
Total
30 (75%)
Tamoxifen
12 (30%)
Letrozole
7 (17.5%)
Exemestane
5 (12.5%)
Anastrozole
4 (10%)
Fulvestrant
1 (2.5%)
Megestrol
1 (2.5%)
Chemotherapy administration
Total
9 (22.5%)
Capecitabine
4 (10%)
Docetaxel
2 (5%)
Doxorubicin/cyclophosphamide
1 (2.5%)
Trastuzumab
1 (2.5%)
Other
1 (2.5%)
History of skeletal-related events at baseline 6 (15%)
Original Article
286 Cancer January 15, 2010
Page 3
Palliative Response
There were no significant changes in any parameters from
the Brief Pain Inventory. ‘Worst pain’ did not change
significantly when assessed at each month relative to base-
line and after adjustment for analgesic consumption.
Likewise, the average pain score or the ‘pain right now’
score did not change significantly (Fig. 1). However, there
was a significant reduction in the number of pain sites
during the study period when assessed at Month 2, 3, and
4 relative to baseline, using ordinal logistic regression
analysis adjusted for analgesic consumption (at each time
point, the respective P ¼ .036, .034, and .010) (Fig. 2).
There was no significant change in daily morphine
Table 2. Changes in Urinary and Serum Biomarkers
Biomarker Baseline Month 1 Month 2 Month 3 Month 4
Urinary N-telopeptide, nmol/mmol creatinine
Mean
48.6 46.3 46.1 45.7 45.8
Median
33 29.5 31 36 37
Range
10-204 9-189 9-143 9-175 8-148
Urinary calcium, mmol/L
Mean
2.72 2.58 3.07 2.36 2.33
Median
2.15 1.60 2.80 1.70 2.20
Range
0.04-15.2 0.14-13.0 0.37-7.8 0.68-8.7 0.17-6.9
Serum PTH, pmol/L
a
Mean
6.82 4.57 4.35 4.00 4.26
Median
5.65 3.95 3.4 3.7 3.4
Range
2.0-17.7 1.6-12.1 1.3-13.0 0.6-11.4 1.3-11.8
Serum 25(OH)D, nmol/L
b
Mean
72 115 140 151 155
Median
69.5 116 134 145 162
Range
19-169 62-194 70-239 82-261 74-226
Corrected serum calcium, mmol/L
Mean
2.25 2.31 2.33 2.31 2.31
Median
2.27 2.29 2.31 2.30 2.31
Range
1.86-2.67 2.09-2.77 2.15-3.06 1.78-2.85 2.10-2.53
PTH indicates parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D.
a
See Figure 3.
b
See Figure 4.
Figure 1. Changes in average pain score over time are shown.
Mon indicates month; Std. Err., standard error.
Figure 2. Changes in the number of pain sites over time are
shown. Mon indicates month; 95% CI, 95% confidence inter-
val; Std. Err., standard error.
High-Dose Vitamin D and Bone Metastases/Amir et al
Cancer January 15, 2010 287
Page 4
equivalent analgesia use (P ¼ not significant [NS]). There
was a no significant change in the mean total score from
the Functional Assessment of Cancer Therapy-Bone Pain
questionnaire. The median value documented at baseline
was 15.45 (95% confidence interval [95% CI], 12.53-
18.37), compared with the median value at 4 months,
which was 14.06 (95% CI, 10.64-17.48) (P ¼ NS on
repeated-measures analysis).
Biochemical Changes
Table 2 summarizes changes seen in the urinary and se-
rum biomarkers measured. Mean baseline values of uri-
nary N-telopeptide were 48.6 (median, 33; range, 10-
204), and these were consistent with the extreme upper
range of the first tertile of values derived for urinary N-
telopeptide in previous studies.
24,25
Administration of
10,000 IU per day of vitamin D
3
did not have a signifi-
cant effect on the urinary bone resorption marker urinary
N-telopeptide (P ¼ NS). As expected, serum PTH
decreased over time (P < .001) (Fig. 3), whereas serum
25-hydroxyvitamin D increased (P < .001) (Fig. 4).
Compared with the pretreatment value, serum calcium
was modestly increased at each assessment point during
treatment (P < .05 across all assessment points). There
was no significant change detected in urinary calcium
excretion (P ¼ NS).
Toxicity
Treatment was generally well tolerated. Expected toxicity
in terms of increase in urinary calcium excretion with con-
sequential risk of nephrocalcinosis was not observed in
this 4-month study. Hypercalcemia was detected in 2
(5%) patients, and these patients were removed from the
study. Both these patients were subsequently discovered
to have primary hyperparathyroidism. In 1 of these
patients, the baseline value for protein-corrected calcium
was in the normal range (2.67 mmol/L), but the uncor-
rected level was elevated (2.8 mmol/L), with an inap-
propriately elevated PTH (15.4 pmol/L). In the second
patient, baseline calcium was in the normal range (2.4
mmol/L), but PTH was marginally elevated (8.6 pmol/L)
and despite falling after administration of study drug, did
not demonstrate appropriate suppression with the devel-
opment of hypercalcemia. One of these patients required
hospitalization for management of her hypercalcemia.
DISCUSSION
Several in vitro,
1-3
epidemiologic,
5,6
and in vivo
7,8
studies
suggest a role for vitamin D and calcium metabolism in
the development of breast cancer and regulation of carci-
nogenesis. The exact mechanism by which vitamin D may
play a role in the development and progression of breast
cancer remains unknown, but it is hypothesized that it
may affect the regulation of cellular proliferation and dif-
ferentiation as well as inhibiting angiogenesis.
26
These
anticancer properties have been attributed primarily to
the active hormone 1,25-dihydroxyvitamin D. Cancer
cells are known to express the intracellular receptors (vita-
min D receptors [VDRs]) for 1,25-dihydroxyvitamin D.
When VDR is activated by 1,25-dihydroxyvitamin D
binding and translocated to the nucleus, it binds to
vitamin D response elements on >60 genes, resulting in
an up-regulation of differentiation, proliferation, and
metastasis.
18
Figure 3. Changes in PTH levels over time are shown. Se indi-
cates serum; PTH, parathyroid hormone; Mon, month; 95% CI,
95% confidence interval; Std. Err., standard error.
Figure 4. Changes in 25-hydroxyvitamin D levels over time
are shown. Mon indicates month; Min-Max, minimum-
maximum.
Original Article
288 Cancer January 15, 2010
Page 5
Vitamin D has been recommended as an adjunct to
bisphosphonate therapy in patients with metastatic breast
cancer and bone metastases.
27
Unfortunately, to the best
of our knowledge, there are no robust data as to the opti-
mal dosing of vitamin D in metastatic breast cancer
patients treated with bisphosphonates. Our group and
others have shown that vitamin D supplementation of
400 IU/d was insufficient to completely correct the result-
ant secondary hyperparathyroidism seen with long-term
bisphosphonate use.
13,28
It was therefore hypothesized
that higher vitamin D dosing may be required in this set-
ting, at least for some subjects.
In both North America and Europe, the upper level
for recommended vitamin D supplementation is currently
2000 IU/d.
29,30
However, because exposure to sunlight
can provide an adult with vitamin D in an amount
equivalent to daily oral consumption of up to 10,000 IU/
day,
15-18
this dose would appear to be intuitively safe. A
review of the toxicities of vitamin D has shown that except
in patients with conditions causing hypersensitivity, there
is no evidence of adverse effects with serum 25-hydroxyvi-
tamin D concentrations equivalent to 10,000 IU/day.
19
Furthermore, a recent phase 1 clinical trial of vitamin D
3
indicates safety at daily levels >10,000 IU.
31
This preliminary phase 2 trial assessed the effects of
10,000 IU of vitamin D
3
per day on palliation, bone
resorption markers, biochemical markers of calcium and
bone metabolism, and toxicity. Results indicated that,
despite significant increases in serum 25-hydroxyvitamin
D and calcium with an associated fall in PTH, there was
no significant change in overall palliation or in bone
resorption markers. Of interest, results showed that there
were significantly fewer sites of pain with study treatment.
However, in the context of nonsignificant changes in
global pain measures, the clinical implication of this is
unclear. This finding therefore needs to be evaluated in
further studies. It was noted that 10,000 IU a day of vita-
min D
3
for 4 months is safe in patients without comorbid
conditions causing hypersensitivity to vitamin D.
A potential explanation for the results noted above
may lie in the nature of the bisphosphonate protocols.
Bisphosphonates can potently reduce telopeptide lev-
els,
32,33
which correlate well with reduced pain.
34,35
Patients in this study had already been treated with
bisphosphonates for a mean duration of 15.2 months and
it is possible that these patients had therefore already expe-
rienced the maximal suppression of their bone turnover.
If suppression was maximal, then neither telopeptide lev-
els nor pain scores would be expected to change as a result
of a high dose of vitamin D. It should be emphasized that
patients in this study were administered different
bisphosphonates, and these were given both orally and
intravenously. As the bioavailability of oral bisphospho-
nates is highly variable,
36
it could be argued that this may
impact on the results of the study. However, the authors
believe that the cumulative doses of bisphosphonates
administered in the oncology setting are so high that dif-
ferences in bioavailability are not likely to be significant in
these cases.
Baseline levels of 25-hydroxyvitamin D showed that
despite the majority (72.5%) of patients receiving prior
supplementation with between 400 and 800 IU of vita-
min D, only 17 (42.5%) patients had optimal levels of
vitamin D (defined as 25-hydroxyvitamin D level >75
nmol/L). Of those with suboptimal levels (57.5%), 5
patients (12.5%) had insufficient levels, defined as 25-
hydroxyvitamin D between 20 and 39 nmol/L, and 1
patient (2.5%) had a frankly deficient level, defined as 25-
hydroxyvitamin D <20 nmol/L. Furthermore, baseline
serum PTH was in the upper tertile of the normal range
and, subsequent to administration of 10,000 IU of daily
vitamin D
3
, levels fell markedly. These findings support
the hypothesis that despite the majority of patients already
being supplemented with vitamin D at current recom-
mended levels, further supplementation at high physio-
logic doses further reduces the assumed secondary
hyperparathyroidism. This evidence supports the hypoth-
esis that higher doses of vitamin D supplementation may
be required in metastatic breast cancer patients with bone
metastases.
In the majority of patients (95%), an adverse effect
as reflected by serum or urinary calcium levels was not
found. Two (5%) patients did develop hypercalcemia
with associated increases in their urinary calcium excre-
tion. On reviewing the records of these patients, 1 had
baseline hypercalcemia with an inappropriately high
PTH, and the other patient had a baseline serum calcium
in the upper tertile with a PTH above the normal range. It
was therefore concluded that both patients had occult pri-
mary hyperparathyroidism, which was unmasked by vita-
min D administration. In the latter patient, the
hypercalcemia that normally accompanies primary hyper-
parathyroidism was no doubt blunted by the initial vita-
min D insufficiency. The hypercalcemic patient was
treated successfully with parathyroidectomy, with subse-
quent increases in bone mineral density. It would there-
fore appear that high-dose vitamin D can uncover
compensated primary hyperparathyroidism, a condition
High-Dose Vitamin D and Bone Metastases/Amir et al
Cancer January 15, 2010 289
Page 6
associated with breast cancer.
37
Whether these patients
can be considered to have suffered from vitamin D toxic-
ity is a matter of some contention. It could be argued that
neither patient developed treatment toxicity, as treatment
simply exposed a pre-existing condition rather causing
direct toxicity. However, in view of the increased preva-
lence of hyperparathyroidism among breast cancer
patients,
37
this limitation in the administration of high-
dose vitamin D needs to be highlighted, despite it having
been described previously.
38
Furthermore, although the
results of this study do not support high-dose supplemen-
tation, many patients choose to supplement with signifi-
cant doses of vitamin D on their own accord. Patients
considering supplementation above currently recom-
mended levels should be made aware of the possible toxic-
ities of treatment with vitamin D, and baseline calcium
and PTH should be ascertained. Clinicians should also be
aware of described toxicities from high doses of vitamin
D. These have been comprehensively described in the lit-
erature and include hypercalcemia, hypercalciuria, neph-
rocalcinosis, and even renal impairment.
39,40
In summary, although this study did not meet its
primary endpoint of demonstrating significant changes in
pain or bone turnover markers, the effects of high physio-
logic doses of vitamin D did show some indication of clin-
ical benefit, as manifested by a reduction in the number of
sites of pain. Furthermore, this therapy helped unmask
underlying endocrinopathy, specifically primary hyper-
parathyroidism. Interestingly, there was also an apparent
correction of the presumed secondary hyperparathyroid-
ism in this heavily bisphosphonate-pretreated population,
and the role of higher doses of vitamin D for this purpose
warrants further investigation. The results of this study
therefore lend some support to the notion that there is an
overall need for higher-dose vitamin D supplementation
in metastatic breast cancer with bone metastases. Further
trials will help clarify the optimal dose of supplementation
in this population, but should screen and follow diligently
for masked hyperparathyroid states.
CONFLICT OF INTEREST DISCLOSURES
This study was funded in part by a grant from the Vitamin D
Society.
REFERENCES
1. Chouvet C, Vicard E, Devonec M, Saez S. 1,25-Dihydroxy-
vitamin-D3 inhibitory effect on growth of 2 human breast
cancer cell lines (MCF-7, BT-20). J Steroid Biochem.
1986;24:373-376.
2. James SY, Mackay AG, Colston KW. Effects of 1,25 dihy-
droxyvitamin-D3 and its analogues on induction of apopto-
sis in breast cancer cells. J Steroid Biochem Mol Biol.
1996;58:395-401.
3. Colston KW, Chander SK, Mackay AG, Coombes RC. Effects
of synthetic vitamin-D analogues on breast cancer cell prolifera-
tion in vivo and in vitro. Biochem Pharmacol. 1992;44:693-702.
4. Anzano MA, Smith JM, Uskokoviv MR, et al. 1 alpha,
25-Dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol
(Ro24-5531), a new deltanoid (vitamin D analogue) for pre-
vention of breast cancer in the rat. Cancer Res. 1994;54:
1653-1656.
5. Garland FC, Garland CF, Gorham ED, Young JF. Geo-
graphic variation in breast cancer mortality in the United
States: a hypothesis involving exposure to solar radiation.
Prev Med. 1990;19:614-622.
6. Gorham ED, Garland FC, Garland CF. Sunlight and breast
cancer incidence in the USSR. Int J Epidemiol.
1990;19:820-824.
7. Palmieri C, MacGregor T, Girgis S, Vigushin D. Serum
25-hydroxyvitamin-D levels in early and advanced breast
cancer. J Clin Pathol. 2006;59:1334-1336.
8. Goodwin PJ, Ennis M, Pritchard KI, Koo J, Hood N. Prog-
nostic effects of 25-hydroxyvitamin D levels in early breast
cancer. J Clin Oncol. 2009;27:3757-3763.
9. Gissel T, Rejnmark L, Mosekilde L, Vestergaard P. Intake
of vitamin D and risk of breast cancer—a meta-analysis.
J Steroid Biochem Mol Biol. 2008;111:195-199.
10. Chlebowski RT, Johnson KC, Kooperberg C, et al. Calcium
plus vitamin D supplementation and the risk of breast can-
cer. J Natl Cancer Inst. 2008;100:1581-1591.
11. Landman JO, Schweitzer DH, Frolich M, Hamdy NA,
Papapoulos SE. Recovery of serum calcium concentrations
following acute hypocalcemia in patients with osteoporosis
on long-term oral therapy with the bisphosphonate pamidr-
onate. J Clin Endocrinol Metab. 1995;80:524-528.
12. Raisz LG. Clinical practice. Screening for osteoporosis. N
Engl J Med. 2005;353:164-171.
13. Simmons C, Amir E, Dranitsaris G, et al. Altered calcium me-
tabolism in patients on long-term bisphosphonate therapy for
metastatic breast cancer. Anticancer Res. 2009;29:2707-2711.
14. de Torrente de la Jara G, Pecoud A, Favrat B. Musculoskel-
etal pain in female asylum seekers and hypovitaminosis D3.
BMJ. 2004;329:156-157.
15. Stamp TC. Factors in human vitamin D nutrition and in
the production and cure of classical rickets. Proc Nutr Soc.
1975;34:119-130.
16. Davie MW, Lawson DE, Emberson C, Barnes JL, Roberts
GE, Barnes ND. Vitamin D from skin: contribution to vita-
min D status compared with oral vitamin D in normal and
anticonvulsant-treated subjects. Clin Sci. 1982;63:461-472.
17. Holick MF. Environmental factors that influence the cuta-
neous production of vitamin D. Am J Clin Nutr . 1995;
61(suppl):638S-645S.
18. Chel VG, Ooms ME, Popp-Snijders C, et al. Ultraviolet
irradiation corrects vitamin D deficiency and suppresses sec-
ondary hyperparathyroidism in the elderly. J Bone Miner
Res. 1998;13:1238-1242.
19. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment
for vitamin D. Am J Clin Nutr. 2007;85:6-18.
20. Gertner JM, Domenech M. 25-hydroxyvitamin D levels in
patients treated with high-dosage ergo- and cholecalciferol.
Clin Pathol. 1977;30:144-150.
Original Article
290 Cancer January 15, 2010
Page 7
21. Cleeland CS, Ryan KM. Pain assessment: global use of the
Brief Pain Inventory. Ann Acad Med Singapore. 1994;23:
129-138.
22. Cella DF, Tulsky DS, Gray G, et al. The Functional Assess-
ment of Cancer Therapy scale: development and validation of
the general measure. J Clin Oncol. 1993;11:570-579.
23. Broom R, Du H, Clemons M, et al. Switching breast cancer
patients with progressive bone metastases to third-generation
bisphosphonates: measuring impact using the Functional
Assessment of Cancer Therapy-Bone Pain. J Pain Symptom
Manage. 2009;38:244-257.
24. Garnero P, Mulleman D, Munoz F, Sornay-Rendu E, Del-
mas P. Long-term variability of markers of bone turnover in
postmenopausal women and implications for their clinical
use: the OFELY study. J Bone Miner Res. 2003;18:
1789-1794.
25. Black DM, Delmas PD, Eastell R, et al. Once-yearly zole-
dronic acid for treatment of postmenopausal osteoporosis. N
Engl J Med. 2007;356:1809-1822.
26. Oikawa T, Hirotani K, Ogasawara H, et al. Inhibition of
angiogenesis by vitamin D3 analogues. Eur J Pharmacol.
1990;178:247-250.
27. Reid DM, Doughty J, Eastell R, et al. Guidance for the
management of breast cancer treatment-induced bone loss: a
consensus position statement from a UK Expert Group.
Cancer Treat Rev. 2008;34(suppl 1):S3-S18.
28. Autier P, Gandini S. Vitamin D supplementation and total
mortality: a meta-analysis of randomized controlled trials.
Arch Intern Med. 2007;167:1730-1737.
29. Standing Committee on the Scientific Evaluation of Die-
tary Reference Intakes, Food and Nutrition Board, Institute
of Medicine. Dietary Reference Intakes for Calcium, Phos-
phorus, Magnesium, Vitamin D, and Fluoride. Washington,
DC: National Academy Press; 1997.
30. Health and Consumer Protection Directorate-General.
Opinion of the Scientific Committee on Food on the Toler-
able Upper Intake Level of Vitamin D. Brussels, Belgium:
European Commission; 2002.
31. Kimball SM, Ursell MR, O’Connor P, Vieth R. Safety of
vitamin D3 in adults with multiple sclerosis. Am J Clin
Nutr. 2007;86:645-651.
32. Lipton A, Demers L, Curley E, et al. Markers of bone
resorption in patients treated with pamidronate. Eur J Cancer.
1998;34:2021-2026.
33. Coleman RE, Major P, Lipton A, et al. Predictive value of
bone resorptive and formation markers in cancer patients
with bone metastases receiving the bisphosphonate zole-
dronic acid. J Clin Oncol. 2005;23:4925-4935.
34. Clemons M, Dranitsaris G, Ooi WS, et al. A phase II trial
evaluating the palliative benefit of second-line zoledronic acid
in breast cancer patients with either a skeletal related event or
progressive bone metastases despite first line bisphosphonate
therapy. J Clin Oncol. 2006;24:4895-4900.
35. Clemons M, Dranitsaris G, Ooi W, Col e DE. A phase II trial
evaluating the palliative benefit of second-line oral ibandronate in
breast cancer patients with either a skeletal related event (SRE) or
progressive bone metastases (BM) despite standard bisphospho-
nate (BP) therapy. Breast Cancer Res Treat. 2008;108:79-85.
36. Gertz BJ, Holland SD, Kline WF, et al. Studies of the oral
bioavailability of alendronate. Clin Pharmacol Ther. 1995;
58:288-298.
37. Fierabracci P, Pinchera A, Miccoli P, et al. Increased preva-
lence of primary hyperparathyroidism in treated breast can-
cer. J Endocrinol Invest. 2001;24:315-320.
38. Vieth R, Bayley TA, Walfish PG, Rosen IB, Pollard A.
Relevance of vitamin D metabolite concentrations in sup-
porting the diagnosis of primary hyperparathyroidism. Sur-
gery. 1991;110:1043-1047.
39. Adams JS, Lee G. Gains in bone mineral density with reso-
lution of vitamin D intoxication. Ann Intern Med. 1997;
127:203-206.
40. Better OS, Shabtai M, Kedar S, Melamud A, Berenheim J,
Chaimovitz C. Increased incidence of nephrolithiasis in life-
guards in Israel. In: Massry SG, Ritz E, Jahreis G, eds.
Phosphate and Minerals in Health and Disease. New York,
NY: Plenum Press; 1980:467-472.
High-Dose Vitamin D and Bone Metastases/Amir et al
Cancer January 15, 2010 291
Page 8
  • Source
    • "While vitamin D is relatively safe, a review of randomized or quasi-randomized trials found adverse effects of hypercalcemia, gastrointestinal symptoms and renal disease significantly increased by vitamin D administration in conventional dosage (<1,000 IU/day) [43], the latter being of importance given the prevalence of renal deficiency in breast cancer patients [78]. While several pilot studies of short-term, parental high-dose vitamin D on safety have been reported [60,79], the side efforts of high-dose regimens for long duration use are unknown. Finally, the IOM report has identified safety concerns potentially associated with 25(OH)D levels >503 ng/ml (>125 nmol/l) [9,10]. "
    [Show abstract] [Hide abstract] ABSTRACT: Preclinical investigations and selected clinical observational studies support an association between higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk. However, the recently updated report from the Institute of Medicine concluded that, for cancer and vitamin D, the evidence was 'inconsistent and insufficient to inform nutritional requirements'. Against this background, reports examining vitamin D intake, 25-hydroxyvitamin D levels and breast cancer incidence and outcome were reviewed. Current evidence supports the pursuit of several research questions but not routine 25-hydroxyvitamin D monitoring and vitamin D supplementation to reduce breast cancer incidence or improve breast cancer outcome.
    Preview · Article · Aug 2011 · Breast cancer research: BCR
  • Source
    • "In general, 50,000 IU of vitamin D 2 (ergocalciferol) can be given one to two times per week for 8 weeks, followed by a maintenance dose of vitamin D 3 of 1000 to 2000 IU/day [69, 104]. Toxicity is rare even if a daily dosage of 10,000 IU vitamin D 3 is given for up to 4 months [3]. Bone remodeling is a complex process that is regulated by both local and systemic factors. "
    [Show abstract] [Hide abstract] ABSTRACT: Bone quantity, quality, and turnover contribute to whole bone strength. Although bone mineral density, or bone quantity, is associated with increased fracture risk, less is known about bone quality. Various conditions, including disorders of mineral homeostasis, disorders in bone remodeling, collagen disorders, and drugs, affect bone quality. The objectives of this review are to (1) identify the conditions and diseases that could adversely affect bone quality besides osteoporosis, and (2) evaluate how these conditions influence bone quality. We searched PubMed using the keywords "causes" combined with "secondary osteoporosis" or "fragility fracture." After identifying 20 disorders/conditions, we subsequently searched each condition to evaluate its effect on bone quality. Many disorders or conditions have an effect on bone metabolism, leading to fragility fractures. These disorders include abnormalities that disrupt mineral homeostasis, lead to an alteration of the mineralization process, and ultimately reduce bone strength. The balance between bone formation and resorption is also essential to prevent microdamage accumulation and maintain proper material and structural integrity of the bone. As a result, diseases that alter the bone turnover process lead to a reduction of bone strength. Because Type I collagen is the most abundant protein found in bone, defects in Type I collagen can result in alterations of material property, ultimately leading to fragility fractures. Additionally, some medications can adversely affect bone. Recognizing these conditions and diseases and understanding their etiology and pathogenesis is crucial for patient care and maintaining overall bone health.
    Full-text · Article · Nov 2010 · Clinical Orthopaedics and Related Research
  • [Show abstract] [Hide abstract] ABSTRACT: Not Available
    No preview · Conference Paper · Feb 2002
Show more