A phase 2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D(3) in breast cancer patients with bone metastases.
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.
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ABSTRACT: The vitamin D hormone, [1,25(OH) 2D, calcitriol], inhibits proliferation and angiogenesis in breast cancer but its therapeutic use is limited by hypercalcemia. Synthetic analogs of 1,25(OH) 2D that are less calcemic, such as paricalcitol (19-nor-1,25-Dihydroxyvitamin D 2), are used to treat hyperparathyroidism associated with chronic kidney disease. We sought to determine the safety and feasibility of taking oral paricalcitol with taxane-based chemotherapy in women with metastatic breast cancer (MBC). Oral paricalcitol was considered safe if it did not result in excessive toxicity, defined as grade 3 or higher serum calcium levels. It was considered feasible if the majority of women could take eight weeks of continuous therapy in the first three months. Serum calcium was monitored weekly and the paricalcitol dose was adjusted based on its calcemic effect. Intact parathyroid hormone (iPTH) was monitored as a marker of paricalcitol activity. Twenty-four women with MBC were enrolled. Twenty women (83%) received eight weeks of continuous therapy. Paricalcitol was well-tolerated with no instances of hypercalcemia grade 2 or greater. Fourteen women (54%) were able to escalate the dose. The dose range of paricalcitol in the first 3 mo was 2-7 ug/day. Serum iPTH levels at baseline were significantly higher in women with serum 25-Hydroxyvitamin D (25-OHD) levels less than 30 ng/ml (96.4 ± 40.9 pg/ml) vs. 46.2 ± 20.3 pg/ml (p = 0 0.001) (iPTH reference 12-72 pg/ml). We conclude that paricalcitol is safe and feasible in women with MBC who are receiving chemotherapy.Cancer biology & therapy 06/2013; 14(6):476-80. · 3.29 Impact Factor
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ABSTRACT: Objective: It has been suggested that vitamin D may play a role in the pathogenesis of several endocrine diseases such as hyperparathyroidism, type 1 diabetes, type 2 diabetes, autoimmune thyroid diseases, Addison's disease, and polycystic ovary syndrome. In this review, we debate the role of vitamin D in the pathogenesis of endocrine diseases. Methods: Narrative overview of the literature synthesizing the findings of literature retrieved from searches of computerized databases, hand searches, and authoritative texts. Results: Evidence from basic science supports a role for vitamin D in many endocrine conditions. In humans, inverse relationships exist between not only blood 25-hydroxyvitamin D and parathyroid hormone concentrations but also between 25-hydroxyvitamin D and risk of type 1 diabetes, type 2 diabetes and polycystic ovary syndrome. There is less evidence for an association with Addison's disease or autoimmune thyroid disease. Vitamin D supplementation may have a role for prevention of type 2 diabetes, but the available evidence is preliminary and not consistent. Conclusions: Although observational studies support a potential role of vitamin D in endocrine disease, high quality evidence from clinical trials does not exist to establish a place for vitamin D supplementation in optimizing endocrine health. Randomized controlled trials are expected to provide insight into the efficacy and safety of vitamin D in the management of endocrine disease.European journal of endocrinology / European Federation of Endocrine Societies. 05/2014;
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ABSTRACT: Results of recent studies suggest that circulating levels of vitamin D may play an important role in cancer-specific outcomes. The present systematic review was undertaken to determine the prevalence of vitamin D deficiency (<25 nmol/L) and insufficiency (25-50 nmol/L) in cancer patients and to evaluate the association between circulating calcidiol (the indicator of vitamin D status) and clinical outcomes. A systematic search of original, peer-reviewed studies on calcidiol at cancer diagnosis, and throughout treatment and survival, was conducted yielding 4,706 studies. A total of 37 studies met the inclusion criteria for this review. Reported mean blood calcidiol levels ranged from 24.7 to 87.4 nmol/L, with up to 31% of patients identified as deficient and 67% as insufficient. The efficacy of cholecalciferol supplementation for raising the concentration of circulating calcidiol is unclear; standard supplement regimens of <1,000 IU D3 /day may not be sufficient to maintain adequate concentrations or prevent decreasing calcidiol. Dose-response studies linking vitamin D status to musculoskeletal and survival outcomes in cancer patients are lacking.Nutrition Reviews 09/2013; 71(9):611-21. · 4.60 Impact Factor
A Phase 2 Trial Exploring the Effects of
High-Dose (10,000 IU/Day) Vitamin D3in
Breast Cancer Patients With Bone Metastases
Eitan Amir, MB, ChB1; Christine E. Simmons, MD2; Orit C. Freedman, MD1; George Dranitsaris, MPharm1;
David E. C. Cole, MD3; Reinhold Vieth, MD4; Wei S. Ooi, MD1; and Mark Clemons, MD1
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 D3. This study therefore aimed to assess the effect of this dose of vitamin D3in 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 D3and 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 D3for 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.
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
els of vitamin D metabolites (25-hydroxyvitamin D) have been shown to correlate with poor prognosis from breast can-
cer.7,8These observations are countered by other evidence, including a recent meta-analysis of vitamin D and breast
cancer risk9as well as a large randomized trial of vitamin D supplementation10that 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 beof significantbenefit.
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
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; firstname.lastname@example.org
1Department of Medical Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada;2Department of Medical Oncology, Odette Cancer Centre, Toronto, On-
tario, Canada;3Department of Biochemistry, Women’s College Hospital, Toronto, Ontario, Canada;4Department of Biochemistry, Mount Sinai Hospital, Toronto,
The first 2 authors contributed equally to this article.
We thank Esther Lee for her role as research coordinator for this study.
January 15, 2010
patients receiving long-term bisphosphonate therapy.11In
metastatic disease, there is, to our knowledge, a paucity of
data on the extent of calciumand vitamin D supplementa-
tion, although in many centers such supplementation has
been recommended.12Work in the metastatic breast can-
cer setting has shown that supplementation with 400 IU/
day vitamin D3(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.13In 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% ofpatients hadsuboptimallevelsofserum 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 D3.14Consequently, it
tion of vitamin D should be considered,13and that it
would be reasonable to expect improvements in palliation
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 D3intake of 10,000 IU/day.15-18Furthermore, 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 D3per day,
suggesting that this dose may be a physiologic upper
limit.19The 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
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 hadall vitaminDsupplementsstopped.
The primary objectives of this prospective study were to
assess the palliative benefit of 10,000 IU of vitamin D3
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
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 D3) at a daily dose of 10,000 IU for 4 months, along
with 1000 mg/d elemental calcium. Vitamin D3 was
administered in liquid form (Ddrops, 1000 IU per oil
drop, Toronto, Canada) to reduce the quantity of tablets
Most previous studies describing the biochemical
response and safety of high-dose vitamin D were con-
ducted for up to 20 weeks.15-18Furthermore, toxicities
have been described at doses of 20,000 IU for 12 weeks20;
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
January 15, 2010
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
Palliative response was assessed using the Brief Pain
Inventory21and the Functional Assessment of Cancer
Therapy-Bone Pain,22,23both 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
PTHweredrawnin themorningto avoidanydiurnal var-
iation and analyzed immediately. The laboratory refer-
ence interval for PTH (Roche Diagnostics, Montreal,
ficientsof variationwere <3%.
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
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 ofnormalizingthe distributionbytakingitsnatu-
ral logarithm was used. The adequacy of the procedure
tion of the Skew test. All of the statistical analyses were
performed using Stata statistical software (release 9.0; Sta-
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
requireddosesofboth vitaminD3and calcium.
Table 1. Patient Demographics
Estrogen receptor status
Sites of metastatic disease
Bisphosphonate therapy at baseline
Duration of bisphosphonate use at baseline, mo
Endocrine therapy administration
History of skeletal-related events at baseline6 (15%)
January 15, 2010
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
BiomarkerBaselineMonth 1Month 2 Month 3 Month 4
Urinary N-telopeptide, nmol/mmol creatinine
Urinary calcium, mmol/L
Serum PTH, pmol/La
Serum 25(OH)D, nmol/Lb
Corrected serum calcium, mmol/L
PTH indicates parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D.
aSee Figure 3.
bSee 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
January 15, 2010
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
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.24,25Administration of
10,000 IU per day of vitamin D3did 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
Treatment was generally well tolerated. Expected toxicity
in termsof increasein urinarycalciumexcretionwithcon-
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 formanagementof herhypercalcemia.
Several in vitro,1-3epidemiologic,5,6and in vivo7,8studies
suggest a role for vitamin D and calcium metabolism in
the development of breast cancer and regulation of carci-
nogenesis. The exact mechanismby 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.26These
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
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
January 15, 2010
Vitamin D has been recommended as an adjunct to
bisphosphonate therapy in patients with metastatic breast
cancer and bone metastases.27Unfortunately, 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.13,28It was therefore hypothesized
that higher vitamin D dosing may be required in this set-
In both North America and Europe, the upper level
2000 IU/d.29,30However, 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,15-18this dose would appear to be intuitively safe. A
review of thetoxicities of vitaminD hasshown thatexcept
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 D3
This preliminary phase 2 trial assessed the effects of
10,000 IU of vitamin D3per 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 D3for 4 months is safe in patients without comorbid
A potential explanation for the results noted above
may lie in the nature of the bisphosphonate protocols.
Bisphosphonates can potently reduce telopeptide lev-
els,32,33which 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
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,36it 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
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 D3, levels fell markedly. These findings support
thehypothesisthat despitethe majorityof patientsalready
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
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
January 15, 2010
associated with breast cancer.37Whether 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,37this limitation in the administration of high-
dose vitamin D needs to be highlighted, despite it having
been described previously.38Furthermore, 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 renalimpairment.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-
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
in this population, but should screen and follow diligently
CONFLICT OF INTEREST DISCLOSURES
This study was funded in part by a grant from the Vitamin D
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