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First Published Online July 9, 2008
The Oncologist, Vol. 13, No. 7, 821-827, July 2008; doi:10.1634/theoncologist.2008-0013
© 2008 AlphaMed Press

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Symptom Management and Supportive Care

Evaluation of Vitamin D Deficiency in Breast Cancer Patients on Bisphosphonates

Andrea Wang-Gillama, Dorothy A. Milesb, Laura F. Hutchinsb

aDivision of Oncology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA; bDivision of Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

Key Words. Vitamin D deficiency • Breast cancer • Bisphosphonates • 25-Hydroxyvitamin D • Hyperparathyroidism

Correspondence: Laura F. Hutchins, M.D., Division of Hematology/Oncology, Slot 508, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. Telephone: 501-686-8511; Fax: 501-686-6342; e-mail: HutchinsLauraF{at}uams.edu

Received January 15, 2008; accepted for publication April 14, 2008; first published online in THE ONCOLOGIST Express on July 9, 2008.

Disclosure: The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.


   Learning Objectives
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 Learning Objectives
Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Author Contributions
 Acknowledgments
 References
 
After completing this course the reader should be able to:

  1. Recognize and treat vitamin D deficiency in cancer patients.
  2. Avoid the potential complications of occult vitamin D deficiency in cancer patients on bisphosphonates.
  3. Administer the appropriate dose of vitamin D supplementation to cancer patients.

This article is available for continuing medical education credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Author Contributions
 Acknowledgments
 References
 
Background. Bisphosphonates are very effective in treating osteoporosis and metastatic bone disease; however, unfavorable outcomes can occur when they are given to patients with occult vitamin D deficiency. No clear consensus exists on the assessment of vitamin D status in cancer patients undergoing bisphosphonate therapy. This study examines the prevalence of vitamin D deficiency among breast cancer patients treated with bisphosphonates for osteoporosis or metastatic bone disease, and observes the use of calcium and vitamin D supplementation in these patients.

Methods. This retrospective study reviewed the electronic records of 321 breast cancer patients treated with bisphosphonates. Information on age, race, and serum levels of 25-hydroxyvitamin D (25-OHD), parathyroid hormone, and calcium were collected, and intakes of calcium and vitamin D supplements were queried in an outpatient pharmacy database.

Results. Of the 321 patients treated with bisphosphonates, 209 (65.1%) had their 25-OHD levels checked at least once. Of these patients, 57 (27.3%) had a serum 25-OHD level <20 ng/ml. Of the 209 patients with a known 25-OHD level, only eight (3.8%) received >600 IU of vitamin D per day, and 41 (19.6%) patients received 400–600 IU of vitamin D daily.

Conclusion. Especially in the setting of metastatic bone disease in breast cancer patients, we advocate routine 25-OHD concentration screening for vitamin D deficiency in general. Clear guidelines for the diagnosis of vitamin D deficiency in cancer patients would be extremely beneficial to have, as would identification of the proper dose of vitamin D supplementation. We recommend 1,000 IU daily to our metastatic cancer patients.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Author Contributions
 Acknowledgments
 References
 
Vitamin D plays an important role in calcium, phosphate, and bone metabolism. Deficiency of vitamin D results in poor mineralization of bone, causing rickets in children and osteomalacia in adults. Low vitamin D levels are associated with higher risks for many chronic diseases, including autoimmune diseases, cardiovascular diseases, and diabetes mellitus [1]. Emerging epidemiological data have suggested that vitamin D status is inversely associated with the risk for various cancers, such as colon cancer [2], breast cancer [3–6], and prostate cancer [7]. Moreover, vitamin D has a demonstrated antitumor effect in preclinical models [8]. Despite our clear understanding of vitamin D metabolism, an unexpectedly high prevalence of vitamin D insufficiency has been reported in otherwise healthy adults living in Canada and the U.S. [9]. An even higher prevalence has been observed among hospitalized patients (57%) [10] and homebound elderly persons (42%) [11].

Bisphosphonates are a class of drugs that slow bone resorption by suppressing osteoclastic activity. Developed initially to treat osteoporosis, these drugs are now widely used in oncology to treat hypercalcemia and slow metastatic bone disease, although they are given at a much higher dose in these cases than in the treatment of osteoporosis [12, 13]. Many ongoing clinical trials have incorporated bisphosphonates as part of adjuvant therapy for early-stage cancer patients under the rationale that the drugs may reduce micrometastases, and therefore delay metastatic spread to bone.

When a bisphosphonate is prescribed for osteoporosis, a patient's vitamin D status is routinely assessed as part of the workup. When a bisphosphonate is prescribed for metastatic bone disease or hypercalcemia, however, examination of a patient's vitamin D status is entirely subject to the individual oncologist's practice. Unfortunately, case reports have emerged showing that bisphosphonate treatment of patients who have an occult vitamin D deficiency results in catastrophic hypocalcemia and worsens secondary hyperparathyroidism, osteopenia, and bone fracture [14–18].

Although the potential role of vitamin D in cancer prevention has attracted increasing public attention, it is not clear how well cancer patients are assessed with regard to their vitamin D status, and whether they are on adequate vitamin D supplementation. Currently, no clear guidance exists on the assessment and management of vitamin D insufficiency in cancer patients, especially when they are being treated with a bisphosphonate. Because there is avoidable morbidity associated with bisphosphonate therapy in cancer patients with occult vitamin D deficiency, it is first necessary to determine the prevalence of vitamin D deficiency in this population. We therefore undertook a retrospective study reviewing the medical records of breast cancer patients being treated with a bisphosphonate for osteoporosis or metastatic bone disease. We analyzed the vitamin D screening status of these patients and examined their intake of calcium and vitamin D supplements.


   MATERIALS AND METHODS
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 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Author Contributions
 Acknowledgments
 References
 
We retrospectively reviewed the outpatient electronic medical records of 321 women diagnosed with breast cancer who were treated with a bisphosphonate at the Winthrop P. Rockefeller Cancer Institute in Little Rock, AR, between June 1, 2002 and September 30, 2006. The indications for bisphosphonate treatment in these patients included diagnoses of osteoporosis, metastatic bone disease, and hypercalcemia. Information on age, race, and laboratory data, including serum 25-hydroxyvitamin D (25-OHD), parathyroid hormone (PTH), and calcium levels, were collected by an automatic data collection system and independently verified against patients' medical records. Calcium and vitamin D supplement intake was queried with the use of an outpatient pharmacy database.

Various cutoff points were used to define patients' serum 25-OHD status: <10 ng/ml, 10–19 ng/ml, 20–30 ng/ml, and >30 ng/ml. A laboratory value <10 ng/ml for 25-OHD is abnormal; most endocrinologists recommend 20 ng/ml as the minimum acceptable level of 25-OHD to maintain calcium–phosphorus homeostasis [19]. Some experts have suggested that 25-OHD levels up to 30 ng/ml maximize cellular function [20]. Secondary hyperparathyroidism was defined by a PTH level >65 pg/ml and a low or normal calcium level.

On the basis of the indication for which the bisphosphonate was prescribed, the study population was divided into two subgroups: those treated for osteoporosis and those treated for metastatic bone disease.

The protocol for this study was approved by the Institutional Review Board and Protocol Review and Monitoring Committee of the University of Arkansas for Medical Sciences.

Descriptive analyses, including mean values and standard deviations, were calculated with Excel software.


   RESULTS
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 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Author Contributions
 Acknowledgments
 References
 
Vitamin D Status Examination
Among 321 breast cancer patients who were treated at the ACRC taking a bisphosphonate, 267 were taking the drug for osteoporosis and 54 were taking the drug for metastatic bone disease (Table 1). Of these 321 patients, 209 patients (65.1%) had had their 25-OHD level examined at least once, while 112 patients (34.9%) had no documentation of 25-OHD testing. The average age of the patients whose 25-OHD level was known was 63.4 ± 11.1 years, which was similar to that (63.7 ± 12.0 years) of the group whose 25-OHD status had not been checked at least once. The race distributions of the groups whose 25-OHD status had been checked and not checked were comparable, with approximately 92% of patients in each group being white.


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  		Table 1. Baseline features of breast cancer patients taking a bisphosphonate for osteoporosis or metastatic bone disease

 
Among 267 breast cancer patients being treated with a bisphosphonate for osteoporosis, 188 patients (70.4%) had a known 25-OHD level while 79 patients (29.6%) had no documented levels (Table 1). In contrast, among 54 breast cancer patients being treated with a bisphosphonate for metastatic bone disease, 21 patients (38.9%) had their 25-OHD levels checked at least once while 33 patients (61.1%) had an unknown 25-OHD status.

Vitamin D Insufficiency in Examined Patients
Among the 209 breast cancer patients treated with a bisphosphonate who had a known serum 25-OHD level, 15 patients (7.2%) had a 25-OHD level <10 ng/ml, 42 patients (20.1%) had a level in the range of 10–19 ng/ml, 71 patients (34.0%) had a level in the range of 20–30 ng/ml, and 81 (38.8%) patients had a 25-OHD level >30 ng/ml (Table 1). Serum PTH levels rose as serum 25-OHD concentrations declined to <30 ng/ml (Fig. 1), indicating a physiological response to the low serum 25-OHD level, presumably through hypocalcemia. In the metastatic breast cancer setting, 21 (38.9%) of 54 patients treated with a bisphosphonate had documented 25-OHD levels, and 10 (47.6%) of these 21 patients had a serum 25-OHD level <20 ng/ml (Table 1). The relationship between PTH and 25-OHD levels in the metastatic bone disease group may be complicated by other factors in addition to the physiological response to 25-OHD (Fig. 2). Among the patients who had a serum 25-OHD level in the range of 20–30 ng/ml, 12 of 67 patients (17.9%) in the osteoporosis group had secondary hyperparathyroidism manifested as a low or normal calcium level and PTH >65 ng/ml (Table 2). Even in the group of patients with a serum 25-OHD level >30 ng/ml, four of 74 (5.4%) had secondary hyperparathyroidism (Table 2).


Figure 1
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  		Figure 1. Serum vitamin D levels in breast cancer patients. Relationship between serum 25 hydroxyvitamin D (25-OHD) level and mean serum concentration of parathyroid hormone (PTH) in 209 breast cancer patients with a known vitamin D level being treated with a bisphosphonate.

 


Figure 2
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  		Figure 2. Vitamin D levels in breast cancer patients with bone metastasis. Relationship between the serum 25 hydroxyvitamin D (25-OHD) level and parathyroid hormone (PTH) level in breast cancer patients being treated with an i.v. bisphosphonate for metastatic bone disease.

 


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  		Table 2. Secondary hyperparathyroidism in patients whose 25-OHD level was checked (n = 209)

 
Calcium and Vitamin D Supplementation
Calcium supplementation did not differ between the groups with known and unknown 25-OHD levels (53.6% versus 52.7%, respectively) (Table 1). Our study showed that 120 (37.4%) of 321 breast cancer patients treated with a bisphosphonate took vitamin D supplements. Vitamin D supplementation was also comparable between the 25-OHD-checked and 25-OHD-unchecked groups (38.8% versus 34.84%, respectively). In the patients with a known 25-OHD level, only eight (3.8%) patients received >600 IU of vitamin D per day, and 41 (19.6%) patients received 400–600 IU of vitamin D daily (Table 3). It is important to note that five patients who received vitamin D supplementation still suffered from vitamin D deficiency as evidenced by a 25-OHD level <10 ng/ml.


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  		Table 3. Vitamin D supplementation in breast cancer patients with known 25-OHD level (n = 81)

 

   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Author Contributions
 Acknowledgments
 References
 
This study revealed that vitamin D insufficiency has a high prevalence among breast cancer patients being treated with a bisphosphonate for osteoporosis or metastatic bone disease and that supplementation of calcium and vitamin D is underused in the care of these patients.

In our study population of breast cancer patients, about 65% had documentation in their medical charts of at least one assay of their 25-OHD level (Table 1). The lack of any difference in age and race distribution between the groups that did and did not have at least one 25-OHD determination suggests that neither factor played a role in influencing clinicians to screen for vitamin D deficiency, even though old age and African-American heritage are known independent risk factors for vitamin D deficiency [10, 21]. When we compared the metastatic bone disease group with the osteoporosis group, 38.9% versus 70.4% were found to have had their 25-OHD level examined (Table 1). This suggests that the vitamin D status of metastatic breast cancer patients had not been assessed frequently by oncologists, compared with the higher rate of routine screening for osteoporosis performed by either oncologists or primary care physicians. It is quite alarming that 61.1% of metastatic breast cancer patients received a bisphosphonate without having their vitamin D status checked (Table 1).

Vitamin D insufficiency was found in the majority of patients with known vitamin D status in our study. There is no consensus on the range constituting borderline values between a vitamin D–deficient state and a vitamin D–sufficient state. In the osteoporosis group, we found that 47 patients (25%) had a 25-OHD level <20 ng/ml and 114 patients (60.6%) had a 25-OHD level ≤30 ng/ml (Table 2). Similar results were reported in a study of postmenopausal women receiving oral bisphosphonates for osteoporosis, 18% of whom had a serum 25-OHD level <20 ng/ml and 52% of whom had a level <30 ng/ml [22]. Our study showed that 17.9% of patients in the osteoporosis group with a serum 25-OHD level of 20–30 ng/ml had secondary hyperparathyroidism (Table 2). This finding suggests that it is probably more appropriate to set the level for vitamin D adequacy to a screening 25-OHD level of >30 ng/ml. In our group of metastatic breast cancer patients being treated with a bisphosphonate, 47.6% had a 25-OHD level <20 ng/ml and 66.7% had a level ≤30 ng/ml (Table 2). The observation of a higher frequency of vitamin D insufficiency in the metastatic bone disease group than in the osteoporosis group is echoed in a recent report showing that patients' vitamin D levels were much lower in a metastatic disease setting than in an adjuvant treatment setting [23]. Although we were not able to collect the data on potential complications in our vitamin D–deficient patients who were taking bisphosphonates, unfavorable outcomes have been documented in several case reports [14–18].

In addition to the potential complications, the efficacy of bisphosphonates in vitamin D–deficient patients is questionable. In the case of etidronate (Didronel®; P&G Pharmaceuticals, Cincinnati, OH), for example, the benefit of treatment may be attenuated by concomitant vitamin D deficiency [24]. It is not known, however, whether imbalanced bone metabolism resulting from vitamin D deficiency can potentially be exacerbated by bisphosphonates, resulting in bone fracture or even necrosis.

To our surprise, only 113 (42.3%) of 267 patients who were prescribed a bisphosphonate for osteoporosis also took a daily vitamin D supplement, and among metastatic bone disease patients, the rate for vitamin D supplementation was even lower, 13.0% (Table 1). Calcium and vitamin D are essential components of management strategies for the prevention and treatment of osteoporosis [25]. Low rates of vitamin D supplementation could be one reason for vitamin D deficiency. Cancer patients are at an additional high risk for vitamin D insufficiency in general, because they are usually older and tend to suffer from low sun exposure, poor oral intake, decreased gastrointestinal absorption, and kidney insufficiency.

Current recommendations for daily vitamin D intake are 200 IU for children and adults up to age 50 years, 400 IU for individuals between 51 and 70 years of age, and 600 IU for adults >70 years of age [26]. For high-risk groups, such as cancer patients, a vitamin D intake of 1,000 IU per day is endorsed by the Dietary Guidelines for Americans [27]. A high vitamin D intake level of 2,000 IU per day was proposed as a tolerable upper intake level by the Food and Nutrition Board in 1997, but experts consider the dose to be too low to achieve an optimized serum 25-OHD level (>32 ng/ml) in the general population [28]. In our study, among the 209 patients with known vitamin D status, only 41 patients (19.6%) were taking a daily supplement at a dose of 400–600 IU. Vitamin D insufficiency still developed in patients who were receiving vitamin D supplementation (Table 3). For the majority of patients with diagnosed vitamin D deficiency, 50,000 IU of vitamin D twice weekly for 8–10 weeks was administered. However, there was no clear consensus on the vitamin D supplementation level for maintenance. This reflects the fact that our physicians are well equipped to treat vitamin D deficiency, but do not diagnose it or promote vitamin D supplementation.

This study is limited by its retrospective nature. It consisted of a chart review of medical records from a single institution. Patients whose vitamin D levels were determined at another institution were missed in this analysis. Also, the amount of calcium and vitamin D supplementation documented in the chart may not accurately reflect patients' actual intakes. Our study provided a glimpse at vitamin D assessment and management in our institution. A larger, prospective study is needed to address the incidence, prevalence, and potential complications of vitamin D deficiency in cancer patients in general and in groups that receive bisphosphonates. The proper dose of vitamin D supplements should also be addressed in the prospective study as well.

In conclusion, the high prevalence of vitamin D insufficiency among breast cancer patients being treated with a bisphosphonate for osteoporosis or metastatic bone disease underscores the need for practicing oncologists to be alert in assessing patients' vitamin D status. Clinical risk factors can only predict vitamin D deficiency with an accuracy of 59%–68%, making them poor predictors [10]. In the setting of metastatic bone disease in breast cancer patients, in particular, we advocate routine screening of the 25-OHD concentration for vitamin D deficiency in general. This recommendation echoes those from other groups [29]. Clear guidelines for the diagnosis of vitamin D deficiency in cancer patients would be extremely beneficial to have, as would identification of the proper dose of vitamin D supplementation.


   AUTHOR CONTRIBUTIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Author Contributions
Acknowledgments
 References
 
Conception/design: Andrea Wang-Gillam, Laura F. Hutchins

Financial support: Andrea Wang-Gillam

Administrative support: Andrea Wang-Gillam, Dorothy A. Miles

Provision of study materials or patients: Andrea Wang-Gillam, Laura F. Hutchins

Collection/assembly of data: Andrea Wang-Gillam

Data analysis and interpretation: Andrea Wang-Gillam, Laura F. Hutchins

Manuscript writing: Andrea Wang-Gillam, Dorothy A. Miles

Final approval of manuscript: Andrea Wang-Gillam, Dorothy A. Miles, Laura F. Hutchins


   ACKNOWLEDGMENTS
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Author Contributions
 Acknowledgments
References
 
This work was conducted at the University of Arkansas for Medical Sciences.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Author Contributions
 Acknowledgments
 References
 

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  13. Ross JR, Saunders Y, Edmonds PM et al. Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 2003;327:469.[Abstract/Free Full Text]
  14. Schussheim DH, Jacobs TP, Silverberg SJ. Hypocalcemia associated with alendronate. Ann Intern Med 1999;130:329.[Free Full Text]
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  18. Breen TL, Shane E. Prolonged hypocalcemia after treatment with zoledronic acid in a patient with prostate cancer and vitamin D deficiency. J Clin Oncol 2004;22:1531–1532.[Free Full Text]
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  23. Palmieri C, MacGregor T, Girgis S et al. Serum 25-hydroxyvitamin D levels in early and advanced breast cancer. J Clin Pathol 2006;59:1334–1336.[Abstract/Free Full Text]
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