Prescriptions for Vitamin D Among Patients Taking Antiresorptive Agents in Canada

By Hanley, David A Zhang, Qiaoyi; Meilleur, Marie-Claude; Mavros, Panagiotis; Sen, Shuvayu S

Key words: Antiresorptive medications – Osteoporosis – Vitamin D – Vitamin D deficiency ABSTRACT

Background: Data on the rate of concomitant vitamin D use with antiresorptive medications are limited. Such information is important because vitamin D is indicated in patients with osteoporosis, including those receiving bisphosphonates, and there is evidence of inadequate use by these patients.

Objective: To examine prescription vitamin D utilization patterns.

Research design and methods: A retrospective analysis of patients aged >/= 65 years was conducted in a Canadian pharmacy-insurance organization (RAMQ) who received at least one prescription for an antiresorptive agent (i.e., alendronate, risedronate, raloxifene) from January 1,1996, through December 31, 2003, and did not switch to any other agent during the 1-year post period. Data on prescriptions of vitamin D formulations on the RAMQ formulary (e.g., alfacalcidol, calcitriol, cholecalciferol, doxercalciferol, ergocalciferol) were also captured. No data on generic or over-the- counter vitamin D preparations were available. A vitamin D and antiresorptive agent possession ratio (R^sub p^) was computed as:

…

where [n-ary summation]D^sub SPVD^ = the sum of the days of supply with prescription vitamin D and [n-ary summation]D^sub SPVD^ = the sum of days of supply with alendronate, risedronate, or raloxifene

A vitamin D and antiresorptive agent overlap ratio (R^sub o^) was computed as:

…

where [n-ary summation]D^sub SPVDOARR^ = the sum of days of supply of prescription vitamin D overlapping with alendronate, risedronate, or raloxifene, and [n-ary summation]D^sub SARR^ = the sum of the days of supply with alendronate, risedronate, or raloxifene.

Results: A total of 46 226 antiresorptive treatment users were identified, > 90% of whom were women. A total of 17 151 (37.1%) had concomitant vitamin D prescriptions. The average duration of prescription therapy with alendronate, risedronate, or raloxifene was 247 days; and the mean duration of prescription vitamin D therapy was 83 days. Patients had a supply of vitamin D for 55% of days of antiresorptive agents therapy (R^sub p^ = 0.55) and a vitamin D supply overlapping with 24% of their days on antiresorptive agents (R^sub o^ = 0.24). Possession and overlap ratios were significantly higher in patients receiving once-weekly bisphosphonate prescriptions compared with once-daily regimens (bisphosphonates or raloxifene). Vitamin D prescriptions were also significantly more likely in patients receiving prescriptions for once-weekly bisphosphonates (odds ratio (OR) = 4.65; 95% Cl = 4.29- 5.05; p < 0.0001) and once-daily bisphosphonates (OR = 1.91; 95% Cl = 1.76-2.07; p < 0.0001) compared with once-daily raloxifene.

Conclusions: Despite the benefits of vitamin D for osteoporosis, most patients ([asymptotically =]63%) receiving prescriptions for antiresorptive agents were not taking vitamin D, indicating a substantial treatment gap. The study is limited by including data only on (1) pharmacy claims, which do not equate to patient behaviors, such as filling or refilling prescriptions and/or taking the medications; and (2) prescription (but not generic or over-the- counter) vitamin D formulations.

(ProQuest-CSA LLC: … denotes formulae omitted.)

Introduction

Osteoporosis is a chronic condition associated with increased fragility of bone and increased risk of fracture. Oral bisphosphonates are clinical mainstays in the management of osteoporosis that should be administered together with vitamin D.

A fat-soluble steroid that is considered instrumental to calcium homeostasis, musculoskeletal function, and optimal bone health, vitamin D possesses antiresorptive and bone anabolic properties in vivoIn bone, vitamin D protects osteoblasts from apoptosis, while in muscle it helps to preserve muscle strength by maintaining type II fiber function2, thus helping to prevent falls14. Falls and attendant fractures constitute a major cause of morbidity and mortality in individuals aged >655 (=33% of individuals aged >65 years fall at least once each year1’8), in part because falls often lead to fracture8. The lifetime risk of hip fracture from the age of 50 years onward is estimated at 17% for white women’1. By one estimate1″, 10% of patients are disabled by hip fractures and 19% need to be institutionalized, accounting for nearly 140000 admissions to nursing homes in the US each year. Because of demographic and other trends, the annual number of hip fractures across the world each year could increase from 1.7 million in 1990 to as high as 21 million in 2050″.

Adequate vitamin D intake, as indicated by serum 25(OH)D concentrations >750 -80nmol/L (> 20-32 ng/mL), is needed for optimal bone health. Vitamin D status has been positively and significantly related to bone mineral density12 l4, and vitamin D supplementation can prevent osteoporotic fractures in certain populations, including community-dwelling patients aged >65 with vitamin D deficiency15. Although vitamin D is generated by the skin upon exposure to sunlight (ultraviolet B radiation), there is an age-related decrease in cutaneous synthesis such that individuals aged >65 are more dependent on dietary intake1617. Consistent with these factors, a number of health authorities recommend adequate intake of vitamin D to reduce fracture risk, particularly in patients with osteoporosis, peri- and postmenopausal women, and/ or institutionalized patients aged >65 with vitamin D deficiency and secondary hyperparathyroidism. Further, almost all clinical trials evaluating antiresorptive agents for treatment of osteoporosis included vitamin D as part of the treatment regimen. Therapeutic responses to a bisphosphonate (etidronate) were also significantly lower in vitamin D-deficient women compared with vitamin Dsufficient women, with bone mineral density increasing by 0.5% in vitamin D-deficient women compared with 5.2% in vitamin D-sufficient patients (p < 0.05)'8.

Despite the important role of vitamin D in the management of osteoporosis, some investigators contend that inadequate vitamin D status has reached ‘epidemic’ proportions19 and is particularly common in sick, inactive, and/or institutionalized patients aged >65, postmenopausal women, and/or individuals with a history of fracture, including minimal-trauma fracture2″21. Vitamin D inadequacy was virtually universal in a recent retrospective audit of 103 British patients hospitalized for hip fracture22.

In a recent study involving 1536 North American community- dwelling postmenopausal women, serum 25(OH)D was <30ng/mL in 52%, and the prevalence of vitamin D inadequacy was significantly higher in women who took < 400IU vitamin D compared with > 400IU daily2″. Inadequate vitamin D intake among patients with osteoporosis or at elevated risk of this condition is part of a larger problem of undertreatment and suboptimal compliance2324. Limited data are available concerning concomitant use of prescription vitamin D together with bisphosphonates and raloxifene. The objective of the present study was to examine utilization patterns of prescription vitamin D concurrently with prescription antiresorptive agents (i.e., alendronate, risedronate, raloxifene) among patients aged >65 years.

Methods

Study design and patients

This retrospective study involved patients in the Regie de l’assurance maladie du Quebec (RAMQ; Sillery, Quebec; www.ramq.gouv.qc.ca), a provinceowned organization that administers health insurance and prescription drug insurance plans and is a claims adjudicator. Established in 1969 to administer the public Health Insurance Plan, RAMQ pays for medical services offered by 26000 health professionals to 7.3 million Quebec residents. The organization processes up to 140 million medical claims representing =$5.3 billion annually and involves 1500 interconnected pharmacies.

A random sample constituting 25% of all patients aged >65 (N= 125000) with at least one pharmacy claim for a prescription of alendronate, risedronate, or raloxifene or vitamin D from January 1, 1996 to December 31, 2004 in the RAMQ database was initially taken for this study. Only data concerning prescription medications on the RAMQ formulary were available. Throughout this study report, the term ‘antiresorptive agent’ refers to prescription alendronate, risedronate, or raloxifene. (Ibandronate was not approved in Canada and was thus not on the RAMQ formulary.) Prescription vitamin D formulations available on the RAMQ formulary included alfacalcidol, calcitriol, cholecalciferol, doxercalciferol, and ergocalciferol. As a pharmacy-claims database, the RAMQ did not include data on over- the-counter or generic vitamin D preparations or other nonprescription products containing vitamin D.

Pharmacy claims of patients aged >65 years with at least one prescription for the bisphosphonates, i.e. alendronate or risedronate, or the selective estrogen receptor modulator, i.e. raloxifene, from January 1, 1996 to December 31, 2003 (the index period] from this sample of patients were reviewed. Based on the first (index) alendronate, risedronate, or raloxifene prescription during the index period, patients were classified into one of three treatment groups: bisphosphonates once weekly (BOW], bisphosphonates once daily (BOD), or raloxifene once daily (ROD). Baseline data were collected over a 1 -year period before the index prescription date. Each patient was followed for 1 year after the index prescription date (follow-up period) (Figure 1). Only patients who remained on their index alendronate, risedronate, or raloxifene prescription without changing to another treatment throughout the follow-up period were eligible for the analysis, in part because a vitamin D overlap ratio (see below) cannot be computed in patients changing from one antiresorptive therapy (i.e., alendronate, risedronate, raloxifene) to another. Patients receiving other forms of osteoporosis therapy were excluded. Prescriptions for concomitant medications were also captured and categorized as cardiovascular, estrogen, musculoskeletal, oral corticosteroid, and gastroprotective agents. All data were anonymous. Outcome measures

The outcome estimates included the (1) proportion of patients with a prescription for vitamin D >400IU, including vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol); (2) the vitamin D and antiresorptive possession ratio (R ), and (3) the vitamin D and antiresorptive agent overlap ratio (R0) over the 1 -year follow-up period.

Statistical analyses

?’-tests were conducted to compare the proportions of patients receiving at least one vitamin D prescription across the bisphosphonate once-weekly, bisphosphonate once-daily, and raloxifene once-daily categories. An analysis of variance (ANOVA) with Duncan’s multiple range test was performed to compare Ry and R0 values across bisphosphonate once-weekly, bisphosphonate once- daily, and raloxifene once-daily categories.

To estimate the impact of type of osteoporosis treatment and other factors on the likelihood of having a vitamin D prescription, multiple logistic regression analyses adjusting for age group, gender, year of index prescription, and filled prescription of any cardiovascular medication, gynecological/hormonal therapy, gastro- protective agent, oral steroid or nonsteroidal anti-inflammatory drugs (each separately dummy-coded as present = 1 or absent = O) were conducted. Odds ratios (OR) and 95% confidence intervals (95% CI) were computed using raloxifene once daily as the reference group. A multiple linear regression with R1, as outcomes variable while controlling for the same variables as in the previously mentioned logistic regression were carried out to estimate the impact of the type of osteoporosis treatments and other factors on vitamin D and antiresorptive agent R1,. A similar multiple linear regression on R0 with the same set of co-variates was conducted to estimate the impact of the type of osteoporosis treatments and other factors on vitamin D and antiresorptive agent R0

Figure 1. Individual observation timeline and study timeline

Significance level was at two-tailed a = 0.05. Statistical analyses were conducted using SAS 8.2 (SAS Institute, Gary, NC).

Results

Patient characteristics

Of the total of 46226 users of antiresorptive agents included in this analysis, 41 746 (90.3%) were women (Table 1). For the majority of patients (72.4%), the year of the index prescription was after 1999. Almost all patients on once-weekly bisphosphonates (100%) and once-daily raloxifene (99.7%) had their index prescriptions after 1999, whereas 55.4% of bisphosphonate once-daily patients had their index prescription after 1999. Prescriptions for gastrointestinal protection, musculoskeletal problems and cardiovascular diseases were the three most common concomitant medications. The vast majority (93.9%) of vitamin D prescriptions were for vitamin D1 (cholecalciferol).

A total of 17 151 (37.1%) patients had vitamin D prescriptions during the 1-year follow-up period. Proportions of patients with vitamin D prescription were significantly higher in the BOW group (61.5%) than in the BOD group (27.6%) or in the ROD group (23.3%) (p < 0.0001). The average number of vitamin D prescriptions over the 1 - year period was also significantly higher in the BOW group (10.8) than that in the other two groups (7.6 for BOD group and 7.4 for ROD group) (p < 0.0001).

The mean duration of therapy with alendronate, risedronate, or raloxifene was 247 days (standard deviation = 130.5) during the observation period. The mean duration of prescription vitamin D therapy was 83 days (standard deviation = 132.9). The mean vitamin D and antiresorptive agent possession ratio (R1,) was 0.55 (+-3.05), which indicates that patients had a supply of vitamin D for 55% of the days of their antiresorptive agent therapy (Figure 2). The mean vitamin D and antiresorptive overlap ratio (R0) was 0.24 (+-0.38), which indicates that patients had a supply of vitamin D overlapping with 24% of their days on antiresorptive agents. The mean R1, of patients with BOW (77%) was significantly (p < 0.05) higher than that of BOD (47%) and ROD (42%) patients. These findings indicate that patients with BOW prescriptions had a significantly greater supply of vitamin D as a proportion of their antiresorptive agents' supply as compared with ROD or BOD.

The mean R0 of patients with BOW prescriptions (45%) was significantly higher than the mean R0 of BOD patients (16%), which in turn was significantly higher than that of ROD patients (12%). Thus, on average, patients with BOW prescriptions had a significantly [p < 0.05) higher proportion of their antiresorptive therapy days covered with prescription vitamin D than did patients with BOD or ROD prescriptions. Oncedaily bisphosphonate patients had a significantly [p < 0.05) higher portion of their antiresorptive therapy days covered with prescription vitamin D.

Table 1. Patient characteristics

Figure 2. Vitamin D and antiresorptive agent possession ratio (“R1J and overlap ratio (R0) by treatment group. For methods of calculating R1 and R11, see text. BOVK bisphosphonate once weekly; BOD, bisphosphonate once daily; ROD, raloxifene mice daily. Different superscripts denote significant differences (p < 0.05) among groups derived using Duncan's test. For Rpl BOVK was significantly higher than either BOD or ROD while BOD and ROD were similar. For R1, till three groups were significantly different: BOW > BOD > ROD

Compared with patients receiving ROD prescriptions, patients receiving BOW prescriptions were more than 4.6 times more likely (OR = 4.65; 95% CI = 4.29-5.05; n < 0.0001) to have a concurrent vitamin D prescription, whereas those receiving BOD prescriptions were nearly 2 times more likely (OR =1.91; 95% CI = 1.76-2.07; n < 0.0001). These findings were according to a multiple logistic regression analysis that controlled for age group, gender, year of index prescription, and concomitant medications. Other factors, including age 70 years or older, antiresorptive agent prescription after 1999, and concomitant use of cardiovascular, oral corticosteroid, and gastro-protective agents, were also associated with a higher likelihood of vitamin D prescription use (Table 2). Finally, according to the multiple linear regression controlling for the same covariates (Table 3), patients receiving BOW prescriptions had a 0.28 increase in R1, and a 0.30 increase in R0, whereas those receiving BOD prescriptions had a 0.27 and a 0.10 increase, respectively, compared with patients receiving ROD (p < 0.0001).

Discussion

In a retrospective cohort study involving more than 46000 participants in the Canadian RAMQ pharmacybenefit organization, most patients (=63%) with prescriptions for antiresorptive agents did not have concomitant vitamin D prescriptions. Patients received prescription vitamin D supplies for approximately half (55%) of their days of antiresorptive therapy, while only about one-quarter (24%) of their vitamin D supplies overlapped with their antiresorptive treatment days. It should be noted that, unlike other Canadian provinces’ drug plans, RAMQ provides patient coverage for vitamin D, so a patient’s physician is likely to write a prescription for vitamin D. In other provinces, there is no reimbursement for nutritional supplements, so patients purchase vitamin D without a prescription.

These findings are broadly consistent with recent data showing low vitamin D treatment rate among patients with osteoporosis or at elevated risk. In a recent pilot audit of nine demographically representative UK general practices including 61 202 persons, 34.1% of patients receiving osteoporosis treatments were also prescribed calcium alone or calcium and vitamin D25. In a retrospective chart analysis involving patients ages >60 (mean = 73) years in an academic internalmedicine clinic26, only 48 (23.2%) of 207 women with osteoporosis or osteopenia used adequate doses of vitamin D according to US consensus guidelines27. Finally, a cross-sectional chart review of 177 residents aged >65 in an academic long-term care facility demonstrated that only 9% of patients received prescriptions for vitamin D supplements, including only 25% of those with a history of hip fracture2″.

The overall proportion of vitamin D use (61.5%), as well as possession (0.77) and overlap (0.45) ratios were significantly higher in patients receiving prescriptions for once-weekly bisphosphonate regimens compared with those receiving once-daily regimens (either hisphosphonates or raloxifene) in this study. Physicians might be less inclined to prescribe additional medications to patients receiving daily antiresorptive regimens compared with weekly regimens out of concern that the additional regimen complexity might jeopardize compliance with the antiresorptive treatment; regimen complexity is often inversely related to medication compliance in general21, and osteoporosis treatment in particular1″. As shown in Table 1, polypharmacy was common in this patient population. Thus, the approach of combining vitamin D and an antiresorptive osteoporosis treatment, as has recently been done with alendronate and cholecalciferol, may be of benefit to patients by simplifying osteoporosis therapy. Table 2. The likelihood of having concurrent vitamin D prescription

Table 3. Multiple linear regression on vitamin D and bisphosphonate possession ratio and overlap ratio

Patients receiving weekly or daily bisphosphonates were also significantly more likely to have vitamin D prescriptions than those receiving raloxifene, even though vitamin D supplementation is recommended (if dietary intake is insufficient) for fracture prevention in patients receiving the selective estrogen receptor modulator. The recent Multiple Outcomes of Raloxifene Evaluation (MORE) showed that vitamin D status at the onset of raloxifene treatment did not affect bone mineral density responses to this medication, provided that raloxifene was taken along with 400600IU cholecalciferol and 500 mg calcium daily31. One potential reason why prescription of vitamin D was less likely with raloxifene compared with bisphosphonates is that raloxifene is known to exert its own positive effects on calcium homeostasis via selective estrogen receptor actions on the intestine32.

Eimitations of the study include the fact that pharmacy-claims data showing a particular medication prescription do not equate to patient behavior, including filling or refilling prescriptions and actually taking the medicine; or patient biology, in that there are interindividual differences in the capacity to absorb exogenous vitamin D. Compliance with vitamin D and calcium is known to be suboptimal”3J. In the recent Randomised Evaluation of Calcium OR vitamin D (RECORD) trial, only approximately half of subjects who were randomized to treatment (oral vitamin D3 800IU/day, calcium 1000mg/day, or a combination of the two), or placebo were taking >80% of their assigned therapy after 2 years33. Given the likelihood of suboptimal compliance, the 37.1% rate of vitamin D use suggested by the prescription data reported here might actually overestimate actual vitamin D use. On the other hand, the present data on vitamin D prescriptions could also underestimate overall use because vitamin D was also available over the counter. However, given that prescription vitamin D use was reimbursed, there would be no tangible monetary incentive to use over-the-counter rather than prescription vitamin D. Because this is a pharmacy-claims database analysis of patients receiving a prescription for either alendronate, risedronate, raloxifene, or vitamin D, information on the actual indications for vitamin D could not be captured (baseline insufficiency). In addition, information on patient exposure to sun, which stimulates endogenous vitamin D synthesis, could not be captured. Vitamin D would be indicated in any patient who received a prescription bisphosphonate or raloxifene. There is also a potential bias in that the index prescription date for all patients receiving once-weekly bisphosphonates was after 1999, whereas 45% of patients in the oncedaily bisphosphonate group had index dates of 1999 or earlier. Because much of the evidence supporting the use of vitamin D supplements in patients with osteoporosis and other at-risk populations has emerged since 1999, the finding of higher vitamin D prescription rates in patients receiving once-weekly bisphosphonates may have been biased by their later time of introduction to the market. Finally, although vitamin D prescriptions were higher in patients receiving weekly compared with daily regimens, no trend can be extrapolated to even less frequent and/or parenteral treatments under clinical development (e.g., monthly bisphosphonates). The data also do not necessarily apply to vitamin D analogues and vitamin D receptor ligands under development.

Conclusion

Vitamin D was prescribed along with bisphosphonates and raloxifene in only 37% of Canadian pharmacy claimants over a 1-year follow-up period, and patients had overlapping supplies of vitamin D for only 24% of their days on these antiresorptive agents. These findings underscore the potential importance of management strategies that deliver vitamin D or otherwise promote its use in concert with antiresorptive agents.

Acknowledgment

Declaration of interest: The study was funded by Merck & Co., Inc., Whitehouse Station, NJ, USA. QZ, MCM, PM, and SSS are employees of and/or shareholders (stock and stock options) in Merck & Co. and Merck Frosst Canada. Assistance in manuscript preparation was provided by Stephen W. Gutkin, Rete Biomedical Communications Corp., Ridgewood, NJ, USA.

References

1. Erben RG. Vitamin D analogs and bone. J Musculoskelet Neuronal Interact 2001;2:59-69

2. Montero-Odasso M, Duque G. Vitamin D in the aging musculoskeletal system: an authentic strength preserving hormone. Mol Aspects Med 2005;26:203-19

3. Bischoff-Ferrari HA, Conzelmann M, Stahelin HB, et al. Is fall prevention by vitamin D mediated by a change in postural or dynamic balance? Osteoporos Int 2006; 17:656-63

4. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al. Effect of vitamin D on falls: a meta-analysis. JAMA 2004;291:1999- 2006

5. Staud R. Vitamin D: more than just affecting calcium and bone. Curr Rheumatol Rep 2005;7:356-64

6. Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ 2003;81:646-56

7. Blake AJ, Morgan K, Bendall MJ, et al. Falls by elderly people at home: prevalence and associated factors. Age Ageing 1988;17:365- 72

8. Cummings SR, Nevitt MC. Falls. N Engl J Med 1994)331:872-3

9. Melton LJ 111. Who has osteoporosis? A conflict between clinical and public health perspectives. J Bone Miner Res 2000; 15: 2309-14

10. Melton LJ III. Adverse outcomes of osteoporosis fractures in the general population. J Bone Miner Res 2003; 18:1139-41

11. Cummings SR, Melton IJ III. Epidemiology and outcomes of osteoporotic fractures. Lancet 2002;359:1761-7

12. Malavolta N, Pratelli L, Frigato M, et al. The relationship of vitamin D status to bone mineral density in an Italian population of postmenopausal women. Osteoporos Int 2005; 16:1691-7

13. Bischoff-Ferrari HA, Dietrich T, Orav EJ, et al. Positive association between 25-hydroxy vitamin D levels and bone mineral density: a population-based study of younger and older adults. AmJ Med 2004; 116:634-9

14. von Muhlen DG, Greendale GA, Garland CF, et al. Vitamin D, parathyroid hormone levels and bone mineral density in community- dwelling older women: the Rancho Bernardo Study. Osteoporos Int 2005; 16:1721-6

15. Larsen ER, Mosekilde L, Foldspang A. Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study. J Bone Miner Res 2004; 19:370-8

16. MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest 1985;76:1536-8

17. Holick MF, Matsuoka LY, Wortsman J. Age, vitamin D, and solar ultraviolet. Lancet 1989;2:1104-5

18. Koster JC, Hackeng WH, Mulder H. Diminished effect of etidronate in vitamin D deficient osteopenic postmenopausal women. Fur J Clin Pharmacol 1996;51:145-7

19. Holick MF. The vitamin D epidemic and its health consequences. J Nutr 2005; 135:27395-485

20. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo CHn Proc 2006;81:353-73

21. Simonelli C, Weiss TW, Morancey J, et al. Prevalence of vitamin D inadequacy in a minimal trauma fracture population. Curr Med Res Opin 2005;21:1069-74

22. Moniz C, Dew T, Dixon T. Prevalence of vitamin D inadequacy in osteoporotic hip fracture patients in London. Curr Med Res Opin 2005;21:1891-4

23. Solomon DH, Morris C, Chcng H, et al. Medication use patterns for osteoporosis: an assessment of guidelines, treatment rates, and quality improvement interventions. Mayo Clin Proc 2005;80:194-2U2

24. Huybrechts KF, Ishak KJ, Caro JJ. Assessment of compliance with osteoporosis treatment and its consequences in a managed care population. Bone 2006;38:922-8

25. Bayly JR, Hollands RD, Riordan-Jones SE, et al. Prescribed vitamin D and calcium preparations in patients treated with bone remodelling agents in primary care: a report of a pilot study. Curr Med Res Opin 2006;22:131-7

26. Ness J, Aronow WS, Newkirk E, et al. Underutilization of calcium and vitamin D by older adults in a large general internal medicine practice. Am J Ther 2005; 12:113-6

27. National Institutes of Health. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785-95

28. Kamel HK. Underutilization of calcium and vitamin D supplements in an academic long-term care facility. J Am Med Dir Assoc 2004;5:98-100

29. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther 2001;23:1296-1310

30. Cramer JA, Amonkar MM, Hebborn A, et al. Compliance and persistence with bisphosphonate dosing regimens among women with postmenopausal osteoporosis. Curr Med Res Opin 2005;21:1453-60

31. Antoniucci DM, Vittinghoff E, Blackwell T, et al. Vitamin D insufficiency does not affect bone mineral density response to raloxifene. J Clin Endocrinol Metab 2005;90:4566-72

32. Heaney RP, Draper MW. Raloxifene and estrogen: comparative bone-remodeling kinetics. J Clin Endocrinol Metab 1997;82:3425-9

33. Grant AM, Avenell A, Campbell MK, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 2005;365:1621-8

34. Porthouse J, Cockayne S, King C, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ 2005;330:1003

David A. Hanley(a), Qiaoyi Zhang(b), Marie-Claude Meilleurc, Panagiotis Mavros(b) and Shuvayu S. Sen(b)

a Departments of Medicine and Community Health Sciences and Oncology, Faculty of Medicine, University of Calgary, Alberta, Canada

b Outcomes Research, Merck & Co., Inc., Whitehouse Station, NJ. USA

c Merck Frosst Canada, Quebec, Canada Address for correspondence: Shuvayu S. Sen, PhD, Outcomes Research, WHHM, 1 Merck Drive, WS 2E- 85, Whitehouse Station, NJ 08889, USA Tel.: +1 908 423 3934; Fax: +1 908 735 1688; shuvayu_sen@merck.com

Copyright Librapharm Jun 2007

(c) 2007 Current Medical Research and Opinion. Provided by ProQuest Information and Learning. All rights Reserved.