Calcium supplements increase heart attack risk - BBC article

Discussion in 'Fibromyalgia Main Forum' started by KerryK, Jul 29, 2010.

  1. KerryK

    KerryK Member

    http://www.bbc.co.uk/news/health-10805062
  2. TigerLilea

    TigerLilea Active Member

    Doctor Oz talked a bit about calcium supplements on one of his shows. According to him if you take calcium supplements without taking either magnesium or Vitamin D3, then the calcium does nothing to help build bone and goes straight to the heart. When you take the combination of calcium and the magnesium or Vitamin D3, then the calcium gets used more by the bone and doesn't damage the heart.
  3. KerryK

    KerryK Member

    Since it seems one never sees calcium supplements without d3, I would bet that Dr. Oz is mistaken, especially since this study came out after the Dr. Oz statement. Further, I had read some time ago that a study showed that Calcium supplements for osteoporosis(sic?) were worthless.
  4. SnooZQ

    SnooZQ New Member

    as I understand it, excluded those who took calcium w/D. It looked at 11 studies of those who took calcium (only) supps. The conclusions are based on the findings of 5/11 studies.

    As far as calcium always coming with D -- not so. Many, many women I know simply take Tums or any old cheap form of cal carbonate. No D3 with that.

    In my town it's very easy to find calcium only tablets at grocery stores, Walmart, Target, etc. Even the chain drugstores have quite a few Ca only supps. Higher-quality supps with D3 can sometimes also often be found at these stores, however generally at a significantly higher cost-per-tablet.
    [This Message was Edited on 07/30/2010]
  5. KerryK

    KerryK Member

    At least from the BBC report, the authors are silent on D3. However, the researchers say that doctors should review their rationale for prescribing the supplements. I doubt many doctors would suggest calcium without d3. Further, things must be different in the U.S. than here, because calcium with d3 tablets are very cheap and usually the only way one can buy it.
  6. SnooZQ

    SnooZQ New Member

    According to Web MDs analysis, as well as that of another med site I frequent, the researchers did not include those who took calcium plus D.

    http://www.webmd.com/heart/news/20100729/study-calcium-may-increase-heart-attack-risk

    >>> Study: Calcium May Increase Heart Attack Risk
    WebMD Health News

    July 29, 2010 … Researcher Ian Reid, MD, of New Zealand’s University of Aukland says it is time to reassess the role of calcium supplementation for the treatment and prevention of osteoporosis.

    “I think we need to seriously consider whether calcium supplementation is a good thing for most people, given that it is associated with a very small decrease in fracture risk,” he tells WebMD.

    Just over two years ago, Reid’s own research unexpectedly showed a slight increase in heart attacks among healthy, older women who took calcium supplements to prevent fractures.
    “Our hypothesis when we started the study was that calcium would protect the heart,” he says.

    In an effort to confirm the earlier findings, Reid and colleagues from the University of Aberdeen in the U.K. and Dartmouth University in the U.S. combined and analyzed the findings from 11 randomized trials in which participants took calcium supplements (500 milligrams or more per day) without vitamin D.

    After adjusting for differences in study design, the researchers concluded that calcium supplementation was associated with a modest increase in risk for heart attacks, but not for strokes or death from heart disease. …

    Goldberg, who is a spokeswoman for the American Heart Association, echoes concerns about the newly published analysis.
    “It is hard to understand how calcium could increase the risk for heart attack and not for stroke or death if this association is real,” she said. >>>


    [This Message was Edited on 07/30/2010]
  7. TigerLilea

    TigerLilea Active Member

    I've never bought calcium supplements that had Vitamin D3 in them. They were straight calcium. The study doesn't mention anything about magnesium or Vitamin D3.

    I'm ETA that as Dr. Oz is a cardiologist and considered one of the best in the US, I would imagine that he has his facts correct.[This Message was Edited on 07/30/2010]
  8. skeptik2

    skeptik2 Member

    I read this too...and then, I saw a small paragraph that said something to
    the effect that if one does NOT eat calcium foods (dairy, etc.), then the
    supplements do not seem to do as much harm as in those who do eat
    up to 830 mg of calcium per day.

    I had to reread this article twice, and am not sure I really saw that
    because my brain is not working well lately, so could someone recheck
    that?

    Thanks,

    skeptik2
  9. KerryK

    KerryK Member

    It is interesting that the study seems to have ignored calcium with D3. However, even if you accept that D3 is a useful add-on, you would have to assume that ALL the calcium goes to the bones and none to the cardiovascular system if you still believe in it. Further, one could reason that if one's blood levels of vit. D are not deficient, then a D3 supplement would make no difference. So, for most study participants, it is likely irrelevant that D3 was not part of the study. In any case, there seems to be good reason to be cautious of any calcium supplements and the burden of proof otherwise is on those advocating them. Also, there was a recent study that calcium supplements do nothing for bone disease. So, why bother?
  10. TigerLilea

    TigerLilea Active Member

    Hi Kerry - Here in Vancouver, you can buy calcium supplements that do not contain D3 or magnesium. Aviva, who are in Winnipeg, also sell plain calcium.
  11. TigerLilea

    TigerLilea Active Member

    It's true that calcium supplements do nothing for preventing thinning bones. However, calcium supplements along with magnesium and/or vitamin D3 supplements do help build and maintain bone. In the past it wasn't known that calcium used alone was worthless. This is a recently new discovery. So for someone who doesn't get much dietary calcium, a combination of calcium and magnesium/Vitamin D3 is worth bothering with.
  12. JaneSmith

    JaneSmith New Member

    Thank you for writing. I was worried so I called my doctor. Unfortunately, he doesn't know that you have to add the mag. and vit d. I knew that. And that's what I've been doing for year's without the doctor telling me. Glad you clarified that bit of important information for all of us!

    Jane
  13. JaneSmith

    JaneSmith New Member

    No disrespect on your post. Are you very sure that calcium supplements are worthless? I can't take Fosamax and I do eat well. However, professionals that I speak with want me to take the calcium supplemments.

    Jane


    Thank you for the info.[This Message was Edited on 08/02/2010]
  14. KerryK

    KerryK Member

    It isn't disrespectful to disagree.

    Anyway here is some evidence. First, the BBC article itself mentions that supplements are of dubious benefit. In addition, there is the following New England Journal of Medicine article on a large placebo study using calcium and D3. Again, minimal gains in bone density yet non-statistically significant improvement in fractures. There are other studies that confirm this finding. One has to consider that against the known risks. It seems many doctors suggest supplementing out of unproven assumptions and faint hope.

    http://www.nejm.org/doi/pdf/10.1056/NEJMoa055218

    n engl j med 354;7 www.nejm.org february 16, 2006 669
    The new england
    journal of medicine
    established in 1812 february 16, 2006 vol. 354 no. 7
    Calcium plus Vitamin D Supplementation
    and the Risk of Fractures
    Rebecca D. Jackson, M.D., Andrea Z. LaCroix, Ph.D., Margery Gass, M.D., Robert B. Wallace, M.D.,
    John Robbins, M.D., Cora E. Lewis, M.D., Tamsen Bassford, M.D., Shirley A.A. Beresford, Ph.D., Henry R. Black, M.D.,
    Patricia Blanchette, M.D., Denise E. Bonds, M.D., Robert L. Brunner, Ph.D., Robert G. Brzyski, M.D.,
    Bette Caan, Dr.P.H., Jane A. Cauley, Dr.P.H., Rowan T. Chlebowski, M.D., Steven R. Cummings, M.D.,
    Iris Granek, M.D., Jennifer Hays, Ph.D., Gerardo Heiss, M.D., Susan L. Hendrix, D.O., Barbara V. Howard, Ph.D.,
    Judith Hsia, M.D., F. Allan Hubbell, M.D., Karen C. Johnson, M.D., Howard Judd, M.D., Jane Morley Kotchen, M.D.,
    Lewis H. Kuller, M.D., Robert D. Langer, M.D., Norman L. Lasser, M.D., Marian C. Limacher, M.D., Shari Ludlam, M.P.H.,
    JoAnn E. Manson, M.D., Karen L. Margolis, M.D., Joan McGowan, Ph.D., Judith K. Ockene, Ph.D.,
    Mary Jo O’Sullivan, M.D., Lawrence Phillips, M.D., Ross L. Prentice, Ph.D., Gloria E. Sarto, M.D.,
    Marcia L. Stefanick, Ph.D., Linda Van Horn, Ph.D., Jean Wactawski-Wende, Ph.D., Evelyn Whitlock, M.D.,
    Garnet L. Anderson, Ph.D., Annlouise R. Assaf, Ph.D., and David Barad, M.D.,
    for the Women’s Health Initiative Investigators*
    ABSTRACT
    Address reprint requests to Dr. Jackson
    at the Division of Endocrinology, Ohio
    State University, 485 McCampbell, 1581
    Dodd Dr., Columbus, OH 43210, or at
    jackson.20@osu.edu.
    *The Women’s Health Initiative investigators
    are listed in Appendix 1. The authors’
    affiliations are listed in Appendix 2.
    N Engl J Med 2006;354:669-83.
    Copyright © 2006 Massachusetts Medical Society.
    Background
    The efficacy of calcium with vitamin D supplementation for preventing hip and other
    fractures in healthy postmenopausal women remains equivocal.
    Methods
    We recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already
    enrolled in a Women’s Health Initiative (WHI) clinical trial. We randomly assigned
    participants to receive 1000 mg of elemental calcium as calcium carbonate with
    400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average
    follow-up period of 7.0 years. Bone density was measured at three WHI centers.
    Results
    Hip bone density was 1.06 percent higher in the calcium plus vitamin D group than
    in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants
    receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip
    fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture
    (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi
    increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence
    interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to
    the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent
    confidence interval, 0.52 to 0.97). Effects did not vary significantly according to
    prerandomization serum vitamin D levels.
    Conclusions
    Among healthy postmenopausal women, calcium with vitamin D supplementation
    resulted in a small but significant improvement in hip bone density, did not significantly
    reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov
    number, NCT00000611.)
    The New England Journal of Medicine as published by New England Journal of Medicine.
    Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
    Copyright © 2006 Massachusetts Medical Society. All rights reserved.
    The new england journal o f medicine
    670 n engl j med 354;7 www.nejm.org february 16, 2006
    O steoporosis, a major cause of injury,
    loss of independence, and death,1,2
    contributes to more than 300,000 hip
    fractures in the United States annually.3 Observational
    evidence4 and data from randomized clinical
    trials5,6 suggest that calcium or vitamin D
    supplements or both may slow bone loss5,6 and
    reduce the risk of falls7,8 in postmenopausal and
    elderly women. However, evidence from trials,5,9-19
    observational studies,20,21 and meta-analyses6,22,23
    of calcium and vitamin D supplementation with
    respect to hip and other fractures is limited. In
    two recent randomized trials, calcium plus vitamin
    D supplements (1000 mg of calcium and 800
    IU of vitamin D3) did not reduce the risk of nonvertebral
    fractures among older women.18,19 When
    the calcium plus vitamin D trial of the Women’s
    Health Initiative (WHI) was designed, in the early
    1990s, guidelines recommended daily intakes
    of 800 to 1200 mg of calcium with 400 IU of vitamin
    D for the prevention of osteoporosis. Many
    American women consumed less.
    In this context, the WHI calcium with vitamin
    D trial was designed to test the primary hypothesis
    that postmenopausal women randomly
    assigned to calcium plus vitamin D supplementation
    would have a lower risk of hip fracture and,
    secondarily, of all fractures than women assigned
    to placebo.24 Another secondary hypothesis was
    that women receiving calcium with vitamin D
    supplementation would have a lower rate of colorectal
    cancer than those receiving placebo; the results
    of that investigation are reported elsewhere
    in this issue of the Journal.25
    Methods
    Participants and Study Design
    Participants enrolled in the WHI Dietary Modification
    trial, WHI Hormone Therapy trials, or both
    were invited to join the calcium with vitamin D
    trial at their first or second annual follow-up visit.
    Detailed descriptions of the eligibility criteria and
    recruitment methods have been published previously.
    24
    Eligible women were 50 to 79 years of age at
    the initial screening and had no evidence of a
    medical condition associated with a predicted
    survival of less than three years and no safety,
    adherence, or retention risks. Exclusion criteria
    included hypercalcemia, renal calculi, corticosteroid
    use, and calcitriol use. Personal supplemental
    calcium (up to 1000 mg per day) and vitamin
    D (up to 600 IU per day) were allowed. In
    1999, after the publication of reports from the
    Institute of Medicine,26,27 the upper limit of personal
    vitamin D intake was raised to 1000 IU.
    The calcium with vitamin D trial permitted the
    use of bisphosphonates and calcitonin. Use of
    estrogen (with or without a progestin) was according
    to randomization among women in the
    Hormone Therapy trials. Independent use of hormone
    therapy or selective estrogen-receptor modulators
    was permitted for women in the Dietary
    Modification trial.
    Eligible women were randomly assigned in a
    double-blind fashion to receive supplements or
    placebo (provided by GlaxoSmithKline) in equal
    proportions with use of a permuted-block algorithm
    stratified according to clinical center and
    age. Active tablets, chewable or swallowable (after
    July 1997), contained 500 mg of elemental calcium
    (as calcium carbonate) and 200 IU of vitamin
    D3. Participants were instructed to take two
    tablets per day in divided doses and with meals
    to maximize absorption. Cross-sectional comparison
    of 25-hydroxyvitamin D levels from 227
    women taking active supplements and 221 women
    taking placebo two years after randomization
    revealed that the 25-hydroxyvitamin D level was
    28 percent higher among the women assigned to
    active calcium plus vitamin D than among those
    assigned to placebo.
    The protocol was approved by the institutional
    review board at each participating institution.
    Written informed consent was obtained from
    each woman at the calcium with vitamin D randomization
    visit. The WHI Investigators and National
    Institutes of Health sponsors all contributed
    to the design and execution of the study. All
    the authors contributed to drafts or revisions of
    the manuscript. Statistical analyses and data management
    were conducted at the WHI Clinical
    Coordinating Center, and the investigators and
    statistical team vouch for the completeness and
    veracity of the data and statistical analyses.
    Follow-up and Data Collection
    The presence and severity of symptoms, safety
    concerns, and outcomes were ascertained at annual
    clinic visits and telephone or clinic visits at
    intervening six-month intervals.24 Adherence to
    the study medication was established by weighing
    returned pill bottles during clinic visits. Par-
    The New England Journal of Medicine as published by New England Journal of Medicine.
    Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
    Copyright © 2006 Massachusetts Medical Society. All rights reserved.
    calcium, vitamin d, and the risk of fractures
    n engl j med 354;7 www.nejm.org february 16, 2006 671
    ticipants were followed for major outcomes, regardless
    of their adherence to the study medication,
    until death, loss to follow-up, or study close-out.
    Risk factors for fracture were assessed by questionnaire,
    interview, and clinical examination.
    The total daily calcium intake before randomization
    was defined as the sum of the following: the
    dietary calcium intake (assessed with the use of
    a modification of the Block food-frequency questionnaire28),
    the intake of calcium from supplements
    in the previous two weeks, and the intake
    of calcium from prescription medications (assessed
    through an interviewer-administered medication
    survey). Total vitamin D intake was similarly determined
    on the basis of diet and supplement use.
    Discontinuation of Study Medications
    During the trial, intolerable gastrointestinal symptoms
    were managed without unblinding by reducing
    the number of times per day or days per
    week that the study medication was taken. If renal
    calculi or hypercalcemia developed or renal
    dialysis was required, calcium with vitamin D
    study medication was permanently discontinued,
    according to the protocol.
    Ascertainment of Outcomes
    Total fractures were defined as all reported clinical
    fractures other than those of the ribs, sternum,
    skull or face, fingers, toes, and cervical vertebrae.
    All included fractures were verified by
    review of radiologic, magnetic resonance imaging,
    or operative reports by centrally trained and blinded
    physician adjudicators at each clinical center.
    24 Final adjudication of hip fractures was performed
    centrally by blinded adjudicators; agreement
    between central and local adjudication was 94
    percent.
    A subgroup of 2431 women (1230 in the calcium
    with vitamin D group and 1201 in the placebo
    group) at 3 of the 40 clinical centers (Pittsburgh;
    Birmingham, Ala.; and Tucson, Ariz.)
    underwent dual-energy x-ray absorptiometry of
    the lumbar spine (L2, L3, and L4), total hip, and
    total body (QDR 2000, QDR 2000+, or QDR
    4500W; Hologic). Bone mineral density was measured
    at the calcium with vitamin D randomization
    visit and at annual visits 3, 6, and 9 according
    to standard protocols.24 Three Hologic phantoms
    (spine, hip, and linearity) were exchanged among
    these three centers and measured in array mode
    five times, once each day for five consecutive days,
    to assess cross-calibration. Spine, hip, and linearity
    phantoms were in close agreement (interscanner
    variability, <1.5 percent for the spine, 4.8 percent
    for the hip, and 1.7 percent for linearity).
    Analysis of Vitamin D Levels
    Blood specimens, which were obtained after an
    overnight fast, were collected at the randomization
    visit. To determine whether the effect of calcium
    plus vitamin D on the risk of fracture varied
    according to prerandomization 25-hydroxyvitamin
    D levels, a nested case–control study was performed
    with all adjudicated cases of hip, spine,
    and lower arm or wrist fracture used as cases
    (357 case–control pairs for hip fracture and 1491
    pairs for total fracture). Controls were free of fracture
    for the duration of the study and were individually
    matched to case participants according to
    age, latitude of the clinical center, race or ethnic
    group, and date of venipuncture. Levels of 25-
    hydroxyvitamin D were measured with the use of
    the DiaSorin Liaison chemiluminescent immunoassay
    system at DiaSorin headquarters (Stillwater,
    Minn.) in one continuous batch with blinded
    control runs at periodic intervals (coefficient of
    variation, 11.8 percent).
    Statistical Analysis
    All primary outcomes were analyzed on a timeto-
    event basis according to the intention-to-treat
    principle. We present both the total number of
    events and the annualized percentage for these
    fracture rates for each group. Comparisons are
    represented with hazard ratios and nominal 95
    percent confidence intervals from Cox proportional-
    hazards models, stratified according to
    age group, prior fracture, and randomization status
    (randomly assigned to active hormone therapy
    or placebo, dietary intervention vs. dietary control,
    or both) in the Hormone Therapy and Dietary
    Modification trials.
    To assess whether the effect of calcium with
    vitamin D on the risk of fracture varied according
    to baseline levels of risk factors, the same Cox
    proportional-hazards models were extended. In
    formal tests for interaction, continuous variables
    were used whenever possible. Fifteen participant
    characteristics were examined for each of four
    fracture outcomes. Up to three statistically significant
    interaction tests (P<0.05) would be expected
    on the basis of chance alone.
    To examine the effect of nonadherence (to ac-
    The New England Journal of Medicine as published by New England Journal of Medicine.
    Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
    Copyright © 2006 Massachusetts Medical Society. All rights reserved.
    The new england journal o f medicine
    672 n engl j med 354;7 www.nejm.org february 16, 2006
    Table 1. Characteristics of the Participants in the Calcium with Vitamin D Trial at the Time of the WHI Screening,
    According to Randomly Assigned Group.*
    Characteristic
    Calcium + Vitamin D
    (N = 18,176)
    Placebo
    (N = 18,106)
    Age at screening
    Mean — yr 62.4±7.0 62.4±6.9
    50 to 59 yr — no. (%) 6,728 (37.0) 6,694 (37.0)
    60 to 69 yr — no. (%) 8,275 (45.5) 8,245 (45.5)
    70 to 79 yr — no. (%) 3,173 (17.5) 3,167 (17.5)
    Race or ethnic group — no. (%)†
    White 15,047 (82.8) 15,106 (83.4)
    Black 1,682 (9.3) 1,635 (9.0)
    Hispanic 789 (4.3) 718 (4.0)
    American Indian or Native American 77 (0.4) 72 (0.4)
    Asian or Pacific Islander 369 (2.0) 353 (1.9)
    Unknown or not identified 212 (1.2) 222 (1.2)
    Family history of fracture after 40 yr of age — no. (%) 6,835 (37.6) 6,692 (37.0)
    History of fracture — no. (%)
    At any age 6,311 (34.7) 6,228 (34.4)
    At age ?55 yr 1,948 (10.7) 1,968 (10.9)
    No. of falls in previous 12 mo — no. (%)
    None 11,193 (61.6) 11,200 (61.9)
    1 3,421 (18.8) 3,386 (18.7)
    2 1,462 (8.0) 1,426 (7.9)
    ?3 732 (4.0) 701 (3.9)
    Weight <58 kg — no. (%) 1,660 (9.1) 1,676 (9.3)
    Body-mass index
    Mean 29.1±5.9 29.0±5.9
    <25 — no. (%) 4,745 (26.1) 4,833 (26.7)
    25 to <30 — no. (%) 6,472 (35.6) 6,483 (35.8)
    ?30 — no. (%) 6,867 (37.8) 6,695 (37.0)
    Physical activity
    Mean — MET/wk 10.7±12.7 10.6±12.4
    0 to 3.00 MET/wk — no. (%) 5,517 (30.4) 5,478 (30.3)
    >3.00 to <11.75 MET/wk — no. (%) 5,463 (30.1) 5,477 (30.2)
    ?11.75 MET/wk — no. (%) 5,566 (30.6) 5,493 (30.3)
    Calcium supplementation ?500 mg/day — no. (%) 5,192 (28.6) 5,313 (29.3)
    Total calcium intake (supplements, diet, and medications)
    Mean — mg/day 1148±654 1154±658
    <800 mg/day — no. (%) 6,104 (33.6) 6,003 (33.2)
    800 to <1200 mg/day — no. (%) 4,715 (25.9) 4,655 (25.7)
    ?1200 mg/day — no. (%) 7,002 (38.5) 7,095 (39.2)
    Total vitamin D intake (supplements and diet)
    Mean — IU/day 365±265 368±266
    <200 IU/day 6,827 (37.6) 6,671 (36.8)
    200 to <400 IU/day 3,379 (18.6) 3,423 (18.9)
    400 to <600 IU/day 4,188 (23.0) 4,295 (23.7)
    ?600 IU/day 3,427 (18.9) 3,364 (18.6)
    The New England Journal of Medicine as published by New England Journal of Medicine.
    Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
    Copyright © 2006 Massachusetts Medical Society. All rights reserved.
    calcium, vitamin d, and the risk of fractures
    n engl j med 354;7 www.nejm.org february 16, 2006 673
    Table 1. (Continued.)
    Characteristic
    Calcium + Vitamin D
    (N = 18,176)
    Placebo
    (N = 18,106)
    Solar irradiance of region‡
    Mean 382±60 382±60
    300 to 325 Langleys 5,366 (29.5) 5,351 (29.6)
    350 Langleys 3,920 (21.6) 3,880 (21.4)
    375 to 380 Langleys 2,012 (11.1) 2,009 (11.1)
    400 to 430 Langleys 3,018 (16.6) 3,015 (16.7)
    475 to 500 Langleys 3,860 (21.2) 3,851 (21.3)
    Alcohol use — no. (%)
    None 1,863 (10.2) 1,891 (10.4)
    Use in the past 3,192 (17.6) 3,209 (17.7)
    <1 drink/mo 2,529 (13.9) 2,520 (13.9)
    <1 drink/wk 3,863 (21.3) 3,758 (20.8)
    1 to <7 drinks/wk 4,683 (25.8) 4,706 (26.0)
    ?7 drinks/wk 1,910 (10.5) 1,900 (10.5)
    Smoking — no. (%)
    Never 9,325 (51.3) 9,428 (52.1)
    Past 7,255 (39.9) 7,133 (39.4)
    Current 1,405 (7.7) 1,356 (7.5)
    Enrollment in Dietary Modification trial — no. (%)
    Not enrolled 5,582 (30.7) 5,490 (30.3)
    Assigned to intervention 4,767 (26.2) 4,878 (26.9)
    Assigned to control 7,827 (43.1) 7,738 (42.7)
    Enrollment in Hormone Therapy trial — no. (%)
    Not enrolled 10,122 (55.7) 10,071 (55.6)
    Assigned to active hormone therapy 4,039 (22.2) 4,078 (22.5)
    Assigned to placebo 4,015 (22.1) 3,957 (21.9)
    Use of hormone therapy — no. (%)§
    Never 5,814 (32.0) 5,690 (31.4)
    Past 3,004 (16.5) 2,932 (16.2)
    Current 9,358 (51.5) 9,484 (52.4)
    Hip BMD at annual visit 1 — total no.¶ 1,230 1,201
    Mean 0.87±0.14 0.86±0.14
    Hip T score at annual visit 1 — total no.¶ 1,230 1,201
    Mean ?0.65±1.03 ?0.77±1.05
    T score above ?1.0 757 (61.5) 694 (57.8)
    T score below ?1.0 and above ?2.5 436 (35.4) 459 (38.2)
    T score below ?2.5 37 (3.0) 48 (4.0)
    * Plus–minus values are means ±SD. Because of rounding or missing data, not all percentages total 100. MET denotes
    metabolic equivalent, and BMD bone mineral density.
    † Race or ethnic group was self-reported.
    ‡ The Langley is a unit of solar radiance and relates to the amount that reaches a given area of the earth’s surface. The
    information is from national weather data on total solar irradiance in the United States and is adapted from Garland
    and Garland.30
    § Values reflect hormone-therapy use during year 1 of the clinical trial, including exposure in the Hormone Therapy trials.
    ¶ The data are from the subgroup of women in whom bone mineral density was measured. The T score represents the
    bone mineral density of an individual subject as compared with the mean (±SD) score in a young, healthy population.
    The New England Journal of Medicine as published by New England Journal of Medicine.
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    Copyright © 2006 Massachusetts Medical Society. All rights reserved.
    The new england journal o f medicine
    674 n engl j med 354;7 www.nejm.org february 16, 2006
    tive supplements or placebo), sensitivity analyses
    were conducted in which participants were allowed
    to contribute follow-up time until six months after
    the first visit at which nonadherence, defined
    as use of less than 80 percent of the study medication,
    was detected. Full-adherence hazard ratios
    were also estimated with inverse probability of
    censoring weighted estimators with adjustment for
    10 covariates associated with adherence.29
    Changes in bone mineral density during follow-
    up were calculated as mean percent differences
    (and standard errors) from bone mineral
    density at the time of enrollment in the calcium
    plus vitamin D trial. Linear regression was used
    to compare rates of change in bone mineral density
    between the groups, after adjustment for
    clinical center and race or ethnic group.
    The calcium with vitamin D trial was designed
    to have 85 percent power to detect an intervention
    effect of 18 percent for hip fracture, assuming
    a sample size of 35,000 women and an annual
    hip-fracture rate in the placebo group of 33.6 per
    10,000 persons per year. The power to detect an
    intervention effect of similar magnitude for total
    fracture was greater than 99 percent.
    Results
    Baseline Characteristics
    Between 1995 and 2000, 36,282 women were randomly
    assigned in the calcium with vitamin D
    trial: 18,176 were assigned to active supplementation,
    and 18,106 to placebo. Demographic characteristics,
    health behavior, and medical history
    were well balanced between the groups at baseline
    (Table 1). The women had a mean age of 62
    years and a mean body-mass index (the weight in
    kilograms divided by the square of the height in
    meters) of 29. Sixteen percent were not white.
    The average calcium intake was approximately
    1150 mg per day. More than half the women (52
    percent) were taking hormone therapy (10,725
    reported personal use of hormones, and 8117 had
    been randomly assigned to receive active-hormone
    study medication). The rate of use of other osteoporosis
    medications was 1 percent (1 used a selective
    estrogen-receptor modulator, 366 bisphosphonate,
    and 33 calcitonin).
    Retention and Adherence
    At the termination of the trial, on March 31, 2005,
    1551 participants (4.3 percent) had died and 2.7
    percent had withdrawn or had been lost to follow-
    up (Fig. 1). The rate of adherence (defined as
    use of 80 percent or more of the assigned study
    medication) ranged from 60 to 63 percent during
    the first three years of follow-up, with an additional
    13 to 21 percent of the participants taking
    at least half of their study pills. At the end of the
    trial, 76 percent were still taking the study medication,
    and 59 percent were taking 80 percent or
    more of it.
    Bone Mineral Density
    Women receiving calcium with vitamin D supplements
    had greater preservation of total-hip bone
    mineral density at annual visits 3, 6, and 9 than
    women assigned to placebo (Fig. 2). The mean
    differences between the treatment groups, all in
    favor of calcium with vitamin D, were 0.59 per-
    36,282 Women randomly assigned
    33,070 in year 1
    3,212 in year 2
    68,132 Women in the WHI clinical trials
    27,347 in the HT trial
    48,835 in the DM trial
    31,850 Women ineligible
    13,481 Were not interested in CaD
    12,765 Refused consent
    3,230 Were not eligible
    2,226 Eligibility criteria unknown
    148 Died in year 1
    18,176 Women in CaD group
    1,230 Women in BMD subgroup
    Status at close-out
    16,936 Alive and outcomes data
    submitted in last 18 mo
    352 Withdrew
    144 Lost to follow-up
    744 Died
    Status at close-out
    16,815 Alive and outcomes data
    submitted in last 18 mo
    332 Withdrew
    152 Lost to follow-up
    807 Died
    18,106 Women in placebo group
    1,201 Women in BMD subgroup
    Figure 1. Profile of the Calcium with Vitamin D Trial of the Women’s Health
    Initiative (WHI).
    HT denotes hormone therapy, DM dietary modification, CaD calcium with
    vitamin D, and BMD bone mineral density.
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    calcium, vitamin d, and the risk of fractures
    n engl j med 354;7 www.nejm.org february 16, 2006 675
    cent at annual visit 3, 0.86 percent at annual visit
    6, and 1.06 percent at annual visit 9. Nonsignificant
    differences favoring the calcium with vitamin
    D group were observed in spine and wholebody
    bone mineral density.
    Hip and Other Fractures
    During a mean of 7.0 years of follow-up, there
    were 2102 fractures (including 175 hip fractures)
    among women assigned to calcium with vitamin
    D and 2158 fractures (including 199 hip fractures)
    among women assigned to placebo (Table 2).
    Annualized fracture rates per 10,000 person-years
    in the calcium with vitamin D and placebo groups,
    respectively, were as follows: hip fracture, 14 and
    16; fracture of the lower arm or wrist, 44 and 44;
    clinical vertebral fracture, 14 and 15; and total
    fractures, 164 and 170.
    1067
    1079
    1181
    1162
    949
    933
    406
    415
    Mean Change in BMD
    from Year 1 (%)
    5
    3
    2
    0
    4
    1
    ¡2
    ¡1
    Year 1 Year 3 Year 6 Year 9
    Annual Visit
    CaD
    Placebo
    Mean Change in BMD
    from Year 1 (%)
    5
    3
    2
    0
    4
    1
    ¡2
    ¡1
    Year 1 Year 3 Year 6 Year 9
    Annual Visit
    CaD Placebo
    Mean Change in BMD
    from Year 1 (%)
    5
    3
    2
    0
    4
    1
    ¡2
    ¡1
    Year 1 Year 3 Year 6 Year 9
    Annual Visit
    CaD Placebo
    P<0.001
    P<0.001
    P=0.01
    P=0.11
    P=0.33
    P=0.41
    P=0.02
    P=0.16
    P=0.35
    A
    B
    Total Hip
    Total Spine
    C Whole Body
    Minimum No.
    CaD
    Placebo
    Figure 2. Hip, Spine, and Total-Body Bone Mineral
    Density (BMD).
    P values for the comparison between the group
    assigned to calcium with vitamin D supplementation
    and the placebo group were <0.001, <0.001, and 0.01
    at years 3, 6, and 9, respectively, for total-hip values
    and 0.02 at year 3 for whole-body values, according to
    linear models adjusted for clinical center and race or
    ethnic group. The numbers of participants shown
    below the graphs are the minimum sample sizes for
    comparison between the visit year and year 1.
    Table 2. Effect of Calcium with Vitamin D Supplementation on Clinical
    Outcomes, According to Randomly Assigned Group.*
    Analysis
    Calcium +
    Vitamin D Placebo
    Hazard Ratio
    (95% CI)†
    Intention-to-treat analysis
    Follow-up time — yr 7.0±1.4 7.0±1.4
    Rate of fracture — no. of cases
    (annualized %)
    Hip 175 (0.14) 199 (0.16) 0.88 (0.72–1.08)
    Clinical vertebral 181 (0.14) 197 (0.15) 0.90 (0.74–1.10)
    Lower arm or wrist 565 (0.44) 557 (0.44) 1.01 (0.90–1.14)
    Total 2102 (1.64) 2158 (1.70) 0.96 (0.91–1.02)
    Analysis excluding follow-up
    time for participants
    6 mo after nonadherence
    detected
    Follow-up time — yr 3.8±2.9 3.9±2.9
    Rate of fracture — no. of cases
    (annualized %)
    Hip 68 (0.10) 99 (0.14) 0.71 (0.52–0.97)
    Clinical vertebral 91 (0.13) 104 (0.15) 0.89 (0.67–1.19)
    Lower arm or wrist 312 (0.45) 308 (0.43) 1.05 (0.90–1.23)
    Total 1119 (1.63) 1222 (1.72) 0.94 (0.87–1.02)
    * Plus–minus values are means ±SD. CI denotes confidence interval.
    † The hazard ratios are for the group assigned to calcium with vitamin D as
    compared with the placebo group. Hazard ratios, 95 percent confidence intervals,
    and P values were calculated in Cox proportional-hazards analyses stratified
    according to age; randomization assignment in the Hormone Therapy
    and Dietary Modification trials; and presence or absence of prior fracture.
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    The new england journal o f medicine
    676 n engl j med 354;7 www.nejm.org february 16, 2006
    Women assigned to calcium with vitamin D
    supplements had a nonsignificant, 12 percent
    lower risk of hip fracture than women assigned
    to placebo (hazard ratio, 0.88; 95 percent confidence
    interval, 0.72 to 1.08). There were no significant
    reductions in clinical vertebral fracture,
    fracture of the lower arm or wrist, or total fractures
    (Table 2).
    Secondary and Subgroup Analyses
    Among women who were adherent (i.e., those who
    took at least 80 percent of their study medication),
    calcium with vitamin D supplementation resulted
    in a 29 percent reduction in hip fracture (hazard
    ratio, 0.71; 95 percent confidence interval,
    0.52 to 0.97); there were 167 cases of hip fracture
    among these women (Table 2). The hazard ratio
    Table 3. Effect of Calcium with Vitamin D Supplementation on Hip Fractures, According to Baseline Characteristics.*
    Outcome Calcium + Vitamin D Placebo Hazard Ratio (95% CI)†
    P Value for
    Interaction‡
    no. of cases (annualized %)
    Overall 175 (0.14) 199 (0.16) 0.88 (0.72–1.08)
    Age group at screening — yr 0.05
    50 to 59 29 (0.06) 13 (0.03) 2.17(1.13–4.18)
    60 to 69 53 (0.09) 71 (0.13) 0.74 (0.52–1.06)
    70 to 79 93 (0.44) 115 (0.54) 0.82 (0.62–1.08)
    Race or ethnic group§ 0.87
    White 167 (0.16) 189 (0.18) 0.89 (0.72–1.09)
    Black 3 (0.03) 4 (0.04) 0.73 (0.16–3.32)
    Hispanic 0 (0.00) 3 (0.06)
    American Indian 1 (0.19) 1 (0.20)
    Asian or Pacific Islander 4 (0.16) 1 (0.04) 2.98 (0.33–27.01)
    Unknown or not identified 0 (0.00) 1 (0.07)
    Weight 0.44
    <58 kg 23 (0.20) 21 (0.18) 1.18 (0.65–2.14)
    ?58 kg 152 (0.13) 178 (0.15) 0.86 (0.69–1.06)
    Body-mass index 0.36
    <25 69 (0.20) 66 (0.19) 1.05 (0.75–1.47)
    25 to <29 63 (0.14) 74 (0.16) 0.87 (0.62–1.22)
    ?30 43 (0.09) 59 (0.13) 0.73 (0.49–1.09)
    Smoking 0.97
    Never or past 159 (0.14) 178 (0.15) 0.90 (0.72–1.11)
    Current 14 (0.14) 16 (0.17) 0.85(0.41–1.74)
    Region by solar irradiance¶ 0.73
    300 to 325 Langleys 46 (0.12) 53 (0.14) 0.86 (0.58–1.28)
    350 Langleys 37 (0.14) 49 (0.18) 0.74 (0.48–1.14)
    375 to 380 Langleys 25 (0.18) 17 (0.12) 1.64 (0.88–3.08)
    400 to 430 Langleys 25 (0.12) 37 (0.17) 0.67 (0.40–1.11)
    475 to 500 Langleys 42 (0.16) 43 (0.16) 0.97 (0.63–1.49)
    No. of falls in past 12 mo 0.05
    0 87 (0.11) 117 (0.15) 0.74 (0.56–0.98)
    1 39 (0.16) 41 (0.17) 0.96 (0.62–1.49)
    2 22 (0.22) 19 (0.19) 1.16 (0.63–2.16)
    ?3 16 (0.32) 6 (0.12) 2.51 (0.97–6.48)
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    calcium, vitamin d, and the risk of fractures
    n engl j med 354;7 www.nejm.org february 16, 2006 677
    based on the inverse-probability weighting method
    was nearly identical. For all other fracture outcomes,
    the hazard ratios were similar to those obtained
    in the intention-to-treat analyses.
    The hazard ratio for hip fracture among women
    60 years of age or older was 0.79 (95 percent confidence
    interval, 0.64 to 0.98), with an indication
    of increased risk among women 50 to 59 years of
    age (P for interaction = 0.05) (Table 3). There was
    a lower hazard ratio among women with no falls
    than among women with at least one fall (P for
    interaction = 0.05). No other significant interactions
    were observed for any fracture outcome.
    There was no evidence that either baseline
    Table 3. (Continued.)
    Outcome Calcium + Vitamin D Placebo Hazard Ratio (95% CI)†
    P Value for
    Interaction‡
    no. of cases (annualized %)
    Physical activity 0.57
    0 to 3.00 MET 53 (0.14) 63 (0.17) 0.84 (0.58–1.21)
    >3.00 to <11.75 MET 49 (0.13) 63 (0.17) 0.81 (0.56–1.18)
    ?11.75 MET 59 (0.15) 56 (0.15) 1.04 (0.72–1.50)
    Prior fracture 0.71
    No 77 (0.11) 83 (0.12) 0.92 (0.68–1.26)
    Yes 81 (0.19) 98 (0.23) 0.84 (0.63–1.13)
    Total calcium intake: supplements,
    diet, and medications
    0.29
    <800 mg/day 58 (0.13) 71 (0.17) 0.80 (0.57–1.14)
    800 to <1200 mg/day 41 (0.12) 53 (0.16) 0.76 (0.51–1.15)
    ?1200 mg/day 73 (0.15) 68 (0.14) 1.12 (0.80–1.55)
    Total vitamin D intake: supplements
    and diet
    0.82
    <200 IU/day 65 (0.13) 65 (0.14) 0.95 (0.67–1.35)
    200 to <400 IU/day 32 (0.13) 42 (0.17) 0.79 (0.50–1.26)
    400 to <600 IU/day 34 (0.12) 46 (0.15) 0.77 (0.49–1.20)
    ?600 IU/day 41 (0.17) 39 (0.17) 1.00 (0.65–1.55)
    Hormone therapy 0.23
    Never 73 (0.18) 86 (0.22) 0.83 (0.61–1.14)
    Past 46 (0.22) 38 (0.18) 1.20 (0.78–1.85)
    Current 56 (0.08) 75 (0.11) 0.75 (0.53–1.06)
    Assignment in Hormone Therapy trial 0.07
    Placebo 67 (0.24) 61 (0.22) 1.15 (0.81–1.63)
    Active hormone therapy 28 (0.10) 49 (0.17) 0.58 (0.37–0.93)
    * Plus–minus values are means ±SD. CI denotes confidence interval, and MET metabolic equivalent.
    † The hazard ratios are for the group assigned to calcium with vitamin D as compared with placebo. Hazard ratios, 95
    percent confidence intervals, and P values were calculated in Cox proportional-hazards analyses stratified according to
    age; randomization assignment in the Hormone Therapy and Dietary Modification trials; and presence or absence of
    prior fracture.
    ‡ P values were obtained from an interaction term between treatment assignment and potential risk factor of interest in a
    Cox proportional-hazards analysis stratified according to age; status of enrollment in the Hormone Therapy and Dietary
    Modification trials, and prior fracture.
    § Race or ethnic group was self-reported.
    ¶ The Langley is a unit of solar radiance and relates to the amount that reaches a given area of the earth’s surface. The
    information is from national weather data on total solar irradiance in the United States and is adapted from Garland
    and Garland.30 Values reflect hormone-therapy use during year 1 of the clinical trial, including exposure in the
    Hormone Therapy trial.
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    The new england journal o f medicine
    678 n engl j med 354;7 www.nejm.org february 16, 2006
    levels of total calcium or total vitamin D intake
    modified the association between calcium with
    vitamin D supplementation and fracture (Table 3).
    Dietary calcium intake remained stable during
    follow-up, whereas the intake of calcium from
    supplements increased by approximately 100 mg
    daily in both treatment groups. In both treatment
    groups, participants with initially low levels of
    total calcium intake (<400 mg daily) had larger
    increases (200 mg daily) in supplemental calcium
    intake than did other participants. The effects of
    calcium with vitamin D intervention on the risk
    of hip fracture tended to be greater among participants
    not using personal calcium supplements
    during follow-up: the hazard ratio was 0.70 (95
    percent confidence interval, 0.51 to 0.98) among
    nonusers, 0.87 (95 percent confidence interval,
    0.61 to 1.24) among those taking less than 500 mg
    per day, and 1.22 (95 percent confidence interval,
    0.83 to 1.79) among those taking 500 mg or
    more per day (P for interaction = 0.11).
    Use of osteoporosis medications increased during
    follow-up, with 3890 of the women (10.7
    percent) taking alendronate, 654 (1.8 percent) taking
    risedronate, 1094 (3.0 percent) taking raloxifene,
    and 451 (1.2 percent) taking calcitonin.
    Censoring data from these participants after their
    first recorded use of these medications yielded
    hazard ratios of 0.87 (95 percent confidence interval,
    0.69 to 1.09) for hip fracture and 0.93 (95
    percent confidence interval, 0.74 to 1.18) for clinical
    vertebral fracture.
    Serum Vitamin D Levels
    In the nested case–control assessment of 25-
    hydroxyvitamin D, the mean (±SD) baseline 25-
    hydroxyvitamin D level was 46.0±22.6 nmol per
    liter among the participants who had hip fracture
    and 48.4±23.5 nmol per liter among their
    controls (P = 0.17). No statistically significant interactions
    were found between calcium with vitamin
    D supplementation and baseline 25-hydroxyvitamin
    D level with respect to either hip or total
    fractures (Table 4).
    Interaction between calcium with vitamin D
    and Hormone Therapy
    Of the women in the WHI calcium with vitamin
    D trial, 16,089 were concomitantly enrolled in the
    WHI Hormone Therapy trial, in which estrogen
    was found to have strong effects on hip and other
    fractures.31,32 The hazard ratios for hip fracture
    with calcium with vitamin D supplementation
    were 0.58 (95 percent confidence interval,
    0.37 to 0.93) among women assigned to active
    hormone therapy and 1.15 (95 percent confidence
    interval, 0.81 to 1.63) among those assigned to
    placebo (P for interaction = 0.07). When the analyses
    included both exposure in the randomized
    Hormone Therapy trial and personal use, the trend
    toward an interaction between calcium with vitamin
    D supplementation and hormone therapy with
    respect to hip fracture was no longer present.
    Safety and Tolerability
    As of March 31, 2005, there were 744 deaths in
    the calcium with vitamin D group and 807 deaths
    in the placebo group (hazard ratio, 0.91; 95 percent
    confidence interval, 0.83 to 1.01). No statistically
    significant risks or benefits were seen
    with regard to any major disease outcomes, including
    cardiovascular diseases and cancer. Kidney
    stones were reported by 449 women in the
    calcium with vitamin D group, as compared with
    381 women in the placebo group (hazard ratio,
    1.17; 95 percent confidence interval, 1.02 to 1.34),
    and appeared to be unrelated to high baseline
    calcium intake. There were no significant differences
    in gastrointestinal symptoms: 8.9 percent
    of the participants in the placebo group and 10.3
    percent of those in the calcium with vitamin D
    group reported moderate-to-severe constipation,
    and 19.5 percent and 20.4 percent, respectively,
    reported bloating or gas.
    Discussion
    The WHI calcium with vitamin D study was a
    large-scale, randomized, double-blind, placebocontrolled
    trial designed to test whether calcium
    and vitamin D supplementation reduced the risk
    of hip fracture in a large population of healthy
    postmenopausal women. The trial demonstrated
    that calcium with vitamin D supplementation diminishes
    bone loss at the hip, but the observed
    12 percent reduction in the incidence of hip fracture
    (the primary outcome) was not statistically
    significant. There were no significant reductions
    in the incidence of clinical vertebral fractures,
    fractures of the lower arm or wrist, or total fractures.
    The main adverse effect noted was a small
    but significant increase in the proportion of
    women with renal calculi.
    There are several plausible alternative expla-
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    calcium, vitamin d, and the risk of fractures
    n engl j med 354;7 www.nejm.org february 16, 2006 679
    nations for the results seen in the intention-totreat
    analyses. It is conceivable that calcium with
    vitamin D, at the doses studied in the WHI, has
    no significant effect on fracture reduction. The
    observed lack of efficacy in reducing clinical vertebral
    fractures is discordant with the results of
    meta-analyses of clinical trials that suggest a
    trend toward a small reduction in vertebral fractures
    with calcium alone6 and a significant, 37
    percent reduction in vertebral fractures with vitamin
    D supplementation.22 The lack of a reduction
    in the risk of hip or total fractures would be
    consistent with the findings of recent studies that
    showed no evidence of reduction in nonvertebral
    fractures in healthy, older women living in the
    community.15,18,19
    The effect of calcium with vitamin D supplementation
    on fracture reduction might require
    higher doses of vitamin D than were used in the
    WHI. This dose–response concept33 is supported
    by studies indicating that supplementation with
    400 IU of vitamin D has a small effect or no effect
    on the risk of fracture,16,17 whereas the majority
    of studies supporting a benefit from calcium with
    vitamin D supplements evaluated vitamin D at
    doses that were the equivalent of 600 IU or
    higher.8,10,13,14,33
    It is also plausible that there was a benefit
    only among the women who adhered to the study
    treatment. Although 76 percent of the women in
    this trial were still taking study pills at the end
    of the trial, only 59 percent were taking the intended
    dose. In sensitivity analyses, there was a
    decrease in the risk of hip fracture among adherent
    participants, yielding an absolute benefit
    of four fewer hip fractures per 10,000 women, or
    a significant, 29 percent relative decrease — a
    finding consistent with the results of other trials
    that showed that efficacy in fracture reduction is
    enhanced among women adherent to calcium with
    vitamin D supplementation11 or is present only
    in this group.
    This trial cannot separate the independent effects
    of calcium and vitamin D. The study popu-
    Table 4. Odds Ratios for Hip Fracture and Total Fractures According to Quartiles of Serum 25-Hydroxyvitamin D Level
    and Study Group, as Determined in a Nested Case–Control Study.*
    Fracture Category and
    25-Hydroxyvitamin D
    Level†
    Main-Effect Odds Ratio
    (95% CI)‡
    Calcium +
    Vitamin D Placebo
    Intervention
    Odds Ratio
    (95% CI)§
    P Value for
    Interaction¶
    no. of case participants/
    no. of controls
    Hip fracture 0.64
    ?60.2 nmol/liter 1.00 32/49 42/40 0.61 (0.32–1.15)
    43.7–60.1 nmol/liter 1.51 (0.96–2.37) 44/40 52/39 0.86 (0.48–1.53)
    32.2–43.6 nmol/liter 1.17 (0.73–1.89) 43/48 48/49 0.92 (0.53–1.62)
    <32.2 nmol/liter 1.32 (0.82–2.13) 47/44 49/48 1.06 (0.60–1.86)
    Total fractures 0.15
    ?60.2 nmol/liter 1.00 178/185 177/201 1.09 (0.81–1.47)
    43.7–60.1 nmol/liter 1.12 (0.91–1.38) 170/179 205/191 0.89 (0.66–1.18)
    32.2–43.6 nmol/liter 1.18 (0.94–1.47) 179/183 204/181 0.87 (0.66–1.16)
    <32.2 nmol/liter 1.14 (0.91–1.44) 196/167 182/204 1.32 (0.99–1.76)
    * CI denotes confidence interval.
    † 25-Hydroxyvitamin D levels were measured by Bruce Hollis, Ph.D., with use of the DiaSorin Liaison chemiluminescent
    immunoassay system at DiaSorin headquarters (Stillwater, Minn.) in one continuous batch with blinded control runs at
    periodic intervals (coefficient of variation, 11.8 percent). To convert the values for 25-hydroxyvitamin D from nanomoles
    per liter to nanograms per milliliter, multiply by 0.401.
    ‡ The odds ratios were obtained from a logistic-regression model, conditioned on case–control pairs, and estimated the
    main effect of serum 25-hydroxyvitamin D on the risk of fracture. P = 0.51 for trend with regard to hip fracture. P = 0.23
    for trend with regard to total fractures.
    § The odds ratios were obtained from a logistic-regression model, conditioned on case–control pairs, and estimated the
    effect of calcium with vitamin D intervention on the risk of fracture according to 25-hydroxyvitamin D level.
    ¶ P values for interaction were computed by maximum likelihood from a conditional logistic model including the main effects
    of randomized study group and 25-hydroxyvitamin D as a continuous covariate and their interaction.
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    680 n engl j med 354;7 www.nejm.org february 16, 2006
    lation was not selected to be deficient in calcium
    and vitamin D, since the participants were allowed
    to take multivitamins as well as calcium and vitamin
    D up to specified levels during the trial. The
    average daily total calcium intake at randomization
    was estimated to be 1100 to 1200 mg; only
    7.2 percent of the participants had an intake of
    less than 400 mg.
    The effect of calcium with vitamin D supplements
    may also differ according to baseline vitamin
    D levels. Chapuy et al. reported that calcium
    with vitamin D (1000 mg of calcium and 800 IU
    of vitamin D per day) significantly reduced the
    risk of hip and nonvertebral fractures among elderly
    women who were believed to be vitamin D–
    deficient (on the basis of low vitamin D levels in
    a subgroup analysis at baseline).10 Studies involving
    persons who were potentially less deficient
    in vitamin D have failed to confirm this benefit.
    18 We found no significant interactions between
    baseline serum 25-hydroxyvitamin D levels and
    a calcium with vitamin D treatment effect.
    Finally, it is also plausible that calcium with
    vitamin D supplementation has a real but small
    effect in reducing the risk of hip fracture among
    postmenopausal women, but the WHI calcium
    with vitamin D trial was not sufficiently powered
    to detect such a small effect, even with 36,282
    women enrolled. The trial design assumed an 18
    percent reduction in the risk of hip fracture and
    projected a hip-fracture rate (approximately 34 per
    10,000 persons per year) that was more than
    twice that observed (16 per 10,000). The lowerthan-
    projected hip-fracture rate reduced the power
    of the study to approximately 48 percent. This
    may be attributable to the higher-than-anticipated
    body-mass index, the recruitment of fewer
    women over the age of 70 years than was projected,
    or a fracture rate already suppressed by high personal
    calcium intake or hormone-therapy use.
    Some support is provided by subgroup analyses
    suggesting that among women over the age of
    60 years who had a higher absolute risk of hip
    fracture, calcium with vitamin D supplementation
    significantly reduced the risk of hip fractures.
    The trend toward a reduction in the incidence
    of hip fracture, with no benefit at other skeletal
    sites, could be consistent with the pathophysiology
    of hip fracture relative to other osteoporotic
    fractures. Up to 60 percent of patients with hip
    fractures have one or more biomarkers consistent
    with a negative calcium balance, such as secondary
    hyperparathyroidism, low 25-hydroxyvitamin
    D levels, or low urine calcium excretion.34 These
    perturbations in calcium metabolism associated
    with hip fracture might be amenable to treatments
    that would improve the calcium balance.
    The trial yielded conflicting data regarding hip
    fracture and the interaction between hormone use
    and calcium with vitamin D supplementation.
    Though not statistically significant, the observed
    interaction between active calcium with vitamin
    D and hormone therapy may reflect a synergistic
    role of enhanced calcium balance with hormone
    therapy. This possibility is consistent with the
    previously reported additive effects of calcium
    with vitamin D and hormone therapy on bone
    mineral density.35,36 However, when hormonetherapy
    use outside the trial was included, there
    was no interaction, and a 17 percent reduction in
    the incidence of hip fracture with calcium with
    vitamin D was observed among participants who
    had never used hormone therapy (hazard ratio,
    0.83; 95 percent confidence interval, 0.61 to 1.14).
    Participants in the WHI trial were healthy,
    postmenopausal women living in the community
    who were generally free of disability. The average
    calcium intake at baseline exceeded 1000 mg per
    day, close to the current national recommendations.
    37 Nevertheless, we found significantly higher
    hip bone density but a nonsignificant reduction
    (12 percent) in the rate of hip fracture among
    those assigned to calcium with vitamin D. In secondary
    analyses, the intervention effect appeared
    greater among women who adhered to the regimen,
    women over 60 years of age, and women not
    taking personal calcium supplements. Using the
    intention-to-treat results from this study, we estimate
    that for healthy postmenopausal women
    over the age of 50 years, the number needed to
    treat to prevent one hip fracture per year is 5045.
    This number would be reduced to 1914 among
    women over the age of 60 years, who are at higher
    absolute risk for hip fracture. Although the statistically
    null primary effect argues against recommending
    universal calcium with vitamin D
    supplementation for already calcium-replete women,
    the findings provide evidence of a positive
    effect of calcium with vitamin D on bone health
    in older postmenopausal women.
    The New England Journal of Medicine as published by New England Journal of Medicine.
    Downloaded from www.nejm.org on August 2, 2010. For personal use only. No other uses without permission.
    Copyright © 2006 Massachusetts Medical Society. All rights reserved.
    calcium, vitamin d, and the risk of fractures
    n engl j med 354;7 www.nejm.org february 16, 2006 681
    Supported by the National Heart, Lung, and Blood Institute
    and the General Clinical Research Center program of the National
    Center for Research Resources, Department of Health
    and Human Services. The active study drug and placebo were
    supplied by Glaxo SmithKline Consumer Healthcare (Pittsburgh).
    Dr. Jackson reports having received consulting fees from
    Procter & Gamble Pharmaceuticals and lecture fees from the
    Alliance for Better Bone Health; she also reports that she currently
    receives grant support from Novartis. Dr. LaCroix reports
    having received consulting fees from Pfizer, Procter & Gamble,
    and the Alliance for Better Bone Health and having received a
    lecture fee from Schering-Plough. Dr. Robbins reports that he
    has worked on grants with industry support but that he has received
    no salary support. Dr. Lewis reports that she currently
    has grant support from Pfizer and Novartis. Dr. Brunner reports
    that he is principal investigator for a study funded by the National
    Cancer Institute of Canada and Pfizer through March 31,
    2007. Dr. Cauley reports having received consulting fees from
    Novartis for serving on the HORIZON Study steering committee
    and grant support from Lilly, Pfizer, and Novartis. Dr. Hays reports
    having received lecture fees for conferences sponsored by
    Procter & Gamble Pharmaceuticals. Dr. Howard reports having
    received lecture fees from Schering-Plough and having served as
    a consultant for Merck, the Egg Nutrition Council, and General
    Mills. Dr O’Sullivan reports that she currently receives grant
    support from Pfizer. Dr. Assaf reports having been an employee
    of Pfizer since December 2002 and owning Pfizer stock and
    stock options. No other potential conflict of interest relevant to
    this article was reported.
    We are indebted to the investigators and staff at the WHI Clinical
    Centers, the WHI Clinical Coordinating Center, and the National
    Heart, Lung, and Blood Institute program office for their
    dedicated efforts; to Joseph Larson for his invaluable expertise in
    completing the statistical analysis reported in this article; and
    most important, to the WHI participants for their extraordinary
    commitment to the WHI calcium with vitamin D study.
    APPENDIX 1
    The WHI investigators are as follows: Program Office (National Heart, Lung, and Blood Institute, Bethesda, Md.): B. Alving, J. Rossouw,
    L. Pottern, S. Ludlam, J. McGowan, N. Geller, and L. Ford. Clinical Coordinating Centers: Fred Hutchinson Cancer Research Center, Seattle
    — R. Prentice, G. Anderson, A. LaCroix, R. Patterson, A. McTiernan, B. Cochrane, J. Hunt, L. Tinker, C. Kooperberg, M. McIntosh,
    C.Y. Wang, C. Chen, D. Bowen, A. Kristal, J. Stanford, N. Urban, N. Weiss, and E. White; Wake Forest University School of Medicine,
    Winston-Salem, N.C. — S. Shumaker, R. Prineas, and M. Naughton; Medical Research Laboratories, Highland Heights, Ky. — E. Stein,
    P. Laskarzewski; San Francisco Coordinating Center, San Francisco — S.R. Cummings, M. Nevitt, and L. Palermo; University of Minnesota,
    Minneapolis — L. Harnack; Fisher BioServices, Rockville, Md. — F. Cammarata and S. Lindenfelser; University of Washington,
    Seattle — B. Psaty and S. Heckbert. Clinical Centers: Albert Einstein College of Medicine, Bronx, N.Y. — S. Wassertheil-Smoller, W. Frishman,
    J. Wylie-Rosett, D. Barad, and R. Freeman; Baylor College of Medicine, Houston — J. Hays, R. Young, J. Anderson, S. Lithgow,
    and P. Bray; Brigham and Women’s Hospital, Harvard Medical School, Boston — J.E. Manson, J.M. Gaziano, C. Chae, K. Rexrode, and
    C. Solomon; Brown University, Providence, R.I. — A.R. Assaf, C. Wheeler, C. Eaton, and M. Cyr; Emory University, Atlanta — L. Phillips,
    M. Pedersen, O. Strickland, M. Huber, and V. Porter; Fred Hutchinson Cancer Research Center, Seattle — S.A.A. Beresford, V.M.
    Taylor, N.F. Woods, M. Henderson, and R. Andersen; George Washington University, Washington, D.C. — J. Hsia, N. Gaba, and J.
    Ascensao; Harbor–UCLA Research and Education Institute, Torrance, Calif. — R. Chlebowski, R. Detrano, A. Nelson, and M. Geller;
    Kaiser Permanente Center for Health Research, Portland, Oreg. — E. Whitlock, P. Elmer, V. Stevens, and N. Karanja; Kaiser Permanente
    Division of Research, Oakland, Calif. — B. Caan, S. Sidney, G. Bailey, and J. Hirata; Medical College of Wisconsin, Milwaukee — J.M.
    Kotchen, V. Barnabei, T.A. Kotchen, M.C. Gilligan, and J. Neuner; MedStar Research Institute and Howard University, Washington,
    D.C. — B.V. Howard, L. Adams-Campbell, L. Lessin, M. Rainford, and G. Uwaifo; Northwestern University, Chicago and Evanston, Ill.
    — L. Van Horn, P. Greenland, J. Khandekar, K. Liu, and C. Rosenberg; Rush University Medical Center, Chicago — H. Black, L. Powell,
    E. Mason, and M. Gulati; Stanford Prevention Research Center, Stanford, Calif. — M.L. Stefanick, M.A. Hlatky, B. Chen, R.S. Stafford,
    and S. Mackey; State University of New York at Stony Brook, Stony Brook — D. Lane, I. Granek, W. Lawson, G. San Roman, and
    C. Messina; Ohio State University, Columbus — R. Jackson, R. Harris, E. Paskett, W.J. Mysiw, and M. Blumenfeld; University of Alabama
    at Birmingham, Birmingham — C.E. Lewis, A. Oberman, J.M. Shikany, M. Safford, and M. Fouad; University of Arizona, Tucson
    and Phoenix — T. Bassford, C. Thomson, M. Ko, A.M. Lopez, and C. Ritenbaugh; University at Buffalo, Buffalo, N.Y. — J. Wactawski-
    Wende, M. Trevisan, E. Smit, S. Graham, and J. Chang; Universit