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Serum 25-Hydroxyvitamin D Concentrations and Risk for Hip Fractures

Jane A. Cauley, DrPH; Andrea Z. LaCroix, PhD; LieLing Wu, MS; Mara Horwitz, MD; Michelle E. Danielson, PhD; Doug C. Bauer, MD; Jennifer S. Lee, MD; Rebecca D. Jackson, MD; John A. Robbins, MD; Chunyuan Wu, MS; Frank Z. Stanczyk, PhD; Meryl S. LeBoff, MD; Jean Wactawski-Wende, PhD; Gloria Sarto, MD; Judith Ockene, PhD; and Steven R. Cummings, MD
[+] Article and Author Information

From University of Pittsburgh, Pittsburgh, Pennsylvania; University of Washington, Seattle, Washington; University of California, San Francisco, and San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, California; University of California, Davis, Davis, California; Ohio State University, Columbus, Ohio; University of Southern California, Los Angeles, California; Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts; University at Buffalo, Buffalo, New York; University of Wisconsin-Madison, Madison, Wisconsin; and University of Massachusetts Amherst, Amherst, Massachusetts.


Acknowledgment: The authors thank the WHI investigators. For a list of WHI investigators, see the Appendix.

Grant Support: By the National Heart, Lung and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services. Additional support was provided by U.S. Public Health Service Research grants AR052105 and AR048919. Dr. Lee is supported by National Center for Research Resources grant UL 1 RR024146.

Potential Financial Conflicts of Interest:Consultancies: J.A. Cauley (Novartis, Eli Lilly), D.C. Bauer (Merck, Roche Diagnostics), J. Wactawski-Wende (Johnson & Johnson), S.R. Cummings (Eli Lilly, Procter & Gamble, Amgen, GlaxoSmithKline, Zelos). Honoraria: J.A. Cauley (Eli Lilly), R.D. Jackson (Sanofi-Aventis, Procter & Gamble), J. Wactawski-Wende (Merck), S.R. Cummings (Eli Lilly). Stock ownership or options (other than mutual funds): M.S. LeBoff (Amgen, General Electric). Expert testimony: S.R. Cummings (Eli Lilly). Grants received: J.A. Cauley (Merck, Pfizer, Novartis), D.C. Bauer (Novartis, Amgen, Procter & Gamble, Merck), R.D. Jackson (MicroMRI, Procter & Gamble), M.S. LeBoff (Abbott), J. Ockene (National Heart, Lung, and Blood Institute), S.R. Cummings (Amgen, Eli Lilly).

Reproducible Research Statement:Study protocol: WHI study protocols are available at http://whiscience.org. Statistical code and data set: Not available.

Requests for Single Reprints: Jane A. Cauley, DrPH, University of Pittsburgh, Department of Epidemiology, 130 DeSoto Street, Crabtree A524, Pittsburgh, PA 15261; e-mail, jcauley@edc.pitt.edu.

Current Author Addresses: Dr. Cauley: University of Pittsburgh, Department of Epidemiology, 130 DeSoto Street, Crabtree A524, Pittsburgh, PA 15261.

Dr. LaCroix, Ms. L. Wu, and Ms. C. Wu: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109.

Dr. Horwitz: University of Pittsburgh Medical Center, Falk 580, 3601 Fifth Avenue, Pittsburgh, PA 15261.

Dr. Danielson: University of Pittsburgh, Department of Epidemiology, 130 DeSoto Street, Crabtree A543, Pittsburgh, PA 15261.

Dr. Bauer: University of California, San Francisco, 185 Berry Street, #5700, San Francisco, CA 94105.

Dr. Lee: University of California, Davis, 4150 V Street, Suite 6400, Sacramento, CA 75817.

Dr. Jackson: The Ohio State University, 485 McCampbell Hall, 1581 Dodd Drive, Columbus, OH 43210.

Dr. Robbins: Lawrence J. Ellison Ambulatory Care Center, 4860 Y Street, Sacramento, CA 95817.

Dr. Stanczyk: USC Keck School of Medicine, Women's & Children's Hospital, 1240 North Mission Road, Room 1M2, Los Angeles, CA 90033.

Dr. LeBoff: Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115.

Dr. Wactawski-Wende: State University of New York at Buffalo, 270 Farber Hall, Buffalo, NY 14214.

Dr. Sarto: University of Wisconsin-Madison, 700 Regent Street, Madison, WI 53715.

Dr. Ockene: University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655.

Dr. Cummings: San Francisco Coordinating Center, 185 Berry Street, Lobby 4, Suite 5700, San Francisco, CA 94107.

Author Contributions: Conception and design: J.A. Cauley, D.C. Bauer, R.D. Jackson, M.S. LeBoff, J. Wactawski-Wende, S.R. Cummings.

Analysis and interpretation of the data: J.A. Cauley, A.Z. LaCroix, M. Horwitz, L. Wu, D.C. Bauer, J.S. Lee, R.D. Jackson, C. Wu, M.S. LeBoff, G. Sarto.

Drafting of the article: J.A. Cauley, L. Wu, M. Horwitz, M.E. Danielson, M.S. LeBoff.

Critical revision of the article for important intellectual content: A.Z. LaCroix, L. Wu, M. Horwitz, M.E. Danielson, D.C. Bauer, J.S. Lee, R.D. Jackson, F.Z. Stanczyk, M.S. LeBoff, J. Wactawski-Wende, G. Sarto, S.R. Cummings.

Final approval of the article: J.A. Cauley, A.Z. LaCroix, L. Wu, M. Horwitz, M.E. Danielson, D.C. Bauer, R.D. Jackson, J.A. Robbins, F.Z. Stanczyk, J. Wactawski-Wende, J. Ockene, S.R. Cummings.

Provision of study materials or patients: J.A. Cauley, J.S. Lee, R.D. Jackson, J.A. Robbins, F.Z. Stanczyk, J. Wactawski-Wende, G. Sarto, J. Ockene.

Statistical expertise: L. Wu.

Obtaining of funding: J.A. Cauley, M.E. Danielson, J.S. Lee, R.D. Jackson, J.A. Robbins, J. Wactawski-Wende, J. Ockene, S.R. Cummings.

Administrative, technical, or logistic support: J.A. Cauley, M.E. Danielson, J.S. Lee, R.D. Jackson, J. Wactawski-Wende.

Collection and assembly of data: J.A. Cauley, A.Z. LaCroix, J.S. Lee, R.D. Jackson, J.A. Robbins, J. Wactawski-Wende, G. Sarto, J. Ockene.


Ann Intern Med. 2008;149(4):242-250. doi:10.7326/0003-4819-149-4-200808190-00005
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In our prospective, nested case–control study, we found that women with the lowest 25(OH) vitamin D concentrations (<47.6 nmol/L) at study entry had a significantly greater increased risk for subsequent hip fracture during the next 7 years than did women with the highest concentrations (≥70.7 nmol/L). The association between 25(OH) vitamin D concentration and hip fracture was linear and did not seem to differ by age.

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Hypovitaminosis D and Health
Posted on August 28, 2008
Francisco Ramirez-Lafita
Gabinet Mèdic. 43850 Cambrils.Baix Camp. Spain
Conflict of Interest: None Declared

Vitamin D deficiency is a widespread problem mostly in the elderly, affecting not only bone health but increasing risk of common cancers, autoimmune diseases, hypertension and infectious diseases (1). Circulating levels of 25OH vitamin D levels > 75 nmol/L (>30 ng/ml) are required to maximize its health effects (2). In their recent article, Cauley and colleagues (3) have performed a nested case-control study where the relationship between low serum 25(OHD vitamin D concentrations and risk for hip fractures is reported. Previous and several studies have found similar results reporting the presence of secondary hyperparathyroidism in more than 50% of patients who presented hypovitaminosis D and hip fracture (4). Beside the lack of Calcium, Phosphate, Alkaline Phosphatase and PTH levels determination, and BMD measurements in the study by Cauley and colleagues, they have actually found interesting results. Case-patients were found to present higher levels of C-terminal telopeptide of type I collagen (a bone resorption marker) mostly among those patients with lowest concentration of 25 OH vitamin D, suggesting a relationship between low 25 OH vitamin D levels and increased bone resorption, probably in the frame of secondary hyperparathyroidism. A recent paper (5) reported that hypovitaminosis D was not always accompanied by increases in PTH, but those patients with secondary hyperparathyroidism had higher mortality rates. Hypovitaminosis D should be considered in postmenopausal women and elderly patients. Cauley and colleagues article emphasizes that calcium/phosphate balance, bone resorption markers and secondary hypoparathyroidism should be screened in order to ensure the right calcium and vitamin D supplements in addition to anti-resorptives therapies.

1. Cherniack EP, Levis S, Troen BR. Hypovitaminosis D: a widespread epidemic. Geriatrics. 2008; 63(4):24-30 2. Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008; 87(4):1080S-6S. 3. Cauley JA, LaCroix AZ, Wu LL, Horwitz M, Damielson ME, Bauer DC et al. Serum 25-Hydroxivitamin D concentrations and risk for hip fractures. Ann Intern Med. 2008; 149: 242-250 4. Larrosa M, Casado E, Gómez A, Moreno M, Berlanga E, Ramón J, Gratacós J. Vitamin D deficiency and related factors in patients with osteoporotic hip fracture. Med Clin (BCN). 2008; 19; 130 (1): 6-9 5. Chen JS, Sambrook PN, March L, Cameron ID, Cumming RG, Simpson JM, Seibel MJ. Hypovitaminosis D and parathyroid hormone response in the elderly: effects on bone turnover and mortality. Clin Endocrinol (Oxf). 2008; 68 (2):290-298

Conflict of Interest:

None declared

What vitamin D levels are too high?
Posted on August 28, 2008
Susan M Ott
University of Washington
Conflict of Interest: None Declared

The recent paper by Cauley et al (1) provides further evidence that low levels of vitamin D are associated with an increased risk of hip fractures. Statistically, the increase in fracture risk was linear across quartiles. The numerical risks, however, showed that the lowest risk was in the third quartile, with an odds ratio of 0.82 compared to the fourth (highest) quartile. The mean vitamin D levels in this quartile with the lowest risk were 60.2-70.6 nmol/L (24-28 ng/dL). It is interesting to note that the same pattern has been reported from the NHANES III study, where the lowest risk of fracture was also in their third quartile (61.1-82.5 nmol/L) (2). Cauley et al stated that there were "few women with levels greater than 75 nmol/L, so we could not test whether even higher concentrations offer greater protection against hip fracture risk." I wonder if higher levels could, instead, increase the hip fracture risk. The results of clinical trials are inconsistent (3) and the optimal levels of vitamin D are controversial (4,5). A recent study found that serum vitamin D in Hawaiian surfers did not exceed 155 nmol/L, which could be considered the highest physiological level (6). Despite the uncertainty about effects of long-term supra-physiological levels of vitamin D, many clinical laboratories are reporting a normal range for 25-OH-vitamin D of 75-250 nmol/L (30 - 100 ng/dL). When treating low levels of vitamin D, physicians should remember that this "vitamin" is actually a steroid hormone, and both excessive and inadequate levels could be harmful.

References: 1. Cauley JA, Lacroix AZ, Wu L, et al. Serum 25-hydroxyvitamin D concentrations and risk for hip fractures. Ann Intern Med. 2008;149(4):242-50. 2. Looker AC, Mussolino ME. Serum 25-hydroxyvitamin d and hip fracture risk in older U.S. white adults. J Bone Miner Res. 2008;23(1):143-50. 3. Cranney A, Horsley T, O'Donnell S, et al. Effectiveness and safety of vitamin D in relation to bone health. Evid Rep Technol Assess (Full Rep). 2007(158):1-235. 4. Hansen KE, Jones AN, Lindstrom MJ, Davis LA, Engelke JA, Shafer MM. Vitamin D insufficiency: disease or no disease? J Bone Miner Res. 2008;23(7):1052-60. 5.Bouillon R, Bischoff-Ferrari H, Willett W. Vitamin D and health: perspectives from mice and man. J Bone Miner Res. 2008;23(7):974-9. 6. Binkley N, Novotny R, Krueger D, et al. Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab. 2007;92(6):2130-5.

Conflict of Interest:

None declared

Vitamin D seems to be a hot topic.
Posted on September 2, 2008
Birju B. Patel
Emory University School of Medicine
Conflict of Interest: None Declared

We read with great interest the study by Cauley and colleagues linking vitamin D deficiency to risk of hip fractures. In our clinical practice of geriatrics, vitamin D deficiency is common and under diagnosed. Vitamin D deficiency is a well established risk factor for falls and osteoporosis. It has been related to many disorders seen in the elderly including type 2 diabetes, malignancies (prostate, colon, breast cancers), and cardiovascular disorders including hypertension . Limitation to sun exposure and diminished dermal production of vitamin D related to atrophic skin changes are the primary etiologies for deficiency in the elderly.

As a part of our clinical evaluation of elderly patients, we routinely check for and follow 25-Hydroxyvitamin D levels. We recommend supplementation with 800 IU per day in frail elderly who have a normal level of 25-Hydroxyvitamin D and more aggressive repletion in those that have deficiency. In view of the data available linking this vitamin deficiency to multiple problems, we feel that more clinicians should check for and supplement vitamin D to normalize levels in high risk populations.

The potential link between vitamin D and pain syndromes is less well known. There has been a recent study by Hicks and colleagues showing the relationship of back pain and low vitamin D levels in women. Previous to this there have been case reports of patients studied that were supplemented for vitamin D deficiency and had improvement of pain. In our practice both pain and vitamin D deficiency are common and we find that identifying and treating those with deficiency is important.

Conflict of Interest:

None declared

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Summary for Patients

Do Low Vitamin D Levels Increase Risk for Hip Fracture?

The summary below is from the full report titled “Serum 25-Hydroxyvitamin D Concentrations and Risk for Hip Fractures.” It is in the 19 August 2008 issue of Annals of Internal Medicine (volume 149, pages 242-250). The authors are J.A. Cauley, A.Z. LaCroix, L. Wu, M. Horwitz, M.E. Danielson, D.C. Bauer, J.S. Lee, R.D. Jackson, J.A. Robbins, C. Wu, F.Z. Stanczyk, M.S. LeBoff, J. Wactawski-Wende, G. Sarto, J. Ockene, and S.R. Cummings.

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