[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.158.119.60. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Download PDF
Figure 1.
Participant Flow Diagram
Participant Flow Diagram

The calcium isotope doses were not recorded in 2 individuals, and a urine sample was mishandled in 1 individual. Muscle tests were not performed in 4 individuals because of pain and/or an injury. 25(OH)D indicates 25-hydroxyvitamin D; TFCA, total fractional calcium absorption; BMD, bone mineral density.

Figure 2.
Serum 25-Hydroxyvitamin D (25[OH]D) Levels by Treatment Assignment
Serum 25-Hydroxyvitamin D (25[OH]D) Levels by Treatment Assignment

Serum 25(OH)D levels were summarized using mean (SD) and compared across treatment arms by analysis of variance, with correction of P values to control for the false discovery rate using the Benjamini and Hochberg method.21 The 25(OH)D levels were not significantly different across treatment groups at the screening (P = .89) and randomization (P = .89) visits. At all subsequent visits, serum 25(OH)D levels were significantly different (P < .001) across all 3 treatment arms. Pairwise comparisons likewise had P < .001. To convert 25(OH)D to nanomoles per liter, multiply by 2.496.

Figure 3.
Annualized Percent Change in Bone Mineral Density by Treatment Assignment
Annualized Percent Change in Bone Mineral Density by Treatment Assignment

We found no significant between-arm differences for the change in spine, mean total-hip, mean femoral neck, or total-body bone mineral density. Kruskal-Wallis tests were used to calculate the overall P value, with correction of P values to control for the false discovery rate using the Benjamini and Hochberg method.21

Table 1.  
Baseline Characteristics of the Randomized Study Participants
Baseline Characteristics of the Randomized Study Participants
Table 2.  
One-Year Changes in Muscle Outcomes
One-Year Changes in Muscle Outcomes
1.
Melton  LJ  III.  Adverse outcomes of osteoporotic fractures in the general population. J Bone Miner Res. 2003;18(6):1139-1141.
PubMedArticle
2.
Cummings  SR, Melton  LJ.  Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002;359(9319):1761-1767.
PubMedArticle
3.
Holick  MF, Garabedian  M. Vitamin D: photobiology, metabolism, mechanism of action, and clinical applications. In: Favus  MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism.6th ed. Washington, DC: American Society for Bone and Mineral Research; 2006:106-114.
4.
Dawson-Hughes  B, Heaney  RP, Holick  MF, Lips  P, Meunier  PJ, Vieth  R.  Estimates of optimal vitamin D status. Osteoporos Int. 2005;16(7):713-716.
PubMedArticle
5.
Holick  MF.  Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.
PubMedArticle
6.
Dawson-Hughes  B, Bischoff-Ferrari  HA.  Therapy of osteoporosis with calcium and vitamin D. J Bone Miner Res. 2007;22(suppl 2):V59-V63.
PubMedArticle
7.
Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press; 2011.
8.
Looker  AC, Pfeiffer  CM, Lacher  DA, Schleicher  RL, Picciano  MF, Yetley  EA.  Serum 25-hydroxyvitamin D status of the US population: 1988-1994 compared with 2000-2004. Am J Clin Nutr. 2008;88(6):1519-1527.
PubMedArticle
9.
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):1052-1060.
PubMedArticle
10.
Lensmeyer  GL, Wiebe  DA, Binkley  N, Drezner  MK.  HPLC method for 25-hydroxyvitamin D measurement: comparison with contemporary assays. Clin Chem. 2006;52(6):1120-1126.
PubMedArticle
11.
Schrager  S, Girard  M, Mundt  M.  Dietary calcium intake among women attending primary care clinics in Wisconsin. WMJ. 2005;104(6):47-50.
PubMed
12.
Alaimo  K, McDowell  MA, Briefel  RR,  et al.  Dietary intake of vitamins, minerals, and fiber of persons ages 2 months and over in the United States: Third National Health and Nutrition Examination Survey, Phase 1, 1988-91. Adv Data. 1994;(258):1-28.
PubMed
13.
Weaver  CM, Fleet  JC.  Vitamin D requirements: current and future. Am J Clin Nutr. 2004;80(6)(suppl):1735S-1739S.
PubMed
14.
Deroisy  R, Collette  J, Albert  A, Jupsin  I, Reginster  JY.  Administration of a supplement containing both calcium and vitamin D is more effective than calcium alone to reduce secondary hyperparathyroidism in postmenopausal women with low 25(OH)vitamin D circulating levels. Aging Clin Exp Res. 2002;14(1):13-17.
PubMedArticle
15.
McKane  WR, Khosla  S, Egan  KS, Robins  SP, Burritt  MF, Riggs  BL.  Role of calcium intake in modulating age-related increases in parathyroid function and bone resorption. J Clin Endocrinol Metab. 1996;81(5):1699-1703.
PubMed
16.
Pattanaungkul  S, Riggs  BL, Yergey  AL, Vieira  NE, O’Fallon  WM, Khosla  S.  Relationship of intestinal calcium absorption to 1,25-dihydroxyvitamin D [1,25(OH)2D] levels in young versus elderly women: evidence for age-related intestinal resistance to 1,25(OH)2D action. J Clin Endocrinol Metab. 2000;85(11):4023-4027.
PubMed
17.
Marks  HD, Fleet  JC, Peleg  S.  Transgenic expression of the human Vitamin D receptor (hVDR) in the duodenum of VDR-null mice attenuates the age-dependent decline in calcium absorption. J Steroid Biochem Mol Biol. 2007;103(3-5):513-516.
PubMedArticle
18.
Levey  AS, Bosch  JP, Lewis  JB, Greene  T, Rogers  N, Roth  D; Modification of Diet in Renal Disease Study Group.  A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130(6):461-470.
PubMedArticle
19.
Holick  MF, Siris  ES, Binkley  N,  et al.  Prevalence of Vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab. 2005;90(6):3215-3224.
PubMedArticle
20.
Gilbert  MP, Pratley  RE.  The impact of diabetes treatments on bone health in patients with type 2 diabetes mellitus. Endocr Rev. 2015;36(2):194-213.
PubMedArticle
21.
Benjamini  Y, Hochberg  Y.  Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc, B. 1995;57(1):289-300.
22.
Hansen  KE, Bartels  CM, Gangnon  RE, Jones  AN, Gogineni  J.  An evaluation of high-dose vitamin D for rheumatoid arthritis. J Clin Rheumatol. 2014;20(2):112-114.
PubMed
23.
Brot  C, Vestergaard  P, Kolthoff  N, Gram  J, Hermann  AP, Sørensen  OH.  Vitamin D status and its adequacy in healthy Danish perimenopausal women: relationships to dietary intake, sun exposure and serum parathyroid hormone. Br J Nutr. 2001;86(suppl 1):S97-S103.
PubMedArticle
24.
Souberbielle  JC, Cormier  C, Kindermans  C,  et al.  Vitamin D status and redefining serum parathyroid hormone reference range in the elderly. J Clin Endocrinol Metab. 2001;86(7):3086-3090.
PubMed
25.
Sahota  O, Mundey  MK, San  P, Godber  IM, Lawson  N, Hosking  DJ.  The relationship between vitamin D and parathyroid hormone: calcium homeostasis, bone turnover, and bone mineral density in postmenopausal women with established osteoporosis. Bone. 2004;35(1):312-319.
PubMedArticle
26.
Webb  AR, Kline  L, Holick  MF.  Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab. 1988;67(2):373-378.
PubMedArticle
27.
Abrams  SA.  Using stable isotopes to assess mineral absorption and utilization by children. Am J Clin Nutr. 1999;70(6):955-964.
PubMed
28.
Griffin  IJ, Abrams  SA.  Methodological considerations in measuring human calcium absorption: relevance to study the effects of inulin-type fructans. Br J Nutr. 2005;93(suppl 1):S105-S110.
PubMedArticle
29.
Sterility Tests. Vol USP XXII, NF XVII. Easton, PA: Mack Printing Co; 1989.
30.
Sturup  S, Hansen  M, Molgaard  C.  Measurement of 44Ca: 43Ca and 42Ca: 43Ca istopic ratios in urine using high resolution inductively coupled plasma mass spectrometry. J Anal Spectrom.1997;12:919-923.Article
31.
Field  M, Shapses  S, Cifuentes  M, Sherrell  R.  Precise and accurate determination of calcium isotope ratios in urine using HR-ICP-SFMS. J Anal Spectrom.2003;18:727-733.Article
32.
Eastell  R, Vieira  NE, Yergey  AL, Riggs  BL.  One-day test using stable isotopes to measure true fractional calcium absorption. J Bone Miner Res. 1989;4(4):463-468.
PubMedArticle
33.
Podsiadlo  D, Richardson  S.  The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991;39(2):142-148.
PubMedArticle
34.
Tiedemann  A, Shimada  H, Sherrington  C, Murray  S, Lord  S.  The comparative ability of eight functional mobility tests for predicting falls in community-dwelling older people. Age Ageing. 2008;37(4):430-435.
PubMedArticle
35.
Washburn  RA, Smith  KW, Jette  AM, Janney  CA.  The Physical Activity Scale for the Elderly (PASE): development and evaluation. J Clin Epidemiol. 1993;46(2):153-162.
PubMedArticle
36.
Beaudart  C, Reginster  JY, Slomian  J, Buckinx  F, Locquet  M, Bruyère  O.  Prevalence of sarcopenia: the impact of different diagnostic cut-off limits. J Musculoskelet Neuronal Interact. 2014;14(4):425-431.
PubMed
37.
Shapses  SA, Kendler  DL, Robson  R,  et al.  Effect of alendronate and vitamin D₃ on fractional calcium absorption in a double-blind, randomized, placebo-controlled trial in postmenopausal osteoporotic women. J Bone Miner Res. 2011;26(8):1836-1844.
PubMedArticle
38.
Hansen  KE, Jones  AN, Lindstrom  MJ,  et al.  Do proton pump inhibitors decrease calcium absorption? J Bone Miner Res. 2010;25(12):2786-2795.
PubMedArticle
39.
Peto  R, Pike  MC, Armitage  P,  et al.  Design and analysis of randomized clinical trials requiring prolonged observation of each patient, I: introduction and design. Br J Cancer. 1976;34(6):585-612.
PubMedArticle
40.
Haybittle  JL.  Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol. 1971;44(526):793-797.
PubMedArticle
41.
Roux  C, Bischoff-Ferrari  HA, Papapoulos  SE, de Papp  AE, West  JA, Bouillon  R.  New insights into the role of vitamin D and calcium in osteoporosis management: an expert roundtable discussion. Curr Med Res Opin. 2008;24(5):1363-1370.
PubMedArticle
42.
Need  AG, O’Loughlin  PD, Morris  HA, Coates  PS, Horowitz  M, Nordin  BE.  Vitamin D metabolites and calcium absorption in severe vitamin D deficiency. J Bone Miner Res. 2008;23(11):1859-1863.
PubMedArticle
43.
Gallagher  JC, Yalamanchili  V, Smith  LM.  The effect of vitamin D on calcium absorption in older women. J Clin Endocrinol Metab. 2012;97(10):3550-3556.
PubMedArticle
44.
Aloia  JF, Dhaliwal  R, Shieh  A,  et al.  Vitamin D supplementation increases calcium absorption without a threshold effect. Am J Clin Nutr. 2014;99(3):624-631.
PubMedArticle
45.
Chan  EL, Lau  E, Shek  CC,  et al.  Age-related changes in bone density, serum parathyroid hormone, calcium absorption and other indices of bone metabolism in Chinese women. Clin Endocrinol (Oxf). 1992;36(4):375-381.
PubMedArticle
46.
Hoover  PA, Webber  CE, Beaumont  LF, Blake  JM.  Postmenopausal bone mineral density: relationship to calcium intake, calcium absorption, residual estrogen, body composition, and physical activity. Can J Physiol Pharmacol. 1996;74(8):911-917.
PubMedArticle
47.
Nordin  BE, Robertson  A, Seamark  RF,  et al.  The relation between calcium absorption, serum dehydroepiandrosterone, and vertebral mineral density in postmenopausal women. J Clin Endocrinol Metab. 1985;60(4):651-657.
PubMedArticle
48.
Ensrud  KE, Duong  T, Cauley  JA,  et al; Study of Osteoporotic Fractures Research Group.  Low fractional calcium absorption increases the risk for hip fracture in women with low calcium intake. Ann Intern Med. 2000;132(5):345-353.
PubMedArticle
49.
Uusi-Rasi  K, Patil  R, Karinkanta  S,  et al.  Exercise and vitamin D in fall prevention among older women: a randomized clinical trial. JAMA Intern Med. 2015;175(5):703-711.
PubMedArticle
50.
Sanders  KM, Stuart  AL, Williamson  EJ,  et al.  Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303(18):1815-1822.
PubMedArticle
51.
Sanders  KM, Ebeling  P, McCorquodale  T, Herrman  M, Shore-Lorenti  C, Nicholson  G.  The efficacy of high-dose oral vitamin D3 administered once a year: increased fracture risk is associated with 1,25 vitamin D level at 3-months post dose. J Bone Miner Res. 2012;27(suppl 1):S1.
PubMedArticle
52.
Cranney  A, Horsley  T, O’Donnell  S,  et al. Effectiveness and Safety of Vitamin D in Relation to Bone Health. Evidence Report/Technology Assessment No. 158. Rockville, MD: Agency for Healthcare Research and Quality; 2007. AHRQ publication 07-E013.
53.
Brockstedt  H, Kassem  M, Eriksen  EF, Mosekilde  L, Melsen  F.  Age- and sex-related changes in iliac cortical bone mass and remodeling. Bone. 1993;14(4):681-691.
PubMedArticle
Original Investigation
October 2015

Treatment of Vitamin D Insufficiency in Postmenopausal WomenA Randomized Clinical Trial

Author Affiliations
  • 1Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison
  • 2Quality and Patient Safety Analysis, Saint Luke’s Health System, Kansas City, Missouri
  • 3Department of Computing and Biometry, University of Wisconsin College of Agriculture and Life Sciences, Madison
JAMA Intern Med. 2015;175(10):1612-1621. doi:10.1001/jamainternmed.2015.3874
Abstract

Importance  Experts debate optimal 25-hydroxyvitamin D (25[OH]D) levels for musculoskeletal health.

Objective  To compare the effects of placebo, low-dose cholecalciferol, and high-dose cholecalciferol on 1-year changes in total fractional calcium absorption, bone mineral density, Timed Up and Go and five sit-to-stand tests, and muscle mass in postmenopausal women with vitamin D insufficiency.

Design, Setting, and Participants  This randomized, double-blind, placebo-controlled clinical trial was conducted at a single center in Madison, Wisconsin, from May 1, 2010, through July 31, 2013, and the final visit was completed on August 8, 2014. A total of 230 postmenopausal women 75 years or younger with baseline 25(OH)D levels of 14 through 27 ng/mL and no osteoporosis were studied.

Interventions  Three arms included daily white and twice monthly yellow placebo (n=76), daily 800 IU vitamin D3 and twice monthly yellow placebo (n=75), and daily white placebo and twice monthly 50,000 IU vitamin D3 (n=79). The high-dose vitamin D regimen achieved and maintained 25(OH)D levels ≥30 ng/mL.

Main Outcomes and Measures  Outcome measures were 1-year change in total fractional calcium absorption using 2 stable isotopes, bone mineral density and muscle mass using dual energy x-ray absorptiometry, Timed Up and Go and five sit-to-stand tests, functional status (Health Assessment Questionnaire), and physical activity (Physical Activity Scale for the Elderly), with Benjamini-Hochberg correction of P values to control for the false discovery rate.

Results  After baseline absorption was controlled for, calcium absorption increased 1% (10 mg/d) in the high-dose arm but decreased 2% in the low-dose arm (P = .005 vs high-dose arm) and 1.3% in the placebo arm (P = .03 vs high-dose arm). We found no between-arm changes in spine, mean total-hip, mean femoral neck, or total-body bone mineral density, trabecular bone score, muscle mass, and Timed Up and Go or five sit-to-stand test scores. Likewise, we found no between-arm differences for numbers of falls, number of fallers, physical activity, or functional status.

Conclusions and Relevance  High-dose cholecalciferol therapy increased calcium absorption, but the effect was small and did not translate into beneficial effects on bone mineral density, muscle function, muscle mass, or falls. We found no data to support experts’ recommendations to maintain serum 25(OH)D levels of 30 ng/mL or higher in postmenopausal women. Instead, we found that low- and high-dose cholecalciferol were equivalent to placebo in their effects on bone and muscle outcomes in this cohort of postmenopausal women with 25(OH)D levels less than 30 ng/mL.

Trial Registration  clinicaltrials.gov Identifier: NCT00933244

Introduction

Quiz Ref IDNearly half of postmenopausal women sustain an osteoporotic fracture.1,2 Low vitamin D levels contribute to osteoporosis via decreased total fractional calcium absorption (TFCA), secondary hyperparathyroidism, increased bone resorption, and decreased bone mineral density (BMD).3 Unfortunately, experts disagree on the optimal vitamin D level for skeletal health. Quiz Ref IDSome46 contend that optimal serum 25-hydroxyvitamin D (25[OH]D) levels are 30 ng/mL or greater (to convert to nanomoles per liter, multiply by 2.496) and define vitamin D insufficiency (VDI) as 25(OH)D levels less than 30 ng/mL. By contrast, the Institute of Medicine7 recommends levels of 20 ng/mL or greater. Disagreement continues because many previous clinical trials did not recruit participants based on initial 25(OH)D levels, failed to target or achieve 25(OH)D levels of 30 ng/mL or greater, and/or coadministered calcium supplements.

Defined as a serum 25(OH)D level less than 30 ng/mL, VDI is widespread and affects approximately 75% of postmenopausal US women.8 Therefore, determining the ideal 25(OH)D level for optimal calcium homeostasis and bone health is important. The aims of this randomized double-blind, placebo-controlled clinical trial were to evaluate the effects of high- and low-dose cholecalciferol on 1-year changes in TFCA, BMD, and muscle fitness in postmenopausal women with VDI. Women with osteoporosis were excluded. On the basis of a prior pilot study,9 we hypothesized that a high-dose cholecalciferol regimen, administered to achieve and maintain 25(OH)D levels greater than 30 ng/mL for 1 year, would increase TFCA and BMD more than low-dose cholecalciferol or placebo would.

Methods
Study Design

Quiz Ref ID With approval of the University of Wisconsin Institutional Review Board, we conducted a randomized, double-blind, placebo-controlled clinical trial of postmenopausal women from a single center living around Madison, Wisconsin. The study protocol can be found in Supplement 1. Recruitment (Figure 1) occurred from May 1, 2010, through July 31, 2013, and the final visit was completed on August 8, 2014. Individuals called in response to local advertisements and were screened by telephone for eligibility. After written consent, we measured eligible participants’ serum 25(OH)D, calcium, albumin, creatinine, and parathyroid hormone (PTH) levels.

We enrolled women with a 25(OH)D level of 14 ng/mL through 27 ng/mL, instead of less than 30 ng/mL, to allow for laboratory variability in measurements.10 Individuals were 5 years or more past menopause or oophorectomy or 60 years or older if they had undergone a prior hysterectomy without oophorectomy. Eligible individuals consuming less than 600 mg or more than 1400 mg/d of calcium identified via questionnaire11 were counseled to consume 600 to 1400 mg/d by modifying their dietary and/or supplemental calcium intake. We targeted typical calcium intake of postmenopausal US women12 to ensure generalizability and minimize the harms of high-dose cholecalciferol and because passive calcium absorption lessens the import of vitamin D–mediated active absorption.1315

We excluded women older than 75 years because increasing age is associated with intestinal resistance to vitamin D.16,17 We excluded women with hypercalcemia; nephrolithiasis; cancer within 5 years (excluding skin cancer); inflammatory bowel disease; malabsorption; celiac sprue; chronic diarrhea; glomerular filtration rate less than 45 mL/min18; adult fragility; fracture of the hip, spine, or wrist; and use of bone-active medications within the past 6 months, including bisphosphonates, estrogens, calcitonin, teriparatide, oral corticosteroids, anticonvulsants, or cholecalciferol at a dosage of more than 400 IU/d.19 Women with diabetes mellitus were also excluded because the disease and associated medications affect skeletal health.20 We measured individuals’ spine, total-hip, and total-body BMD and excluded those with T scores of −2.5 or less.

Participants completed 4- to 7-day food diaries within 1 month of the TFCA studies, using scales and household measuring tools to record intake. Food diaries were analyzed using Food Processor software (ESHA Research) to calculate individuals’ customary intake of nutrients (Table 1), caffeine, and alcohol. Dietary intake, except alcohol, was reproduced during the TFCA studies.

We purchased low-dose cholecalciferol (800 IU, white capsules), high-dose cholecalciferol (50 000 IU, yellow capsules), and identical placebo capsules (Tischon Corporation) and independently verified capsule content before use. Participants randomized to high-dose cholecalciferol received a loading dose (50 000 IU/d for 15 days) to quickly raise their 25(OH)D levels to greater than 30 ng/mL,22 with sham loading of yellow placebo capsules in other arms to maintain masking. After loading, participants in the high-dose arm took one 50 000-IU capsule every 15th day for the next 11.5 months. Participants in the low-dose arm took 800 IU/d of cholecalciferol and yellow placebo capsules every 15th day. Participants in the placebo arm ingested white placebo capsules daily and yellow placebo capsules every 15th day (eFigure 1 in Supplement 2). We dispensed prefilled 31-day pill boxes and counted remaining capsules at postrandomization visits to monitor adherence.

The University of Wisconsin Pharmaceutical Research Center (PRC) personnel randomized eligible individuals into treatment arms in forced blocks of 6 (eFigure 1 in Supplement 2), stratifying by high PTH level and calcium intake greater than 1000 mg/d. Stratification by PTH level occurred because secondary hyperparathyroidism occurs in only 10% to 33% of people with VDI,9,2325 and individuals without it might not benefit from vitamin D. Stratification by high calcium intake occurred because passive calcium absorption, facilitated by high calcium intake, lessens the import of vitamin D–mediated active absorption.1315 Only PRC personnel, who had no direct contact with participants, knew the treatment allocation. We dispensed Total Block sunscreen to participants for use between April and October.22,26

Outcome Measures

The 1-year change in TFCA was the primary outcome, and change in BMD was the secondary outcome. Additional outcomes were the effect of placebo, low-dose cholecalciferol, and high-dose cholecalciferol on muscle function, muscle mass, trabecular bone score, and bone turnover. We also evaluated pain, functional status, and physical activity during the study.

We measured TFCA using the gold standard dual stable calcium isotope method in which the intravenous isotope tracks renal reabsorption and endogenous fecal calcium excretion.27,28 Isotopes were purchased as calcium carbonate powder (Trace Sciences International); purity and enrichment were confirmed by mass spectrometry. Waisman Clinical Biomanufacturing Facility personnel reconstituted isotopes9 and tested solutions for sterility and pyrogenicity.29 Solutions were stored and dispensed by the PRC.

For TFCA measurements, women fasted from midnight and attended the University of Wisconsin Clinical Research Unit (CRU) at approximately 7 am. After phlebotomy, participants consumed breakfast along with 50 mL or less of calcium-fortified orange juice that contained approximately 8 mg of 44Ca for a total oral calcium load of approximately 300 mg. The glass was rinsed with deionized water, which participants also drank. Simultaneously, nurses infused approximately 3 mg of 42Ca during 5 minutes followed by 50 mL or less of normal saline. Nurses weighed isotope syringes and recorded 42Ca and 44Ca doses. Participants remained in the CRU during the 24-hour urine collection, consuming meals that replicated usual nutrient intake based on food diaries. Participants continued taking outpatient medications and supplements and began taking study capsules on discharge.

Wisconsin State Laboratory of Hygiene personnel quantified concentrations and ratios of calcium isotopes in 24-hour urine specimens by high-resolution inductively coupled plasma mass spectrometry as previously described.9,30,31 Participants’ baseline and final urine samples were analyzed simultaneously. We calculated TFCA as the dose-corrected ratio of the 2 calcium isotopes in a 24-hour urine collection.9,32

Participants returned for study visits approximately 30, 60, 120, 240, and 365 days after randomization. At each visit, we measured 25(OH)D and calcium levels and performed Timed Up and Go (TUG)33 and five sit-to-stand (STS)34 tests. Participants reported pain during the prior week (10-cm scale), functional status (modified Stanford Health Assessment Questionnaire), and activity (Physical Activity for the Elderly Scale).35 Participants reported all adverse events, and specifically, nephrolithiasis, fracture, fall, infection, and hospitalization. At 0, 60, 120, and 365 days, participants’ 24-hour urine calcium levels were measured.

The PRC reviewed 25(OH)D levels at approximately 30, 60, 120, and 240 days. If a woman in the high-dose treatment arm had a 25(OH)D level less than 30 ng/mL, the PRC adjusted her cholecalciferol dose. For example, a woman whose 25(OH)D level was 25 ng/mL received 50 000 IU/d of cholecalciferol for 7 days then 50 000 IU once weekly to achieve and maintain repletion. To preserve masking, approximately 8% of participants in the other arms received sham adjustments of yellow placebo capsules.

One year after randomization, the BMD was again measured using the same Lunar bone densitometry machine (GE Healthcare). The trabecular bone score was determined using TBS iNsight software, version 2.1.0.0 (Medimaps Group). Muscle mass was calculated as the appendicular lean mass in kilograms divided by height in square meters.36 Serum 25(OH)D was measured at the University of Wisconsin using a high-performance liquid chromatography assay10 with between-run coefficients of variation of 3.2% to 13% for 1.25-dihydroxyvitamin D (1,25[OH]D2) and 2.6% to 4.9% for 25(OH)D3. Methods for other laboratory tests are listed in Table 1.

Sample Size

The primary outcome was the effect of cholecalciferol on TFCA. With high-dose cholecalciferol,9 the SD for absolute change in TFCA was 1%. With low-dose cholecalciferol,37 the SD for change in TFCA was 7%. Without intervention, the SD for monthly change in TFCA was 1%.38 Thus, recruitment of 70 women per arm (n = 210) provided approximately 90% power to detect a 3% difference in the change in TFCA between high-dose and placebo arms and approximately 80% power to detect a 3% difference between high-dose and low-dose cholecalciferol arms, with a 2-sided α of .05. To compensate for attrition, we planned to randomize up to 250 women.

Statistical Analysis

Data were graphed to determine distribution and outliers. Normal data were summarized using the mean (SD) and analyzed by analysis of variance. Skewed data were summarized using the median (interquartile range [IQR]) and analyzed using the Kruskal-Wallis test. To control for the false discovery rate, we corrected P values using the Benjamini and Hochberg method21 for participants’ baseline characteristics (Table 1), participants’ paired changes in dietary habits, between-arm changes in absolute and percentage of BMD, trabecular bone score, bone turnover, and adverse events. Between-arm 1-year changes in muscle outcomes were summarized using means and 95% CIs corrected for multiple comparisons using the Tukey honest significant difference test (Table 2). All outcomes were analyzed by the intent-to-treat principle, using R (The R Project for Statistical Computing, http://www.r-project.org). LASSO and StepAIC R programs were used for modeling.

A data safety monitoring board (DSMB) met every 18 months to monitor the trial’s progress and safety. Withdrawal occurred for 3 predefined events: nephrolithiasis, hypercalcemia (defined as a serum calcium level ≥10.4 mg/dL twice during approximately 2 weeks), or fragility fracture (spine, wrist, or hip). If participants developed hypercalciuria (defined as a calcium level >400 mg/24 h), we performed the test again. For persistent hypercalciuria, we counseled participants to reduce calcium intake. Because hypercalciuria is common and often asymptomatic,34 its presence did not require withdrawal. All adverse events were categorized by system in the OnCore Database of the University of Wisconsin.

We reported serious adverse events (death, hospitalization, or predefined event) to the DSMB within 24 hours and cumulative adverse events at DSMB meetings. To prepare reports, the team submitted participants’ adverse events to the PRC, whose staff entered treatment assignment and forwarded reports to the DSMB. We defined an excess harm z value greater than −3.039,40 as an indication to prematurely stop the study.

Results

Figure 1 summarizes participant recruitment, randomization, and completion. Nine women (3.9%) who withdrew from the study were similar to the remaining 221 participants in age, race, and 25(OH)D levels; all withdrew for personal reasons. Baseline demographics did not differ across treatment arms (Table 1). Serum 25(OH)D levels were significantly different among the arms at all postrandomization visits (P < .001, Figure 2). From 30 days to 365 days after randomization, the mean (SD) 25(OH)D levels were 19 (5) ng/mL in the placebo arm, 28 (5) ng/mL in the low-dose cholecalciferol arm, and 56 (12) ng/mL in the high-dose cholecalciferol arm (P < .001). Five participants (6.3%) of the 79 in the high-dose cholecalciferol arm required additional cholecalciferol to maintain 25(OH)D levels of 30 ng/mL or greater. Adherence to therapy was approximately 100% across all arms (n = 221; eTable 1 in Supplement 2). Participants exhibited no significant pairwise changes in dietary habits during the study (eTable 2 in Supplement 2).

Main Outcome Measures

eFigure 2 in Supplement 2 summarizes TFCA, which increased 0.6% in the high-dose arm and decreased 4.5% in the low-dose arm (P = .009) and 0.9% in the placebo arms (P = .46 vs high-dose arm). By chance, the low-dose arm had a higher baseline TFCA. In models controlling for baseline calcium absorption, TFCA increased 1% in the high-dose arm but decreased 2% in the low-dose arm (P = .005 vs high-dose arm) and 1.3% in the placebo arm (P = .03 vs high-dose arm) (eFigure 2 in Supplement 2). In models (eTable 3 in Supplement 2), the 1-year change in TFCA was inversely associated with the baseline TFCA, 25(OH)D level, and dietary sodium level and positively associated with body mass index, serum estradiol level, glomerular filtration rate, and 60-day 25(OH)D level.

We found no between-arm differences for the absolute or annualized percentage change in lumbar spine, mean total-hip, or total-body BMD (Figure 3 and eTable 4 in Supplement 2). Likewise, we found no significant between-arm differences for absolute or annualized percentage changes in trabecular bone score (eTable 4 in Supplement 2). High-dose cholecalciferol had a small, beneficial effect on femoral neck BMD. The absolute change in median (IQR) femoral neck BMD was −0.003 g/cm2 (−0.012 to 0.005 g/cm2) with high-dose cholecalciferol, −0.009 g/cm2 (−0.02 to 0.001 g/cm2) with low-dose cholecalciferol, and −0.008 g/cm2 (−0.016 to −0.001 g/cm2) with placebo. The overall P value for between-arm changes was .03, but with adjustment to control for the false discovery rate, the P value was no longer significant (P = .12). Annualized changes in hip BMD were associated with change in TFCA, but only in participants randomized to high-dose cholecalciferol (ρ = 0.24, P = .04).

The within-arm and between-arm 1-year changes in muscle outcomes are summarized in Table 2. All treatment arms experienced slightly faster TUG and STS test results during the study. However, we found no between-arm differences for the degree of improvement in either of these tests. We likewise detected no between-arm differences in muscle mass, number of falls, or number of fallers. Finally, we found no between-arm differences for the 1-year change in Health Assessment Questionnaire score or Physical Activity for the Elderly score.

We measured bone turnover markers in individuals who attended all study visits before 10 am, fasting since midnight (n = 149 [64.8%]). We found no consistent between-arm differences in C-telopeptide or bone-specific alkaline phosphatase, when analyzed as changes from baseline (eTable 5 in Supplement 2) or in models.

Predefined adverse events are summarized in eTable 6 in Supplement 2. Nephrolithiasis was incidentally detected in a woman in the low-dose arm who underwent abdominal imaging for other reasons; lack of prior imaging precluded ability to determine timing of the stone. Falls, fractures, and hospitalizations were evenly distributed across arms. Two participants in the low-dose cholecalciferol arm experienced transient asymptomatic hypercalcemia. Hypercalciuria occurred 9 times: 7 times in the high-dose arm (4 participants), once in the low-dose arm, and once in the placebo arm (P = .19). Serum calcium and phosphorus levels were similar in all arms (eTable 7 in Supplement 2). At 60 days, the high-dose arm had higher urine calcium levels than the low-dose (P = .007) and placebo (P = .001) arms (eTable 7 and eTable 8 in Supplement 2). Likewise, at 120 and 365 days, the high-dose arm experienced higher urine calcium levels than the placebo arm (eTable 7 and eTable 8 in Supplement 2). We found no other differences in adverse effects across treatment arms (eTable 9 in Supplement 2).

Discussion

Experts have debated the optimal 25(OH)D levels needed to optimize musculoskeletal health. Although some groups46,41 advocate levels of 30 ng/mL or greater, the Institute of Medicine7 defines vitamin D repletion as a level of 20 ng/mL or greater. We designed a clinical trial to directly address ongoing controversy about optimal vitamin D levels for musculoskeletal health. Quiz Ref IDWe found that compared with placebo, high-dose cholecalciferol had a very small effect on calcium absorption (1%) that did not translate into meaningful changes in lumbar spine, mean total-hip, femoral neck, or total-body BMD, trabecular bone score, TUG score, STS test score, muscle mass, number of falls, or number of fallers. Study results do not support the recommendation to maintain serum 25(OH)D levels at 30 ng/mL or greater.

In a retrospective study42 of 316 postmenopausal women with serum 25(OH)D levels less than 17 ng/mL, women with levels of 4 ng/mL or less had lower calcium absorption than those with higher 25(OH)D levels. Of interest, 1,25(OH)D2 levels were low only in women with 25(OH)D levels of 4 ng/mL or less. Those study authors concluded that profound vitamin D deficiency must exist to impair calcium absorption. However, the study did not test changes in calcium absorption with vitamin D therapy, limiting the ability to conclude that calcium absorption was “optimal” in women with 25(OH)D levels of 5 ng/mL or greater.

Two randomized clinical trials43,44 found that when controlling for baseline calcium absorption, high-dose cholecalciferol increased calcium absorption in postmenopausal women. In 163 women with 25(OH)D levels less than 20 ng/mL,43 calcium absorption increased in the 4800-IU/d arm compared with placebo. However, the actual difference in calcium absorption between the placebo and high-dose cholecalciferol arms was only 6 mg/d. In another trial, researchers44 randomized 67 women with 25(OH)D levels less than 30 ng/mL to 0, 800, 2000, or 4000 IU/d of cholecalciferol for 8 weeks. Calcium absorption decreased 2.6% in the placebo arm and increased 6.7% in the 4000-IU/d arm. In both studies, baseline calcium absorption was a strong independent predictor of change in calcium absorption with cholecalciferol therapy.

Few studies have evaluated the association between calcium absorption and BMD. Most cross-sectional studies4547 report no association. In the prospective Study of Osteoporotic Fractures, calcium absorption (measured by single serum radioisotope level) in 5453 white postmenopausal women48 was weakly but significantly associated with femoral neck BMD (r = 0.06, P < .001). Researchers subsequently recorded incident fractures for approximately 5 years. In models adjusting for age, each SD decrease (7.7%) in calcium absorption was associated with a 1.24-fold (95% CI, 1.05–1.48) increase in hip fracture but not with fractures at other skeletal sites. That study, along with our own data, suggests that large increases in calcium absorption are needed to increase BMD and reduce fracture risk.

Even if high-dose cholecalciferol did not increase BMD, its use would be warranted if such therapy reduced falls, which almost always precede an osteoporotic fracture. A randomized clinical trial49 of 409 women aged 70 to 80 years was specifically designed to evaluate the effect of cholecalciferol or placebo on the risk of falls. The authors detected no reduction in falls with cholecalciferol therapy, administered as 800 IU/d for 2 years.

Sanders and colleagues50 reported that 500 000 IU of cholecalciferol administered intramuscularly once yearly caused more fractures and falls than placebo. In a post hoc analysis of a subset of participants,51 those randomized to cholecalciferol had higher 1,25(OH)2D levels and bone resorption 3 months after randomization, potentially explaining the higher fracture rate. Although we found no significant increase in bone resorption or decreases in BMD associated with high-dose cholecalciferol, the benefits of high-dose cholecalciferol were too small to justify its routine use.

Our trial has several strengths. We recruited a large number of highly motivated participants. Adherence to study medication was excellent, and attrition was low (4%). We replicated typical dietary habits during the TFCA study visits. We used the gold standard method to measure TFCA and participants remained inpatients, permitting a complete 24-hour urine collection. Participants received sunscreen to minimize sun-mediated increases in vitamin D levels. Cholecalciferol study capsule content was independently verified before study use. We measured covariates that could influence TFCA, BMD, and/or muscle tests besides 25(OH)D, including participants’ dietary habits; serum PTH, estradiol, and 1,25(OH)2D levels; pain; and activity. The 25(OH)D levels were measured by high-performance liquid chromatography, 1 of 2 gold standard assays.52 Finally, the PRC adjusted cholecalciferol doses to maintain 25(OH)D levels greater than 30 ng/mL in the high-dose arm, with sham adjustments in other arms to maintain masking.

Quiz Ref IDWe also note some study limitations. Few African American women participated, limiting our ability to detect differential responses to cholecalciferol based on race. Results cannot be used to guide cholecalciferol therapy for young adults, men, or women older than 75 years. Individuals participated for only 1 year; perhaps longer exposure to high-dose cholecalciferol through more remodeling cycles would yield greater effects on BMD.53

Conclusions

One year of high-dose cholecalciferol given to postmenopausal women with 25(OH)D levels less than 30 ng/mL (mean [SD], 21 [3] ng/mL at baseline) had a negligible effect on calcium absorption and no clinically meaningful beneficial effects on BMD, muscle function, or falls. Study results do not justify the common and frequently touted46,41 practice of administering high-dose cholecalciferol to older adults to maintain serum 25(OH)D levels of 30 ng/mL or greater. Rather, study results support the Institute of Medicine’s conclusion that vitamin D repletion is a serum 25(OH)D level of 20 ng/mL or greater.

Back to top
Article Information

Accepted for Publication: May 2, 2015.

Corresponding Author: Karen E. Hansen, MD, MS, Department of Medicine, University of Wisconsin School of Medicine and Public Health, 1685 Highland Ave, Room 4124, Medical Foundation Centennial Building, Madison, WI 53792 (keh@medicine.wisc.edu).

Published Online: August 3, 2015. doi:10.1001/jamainternmed.2015.3874.

Author Contributions: Dr Hansen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Hansen.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Hansen, Chambers, Lemon, Vo.

Critical revision of the manuscript for important intellectual content: Hansen, R.E. Johnson, M.G. Johnson, Lemon, Marvdashti.

Statistical analysis: Hansen, Chambers, Vo, Marvdashti.

Obtained funding: Hansen.

Administrative, technical, or material support: Hansen, R.E. Johnson, M.G. Johnson, Lemon, Marvdashti.

Study supervision: Hansen, R.E. Johnson, Lemon.

Conflict of Interest Disclosures: Dr Hansen reported working as a local principal investigator for a Takeda clinical trial. No other disclosures were reported.

Funding/Support: The study was supported by grant R01 AG028739 from the National Institute on Aging and grant R01 AG028739 (supplement) from the Office of Dietary Supplements (Dr Hansen).

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Additional Contributions: We thank all participants, who devoted more than 1 year to the trial. We thank the Clinical Research Unit and Pharmaceutical Research Center staff for their excellent assistance in conducting the study. We are grateful for discussions about the manuscript with Alan J. Bridges, MD (professor of medicine and chief of staff, William S. Middleton Memorial Veterans Affairs Hospital, Madison, Wisconsin), and Kevin McKown, MD (professor of medicine and chief, Rheumatology Division, University of Wisconsin School of Medicine and Public Health). Finally, we thank the Data Safety Monitoring Board members J. Christopher Gallagher, MD (professor of medicine and chief, Bone Metabolism Section, Creighton University, Omaha, Nebraska), Kristine Ensrud, MD, MPH (professor of medicine and director of epidemiology, Clinical Research Center, University of Minnesota), Yvette Schuster, PhD (professor of statistics, Rutgers University), and Judy Hannah, PhD (professor and head, Nutrition Office, National Institute on Aging). We thank the laboratory of Hector DeLuca, PhD, from the University of Wisconsin for independently verifying the content of study capsules.

Correction: This article was corrected on October 2, 2015, to fix a typographical error.

References
1.
Melton  LJ  III.  Adverse outcomes of osteoporotic fractures in the general population. J Bone Miner Res. 2003;18(6):1139-1141.
PubMedArticle
2.
Cummings  SR, Melton  LJ.  Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002;359(9319):1761-1767.
PubMedArticle
3.
Holick  MF, Garabedian  M. Vitamin D: photobiology, metabolism, mechanism of action, and clinical applications. In: Favus  MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism.6th ed. Washington, DC: American Society for Bone and Mineral Research; 2006:106-114.
4.
Dawson-Hughes  B, Heaney  RP, Holick  MF, Lips  P, Meunier  PJ, Vieth  R.  Estimates of optimal vitamin D status. Osteoporos Int. 2005;16(7):713-716.
PubMedArticle
5.
Holick  MF.  Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.
PubMedArticle
6.
Dawson-Hughes  B, Bischoff-Ferrari  HA.  Therapy of osteoporosis with calcium and vitamin D. J Bone Miner Res. 2007;22(suppl 2):V59-V63.
PubMedArticle
7.
Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press; 2011.
8.
Looker  AC, Pfeiffer  CM, Lacher  DA, Schleicher  RL, Picciano  MF, Yetley  EA.  Serum 25-hydroxyvitamin D status of the US population: 1988-1994 compared with 2000-2004. Am J Clin Nutr. 2008;88(6):1519-1527.
PubMedArticle
9.
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):1052-1060.
PubMedArticle
10.
Lensmeyer  GL, Wiebe  DA, Binkley  N, Drezner  MK.  HPLC method for 25-hydroxyvitamin D measurement: comparison with contemporary assays. Clin Chem. 2006;52(6):1120-1126.
PubMedArticle
11.
Schrager  S, Girard  M, Mundt  M.  Dietary calcium intake among women attending primary care clinics in Wisconsin. WMJ. 2005;104(6):47-50.
PubMed
12.
Alaimo  K, McDowell  MA, Briefel  RR,  et al.  Dietary intake of vitamins, minerals, and fiber of persons ages 2 months and over in the United States: Third National Health and Nutrition Examination Survey, Phase 1, 1988-91. Adv Data. 1994;(258):1-28.
PubMed
13.
Weaver  CM, Fleet  JC.  Vitamin D requirements: current and future. Am J Clin Nutr. 2004;80(6)(suppl):1735S-1739S.
PubMed
14.
Deroisy  R, Collette  J, Albert  A, Jupsin  I, Reginster  JY.  Administration of a supplement containing both calcium and vitamin D is more effective than calcium alone to reduce secondary hyperparathyroidism in postmenopausal women with low 25(OH)vitamin D circulating levels. Aging Clin Exp Res. 2002;14(1):13-17.
PubMedArticle
15.
McKane  WR, Khosla  S, Egan  KS, Robins  SP, Burritt  MF, Riggs  BL.  Role of calcium intake in modulating age-related increases in parathyroid function and bone resorption. J Clin Endocrinol Metab. 1996;81(5):1699-1703.
PubMed
16.
Pattanaungkul  S, Riggs  BL, Yergey  AL, Vieira  NE, O’Fallon  WM, Khosla  S.  Relationship of intestinal calcium absorption to 1,25-dihydroxyvitamin D [1,25(OH)2D] levels in young versus elderly women: evidence for age-related intestinal resistance to 1,25(OH)2D action. J Clin Endocrinol Metab. 2000;85(11):4023-4027.
PubMed
17.
Marks  HD, Fleet  JC, Peleg  S.  Transgenic expression of the human Vitamin D receptor (hVDR) in the duodenum of VDR-null mice attenuates the age-dependent decline in calcium absorption. J Steroid Biochem Mol Biol. 2007;103(3-5):513-516.
PubMedArticle
18.
Levey  AS, Bosch  JP, Lewis  JB, Greene  T, Rogers  N, Roth  D; Modification of Diet in Renal Disease Study Group.  A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130(6):461-470.
PubMedArticle
19.
Holick  MF, Siris  ES, Binkley  N,  et al.  Prevalence of Vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab. 2005;90(6):3215-3224.
PubMedArticle
20.
Gilbert  MP, Pratley  RE.  The impact of diabetes treatments on bone health in patients with type 2 diabetes mellitus. Endocr Rev. 2015;36(2):194-213.
PubMedArticle
21.
Benjamini  Y, Hochberg  Y.  Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc, B. 1995;57(1):289-300.
22.
Hansen  KE, Bartels  CM, Gangnon  RE, Jones  AN, Gogineni  J.  An evaluation of high-dose vitamin D for rheumatoid arthritis. J Clin Rheumatol. 2014;20(2):112-114.
PubMed
23.
Brot  C, Vestergaard  P, Kolthoff  N, Gram  J, Hermann  AP, Sørensen  OH.  Vitamin D status and its adequacy in healthy Danish perimenopausal women: relationships to dietary intake, sun exposure and serum parathyroid hormone. Br J Nutr. 2001;86(suppl 1):S97-S103.
PubMedArticle
24.
Souberbielle  JC, Cormier  C, Kindermans  C,  et al.  Vitamin D status and redefining serum parathyroid hormone reference range in the elderly. J Clin Endocrinol Metab. 2001;86(7):3086-3090.
PubMed
25.
Sahota  O, Mundey  MK, San  P, Godber  IM, Lawson  N, Hosking  DJ.  The relationship between vitamin D and parathyroid hormone: calcium homeostasis, bone turnover, and bone mineral density in postmenopausal women with established osteoporosis. Bone. 2004;35(1):312-319.
PubMedArticle
26.
Webb  AR, Kline  L, Holick  MF.  Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab. 1988;67(2):373-378.
PubMedArticle
27.
Abrams  SA.  Using stable isotopes to assess mineral absorption and utilization by children. Am J Clin Nutr. 1999;70(6):955-964.
PubMed
28.
Griffin  IJ, Abrams  SA.  Methodological considerations in measuring human calcium absorption: relevance to study the effects of inulin-type fructans. Br J Nutr. 2005;93(suppl 1):S105-S110.
PubMedArticle
29.
Sterility Tests. Vol USP XXII, NF XVII. Easton, PA: Mack Printing Co; 1989.
30.
Sturup  S, Hansen  M, Molgaard  C.  Measurement of 44Ca: 43Ca and 42Ca: 43Ca istopic ratios in urine using high resolution inductively coupled plasma mass spectrometry. J Anal Spectrom.1997;12:919-923.Article
31.
Field  M, Shapses  S, Cifuentes  M, Sherrell  R.  Precise and accurate determination of calcium isotope ratios in urine using HR-ICP-SFMS. J Anal Spectrom.2003;18:727-733.Article
32.
Eastell  R, Vieira  NE, Yergey  AL, Riggs  BL.  One-day test using stable isotopes to measure true fractional calcium absorption. J Bone Miner Res. 1989;4(4):463-468.
PubMedArticle
33.
Podsiadlo  D, Richardson  S.  The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991;39(2):142-148.
PubMedArticle
34.
Tiedemann  A, Shimada  H, Sherrington  C, Murray  S, Lord  S.  The comparative ability of eight functional mobility tests for predicting falls in community-dwelling older people. Age Ageing. 2008;37(4):430-435.
PubMedArticle
35.
Washburn  RA, Smith  KW, Jette  AM, Janney  CA.  The Physical Activity Scale for the Elderly (PASE): development and evaluation. J Clin Epidemiol. 1993;46(2):153-162.
PubMedArticle
36.
Beaudart  C, Reginster  JY, Slomian  J, Buckinx  F, Locquet  M, Bruyère  O.  Prevalence of sarcopenia: the impact of different diagnostic cut-off limits. J Musculoskelet Neuronal Interact. 2014;14(4):425-431.
PubMed
37.
Shapses  SA, Kendler  DL, Robson  R,  et al.  Effect of alendronate and vitamin D₃ on fractional calcium absorption in a double-blind, randomized, placebo-controlled trial in postmenopausal osteoporotic women. J Bone Miner Res. 2011;26(8):1836-1844.
PubMedArticle
38.
Hansen  KE, Jones  AN, Lindstrom  MJ,  et al.  Do proton pump inhibitors decrease calcium absorption? J Bone Miner Res. 2010;25(12):2786-2795.
PubMedArticle
39.
Peto  R, Pike  MC, Armitage  P,  et al.  Design and analysis of randomized clinical trials requiring prolonged observation of each patient, I: introduction and design. Br J Cancer. 1976;34(6):585-612.
PubMedArticle
40.
Haybittle  JL.  Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol. 1971;44(526):793-797.
PubMedArticle
41.
Roux  C, Bischoff-Ferrari  HA, Papapoulos  SE, de Papp  AE, West  JA, Bouillon  R.  New insights into the role of vitamin D and calcium in osteoporosis management: an expert roundtable discussion. Curr Med Res Opin. 2008;24(5):1363-1370.
PubMedArticle
42.
Need  AG, O’Loughlin  PD, Morris  HA, Coates  PS, Horowitz  M, Nordin  BE.  Vitamin D metabolites and calcium absorption in severe vitamin D deficiency. J Bone Miner Res. 2008;23(11):1859-1863.
PubMedArticle
43.
Gallagher  JC, Yalamanchili  V, Smith  LM.  The effect of vitamin D on calcium absorption in older women. J Clin Endocrinol Metab. 2012;97(10):3550-3556.
PubMedArticle
44.
Aloia  JF, Dhaliwal  R, Shieh  A,  et al.  Vitamin D supplementation increases calcium absorption without a threshold effect. Am J Clin Nutr. 2014;99(3):624-631.
PubMedArticle
45.
Chan  EL, Lau  E, Shek  CC,  et al.  Age-related changes in bone density, serum parathyroid hormone, calcium absorption and other indices of bone metabolism in Chinese women. Clin Endocrinol (Oxf). 1992;36(4):375-381.
PubMedArticle
46.
Hoover  PA, Webber  CE, Beaumont  LF, Blake  JM.  Postmenopausal bone mineral density: relationship to calcium intake, calcium absorption, residual estrogen, body composition, and physical activity. Can J Physiol Pharmacol. 1996;74(8):911-917.
PubMedArticle
47.
Nordin  BE, Robertson  A, Seamark  RF,  et al.  The relation between calcium absorption, serum dehydroepiandrosterone, and vertebral mineral density in postmenopausal women. J Clin Endocrinol Metab. 1985;60(4):651-657.
PubMedArticle
48.
Ensrud  KE, Duong  T, Cauley  JA,  et al; Study of Osteoporotic Fractures Research Group.  Low fractional calcium absorption increases the risk for hip fracture in women with low calcium intake. Ann Intern Med. 2000;132(5):345-353.
PubMedArticle
49.
Uusi-Rasi  K, Patil  R, Karinkanta  S,  et al.  Exercise and vitamin D in fall prevention among older women: a randomized clinical trial. JAMA Intern Med. 2015;175(5):703-711.
PubMedArticle
50.
Sanders  KM, Stuart  AL, Williamson  EJ,  et al.  Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303(18):1815-1822.
PubMedArticle
51.
Sanders  KM, Ebeling  P, McCorquodale  T, Herrman  M, Shore-Lorenti  C, Nicholson  G.  The efficacy of high-dose oral vitamin D3 administered once a year: increased fracture risk is associated with 1,25 vitamin D level at 3-months post dose. J Bone Miner Res. 2012;27(suppl 1):S1.
PubMedArticle
52.
Cranney  A, Horsley  T, O’Donnell  S,  et al. Effectiveness and Safety of Vitamin D in Relation to Bone Health. Evidence Report/Technology Assessment No. 158. Rockville, MD: Agency for Healthcare Research and Quality; 2007. AHRQ publication 07-E013.
53.
Brockstedt  H, Kassem  M, Eriksen  EF, Mosekilde  L, Melsen  F.  Age- and sex-related changes in iliac cortical bone mass and remodeling. Bone. 1993;14(4):681-691.
PubMedArticle
×