Treatment of Vitamin D Insufficiency in Postmenopausal Women: A Randomized Clinical Trial

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Hansen KE, et al. "Treatment of Vitamin D Insufficiency in Postmenopausal Women: A Randomized Clinical Trial". JAMA Internal Medicine. 2015. epub:.
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Clinical Question

In postmenopausal females with vitamin D insufficiency, does high-dose cholecalciferol, as compared to low-dose cholecalciferol or placebo, lead to 1-year changes in total fractional calcium absorption or bone mineral density (BMD)?

Bottom Line

Cholecalciferol, regardless of dosage, may not have clinically significant positive effects on the disease-oriented outcomes of bone mineral density and calcium absorption, and the patient-oriented outcomes still need to be studied further. The recommendation to maintain serum 25(OH)D levels at 30 ng/mL is not supported by this study.

Major Points

Vitamin D insufficiency is an important condition to analyze due to its’ high prevalence. Studies have been completed in the past that have tried to establish the optimal level of vitamin D for skeletal health in postmenopausal women, but they often disagree, which leads to clinical confusion. Previous recommendations have stated that serum vitamin D levels should be maintained above a level of 30 ng/mL, but some have stated that a level maintained above 20 ng/mL is appropriate

Women who were diagnosed with osteoporosis were excluded from the study, in which it was noted that low-dose cholecalciferol and placebo had similar levels of effectiveness with regards to the outcomes. This study concludes that high-dose cholecalciferol can lead to minor increases in calcium absorption (1%) with debatable clinical significance, and has no significant effects on BMD, TUG score, STS score, and other morbidity outcomes. Thus, this study does not support the recommendation to maintain serum vitamin D levels at that specific level. It supports the recommendation to maintain vitamin D levels around 20 ng/mL.

Guidelines

There are no official guidelines from professional organizations regarding the use of cholecalciferol therapy for the desired outcomes discussed in this study. However, the AACE (American Association of Clinical Endocrinologists) does recommend the use of vitamin D in postmenopausal females with osteoporosis.

Design

  • Single-center, double-blind, randomized, placebo-controlled trial
  • N = 230
    • Placebo (N = 76)
    • Low-dose cholecalciferol (N = 75)
    • High-dose cholecalciferol (N = 79)
  • Setting: One center in Madison, Wisconsin
  • Enrollment: May 1, 2010-July 31, 2013, with final visits completed on August 8, 2014
  • Intention-to-treat
  • Primary Outcome: 1-year change in total fractional calcium absorption
  • Secondary Outcome: Bone mineral density change

Population

Inclusion Criteria

  • Women with vitamin D insufficiency, defined as serum 25(OH)D levels of 14 to 27 ng/mL
  • 5 years or more past the date of last menses or bilateral oophorectomy
    • 60 years old or more if they had a prior hysterectomy without bilateral oophorectomy
  • Dietary and supplemental Ca intake of >600 mg or <1400 mg

Exclusion Criteria

  • Women >75 years old
  • Osteoporosis
  • Hypercalcemia, noted as serum Ca > 10.4 mg/dL
  • Nephrolithiasis
  • IBD
  • CKD, with GFR < 45 mL/minute
  • Use of “bone-active” medications within past 6 months of the study
    • Bisphosphonates
    • Estrogen compounds
    • Calcitonin
    • Teriparatide
    • Oral corticosteroids
    • Anticonvulsants
  • Diabetes
  • Active cancer within past 5 years
  • Use of high-dose vitamin D supplements (>400 IU./day)
  • Prior fracture of the hip, spine, or wrist
    • T-score below -2.5

Baseline Characteristics

  • Mean age: 61 years
  • Mean weight: 81 kg
  • Mean height: 163 cm
  • Mean BMI: 30.8 kg/m2
  • Mean dietary “all” calcium intake: 967 mg/day
  • Mean serum laboratory calcium levels: 9.1 mg/dL

Interventions

  • Randomized to placebo (0 IU), high-dose (50,000 IU) or low-dose (800 IU) cholecalciferol
    • High-dose: Loading dose of 50,000 IU/day for 15 days, then 50,000 IU every 15 days for next 11.5 months
    • Low-dose: Sham loading with placebo to maintain masking, but 800 IU/day of cholecalciferol with placebo capsule every 15th day
    • Placebo: Placebo capsules daily.
  • Participants in all treatment arms returned for study visits 30, 60, 120, 240, and 365 days after randomization
    • Each visit had 25(OH)D measurement, Ca level measurement, Timed Up and Go performance tests, and five sit-to-stand tests.
    • Participants would also record pain levels, functional status (through a questionnaire), and activity (through a scale)
  • Note: If a woman in the high-dose arm had a 25(OH)D level of less than 30 ng/mL during one of the measurements, the cholecalciferol dose would be adjusted to achieve and maintain repletion.
    • 8% of participants in the other arms received sham adjustments with placebo capsules to maintain masking.

Outcomes

Comparisons are high-dose cholecalciferol vs. low-dose cholecalciferol first, followed by high-dose cholecalciferol vs. placebo

Primary Outcome

1-year change in total fractional calcium absorption
+1% vs. -2% (P=0.005)
+1% vs. -1.3% (P=0.03)

Secondary Outcome

Bone mineral density changes (Total Body)
-0.004 g/cm2 vs. -0.006 g/cm2 (P=0.93)
-0.004 g/cm2 vs. -0.006 g/cm2 (P=0.93)

Additional outcomes

At one year. See table 2 in the full text.

Timed Up and Go Test (change, mean)
-0.38 vs. -0.44 (P=0.97)
-0.38 vs. -0.35 (P=0.91)
Five Sit-to-Stand Test (change, mean)
-1.04 vs. -0.98 (P=0.98)
-1.04 vs. -0.55 (P=0.30)
Health Assessment Questionnaire (change, mean)
0.02 vs. -0.02 (P=0.48)
0.02 vs. 0.01 (P=0.99)
Physical Activity Scale for the Elderly (change, mean)
-4.04 vs. -21.64 (P=0.38)
-4.04 vs. -17.25 (P=0.57)
Muscle mass (change, mean)
0.002 vs. 0.1 (P=0.83)
0.002 vs. 0.05 (P=0.39)
Falls (# of falls per arm)
35 vs. 33 (P=0.92)
35 vs. 36 (P=0.92)
Fallers (% of arm who fell)
29.7% vs. 30.3% (P=0.92)
29.7% vs. 32.9% (P=0.92)


Adverse Events

  • Nephrolithiasis (in one patient in the low-dose arm)
  • Falls, fractures, hospitalizations (grouped together in one category by study designers)
    • Evenly distributed between the three arms
  • Transient asymptomatic hypercalcemia (two patients)

Criticisms

  • The study authors noted that they were only able to enroll few African-American women, so potential racial differences could not be adequately analyzed.
  • Cholecalciferol therapy cannot be guided for young adults, men, or women older than 75 years with these study results, including those patients in those populations who may need cholecalciferol therapy.
  • With a participation period of one year, the authors believe that BMD changes could have been more significant if there was more time allocated for the trial. The editor of the online version of this article, Dr. Deborah Grady, MD, MPH added a note that was published alongside the original study, which can be found on the sidebar of the JAMA Internal Medicine page that houses the study. No official criticisms of this study have been published at this time.

Funding

The study was funded by grants from the National Institute on Aging, as well as the Office of Dietary Supplements. There were no reported conflicts of interest for primary author Dr. Hansen, aside from working as a local investigator for a Takeda clinical trial.

Further Reading

  • Hansen KE, Jones AN, Lindstrom MJ, et. al. Vitamin D insufficiency: disease or no disease? J Bone Miner Res. 2008;23(7):1052-1060. [[1]]
  • Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.
  • 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.
  • Watts NB, Bilezikian JP, Camacho, PM, et. al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis. Endocr Pract. 2010;16(Suppl 3): 1-36