Adarsh Sai

BACKGROUND: Serum 25-hydroxyvitamin D (25-[OH]D) is considered the best biomarker of clinical vitamin D status. OBJECTIVE: To determine the effect of increasing oral doses of vitamin D(3) on serum 25-(OH)D and serum parathyroid hormone (PTH) levels in postmenopausal white women with vitamin D insufficiency (defined as a 25-[OH]D level ≤50 nmol/L) in the presence of adequate calcium intake. These results can be used as a guide to estimate the Recommended Dietary Allowance (RDA) (defined as meeting the needs of 97.5% of the population) for vitamin D(3). DESIGN: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00472823) SETTING: Creighton University Medical Center, Omaha, Nebraska. PARTICIPANTS: 163 healthy postmenopausal white women with vitamin D insufficiency enrolled in the winter or spring of 2007 to 2008 and followed for 1 year. INTERVENTION: Participants were randomly assigned to receive placebo or vitamin D(3), 400, 800, 1600, 2400, 3200, 4000, or 4800 IU once daily. Daily calcium supplements were provided to increase the total daily calcium intake to 1200 to 1400 mg. MEASUREMENTS: The primary outcomes were 25-(OH)D and PTH levels at 6 and 12 months. RESULTS: The mean baseline 25-(OH)D level was 39 nmol/L. The dose response was curvilinear and tended to plateau at approximately 112 nmol/L in patients receiving more than 3200 IU/d of vitamin D(3). The RDA of vitamin D(3) to achieve a 25-(OH)D level greater than 50 nmol/L was 800 IU/d. A mixed-effects model predicted that 600 IU of vitamin D(3) daily could also meet this goal. Compared with participants with a normal body mass index (<25 kg/m(2)), obese women (≥30 kg/m(2)) had a 25-(OH)D level that was 17.8 nmol/L lower. Parathyroid hormone levels at 12 months decreased with an increasing dose of vitamin D(3) (P = 0.012). Depending on the criteria used, hypercalcemia occurred in 2.8% to 9.0% and hypercalciuria in 12.0% to 33.0% of participants; events were unrelated to dose. LIMITATION: Findings may not be generalizable to other age groups or persons with substantial comorbid conditions. CONCLUSION: A vitamin D(3) dosage of 800 IU/d increased serum 25-(OH)D levels to greater than 50 nmol/L in 97.5% of women; however, a model predicted the same response with a vitamin D(3) dosage of 600 IU/d. These results can be used as a guide for the RDA of vitamin D(3), but prospective trials are needed to confirm the clinical significance of these results. PRIMARY FUNDING SOURCE: National Institute on Aging.

CONTEXT: There is a controversy regarding the definition of vitamin D insufficiency as it relates to bone health. OBJECTIVE: The objective of the study was to examine the evidence for a threshold value of serum 25-hydroxyvitamin D (25OHD) that defines vitamin D insufficiency as it relates to bone health. DESIGN AND PARTICIPANTS: This was a cross-sectional analysis of baseline data in 488 elderly Caucasian women, mean age 71 yr, combined with a literature review of 70 studies on the relationship of serum PTH to serum 25OHD. SETTING: The study was conducted in independent-living women in the midwest United States. MAIN OUTCOME MEASURE: The relationship between serum 25OHD, serum PTH, and serum osteocalcin and 24-h urine N-telopeptides was evaluated. RESULTS: Serum PTH was inversely correlated with serum 25OHD (r = -0.256, P < 0.0005), but no threshold as defined by suppression of serum PTH was found within the serum 25OHD range 6-60 ng/ml (15-150 nmol/liter). However, in contrast, there was a threshold for bone markers, serum osteocalcin and urine N-telopeptides, that increased only below a serum 25OHD of approximately 18 ng/ml (45 nmol/liter). Calcium absorption was not correlated with serum PTH and serum 25OHD, and no threshold was found. A literature review of 70 studies generally showed a threshold for serum PTH with increasing serum 25OHD, but there was no consistency in the threshold level of serum 25OHD that varied from 10 to 50 ng/ml (25-125 nmol/liter). CONCLUSIONS: Vitamin D insufficiency should be defined as serum 25OHD less than 20 ng/ml (50 nmol/liter) as it relates to bone.

There has been increasing interest in the potential benefits of vitamin D. Much of the stimulus came from meta-analysis of vitamin D and calcium in osteoporotic fracture studies as well as association studies relating increased prevalence of diseases such as cancer, diabetes, multiple sclerosis, and cardiovascular events with lower levels of serum 25-hydroxyvitamin D (25OHD). Vitamin D from diet or sun is converted in the liver to 25OHD and then in the kidney to 1,25-dihydroxyvitamin D [1,25(OH)2D], the active form of vitamin D. Normally, the main source of 1,25(OH)2D is the kidney, and serum 1,25(OH)2D is regulated by changes in serum calcium, phosphorus, fibroblast growth factor-23, and PTH; serum levels are held constant through homeostatic regulation. Circulating 1,25(OH)2D binds to the target tissues in the body that have a vitamin D receptor where it expresses vitamin D-responsive genes. In addition, many tissues (for example, breast, colon, prostate, bone, and immune cells) express 25OHD-1hydroxylase that converts 25OHD to 1,25-dihydroxyvitamin D locally. These local effects cause decreased proliferation of cells, increased cell differentiation, and cell survival. The importance of the peripheral conversion of 25OHD to 1,25(OH)2D relative to systemic production is difficult to assess, and nothing is known about the level of serum25OHDwhenperipheralconversionmightbe impaired. It is difficult to define adequate vitamin D nutrition because circulating vitamin D is derived from both dietary sources and sunlight; however, serum 25OHD is stable over weeks and serves as a biomarker of the adequacy of vitamin D supplies. The sunlight effect depends on distance from the equator, so for example in northern countries at 40° latitude, sunlight–or rather UVB radiation–is effective in converting 7-dehydrocholesterol to vitamin D3 in skin for about 7 months of the year and in Sweden at 55–65° latitude, monthly exposure to UVB is 5 months. The length of effective UVB exposure depends on the angle of the sun and atmospheric pollution, and the sun needs to be above 35° to be effective. With the ready availability of accurate serum 25OHD measurements, results from different countries show a lot of variation in levels, and the discussion centers on the significance of the values. What is a low level? In the past, vitamin D deficiency was defined as serum 25OHD below 10 ng/ml because both serum 1,25(OH)2D and calcium absorption declined significantly at this level (1, 2). The World Health Organization (WHO) defined vitamin D insufficiency as serum 25OHD below 20 ng/ml (50 nmol/ liter) (3). However, others recently started to define vitamin D deficiency as serum 25OHD level below 20 ng/ml and vitamin D insufficiency as less than 30 ng/ml (75 nmol/ liter) (4). The primary argument for this change in definition is based on the finding that serum PTH, which is inversely related to serum 25OHD, decreases as serum 25OHD increases and reaches a plateau at a serum 25OHD of approximately 30 ng/ml (75 nmol/liter). This is certainly controversial because numerous studies show a large variation in the plateau level of PTH ranging from a serum 25OHD of 18 ng/ml (45 nmol/liter) (5) to 30 ng/ml (75 nmol/liter) (6). This change in definition of vitamin D insufficiency actually has major significance because the dose of vitamin D required to increase people to a minimum serum 25OHD of 20 ng/ml (50 nmol/liter) is approximately 800 IU daily (7), whereas increasing people to a minimum level of 30 ng/ml (75 nmol/liter) would require approximately 4,000 IU daily (8). Unfortunately, there are no long-term prospective studies of either the efficacy or safety of these larger doses of vitamin D. There are two important questions: what data support recommending a minimum serum 25OHD level of either 20 ng/ml (50 nmol/liter) or 30

OBJECTIVES: To ascertain the risk factors for falls, stumbles and recurrent falls in a cohort of elderly people with mean age of 76.7-/+6.1 years. METHODS: 137 community dwelling elderly living independently or in assisted living institutions participated in the study. Each subject was assessed by history, physical examination and physical performance tests at the beginning and end of study. Falls and stumbles were recorded in a falls dairy for 1 year. RESULTS: Significant predictors of being a faller were a history of falls at baseline (Odds Ratio (OR) = 3.85, 95% Confidence Interval (CI) = 1.56 - 9.50), depression (OR = 1.19, 95% CI = 1.02 - 1.38) and timed rise (Incident Rate Ratio (IRR) = 1.24, 95% CI = 1.03 - 1.50). For predicting recurrent fallers Receiver Operator Characteristic (ROC) curves were as follows: 0.71 (95%CI 0.61-0.81) for timed up and go, 0.67 (95%CI 0.56-0.78) for timed rise and 0.70 (95%CI 0.60-0.80) for timed walk fast pace. CONCLUSIONS: Timed rise was the single most important test that was able to predict both a first time faller and recurrent faller. Timed up and go was the most significant test to predict recurrent fallers.