Can serum isotope levels accurately measure intestinal calcium absorption compared to gold-standard methods?

BACKGROUND: Low fractional calcium absorption (FCA) contributes to osteoporosis but is not measured clinically, as the gold-standard method requires administration of two calcium tracers and a subsequent 24-h urine collection. We evaluated alternate methods to measure FCA, compared to the gold standard method. METHODS: We administered two stable calcium isotope tracers (~8 mg oral (44)Ca and ~3 mg intravenous (42)Ca) with breakfast to 20 fasting post-menopausal women (Cohort 1) 59 ± 7 years old with vitamin D insufficiency. We measured subsequent calcium isotope concentrations in 24-h urine samples and serum collected 1, 3 and 5 h post tracer administration during an inpatient research stay. We assessed the candidate serum estimates in a second cohort of 9 women with similar characteristics. Methods of measuring FCA were compared using correlation coefficients and Bland-Altman tests. RESULTS: FCA estimated from a 3-h serum sample correlated highest with the levels from the 24-h urine collection (ρ 0.78, p < 0.001), but explained only 58 % of the variance in FCA. The total variance explained by 3-h estimates improved to 61 % with incorporation of glomerular filtration rate (GFR). FCA estimates from the 3-h serum measurement were assessed in a second group of nine women (Cohort 2) 60 ± 7 years old. In this cohort, however, FCA estimated by 3-h serum isotope levels did not correlate with gold-standard FCA measurements, whether determined with (ρ 0.02, p = 0.97) or without GFR values (ρ 0.03, p = 0.93). By contrast, FCA in Cohort 2 correlated best with 5-h serum isotope levels (ρ 0.75, p = 0.02). CONCLUSIONS: We conclude that serum isotope levels correlate with true fractional calcium absorption, but do not reliably estimate FCA when analyzed using Bland-Altman tests, compared to gold-standard methods. TRIAL REGISTRATION: ClinicalTrials.gov.Identifier: NCT00933244.

Characteristics associated with bone mineral density responses to alendronate in men.

Some patients experience reduced bone mineral density (BMD) despite bisphosphonate therapy. We performed a retrospective chart review study to detect factors associated with decreased BMD in men prescribed alendronate. Two investigators reviewed eligible medical records and used a standardized form to record potential characteristics predicting men's response to alendronate. We analyzed patient characteristics associated with annualized change in hip and spine BMD (D-BMD). Among 115 eligible men, 19 (17 %) experienced significantly decreased BMD at the hip or spine, defined as a change exceeding precision error. Eleven men (10 %) fractured during therapy. Spine D-BMD was positively associated with adherence to alendronate (R = 0.23, p = 0.02) and inversely associated with baseline body weight (R = -0.21, p = 0.03). Hip D-BMD was positively associated with annualized weight change (R = 0.19, p = 0.0498) and negatively associated with patient age and number of concomitant medications (R = -0.21, p = 0.03; R = -0.20, p = 0.03, respectively). In stepwise linear models, spine D-BMD was associated positively with alendronate adherence and multivitamin use and negatively with baseline body weight. Hip D-BMD was negatively associated with age. Fracture during treatment was associated with fracture prior to therapy (p = 0.03). In this small study of men prescribed alendronate, BMD response showed a positive association with adherence to therapy, weight gain, and use of a multivitamin. By contrast, older age, higher baseline body weight, and higher number of medications were each associated with a decrease in BMD. Larger studies are needed to confirm and extend these findings.

The effect of physician workload on an educational intervention to increase vitamin D screening.

RATIONALE, AIMS AND OBJECTIVE: Changes in physician behavior are difficult to accomplish. We hypothesized measuring physicians' vitamin D levels would increase measurement of their patients' levels. METHODS: We recruited faculty via e-mail. We measured physicians' serum 25(OH)D levels and asked them to complete a questionnaire created to assess the risk of vitamin D deficiency. Physicians received their vitamin D test results by mail. We monitored physicians' vitamin D testing rate per 100 patient visits in the 12 weeks before and after receipt of their own vitamin D test result. RESULTS: Twenty-eight (22%) of 126 primary care physicians participated in the study; all were Caucasian and 17 (61%) were women. Gender, practic type, and year of graduation from medical school were similar in participants and non-participants. Over half of participants took a multivitamin and a third took a vitamin D supplement. Although 6 (21%) reported a recent fracture, only 1 physician carried a diagnosis of osteopenia or osteoporosis. At baseline, geriatricians ordered 14 vitamin D tests per 100 patient visits, while internists and family practitioners ordered substantially fewer tests (2 and <1 tests per 100 visits, respectively). After study participation, vitamin D testing rates increased significantly among family practitioners (rate ratio 3.27, 95% CI 1.29-8.33) and internists (rate ratio 3.19, 95% CI 1.12-9.07). Physicians with heavier clinic workloads were half as likely (rate ratio 0.50, 95% CI 0.32-0.76) as those with lighter clinic workloads to increase vitamin D testing rates. Surprisingly, physicians with hypovitaminosis D demonstrated no change in vitamin D testing rates. CONCLUSIONS: Physicians with low vitamin D testing rates were receptive to a personal intervention involving measurement of their own vitamin D levels. High workload appeared to attenuate this effect. These novel but preliminary observations require confirmation in future studies.

Do proton pump inhibitors decrease calcium absorption?

Proton pump inhibitors (PPIs) increase osteoporotic fracture risk presumably via hypochlorhydria and consequent reduced fractional calcium absorption (FCA). Existing studies provide conflicting information regarding the direct effects of PPIs on FCA. We evaluated the effect of PPI therapy on FCA. We recruited women at least 5 years past menopause who were not taking acid suppressants. Participants underwent three 24-hour inpatient FCA studies using the dual stable isotope method. Two FCA studies were performed 1 month apart to establish baseline calcium absorption. The third study occurred after taking omeprazole (40 mg/day) for 30 days. Each participant consumed the same foods during all FCA studies; study meals replicated subjects' dietary habits based on 7-day diet diaries. Twenty-one postmenopausal women ages 58 ± 7 years (mean ± SD) completed all study visits. Seventeen women were white, and 2 each were black and Hispanic. FCA (mean ± SD) was 20% ± 10% at visit 1, 18% ± 10% at visit 2, and 23% ± 10% following 30 ± 3 days of daily omeprazole (p = .07, ANOVA). Multiple linear regression revealed that age, gastric pH, serum omeprazole levels, adherence to omeprazole, and 25-hydroxyvitamin D levels were unrelated to changes in FCA between study visits 2 and 3. The 1,25-dihydroxyvitamin D(3) level at visit 2 was the only variable (p = .049) associated with the change in FCA between visits 2 and 3. PPI-associated hypochlorhydria does not decrease FCA following 30 days of continuous use. Future studies should focus on identifying mechanisms by which PPIs increase the risk of osteoporotic fracture.

Vitamin D repletion does not alter urinary calcium excretion in healthy postmenopausal women.

OBJECTIVE: To evaluate, in a posthoc analysis of a previous study, whether vitamin D repletion in postmenopausal women with insufficient vitamin D increases urinary calcium excretion, as vitamin D therapy might contribute to hypercalciuria and calcium stones in susceptible individuals, and the effect of vitamin D on the risk of urolithiasis warrants attention. SUBJECTS AND METHODS: We recruited 18 women at > or =5 years after menopause who had vitamin D insufficiency (serum 25(OH)-vitamin D, 16-24 mg/dL). We excluded women with a history of urolithiasis and kidney disease. Women had one calcium absorption study when vitamin D-insufficient, received vitamin D therapy, and completed a second calcium absorption study when vitamin D-replete. We fed subjects meals that mirrored the nutrient composition from self-reported 7-day diet diaries. To measure calcium absorption, we collected urine for 24 h during both visits. RESULTS: We achieved vitamin D repletion in all women (25(OH)-vitamin D before and after treatment, 22 and 63 mg/dL, respectively; P < 0.001). The mean calcium intake was 832 mg/day. Residual urine specimens were available for 16 women, allowing a measurement of 24-h urinary calcium. Calcium excretion did not change after vitamin D therapy (212 before vs 195 mg/day after; P = 0.60). Of four women with hypercalciuria (>247 mg/day), calcium excretion decreased in three (377-312 mg/day, not significant). CONCLUSION: Vitamin D supplementation did not increase the urinary calcium excretion in healthy postmenopausal women. Many stone formers are at risk of premature bone loss, vitamin D insufficiency, or both. Based on the present results we suggest a study of patients with hypercalciuria and nephrolithiasis to determine the risks of vitamin D therapy.

Recognizing the musculoskeletal manifestations of vitamin D deficiency.

A disruption in any part of the vitamin D physiological pathway can result in vitamin D deficiency, which may lead to bone pain, muscle weakness, falls, low bone mass, and fractures. Recognizing the signs and symptoms helps physicians make a proper diagnosis and prescribe appropriate treatment. Physicians should suspect osteomalacia in patients who have prolonged vitamin D deficiency, a low serum calcium level, or a low serum phosphorus level. Patients with cystic fibrosis are at increased risk for deficiencies in fat-soluble vitamins, including vitamin D. Secondary hyperparathyroidism can develop in patients with chronic kidney disease as a result of low 25-hydroxyvitamin D levels or impaired conversion to 1,25-dihydroxyvitamin D. Patients may experience abnormal vitamin D metabolism as a result of taking anticonvulsants and other medications.

Vitamin D and musculoskeletal health.

Vitamin D is critical for calcium homeostasis. Following cutaneous synthesis or ingestion, vitamin D is metabolized to 25(OH)D and then to the active form 1,25(OH)2D. Low serum vitamin D levels are common in the general population and cause a decline in calcium absorption, leading to low serum levels of ionized calcium, which in turn trigger the release of parathyroid hormone, promoting skeletal resorption and, eventually, bone loss or osteomalacia. Vitamin D deficiency is generally defined as a serum 25(OH)D concentration <25-37 nmol/l (<10-15 ng/ml), but the definition of the milder state of vitamin D insufficiency is controversial. Three recent meta-analyses concluded that vitamin D must be administered in combination with calcium in order to substantially reduce the risk of nonvertebral fracture in adults over the age of 50 years. Fracture protection is optimal when patient adherence to medication exceeds 80% and vitamin D doses exceed 700 IU/day. In addition to disordered calcium homeostasis, low vitamin D levels might have effects on cell proliferation and differentiation and immune function. Randomized, double-blind, placebo-controlled trials are needed to clarify whether vitamin D supplementation is beneficial in cancer, autoimmune disease and infection. This Review focuses on the pathophysiology, clinical correlates, evaluation and treatment of hypovitaminosis D.

Vitamin D insufficiency: disease or no disease?

Vitamin D insufficiency (VDI) is widely reported. In patients with normal PTH, the diagnosis rests on increases in fractional calcium absorption (FCA) when 25(OH)D increases above 30 ng/ml. However, estimates of increased FCA after correction of VDI vary dramatically, depending on study methods. We used a dual stable calcium isotope to clarify the impact of vitamin D repletion on FCA in postmenopausal women with VDI. We hypothesized that FCA would increase with vitamin D repletion. We studied postmenopausal women with VDI [25(OH)D = 16-24 ng/ml] and an estimated calcium intake