Impaired vitamin D metabolism with aging in women. Possible role in pathogenesis of senile osteoporosis.

Tsai, Keh–Sung; Heath, Hunter; Kumar, Rajiv; Riggs, B. Lawrence

doi:10.1172/jci111373

Cited by 337 publications

(98 citation statements)

References 23 publications

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“…The low D-hormone serum levels observed with a creatinine clearance of <65 ml/min may also be one reason for the increased osteopenia and osteoporosis observed with low creatinine clearance by other authors [15,16]. Our result enhances the theory suggested by other studies [4,5,6,7,17,18,19,20,21,22] that D-hormone is an independent risk factor for falls [1,2,5,23], and that D-hormone is directly involved in the causal pathogenic pathway of decreased muscle strength related falls [9,23,24]. It has been recently confirmed in VDR gene deleted mice that the absence of VDR causes muscle abnormality independently of secondary metabolic changes, e.g.…”

Section: Discussionsupporting

confidence: 87%

“…We therefore conclude that our previously observed approximately 4 times increased risk of falls observed in participants with a low creatinine clearance is due to a creatinine clearance dependent decrease in D-hormone serum levels. Therefore treatment options for patients at risk for falls should clearly differentiate between nutritive vitamin D deficiency and metabolic low D-hormone syndrome [18,19,20,21].…”

Section: Discussionmentioning

confidence: 99%

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Treatment with alfacalcidol in elderly people significantly decreases the high risk of falls associated with a low creatinine clearance of <65�ml/min

et al. 2004

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We previously observed that a creatinine clearance (CrCl) of <65 ml/min is a significant and independent risk factor for the number of fallers and falls in a community-dwelling elderly population and postulated that this increased risk is due to the associated significant lower D-hormone serum levels. To test our hypothesis, we investigated in a post hoc analysis of a double-blind randomized study whether treatment with alfacalcidol, a synthetic prodrug of the D-hormone, can reduce the high incidence of fallers and the high risk of falls associated with low CrCl. Of 378 Swiss community-dwelling women (n=191) and men (n=187), aged 70 years and older, 191 received randomly 1 lg capsules of alfacalcidol (AlphaD3: Teva), and 187 received one capsule of placebo daily. With the help of questionnaires we regularly assessed the incidence and frequency of falls. The risk of becoming a faller and the risk of falling were assessed in multivariate-controlled logistic regression models according to treatment groups and according to a CrCl cut-off of 65 ml/min. The presented results are from ITT analyses. In participants with a CrCl of <65 ml/min, the 36 weeks of treatment with alfacalcidol was, compared with placebo, associated with a significant reduction in the number of fallers (14/72 versus 25/70; OR 0.26, 95% CI 0.08-0.80, P=0.019), and a significant reduction of the number of falls (16/72 versus 28/70; OR 0.29, 95% CI 0.09-0.88, P=0.028). No such association was observed in participants with a CrCl of ‡65 ml/min (for fallers 26/120 versus 21/116; OR 0.92 95% CI 0.34-2.52, P=0.875; for falls 32/120 versus 23/116; OR 0.93 95% CI 0.34-2.54, P=0.885). In the placebo group frequency of falls was dependent on CrCl (P=0.006), whereas in the alfacalcidol treatment group frequency of falls was independent of CrCl (P=0.494). No cases of clinically relevant hypercalcemia were observed. In a community-dwelling population of elderly men and women with a CrCl of <65 ml/min, treatment with alfacalcidol can significantly and safely reduce the low CrCl associated increased number of fallers and the high risk of falls.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Treatment with alfacalcidol in elderly people significantly decreases the high risk of falls associated with a low creatinine clearance of <65�ml/min

et al. 2004

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“…However, functional parameters that have been related to vitamin D and 1.25(OH) 2 D 3 decline at serum levels which are above the defined deficiency levels. Serum concentrations of 1.25(OH) 2 D 3 , which are significantly above the lowest defined normal value of 1.25(OH) 2 D 3 , respectively associated increases in iPTH serum levels, have been shown to have a negative impact on muscle strength and functional mobility [8,9] and have been related to myopathy [9,10,11,28,34]. Serum levels of 1.25(OH) 2 D 3 have been associated with decreased muscle strength, lower endurance [8,9,10,11,12], reduced functional mobility [13,14], and atrophy of fast-twitch muscle fibers [35].…”

Section: Discussionmentioning

confidence: 99%

“…Aging is associated with a deterioration of renal function, easily measurable as deterioration of the creatinine clearance, and several studies suggest that a significant number of elderly people, even with normal vitamin D serum levels (>12 ng/ml), may suffer from a deficiency of 1.25(OH) 2 D 3 [27,28,29], due to the age-related impaired renal function and the consecutively decreased activity of the renal 1a-hydroxylase [21,30].…”

Section: Introductionmentioning

confidence: 99%

A new significant and independent risk factor for falls in elderly men and women: a low creatinine clearance of less than 65�ml/min

et al. 2004

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Objectives: Because impaired renal function is detrimental for the conversion of calcidiol to calcitriol (D-hormone) and since D-hormone analogues have been shown to decrease the risk of falls, we investigated whether creatinine clearance (CrCl) is associated with the number of fallers and falls in elderly men and women. Methods: Within a randomized controlled study, we observed for 36 weeks 186 placebo-treated community-dwelling elderly men and women over 70, in an attempt to determine the influence of baseline CrCl on calcitropic hormone serum levels, as well as the influence of baseline CrCl on the number of fallers and falls over time. With the help of questionnaires, we regularly assessed fall incidence and frequency. The risk of falls and the risk of becoming a faller were assessed in multivariate-controlled logistic regression models according to a cutoff value of the CrCl set at 65 ml/min. Results: At baseline, serum levels of 1.25(OH) 2 D 3 and iPTH were, in multivariate-controlled analyses, significantly associated with CrCl (p<0.0001, p=0.001, respectively), whereas serum levels of 25(OH)D 3 were not associated with CrCl. Below a CrCl of 65 ml/min, 1.25(OH) 2 D 3 serum levels steadily declined. We therefore chose a CrCl of 65 ml/min as cutoff for further analyses. During the 36 weeks of observation, elderly people with a CrCl of <65 ml/min had, in multivariate controlled analyses, compared with elderly with a CrCl of ‡65 ml/min, a significantly higher incidence of number of fallers (25/70 vs 21/116; OR=4.01; 95% CI, 1.48-10.98; p=0.006), and a significantly higher incidence of falls (28/70 vs 23/ 116; OR=3.68; 95% CI, 1.38-9.82; p=0.009). Conclusions: For the first time we showed that in a communitydwelling population of elderly men and women, a CrCl of less than 65 ml/min is a significant and independent risk factor for fallers and falls.

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“…This situation is further influenced by a decreased cellular response to PTH, and in women, by the hypo-estrogenism following menopause (Tsai et al, 1984;Gennari et al, 1990;Eastell et al, 1991;Nuti and Martini, 1994;Ooms et al, 1995). Therefore, the intestinal calcium absorption is reduced to an extent similar to malabsorptive syndromes (i.e.…”

Section: Bone Metabolism During Agingmentioning

confidence: 99%

Calcium metabolism and vitamin D in the extreme longevity

Passeri

Vescovini

Sansoni

et al. 2008

Experimental Gerontology

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Skeletal remodelling is a continuous process during life and is still active also in extreme senescence. In the elderly, bone resorption often prevails over bone formation, causing bone loss and fragility. Elderly subjects are exposed to the risk of fractures, and loss of self-sufficiency, if considering that the proximal femur is the most frequently involved site. Bone remodelling can maintain circulating calcium within physiological ranges, at the expense of a substantial loss of this ion from the skeleton, particularly during senescence. Calcium metabolism is regulated at cellular/molecular level by a network of cytokines, growth factors, systemic hormones that act on bone in paracrine/autocrine/ systemic fashion. Among the molecules involved in bone metabolism, parathyroid hormone (PTH) and vitamin D present some peculiar aspects during senescence. The osteometabolic features in a consistent group of centenarians have been evaluated. It results that a severe hypovitaminosis D was present in 99 out of 104 centenarians (25-OH vitamin D below 5 nmol/L), and that it plays an important role as a factor inducing a vicious circle involving hypocalcemia, secondary hyperparathyroidism, together with biochemical features indicating a consistent bone loss. Serum C-terminal cross-linking telopeptide, a specific marker of bone resorption was elevated in 92% of these subjects. Moreover, it has been found that several femoral fractures had occurred after 90 years of age. These data offer a rational for the possible prevention of elevated bone turnover, bone loss and consequently the reduction of osteoporotic fractures and fractures-induced disability, in the oldest olds, through the simple supplementation with calcium and vitamin D.

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Impaired vitamin D metabolism with aging in women. Possible role in pathogenesis of senile osteoporosis.

Cited by 337 publications

References 23 publications

Treatment with alfacalcidol in elderly people significantly decreases the high risk of falls associated with a low creatinine clearance of <65�ml/min

Treatment with alfacalcidol in elderly people significantly decreases the high risk of falls associated with a low creatinine clearance of <65�ml/min

A new significant and independent risk factor for falls in elderly men and women: a low creatinine clearance of less than 65�ml/min

Calcium metabolism and vitamin D in the extreme longevity

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