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Maintenance of musculoskeletal function and fall prevention are important public health targets in a rapidly aging population. Sarkopenia is prevalent in older persons and resulting in falls among 30% percent of those 65 years or older, and 40­50% of those 80 years or older.

Several beneficial effect of vitamin D have been described, the most established one being improved bone mineral density and fracture prevention. On the other hand, muscle weak­ness is also a prominent feature of the clinical syndrome of vit­amin D deficiency and may plausibly mediate fracture risk through an increased susceptibility to falls. In fact, vitamin D appears to directly improve muscle strength and effects on muscle strength occur within 8-12 weeks.

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D and calcium are important for normal skeletal growth and for maintaining the mechanical and structural integrity of the skeleton. Even though secure inferences from randomized controlled trials on the prevention of osteoporotic fracture with calcium and vitamin D supplementation are very limited, expe- cially in women within the first years of menopause, these com­pounds have been demonstrated to be pharmacologically ac­tive, safe, and cost-effective for the prevention and treatment of osteoporosis. Their use should therefore be encouraged, particularly in the elderly as well as in other conditions of di­etary deficiences. Moreover, over the last 30 years, several clinical trials have reported the efficacy of vitamin D-hormone analogs, calcitriol and alfacalcidiol, as possible additional ther­apies for osteoporosis. In recent comparative studies as well as in meta-analyses these compounds showed an overall in­creased skeletal efficacy compared to plain vitamin D. However, their role in fracture prevention, as well as their relative efficacy with respect to other treatment regimens in osteoporosis (i.e. bisphosphonates), remain un­der-investigated in long-term randomized controlled trials. Cer­tainly, there is consistent and increasing evidence that treat­ment with vitamin D analogs or calcium plus vitamin D supple­mentation exert a synergistic effect with antiresorptive agents on bone, and, thus, most patients will derive further benefit in terms of fracture prevention from the addition of an antiresorp- tive agent.

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In addition to its role in postmenopausal and involutional osteoporosis, calcitriol was used in the treatment of secondary os­teoporosis, especially corticosteroid-induced osteoporosis and post-transplantation bone loss. Corticosteroids result in impaired gastrointestinal absorption of calcium and increased urinary calcium loss leading to sec­ondary hyperparathyroidism with enhanced bone resorption, as well as having direct inhibitory effects on osteoblasts and bone formation. However, even though vitamin D analogs were found to be active in preventing hip and spinal bone loss in cor­ticosteroid induced osteoporosis, their effect appear lower than that observed with bisphosphonates and further data are required regarding fracture prevention in patients receiving glu­cocorticoid therapy. The mechanism of action of calcitriol in preventing transplant osteoporosis may be related to effects on either corticosteroid or cyclosporine pathways, especially secondary hyperparathyroidism, or to its immunomodulatory properties with consequent immunosuppressive agent sparing. Recent clinical trials also suggest an important future role of calcitriol as adjunctive therapy to bisphosphonates and estrogen in the treatment of osteoporosis. In particular, a sig­nificant benefit of calcitriol treatment combined with HRT on BMD at different skeletal sites has been demonstrated in post­menopausal women.

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The 1 a-hydroxylated forms of vitamin D, 1,25-dihydroxychole- calciferol or calcitriol, and 1 a-hydroxy-cholecalciferol or alfacal- cidiol, have been proposed as possible therapies for osteo­porosis. Both compounds strongly stimulate the in­testinal calcium absorption, and the response is dose-depen­dent (Fig. 5). This leads to a suppression of PTH secretion and a decrease in bone turnover. Over the past two decades, sev­eral clinical trials have been performed in osteoporotic patients using calcitriol or alfacalcidiol, at doses from 0.25 to 2.0 |jg/day. A positive effect of both compounds on BMD was seen in some clinical trials, whereas in others there was no change in BMD (13, 50, 103). In addition, there is not yet a definite an­swer as to whether these compounds decrease the incidence of osteoporotic fractures. A meta-analysis on published ran­domised controlled trials showed a consistent, statistically sig­nificant effect of hydroxilated vitamin D compounds in all BMD sites for doses above 0.43 mcg, with an overall effect that was higher than that of standard vitamin D treatment. A more recent meta-analysis revised the overall effect of active vitamin D metabolites (alfacalcidiol and calcitriol) on BMD and fracture rate. A global effect in preventing bone loss in patients not exposed to corticosteroids was demonstrated. Moreover, active vitamin D metabolites significantly reduced the overall fracture rate (RR 0.52, 95% CI 0.46-0.59) and both vertebral (RR 0.53, 95% CI 0.47-0.60) and non-vertebral (RR 0.34, 95% CI 0.16-0.71) fracture rate, respectively. The therapeutic effects seem to be pharmacological rather than physiological, and some concern exists about the potential side effects of this treatment. Hypercalcemia and impairment of renal function are rare with lower doses (up to 0.5 jg/day) but more frequent with higher doses (1-2 jg/day). For these reasons, treatment with calcitriol or alfacalcidiol necessitates monitoring of serum calci­um and renal function, unlike treatment with vitamin D. A number of clinical trials have been conducted over the past few years with the aim of verifying the efficacy of calcitriol in postmenopausal and involutional osteoporosis.

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Moreover, both vitamin D alone (vitamin D2 300,000 IU single injection or oral vitamin D3 800 IU/day) and vitamin D associated with calcium resulted in a small but significant improvement in BMD, suppressed parathyroid hormone, and reduced falls as compared to con­trols in a recent secondary prevention study. Even though most studies documented a positive effect on BMD, the role of vitamin D supplementation on fracture risk is still controversial (Fig. 4). In a retrospective epidemiological case-control study conducted in six European Mediterranean countries (MEDOS study) treatment with vitamin D was report­ed to be associated with a slight but not significant reduction in the incidence of hip fracture. Randomized controlled trials showed conflicting results. A systematic meta-analysis indicated that a clear reduction in hip (pooled RR 0.74, 95% CI 0.61-0.88) and non-vertebral (pooled RR 0.77, 95% CI 0.68-0.87) fracture risk of vitamin D at doses of 700-800 IU/day, but not at 400 IU/day. However, the relative effect of vitamin D alone or vitamin D plus calcium was not investigated. A more recent meta-analysis showed no statistically significant effect of vi­tamin D alone on hip fracture (seven trials, 18,668 participants, RR 1.17, 95% CI 0.98 to 1.41), vertebral fracture (four trials, 5698 participants, RR – random effects 1.13, 95% CI 0.50 to 2.55) or any new fracture (eight trials, 18,903 participants, RR 0.99, 95% CI 0.91 to 1.09). Conversely, vitamin D with calcium marginally reduced hip fractures (seven trials, 10,376 participants, RR 0.81, 95% CI 0.68 to 0.96), non-vertebral fractures (seven trials, 10,376 participants, RR 0.87, 95% CI 0.78 to 0.97), but there was no evidence of effect of vitamin D with cal­cium on vertebral fractures. The effect appeared to be restricted to those living in institutional care. The first prospective, large, multicenter, randomised, double-blind, placebo controlled study was performed on a French cohort of over 3000 institutionalised elderly women (mean age 84 years) during treatment with either vitamin D (800 IU/day) and calcium (1.2 g/day) or placebo for three years. Active treatment significantly reduced the inci­dence of new hip fractures by 29% and that of all non vertebral fractures by 24% (90). Similar results on hip fracture prevention (RR 1.6; 95% CI 0.96-3.0) were obtained in a multicenter, ran­domised, double-masked, placebo-controlled confirmatory study on 583 French ambulatory institutionalised women (mean age 85.2 years) as well as in a placebo-controlled trial of the effect of calcium (500 mg/day) and vitamin D (700 IU/day) in healthy community-based men and women older that 65 years. After three years 12.9% of subjects treated with placebo and 5.9% of those treated with vitamin D and calcium sustained non-vertebral fractures, a statistically significant difference. Moreover, two different studies showed that vitamin D₃ treat­ment by itself at doses of 100,000 IU every 4 months or 30,000 IU annually reduces the occurrence of fractures in elderly subjects.

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Relatively small changes in vitamin D status may have signifi­cant effects on bone mass. This justifies the use of vitamin D and its active metabolites in the prevention and treatment of osteoporosis, since vitamin D deficiency or insufficiency has been found to be frequent in the elderly as well as in post­menopausal women, particularly during low sun exposure.

Treatment with vitamin D

The most rational approach to reducing vitamin D insufficiency is supplementation. It has been estimated that the body uses on average 3,000-5,000 IU daily of cholecalciferol. Even though both vitamin D₂ and D₃ can be used, ergocalciferol is only about 20-40% as effective as cholecalciferol in maintain­ing serum 25(OH)D concentrations, since is more rapidly ca- tabolized. Fortification of foods with vitamin D provides an alternative approach to direct supplementation. This approach is common in the US, where milk is fortified with vitamin D, and less common in Europe with the exception of some Northern countries (Belgium, Netherlands and United Kingdom) where fortification is compulsory only to margarines. In Europe, the recommended dietary allowances (RDA) for vitamin D have been proposed in 1998 by the report on osteoporosis-action on prevention. The requirement for dietary vitamin D, based on European and Nordic recommendations, depends on the amount of sunshine exposure, with an higher limit estimated for individuals with minimal endogenous synthesis and a lower limit for individuals able to produce adequate vitamin D. How­ever, a common RDAs of 400 IU (10 mg) daily has been pro­posed for people aged 65 years or over. Even though a similar RDA of 400 IU irrespective of age is also established by the US Food and Drug Administration, the proposed Institute of Medicine Adequate Intake (AI) for the US and Canada is 400 IU daily for subjects 70 years or younger, and 600 IU (15 mg) daily for those over age 70 years. Importantly a daily intake of 600 IU of vitamin D₃ is needed to reach a mean serum 25(OH)D level of 50 nmol/l and at least 800-1000 IU (20-25 mg) is needed to attain a mean level of 75 nmol/l, that is close to the suggested threshold for optimal skeletal health. Thus, according to these recent evidences, higher vitamin D intakes than those currently recommended by RDAs and AI should be advised, especially in the elderly or other high-risk populations. As counterpart, excess vitamin D intake should be also avoided. Although the maximum safe dose is still un­known and doses of 4000 IU daily have been given without toxicity, intakes of 50 mg (2000 IU) daily should not be exceeded to avoid some harm full effects, such as hypercalcemia and hypercalciuria.

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Calcium and vitamin D are recognized as essential nutrients throughout life for skeletal growth and maintenance of bone mass. Calcium is the prevalent mineral of bone and its absorption from the intestine depends on vitamin D. Convincing evidence has been given that dietary calcium intake is positively related to BMD in children and adolescents. In adolescent, the higher the calcium intake, the greater the peak bone mass. A posi­tive correlation between bone mass and calcium intake has been demonstrated also in adult. Although there are many fac­tors which modulate the progression of age-related bone loss syndromes, the pathogenesis of this process has been attributed, at least in part, to decreased calcium absorption by an “aging in­testine”, to an associated elevation in circulating PTH, and to de­creased synthesis of 1,25(OH)2D. Decreased 1,25(OH)2D synthesis by the aging kidney results from both age-related pro­gressive loss in the capacity of the renal 1-a-hydroxylase to re­spond to progressive elevation in PTH and an age-related de­crease in the circulating 25(OH)D precursor. Women with osteoporosis have been often demonstrated to be characterized by reduced intestinal calcium absorption when compared with age-matched control subjects. This abnormality is partic­ularly relevant in those women who have a low calcium diet. Moreover, increments in serum osteocalcin levels observed in humans treated with 1,25(OH)₂D, and animal studies demonstrat­ing increased number of bone marrow osteoblast precursors dur­ing 1,25(OH)₂D administration are consistent with the hypothesis that abnormalities in the production and skeletal distribution of 1,25(OH)₂D may also contribute to the defects in osteoblast func­tion and bone formation. Dietary calcium and vitamin D intake as well as solar exposure generally decreases with in­creasing age, and the dermal production of vitamin D following a standard exposure to UVB light can be impaired in elderly sub­jects, due to atrophic skin changes. Moreover, several epidemiological studies, performed in different populations, demonstrated that a low vitamin D status is common among adult and elderly populations, regardless of lati­tude.

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