Potency of a combined alfacalcidol-alendronate therapy to reduce the risk of falls and fractures in elderly patients with glucocorticoid-induced osteoporosis.

This is a preplanned subgroup analysis on 318 patients with glucocorticoid-induced osteoporosis (GIOP) from an open, prospective, multi-centered, uncontrolled study on a large cohort of elderly patients with a high risk of falls and fractures. The entire group of 2579 patients was recruited by 818 practicing physicians and treated for three months with a new combination package containing 4 or 12 self-explanatory one-week blisters, each with one tablet of 70 mg alendronate (CAS 260055-05-8) and 7 capsules of 1 pg alfacalcidol (CAS 41294-56-8) (Tevabone"). The average age of the GIOP patients was 71 years and the mean body mass index 26.7 kg/m2. 58% had a diagnosis of increased risk of falls, prevalent vertebral and non-vertebral fractures were documented in 70% and 65% of the patients, respectively, and a creatinine clearance (CrCl) below 65 ml/min was documented in 55 %. Main outcome parameters were the Chair Rising Test (CRT), Timed Up and Go Test (TUG), back pain and safety at onset and after 3 months. In addition, an evaluation of the package design was done at the end of the study. The percentage of patients able to perform the CRT within 10 sec increased from 21.1% to 39.4% after 3 months (increase 87%, p < 0.0001), while successful performance of TUG within 10 sec increased by 84% (p < 0.0001) from 23.1% at onset to 42.4% after 3 months. The mean time required to perform the CRT decreased after 3 months from an average of 15.92 to 14.02 sec (p = 0.0025) (difference of 1.9 sec) and for the TUG the mean time decreased from 16.86 sec to 14.64 sec (p = 0.0056) (difference of 2.2 sec). Mean back pain measured by a 0-10 visual analogue scale decreased significantly by 43% from 6.0 to 3.4 (p < 0.0001). Throughout the study 23 adverse events (AE) were reported in 11 of the 318 GIOP patients (incidence: 3.5 %). There were no patients who experienced serious AE. Patients using the new combined regimen of alfacalcidol plus alendronate for treating GIOP achieved significant improvements in CRT, TUG and back pain already after 3 months, with a high safety profile and good compliance. This may contribute to the previously shown significant effect on reducing falls and fractures with the same regimen during a controlled long-term trial in primary osteoporosis.

Risk reduction of falls and fractures, reduction of back pain and safety in elderly high risk patients receiving combined therapy with alfacalcidol and alendronate: a prospective study.

Efficacy and safety of a new combination package containing 4 or 12 self-explanatory one-week blisters, each with one tablet of 70 mg alendronate (CAS 260055-05-8) and 7 capsules of 1 microg alfacalcidol (CAS 41294-56-8) (Tevabone) on muscle power, muscle function, balance and back pain was investigated in an open, multi-centered, uncontrolled, prospective study on a cohort of elderly patients with a high risk of falls and fractures. 818 practicing physicians all over Germany recruited 2579 patients for a 3-month observational trial being treated with the above combination package. 92.4% were women [89.7% of the women had postmenopausal osteoporosis (PMO)]. Their average age was 74.1 years and the mean body mass index 26.4 kg/m2. 55.4% had a history of falls. Prevalent vertebral and non-vertebral fractures were documented in 62.9% and 61.4% of the patients, respectively, and a creatinine clearance below 65 ml/min was documented in 65.5%. Main outcome parameters were the Chair Rising Test (CRT), Timed Up and Go Test (TUG), back pain and safety at onset and after 3 months. In addition an evaluation of the package design was done at the end of the study. The percentage of patients able to perform the CRT within 10 sec increased from 26.3% to 42.9% after 3 months (increase 63%, p < 0.0001), while successful performance within 10 sec of TUG increased by 54% (p < 0.0001) from 30.6% at onset to 47.1% after 3 months. The average overall improvement of CRT was 2.3 sec (p < 0.0001) and of TUG amounted to 2.4 sec (p < 0.0001). It was shown in another recently published study that a mean increase of 2.6 sec in the performance of TUG results in a 24% increased risk for non-vertebral fractures. Mean back pain measured by a 0-10 visual analogue scale decreased significantly by 41% from 5.9 to 3.5 (p < 0.0001). Throughout the study, 178 adverse events (AE) were reported in 85 of the 2579 patients (incidence: 3.3 %). Only 3 patients experienced serious AE, 2 without causal relationship to the new combination pack. Patients using the new combined regimen of alfacalcidol plus alendronate achieved significant improvement in CRT, TUG and back pain already after 3 months, with a high safety profile and good compliance. This may contribute to the previously shown significant effect on reducing falls and fractures with the same regimen during a controlled long-term trial. The same trend was found in all mentioned efficacy parameters and no different trend in safety in the large subgroup of 2106 women with documented PMO.

Effect of a six-month therapy with alfacalcidol on muscle power and balance and the number of fallers and falls.

PURPOSE: In an open observational prospective multicentered study on a cohort of patients with a creatinine clearance of < or = 65 ml/min and diagnosed with the "Esslinger Fall Risk Assessment" to be at an increased risk for falls the effect of daily treatment with 1 microg alfacalcidol (CAS 41294-56-8; Alpha-D3) on muscle power, balance and number of fallers and falls was investigated. METHODS: In this open prospective study on 237 participants recruited in Germany, 16.9% men and 83.1% women with a mean age of 75.9 years and a mean body mass index (BMI) of 26.3 kg/m2 underwent at the beginning and after 3 and 6 months different muscle strength and balance tests such as the Timed-up and Go Test (TUG), the Tandem Stand Test (TST) and the Chair Rising Test (CRT). A successful performance in these tests has been associated with a significantly lower risk for falls and non-vertebral fractures in elderly patients (successful test performance: TUG < 12 s, TST > 10 s, CRT < 10 s). RESULTS: Controlled for age, gender and BMI, treatment with alfacalcidol was associated with a significantly increased performance in all three muscle and balance tests already after 3 months. This effect increased after six months of therapy and a significant increase in the number of participants who were able to successfully perform the different tests was observed: plus 74.9% for the TUG (p < .0001), plus 112% for the TST (p < .0001) and plus 108% for the CRT (p < .0001). After six months the mean time used for the TUG was decreased by 2.01 s, by 2.29 s for the CRT, and increased by 2.02 s for the TST. Controlled for age, gender, BMI and CrCI, treatment with alfacalcidol for six moths resulted in a significant 48.1% (p _< or = .0001) decrease in the absolute number of fallers and a significant 51.3% (p .0001) decrease in the absolute number of falls, compared to the 6 months prior to alfacalcidol therapy. CONCLUSIONS: Treatment with alfacalcidol increases muscle power and balance as measured with three different muscle power and balance tests and leads to a highly significant decrease in the number of fallers and falls.

Differential effects of D-hormone analogs and native vitamin D on the risk of falls: a comparative meta-analysis.

The aim of this meta-analysis was to compare the antifall efficacy of native vitamin D to that of its hydroxylated analogs alfacalcidol and calcitriol. Randomized clinical trials comparing oral native vitamin D and its analogs alfacalcidol and calcitriol to a placebo were included. Sources included the Cochrane Controlled Trials Register, EMBASE, MEDLINE, a hand search of abstracts, as well as reference lists. The time range was January 1995 to May 2007. Data were abstracted and scored by two investigators. The core analysis was based on double-blind trials, while open trials were included as a robustness analysis. Relative risks (RRs) for falls while allocated to D-hormone analogs or vitamin D were calculated. Publication bias and robustness were formally tested. Fourteen trials including 21,268 subjects were included. Using double-blind data only, vitamin D-hormone analogs provided a statistically significant lower level of risk for falling compared to native vitamin D: RR = 0.79 (95% confidence interval 0.64-0.96) vs. 0.94 (0.87-1.01) (intergroup difference P = 0.049). The dropout rates observed in the two sets of trials were comparable: 0.33% per month. Publication bias investigation did not report any significant trend for selective publication favoring active treatment arms. Upon current evidence, D-hormone analogs seem to prevent falls to a greater extent than their native compound. Long-term, prospective, head-to-head, confirmatory trials are required to address the exact role of vitamin D and D-hormone analogs in the prevention of falls and fractures.

Alfacalcidol versus plain vitamin D in inflammation induced bone loss.

Inflammatory diseases lead to systemic osteoporosis. Causal factors include increased circulating concentrations of inflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), glucocorticoid medication, and reduced physical activity. In addition, disturbances of vitamin D metabolism play an important role for the development of inflammation induced osteoporosis. Therefore, D-hormone analogs offer an important treatment option. 1,25-dihydroxyvitamin D (D-hormone) prevented bone loss in the rat model of inflammation mediated osteopenia and in an arthritis model. One explanation is that animals and humans with inflammatory diseases exhibit markedly reduced circulating concentrations of D-hormone, partly the result of inhibition of renal 1-alpha-hydroxylase by TNF-alpha. In addition, the number of vitamin D receptors is reduced by glucocorticoids. Moreover, D-hormone has pleiotropic effects not only on calcium homoeostasis but also on muscle (improving power), the nervous system, and the immune system. D-hormone inhibits the release of cytokines (IL-1, IL-6, TNF-alpha) from macrophages and stimulates osteoprotegerin secretion in vitro and improves arthritis in animal models. This article reviews the interaction between inflammatory disease and vitamin D metabolism, summarizes the rationale for the therapeutic use of alfacalcidol, and provides recent data from controlled clinical trials comparing the effect of alfacalcidol versus plain vitamin D in secondary osteoporosis. Alfacalcidol, but not plain vitamin D, has pleiotropic effects improving bone and muscle metabolism and clinical symptoms in patients with rheumatoid arthritis.

Alfacalcidol versus plain vitamin D in the treatment of glucocorticoid/inflammation-induced osteoporosis.

Treatment with plain vitamin D is a nutritional substitute, while the application of alfacalcidol is an active hormonal therapy. Due to strong feedback regulation, plain vitamin D is not activated in the kidney in vitamin-replete patients, while alfacalcidol, having been hydroxylated at position 1, bypasses regulation and increases available amounts of active D-hormone in different target tissues. Nevertheless, a majority of physicians still prescribe plain vitamin D plus calcium as a first-step prevention or even as therapy for glucocorticoid (GC) induced osteoporosis. This article summarizes results of our previous study comparing the therapeutic efficacy of the D-hormone analog alfacalcidol to plain vitamin D in patients with established GC induced osteoporosis with or without vertebral fracture. Patients taking longterm GC therapy were included as well-matched pairs to receive randomly either 1 microg alfacalcidol plus 500 mg calcium per day (group A, n = 103) or 1000 IU vitamin D3 plus 500 mg calcium (group B, n = 101). The mean bone mineral density (BMD) values at baseline for the 2 groups for alfacalcidol and vitamin D3, respectively, were: lumbar spine T score -3.26 and -3.25; femoral neck -2.81 and -2.84. Rates of prevalent vertebral and nonvertebral fractures were not different between groups. In the 3 year study we observed in the alfacalcidol group as compared with the plain vitamin D group, respectively: a 3 year median percentage increase of BMD at the lumbar spine of 2.4% versus -0.8% (p < 0.0001); a median increase at the femoral neck of 1.2% versus 0.8% (p < 0.006). Likewise observed in the alfacalcidol as compared to the vitamin D group, respectively: a 3 year rate of patients with > or = 1 new vertebral fracture of 9.7% versus 24.8% (risk reduction: 0.61; 95% CI 0.24 to 0.81; p = 0.005); a 3 year rate of patients with > or = 1 new nonvertebral fracture of 15% versus 25% (risk reduction: 0.41; 95% CI -0.06 to 0.68; p = 0.081); a 3 year rate of patients with > or = 1 new fracture of any kind of 19.4% versus 40.6% (risk reduction: 0.52; 95% CI 0.25 to 0.71; p = 0.001). In accordance with the observed fracture rates, the alfacalcidol group showed a substantially larger decrease in back pain than the plain vitamin D group (p < 0.0001). Generally, side effects in both groups were mild, and only 3 patients in the alfacalcidol group and 2 patients in the vitamin D group had moderate hypercalcemia. We conclude that alfacalcidol plus calcium is highly superior to plain vitamin D3 plus calcium in the treatment of established GC induced osteoporosis, and the latter should no longer be used as monotherapy.

Low creatinine clearance, glucocorticoid treatment, rheumatoid arthritis--different etiologies for low D-hormone syndrome and its associated increased risk for falls.

Low D-hormone syndrome, a disorder related to low creatinine clearance (CrCl), is associated with a roughly 4-fold increase in risk for falls. Known conditions leading to low D-hormone syndrome are CrCl < 65 ml/min, drug interactions, and chronic inflammatory diseases. This article reviews recent studies showing that treatment with D-hormone analogs, such as alfacalcidol, can reduce the frequency of falls in patients with low D-hormone syndrome.

The D-hormone analog alfacalcidol: the pioneer beyond the horizon of osteoporosis treatment.

Over the last 30 years, several clinical trials have reported the efficacy of D-hormone analogs to treat primary and secondary osteoporosis, and their genomic and nongenomic mode of action have been demonstrated with the progress of biochemical research technologies. Recent metaanalyses reviewed the preventive effect on falls and fractures of "vitamin D3" in the elderly population, mainly based on studies with alfacalcidol and calcitriol. In future a clear differentiation must be made between calcium and plain vitamin D supplementation in very old, vitamin D-deficient women and men (> 75 years) and the pharmacological treatment of patients with established osteoporosis using D-hormone analogs, independent of a patient's vitamin D status. The dual action of D-hormone analogs on bone and muscle is unique, and differentiates them from all other, bone-specific antiosteoporotic drugs. Based on its efficacy in preventing falls, alfacalcidol is an excellent partner for combination therapy to improve the antifracture efficacy, especially in elderly patients. Further research is required to elucidate the mechanism of new actions of D-hormone analogs on muscle, nerves, brain, and on the immune system, to determine their application in different diseases.

In elderly men and women treated for osteoporosis a low creatinine clearance of <65 ml/min is a risk factor for falls and fractures.

Recently, a low creatinine clearance (CrCl) of < 65 ml/min was described as a new significant and independent risk factor for the number of fallers and falls in a community-dwelling elderly population. In this study we investigated if a low creatinine clearance of < 65 ml/min is also a risk factor for falls and fractures in elderly men and women treated for osteoporosis. In a cross-sectional study with the help of questionnaires we assessed the prevalence of having experienced falls within the last 12 months according to renal function in 5,313 German men and women receiving treatment for osteoporosis. The CrCl was calculated using the established Cockcroft-Gault formula. The prevalence of falls and fractures was assessed in multivariate-controlled logistic regression models according to a CrCl cut off of 65 ml/min. The P-values were two-sided. In this study of elderly men and women treated for osteoporosis (n=5,313), 60.9% (n=3,238) had a CrCl of < 65 ml/min, which was associated in multivariate controlled analyses, compared to a CrCl of > or = 65 ml/min (n=2,075), with a significant increased risk of experiencing falls (1,775/3,238 vs. 773/2,075, OR 1.69, 95% CI 1.50-1.91, P<0.0001) and an increased risk for multiple falls (37.1 vs. 22.6%, OR 1.63, 95% CI 1.42-1.87, P<0.0001). Furthermore, compared to a creatinine clearance of > or = 65 ml/min, a creatinine clearance of < 65 ml/min was also associated with a significant increased multivariate controlled risk for hip fractures (OR 1.57, 95%CI 1.18-2.09, P=0.002), for radial fractures (OR 1.79, 95%CI 1.39-2.31, P=<0.0001), for total vertebral fractures (OR 1.31, 95%CI 1.19-1.55, P=0.003) and for fall-associated vertebral fractures (OR 1.24, 95% CI 1.03-1.54, P=0.031). Similar to community-dwelling elderly, in elderly men and women treated for osteoporosis a CrCl of less than 65 ml/min is a significant and independent risk factor for falls. Furthermore, we could show for the first time that a low creatinine clearance in elderly men and women treated for osteoporosis is also associated with a significantly increased risk of vertebral, hip and radial fractures.

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

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 microg 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 >or=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.

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

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 > or =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 community-dwelling 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.

Prevention and therapy of osteoporosis: the roles of plain vitamin D and alfacalcidol.

Severe vitamin D deficiency was identified only in the first decades of the last century as the most common aetiology of rickets in children and osteomalacia in adults. It was later shown that vitamin D is not, as had been supposed, the biologically active principle for healing bone disease but must be hydroxylated in the liver and then finally in the kidney to become 1alpha,25-dihydroxy-cholecalciferol, a biologically highly active renal hormone. This study reviews the various principles, mechanisms, and approaches to the treatment of different forms of osteoporosis using vitamin D, alfacalcidol, and calcitriol therapy regimens.

Alfacalcidol reduces the number of fallers in a community-dwelling elderly population with a minimum calcium intake of more than 500 mg daily.

OBJECTIVES: To study the effect of alfacalcidol (1alpha(OH)D3) on fall risk in community-dwelling elderly men and women. DESIGN: Randomized, double-blind, placebo-controlled intervention trial. SETTING: Basel, Switzerland. PARTICIPANTS: Three hundred seventy-eight community-dwelling elderly (191 women/187 men). INTERVENTION: Participants were randomly assigned to receive 1 microg of alfacalcidol or matched placebo daily for 36 weeks. MEASUREMENTS: Serum 25-hydoxyvitamin D3 (25(OH) D,1,25-dihydroxyvitamin D3 (D-hormone), and intact parathormone (iPTH) levels were measured using radioimmunoassay at baseline and every 12 weeks. Numbers of fallers and falls were assessed using a questionnaire during each study site visit. Dietary calcium intake was assessed at baseline using a food frequency questionnaire. RESULTS: At baseline, participants had, on average, normal vitamin D and D-hormone serum levels. Over 36 weeks, alfacalcidol treatment was associated with fewer fallers (odds ratio (OR)=0.69, 95% confidence interval (CI)=0.41-1.16) than placebo. In a post hoc subgroups analysis by medians of total calcium intake, this reduction reached significance in alfacalcidol-treated subjects with a total calcium intake of more than 512 mg/d (OR=0.45, 95% CI=0.21-0.97, P=.042) but not in those who consumed less than 512 mg/d (OR=1.00, 95% CI= 0.47-2.11, P=.998). Alfacalcidol treatment was also, independent of total calcium intake, associated with a significant 37.9% reduction in iPTH serum levels (P<.0001). No cases of clinically relevant hypercalcemia were observed. CONCLUSION: Provided a minimal calcium intake of more than 512 mg/d, alfacalcidol treatment significantly and safely reduces number of fallers in an elderly community dwelling population.