The effect of Vitamin D on falls and fractures.

Vitamin D (cholecalciferol) is important for normal development and maintenance of the skeleton. The metabolites 25(OH)D and 1,25(OH)(2)D are not only important for treating rickets and osteomalacia but also for all types and clinical stages of osteoporosis. Patients with low calcium intake and a low vitamin D status are at risk to develop secondary hyperparathyroidism, increased bone resorbtion, osteopenia and fractures. This can be counteracted by a lifelong sufficient vitamin D supply plus dietary or supplementary calcium. The effects of vitamin D on muscle, balance and cognitive functions may be an added value in fracture prevention. Today it is generally accepted that a supplementation with vitamin D and calcium should be added to every specific medical treatment of osteoporosis. In contrast to this general recommendation the potency of vitamin D alone with or without calcium to reduce the incidence of falls and/or fractures is still a debated controversy. Studies and meta-analyses during the last two decades on the effect of vitamin D and calcium supplements have not resolved the controversy on the risk of falls and fractures in healthy or osteopenic elderly populations. A thorough analysis of these trials supports our clinical experience that the efficacy of vitamin D-calcium supplementation depends on factors related to patient selection, medical intervention and study design, e.g. age, mobility, preventing falls and fractures, co-morbidity, initial vitamin D status and renal function. We conclude that plain vitamin D (cholecalciferol) with sufficient calcium intake is able to reduce the risk of falls and fractures only when adopting optimal selection criteria for patients and study conditions.

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.

Sustained efficacy of risedronate in men with primary and secondary osteoporosis: results of a 2-year study.

The aim of this study was to assess the effect of treatment with risedronate 5 mg daily relative to control in men with primary or secondary osteoporosis over 2 years. Osteoporosis is a common condition in men that can have serious clinical consequences. In an earlier interim report, we found that 1 year of risedronate therapy resulted in significant increases in bone mineral density (BMD) and a significant reduction in vertebral fractures compared to control in men with osteoporosis. We conducted an open-label, prospective, match-control trial on men with primary or secondary osteoporosis in a single center, outpatient setting. Men with primary or secondary osteoporosis, as defined by a baseline lumbar spine BMD T-score < or = -2.5 and a baseline femoral neck BMD T-score < or = 2.0, were eligible for this study. Patients who had been treated with bisphosphonates or fluoride within the last 12 months were excluded. A total of 316 men were randomized to risedronate (n = 158) or control (n = 158). Patients were stratified by the presence of prevalent vertebral fractures at baseline and case by case allocated to either daily treatment with risedronate 5 mg daily plus calcium (1,000 mg) and vitamin D (800 IU) or to a control group (daily alfacalcidol (1 microg) plus calcium (500 mg) for those with prevalent vertebral fractures; daily vitamin D (800 IU) plus calcium (1,200 mg) for those without previous vertebral fractures). Primary study end points were identified prior to study initiation as the incidence of new vertebral fractures and changes in BMD at the lumbar spine, femoral neck, and total hip. Other end points included incidence of nonvertebral fractures and change in body height and back pain. Compared to control, the incidence of new vertebral fractures was significantly reduced in the risedronate 5 mg daily group at 2 years [14/152 (9.2%) for risedronate vs. 35/148 (23.6%) for control (61% risk reduction; P = 0.0026)]. Treatment with risedronate 5 mg daily also resulted in significant improvements in BMD at 2 years at all three skeletal sites (lumbar spine, 6.5 vs. 2.2%; femoral neck, 3.2 vs. 0.6%; total hip, 4.4 vs. 0.4% (P < 0.001 for all treatment comparisons). Significant reductions in the incidence of nonvertebral fractures (11.8 vs. 22.3%; P = 0.032), average loss in height, and back pain were also observed in risedronate-treated patients relative to control. In this 2-year study, daily 5 mg risedronate significantly reduced the risk of vertebral and nonvertebral fractures, improved BMD, decreased height loss, and reduced back pain in men with osteoporosis. Efficacy was sustained over 2 years; a consistent 60-61% risk reduction in vertebral fractures was observed at 1 and 2 years, respectively. These data demonstrate that daily risedronate is effective long-term therapy for men with primary or secondary osteoporosis.

[Drug therapy for prevention of falls and fractures]. / Medikamentöse Sturz- und Frakturprävention.

The primary goal in the practical management of osteoporosis is to prevent first or subsequent fractures and thereby to avoid acute or chronic pain and progressive skeletal deformity. Therapeutic strategies should always take the complex pathogenetic mechanisms of fractures into account, especially the fact that mechanical impacts and falls play an important role in the majority of fracture events. Accordingly, recommendations to patients and the selection of drugs should aim at both, falls and fractures. In this context there is an increasing interest in the dual effects of vitamin D on bone and muscle. Controlled studies proved that adequate vitamin D supplementation is able to improve muscle strength, coordination and body sway and thereby reduce the risk of falls and fractures. Alendronate has been studied extensively by large trials of high quality and its efficacy to reduce the risk of vertebral and nonvertebral fractures is in line with the criteria of evidence-based medicine. The innovative combination of 70 mg alendronate with 2,800 IU vitamin D in a once-weekly tablet guarantees a basic supply with this important prohormone for bone and muscle. Due to a regular combined intake an improved compliance can be anticipated which will be followed by better therapeutic results in osteoporosis patients with increased fracture risk.

Zoledronic acid in the treatment of Paget's disease and other benign bone disorders.

Zoledronic acid is a potent bisphosphonate widely used to counteract cancer-related bone loss. Once-yearly or even less frequent doses may be an effective therapy for benign bone disorders and may also result in improved compliance and tolerability. Data from two Phase III clinical trials have demonstrated the efficacy and safety of zoledronic acid in the treatment of Paget's disease of bone. Other studies have provided preliminary evidence for the utility of zoledronic acid in osteoporosis and other benign bone disorders. The major adverse effects associated with zoledronic acid infusions are transient flu-like symptoms. Ongoing clinical trials will provide key data on the ability of this agent to treat osteoporosis and prevent fractures in high-risk patients and on its long-term safety profile.

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.

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.