[Male osteoporosis]. / Männliche Osteoporose.

BACKGROUND: Osteoporosis in men is an important public health problem with more than 1 million cases in Germany. Although osteoporotic fractures have a much higher mortality in men than in women, male patients are still underdiagnosed and undertreated. OBJECTIVE: Epidemiology of male osteoporosis and current treatment situation, pathophysiological aspects at the hormonal level, risk factors, diagnostic work-up and therapeutic options. MATERIAL AND METHODS: Overview of data concerning male osteoporosis, recommendations for diagnostic work-up and presentation of the study situation on pharmaceutical therapies. RESULTS: As risk factors for osteoporosis are present in 50-70 % of male patients, a detailed patient history is necessary for assessment of the risk factors. Radiological imaging of the spine is primarily recommended to identify individuals with prevalent vertebral fractures, as approximately 10 % of males above the age of 50 years have suffered a vertebral fracture. Laboratory testing of relevant parameters helps to rule out other metabolic bone diseases. In Germany, specific medications available for the treatment of male osteoporosis comprise the active vitamin D analogue alfacalcidol, the oral bisphosphonates alendronate and risedronate, the intravenous biphosphonate zoledronic acid, the anti- receptor activator of NF-κB ligand (RANKL) antibody denosumab, which can be given as intravenous injection and strontium ranelate, a drug with a complex mode of action. Teriparatide, a recombinant form of the 34 N-terminal amino acid sequence of parathyroid hormone is the only anabolic agent approved for male osteoporosis. CONCLUSION: Osteoporosis in men is increasingly being recognized as an important public health problem and affected patients need to be adequately diagnosed and treated. Nowadays, a broad spectrum of well-proven therapeutic options with different modes of action allow individual treatment strategies for male osteoporosis patients.

The position of strontium ranelate in today's management of osteoporosis.

Osteoporosis accounts for about 3 % of total European health-care spending. The low proportion of costs for the pharmacological prevention of osteoporotic fracture means that it is highly cost saving, especially in patient with severe osteoporosis or patients who cannot take certain osteoporosis medications due to issues of contraindications or tolerability. Following recent regulatory changes, strontium ranelate is now indicated in patients with severe osteoporosis for whom treatment with other osteoporosis treatments is not possible, and without contraindications including uncontrolled hypertension, established, current or past history of ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. We review here today's evidence for the safety and efficacy of strontium ranelate. The efficacy of strontium ranelate in patients complying with the new prescribing information (i.e. severe osteoporosis without contraindications) has been explored in a multivariate analysis of clinical trial data, which concluded that the antifracture efficacy of strontium ranelate is maintained in patients with severe osteoporosis without contraindications and also demonstrated how the new target population mitigates risk. Strontium ranelate is therefore an important alternative in today's management of osteoporosis, with a positive benefit-risk balance, provided that the revised indication and contraindications are followed and cardiovascular risk is monitored. The bone community should be reassured that there remain viable alternatives in patients in whom treatment with other agents is not possible and protection against the debilitating effects of fracture is still feasible in patients with severe osteoporosis.

Management of osteoporosis of the oldest old.

UNLABELLED: This consensus article reviews the diagnosis and treatment of osteoporosis in geriatric populations. Specifically, it reviews the risk assessment and intervention thresholds, the impact of nutritional deficiencies, fall prevention strategies, pharmacological treatments and their safety considerations, the risks of sub-optimal treatment adherence and strategies for its improvement. INTRODUCTION: This consensus article reviews the therapeutic strategies and management options for the treatment of osteoporosis of the oldest old. This vulnerable segment (persons over 80 years of age) stands to gain substantially from effective anti-osteoporosis treatment, but the under-prescription of these treatments is frequent. METHODS: This report is the result of an ESCEO (European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis) expert working group, which explores some of the reasons for this and presents the arguments to counter these beliefs. The risk assessment of older individuals is briefly reviewed along with the differences between some intervention guidelines. The current evidence on the impact of nutritional deficiencies (i.e. calcium, protein and vitamin D) is presented, as are strategies to prevent falls. One possible reason for the under-prescription of pharmacological treatments for osteoporosis in the oldest old is the perception that anti-fracture efficacy requires long-term treatment. However, a review of the data shows convincing anti-fracture efficacy already by 12 months. RESULTS: The safety profiles of these pharmacological agents are generally satisfactory in this patient segment provided a few precautions are followed. CONCLUSION: These patients should be considered for particular consultation/follow-up procedures in the effort to convince on the benefits of treatment and to allay fears of adverse drug reactions, since poor adherence is a major problem for the success of a strategy for osteoporosis and limits cost-effectiveness.

Improved real-life adherence of 6-monthly denosumab injections due to positive feedback based on rapid 6-month BMD increase and good safety profile.

Almost 50 % of osteoporosis (OP) patients discontinue bisphosphonate (BP) therapy within 1-2 years after the start of their treatment. Denosumab's longer dosing interval with its administration every 6 months (Q6M) as a subcutaneous (sc) injection might result in a better real-life treatment adherence and persistence than weekly or monthly oral BP treatment regimen. The objectives of this open, investigator-initiated, prospective, observational, single-center study were to evaluate adherence with denosumab 60 mg sc every 6 months (Q6M) (Prolia(®)) injections in osteoporotic patients in a routine clinical care setting and to describe whether positive feedback to OP patients based on measured bone mineral density (BMD) increases and good safety profile have an impact on patients' real-life adherence. Results indicate that the rarity of adverse events and reduced dosage frequency together with the consistency of rapid and highly significant increases in BMD already after 6 months of denosumab therapy used as a positive reinforcement during doctor-patient interactions had a significant, positive impact on osteoporotic patient's adherence to continue with the 6-monthly sc denosumab injections.

Early changes in biochemical markers of bone formation during teriparatide therapy correlate with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis.

UNLABELLED: Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide. INTRODUCTION: To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO. METHODS: A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 µg/day, n = 45) and risedronate (35 mg/week, n = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables. RESULTS: PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group. CONCLUSIONS: Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients.

Efficacy and safety of strontium ranelate in the treatment of osteoporosis in men.

CONTEXT: Strontium ranelate reduces vertebral and nonvertebral fracture risk in postmenopausal osteoporosis. OBJECTIVE: The objective of this study was to determine the efficacy and safety of strontium ranelate in osteoporosis in men over 2 years (main analysis after 1 year). DESIGN: This was an international, unbalanced (2:1), double-blind, randomized placebo-controlled trial (MALEO [MALE Osteoporosis]). SETTING: This international study included 54 centers in 14 countries. PARTICIPANTS: PARTICIPANTS were 261 white men with primary osteoporosis. INTERVENTION: Strontium ranelate at 2 g/d (n = 174) or placebo (n = 87) was administered. MAIN OUTCOME MEASURES: Lumbar spine (L2-L4), femoral neck, and total hip bone mineral density (BMD), biochemical bone markers, and safety were measured. RESULTS: Baseline characteristics were similar in both groups in the whole population (age, 72.9 ± 6.0 years; lumbar spine BMD T-score, -2.7 ± 1.0; femoral neck BMD T-score, -2.3 ± 0.7). Men who received strontium ranelate over 2 years had greater increases in lumbar spine BMD than those who received placebo (relative change from baseline to end, 9.7% ± 7.5% vs 2.0% ± 5.5%; between-group difference estimate (SE), 7.7% (0.9%); 95% confidence interval, 5.9%-9.5%; P < .001). There were also significant between-group differences in relative changes in femoral neck BMD (P < .001) and total hip BMD (P < .001). At the end of treatment, mean levels of serum cross-linked telopeptides of type I collagen, a marker of bone resorption, were increased in both the strontium ranelate group (10.7% ± 58.0%; P = .022) and the placebo group (34.9% ± 65.8%; P < .001). The corresponding mean changes of bone alkaline phosphatase, a marker of bone formation, were 6.4% ± 28.5% (P = .005) and 1.9% ± 25.4% (P = .505), respectively. After 2 years, the blood strontium level (129 ± 66 µmol/L) was similar to that in trials of postmenopausal osteoporosis. Strontium ranelate was generally well tolerated. CONCLUSIONS: The effects of strontium ranelate on BMD in osteoporotic men were similar to those in postmenopausal osteoporotic women, supporting its use in the treatment of osteoporosis in men.

Vitamin D supplementation in elderly or postmenopausal women: a 2013 update of the 2008 recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).

BACKGROUND: Vitamin D insufficiency has deleterious consequences on health outcomes. In elderly or postmenopausal women, it may exacerbate osteoporosis. SCOPE: There is currently no clear consensus on definitions of vitamin D insufficiency or minimal targets for vitamin D concentrations and proposed targets vary with the population. In view of the potential confusion for practitioners on when to treat and what to achieve, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) convened a meeting to provide recommendations for clinical practice, to ensure the optimal management of elderly and postmenopausal women with regard to vitamin D supplementation. FINDINGS: Vitamin D has both skeletal and extra-skeletal benefits. Patients with serum 25-hydroxyvitamin D (25-(OH)D) levels <50 nmol/L have increased bone turnover, bone loss, and possibly mineralization defects compared with patients with levels >50 nmol/L. Similar relationships have been reported for frailty, nonvertebral and hip fracture, and all-cause mortality, with poorer outcomes at <50 nmol/L. CONCLUSION: The ESCEO recommends that 50 nmol/L (i.e. 20 ng/mL) should be the minimal serum 25-(OH)D concentration at the population level and in patients with osteoporosis to ensure optimal bone health. Below this threshold, supplementation is recommended at 800 to 1000 IU/day. Vitamin D supplementation is safe up to 10,000 IU/day (upper limit of safety) resulting in an upper limit of adequacy of 125 nmol/L 25-(OH)D. Daily consumption of calcium- and vitamin-D-fortified food products (e.g. yoghurt or milk) can help improve vitamin D intake. Above the threshold of 50 nmol/L, there is no clear evidence for additional benefits of supplementation. On the other hand, in fragile elderly subjects who are at elevated risk for falls and fracture, the ESCEO recommends a minimal serum 25-(OH)D level of 75 nmol/L (i.e. 30 ng/mL), for the greatest impact on fracture.

Alfacalcidol in men with osteoporosis: a prospective, observational, 2-year trial on 214 patients.

Due to pleiotropic-synergistic actions on bone, muscle, gut, brain and different other non-skeletal tissues, alfacalcidol is an interesting drug for treating osteoporosis. In studies on glucocorticoid-induced osteoporosis, men have always been treated with calcitriol or this active D-hormone prodrug, but there is no study of male patients only in the literature. The AIM-Trial (Alfacalcidol In Men) is an extension of the control group (n = 158) of our former risedronate study in male osteoporosis (Ringe et al. in Rheumatol Int 29:311-315, 2009). In that study, we treated daily those controls with prevalent vertebral fractures with 1 µg alfacalcidol + 500 mg calcium (group A) and those without prevalent vertebral fractures with 1,000 IU plain vitamin D (Vit. D) + 1,000 mg calcium (group B). Subsequently, we added an additional 56 pairs of patients to these two groups: 28 with and 28 without prevalent vertebral fractures, reaching a total of 214 cases. That means with this design, we are comparing two groups with a different risk at onset. Due to the prevalent vertebral fractures and lower average bone mineral density (BMD) values, there was a higher risk of incident fractures in group A. After 2 years, we found significantly higher increases in lumbar spine BMD (+3.2 vs. +0.8 %) and total hip BMD (+1.9 vs. -0.9 %) in group A and B, respectively. Eighteen incident falls were recorded in the alfacalcidol group and 38 in the group treated with Vit. D (p = 0.041). There were significantly lower rates of patients with new vertebral and non-vertebral fractures in group A than in group B. Back pain was significantly reduced only with alfacalcidol. Concerning the incidence of new non-vertebral fractures, we found that there was a relation to renal function in the two groups. The advantage for alfacalcidol was mainly due to a higher non-vertebral fracture-reducing potency in patients with a creatinine clearance (CrCl) below 60 ml/min (p = 0.0019). There were no serious adverse events (SAE), and the numbers of mild-to-moderate adverse events (AE) were not different between groups. Despite the higher initial fracture risk in the alfacalcidol group, 2-year treatment with this active D-hormone prodrug showed a higher therapeutic efficacy in terms of BMD, falls and fractures. One important advantage of alfacalcidol may be that it is effective even in patients with mild-to-moderate renal insufficiency.

Oral bisphosphonates reduce the risk of clinical fractures in glucocorticoid-induced osteoporosis in clinical practice.

UNLABELLED: This study aims to estimate bisphosphonate effectiveness by comparing fracture incidence over time on therapy in glucocorticoid-induced osteoporosis (GIO). From this observational study, alendronate and risedronate decreased clinical vertebral and nonvertebral fractures over time. The effectiveness of each bisphosphonate is consistent with their efficacies demonstrated on surrogate markers in randomized controlled trials (RCTs). INTRODUCTION: This study aims to estimate bisphosphonate effectiveness by comparing fracture incidence over time on therapy with fracture incidence during a short period after starting a therapy. METHODS: The study population was a subgroup of a larger cohort study comprising two cohorts of women aged ≥65 years, prescribed with alendronate or risedronate. Within the two study cohorts, 11,007 women were identified as having received glucocorticoids. Within each cohort, the baseline incidence of clinical fractures at nonvertebral and vertebral sites was defined by the initial 3-month period after starting therapy. Relative to these baseline data, we then compared the fracture incidence during the subsequent 12 months on therapy. RESULTS: The baseline incidence of clinical nonvertebral and vertebral fractures was similar in the alendronate cohort (5.22 and 5.79/100 person-years, respectively) and in the risedronate cohort (5.51 and 5.68/100 person-years, respectively). Relative to the baseline incidence, fracture incidence was significantly lower in the subsequent 12 months in both cohorts of alendronate (33 % lower at nonvertebral sites and 59 % at vertebral sites) and risedronate (28 % lower at nonvertebral sites and 54 % at vertebral sites). CONCLUSION: From this observational study not designed to compare drugs, both alendronate and risedronate decreased clinical vertebral and nonvertebral fractures over time. The reductions observed in fracture incidence, within each cohort, suggest that the effectiveness of each bisphosphonate in clinical practice is consistent with their efficacies demonstrated on surrogate markers in randomized controlled trials.

Treatment of osteoporosis in men.

SUMMARY: Aspects of osteoporosis in men, such as screening and identification strategies, definitions of diagnosis and intervention thresholds, and treatment options (both approved and in the pipeline) are discussed. INTRODUCTION: Awareness of osteoporosis in men is improving, although it remains under-diagnosed and under-treated. A European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) workshop was convened to discuss osteoporosis in men and to provide a report by a panel of experts (the authors). METHODS: A debate with an expert panel on preselected topics was conducted. RESULTS AND CONCLUSIONS: Although additional fracture data are needed to endorse the clinical care of osteoporosis in men, consensus views were reached on diagnostic criteria and intervention thresholds. Empirical data in men display similarities with data acquired in women, despite pathophysiological differences, which may not be clinically relevant. Men should receive treatment at a similar 10-year fracture probability as in women. The design of mixed studies may reduce the lag between comparable treatments for osteoporosis in women becoming available in men.

A reappraisal of generic bisphosphonates in osteoporosis.

UNLABELLED: The competitive price of generic bisphosphonates has had a marked effect on practice guidelines, but an increasing body of evidence suggests that they have more limited effectiveness than generally assumed. INTRODUCTION: The purpose of this study is to review the impact of generic bisphosphonates on effectiveness in the treatment of osteoporosis. METHODS: This study is a literature review. RESULTS: A substantial body of evidence indicates that many generic formulations of alendronate are more poorly tolerated than the proprietary preparations which results in significantly poorer adherence and thus effectiveness. Poorer effectiveness may result from faster disintegration times of many generics that increase the likelihood of adherence of particulate matter to the oesophageal mucosa. Unfortunately, market authorisation, based on the bioequivalence of generics with a proprietary formulation, does not take into account the potential concerns about safety. The poor adherence of many generic products has implications for guideline development, cost-effectiveness and impact of treatment on the burden of disease. CONCLUSIONS: The impact of generic bisphosphonates requires formal testing to re-evaluate their role in the management of osteoporosis.

[Combination of alendronate plus alfacalcidol in the treatment of osteoporosis. Rationale, preclinical data and clinical evidence]. / Kombinierte Osteoporosetherapie mit Alendronat plus Alfacalcidol. Rationale, präklinische Daten und klinische Evidenz.

BACKGROUND: The therapeutic strategy for the reduction of fracture risk in osteoporosis should not only aim to increase bone strength, but should also improve muscle function and reduce falls without increasing the risk of significant side effects. Since 2008 a combination therapy of the antiresorptive active bisphosphonatealendronate and the pleiotropic active D-hormone-prodrug alfacalcidol is licensed in Germanyfor treatment of postmenopausal osteoporosis (Tevabone). METHODS: In the review the results of numerous preclinical and clinical studies are reported, showing the efficacy of the combination of alendronate plus alfacalcidol. RESULTS: In preclinical trials with ovariectomized rats the combination has shown a significantly better effect on increased bone turnover in comparison with bisphosphonate monotherapy. Presumably the "oversuppression" of bone remodeling and the resulting risk of reduced microfracture healing, which is known to occur after long-term therapy with bisphosphonates, will be reduced by the combination. Clinical studies have shown better efficacy of the combination in the increase of bone density and reduction of fracture rate (vertebral and non-vertebral fractures). Less falls were reported compared to alendronate plus genuine vitamin D. The reduction of increased parathormone levels by the alendronate plus alfacalcidol combination compared to alendronate alone was proven to increase the responder rate of the alendronate therapy. The potential risks of alendronate-induced hypocalcemia as well as alfacalcidol-induced hypercalcemia or hypercalcuria are reduced due to the contrasting mode of action of both compounds. CONCLUSION: Treatment with the alendronate plus alfacalcidol combination meets the demands of an optimized therapy for osteoporosis.With the especially developed, self-explanatory combination package better compliance and less dispensing mistakes can be expected.

[Vitamin D deficiency in Germany, is it a danger for increased morbidityand mortality?]. / Vitamin-D-Unterversorg ung in Deutschland. Gefahr für erhöhte Morbidität und Mortalität?

Vitamin D regulates the calcium-phosphate metabolism and thereby plays an important role for the integrity and functioning of bone, muscle and nerves. Studies have shown furthermore an influence on certain types of cancer, diabetes and cardiovascular diseases. Vitamin D is mainly produced by the skin. During exposure to sunlightthe precursor7-dehydrocholesterol is transformed to colecalciferol (vitamin D3). Smaller amounts are supplied by nutrition. In our latitude vitamin D synthesis takes only place during summertime. The vitamin stored in fat tissue in generally is not sufficient for the whole winter period and accordingly insufficiency is very frequent. In a cross-sectional study all over Germany (DeViD, 2007) only about 8% of the population was vitamin D sufficient in spring time.Two prospective studies (2008) proved a correlation between vitamin D supply and overall mortality. An amelioration of vitamin D supply can be achieved either by increasing sun exposure or daily oral intake of 800-2000 IU (=20-50 microg) colecalciferol.

Strontium ranelate: an effective solution for diverse fracture risks.

Osteoporosis is listed by the WHO among the ten most frequent and socio-economically important, chronic diseases of mankind. The term osteoporosis however comprises a number of different pathophysiological conditions and clinical situations of weakened bones with increased risk of fragility fractures. A modern anti-osteoporotic drug should provide qualified study results proving therapeutic efficacy over this broad range of daily clinical appearances of osteoporosis. The decision for treatment in the individual patients depends no longer only on bone mineral density. Today, the major criterion for decision making is the prospective 10-year risk for fractures. Since this risk is calculated on the basis of age, sex, bone mineral density, prevalent fractures, and a number of other contributing risk factors (Kanis et al., Osteoporos Int 12:989-995, 2001; Kanis et al., Osteoporos Int 19:385-397, 2008), it seems to be of interest to have a look whether the fracture-reducing potency of a drug is influenced by these risk factors. The purpose of this review is to analyze whether the fracture-reducing efficacy of strontium ranelate in patients with osteoporosis can be achieved independently of sex, etiology of osteoporosis, and the major diagnostically relevant risk factors.

Longitudinal change in clinical fracture incidence after initiation of bisphosphonates.

SUMMARY: There are differences in the risk profile of patients prescribed alendronate, risedronate, or ibandronate. Observed reductions in fracture incidence over time suggest that the effectiveness of each bisphosphonate in clinical practice has been consistent with their efficacies demonstrated in randomized controlled trials. INTRODUCTION: Observational studies of bisphosphonate effectiveness for fracture prevention are subject to bias from unknown characteristics of baseline fracture risk at the start of therapy. The fracture incidence during the short period after starting a bisphosphonate and before any expected clinical benefit likely reflects baseline fracture risk. Bisphosphonate effectiveness may then be estimated by measuring the change in fracture incidence over time on therapy. METHODS: Administrative billing data were used to follow three cohorts of women aged 65 and older (total n = 210,144) after starting therapy either on alendronate, risedronate, or ibandronate in the USA between market introduction and 2006. Within each cohort, the baseline incidence of clinical fractures at the hip, vertebral, and nonvertebral sites was defined by the initial 3-month period after starting therapy. Relative to these baselines, we then compared the fracture incidence during the subsequent 12 months on therapy. RESULTS: At the start of therapy, the ibandronate cohort was younger and had fewer prior fractures than either the risedronate or alendronate cohorts. Accordingly, the baseline incidence of hip fractures was higher in the risedronate cohort (0.90 per 100 person-years) and in the alendronate cohort (0.77) than in the ibandronate cohort (0.64). Relative to the baseline incidence, fracture incidence was significantly lower in the subsequent 12 months in both cohorts of alendronate (18% lower at hip, 28% at nonvertebral sites, and 57% at vertebral sites) and risedronate (27% lower at hip, 21% at nonvertebral sites, and 54% at vertebral sites). In the ibandronate cohort, the fracture incidence was lower (31%) only at vertebral sites. CONCLUSIONS: Differences in the baseline fracture incidence among the cohorts may reflect differences in the risk profile of patients prescribed each bisphosphonate. The reductions observed in fracture incidence over time within each cohort suggest that the effectiveness of each bisphosphonate in clinical practice has been consistent with their efficacies demonstrated in randomized controlled trials.

Management of osteoporosis in the elderly.

BACKGROUND: Osteoporosis is predominantly a condition of the elderly, and the median age for hip fracture in women is approximately 83 years. Osteoporotic fracture risk is multifactorial, and often involves the balance between bone strength and propensity for falling. OBJECTIVE: To present an overview of the available evidence, located primarily by Medline searches up to April, 2009, for the different management strategies aimed at reducing the risk of falls and osteoporotic fractures in the elderly. RESULTS: Frailty is an independent predictor of falls, hip fractures, hospitalisation, disability and death in the elderly that is receiving increasing attention. Non-pharmacological strategies to reduce fall risk can prevent osteoporotic fractures. Exercise programmes, especially those involving high doses of exercise and incorporating balance training, have been shown to be effective. Many older people, especially the very elderly and those living in care institutions, have vitamin D inadequacy. In appropriate patients and given in sufficient doses, vitamin D and calcium supplementation is effective in reducing both falls and osteoporotic fractures, including hip fractures. Specific anti-osteoporosis drugs are underused, even in those most at risk of osteoporotic fracture. The evidence base for the efficacy of most such drugs in the elderly is incomplete, particularly with regard to nonvertebral and hip fractures. The evidence base is perhaps most complete for the relatively recently introduced drug, strontium ranelate. Non-adherence to treatment is a substantial problem, and may be exacerbated by the requirements for safe oral administration of bisphosphonates. CONCLUSION: Evidence-based strategies are available for reducing osteoporotic fracture risk in the elderly, and include exercise training, vitamin D and calcium supplementation, and use of evidence-based anti-osteoporotic drugs. A positive and determined approach to optimising the use of such strategies could reduce the burden of osteoporotic fractures in this high-risk group.

Risedronate dosing before breakfast compared with dosing later in the day in women with postmenopausal osteoporosis.

UNLABELLED: Two studies in postmenopausal women with osteoporosis provide information about the efficacy and safety of dosing oral risedronate 5 mg daily at a time other than before breakfast (i.e., 2 h before and 2 h after any food and drink other than plain water). A significant increase in lumbar spine BMD was observed for both treatment regimens in the two studies. However, smaller increases in lumbar spine BMD were observed with flexible dosing versus before-breakfast dosing. Geographic region, compliance, and consistency of dosing time appear to affect the amount of increase in BMD observed with flexible dosing. INTRODUCTION: Two studies in postmenopausal women with osteoporosis provide additional information about the efficacy and safety of dosing oral risedronate 5 mg daily at a time other than before breakfast (i.e., 2 h before and 2 h after any food and drink other than plain water). METHODS: One study, flexible dosing, was a 6-month North American study in 730 patients randomized to before-breakfast dosing or flexible dosing later in the day. A second study, IMPACT, was a large (N = 2382), 1-year multinational study in patients that chose their dosing regimen (before breakfast or later in the day). These studies were used to examine the bone mineral density (BMD) response with different dosing regimens. RESULTS: A significant increase in lumbar spine BMD was observed for both treatment regimens in the two studies. However, in both studies, the flexible dosing group had a smaller increase from baseline compared to the before-breakfast regimen (ratio of flexible dosing to before breakfast: flexible dosing study, 0.52; IMPACT study, 0.75). In addition, a relationship between geographic region and BMD response was observed with flexible dosing in both studies. Patients in the flexible dosing group who had greater dosing compliance (based on the number of times the bottle was opened) and consistency of dosing time (bottle opened within a 1.5-h window) had a greater increase in lumbar spine BMD. CONCLUSION: Results of these two studies demonstrate that overall flexible dosing of risedronate leads to smaller BMD gains compared to before-breakfast dosing. This result may be due to poorer adherence to the flexible dosing instructions that may be more pronounced in patients in certain geographic regions. If patients cannot abide by before-breakfast dosing and flexible dosing is an approved option, one can expect suboptimal BMD results with flexible dosing.

Potential of alfacalcidol for reducing increased risk of falls and fractures.

There are no general accepted strategies for combined drug treatments in osteoporosis, while in other important chronic diseases combinations of different medications are used as a rule to improve therapeutic results and reduce the risk of adverse events. It is suggested that the success of combined treatments is related to the different modes of action of the respective single therapies. On the other hand it was shown that a strong antiresorptive bisphosphonate is able to blunt at least in part the effects of anabolic parathyroid hormone peptides Calcitriol, the active vitamin D-hormone and its prodrug alfacalcidol lead to pleiotropic effects on bone remodelling (antiresorptive, anabolic and enhancing mineralization) and in addition to effects on other important target tissues (e.g. gut, parathyroid glands, muscle). With active D-analogs significant improvements in the therapeutic outcome of osteoporosis can be achieved by the resulting improvements of bone quality, calcium absorption and risk reduction of falling. The same beneficial effects cannot be achieved with plain vitamin D due to feedback controlled, limited renal activation or insufficient conversion in the elderly with impairment of renal function. Accordingly alfacalcidol, approved as a treatment for different forms of osteoporosis, is besides adoption as a mono-therapy an interesting candidate for combined therapies. There are interesting preclinical trials and clinical pilote studies in the literature proving that a parallel therapy with selectively anti-osteoclastic bisphophonates and pleiotropically acting D-analogs is able to optimize therapeutic results in osteoporosis. In the AAC-Trial (Alfacalcidol-Alendronate-Combined) we studied 90 patients with established osteoporosis (57 women, 33 men) over two years after alternate allocation to three treatment arms (alfacalcidol plus calcium, alendronate plus plain vitamin D and Ca, and alendronate plus alfacalcidol and Ca). During the 2-year-study we observed the significantly highest lumbar spine and hip BMD increases in the combined treatment group (p < 0.001). The number of patients with new vertebral and non-vertebral fractures after 2 years was 9 with alfacalcidol alone, 10 with alfacalcidol and plain vitamin D and 2 in the group receiving alendronate plus alfacalidol (p < 0.02). Furthermore there was a lower rate of falls and an earlier reduction in back pain in the patients treated with the active combination. This trial confirms the demonstrated highly significant advantages of this combined treatment regimen used in the pilote studies. Especially in patients with severe osteoporosis this interesting combination of two substances with complete different mechanisms of action should be taken into consideration.