Balancing benefits and risks of glucocorticoids in rheumatic diseases and other inflammatory joint disorders: new insights from emerging data. An expert consensus paper from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).

PURPOSE: This consensus review article considers the question of whether glucocorticoid (GC) therapy is still relevant in the treatment of rheumatic diseases, with a particular focus on rheumatoid arthritis (RA), and whether its side effects can be adequately managed. Recent basic and clinical research on the molecular, cellular and clinical effects of GCs have considerably advanced our knowledge in this field. An overview of the subject seems appropriate. METHODS: This review is the result of a multidisciplinary expert working group, organised by European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. The recent literature was surveyed and the salient evidence synthetized. RESULTS: The pathophysiological basis of RA (and other inflammatory rheumatic diseases) now strongly implicates the adaptive immune system in addition to innate mechanisms. The molecular effect of GCs and differential GC sensitivity is better understood, although exploiting this knowledge is still in its infancy. The newer treatment strategies of early and aggressive control of RA have gr eatly improved clinical outcomes, but improvements are still possible. Newer targeted anti-inflammatory drugs have made an important impact, yet they too are associated with numerous side effects. DISCUSSION: Short durations of moderate doses of GCs are generally well tolerated and have a positive benefit/risk ratio. Patients should be assessed for fracture risk and bone preserving agents and be prescribed calcium and vitamin D supplementation. CONCLUSIONS: Within a strategy of a disease modifying approach to inflammatory disease, combination therapy including a GC is effective approach.

Alfacalcidol improves muscle power, muscle function and balance in elderly patients with reduced bone mass.

We investigated the effect of daily therapy with 1 mcg alfacalcidol (Doss(®)-TEVA/AWD-pharma) on muscle power, muscle function, balance performance and fear of falls in an open, multi-centered, uncontrolled, prospective study on a cohort of patients with reduced bone mass. Among the 2,097 participants, 87.1% were post-menopausal women and 12.9% were men. Mean age was 74.8 years and mean body mass index (BMI) 26.3 kg/m². A total of 75.3% of the study population had osteoporosis, 81% a diagnosis of "increased risk of falls" and 70.1% had a creatinine clearance (CrCl) of <65 ml/min. Participants underwent muscle function and muscle power tests at onset and after 3 and 6 months: the timed up and go test (TUG) and the chair rising test (CRT). At baseline and after 6 months, participants performed the tandem gait test (TGT) and filled out a questionnaire evaluating fear of falling. Successful performance in the muscle tests is associated with a significantly lower risk of falls and non-vertebral fractures in elderly patients (successful test performance: TUG ≤ 10 s (sec), CRT ≤ 10 s, TGT ≥ 8 steps). A significant improvement in the performance of the two muscle tests was proved already after 3 months of treatment with alfacalcidol and further increased by the end of the therapeutic intervention. There were significant increases in the number of participants able to successfully perform the tests: 24.6% at baseline and 46.3% at the end of trial for the TUG (P < 0.0001) and 21.7% at baseline and 44.2% at the end for the CRT test (P = 0.0001). The mean time used for the TUG was decreased by 3.0 s from the average onset value of 17.0 s and by 3.1 s from the initial average 16.5 s for the CRT. The percentage of participants able to perform the balance test (TGT) increased from 36.0% at onset to 58.6% at the end of the trial (P < 0.0001). An increased fear of falling was reduced by the end of the study in 74.4% of the patients. Throughout the study, there were 26 adverse drug reactions in 11 out of 2,097 patients (incidence 0.52%). No serious adverse drug reactions and no cases of hypercalcemia were documented. We conclude that treatment with alfacalcidol is safe, increases muscle power, muscle function and balance and reduces fear of falls. The significant improvement in the three muscle and balance tests and fear of falls may have a preventative effect on falls and fractures. We suggest that the quantitative risk tests used in this study could be reliable surrogate parameters for the risk of falls and fractures in elderly patients.

Absolute risk reduction in osteoporosis: assessing treatment efficacy by number needed to treat.

Postmenopausal osteoporosis is a chronic condition due to decreased bone mass, leading to reduced bone strength and increased fracture risk. Currently available pharmacological treatments include antiresorptive agents (bisphosphonates and raloxifene) and bone-forming agents (strontium ranelate and two different parathyroid peptides). Comparison via reduction in relative risk of fracture may produce artificially high reductions in fracture risk for some agents. Responder analysis based on absolute risk reduction (ARR, the arithmetic difference between events rates with and without treatment over a fixed time) and a related parameter, number needed to treat (NNT, the number of patients needed to treat over a fixed time to prevent one event) may provide more reliable parameters. We reviewed placebo-controlled, randomized, double-blind, pivotal phase 3 trials employed as part of the regulatory process, in order to calculate ARRs and NNTs for vertebral and hip fracture over 3 years for antiosteoporotic agents currently available in Europe. The NNT values to prevent one vertebral fracture over 3 years range from 9 for the strontium ranelate to 21 for ibandronate. NNT values for hip fracture over 3 years range from 48 for strontium ranelate to 91 for three of the bisphosphonates. Our analysis indicates that the bone-forming agent strontium ranelate may have the lowest NNT for the prevention of both vertebral and hip fracture. Responder analysis may enable translation of clinical trial results into guidance for routine clinical practice by indicating the amount of effort needed to prevent the same event in comparable populations with different treatment options.

Plain vitamin D or active vitamin D in the treatment of osteoporosis: where do we stand today?

Osteoporosis is a major cause of morbidity and mortality worldwide and its prevention in order to avert fractures was considered of great importance in maintaining well-being and independence among the elderly. Strategies for osteoporosis prevention are well delineated, but research shows that the treatment options offered today could still be improved. The role of plain vitamin D (cholecalciferol) in bone health and the prevention of osteoporosis are well documented; however, as a treatment for osteoporosis, either with or without calcium, it has been shown to be ineffective. This is due in part to the strong negative feedback mechanisms in place in vitamin D-replete patients. However, other factors linked directly to ageing such as oestrogen depletion, reduced kidney or liver function may also be involved in reducing the body's capability to activate plain vitamin efficiently. This is why active vitamin D analogues such as alfacalcidol, 1-α-(OH)D3, are of clinical interest. Alfacalcidol requires only one hydroxylation reaction to become active 1,25-(OH)2-vitamin D3, and the 25-hydroxylase catalyzing this reaction is found in the liver and also interestingly in osteoblasts suggesting a local effect. Registered for use in postmenopausal osteoporosis, in most countries worldwide, alfacalcidol has also shown efficacy in glucocorticoid-induced and male osteoporosis. The present review provides compelling evidence for the efficacy of this compound in the treatment of osteoporosis and prevention of fractures both in monotherapy and when combined with other osteoporotic drugs where additive effects are clear. The safety profile of alfacalcidol is shown to be highly acceptable and it is considered less likely to induce hypercalcaemia than another more widely used analogue, calcitriol. Therefore, it remains unclear as to why alfacalcidol is not more widely used in clinical practice.

Value of a new fixed-combination pack of bisphosphonate, calcium and vitamin D in the therapy of osteoporosis: results of two quantitative patient research studies.

BACKGROUND: Osteoporotic patients with insufficient calcium intake and/or vitamin D insufficiency need adequate calcium and vitamin D supplementation with their bisphosphonate treatment. However, consistent intake and, therefore, the effectiveness of calcium/vitamin D supplementation may be impaired by several factors in the individual patient: low prescription rate or lack of advice to purchase calcium/vitamin D; reduced compliance because of the complexity of the regimen; or incorrect intake. There is a need to provide patients with a better way of taking bisphosphonate treatment with their calcium/vitamin D supplementation. To this end, a fixed-combination pack to help patients take the combination of bisphosphonate, calcium and vitamin D correctly and regularly has been developed. OBJECTIVE: To evaluate patients' understanding of administration instructions, preferences and their perceptions of compliance, convenience and completeness of a fixed-combination pack of bisphosphonate, calcium and vitamin D compared with those associated with separate packs. METHODS: The new monthly fixed-combination pack of bisphosphonate, calcium and vitamin D contains four weekly boxes. Each box contains a blister pack with one swallowable risedronate 35 mg film-coated tablet and six sachets of calcium/vitamin D effervescent granules (calcium 1000 mg and vitamin D(3) [colecalciferol] 880 IU) for dissolution in water as an oral solution, together constituting 1 week of therapy, accompanied by a patient information leaflet. Two quantitative patient research survey studies were conducted using standard questionnaires in face-to-face interviews with 400 postmenopausal women in several French cities. Participants were given the combined pack and two separate packs (risedronate 35 mg once weekly and calcium/vitamin D effervescent granules in sachets). In the first study, participants' understanding of administration instructions and preferences were evaluated. In the second study, participants' perception of compliance, convenience and completeness of the new combination pack of risedronate 35 mg plus calcium/vitamin D compared with two separate packs were evaluated. RESULTS: Participants asked about the combined pack answered a significantly higher proportion of questions about intake instructions correctly (80.3%) than participants asked about the two separate packs (70.7%) [p = 0.0004]. The combined pack was preferred by 72% of participants (p < 0.0001) for several reasons. Compared with separate packs, the combined pack was considered easier to use by 63% and easier to remember to use by 67% of participants. Participants believed that use of the combined pack would be more likely to help them take their bisphosphonate regularly (66%) and correctly (67%), and to take their calcium/vitamin D supplementation more regularly and correctly (68%), than use of separate packs. Seventy percent of participants believed that use of the combination pack would help them to not forget to take calcium/vitamin D supplementation. CONCLUSION: Use of the fixed-combination pack of risedronate 35 mg plus calcium/vitamin D once weekly could increase the likelihood that postmenopausal osteoporotic patients will receive a complete bisphosphonate, calcium and vitamin D therapy course and is likely to enhance correct intake of combination therapy. Use of this fixed-combination product will provide patients with a tool for improving adherence to recommended osteoporosis therapy and optimize the effectiveness of such treatment.

Differences in persistence, safety and efficacy of generic and original branded once weekly bisphosphonates in patients with postmenopausal osteoporosis: 1-year results of a retrospective patient chart review analysis.

The objective of this study was to compare the changes on bone mineral density, and the effects on persistence and adverse events in patients treated for postmenopausal osteoporosis with generic alendronate or with branded alendronate (Fosamax®) or branded risedronate (Actonel®) once weekly. In this retrospective patient chart analysis, we reviewed the 1-year observational treatment results for 186 women (ITT population) with postmenopausal osteoporosis. Patients from our outpatient department, who had started with once-weekly bisphosphonate therapy between 36 and at least 12 months before this chart review, were included in this comparative three-arm study according to their treatment: A, Generic Alendonate 70 mg products; B, Branded Alendronate (Fosamax®) 70 mg once weekly and C, Branded Risedronate (Actonel®) 35 mg once weekly. All patients received basic therapy with 1,200 mg calcium and 800 IU vitamin D per day. Patient's bone mineral density (BMD) at lumbar spine and total hip was below −2.5 T-score, and they were with or without prevalent vertebral and non-vertebral fractures. Data analysis regarding the 186 patients shows an average increase in LS-BMD after 12 months of 2.8, 5.2 and 4.8% for the groups A, B and C, respectively. The respective mean changes at total hip were 1.5, 2.9, and 3.1%. At both sites, the mean increases in BMD were not different between the two groups receiving branded bisphosphonates (B, C) but for both were significantly higher than for the group treated with generic alendronate (A). At 12 months, 68% of group A, 84% of group B and 94% of group C were still on bisphosphonate therapy. The persistence of patients treated with generic alendronate was significantly lower as compared to each of the two with branded bisphosphonate-treated groups. The total numbers of patients reporting gastrointestinal adverse events were 32, 15 and 9 for group A, group B, and group C, respectively. Significantly lower increases of lumbar spine and total hip BMD with generic alendronate once weekly as compared to the two branded bisphosphonate originals (Fosamax®, Actonel®) were observed. The reasons for the 40­50% lower BMD increase rates when using the generic compounds are not known yet. At least in part the lower efficacy can be explained by a significantly lower degree of persistence with generic alendronate, which could be related to a higher incidence of gastrointestinal adverse events. Other reasons could be lower bioavailability or potency of generic alendronate.

Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis.

CONTEXT: Persistence with osteoporosis treatment is poor but is important for maximum benefit. OBJECTIVE: The objective of the study was to assess the impact of physician reinforcement using bone turnover markers (BTMs) on persistence with risedronate treatment. DESIGN AND SETTING: This was a 1-yr multinational prospective, open-label, blinded study in 171 osteoporosis centers in 21 countries. PATIENTS: A total of 2382 postmenopausal women (65-80 yr old) with spine/hip T-score -2.5 or less or T-score -1.0 or less with a low-trauma fracture. INTERVENTION: Intervention included calcium 500 mg/d, vitamin D 400 IU/d, and risedronate 5 mg/d for 1 yr. Centers were randomized to reinforcement (RE+) or no reinforcement (RE-). At 13 and 25 wk, reinforcement based on urinary N-telopeptide of type I collagen change from baseline was provided to the RE+ patients using the following response categories: good (>30% decrease), stable (-30% to +30% change), or poor (>30% increase). MAIN OUTCOME MEASURES: Persistence assessed with electronic drug monitors was measured. RESULTS: In the overall efficacy population (n=2302), persistence was unexpectedly high and was similar for both groups (RE-, 77%; RE+, 80%; P=0.160). A significant relationship between the type of message and persistence was observed (P=0.017). Compared with RE-, intervention based on a good BTM response was associated with a significant improvement in persistence [hazard ratio (HR) 0.71; 95% confidence interval (CI) 0.53-0.95]. Persistence was unchanged (HR 1.02; 95% CI 0.74-1.40) or lower (HR 2.22; 95% CI 1.27-3.89) when reinforcement was based on a stable or poor BTM response, respectively. Reinforcement was associated with a lower incidence of new radiologically determined vertebral fractures (odds ratio 0.4; 95% CI, 0.2-1.0). CONCLUSIONS: Reinforcement using BTMs influences persistence with treatment in postmenopausal women with osteoporosis, depending on the BTM response observed.

Advances in the management of corticosteroid-induced osteoporosis with bisphosphonates.

Corticosteroids are widely used as anti-inflammatory and immunosuppressive agents to treat a variety of chronic conditions. Long-term (>1 year) corticosteroid use can lead to bone loss, and therefore, osteopenia or osteoporosis. Corticosteroid-induced osteoporosis (CIO) leads to increased bone fragility and subsequently fractures, which, in turn, lead to a loss of physical, emotional and social health for the patient and increased costs for healthcare providers. A wealth of data exists demonstrating the efficacy of the oral bisphosphonates, etidronate, alendronate and risedronate in increasing bone mineral density in patients with CIO or preventing bone loss in patients commencing corticosteroid therapy. Data regarding fracture prevention are less clear, as statistically significant reductions in the incidence of fractures have only been reported for patient subgroups or meta-analyses. However, many treatment guidelines recommend the use of oral bisphosphonates for the prevention and treatment of CIO. These guidelines are, however, not reflected in prescribing practice, and the majority of patients do not receive adequate concomitant therapy. This review summarizes the available data for bisphosphonates in CIO. Therapeutic adherence with oral bisphosphonates is an issue, with approximately 50% of patients discontinuing therapy within the first year. The primary reasons for this are poor gastrointestinal tolerability and the frequency with which complex dosing requirements must be followed. The inconvenience of taking daily or weekly bisphosphonate therapy is of particular importance in patients with CIO who may be regularly taking several other medications. Data obtained in studies with ibandronate indicate that bisphosphonate administration by rapid intravenous injection provides an effective, well-tolerated and practical alternative to current oral regimens in the management of patients with CIO.

Importance of calcium co-medication in bisphosphonate therapy of osteoporosis: an approach to improving correct intake and drug adherence.

BACKGROUND AND OBJECTIVE: In all of the large, pivotal, multicentre trials of bisphosphonate therapy, patients have received added calcium in amounts ranging from 500 to 1000 mg/day above individual dietary intake. Accordingly, calcium supplements or calcium/vitamin D combinations are currently recommended as co-medication with anti-resorptive therapy in all recently published guidelines on the treatment of osteoporosis. However, the consistent use or effectiveness of calcium may be impaired by several factors in the individual patient, including low prescription rate or lack of advice to purchase calcium, reduced adherence because of the complexity of the regimen, and incorrect intake (e.g. taking calcium with bisphosphonates at the same time). Patients with osteoporosis who adhere to drug therapy experience a significantly lower fracture rate. Therefore, there is a need to improve correct intake of bisphosphonates together with calcium supplementation, which may enhance adherence. The dosage regimen could be simplified by providing the two compounds in an integrated pack. Such a pack, containing one tablet of risedronic acid and six calcium carbonate tablets (Actonel), Procter & Gamble Pharmaceuticals, Weiterstadt, Germany), has been developed to facilitate correct intake. In this study, the impact of this fixed-combination pack on patient understanding of dosing instructions and on preference was tested by comparing the fixed combination with separate risedronic acid and calcium packages. PATIENTS AND METHODS: A new blister strip was developed containing one tablet of risedronic acid 35mg and six tablets of calcium carbonate 1250mg (500mg elemental calcium), representing 1 week of therapy; the control was the same medications in separate packaging. The study was conducted in a cohort of 164 postmenopausal women (mean age 69 years). Half of the participants were bisphosphonate users (n = 83). The combined understanding of five instructions - risedronic acid intake in the morning, only with water, without food, without other medication, and separate from calcium - was tested in a crossover design. Participants were also asked to state their preference for the combination packaging versus separate packs. RESULTS: Understanding of the five instructions for the separate packaging was 70%. The combination pack significantly improved understanding of these instructions to 80% (p < 0.05). Eighty-three percent of participants preferred the combination pack over separate packs (p < 0.05). The most frequently given reasons for preferring the combination pack were prefer one pack over two packs, easy/convenient to use/practical/handy, easy to understand/less confusion, and easier to remember/less likely to forget. CONCLUSIONS: The availability of a fixed-combination pack of risedronic acid 35 mg/week and calcium tablets can increase the likelihood that postmenopausal osteoporotic patients will receive both a bisphosphonate and calcium, which in turn is likely to enhance the correct intake of combination therapy.

Recommendations for the registration of agents to be used in the prevention and treatment of glucocorticoid-induced osteoporosis: updated recommendations from the Group for the Respect of Ethics and Excellence in Science.

OBJECTIVES: The Group for the Respect and Excellence in Science (GREES) has reviewed and updated their recommendations for clinical trials to evaluate the efficacy and safety of new chemical entities to be used in the treatment and prevention of glucocorticoid-induced osteoporosis (GIOP). METHODS: Consensus discussion of the committee. RESULTS: With the exception of steroid use posttransplantation, there is no need to differentiate between underlying diseases. Prevention and treatment for GIOP are dependent on exposure to glucocorticoids rather than T-scores as in postmenopausal osteoporosis (PMO). If fracture data are obtained for PMO, it need not be repeated for GIOP, relying instead on bone mineral density (BMD) trials of at least 1 year. GREES recommends several changes in the previous guidance for GIOP. The committee saw no need to repeat preclinical studies if those have been previously done to assure bone quality in PMO. Similarly, phase I and phase II trials, if careful dose selection has been done for PMO, should not be repeated. The "prevention" and "treatment" claims should remain. Since the most recent evidence suggests significant increase in fracture risk for daily doses of prednisone of 5 mg/day or equivalent, clinical trials should concentrate on patients receiving at least this daily dosage. The emergence of bisphosphonates as the reference treatment, together with the rapid bone loss and high fracture incidence in glucocorticoid users, necessitates recommending a noninferiority trial design with lumbar spine BMD as the primary endpoint after 1 year. CONCLUSIONS: Registration of new chemical entities to be used in the management of GIOP should be granted, based on a 1-year noninferiority trial, using BMD as primary outcome and alendronate or risedronate as comparator. Demonstration of antifracture efficacy should have been previously demonstrated in PMO.

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.

The clinical use of vitamin D metabolites and their potential developments: a position statement from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the International Osteoporosis Foundation (IOF).

Several compounds are produced along the complex pathways of vitamin D3 metabolism, and synthetic analogs have been generated to improve kinetics and/or vitamin D receptor activation. These metabolites display different chemical properties with respect to the parental or native vitamin D3, i.e., cholecalciferol, which has been, so far, the supplement most employed in the treatment of vitamin D inadequacy. Hydrophilic properties of vitamin D3 derivatives facilitate their intestinal absorption and their manageability in the case of intoxication because of the shorter half-life. Calcidiol is a more hydrophilic compound than parental vitamin D3. Active vitamin D analogs, capable of binding the vitamin D receptor evoking vitamin D-related biological effects, are mandatorily employed in hypoparathyroidism and kidney failure with impaired 1α-hydroxylation. They have been shown to increase BMD, supposedly ameliorating calcium absorption and/or directly affecting bone cells, although their use in these conditions is jeopardized by the development of hypercalciuria and mild hypercalcemia. Further studies are needed to assess their overall safety and effectiveness in the long-term and new intermittent regimens, especially when combined with the most effective antifracture agents.

Comparative effects of teriparatide and risedronate in glucocorticoid-induced osteoporosis in men: 18-month results of the EuroGIOPs trial.

Data on treatment of glucocorticoid-induced osteoporosis (GIO) in men are scarce. We performed a randomized, open-label trial in men who have taken glucocorticoids (GC) for ≥3 months, and had an areal bone mineral density (aBMD) T-score ≤ -1.5 standard deviations. Subjects received 20 µg/d teriparatide (n = 45) or 35 mg/week risedronate (n = 47) for 18 months. Primary objective was to compare lumbar spine (L1 -L3 ) BMD measured by quantitative computed tomography (QCT). Secondary outcomes included BMD and microstructure measured by high-resolution QCT (HRQCT) at the 12th thoracic vertebra, biomechanical effects for axial compression, anterior bending, and axial torsion evaluated by finite element (FE) analysis from HRQCT data, aBMD by dual X-ray absorptiometry, biochemical markers, and safety. Computed tomography scans were performed at 0, 6, and 18 months. A mixed model repeated measures analysis was performed to compare changes from baseline between groups. Mean age was 56.3 years. Median GC dose and duration were 8.8 mg/d and 6.4 years, respectively; 39.1% of subjects had a prevalent fracture, and 32.6% received prior bisphosphonate treatment. At 18 months, trabecular BMD had significantly increased for both treatments, with significantly greater increases with teriparatide (16.3% versus 3.8%; p = 0.004). HRQCT trabecular and cortical variables significantly increased for both treatments with significantly larger improvements for teriparatide for integral and trabecular BMD and bone surface to volume ratio (BS/BV) as a microstructural measure. Vertebral strength increases at 18 months were significant in both groups (teriparatide: 26.0% to 34.0%; risedronate: 4.2% to 6.7%), with significantly higher increases in the teriparatide group for all loading modes (0.005 < p < 0.015). Adverse events were similar between groups. None of the patients on teriparatide but five (10.6%) on risedronate developed new clinical fractures (p = 0.056). In conclusion, in this 18-month trial in men with GIO, teriparatide showed larger improvements in spinal BMD, microstructure, and FE-derived strength than risedronate.

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.

Vitamin D-insufficiency: An estimate of the situation in Germany.

BACKGROUND: Vitamin D insufficiency is increasingly recognized as an important risk factor in the pathogenesis of falls and fractures and may increase the risk of other diseases. The aim of this study was to obtain information about the vitamin D supply from a representative cohort of the German population.   METHODS: 264 General practitioners participated in the DeViD-Trial (D-Vitamin in Deutschland) by taking blood samples from their consenting daily ambulant patients regardless of the actual reason for consultation. In these blood samples vitamin D [25(OH)D] and other related parameters were measured at a central laboratory. The patients filled in a simple questionnaire (i.e., age, sex, etc.). The trial was performed between February 26 and May 25, 2007. RESULTS: Laboratory and personal data were documented for 1,343 individuals (615 men, 728 women). The age distribution ranged from 20 to 99 y, the mean age of the whole cohort was 57.6 y (men 58.2, women 57.2). The mean 25-OH-D-value for the whole cohort was 16.2 ng/ml (range: 6.0 to 66.8, median 14.1 ng/ml). Ten percent of the patients had 25(OH)D-values below 7 ng/ml, 65% below 20 ng/ml and 92% showed values below 30 ng/ml. In the more recent literature, 25(OH)D values below 30 ng/ml are regarded as sub-optimal for bone, muscle and general health. Correspondingly it can be stated that in this representative population there is a high prevalence of moderate to severe vitamin D-insufficiency regardless of young or old age.