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.

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.

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.

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.

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.

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.

Use of OROS® hydromorphone in the treatment of osteoarthritis and osteoporosis: A pooled analysis of three non-interventional studies focusing on different starting doses.

OBJECTIVE: To determine the effect of a lower starting dose of OROS® hydromorphone compared with a higher starting dose. DESIGN: Data from the first 15 days of treatment were compared in a combined analysis of three prospective, non-interventional studies. SETTING: Non-interventional, carried out in daily routine settings. PATIENTS: Patients had chronic severe pain due to osteoarthritis or from fragility fractures related to osteoporosis. INTERVENTIONS: OROS-ANA-4001 and OROS-ANA-4002 had a daily starting dose of 8 mg of OROS® hydromorphone; OROS-ANA-4003 had a daily starting dose of 4 mg. MAIN OUTCOME MEASURE(S): A post-hoc analysis to assess the effect of a low starting dose of OROS® hydromorphone on tolerability, pain control, and treatment satisfaction overall and for subgroups of opioid-naïve patients versus patients previously treated with opioids, and patients aged >65 years versus patients aged ≤65 years. RESULTS: Treatment satisfaction and pain control improved in all studies; treatment satisfaction improved in a higher percentage of patients in the lower starting dose group. Gastrointestinal disorders were the most frequent treatment-emergent adverse events. Incidence of nausea was comparable between studies. Incidence of constipation, vomiting, fatigue, and pruritus was less frequent with the lower starting dose. In elderly and opioid-naïve patients, a lower starting dose was associated with lower overall incidence of adverse events, treatment-related adverse events, and those leading to discontinuation. CONCLUSIONS: A lower starting dose was associated with better tolerability and a lower number of treatment terminations at a comparable level of pain control with high treatment satisfaction.

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.

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.

Bone turnover markers and bone mineral density response with risedronate therapy: relationship with fracture risk and patient adherence.

Surrogate markers of fracture risk--bone turnover markers (BTMs) and bone mineral density (BMD)--can be used to monitor treatment response. We assessed whether changes in these markers greater than the least significant change (LSC) were associated with fracture risk reduction and greater adherence. This secondary analysis of the Improving Measurements of Persistence on ACtonel Treatment (IMPACT) study--a multinational prospective, open-label, cluster-randomized study of postmenopausal women on oral risedronate 5 mg/d for 52 weeks-assessed adherence by electronic monitors. Urinary N-terminal cross-linked telopeptide of type 1 collagen (uNTX) and serum C-terminal cross-linked telopeptide of type 1 collagen (sCTX) levels were assessed at baseline and weeks 10 and 22, and BMD at baseline and week 52. Fractures were recorded as adverse events. In 2302 women, responses beyond LSC in BTMs (uNTX and sCTX) and BMD (spine only) were associated with a reduced risk of nonvertebral fractures (NVFs) and all fractures. NVF incidence was about 50% lower in patients with 30% or more of uNTX reduction at week 22 (1.6%) than in those with less than 30% reduction (3.2%, p = .015). NVFs also were reduced in patients with more than 3% spine BMD increase at 52 weeks than those with 3% or less. Responses greater than LSC in BTMs and BMD were associated with greater adherence, but there was no association between adherence and fracture outcomes at 52 weeks. Changes greater than the LSC in BTMs and BMD reflect better treatment adherence, were associated with fracture risk reduction, and identify differences in individual responsiveness to risedronate.

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.

Development of clinical utility of zoledronic acid and patient considerations in the treatment of osteoporosis.

Osteoporosis is a major health concern, which results in the increased risk of fractures. There is a high risk for the first or consecutive fractures leading to considerable morbidity and debilitating consequences if osteoporosis is untreated. Currently, bisphosphonates are the mainstay of treatment for osteoporosis though long-term persistence and adherence to bisphosphonates, especially those taken orally, remain low. This medication noncompliance has serious consequences on osteoporotic patients as it is associated with a significantly higher fracture risk. Intravenous (IV) zoledronic acid (ZOL), developed to increase compliance by overcoming the frequent and burdensome dosing requirements of oral bisphosphonates, is the first and the only once-yearly bisphosphonate globally approved for use in the treatment of up to 6 indications of osteoporosis. Several clinical studies have documented that a single infusion of IV ZOL resulted in decreased bone turnover and improved bone density for at least 12 months post infusion. This article traces the development of ZOL's clinical utility and evaluates its patient preference by collating data from all major clinical trials, studying the efficacy and safety of ZOL in the treatment of osteoporosis and other benign bone disorders.

Efficacy of strontium ranelate on bone mineral density in men with osteoporosis.

In an open-label, prospective, controlled, 12-month study the effects of strontium ranelate (SR, CAS 135459-87-9) or alendronate (CAS 129318-43-0) on bone mineral density (BMD) were compared in 152 men with primary osteoporosis. Patients were randomized to SR 2 g/day (n = 76) or alendronate 70 mg/week (n = 76) supplemented daily with 1200 mg calcium and 800 IU vitamin D. The main outcome measure was percent change in lumbar spine and total hip BMD from baseline. Mean BMD (+/- SD) increased by 5.8 +/- 3.7% at the lumbar spine and 3.5 +/- 2.8% at the total hip with SR compared to increases of 4.5 +/- 3.4 % and 2.7 +/- 3.2%, respectively, with alendronate. Increases in BMD in the SR group are consistent with 1-year results from two pivotal fracture studies in postmenopausal women with osteoporosis. SR was associated with a 22% greater increase in BMD at the lumbar spine (p = 0.033) and 23% greater increase at the total hip (p = 0.002) than alendronate. New fractures were observed in 7 SR and 10 alendronate patients. Height loss (-0.1 +/- 0.7 cm) was less with SR compared with alendronate (-0.5 +/- 0.8 cm) (p = 0.026). SR was also associated with significantly greater reductions in back pain and analgesic use scores. Adverse events were experienced by 28 (37%) patients in the SR group and 38 (50%) patients in the alendronate group, none of which were serious. In men with osteoporosis, SR produced significantly greater mean increases in BMD over 12 months compared with alendronate, an agent already approved for male osteoporosis. Mean increases in BMD with SR in men were similar to those previously documented for this agent in postmenopausal women, suggesting that similar benefits on anti-fracture efficacy may be expected.

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.

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.