History of etidronate.

Etidronate is a non-nitrogen-containing bisphosphonate. Because it binds with calcium and inhibits crystal formation and dissolution, it was considered by Procter & Gamble as an additive to toothpaste (to prevent build-up of tartar) and detergent (to bind calcium and increase sudsing in "hard" water). The first clinical use (1968) was for fibrodysplasia ossificans progressiva. The first approved clinical use (1977) was for treatment of Paget's disease of bone. Other approved indications are hypercalcemia of malignancy and heterotopic ossification, with a host of off-label uses (including fibrous dysplasia, periodontal disease, multiple myeloma, neuropathic arthropathy, pulmonary microlithiasis, diabetic retinopathy, bone metastases, melorheostosis, urinary stone disease, periodontal disease, etc.). Unique among bisphosphonates, etidronate (oral therapy) results in hyperphosphatemia, increased tubular reabsorption of phosphorus and increased levels of 1,25-dihydroxyvitamin D. The dose that reduces bone resorption is close to the dose that impairs mineralization; prolonged high-dose use can result in osteomalacia and bone fractures. Intermittent cyclic etidronate for osteoporosis resulted in favorable changes in bone density and histomorphometry (no mineralization defect) as well as a decrease in vertebral fracture rates in postmenopausal women with osteoporosis. Later studies showed similar effects in men with osteoporosis and patients with glucocorticoid-induced osteoporosis. Although its use for osteoporosis has given way to newer bisphosphonates and other agents, because of its unique properties, it remains the bisphosphonate of choice for treatment of heterotopic ossification.

Asymmetric bone mineral density in the bilateral femoral necks due to gluteal implants: a case report.

Interpreting asymmetric bone mineral density in the bilateral hips on dual energy x-ray absorptiometry requires investigation into the potential causes, both real and artifactual. Silicone gluteal implants have been reported to cause abnormally elevated bone mineral density. We report a case of abnormally low bone mineral density in a patient with bilateral gluteal implants. This is likely due to patient positioning and inability of the computer to identify the superior margin of the proximal femur and the femoral neck.

Outcomes of early ileocolectomy after percutaneous drainage for perforated ileocolic Crohn's disease.

BACKGROUND: The optimal treatment for an intra-abdominal abscess/infection secondary to perforating ileocolic Crohn's disease (PCD) is unclear. METHODS: Forty-seven consecutive PCD patients treated via an institutional protocol of ileocolectomy after a 7-day period of percutaneous abscess drainage were retrospectively compared with 160 consecutive patients who underwent an elective ileocolectomy for Crohn's disease (ECD) between 1992 and 2014. Outcomes were compared using univariate analysis and propensity score matching. RESULTS: Univariate analysis demonstrated significant differences in ileostomy rates (PCD: 48.9% vs ECD: 18.8%; P = .001), 30-day readmissions (PCD: 38.3% vs ECD: 18.8%; P = .01), and overall 30-day postoperative complications (PCD: 29.8% vs ECD: 15%; P = .03). After matching, a statistically significant difference was retained in ileostomy rates (P = .02) and 30-day readmissions (P = .01). CONCLUSIONS: Early operative intervention after percutaneous drainage in perforating CD may be associated with a high incidence of diversions and readmissions.

Penetrating Cardiac Nail Gun Injury in a Child.

Nail gun injuries primarily occur in the extremities of adult males as a consequence of accidental occupational trauma. Such injury involving the thorax is much less common, and penetrating cardiac injury secondary to pneumatic nail gun discharge is rare. Although potentially lethal, most cases with cardiac trauma are survivable with expedient surgical intervention. Despite improvements in engineered safety mechanisms, the incidence of nail gun injuries has risen as use of the devices has increased. The widespread availability of these tools to nonprofessional consumers exposes a broader population to the potential hazards associated with these devices. We describe the presentation and successful management of the first reported case of penetrating cardiac nail gun injury in a young child.

The profile of successful applicants for endocrine surgery fellowships: results of a national survey.

BACKGROUND: The American Association of Endocrine Surgeons initiated a fellowship match in 2007. The profile of applicants who successfully match into an endocrine surgery (ES) fellowship has not previously been characterized. METHODS: An institutional review board-approved, web-based survey was distributed to recent and current ES fellows. RESULTS: The survey response rate was 62% (56/90). The overall mean age was 33 years (standard deviation ±3), 54% were female, and 37% self-identified as non-white. Only 5% entered their surgical training with the aim of specializing in ES. During residency, respondents were exposed to high volumes of index ES cases. Sixty-two percent had dedicated research time. At the time of fellowship application, the median number of publications was 5 (range, 0 to 25), and 30% of respondents had additional advanced degrees. CONCLUSION: Entering ES fellows has diverse backgrounds, with strong academic credentials. These data help inform the career mentoring of aspiring ES applicants.

Successful operative rib fixation of traumatic flail chest in a patient with osteogenesis imperfecta.

Increasing attention has been directed towards operative rib fixation of traumatic flail chest; reported benefits include more rapid weaning from the ventilator, decreased intensive care unit stays, decreased complications and improved functional results. The outcomes of this surgical intervention in patients with osteogenesis imperfecta, a rare condition characterized by low bone density and bone fragility, are unknown. This case demonstrates that, in the management of traumatic flail chest in a patient with osteogenesis imperfecta, surgical fixation can be successful and should be considered early.

Can PET-CT imaging and radiokinetic analyses provide useful clinical information on atypical femoral shaft fracture in osteoporotic patients?

Atypical femoral shaft fractures are associated with the extended usage of nitrogen-containing bisphosphonates as therapy for osteoporosis. For such fractures, the positron emission tomography (PET) procedure, coupled with computerized tomography (CT), provides a potential imaging modality for defining aspects of the pathogenesis, site specificity, and possible prodromal abnormalities prior to fracture. PET-CT may assess the radiokinetic variables K1 (a putative marker for skeletal blood flow) and Ki (a putative marker for skeletal bone formation), and when combined with PET imaging modalities and CT skeletal site localization, may define the site of such radiokinetic findings. Further studies into the clinical usage of PET-CT in patients with atypical femoral shaft fractures are warranted.

Safety of bazedoxifene in a randomized, double-blind, placebo- and active-controlled Phase 3 study of postmenopausal women with osteoporosis.

BACKGROUND: We report the safety findings from a 3-year phase 3 study (NCT00205777) of bazedoxifene, a novel selective estrogen receptor modulator under development for the prevention and treatment of postmenopausal osteoporosis. METHODS: Healthy postmenopausal osteoporotic women (N = 7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. Safety and tolerability were assessed by adverse event (AE) reporting and routine physical, gynecologic, and breast examination. RESULTS: Overall, the incidence of AEs, serious AEs, and discontinuations due to AEs in the bazedoxifene groups was not different from that seen in the placebo group. The incidence of hot flushes and leg cramps was higher with bazedoxifene or raloxifene compared with placebo. The rates of cardiac disorders and cerebrovascular events were low and evenly distributed among groups. Venous thromboembolic events, primarily deep vein thromboses, were more frequently reported in the active treatment groups compared with the placebo group; rates were similar with bazedoxifene and raloxifene. Bazedoxifene showed a neutral effect on the breast and an excellent endometrial safety profile. The incidence of fibrocystic breast disease was lower with bazedoxifene 20 and 40 mg versus raloxifene or placebo. Reductions in total and low-density lipoprotein levels and increases in high-density lipoprotein levels were seen with bazedoxifene versus placebo; similar results were seen with raloxifene. Triglyceride levels were similar among groups. CONCLUSION: Bazedoxifene showed a favorable safety and tolerability profile in women with postmenopausal osteoporosis. TRIAL REGISTRATION NUMBER: NCT00205777; Trial registration date: September 16, 2005.

Vertebral fracture diagnosis in the multinational BONE study of oral ibandronate: quality management in radiology.

A multicenter trial has established the antifracture efficacy of oral daily (2.5mg) as well as intermittent (20mg every other day for 12 doses every 3 mo) ibandronate in women with postmenopausal osteoporosis. As diagnostic spinal radiographs for this trial were read at 2 centers, the study protocol included rigorous procedures for diagnosis of morphometric vertebral fractures. These included standardized qualitative and morphometric assessment methods for diagnosing vertebral osteoporotic fractures and consensus cross-validation procedures for maximizing fracture diagnostic accuracy and consistency between the 2 radiographic reading centers. Using these stringent measures, the between-center discrepancy in the diagnosis of prevalent fractures was only 8%. Furthermore, after cross-validation, discrepancy in the final diagnosis of incident fractures between centers was found for only 4 patients, resulting in a net gain of only 2 fractures in the trial. This meticulous methodology provided a highly effective means of identifying vertebral fractures and recruiting the trial population in which to assess the efficacy of ibandronate in postmenopausal osteoporosis.

Progression of efficacy with ibandronate: a paradigm for the development of new bisphosphonates.

While initial preclinical studies provide an important starting point for dose selection, they may not provide adequate information to identify the optimal dosage for an extended treatment regimen. Determining the best dose for use in an extended dosing regimen requires ongoing development, illustrated best with the bisphosphonate, ibandronate. As mandated for regulatory purposes, the daily oral regimen of ibandronate was proven effective in significantly reducing the rate of new vertebral fractures assessed prospectively, and nonvertebral fractures in a high-risk population, assessed retrospectively. Extended dosing regimens, namely monthly and quarterly intravenous formulations, were developed subsequently to improve the convenience and enhance persistence, while maintaining or increasing efficacy. The continuing and progressive evolution of data led to the understanding that extension of drug-free interval requires higher annual cumulative skeletal exposures (ACE), which were not simply numerical multipliers of the interval and daily dose. For ibandronate, this led to dose selection for the oral monthly 150 mg (ACE 10.8 mg) and intravenous quarterly 3 mg (ACE 12 mg) formulations that proved superior in increasing bone mineral density (BMD) compared with oral daily 2.5 mg (ACE 5.5 mg) ibandronate. Pooling data from clinical trials with high ACE regimens (monthly and quarterly) led to the evolution of statistical evidence for a reduction in clinical and nonvertebral fractures with ibandronate. The ibandronate story should serve as an important future paradigm for bisphosphonate development.

Bisphosphonate therapy for reduced bone mineral density in children with chronic graft-versus-host disease.

Reduced bone mineral density (BMD) occurs frequently in children after hematopoietic cell transplantation (HCT), but therapy for this complication is undefined. To determine the impact of bisphosphonate therapy on reduced BMD after HCT, we compared baseline and follow-up dual energy X-ray absorptiometry (DEXA) scans of 48 patients (controls) who received calcium and vitamin D to 18 patients who also received bisphosphonate therapy. Among the controls, median annualized increase in standardized BMD (sBMD) was 10% (range, -26% to +41%), but the deviation of sBMD from normal, as indicated by the Z-score, did not improve from baseline, -2.46 (range: -5.15 to -1.16) compared to follow-up, -2.79 (range: -5.76 to +0.07). For the bisphosphonate-treated patients, the median annualized increase in sBMD was 33% (range 3% to 147%, P = .0002) and the median Z-score improved from -3.57 (range: -5.13 to -0.86) at baseline, to -1.80 (-4.89 to +0.47) at follow-up (P = .06). The annualized median change in BMD Z-scores per year was +0.12 (-2.28 to +4.24) among the controls and +1.43 (-0.29 to +3.72) for the bisphosphonate group (P = .0002). The greatest improvement in BMD was observed in children who received therapy with bisphosphonates.

Treating osteoporosis with bisphosphonates and addressing adherence: a review of oral ibandronate.

Osteoporosis is a common, chronic condition, affecting approximately half of all postmenopausal Caucasian women in the US. Vertebral fractures occur as a result of osteoporosis and lead to increased hospitalisation and mortality, and adversely affect patient quality of life. The burden of osteoporosis on healthcare systems is expected to rise as the elderly population continues to grow. Yet there are many medications for preventing and treating osteoporosis. Oral bisphosphonates are first-line treatment for osteoporosis, with demonstrated efficacy in increasing bone mineral density and reducing bone turnover, which reduces the incidence of fractures. However, adherence to medication is suboptimal, with approximately 40% of patients discontinuing treatment within 6 months. Recent reports have suggested simplifying the dosage regimen as a strategy to help address this issue. Ibandronate is a potent, nitrogen-containing bisphosphonate which is administered once-monthly. Preclinical studies initially revealed the feasibility of extending the between-dose interval. Subsequent clinical studies have provided further evidence of the positive effects of extended-interval ibandronate administration in reducing the risk of vertebral fractures through increasing bone mineral density and reducing bone turnover without compromising bone quality. These studies have also demonstrated that ibandronate has a safety profile similar to placebo. Ibandronate has recently been approved for use in the US to treat postmenopausal osteoporosis. This review summarises the efficacy and safety of once-monthly oral ibandronate and discusses the implications of such a treatment in primary care in the US.

Denosumab in postmenopausal women with low bone mineral density.

BACKGROUND: Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for osteoclast differentiation, activation, and survival. The fully human monoclonal antibody denosumab (formerly known as AMG 162) binds RANKL with high affinity and specificity and inhibits RANKL action. METHODS: The efficacy and safety of subcutaneously administered denosumab were evaluated over a period of 12 months in 412 postmenopausal women with low bone mineral density (T score of -1.8 to -4.0 at the lumbar spine or -1.8 to -3.5 at the proximal femur). Subjects were randomly assigned to receive denosumab either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100, or 210 mg), open-label oral alendronate once weekly (at a dose of 70 mg), or placebo. The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Changes in bone turnover were assessed by measurement of serum and urine telopeptides and bone-specific alkaline phosphatase. RESULTS: Denosumab treatment for 12 months resulted in an increase in bone mineral density at the lumbar spine of 3.0 to 6.7 percent (as compared with an increase of 4.6 percent with alendronate and a loss of 0.8 percent with placebo), at the total hip of 1.9 to 3.6 percent (as compared with an increase of 2.1 percent with alendronate and a loss of 0.6 percent with placebo), and at the distal third of the radius of 0.4 to 1.3 percent (as compared with decreases of 0.5 percent with alendronate and 2.0 percent with placebo). Near-maximal reductions in mean levels of serum C-telopeptide from baseline were evident three days after the administration of denosumab. The duration of the suppression of bone turnover appeared to be dose-dependent. CONCLUSIONS: In postmenopausal women with low bone mass, denosumab increased bone mineral density and decreased bone resorption. These preliminary data suggest that denosumab might be an effective treatment for osteoporosis. (ClinicalTrials.gov number, NCT00043186.).

Review of treatment modalities for postmenopausal osteoporosis.

This review summarizes and updates data presented at recent annual Southern Medical Association conferences on postmenopausal osteoporosis. As part of any osteoporosis treatment program, it is important to maintain adequate calcium and 25-hydroxyvitamin D levels either through diet or supplementation. Among the available pharmacologic therapies, the bisphosphonates alendronate and risedronate have demonstrated the most robust fracture risk reductions-approximately 40 to 50% reduction in vertebral fracture risk, 30 to 40% in nonvertebral fracture risk, and 40 to 60% in hip fracture risk. Ibandronate, a new bisphosphonate, has demonstrated efficacy in reducing vertebral fracture risk. Salmon calcitonin nasal spray and raloxifene demonstrated significant reductions in vertebral fracture risk in pivotal studies. Teriparatide significantly reduced vertebral and nonvertebral fracture risk. Drugs on the horizon include strontium ranelate, which has been shown to reduce vertebral and nonvertebral fracture risk, and zoledronic acid, an injectable bisphosphonate that increased bone density with once-yearly administration.

Effects of salmon calcitonin on trabecular microarchitecture as determined by magnetic resonance imaging: results from the QUEST study.

UNLABELLED: The unique noninvasive MRI technique was used to assess trabecular microarchitecture at multiple skeletal sites in 91 postmenopausal osteoporotic women receiving nasal spray salmon calcitonin (CT-NS) or placebo over 2 years. In the distal radius and lower trochanter of the hip, individuals treated with CT-NS exhibited significant preservation of trabecular bone microarchitecture compared with placebo, where significant deterioration was shown. MRI analyses of os calcis or microCT/histomorphometric analyses of bone biopsies did not reveal consistent differences in architecture between CT-NS and placebo. INTRODUCTION: It is postulated that the reduction in osteoporotic fracture risk in response to certain antiresorptive osteoporosis therapies is caused less by effects on bone quantity than on bone quality (specifically trabecular microarchitecture). To test this hypothesis, the QUEST study was conducted to assess the effects of nasal spray salmon calcitonin (CT-NS) or placebo on parameters of trabecular microarchitecture at multiple skeletal sites using noninvasive MRI technology and iliac crest bone biopsies by microCT/histomorphometry. MATERIALS AND METHODS: Ninety-one postmenopausal osteoporotic women were followed for 2 years (n = 46 for CT-NS, n = 45 for placebo); all women received 500 mg calcium daily. MRI measurements at distal radius, hip (T2 relaxation time [T2*]), and os calcis (obtained yearly), iliac crest bone biopsies with 2D histomorphometry and 3D microCT (obtained at study onset and conclusion), DXA-BMD at spine/hip/wrist/os calcis (obtained yearly), and markers of bone turnover (obtained at 2-week to 12-month intervals) were analyzed, with an analysis of covariance model used to assess treatment effect for parameters of interest. RESULTS AND CONCLUSIONS: MRI assessment of trabecular microarchitecture at individual regions of the distal radius revealed significant improvement, or preservation (no significant loss), in the CT-NS-treated group compared with significant deterioration in the placebo control group, as reflected in apparent BV/TV (p < 0.03), apparent trabecular number (p < 0.01), and apparent trabecular spacing (p < 0.01). Also, at the hip, the CT-NS group exhibited preservation of trabecular microarchitecture at the lower trochanter (p < 0.05) as determined by T2* MRI technology. Significant deterioration of trabecular bone architecture was noted in the placebo group at the femoral neck, Ward's triangle, and lower trochanteric sites. Apart from a significant increase in apparent trabecular number in the CT-NS group, significant changes within or between groups were not noted at the os calcis. Combined microCT/histomorphometric analysis of iliac crest bone biopsies did not reveal significant differences between treated and placebo groups. In the CT-NS group, regardless of the change in BMD (gain or loss) at the spine, hip, or distal radius, preservation of parameters of trabecular microarchitecture was noted, whereas in the placebo group, regardless of the change in BMD (gain or loss) at the spine, hip, or distal radius, loss or preservation was noted; however, changes in DXA/BMD (of the spine, hip, wrist, os calcis) between CT-NS and placebo groups were not significant. Serum C-telopeptide (S-CTx), a specific bone resorption marker, was reduced by 22.5% at 24 months (p = 0.056). The results of the QUEST study suggest therapeutic benefit of CT-NS compared with placebo in maintaining trabecular microarchitecture at multiple skeletal sites and support the use of MRI technology for assessment of trabecular microarchitecture in clinical research trials. However, the results also highlight site specific differences in response to antiresorptive therapies and the importance of sufficiently large sampling volumes (areas) to obtain reliable assessment of bone architecture.

Vertebral fracture risk reduction with risedronate in post-menopausal women with osteoporosis: a meta-analysis of individual patient data.

BACKGROUND AND AIMS: The effect of risedronate, a potent pyridinyl bisphosphonate, on vertebral fractures in post-menopausal women was evaluated in randomized, placebo-controlled clinical trials. These trials included two large vertebral fracture studies that used time-to-event methods to evaluate the effects of treatment on fracture risk, thereby allowing both the occurrence and the timing of fractures to be considered. METHODS: We used individual patient data (IPD) and time-to-event methods to perform a meta-analysis of the anti-fracture efficacy of risedronate (2.5 or 5 mg daily) in osteoporotic women enrolled in five double-blind, placebo-controlled clinical trials. Women were included in the analysis if, at baseline, they had either at least one prevalent vertebral fracture or a femoral neck bone mineral density (BMD) T-score of less than -2.5, were at least 1 year post-menopausal, and had had vertebral fracture assessments (N = 3331). RESULTS: Risedronate 5 mg daily reduced the risk of radiographically defined vertebral fracture by 64% (95% CI, 46 to 76%, p < 0.001) in the first year of treatment and 45% (95% CI, 31 to 57%, p < 0.001) in 3 years. The numbers of patients who needed to be treated with risedronate 5 mg to prevent one new vertebral fracture over 1 and 3 years were 21 and 13, respectively. Comparable findings were observed in sub-populations defined on the basis of either prevalent vertebral fracture without regard to femoral neck BMD, or femoral neck BMD without regard to vertebral fracture status. Risedronate significantly reduced the incidence of clinical (symptomatic) vertebral fractures in the first 6 months of treatment (p < 0.001). CONCLUSIONS: This meta-analysis, based upon five trials and using IPD and time-to-event statistical methods, provides a more precise estimate of the effect of risedronate in reducing vertebral fracture risk in postmenopausal osteoporotic women than a meta-analysis using summary statistics from the literature.

Ibandronate produces significant, similar antifracture efficacy in North American and European women: new clinical findings from BONE.

OBJECTIVES: BONE (oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) determined whether less frequent dosing of ibandronate (dose-free interval > 2 months) provided similar antifracture efficacy to daily dosing. As osteoporosis medications must be effective across different populations, an additional objective of BONE was to investigate and report the effect of oral ibandronate in North American and European women, as described here. PATIENTS AND METHODS: BONE was a randomized, double-blind, placebo-controlled, fractureprevention study in 2946 postmenopausal women (age 55 years-80 years; > or = 5 years since menopause) with osteoporosis (low lumbar spine bone mineral density and one to four prevalent vertebral fractures [T4-L4]). Participants received daily calcium (500 mg) and vitamin D (400 IU) plus either placebo, oral daily ibandronate (2.5 mg) or oral intermittent ibandronate (20 mg every other day for 12 doses every 3 months). The efficacy and tolerability of ibandronate were assessed independently in both North American and European populations. RESULTS: Consistent, significant efficacy was observed in the North American (new vertebral fracture risk reduction: 60% and 54% with daily and intermittent ibandronate, respectively) and European patient populations (50% and 48%, respectively). Both ibandronate regimens also significantly reduced the incidence of new, worsening, and acute clinical, vertebral fractures. Daily and intermittent ibandronate significantly increased bone density at the spine in both North American (5.4% and 4.4% vs. baseline with daily and intermittent ibandronate, respectively) and European (7.1% and 6.3% vs. baseline, respectively) populations. Significant increases were also observed for total hip bone density (2.6% and 3.7% vs. baseline for daily, and 2.5% and 3.1% for intermittent; North American and European populations, respectively). Comparable, significant decreases in biochemical markers of bone turnover (reductions in urinary excretion of C-telopeptide levels of 53.5% and 67.1% vs. baseline for daily, and 50.0% and 53.8% for intermittent; North American and European populations, respectively) were also observed in both populations (p < 0.004 for all cited measurements in each ibandronate group vs. placebo). Oral ibandronate was well tolerated in both North American and European patients, with a safety profile similar to placebo. CONCLUSIONS: Oral ibandronate, administered daily or intermittently, effectively reduced vertebral fracture risk in North American and European women with postmenopausal osteoporosis. These results demonstrate the efficacy of ibandronate administered with extended dose-free intervals, regardless of patients' geographical origin. Research investigating other less frequent ibandronate regimens, such as once-monthly oral administration, is underway.

Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis.

UNLABELLED: Oral daily (2.5 mg) and intermittent ibandronate (between-dose interval of >2 months), delivering a similar cumulative exposure, were evaluated in 2946 osteoporotic women with prevalent vertebral fracture. Significant reduction in incident vertebral fracture risk by 62% and 50%, respectively, was shown after 3 years. This is the first study to prospectively show antifracture efficacy for the intermittent administration of a bisphosphonate. INTRODUCTION: Bisphosphonates are important therapeutics in postmenopausal osteoporosis. However, they are currently associated with stringent dosing instructions that may impair patient compliance and hence therapeutic efficacy. Less frequent, intermittent administration may help to overcome these deficiencies. This study assessed the efficacy and safety of oral ibandronate administered either daily or intermittently with a dose-free interval of >2 months. MATERIALS AND METHODS: This randomized, double-blind, placebo-controlled, parallel-group study enrolled 2946 postmenopausal women with a BMD T score < or = -2.0 at the lumbar spine in at least one vertebra (L1-L4) and one to four prevalent vertebral fractures (T4-L4). Patients received placebo or oral ibandronate administered either daily (2.5 mg) or intermittently (20 mg every other day for 12 doses every 3 months). RESULTS AND CONCLUSIONS: After 3 years, the rate of new vertebral fractures was significantly reduced in patients receiving oral daily (4.7%) and intermittent ibandronate (4.9%), relative to placebo (9.6%). Thus, daily and intermittent oral ibandronate significantly reduced the risk of new morphometric vertebral fractures by 62% (p = 0.0001) and 50% (p = 0.0006), respectively, versus placebo. Both treatment groups also produced a statistically significant relative risk reduction in clinical vertebral fractures (49% and 48% for daily and intermittent ibandronate, respectively). Significant and progressive increases in lumbar spine (6.5%, 5.7%, and 1.3% for daily ibandronate, intermittent ibandronate, and placebo, respectively, at 3 years) and hip BMD, normalization of bone turnover, and significantly less height loss than in the placebo group were also observed for both ibandronate regimens. The overall population was at low risk for osteoporotic fractures. Consequently, the incidence of nonvertebral fractures was similar between the ibandronate and placebo groups after 3 years (9.1%, 8.9%, and 8.2% in the daily, intermittent, and placebo groups, respectively; difference between arms not significant). However, findings from a posthoc analysis showed that the daily regimen reduces the risk of nonvertebral fractures (69%; p = 0.012) in a higher-risk subgroup (femoral neck BMD T score < -3.0). In addition, oral ibandronate was well tolerated. Oral ibandronate, whether administered daily or intermittently with an extended between-dose interval of >2 months, is highly effective in reducing the incidence of osteoporotic fractures in postmenopausal women. This is the first time that significant fracture efficacy has been prospectively shown with an intermittently administered bisphosphonate in the overall study population of a randomized, controlled clinical trial. Thus, oral ibandronate holds promise as an effective and convenient alternative to current bisphosphonate therapies.

Oral daily ibandronate prevents bone loss in early postmenopausal women without osteoporosis.

UNLABELLED: Oral daily ibandronate was investigated for the prevention of bone loss in postmenopausal women without osteoporosis (n = 653). BMD at the lumbar spine and hip were significantly increased (3.1% and 1.8%, respectively; p < or = 0.0001 versus placebo) with 2.5 mg ibandronate after 24 months. Oral ibandronate is a promising option for the prevention of postmenopausal bone loss. INTRODUCTION: Further strategies to manage patients most at risk from developing postmenopausal osteoporosis are required. The objectives of this multicenter, double-blind, randomized, placebo-controlled study were to examine the efficacy, tolerability, and optimal dose of oral daily ibandronate in the prevention of bone loss in postmenopausal women. MATERIALS AND METHODS: In total, 653 women (mean bone mineral density [BMD] T-score > -2.5 at the lumbar spine), who had been postmenopausal for at least 1 year, were allocated to one of four strata based on time since menopause and baseline lumbar spine BMD. Women were randomized to receive calcium (500 mg daily) plus either placebo (n = 162) or ibandronate 0.5 mg (n = 162), 1 mg (n = 166), or 2.5 mg (n = 163) as once-daily oral treatment for 2 years. The primary endpoint was the mean percent change in lumbar spine BMD with ibandronate versus placebo. RESULTS AND CONCLUSIONS: After 2 years, oral daily ibandronate produced a dose-related and sustained maintenance or increase in BMD at the lumbar spine and hip (total hip, femoral neck, trochanter), together with a dose-related reduction in the rate of bone turnover. The greatest nominal increases in spinal and hip BMD were observed with the 2.5-mg dose, which produced statistically significant BMD gains compared with placebo at 6 months and all subsequent time-points at the spine and hip (3.1% and 1.8% increase in lumbar spine and total hip BMD, respectively, versus placebo; p < or = 0.0001 after 24 months). Oral daily ibandronate was well tolerated with an incidence of upper gastrointestinal adverse events similar to placebo. No safety concerns were identified. In summary, oral daily ibandronate 2.5 mg decreases bone turnover, preserves or increases BMD in the spine and proximal femur, and is well tolerated. Oral ibandronate provides a promising option for the prevention of bone loss in postmenopausal women.