Vertebral Risk Research Articles

Recent Update on RANKL Inhibitor

The prevalence of osteoporosis is continuing to increase with growing elderly population. A variety of anti-osteoporotic agents have been used for the prevention and treatment of osteoporosis and osteoporotic fractures. Novel therapeutic agents based on the newly discovered mechanisms in bone biology have been recently introduced. Denosmab, a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand, is a new therapeutic agent that inhibits osteoclast differentiation, activity, and survival. In the fracture reduction evaluation of denosumab in osteoporosis every 6 months (FREEDOM) trial, denosumab treatment for 36 months significantly increased bone mineral density at all skeletal sites evaluated, thereby resulting in a significant reduction in the risk of vertebral, nonvertebral, and hip fractures. In the FREEDOM Extension study, in which denosumab treatment was continued for up to 10 years, denosumab showed a continued improvement in bone mineral density and a consistently low fracture risk similar to rates observed in the denosumab group during the FREEDOM trial. Denosumab also offered a favorable safety profile with generally low and stable adverse event rates. Denosumab was indicated for treatment of postmenopausal women with osteoporosis at high risk for fracture, treatment to increase bone mass in men with osteoporosis, treatment of bone loss in men receiving androgen deprivation therapy for prostate cancer, and treatment of bone loss in women receiving adjuvant aromatase inhibitor therapy for breast cancer. For these patients, denosumab is an important option for the prevention and treatment of osteoporosis and osteoporotic fractures. (Korean J Med 2018;93:252-259)

Geography of Fracture Incidence in Postmenopausal Women with Osteoporosis Treated with Abaloparatide

Geographic heterogeneity has been observed in fracture risk and efficacy of therapeutic intervention in postmenopausal osteoporosis. The objectives of these analyses were to assess across geographic and ethnic subgroups the heterogeneity of fracture incidence and baseline risk, and consistency of effect of abaloparatide-SC vs placebo on fracture risk reduction in the 18-month, phase 3, multinational, ACTIVE randomized controlled trial. Prespecified exploratory analyses of geographic subgroups (North America, South America, Europe, Asia) and post hoc analyses of ethnic subgroups (Hispanic or Latino, other) of postmenopausal women with osteoporosis enrolled in the abaloparatide-SC and placebo cohorts (n = 1645) were performed. Country-specific FRAX models were used to calculate 10-year absolute fracture risks. Relative risk reductions for vertebral fractures and hazard ratios for non-vertebral, clinical, and major osteoporotic fractures were calculated. Forest plots were constructed to assess treatment-by-subgroup interactions for each geographic region and ethnicity. Baseline prevalence of vertebral fractures was similar across geographies; baseline prevalence of non-vertebral fractures was more variable. Ten-year major osteoporosis fracture and hip fracture risks were variable across and within regions. The effects of abaloparatide-SC on reducing the risk of vertebral, non-vertebral, clinical, and major osteoporotic fractures were similar across regions, and for Hispanic or Latino vs other ethnicities. A limitation was the limited power to detect interactions with few events. In conclusion, despite geographic variability in fracture incidence and risk at baseline, no differences were detected in the effects of abaloparatide-SC in reducing vertebral, non-vertebral, clinical, and major osteoporotic fracture risk across assessed geographic regions and ethnicities.

New vertebral fractures after vertebroplasty: 2-year results from a randomised controlled trial.

A randomised controlled trial of vertebroplasty (VP) versus placebo assessed the effect of VP on the risk of further vertebral fractures. While no statistically significant between-group differences for new or progressed fracture risk at 12 and 24months were observed, we observed a consistent trend towards higher risk of any type of fracture in the group undergoing VP. Our analysis was underpowered, and further adequately powered studies are needed to be able to draw firm conclusions about further vertebral risk with vertebroplasty. This study seeks to assess the effect of VP on the risk of further radiologically apparent vertebral fracture within two years of the procedure. We conducted a randomised placebo-controlled trial of VP in people with acute osteoporotic vertebral fracture. Eligible participants were randomly assigned to VP (n = 38) or placebo (n = 40). Cement volume and leakage were recorded for the VP group. Plain thoracolumbar radiographs were taken at baseline, 12 and 24months. Two independent radiologists assessed these for new and progressed fractures at the same, adjacent and non-adjacent levels. At 12 and 24months, radiographs were available for 45 (58%) and 47 (60%) participants, respectively. There were no between-group differences for new or progressed fractures: 32 and 40 in the VP group after 12 and 24months compared with 21 and 33 in the placebo group (hazard ratio (HR) 1.80, 95% confidence interval (CI) 0.82 to 3.94). Similar results were seen when considering only adjacent (HR (95% CI) 2.30 (0.57 to 9.29)) and non-adjacent (HR (95% CI) 1.45 (0.55 to 3.81) levels. In all comparisons, there was a consistent trend towards higher risk of any type of fracture in the group undergoing VP. Within the VP group, fracture risk was unrelated to total (HR (95% CI) 0.91 (0.71 to 1.17)) or relative (HR (95% CI) 1.31 (0.15 to 11.48)) cement volume or cement leakage (HR (95% CI) 1.20 (0.63 to 2.31)). For patients undergoing VP, our study did not demonstrate significant increases in subsequent fracture risk beyond that experienced by those with vertebral fractures who did not undergo the procedure. However, because of the non-significant numerical increases observed, studies with adequate power are needed to draw definite conclusions about fracture risk.

Atypical Bilateral Femur Fractures in a Long-Term Bisphosphonate Therapy: A Case Report

Atypical Femur Fractures (AFF) are associated with Bisphosphonate Osteoporosis Therapy. Bisphosphonate therapy is widely used as the Gold-Standard Therapy for Osteoporosis: it increases bone density and reduce the risk of vertebral, non-vertebral and hip fractures. However, long-term alendronic acid administration can causes severely suppressed bone turnover and finally non-traumatic stress fractures. Here we present a case of Non-Traumatic stress fractures of bilateral femoral shafts in a Long-Term Alendronic Acid Therapy.

Denosumab for the treatment of osteoporosis: A systematic literature review

PurposeTo determine the efficacy and safety of denosumab in osteoporosis. MethodsA systematic search was performed in MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials (1950 to July 2010), meeting abstracts (2009–2010), trial registries, and reference lists. The selection criteria were as follows: (population) osteoporosis patients of any age; (intervention) treatment with denosumab; (outcome) efficacy and safety; (study design) randomized clinical trials (RCTs); no language restrictions. Two reviewers independently screened titles and abstracts and subsequently extracted data from the selected studies including quality items, and on outcomes of interest. A meta-analysis was performed for safety issues. ResultsA total of 25 studies were included. Denosumab reduces the risk of new radiographic vertebral fracture in a 68% compared with placebo (p<0.001) and increases bone mineral density (BMD) at lumbar spine, total hip, and one-third radius more than alendronate and placebo. A single subcutaneous dose of denosumab resulted in a dose-dependent, rapid, profound, and sustained decrease bone turnover markers (BTMs). Denosumab was in general well tolerated. A meta-analysis has shown an increase in the incidence of urinary infections (p=0.012) and eczema (p<0.001) in the patients treated with denosumab. Meta-analysis of efficacy was complicated due to the study features. ConclusionsDenosumab given subcutaneously twice yearly is associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. Denosumab is associated with greater and sustained increases in BMD and reductions in BTMs compared with placebo and/or alendronate and with a risk of urinary infections and eczema.

Denosumab for the treatment of osteoporosis: A systematic literature review

PurposeTo determine the efficacy and safety of denosumab in osteoporosis. MethodsA systematic search was performed in MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials (1950 to July 2010), meeting abstracts (2009–2010), trial registries, and reference lists. The selection criteria were as follows: (population) osteoporosis patients of any age; (intervention) treatment with denosumab; (outcome) efficacy and safety; (study design) randomized clinical trials (RCTs); no language restrictions. Two reviewers independently screened titles and abstracts and subsequently extracted data from the selected studies including quality items, and on outcomes of interest. A meta-analysis was performed for safety issues. ResultsA total of 25 studies were included. Denosumab reduces the risk of new radiographic vertebral fracture in a 68% compared with placebo (p<0.001) and increases bone mineral density (BMD) at lumbar spine, total hip, and one-third radius more than alendronate and placebo. A single subcutaneous dose of denosumab resulted in a dose-dependent, rapid, profound, and sustained decrease bone turnover markers (BTMs). Denosumab was in general well tolerated. A meta-analysis has shown an increase in the incidence of urinary infections (p=0.012) and eczema (p<0.001) in the patients treated with denosumab. Meta-analysis of efficacy was complicated due to the study features. ConclusionsDenosumab given subcutaneously twice yearly is associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. Denosumab is associated with greater and sustained increases in BMD and reductions in BTMs compared with placebo and/or alendronate and with a risk of urinary infections and eczema.

Long-term treatment of osteoporosis: safety and efficacy appraisal of denosumab

Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), a member of the tumor necrosis factor receptor superfamily essential for osteoclastogenesis. Denosumab treatment is associated with a rapid, sustained, and reversible reduction in bone turnover markers, a continuous marked increase in bone mineral density at all sites, and a marked decrease in the risk of vertebral, hip, and nonvertebral fractures in women with postmenopausal osteoporosis. Therefore, it could be considered as an effective alternative to previous bisphosphonate treatment as well as first-line treatment of severe osteoporosis. Cost-effectiveness studies support this suggestion. In addition, denosumab seems to be the safest treatment option in patients with impaired renal function. Denosumab is characterized by reversibility of its effect after treatment discontinuation, in contrast with bisphosphonates. Large-scale clinical trials, including the extension of FREEDOM trial for up to 5 years, are reassuring for its safety. However, given its brief post-market period, vigilance regarding adverse events related to putative RANKL inhibition in tissues other than bone, as well as those related to bone turnover oversuppression, is advised.

Spotlight on Denosumab in Postmenopausal Osteoporosis†

Denosumab (Prolia®) is a human recombinant monoclonal antibody that is approved for the treatment of postmenopausal osteoporosis in women at high or increased risk of fracture in the US, the EU, and several other countries. Denosumab has a novel mechanism of action; it binds to receptor activator of nuclear factor κB ligand and inhibits bone resorption by inhibiting osteoclast formation, function, and survival. In postmenopausal women with osteoporosis, denosumab reduced the risk of vertebral, nonvertebral, and hip fractures compared with placebo over 3 years in the large, phase III FREEDOM study. In postmenopausal women with low bone mineral density (BMD) or osteoporosis, treatment with denosumab increased BMD and decreased markers of bone turnover more than alendronate in those who were essentially treatment-naive in the 1-year DECIDE study and also in the 1-year STAND study, in which women were switched from alendronate to denosumab or continued alendronate treatment. Denosumab was generally well tolerated in clinical trials, although long-term effects of very low bone turnover remain to be established. Denosumab is administered once every 6 months via subcutaneous injection, which may be a preferred method of administration and may improve adherence to treatment compared with other osteoporosis treatments. Denosumab is a valuable new option for the treatment of postmenopausal osteoporosis in women at increased or high risk of fractures, and may be useful as a first-line treatment in women at increased risk of fractures who are unable to take other osteoporosis treatments.

Denosumab: A New Injectable Treatment for Postmenopausal Osteoporosis

Background/Introduction: Osteoporosis results in a significant increase in fractures, leading to morbidity and mortality. Adherence is a concern with commonly used antiresorptive agents, the bisphosphonates. Denosumab, which inhibits bone resorption by a different mechanism and is administered subcutaneously every 6 months, may provide an advantage in decreasing fracture risk in those with osteoporosis. Objective: To review the available data with respect to the mechanism of action, efficacy and safety of denosumab for the management of postmenopausal osteoporosis. Methods: Several databases were searched to identify phase III randomized controlled trials (RCT) that examined the effect of denosumab on bone mineral density (BMD) and/or fracture rate and the safety of denosumab in the management of postmenopausal osteoporosis. Results: In 2 of the 4 trials identified, denosumab was significantly better than placebo at increasing BMD, and in 1 trial reduced the risk of vertebral, nonvertebral and hip fractures. No head-to-head trials comparing fracture risk reduction of denosumab to bisphosphonates were found, however, 2 trials did report increased BMD with denosumab compared to alendronate. In the 4 studies reviewed, adverse effects reported more frequently with denosumab included rash and eczema, as well as bronchitis and influenza-like illness. There is potential for an increased risk of other infections and malignancies. Conclusions: The results of RCT trials suggest that denosumab is effective at maintaining or increasing BMD compared to placebo or alendronate in women with either osteopenia or osteoporosis and in 1 trial demonstrated a significant reduction in fracture rate compared to placebo. Overall, denosumab appeared to be well tolerated in the studies reviewed. Continued monitoring is needed to determine long-term safety and efficacy.

Denosumab for the Management of Postmenopausal Osteoporosis

Postmenopausal osteoporosis is a major concern to public health. Fractures are the major clinical consequence of osteoporosis and are associated with substantial morbidity, mortality, and health care costs. Despite the availability of screening and treatment guidelines, osteoporosis diagnosis and treatment remain low. Health care providers may consult guidelines in the clinical management of their patients with osteoporosis, including those from the National Osteoporosis Foundation, and the new fracture risk assessment tool from the World Health Organization. Bisphosphonates are the most commonly used treatment for postmenopausal osteoporosis. Although these agents are effective in preventing fractures and bone loss, the benefits of treatment may be limited by suboptimal adherence and compliance. Denosumab is a human monoclonal antibody that targets and inhibits RANK ligand, an essential mediator of bone resorption. In clinical trials in postmenopausal women with osteoporosis, denosumab 60 mg given subcutaneously every 6 months was well tolerated and statistically significantly reduced the risk of vertebral, nonvertebral, and hip fractures. The introduction of denosumab into clinical practice provides physicians with another option for the treatment of postmenopausal osteoporosis, and the twice-yearly dosing regimen has the potential to improve adherence.

Absolute fracture risk assessment using lumbar spine and femoral neck bone density measurements: Derivation and validation of a hybrid system

The World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX) computes 10-year probability of major osteoporotic fracture from multiple risk factors, including femoral neck (FN) T-scores. Lumbar spine (LS) measurements are not currently part of the FRAX formulation but are used widely in clinical practice, and this creates confusion when there is spine-hip discordance. Our objective was to develop a hybrid 10-year absolute fracture risk assessment system in which nonvertebral (NV) fracture risk was assessed from the FN and clinical vertebral (V) fracture risk was assessed from the LS. We identified 37,032 women age 45 years and older undergoing baseline FN and LS dual-energy X-ray absorptiometry (DXA; 1990-2005) from a population database that contains all clinical DXA results for the Province of Manitoba, Canada. Results were linked to longitudinal health service records for physician billings and hospitalizations to identify nontrauma vertebral and nonvertebral fracture codes after bone mineral density (BMD) testing. The population was randomly divided into equal-sized derivation and validation cohorts. Using the derivation cohort, three fracture risk prediction systems were created from Cox proportional hazards models (adjusted for age and multiple FRAX risk factors): FN to predict combined all fractures, FN to predict nonvertebral fractures, and LS to predict vertebral (without nonvertebral) fractures. The hybrid system was the sum of nonvertebral risk from the FN model and vertebral risk from the LS model. The FN and hybrid systems were both strongly predictive of overall fracture risk (p < .001). In the validation cohort, ROC analysis showed marginally better performance of the hybrid system versus the FN system for overall fracture prediction (p = .24) and significantly better performance for vertebral fracture prediction (p < .001). In a discordance subgroup with FN and LS T-score differences greater than 1 SD, there was a significant improvement in overall fracture prediction with the hybrid method (p = .025). Risk reclassification under the hybrid system showed better alignment with observed fracture risk, with 6.4% of the women reclassified to a different risk category. In conclusion, a hybrid 10-year absolute fracture risk assessment system based on combining FN and LS information is feasible. The improvement in fracture risk prediction is small but supports clinical interest in a system that integrates LS in fracture risk assessment.

Emerging Options for the Treatment of Postmenopausal Osteoporosis: Focus on Denosumab

Objective: Denosumab, a fully human monoclonal antibody, is an antiresorptive drug in a late-stage of clinical development that neutralizes receptor activator of nuclear factor κB ligand (RANKL), thereby inhibiting osteoclast-mediated bone resorption. The purpose of this paper was to discuss the antifracture efficacy and safety of the subcutaneous administration of denosumab for the treatment of postmenopausal osteoporosis. Methods: PubMed was searched and strictly conducted randomized controlled trials (RCTs) regarding the effect of denosumab on skeletal health in postmenopausal women were identified. Results: The results of RCTs showed that a single subcutaneous dose of denosumab rapidly and profoundly reduced bone resorption and sustained (up to 6 months) this effect in postmenopausal women. Denosumab (60 mg, every 6 months) resulted in a sustained decrease in bone turnover, a rapid increase in bone mineral density (BMD), and an improvement of geometric parameters associated with bending and axial strength and cortical stability at purely cortical and mixed cortical/trabecular sites of the proximal femur in postmenopausal women with a low BMD. Denosumab (60 mg every 6 months) reduced the 3-year incidence of vertebral, nonvertebral, and hip fractures (Hazard ratios: 0.32, 0.80, and 0.60, respectively) in postmenopausal women with osteoporosis. Denosumab was well tolerated, and no related severe adverse events were observed. Conclusions: The subcutaneous administration of denosumab every six months effectively decreased bone resorption, increased the BMD, and reduced the risk of vertebral, nonvertebral, and hip fractures in postmenopausal women. Denosumab offers an emerging option for the treatment of postmenopausal osteoporosis.

Denosumab – an emerging treatment for postmenopausal osteoporosis

Importance of the field: Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling. Denosumab is an investigational fully human monoclonal antibody to receptor activator of NF-κB ligand (RANKL), a cytokine member of the TNF family that is the principal mediator of osteoclastic bone resorption.Areas covered in this review: The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009.What the reader will gain: This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis.Take home message: In postmenopausal women with osteoporosis, denosumab (60 mg by subcutaneous injection every 6 months) increased bone mineral density, reduced bone turnover markers, and reduced the risk of vertebral, hip and non-vertebral fractures. Denosumab was well tolerated with a safety profile generally similar to placebo. It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis.

Denosumab for Prevention of Fractures in Postmenopausal Women With Osteoporosis

Denosumab is a fully human monoclonal antibody against the receptor activator of the cytokine, nuclear factor-κB ligand, which is of critical importance for the formation, function, and survival of osteoclasts. This antibody binds nuclear factor-κB ligand and reversibly inhibits osteoclast-mediated bone resorption in osteoclasts and osteoclast precursors. Earlier studies reported that subcutaneous administration of denosumab every 6 months reduced bone turnover and increased bone mineral density. This international, randomized, placebo-controlled trial evaluated the effect of denosumab on the risk of fracture in 7808 postmenopausal women with osteoporosis. Participants had a bone mineral density T score less than -2.5 at the lumbar spine or total hip. Women with T scores less than -4.0 were excluded. Their ages ranged from 60 to 90 years. The study subjects used in the final analysis had been randomized to receive subcutaneous injections of 60 mg of denosumab (n = 3902) or placebo (n = 3906) every 6 months for 36 months. A new vertebral fracture was the primary outcome. The occurrence of nonvertebral fracture and hip fracture were the secondary end points. At 36-months, the cumulative incidence of new radiographic vertebral fracture was reduced by 68% in the denosumab group compared to the placebo group (denosumab: 2.3% vs. placebo: 7.2%); the risk ratio was 0.32, with a 95% confidence interval [CI] of 0.26-0.41; P < 0.001). The risk of hip fracture was reduced by 40% with the drug compared to the placebo group (cumulative incidence of denosumab: 0.7% vs. placebo: 1.2%); the hazard ratio was 0.60, with a 95% CI of 0.37-0.97; P = 0.04. Similarly, denosumab reduced the cumulative incidence of nonvertebral fracture from 8.0% in the placebo group to 6.5% in the denosumab group (hazard ratio, 0.80; 95% CI, 0.67-0.95; P = 0.01)-a 20% relative reduction in risk. During the 36-months of the study, denosumab was not associated with a significant increase in the incidence of infection, cancer, or cardiovascular events. No increase was found in the occurrence of delayed fracture healing or hypocalcemia and other adverse effects associated with potent antiresorptive agents. Osteonecrosis of the jaw was not observed in either group. These findings show that subcutaneous injections of denosumab every 6 months for 36 months is associated with a significant reduction in the risk of vertebral, hip, and nonvertebral fractures among postmenopausal women with osteoporosis.

RANKL inhibition as a targeted approach in the management of osteoporosis

Cortical and trabecular bone undergo a continuous and balanced remodeling process, consisting of an osteoclast-mediated boneresorption phase and an osteoblast-mediated bone-formation phase. An imbalance in this process, which favours bone resorption, results in bone loss and in damage to the skeletal microarchitecture, as seen in clinical conditions such as osteoporosis, rheumatoid arthritis and bone metastases. Currently, treatments are available for preventing or reversing excessive bone resorption through osteoclast inhibition. Among anti-resorptive treatments, nitrogen-containing bisphosphonates bind to hydroxyapatite with high affinity, are internalized by osteoclasts during the resorptionphase and inhibit osteoclast function, suppressing the mevalonate pathway. A more targeted anti-resorptive approach might be achieved through inhibition of RANK ligand (RANKL), which is one of the primary mediators of osteoclast activity, essential for osteoclast differentiation, function and survival. RANKL exerts direct catabolic effects on cortical and trabecular bone, leading to decreases in bone volume, mineral density and strength. Understanding the role of RANKL in the pathogenesis of bone disease has led to investigation of RANKL inhibition in conditions characterized by excessive bone resorption. In many preclinical models of postmenopausal osteoporosis, RANKL inhibition has prevented bone loss and microarchitecture damage, and has been associated with increased vertebral and femoral bone strength. A variety of innovative therapeutic approaches targeting RANKL inhibition are currently under investigation in humans. In randomized, controlled clinical trials, 6monthly subcutaneous administration of an experimental, fully human, monoclonal antibody against RANKL to womenwith osteopenia or postmenopausal osteoporosis significantly increased bone mineral density (BMD) at all skeletal sites (including the lumbar spine, femoral neck and distal radius) and decreased markers of bone turnover in a rapid, pronounced and sustained manner. Moreover, in two clinical studies, this therapeutic approach produced significantly greater increases in BMD than alendronate at all measured skeletal sites after 12 months of treatment. RANKL inhibition with this monoclonal antibody has recently been demonstrated to significantly reduce the risk of vertebral, non-vertebral and hip fractures inwomen with postmenopausal osteoporosis after 3 years of treatment. The frequency and pattern of reported adverse events have been similar to placebo or bisphosphonate treatment, suggesting a good tolerability profile. These data suggest that RANKL inhibition offers an additional and innovative therapeutic approach for the treatment of postmenopausal osteoporosis and, on the basis of comparative BMD results, may provide an incremental clinical benefit compared with currently available antiresorptive treatments.

Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis

Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis. We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)

Zoledronic acid in the management of osteoporosis: the HORIZON trials

Zoledronic acid 5 mg is an annually administered intravenous bisphosphonate that is approved for the treatment of osteoporosis. The Health Outcomes and Reduced Incidence with Zoledronic acid ONce yearly (HORIZON) Pivotal Fracture trial showed an increase in bone mineral density, decrease in bone turnover markers, and significant reduction in the risk of vertebral, hip and other fractures in women with postmenopausal osteoporosis treated over a period of 3 years. The HORIZON Recurrent Fracture Trial demonstrated that an annual infusion of zoledronic acid started within 90 days of surgical repair of a low-trauma hip fracture in women and men was associated with a significant decrease in the risk of new clinical fractures and an increase in survival. The tolerability and safety profile of treatment in both studies was generally favorable, with the most common adverse event being transient flu-like symptoms shortly after infusion.

Prevention and Treatment of Osteoporosis in Postmenopausal Women

Postmenopausal osteoporosis is characterized by an increased rate of bone turnover accompanied by a reduction in bone mineral density (BMD) that results in an increased risk of fracture, especially of the vertebrae, hip, or wrist. Alendronate (Fosamax®, Fosamax Once-Weekly®), an oral bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism, is a first-line therapy for the management of postmenopausal women with, or at risk of developing, osteoporosis. Alendronate produces sustained increases in BMD and reductions in bone turnover from baseline, and reduces the risk of vertebral, hip, wrist, and other fractures in women with postmenopausal osteoporosis. It also prevents bone loss, and reduces the risk of radiographic or clinical vertebral fracture in postmenopausal osteopenia. Provided administration instructions are followed, alendronate is generally well tolerated. Adverse events are usually transient and are associated with the upper gastrointestinal tract (abdominal pain, nausea, acid regurgitation, dyspepsia); moreover, the incidence of these adverse events with alendronate was similar to those with placebo. More serious events (esophagitis, gastric or duodenal ulceration or bleeding) are uncommon. Once-weekly formulations are as effective and as well tolerated as once-daily alendronate in postmenopausal women. Pharmacoeconomic evaluations suggest that alendronate is a viable treatment option in postmenopausal osteoporosis. The reduction in fracture-related healthcare utilization seen with alendronate results in decreased direct costs, including inpatient or long-term care. Markov state-transition models suggest that this could at least partially offset costs incurred with alendronate therapy. Treatment of women with osteoporosis aged 65 years and older, and postmenopausal women with a previous osteoporotic fracture, are cost-effective strategies. Alendronate is also likely to increase quality-adjusted life-years in any postmenopausal women with osteoporosis. In conclusion, clinical and economic data support the use of alendronate in postmenopausal osteoporosis. It effectively reduces bone turnover, increases BMD, and reduces the risk of osteoporotic fracture in postmenopausal women with established osteoporosis, especially older women with a higher risk of fracture. Although its cost effectiveness in postmenopausal women with osteopenia is not clearly established, alendronate is clinically effective in these patients. In addition, it is generally well tolerated when taken as recommended. Consequently, alendronate should be considered a therapy of choice in the prevention and treatment of osteoporosis in postmenopausal women.

Zoledronic acid: an advance in tumour bone disease therapy and a new hope for osteoporosis

The two main therapeutic applications of bisphosphonates are tumour bone disease and osteoporosis. They constitute the standard treatment for cancer hypercalcaemia, and placebo-controlled trials have shown that the prolonged administration of bisphosphonates, such as pamidronate or clodronate, can reduce the frequency of complications from tumour bone disease due to metastatic breast cancer or myeloma by a quarter to one-half. The results obtained with the intravenous route appear to be more impressive and more rapidly obtained than with oral compounds. Both agents can reduce the risk of vertebral, wrist and hip fractures by 30 – 50%, whereas other antiresorptive agents, such as raloxifene (Eli Lilly & Co.) or calcitonin (Unigene Laboratories, Inc.), have only been demonstrated to reduce the incidence of vertebral fractures. The short infusion time (4 mg over 15 min) offers a convenient therapy and constitutes the most evident advantage of zoledronic acid, which will improve patients’ quality of life. Zoledronic acid has the potential to change the treatment of osteoporosis dramatically.

Is diabetes mellitus a teratogen or a coteratogen?

The risk of major and minor congenital malformations was compared in the offspring of diabetic (n = 2,639) and nondiabetic (n = 2,144) women who delivered at the Johns Hopkins Hospital in Baltimore, Maryland, between January 1, 1946 and December 31, 1970. In spite of ample power, there was little evidence of an increased malformation risk in offspring born prior to the onset of overt diabetes in the mother. In offspring born after onset, the overall malformation risk was not increased, but severe multi-organ birth defects occurred at approximately twice the control group rate. It is postulated, therefore, that diabetes may act as a coteratogen enhancing the teratogenic effect of other insults but may not itself cause malformations. That some of its effects may be specific is suggested by the especially high risk of vertebral, lower limb, and urogenital defects, a pattern similar to that reported for the caudal dysgenesis syndrome. To better understand the teratogenic effects associated with diabetes, it may be necessary to consider interactions with other factors and to explore the association between maternal diabetes and caudal dysgenesis.