Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized, Double-Blind, Phase 2, Parallel Group Study.

Over 12 months, romosozumab increased bone formation and decreased bone resorption, resulting in increased bone mineral density (BMD) in postmenopausal women with low BMD (NCT00896532). Herein, we report the study extension evaluating 24 months of treatment with romosozumab, discontinuation of romosozumab, alendronate followed by romosozumab, and romosozumab followed by denosumab. Postmenopausal women aged 55 to 85 years with a lumbar spine (LS), total hip (TH), or femoral neck T-score ≤-2.0 and ≥-3.5 were enrolled and randomly assigned to placebo, one of five romosozumab regimens (70 mg, 140 mg, 210 mg monthly [QM]; 140 mg Q3M; 210 mg Q3M) for 24 months, or open-label alendronate for 12 months followed by romosozumab 140 mg QM for 12 months. Eligible participants were then rerandomized 1:1 within original treatment groups to placebo or denosumab 60 mg Q6M for an additional 12 months. Percentage change from baseline in BMD and bone turnover markers (BTMs) at months 24 and 36 and safety were evaluated. Of 364 participants initially randomized to romosozumab, placebo, or alendronate, 315 completed 24 months of treatment and 248 completed the extension. Romosozumab markedly increased LS and TH BMD through month 24, with largest gains observed with romosozumab 210 mg QM (LS = 15.1%; TH = 5.4%). Women receiving romosozumab who transitioned to denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels with placebo. With romosozumab 210 mg QM, bone formation marker P1NP initially increased after treatment initiation and gradually decreased to below baseline by month 12, remaining below baseline through month 24; bone resorption marker ß-CTX rapidly decreased after treatment, remaining below baseline through month 24. Transition to denosumab further decreased both BTMs, whereas after transition to placebo, P1NP returned to baseline and ß-CTX increased above baseline. Adverse events were balanced between treatment groups through month 36. These data suggest that treatment effects of romosozumab are reversible upon discontinuation and further augmented by denosumab. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

Impaired Bone Microarchitecture Improves After One Year On Gluten-Free Diet: A Prospective Longitudinal HRpQCT Study in Women With Celiac Disease.

We have recently identified a significant deterioration of bone microarchitecture in premenopausal women with newly diagnosed celiac disease (CD) using high-resolution peripheral quantitative computed tomography (HRpQCT). The aim of this work was to assess changes in bone microarchitecture after 1 year on a gluten-free diet (GFD) in a cohort of premenopausal women. We prospectively enrolled 31 consecutive females at diagnosis of CD; 26 of them were reassessed 1 year after GFD. They all underwent HRpQCT scans of distal radius and tibia, areal BMD by DXA, and biochemical tests (bone-specific parameters and CD serology) at both time points. Secondary, we compared 1-year results with those of a control group of healthy premenopausal women of similar age and BMI in order to assess whether the microarchitectural parameters of treated CD patients had reached the values expected for their age. Compared with baseline, the trabecular compartment in the distal radius and tibia improved significantly (trabecular density, trabecular/bone volume fraction [BV/TV] [p < 0.0001], and trabecular thickness [p = 0.0004]). Trabecular number remained stable in both regions. Cortical density increased only in the tibia (p = 0.0004). Cortical thickness decreased significantly in both sites (radius: p = 0.03; tibia: p = 0.05). DXA increased in all regions (lumbar spine [LS], p = 0.01; femoral neck [FN], p = 0.009; ultradistal [UD] radius, p = 0.001). Most parameters continued to be significantly lower than those of healthy controls. This prospective HRpQCT study showed that most trabecular parameters altered at CD diagnosis improved significantly by specific treatment (GFD) and calcium and vitamin D supplementation. However, there were still significant differences with a control group of women of similar age and BMI. In the prospective follow-up of this group of patients we expect to be able to assess whether bone microarchitecture attains levels expected for their age. © 2016 American Society for Bone and Mineral Research.

Denosumab Reduces Cortical Porosity of the Proximal Femoral Shaft in Postmenopausal Women With Osteoporosis.

Hip fractures account for over one-half the morbidity, mortality, and cost associated with osteoporosis. Fragility of the proximal femur is the result of rapid and unbalanced bone remodeling events that excavate more bone than they deposit, producing a porous, thinned, and fragile cortex. We hypothesized that the slowing of remodeling during treatment with denosumab allows refilling of the many cavities excavated before treatment now opposed by excavation of fewer new resorption cavities. The resulting net effect is a reduction in cortical porosity and an increase in proximal femur strength. Images were acquired at baseline and 36 months using multidetector CT in 28 women receiving denosumab and 22 women receiving placebo in a substudy of FREEDOM, a randomized, double-blind, placebo-controlled trial involving women with postmenopausal osteoporosis. Porosity was quantified using StrAx1.0 software. Strength was estimated using finite element analysis. At baseline, the higher the serum resorption marker, CTx, the greater the porosity of the total cortex (r = 0.34, p = 0.02), and the higher the porosity, the lower the hip strength (r = -0.31, p = 0.03). By 36 months, denosumab treatment reduced porosity of the total cortex by 3.6% relative to baseline. Reductions in porosity relative to placebo at 36 months were 5.3% in total cortex, 7.9% in compact-appearing cortex, 5.6% in outer transitional zone, and 1.8% in inner transitional zone (all p < 0.01). The improvement in estimated hip integral strength of 7.9% from baseline (p < 0.0001) was associated with the reduction in total porosity (r = -0.41, p = 0.03). In summary, denosumab reduced cortical porosity of the proximal femoral shaft, resulting in increased mineralized matrix volume and improved strength, changes that may contribute to the reduction in hip and nonvertebral fractures reported with denosumab therapy. © 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

Significant bone microarchitecture impairment in premenopausal women with active celiac disease.

Patients with active celiac disease (CD) are more likely to have osteoporosis and increased risk of fractures. High-resolution peripheral quantitative computed tomography (HR-pQCT) permits three-dimensional exploration of bone microarchitectural characteristics measuring separately cortical and trabecular compartments, and giving a more profound insight into bone disease pathophysiology and fracture. We aimed to determine the volumetric and microarchitectural characteristics of peripheral bones-distal radius and tibia-in an adult premenopausal cohort with active CD assessed at diagnosis. We prospectively enrolled 31 consecutive premenopausal women with newly diagnosed CD (median age 29 years, range: 18-49) and 22 healthy women of similar age (median age 30 years, range 21-41) and body mass index. Compared with controls, peripheral bones of CD patients were significantly lower in terms of total volumetric density mg/cm(3) (mean ± SD: 274.7 ± 51.7 vs. 324.7 ± 45.8, p 0.0006 at the radius; 264.4 ± 48.7 vs. 307 ± 40.7, p 0.002 at the tibia), trabecular density mg/cm(3) (118.6 ± 31.5 vs. 161.9 ± 33.6, p<0.0001 at the radius; 127.9 ± 28.7 vs. 157.6 ± 15.6, p < 0.0001 at the tibia); bone volume/trabecular volume ratio % (9.9 ± 2.6 vs. 13.5 ± 2.8, p<0.0001 at the radius; 10.6 ± 2.4 vs. 13.1 ± 1.3, p < 0.0001 at the tibia); number of trabeculae 1/mm (1.69 ± 0.27 vs. 1.89 ± 0.26, p 0.009 at the radius; 1.53 ± 0.32 vs. 1.80 ± 0.26, p 0.002 at the tibia); and trabecular thickness mm (0.058 ± 0.010 vs. 0.071 ± 0.008, p < 0.0001 at the radius with no significant difference at the tibia). Cortical density was significantly lower in both regions (D comp mg/cm(3) 860 ± 57.2 vs. 893.9 ± 43, p 0.02; 902.7 ± 48.7 vs. 932.6 ± 32.6, p 0.01 in radius and tibia respectively). Although cortical thickness was lower in CD patients, it failed to show any significant inter-group difference (a-8% decay with p 0.11 in both bones). Patients with symptomatic CD (n = 22) had a greater bone microarchitectural deficit than those with subclinical CD. HR-pQCT was used to successfully identify significant deterioration in the microarchitecture of trabecular and cortical compartments of peripheral bones. Impairment was characterized by lower trabecular number and thickness-which increased trabecular network heterogeneity-and lower cortical density and thickness. In the prospective follow-up of this group of patients we expect to be able to assess whether bone microarchitecture recovers and to what extend after gluten-free diet.

Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis.

CONTEXT: Abaloparatide is a novel synthetic peptide analog of parathyroid hormone-related protein (PTHrP) that is currently being developed as a potential anabolic agent in the treatment of postmenopausal osteoporosis. OBJECTIVE: This study sought to assess the effects of abaloparatide on bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck in postmenopausal women with osteoporosis. DESIGN: Multi-center, multi-national, double-blind placebo controlled trial in which postmenopausal women were randomly assigned to receive 24 weeks of treatment with daily sc injections of placebo, abaloparatide, 20, 40, or 80 µg, or teriparatide, 20 µg. A 24-week extension was also performed in a subset of subjects. PARTICIPANTS: Postmenopausal women with osteoporosis (n = 222). MAIN OUTCOME MEASURES: BMD by dual-x-ray absorptiometry and biochemical markers of bone turnover. RESULTS: At 24 weeks, lumbar spine BMD increased by 2.9, 5.2, and 6.7% in the abaloparatide, 20-, 40-, and 80-µg groups, respectively, and 5.5% in the teriparatide group. The increases in the 40- and 80-µg abaloparatide groups and the teriparatide group were significantly greater than placebo (1.6%). Femoral neck BMD increased by 2.7, 2.2, and 3.1% in abaloparatide, 20-, 40-, and 80-µg groups, respectively, and 1.1% in the teriparatide group. The increase in femoral neck BMD with abaloparatide, 80 µg was significantly greater than placebo (0.8%). Total hip BMD increased by 1.4, 2.0, and 2.6% in the abaloparatide, 20-, 40-, and 80-µg groups, respectively. The total hip increases in the 40- and 80-µg abaloparatide groups were greater than both placebo (0.4%) and teriparatide (0.5%). CONCLUSIONS: Compared with placebo, 24 weeks of daily sc abaloparatide increases BMD of the lumbar spine, femoral neck, and total hip in a dose-dependent fashion. Moreover, the abaloparatide-induced BMD increases at the total hip are greater than with the marketed dose of teriparatide. These results support the further investigation of abaloparatide as an anabolic therapy in postmenopausal osteoporosis.

Romosozumab in postmenopausal women with low bone mineral density.

BACKGROUND: Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation. METHODS: In a phase 2, multicenter, international, randomized, placebo-controlled, parallel-group, eight-group study, we evaluated the efficacy and safety of romosozumab over a 12-month period in 419 postmenopausal women, 55 to 85 years of age, who had low bone mineral density (a T score of -2.0 or less at the lumbar spine, total hip, or femoral neck and -3.5 or more at each of the three sites). Participants were randomly assigned to receive subcutaneous romosozumab monthly (at a dose of 70 mg, 140 mg, or 210 mg) or every 3 months (140 mg or 210 mg), subcutaneous placebo, or an open-label active comparator--oral alendronate (70 mg weekly) or subcutaneous teriparatide (20 µg daily). The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Secondary end points included percentage changes in bone mineral density at other sites and in markers of bone turnover. RESULTS: All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in bone mineral density at the total hip and femoral neck, as well as transitory increases in bone-formation markers and sustained decreases in a bone-resorption marker. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups. CONCLUSIONS: In postmenopausal women with low bone mass, romosozumab was associated with increased bone mineral density and bone formation and with decreased bone resorption. (Funded by Amgen and UCB Pharma; ClinicalTrials.gov number, NCT00896532.).

Differing effects of denosumab and alendronate on cortical and trabecular bone.

Vertebral fractures and trabecular bone loss are hallmarks of osteoporosis. However, 80% of fractures are non-vertebral and 70% of all bone loss is cortical and is produced by intracortical remodeling. The resulting cortical porosity increases bone fragility exponentially. Denosumab, a fully human anti-RANKL antibody, reduces the rate of bone remodeling more than alendronate. The aim of this study was to quantify the effects of denosumab and alendronate on cortical and trabecular bone. Postmenopausal women, mean age 61years (range 50 to 70), were randomized double blind to placebo (n=82), alendronate 70mg weekly (n=82), or denosumab 60mg every 6months (n=83) for 12months. Porosity of the compact-appearing cortex (CC), outer and inner cortical transitional zones (OTZ, ITZ), and trabecular bone volume/total volume (BV/TV) of distal radius were quantified in vivo from high-resolution peripheral quantitative computed tomography scans. Denosumab reduced remodeling more rapidly and completely than alendronate, reduced porosity of the three cortical regions at 6months, more so by 12months relative to baseline and controls, and 1.5- to 2-fold more so than alendronate. The respective changes at 12months were [mean (95% CI)]; CC: -1.26% (-1.61, -0.91) versus -0.48% (-0.96, 0.00), p=0.012; OTZ: -1.97% (-2.37, -1.56) versus -0.81% (-1.45, -0.17), p=0.003; and ITZ: -1.17% (-1.38, -0.97) versus -0.78% (-1.04, -0.52), p=0.021. Alendronate reduced porosity of the three cortical regions at 6months relative to baseline and controls but further decreased porosity of only the ITZ at 12months. By 12months, CC porosity was no different than baseline or controls, OTZ porosity was reduced only relative to baseline, not controls, while ITZ porosity was reduced relative to baseline and 6months, but not controls. Each treatment increased trabecular BV/TV volume similarly: 0.25% (0.19, 0.30) versus 0.19% (0.13, 0.30), p=0.208. The greater reduction in cortical porosity by denosumab may be due to greater inhibition of intracortical remodeling. Head to head studies are needed to determine whether differences in porosity result in differing fracture outcomes.

Femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with denosumab.

In the randomized, placebo-controlled FREEDOM study of women aged 60 to 90 years with postmenopausal osteoporosis, treatment with denosumab once every 6 months for 36 months significantly reduced hip and new vertebral fracture risk by 40% and 68%, respectively. To gain further insight into this efficacy, we performed a nonlinear finite element analysis (FEA) of hip and spine quantitative computed tomography (QCT) scans to estimate hip and spine strength in a subset of FREEDOM subjects (n = 48 placebo; n = 51 denosumab) at baseline, 12, 24, and 36 months. We found that, compared with baseline, the finite element estimates of hip strength increased from 12 months (5.3%; p < 0.0001) and through 36 months (8.6%; p < 0.0001) in the denosumab group. For the placebo group, hip strength did not change at 12 months and decreased at 36 months (-5.6%; p < 0.0001). Similar changes were observed at the spine: strength increased by 18.2% at 36 months for the denosumab group (p < 0.0001) and decreased by -4.2% for the placebo group (p = 0.002). At 36 months, hip and spine strength increased for the denosumab group compared with the placebo group by 14.3% (p < 0.0001) and 22.4% (p < 0.0001), respectively. Further analysis of the finite element models indicated that strength associated with the trabecular bone was lost at the hip and spine in the placebo group, whereas strength associated with both the trabecular and cortical bone improved in the denosumab group. In conclusion, treatment with denosumab increased hip and spine strength as estimated by FEA of QCT scans compared with both baseline and placebo owing to positive treatment effects in both the trabecular and cortical bone compartments. These findings provide insight into the mechanism by which denosumab reduces fracture risk for postmenopausal women with osteoporosis.

Improvements in hip trabecular, subcortical, and cortical density and mass in postmenopausal women with osteoporosis treated with denosumab.

In the FREEDOM study, denosumab treatment (60 mg every 6 months) decreased bone resorption, increased bone mineral density (BMD), and reduced new vertebral, nonvertebral, and hip fractures over 36 months in postmenopausal women with osteoporosis. In a subset of these women, hip quantitative computed tomography (QCT) was performed at baseline and months 12, 24, and 36. These scans were analyzed using Medical Image Analysis Framework (MIAF) software, which allowed assessment of total hip integral, trabecular, subcortical, and cortical compartments; the cortical compartment was further divided into 2 areas of interest (outer and inner cortex). This substudy reports changes in BMD and bone mineral content (BMC) from baseline and compared placebo with denosumab over 36 months of treatment (placebo N=26; denosumab N=36). Denosumab treatment resulted in significant improvements in total hip integral volumetric BMD (vBMD) and BMC from baseline at each time point. At month 36, the mean percentage increase from baseline in total hip integral vBMD and BMC was 6.4% and 4.8%, respectively (both p<0.0001). These gains were accounted for by significant increases in vBMD and BMC in the trabecular, subcortical, and cortical compartments. In the placebo group, total hip integral vBMD and BMC decreased at month 36 from baseline by -1.5% and -2.6%, respectively (both p<0.05). The differences between denosumab and placebo were also significant at months 12, 24, and 36 for integral, trabecular, subcortical, and cortical vBMD and BMC (all p<0.05 to <0.0001). While the largest percentage differences occurred in trabecular vBMD and BMC, the largest absolute differences occurred in cortical vBMD and BMC. In summary, denosumab significantly improved both vBMD and BMC from baseline and placebo, assessed by QCT MIAF, in the integral, trabecular, subcortical, and cortical hip compartments, all of which are relevant to bone strength.

Denosumab densitometric changes assessed by quantitative computed tomography at the spine and hip in postmenopausal women with osteoporosis.

FREEDOM was a phase 3 trial in 7808 women aged 60-90yr with postmenopausal osteoporosis. Subjects received placebo or 60 mg denosumab subcutaneously every 6mo for 3yr in addition to daily calcium and vitamin D. Denosumab significantly decreased bone turnover; increased dual-energy X-ray absorptiometry (DXA) areal bone mineral density (aBMD); and significantly reduced new vertebral, nonvertebral, and hip fractures. In a subset of women (N=209), lumbar spine, total hip, and femoral neck volumetric BMD (vBMD) were assessed by quantitative computed tomography at baseline and months 12, 24, and 36. Significant improvement from placebo and baseline was observed in aBMD and vBMD in the denosumab-treated subjects at all sites and time points measured. The vBMD difference from placebo reached 21.8%, 7.8%, and 5.9%, respectively, for the lumbar spine, total hip, and femoral neck at 36mo (all p≤0.0001). Compared with placebo and baseline, significant increases were also observed in bone mineral content (BMC) at the total hip (p<0.0001) largely related to significant BMC improvement in the cortical compartment (p<0.0001). These results supplement the data from DXA on the positive effect of denosumab on BMD in both the cortical and trabecular compartments.

Denosumab significantly increases DXA BMD at both trabecular and cortical sites: results from the FREEDOM study.

Denosumab is an approved therapy for postmenopausal women with osteoporosis at high or increased risk for fracture. In the FREEDOM study, denosumab reduced fracture risk and increased bone mineral density (BMD). We report the spine and hip dual-energy X-ray absorptiometry (DXA) BMD responses from the overall study of 7808 women and from a substudy of 441 participants in which more extensive spine and hip assessments as well as additional skeletal sites were evaluated. Significant BMD improvements were observed as early as 1 mo at the lumbar spine, total hip, and trochanter (all p<0.005 vs placebo and baseline). BMD increased progressively at the lumbar spine, total hip, femoral neck, trochanter, 1/3 radius, and total body from baseline to months 12, 24, and 36 (all p<0.005 vs placebo and baseline). BMD gains above the least significant change of more than 3% at 36 months were observed in 90% of denosumab-treated subjects at the lumbar spine and 74% at the total hip, and gains more than 6% occurred in 77% and 38%, respectively. In conclusion, denosumab treatment resulted in significant, early, and continued BMD increases at both trabecular and cortical sites throughout the skeleton over 36 mo with important gains observed in most subjects.

A novel monthly dosing regimen of risedronate for the treatment of postmenopausal osteoporosis: 2-year data.

This 2-year trial evaluated the efficacy and tolerability of a monthly oral regimen of risedronate. Postmenopausal women with osteoporosis were randomly assigned to double-blind treatment with risedronate 75 mg on 2 consecutive days each month (2CDM) or 5 mg daily. The primary end point was the percentage change from baseline in lumbar spine bone mineral density (BMD) at 12 months. Secondary end points included the change in BMD of the lumbar spine and proximal femur and in bone turnover markers as well as the number of subjects with at least one new vertebral fracture over 24 months. Among 1,229 patients who were randomized and received at least one dose of risedronate, lumbar spine BMD was increased in both treatment groups: mean percentage change from baseline was 4.2 ± 0.19 and 4.3 ± 0.19 % in the 75 mg 2CDM and 5 mg daily groups, respectively, at month 24. The treatment difference was 0.17 (95 % confidence interval -0.35 to 0.68). There were no statistically significant differences between treatment groups on any secondary efficacy parameters. Both treatment regimens were well tolerated. Risedronate 75 mg 2CDM was noninferior in BMD efficacy and did not show a difference in tolerability compared to 5 mg daily after 24 months of treatment in women with postmenopausal osteoporosis. This monthly regimen may provide a more convenient dosing schedule to some patients with postmenopausal osteoporosis.

Denosumab: What's new?

Denosumab is the first fully human monoclonal antibody that inhibits the formation, function, and survival of osteoclasts by blocking the interaction of receptor activator of nuclear factor-κB (RANK) ligand with its osteoclastic receptor RANK. Clinical studies have shown that the decreased bone resorption and increased bone mineral density resulting from the use of denosumab 60 mg twice yearly entail significant risk reduction of vertebral, hip, and nonvertebral fractures in women with postmenopausal osteoporosis, with an acceptable rate of side effects so far. Following its approval by the US Food and Drug Administration and the European Medicines Agency, a number of clinical trials with denosumab are ongoing to demonstrate its value for other indications and to further characterize its effects on immunomodulation. Denosumab offers a new choice for the treatment of postmenopausal osteoporosis in patients at high risk for fracture.

Treatment of postmenopausal women with osteoporosis with PTH(1-84) for 36 months: treatment extension study.

OBJECTIVE: To determine the safety and efficacy of full-length parathyroid hormone, PTH(1-84), treatment for up to 36 months by evaluating bone mineral density (BMD) changes, bone histomorphometric indices, and clinical fracture incidence in postmenopausal women with osteoporosis. BACKGROUND: The TOP trial demonstrated increased lumbar spine BMD (6.9%) versus placebo after 18 months of PTH(1-84) treatment and reduced the incidence of new vertebral fractures (61%; p = 0.001). The therapeutic benefits of long-term treatment of postmenopausal women with PTH(1-84) are unknown. METHODS: The safety and efficacy of 36 months of once-daily dosing with 100 µg PTH(1-84) in postmenopausal women with osteoporosis were assessed. Women receiving placebo during the TOP trial were eligible for PTH(1-84) in the extension study. CLINICAL TRIAL REGISTRATION: NCT00172120. RESULTS: Lumbar spine BMD increased by 8.5% above baseline (p < 0.001) at 36 months of PTH(1-84) treatment, remaining stable during the last 12 months of treatment. Increases in total hip and femoral neck BMD occurred more slowly, reaching 3.2% and 3.4%, respectively above baseline at 36 months (p < 0.001). The total hip BMD showed no signs of reaching a limiting value although the femoral neck plateaued from months 24 to 36. Seven patients had vertebral fractures during the placebo phase of the TOP trial and before entering the extension study, but this rate decreased with the introduction of PTH(1-84) therapy, resulting in a single worsened vertebral fracture in the first 6 months and no further vertebral fractures from months 6 to 36. Treatment over 36 months with PTH(1-84) was well-tolerated and iliac crest biopsies showed no adverse effects on bone. LIMITATIONS: There was no placebo group for BMD comparisons. The number of patients assessed for fracture incidence was small. CONCLUSIONS: PTH(1-84) treatment for 36 months resulted in significant increases in BMD at the lumbar spine and hip, was associated with a lower incidence of vertebral fracture when compared to before therapy initiation, and was well-tolerated. The continuous increases in total hip BMD suggest that prolonged PTH(1-84) treatment may be beneficial for postmenopausal osteoporosis. Increased BMD at the femoral neck and lumbar spine also showed favourable changes but plateaued between 24 and 36 months. Long-term treatment was not associated with abnormalities in bone biopsies.

Effect of transdermal teriparatide administration on bone mineral density in postmenopausal women.

CONTEXT: Treatment of osteoporosis with an anabolic agent, teriparatide [human PTH 1-34 (TPTD)], is effective in reducing incident fractures, but patient resistance to daily sc injections has limited its use. A novel transdermal patch, providing a rapid, pulse delivery of TPTD, may provide a desirable alternative. OBJECTIVE: The aim of the study was to determine the safety and efficacy of a novel transdermal TPTD patch compared to placebo patch and sc TPTD 20-microg injection in postmenopausal women with osteoporosis. DESIGN: Our study consisted of 6-month, randomized, placebo-controlled, positive control, multidose daily administration. PATIENTS: We enrolled 165 postmenopausal women (mean age, 64 yr) with osteoporosis. INTERVENTIONS: A TPTD patch with a 20-, 30-, or 40-microg dose or a placebo patch was self-administered daily for 30-min wear time, or 20 microg of TPTD was injected daily. OUTCOMES: The primary efficacy measure was mean percentage change in lumbar spine bone mineral density (BMD) from baseline at 6 months. RESULTS: TPTD delivered by transdermal patch significantly increased lumbar spine BMD vs. placebo patch in a dose-dependent manner at 6 months (P < 0.001). TPTD 40-microg patch increased total hip BMD compared to both placebo patch and TPTD injection (P < 0.05). Bone turnover markers (procollagen type I N-terminal propeptide and C-terminal cross-linked telopeptide of type I collagen) increased from baseline in a dose-dependent manner in all treatment groups and were all significantly different from placebo patch (P < 0.001). All treatments were well tolerated, and no prolonged hypercalcemia was observed. CONCLUSION: Transdermal patch delivery of TPTD in postmenopausal women with osteoporosis for 6 months is safe and effective in increasing lumbar spine and total hip BMD.

Clinical and metabolic risk factor evaluation in young adults with kidney stones.

INTRODUCTION: The most frequent urine metabolic risk factor in adults is idiopathic hypercalciuria while in children is hypocitraturia. If there is really a change of metabolic abnormalities with age it would be interesting to study risk factors in the intermediate population: young adults. OBJECTIVE: We evaluated metabolic risk factors, clinical presentation and family history of stone formers between 17 and 27 years old. METHODS: A total of 160 patients (87 males and 73 females) were studied with a standard protocol. RESULTS: A single urine metabolic risk factor was present in 64% of the patients, and multiple risk factors were present in 27% of them. No metabolic abnormalities were found in the remaining 9%. The most common urine risk factor was idiopathic hypercalciuria (alone or in combination), which was identified in 42.5% followed by hypocitraturia (alone or in combination) found in 32.9% of the patients. In the subgroup of patients of 17-20 years (n = 75; mean age of 18.8 + or - 1.0 years), hypocitraturia (alone or in combination) was as frequent as idiopathic hypercalciuria (alone or in combination), which was identified in 38% (n = 30) and 36.7% (n = 29), respectively. The most frequent form of presentation was renal colic (72%). A positive family history of stone disease in first degree and second-degree relatives was found in 32.9 and 34.1%, respectively. CONCLUSIONS: Metabolic abnormalities were found in 91% of young adults with renal lithiasis, similar to our adult series. Hypercalciuria was the most frequent metabolic abnormality found. Yet, hypocitraturia (alone or in combination) was very frequent, and in the subgroup of patients of 17-20 years, it was as frequent as idiopathic hypercalciuria, similar to what we found in children.

Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial.

OBJECTIVE: To compare the bone anabolic drug teriparatide (20 microg/day) with the antiresorptive drug alendronate (10 mg/day) for treating glucocorticoid-induced osteoporosis (OP). METHODS: This was a 36-month, randomized, double-blind, controlled trial in 428 subjects with OP (ages 22-89 years) who had received > or =5 mg/day of prednisone equivalent for > or =3 months preceding screening. Measures included changes in lumbar spine and hip bone mineral density (BMD), changes in bone biomarkers, fracture incidence, and safety. RESULTS: Increases in BMD from baseline were significantly greater in the teriparatide group than in the alendronate group, and at 36 months were 11.0% versus 5.3% for lumbar spine, 5.2% versus 2.7% for total hip, and 6.3% versus 3.4% for femoral neck (P < 0.001 for all). In the teriparatide group, median percent increases from baseline in N-terminal type I procollagen propeptide (PINP) and osteocalcin (OC) levels were significant from 1 to 36 months (P < 0.01), and increases in levels of C-terminal telopeptide of type I collagen (CTX) were significant from 1 to 6 months (P < 0.01). In the alendronate group, median percent decreases in PINP, OC, and CTX were significant by 6 months and remained below baseline through 36 months (P < 0.001). Fewer subjects had vertebral fractures in the teriparatide group than in the alendronate group (3 [1.7%] of 173 versus 13 [7.7%] of 169; P = 0.007), with most occurring during the first 18 months. There was no significant difference between groups in the incidence of nonvertebral fractures (16 [7.5%] of 214 subjects taking teriparatide versus 15 [7.0%] of 214 subjects taking alendronate; P = 0.843). More subjects in the teriparatide group (21%) versus the alendronate group (7%) had elevated predose serum calcium concentrations (P < 0.001). CONCLUSION: Our findings indicate that subjects with glucocorticoid-induced OP treated with teriparatide for 36 months had greater increases in BMD and fewer new vertebral fractures than subjects treated with alendronate.

Active comparator trial of teriparatide vs alendronate for treating glucocorticoid-induced osteoporosis: results from the Hispanic and non-Hispanic cohorts.

Glucocorticoid use is a leading cause of secondary osteoporosis. This post hoc analysis compared teriparatide vs alendronate on bone mineral density (BMD) in Hispanic and non-Hispanic patients with glucocorticoid-induced osteoporosis. The 18-mo results from all patients (N=428) in a double-blind trial of teriparatide (20 microg/d) and alendronate (10 mg/d) who had taken glucocorticoids for >or=3 mo were reported (Saag et al. N Engl J Med 2007). The present study analyzed results from the Hispanic (n=61) and non-Hispanic (n=367) cohorts. The BMD was measured by dual-energy X-ray absorptiometry (DXA). In the Hispanic cohort at 18 mo, there were significantly greater increases from baseline in the teriparatide vs alendronate group in lumbar spine BMD (9.8%+/-1.7% vs 4.2%+/-1.4%; p<0.001; mean+/-SE) and total hip BMD (5.9%+/-1.6% vs 1.3%+/-1.3%, p<0.001), with no significant difference between groups at the femoral neck (4.3%+/-2.2% vs 2.0%+/-1.8%, p=0.228). Within each treatment group, the BMD responses were not significantly different in the Hispanic vs non-Hispanic cohort. The number of patients reporting >or=1 adverse event was not significantly different between treatments in either cohort, with more patients reporting nausea in the teriparatide group. In summary, teriparatide was more efficacious than alendronate in increasing BMD in Hispanic and non-Hispanic patients with glucocorticoid-induced osteoporosis. Both treatments were generally well tolerated.

Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial.

In this 3-yr, randomized, double-blind, placebo- and active-controlled study, healthy postmenopausal women with osteoporosis (55-85 yr of age) were treated with bazedoxifene 20 or 40 mg/d, raloxifene 60 mg/d, or placebo. The primary endpoint was incidence of new vertebral fractures after 36 mo; secondary endpoints included nonvertebral fractures, BMD, and bone turnover markers. Among 6847 subjects in the intent-to-treat population, the incidence of new vertebral fractures was significantly lower (p < 0.05) with bazedoxifene 20 mg (2.3%), bazedoxifene 40 mg (2.5%), and raloxifene 60 mg (2.3%) compared with placebo (4.1%), with relative risk reductions of 42%, 37%, and 42%, respectively. The treatment effect was similar among subjects with or without prevalent vertebral fracture (p = 0.89 for treatment by baseline fracture status interaction). The incidence of nonvertebral fractures with bazedoxifene or raloxifene was not significantly different from placebo. In a posthoc analysis of a subgroup of women at higher fracture risk (femoral neck T-score or=1 moderate or severe vertebral fracture or multiple mild vertebral fractures; n = 1772), bazedoxifene 20 mg showed a 50% and 44% reduction in nonvertebral fracture risk relative to placebo (p = 0.02) and raloxifene 60 mg (p = 0.05), respectively. Bazedoxifene significantly improved BMD and reduced bone marker levels (p < 0.001 versus placebo). The incidence of vasodilatation, leg cramps, and venous thromboembolic events was higher with bazedoxifene and raloxifene compared with placebo. In conclusion, bazedoxifene significantly reduced the risk of new vertebral fracture in postmenopausal women with osteoporosis and decreased the risk of nonvertebral fracture in subjects at higher fracture risk.