Increases in BMD correlate with improvements in bone microarchitecture with teriparatide treatment in postmenopausal women with osteoporosis.

Increases in BMD are correlated with improvements in 2D and 3D trabecular microarchitecture indices with teriparatide treatment. Therefore, improvements in trabecular bone microarchitecture may be one of the mechanisms to explain how BMD increases improve bone strength during teriparatide treatment. INTRODUCTION: Bone strength is determined by BMD and other elements of bone quality, including bone microarchitecture. Teriparatide treatment increases BMD and improves both cortical and trabecular bone microarchitecture. Increases in lumbar spine (LS) BMD account for approximately 30-41% of the vertebral fracture risk reduction with teriparatide treatment. The relationship between increases in BMD and improvements in cortical and trabecular microarchitecture has not yet been studied. MATERIALS AND METHODS: The relationship between increases in BMD and improvements in cortical and trabecular microarchitecture after teriparatide treatment was assessed using data from a subset of patients who had areal BMD measurements and structural parameters from transiliac bone biopsies in the Fracture Prevention Trial. 2D histomorphometric and 3D microCT parameters were measured at baseline and 12 (n = 21) or 22 (n = 36) mo. LS BMD was assessed at baseline and 12 and 18 mo, and femoral neck (FN) BMD was measured at baseline and 12 mo. Pearson correlation was performed to assess the relationship between actual changes in BMD and actual changes in microarchitectural parameters. RESULTS: Changes in LS BMD at 12 mo were significantly correlated with improvements in trabecular bone structure at 22 mo: 2D bone volume (r = 0.45, p = 0.02), 2D mean wall thickness (r = 0.41, p = 0.03), 3D bone volume (r = 0.48, p = 0.006), 3D trabecular thickness (r = 0.44, p = 0.01), 3D trabecular separation (r = -0.37, p = 0.04), 3D structural model index (r = -0.54, p = 0.001), and 3D connectivity density (r = 0.41, p = 0.02). Changes in LS BMD at 18 mo had similar correlations with improvements in bone structure at 22 mo. Changes in FN BMD at 12 mo were significantly correlated with changes in 2D mean wall thickness (r = 0.56, p = 0.002), 3D bone volume (r = 0.51, p = 0.004), 3D trabecular thickness (r = 0.44, p = 0.01), 3D trabecular separation (r = -0.46, p = 0.01), and 3D structural model index (r = -0.55, p = 0.001). CONCLUSIONS: Increases in BMD are correlated with improvements in trabecular microarchitecture in iliac crest of patients with teriparatide treatment. Therefore, improvements in trabecular bone microarchitecture may be one of the mechanisms to explain how BMD increases improve bone strength during teriparatide treatment.     

PINP as an aid for monitoring patients treated with teriparatide

Biochemical markers of bone turnover may be useful aids for managing patients with osteoporosis. A 12-month, phase 3, multicenter trial of Japanese patients at high risk of fracture was conducted to assess the effects of teriparatide 20 μg/day on BMD, serum markers of bone turnover, and safety. Two-hundred and seven subjects (93% female; median age 70 years) were randomized in double-blind fashion 2:1 to teriparatide versus placebo. Bone turnover markers including procollagen type I N-terminal propeptide (PINP), bone-specific alkaline phosphatase (bone ALP) and type I collagen cross-linked C-telopeptide (CTX) were collected at baseline, 1, 3, 6, and 12 months. Lumbar spine, femoral neck, and total hip BMD were measured at baseline, 3, 6, and 12 months. Increases in PINP at 1 month correlated best with increases in lumbar spine BMD at 12 months (r=0.76; P<0.01). The proportions of patients with an increase from baseline in PINP >10 μg/L at 1, 3, and 6 months were 3%, 0%, and 2% in the placebo, and 93%, 87%, and 83% in the teriparatide group. The proportions of patients with an increase in PINP >10 μg/L at either 1 or 3 months were 3% in the placebo and 95% in the teriparatide group (P<0.001). The proportions of patients with a significant increase in lumbar spine BMD (increase from baseline ≥3%) at 12 months were 20% in the placebo and 94% in the teriparatide group. The proportions of patients with an increase in PINP >10 μg/L at 1 or 3 months and an increase in lumbar spine BMD ≥3% at 12 months was 0% of placebo group patients and 92% of teriparatide group patients (P<0.001). These data confirm a strong relationship between early change in PINP and later change in lumbar spine BMD during teriparatide therapy. Also, these results suggest that monitoring with PINP and lumbar spine BMD successfully identifies positive responses in most patients taking teriparatide and negative responses in most patients not taking teriparatide. PINP monitoring may be a useful aid in the management of patients with osteoporosis during teriparatide treatment.     

Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy.

Although low absolute values of bone mineral density (BMD) predict increased fracture risk in osteoporosis, it is not certain how well increases in BMD with antiresorptive therapy predict observed reductions in fracture risk. This work examines the relationships between changes in BMD after 1 year or 3 years of raloxifene or placebo therapy and the risk for new vertebral fractures at 3 years. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis were randomized to placebo or raloxifene 60 mg/day or 120 mg/day. Relationships between baseline BMD and changes in BMD from baseline with the risk of new vertebral fractures were analyzed in this cohort using logistic regression models with the raloxifene doses pooled. As has been observed in other populations, women with the lowest baseline lumbar spine or femoral neck BMD in the MORE cohort had the greatest risk for vertebral fractures. Furthermore, for any percentage change, either increase or decrease in femoral neck or lumbar spine BMD at 1 year or 3 years, raloxifene-treated patients had a statistically significantly lower vertebral fracture risk compared with placebo-treated patients. The decrease in fracture risk with raloxifene was similar across the range of percentage change in femoral neck BMD observed at 3 years; patients receiving raloxifene had a 36% lower risk of vertebral fracture compared with those receiving placebo. At any percentage change in femoral neck and lumbar spine BMD observed at 1 year, raloxifene treatment decreased the risks of new vertebral fractures at 3 years by 38% and 41%, respectively. The logistic regression model showed that the percentage changes in BMD with raloxifene treatment accounted for 4% of the observed vertebral fracture risk reduction, and the other 96% of the risk reduction remains unexplained. The present data show that the measured BMD changes observed with raloxifene therapy are poor predictors of vertebral fracture risk reduction with raloxifene therapy.     

Effects of Romosozumab Compared With Teriparatide on Bone Density and Mass at the Spine and Hip in Postmenopausal Women With Low Bone Mass

Romosozumab, a monoclonal antibody that binds sclerostin, has a dual effect on bone by increasing bone formation and reducing bone resorption, and thus has favorable effects in both aspects of bone volume regulation. In a phase 2 study, romosozumab increased areal BMD at the lumbar spine and total hip as measured by DXA compared with placebo, alendronate, and teriparatide in postmenopausal women with low bone mass. In additional analyses from this international, randomized study, we now describe the effect of romosozumab on lumbar spine and hip volumetric BMD (vBMD) and BMC at month 12 as assessed by QCT in the subset of participants receiving placebo, s.c. teriparatide (20 µg once daily), and s.c. romosozumab (210 mg once monthly). QCT measurements were performed at the lumbar spine (mean of L₁ and L₂ entire vertebral bodies, excluding posterior processes) and hip. One year of treatment with romosozumab significantly increased integral vBMD and BMC at the lumbar spine and total hip from baseline, and compared with placebo and teriparatide (all p < 0.05). Trabecular vertebral vBMD improved significantly and similarly from baseline (p < 0.05) with both romosozumab (18.3%) and teriparatide (20.1%), whereas cortical vertebral vBMD gains were larger with romosozumab compared with teriparatide (13.7% versus 5.7%, p < 0.0001). Trabecular hip vBMD gains were significantly larger with romosozumab than with teriparatide (10.8% versus 4.2%, p = 0.01), but were similar for cortical vBMD (1.1% versus –0.9%, p = 0.12). Cortical BMC gains were larger with romosozumab compared with teriparatide at both the spine (23.3% versus 10.9%, p < 0.0001) and hip (3.4% versus 0.0%, p = 0.03). These improvements are expected to result in strength gains and support the continued clinical investigation of romosozumab as a potential therapy to rapidly reduce fracture risk in ongoing phase 3 studies. © 2016 American Society for Bone and Mineral Research.     

Effect of teriparatide on bone mineral density and biochemical markers in Japanese women with postmenopausal osteoporosis: a 6-month dose-response study

The dose-response efficacy and safety with three doses of teriparatide and placebo was assessed, using oncedaily subcutaneous injections for 24 weeks, in Japanese postmenopausal women with osteoporosis at high risk of fracture for reasons of preexisting fracture(s), advanced age, and/or low bone mineral density (BMD). In this multicenter, randomized, placebo-controlled study, 159 subjects were randomized and 154 subjects were included for analysis. Teriparatide (10-μg, 20-μg, and 40-μg doses) showed a statistically significant increase with increasing treatment dose as assessed by the percent change of lumbar spine BMD from baseline to endpoint using Williams’ test when compared with placebo (P < 0.001). The mean (±SD) percent change in lumbar spine, femoral neck, and total hip BMD with the 20-μg dose from baseline to endpoint was 6.40% ± 4.76%, 1.83% ± 7.13%, and 1.91% ± 3.60%, respectively. Rapid and sustained increases in bone formation markers [type I procollagen N-terminal propeptide (PINP), type I procollagen C-terminal propeptide (PICP), and bone-specific alkaline phosphatase (BAP)], followed by late increases in a bone resorption marker [type I collagen cross-linked C-telopeptide (CTX)], were observed for the teriparatide treatment groups (20-μg, 40-μg), suggesting a persistent, positive, balanced anabolic effect of teriparatide. Optimal adherence was achieved by this daily self-injection treatment. Regarding safety, most of the adverse events were mild to moderate in severity. No study drug-or study procedure-related serious adverse events were reported during the treatment period. These results observed in Japanese patients may support the observation that teriparatide stimulates bone formation in patients with osteoporosis at a high risk of fracture.     

Assessing the effect of baseline status of serum bone turnover markers and vitamin D levels on efficacy of teriparatide 20 μg/day administered subcutaneously in Japanese patients with osteoporosis

In this previously reported multicenter study, teriparatide 20 μg/day was administered to elderly Japanese subjects (93 % female; median age 70 years) with osteoporosis and at high risk of fracture during a 12-month, randomized, double-blind, placebo-controlled period, which was followed by a 12 month treatment period in which all subjects received open-label teriparatide. Subjects were randomized 2:1 to teriparatide versus placebo (teriparatide n = 137, placebo-teriparatide n = 70). This was an exploratory analysis to determine whether the baseline status of serum bone turnover markers (BTMs) and vitamin D levels affect the efficacy of teriparatide at 20 μg/day. The BTMs included were type I procollagen N-terminal pro-peptide (P1NP) and type I collagen cross-linked C-telopeptide (CTX). Changes in BMD were analyzed by subgroups: (1) tertile subgroups of BTM; (2) BTM determined by the upper limit of normal; and (3) level of vitamin D. Teriparatide increased lumbar spine BMD in all subgroups by 10 % or more through 24 months. Subgroups with higher baseline BTM levels had greater mean percent changes of lumbar spine BMD through 24 months. The baseline status of vitamin D sufficiency did not impact the mean percent change of lumbar spine BMD through 24 months. Results of this study suggest that clinically significant increases in BMD can be achieved in patients receiving teriparatide regardless of baseline BTM or vitamin D levels. Additionally, when vitamin D is coadministered, vitamin D insufficiency would not be expected to affect the overall efficacy of teriparatide.     

Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study.

In the CORE breast cancer trial of 4011 women continuing from MORE, the incidence of nonvertebral fractures at 8 years was similar between placebo and raloxifene 60 mg/day. CORE had limitations for assessing fracture risk. In a subset of 386 women, 7 years of raloxifene treatment significantly increased lumbar spine and femoral neck BMD compared from the baseline of MORE. INTRODUCTION: The multicenter, double-blind Continuing Outcomes Relevant to Evista (CORE) trial assessed the effects of raloxifene on breast cancer for 4 additional years beyond the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial. MATERIALS AND METHODS: In CORE, placebo-treated women from MORE continued with placebo (n = 1286), whereas those previously given raloxifene (60 or 120 mg/day) received raloxifene 60 mg/day (n = 2725). As a secondary endpoint, new nonvertebral fractures were analyzed as time-to-first event in 4011 postmenopausal women at 8 years. A substudy assessed lumbar spine and femoral neck BMD at 7 years, with the primary analysis based on 386 women (127 placebo, 259 raloxifene) who did not take other bone-active agents from the fourth year of MORE and who were > or =80% compliant with study medication in CORE. RESULTS: The risk of at least one new nonvertebral fracture was similar in the placebo (22.9%) and raloxifene (22.8%) groups (hazard ratio [HR], 1.00; Bonferroni-adjusted CI, 0.82, 1.21). The incidence of at least one new nonvertebral fracture at six major sites (clavicle, humerus, wrist, pelvis, hip, lower leg) was 17.5% in both groups. Posthoc Poisson analyses, which account for multiple events, showed no overall effect on nonvertebral fracture risk, and a decreased risk at six major nonvertebral sites in women with prevalent vertebral fractures (HR, 0.78; 95% CI, 0.63, 0.96). At 7 years after MORE randomization, the differences in mean lumbar spine and femoral neck BMD with raloxifene were 1.7% (p = 0.30) and 2.4% (p = 0.045), respectively, from placebo. Compared with MORE baseline, after 7 years, raloxifene treatment significantly increased lumbar spine (4.3% from baseline, 2.2% from placebo) and femoral neck BMD (1.9% from baseline, 3.0% from placebo). BMDs were significantly increased from MORE baseline at all time-points at both sites with raloxifene. CONCLUSION: Raloxifene therapy had no effect on nonvertebral fracture risk after 8 years, although CORE had limitations for fracture risk assessment. BMD increases were maintained after 7 years of raloxifene.     

Vertebral Fracture Risk Is Reduced in Women Who Lose Femoral Neck BMD With Teriparatide Treatment

Response to osteoporosis therapy is often assessed by serial BMD testing. Patients who lose BMD without secondary causes of bone loss may be considered to be “nonresponders” to treatment. We examined vertebral fracture (VF) risk, change in lumbar spine (LS) BMD, and change in amino‐terminal extension peptide of procollagen type I (PINP) in postmenopausal women whose femoral neck (FN) BMD decreased, increased, or was unchanged after receiving teriparatide (TPTD) or placebo (PL) in the Fracture Prevention Trial. FN and LS BMD were measured at baseline and 12 mo. VFs were assessed by lateral spine radiographs at baseline and study endpoint. A BMD change from baseline of >4% was considered to be clinically significant. Decreases of >4% FN BMD were less common in women receiving TPTD (10%) versus PL (16%, p < 0.05), yet women on TPTD who lost FN BMD still had significant reductions in VF risk compared with PL (RR = 0.11; 95% CI = 0.03–0.45). VF risk reduction with TPTD compared with PL was similar across categories of FN BMD change from baseline at 12 mo (loss >4%, loss 0–4%, gain 0–4%, or gain >4%; interaction p = 0.40). Irrespective of FN BMD loss or gain, TPTD‐treated women had statistically significant increases in LS BMD and PINP compared with PL. In both groups, losses or gains in FN BMD at 12 mo corresponded to losses or gains in BMC rather than changes in bone area. In conclusion, loss of FN BMD at 12 mo in postmenopausal women with osteoporosis treated with TPTD is nevertheless consistent with a good treatment response in terms of VF risk reduction.     

Once‐Weekly Risedronate in Men With Osteoporosis: Results of a 2‐Year,Placebo‐Controlled,Double‐Blind,Multicenter Study

Male osteoporosis is increasingly recognized as a major public health issue. This multinational, 2‐yr, randomized, double‐blind, placebo‐controlled study was conducted to determine the efficacy and safety of 35 mg once‐a‐week risedronate in men with osteoporosis. Patients had to be men ≥30 yr old, with lumbar spine T‐score ≤ ?2.5 and femoral neck T‐score ≤ ?1 SD or lumbar spine T‐score ≤ ?1 and femoral neck T‐score ≤ ?2 SD (based on young normal men). Patients were randomized 2:1 to risedronate 35 mg once a week or placebo for 2 yr; all patients took 1000 mg elemental calcium and 400–500 IU vitamin D daily. Lumbar spine BMD at month 24 using last observation carried forward was the primary endpoint. Other endpoints included lumbar spine BMD at time points other than month 24, proximal femur BMD, bone turnover markers (BTMs), new vertebral fractures, clinical fractures, and adverse event (AE) assessment. There were 284 men enrolled in the study. Treatment with risedronate resulted in a significant increase from baseline to endpoint in lumbar spine BMD compared with placebo (4.5%; 95% CI: 3.5%, 5.6%; p < 0.001). Few new vertebral and nonvertebral fractures were reported, with no differences in fracture rates between the two groups. There was a significant (p < 0.01) reduction from baseline in BTMs for the risedronate group compared with placebo at all time points. No apparent differences in the pattern or distribution of AEs including serious and upper gastrointestinal AEs were observed. Risedronate therapy was well tolerated during this 2‐yr study and was rapidly effective as indicated by significant BTM decreases at month 3 and BMD increases at month 6 (the earliest time points tested). The effects of risedronate treatment on BMD and BTMs in this study were similar to those previously shown to be associated with fracture risk reductions in women with postmenopausal osteoporosis.     

Fracture risk reduction during treatment with teriparatide is independent of pretreatment bone turnover

INTRODUCTION: Teriparatide is a bone formation agent that increases bone turnover and mass, resulting in an increase in bone strength and a decrease in fracture risk. METHODS: The primary purpose of this analysis was to evaluate the association between pretreatment bone turnover marker (BTM) concentrations and the absolute and relative fracture risks after adjusting for baseline femoral neck BMD, number of prevalent vertebral fractures, and age. Because femoral neck BMD is commonly attained in the assessment of patients at risk for osteoporosis, we examined the ability of a multivariate assessment including pretreatment BTM concentration and femoral neck BMD to predict future fracture risk after adjusting for the number of prevalent vertebral fractures. We examined data from the Fracture Prevention Trial, a study designed to determine the effect of teriparatide 20 mcg/day and teriparatide 40 mcg/day on vertebral and nonvertebral fracture risk in postmenopausal women with osteoporosis. BTM were analyzed in two subsets of women within the Fracture Prevention Trial, and included serum bone-specific alkaline phosphatase (BSAP), serum carboxy-terminal extension peptide of procollagen type I (PICP), serum amino-terminal extension peptide of procollagen type I (PINP), urinary free deoxypyridinoline (DPD), and urinary N-terminal telopeptide (NTX). RESULTS: Teriparatide significantly reduced the risk of fracture [four BTM subset (n = 520), placebo = 14.3%, teriparatide = 5.8%, P < 0.05; PINP subset (n = 771), placebo = 17.7%, teriparatide = 5.5%, P < 0.05]. Subjects with the highest pretreatment BTM concentrations had the greatest fracture risk. Teriparatide-mediated absolute risk reduction was greatest for women with high pretreatment bone turnover; however, the relative fracture risk reduction was independent of pretreatment bone turnover. After adjusting for pretreatment BTM and number of prevalent vertebral fractures, baseline femoral neck BMD was not a significant predictor of fracture risk. CONCLUSION: Teriparatide-mediated relative fracture risk reduction was independent of pretreatment bone turnover, demonstrating that this therapy offers clinical benefit to patients across a range of disease severity.     

Effects of Risedronate Treatment on Bone Density and Vertebral Fracture in Patients on Corticosteroid Therapy

Men and women (n = 518) receiving moderate-to-high doses of corticosteroids were enrolled in two studies with similar protocols and randomly assigned to receive either placebo or risedronate (2.5 or 5 mg) for 1 year. All patients received daily calcium supplementation (500–1000 mg), and most also received supplemental vitamin D (400 IU). The primary endpoint was the difference between the placebo and active groups in lumbar spine bone mineral density (BMD) at 1 year; changes in BMD at other sites, biochemical markers of bone turnover, and the incidence of vertebral fractures were also assessed. In the overall population, the mean (SE) lumbar spine BMD increased 1.9 ± 0.38% from baseline in the risedronate 5 mg group (P < 0.001) and decreased 1.0 ± 0.4% in the placebo group (P= 0.005). BMD at the femoral neck, trochanter, and distal radius increased or was maintained with risedronate 5 mg treatment, but decreased in the placebo group. Midshaft radius BMD did not change significantly in either treatment group. The difference in BMD between the risedronate 5 mg and placebo groups was significant at all skeletal sites (P < 0.05) except the midshaft radius at 1 year. The 2.5 mg dose also had a positive effect on BMD, although of a lesser magnitude than that seen with risedronate 5 mg. A significant reduction of 70% in vertebral fracture risk was observed in the risedronate 5 mg group compared with the placebo group (P= 0.01). Risedronate was efficacious in both men and women, irrespective of underlying disease and duration of corticosteroid therapy, and had a favorable safety profile, with a similar incidence of upper gastrointestinal adverse events in the placebo and active treatment groups. Daily treatment with risedronate 5 mg significantly increases BMD and decreases vertebral fracture risk in patients receiving moderate-to-high doses of corticosteroid therapy. Received: 11 October 1999 / Accepted: 1 May 2000 / Online publication: 27 July 2000     

Consistency of fracture risk reduction in Japanese and Caucasian osteoporosis patients treated with teriparatide: a meta-analysis

In the global Fracture Prevention Trial, teriparatide reduced the risk of vertebral and non-vertebral fractures and significantly increased BMD. Recently, a 12-month, phase 3, randomized, multicenter, double-blind, placebo-controlled trial with BMD as a primary endpoint was conducted to assess the effects of teriparatide in Japanese subjects at high risk of fracture. Although BMD was significantly increased in the Japanese study, the study was not statistically powered to assess the anti-fracture efficacy with teriparatide treatment. A meta-analysis was carried out testing whether teriparatide had consistent anti-fracture efficacy in Japanese patients compared to that observed in the global fracture trial. Three studies in which fracture data were available from prospectively scheduled spinal radiographs were included in the analysis. A systematic review of the literature (Medline, Embase) confirmed that no studies with teriparatide had been excluded from this analysis. There was no significant heterogeneity for vertebral and non-vertebral fractures among the studies included in the meta-analysis. Odds ratio estimates (95% CI) were 0.29 (0.20, 0.43) for vertebral fracture and 0.53 (0.32, 0.86) for non-vertebral fracture. There was also a consistent effect of teriparatide to increase BMD across all studies. Furthermore, our analysis demonstrated that teriparatide-mediated increases in spine BMD accounted for 25-32% of the reduction in vertebral fracture risk in the combined population including Caucasian and Japanese patients, which was similar to that derived from Caucasian patients. These results provide evidence for the consistency of anti-fracture efficacy with teriparatide treatment in Japanese patients compared to those observed in Caucasian patients.     

Once-Weekly Injection of Low-Dose Teriparatide (28.2 μg) Reduced the Risk of Vertebral Fracture in Patients with Primary Osteoporosis

We conducted a randomized, double-blind trial to assess the effect of 28.2 μg teriparatide versus placebo (1.4 μg teriparatide) on reduction of the incidence of vertebral fractures. Individuals enrolled in this study included patients with primary osteoporosis with one to five vertebral fractures and capable of self-supported walking. Attention was focused on incident vertebral fractures, change in bone mineral density (BMD) of the lumbar spine, and safety. A total of 316 subjects participated in the study, which lasted up to 131 weeks. Incident vertebral fractures occurred in 3.3 % of subjects in the 28.2 μg teriparatide-treated group and 12.6 % of subjects in the placebo group during the 78-weeks study period. Kaplan–Meier estimates of risk after 78 weeks were 7.5 and 22.2 % in the teriparatide and placebo groups, respectively, with a relative risk reduction of 66.4 % by teriparatide (P = 0.008). Lumbar BMD in the 28.2 μg teriparatide group increased significantly by 4.4 ± 4.7 % at 78 weeks, which was significantly higher than the corresponding data in the placebo group (P = 0.001). Adverse events were observed in 86.7 % of individuals in the teriparatide group and 86.1 % of those in the placebo group. In conclusion, weekly injection of a low-dose of teriparatide (28.2 μg) reduced the risk of incident vertebral fractures and increased lumbar BMD.     

Greater Gains in Spine and Hip Strength for Romosozumab Compared With Teriparatide in Postmenopausal Women With Low Bone Mass

Romosozumab is a monoclonal antibody that inhibits sclerostin and has been shown to reduce the risk of fractures within 12 months. In a phase II, randomized, placebo‐controlled clinical trial of treatment‐naïve postmenopausal women with low bone mass, romosozumab increased bone mineral density (BMD) at the hip and spine by the dual effect of increasing bone formation and decreasing bone resorption. In a substudy of that trial, which included placebo and teriparatide arms, here we investigated whether those observed increases in BMD also resulted in improvements in estimated strength, as assessed by finite element analysis. Participants received blinded romosozumab s.c. (210 mg monthly) or placebo, or open‐label teriparatide (20 μg daily) for 12 months. CT scans, obtained at the lumbar spine (n = 82) and proximal femur (n = 46) at baseline and month 12, were analyzed with finite element software (VirtuOst, O.N. Diagnostics) to estimate strength for a simulated compression overload for the spine (L₁ vertebral body) and a sideways fall for the proximal femur, all blinded to treatment assignment. We found that, at month 12, vertebral strength increased more for romosozumab compared with both teriparatide (27.3% versus 18.5%; p = 0.005) and placebo (27.3% versus –3.9%; p < 0.0001); changes in femoral strength for romosozumab showed similar but smaller changes, increasing more with romosozumab versus teriparatide (3.6% versus –0.7%; p = 0.027), and trending higher versus placebo (3.6% versus ?0.1%; p = 0.059). Compartmental analysis revealed that the bone‐strengthening effects for romosozumab were associated with positive contributions from both the cortical and trabecular bone compartments at both the lumbar spine and hip. Taken together, these findings suggest that romosozumab may offer patients with osteoporosis a new bone‐forming therapeutic option that increases both vertebral and femoral strength within 12 months. © 2017 American Society for Bone and Mineral Research.     

Increases in Hip and Spine Bone Mineral Density are Predictive for Vertebral Antifracture Efficacy with Ibandronate

The relationship between bisphosphonate-induced bone mineral density (BMD) gains and antifracture efficacy remains to be fully elucidated. Data from two antifracture studies were analyzed. Postmenopausal osteoporotic women received oral (2.5 mg daily, 20 mg intermittent) or intravenous (0.5 mg, 1 mg quarterly) ibandronate. Outcome measures included moving averages plots and logistic regression analyses of the relationship between BMD change and vertebral fracture rate. In moving averages plots, ibandronate-induced BMD gains were consistently associated with decreased fracture rates. In the oral study, total-hip BMD increases at years 2 and 3 and lumbar spine BMD increases at year 3 were associated with 3-year vertebral fracture rate (relative risk reduction [RRR] at year 3 for 1% change from baseline: hip, 7.9% [95% CI 2.1–13.5%, P = 0.0084]; lumbar spine, 4.7% [−0.1% to 9.3%, P = 0.0565]). In the intravenous study, total-hip BMD increases at years 1, 2, and 3 and lumbar spine BMD increases at years 2 and 3 were significantly associated with vertebral fracture rate (RRR at year 3 for 1% change from baseline: hip, 11.6% [7.0–16.0%, P < 0.0001]; lumbar spine, 6.9% [2.9–10.6%, P = 0.0008]). In a pooled analysis, changes in total-hip and lumbar spine BMD were associated with 3-year vertebral fracture risk reduction and explained a substantial proportion of the antifracture effect (23–37% at 2 and 3 years). This analysis suggests that ibandronate-induced BMD gain in postmenopausal osteoporotic women is associated with vertebral fracture risk reduction.     

Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month double-blind placebo-controlled trial.

We compared combination treatment with teriparatide plus raloxifene with teriparatide alone in women with postmenopausal osteoporosis in a 6-month double-blind, placebo-controlled trial that measured biochemical markers of bone turnover and BMD. Markers of bone formation and spine BMD increased similarly with teriparatide alone and combination therapy. However, combination therapy induced a significantly smaller increase in bone resorption versus teriparatide alone and significantly increased total hip BMD versus baseline. INTRODUCTION: The effects of combining two approved treatments for osteoporosis with different modes of action were examined by comparing teriparatide [rhPTH(1-34)] monotherapy with combination teriparatide and raloxifene therapy. MATERIALS AND METHODS: A 6-month randomized, double-blind trial comparing teriparatide plus raloxifene (n = 69) versus teriparatide plus placebo (n = 68) was conducted in postmenopausal women with osteoporosis. RESULTS: Bone formation (N-terminal propeptide of type 1 collagen [PINP]) increased similarly in both treatment groups. However, the increase in bone resorption (serum C-terminal telopeptide of type I collagen [CTx]) in the combination group was significantly smaller than in the teriparatide-alone group (p = 0.015). Lumbar spine BMD significantly increased 5.19 +/- 0.67% from baseline in the teriparatide-alone group. In the combination group, lumbar spine (6.19 +/- 0.65%), femoral neck (2.23 +/- 0.64%), and total hip (2.31 +/- 0.56%) BMD significantly increased from baseline to study endpoint, and the increase in total hip BMD was significantly greater than in the teriparatide-alone group (p = 0.04). In the teriparatide-alone group, mean serum calcium levels increased from baseline to endpoint (0.30 +/- 0.06 mg/dl, p < 0.001), whereas mean serum phosphate remained unchanged. In the combination group, mean serum calcium was unchanged, and mean serum phosphate decreased (-0.20 +/- 0.06 mg/dl, p < 0.001) from baseline to endpoint. Changes in serum calcium (p < 0.001) and phosphate (p < 0.004) were significantly different between treatment groups. The safety profile of combination therapy was similar to teriparatide alone. CONCLUSIONS: Combination therapy increased bone formation to a similar degree as teriparatide alone. However, the increase in bone resorption was significantly less and total hip BMD significantly increased for combination therapy compared with teriparatide alone. Combination treatment with raloxifene may thus enhance the bone forming effects of teriparatide. Further studies over longer treatment duration that include fracture endpoints are necessary to fully ascertain the clinical significance of combination raloxifene plus teriparatide therapy in postmenopausal osteoporosis.     

Once-weekly teriparatide reduces the risk of vertebral fracture in patients with various fracture risks: subgroup analysis of the Teriparatide Once-Weekly Efficacy Research (TOWER) trial

Once-weekly teriparatide (human parathyroid hormone [1–34]) (56.5 μg for 72 weeks) injections provided a vertebral fracture risk reduction in Japanese osteoporotic patients evaluated in the Teriparatide Once-Weekly Efficacy Research (TOWER) trial. Using data from the TOWER trial, a subgroup analysis was performed to study the efficacy of once-weekly teriparatide for a variety of baseline clinical risk factors in placebo (n = 281) and teriparatide (n = 261) groups. Significant fracture risk reductions were observed in the subgroups of individuals aged <75 years [relative risk (RR) 0.06, p = 0.007] and ≥75 years (RR 0.32, p = 0.015). A significant risk reduction was observed among patients with prevalent vertebral fracture in the subgroup with 1 (RR 0.08, p = 0.015) or ≥2 (RR 0.29, p = 0.009) prevalent vertebral fractures, and in those with grade 3 deformity (RR 0.26, p = 0.003). Significant risk reduction was observed in the subgroup with lumbar bone mineral density (BMD) < ?2.5 SD (RR 0.25, p = 0.035). In the teriparatide group, no incident fracture was observed in the subgroups with a prevalent vertebral fracture number of 0, with grade 0–2 vertebral deformity, or with lumbar BMD ≥2.5 SD. Significant risk reduction was observed in all of the bone turnover marker and estimated glomerular filtration rate subgroups. In conclusion, once-weekly 56.5 μg teriparatide injection reduced the vertebral fracture risk in patients with varying degrees of fracture risk, age, vertebral fracture number and grade, bone turnover level, and renal function.     

Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk.

The change in BMD is a poor predictor of vertebral fracture risk after raloxifene treatment. One-year percent change in bone turnover and BMD was used to predict vertebral fracture risk. The percent change in osteocalcin was determined to be a better predictor of vertebral fracture risk than BMD. INTRODUCTION: The association between baseline BMD and fracture risk is well understood. However, the relationship between changes in BMD and fracture risk is not well defined. It has previously been demonstrated that BMD change was a poor predictor of vertebral fracture risk in raloxifene-treated women, whereas bone turnover markers were significantly associated with fracture risk. In the current analysis, we explore the prediction of vertebral fracture risk using changes in both BMD and bone turnover. MATERIALS AND METHODS: The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a randomized, placebo-controlled trial of 7705 women with osteoporosis treated with raloxifene 60 or 120 mg/day for 3 years. Markers of bone turnover were measured in one-third of the study population (n = 2503), and the present analyses include these women. Logistic regression models were constructed using one-year percent changes in BMD and bone turnover and relevant baseline demographics to predict the risk of vertebral fracture with pooled raloxifene therapy at 3 years. All covariates were standardized before modeling to facilitate direct comparisons between changes in BMD and bone turnover. RESULTS AND CONCLUSION: Prevalent vertebral fracture status (p < 0.0001), baseline lumbar spine BMD (p < 0.0001), and number of years postmenopausal (p = 0.0005) were independent predictors of fracture risk in raloxifene-treated patients. Therapy-by-change in femoral neck BMD (p = 0.02) and therapy-by-change in osteocalcin (OC; p = 0.01) were also significant for all treatment groups, indicating that changes in BMD and OC have different effects on fracture risk for the placebo and pooled raloxifene groups. The final model included significant baseline variables and change in OC (p = 0.01), whereas change in femoral neck BMD was not significant. After adjustment of each significant baseline variable, the percent change in OC was better able to predict the reduction in vertebral fracture risk than the percent change in femoral neck BMD in patients treated with raloxifene.     

New or worsening lumbar spine vertebral fractures increase lumbar spine bone mineral density and falsely suggest improved skeletal status.

Changes in lumbar spine bone mineral density (BMD) are determined by follow-up dual-energy x-ray absorptiometry (DXA) assessments. Inclusion of new or worsening vertebral fractures in follow-up measurements may increase BMD. To test this hypothesis, we examined pooled data from the placebo groups of two clinical trials that involved postmenopausal women with osteoporosis. DXA measurements of lumbar spine BMD, bone mineral content (BMC), and area were obtained at baseline and at two years in the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial and at baseline and study endpoint in the Fracture Prevention Trial. In these trials, fractured vertebrae identified by expert radiologists during posterioranterior (PA) spine DXA assessment were excluded from the BMD assessment. Lateral spine radiographs were graded using a semi-quantitative (SQ) scale. Most new or worsening vertebral fractures (84%) diagnosed from lateral spine radiographs were not identified by PA spine DXA. While the follow-up BMD of vertebrae without new or worsening fractures did not change significantly, each unit increase in SQ grade was associated with an approximate 7.0% increase in the BMD of affected vertebrae (p < 0.001). Increases in BMD were highly correlated with increases in BMC (r = 0.87, p < 0.001). Inclusion of new or worsening vertebral fractures increased PA spine BMD measurements at follow-up, with the impact being related to the magnitude of change in SQ score. It is difficult to reliably identify vertebral fractures from PA spine DXA assessments. Inclusion of new or worsening vertebral fractures in follow-up DXA measurements may falsely suggest an improvement in spine BMD. Our suggestion is to perform lateral spine imaging concurrently with any assessment of PA spine BMD in patients who, in the opinion of the health care provider, may have vertebral fractures.