Effect of denosumab on trabecular bone score in postmenopausal women with osteoporosis.

Trabecular bone score (TBS) assesses bone quality in the lumbar spine using dual-energy X-ray absorptiometry (DXA) scans. In postmenopausal women with osteoporosis, denosumab significantly improved TBS independently of bone mineral density (BMD). This practical technique may have a role in managing patients with osteoporosis. INTRODUCTION: TBS, a gray-level texture index determined from lumbar spine DXA scans, correlates with bone microarchitecture and enhances assessment of vertebral fracture risk independently of BMD. In the FREEDOM study, denosumab increased BMD and reduced new vertebral fractures in postmenopausal women with osteoporosis. This retrospective analysis explored the effect of denosumab on TBS and the association between TBS and BMD in FREEDOM. METHODS: Postmenopausal women with lumbar spine or total hip BMD T-score <-2.5 and -4.0 or higher at both sites received placebo or denosumab 60 mg subcutaneously every 6 months. TBS indices were determined from DXA scans at baseline and months 12, 24, and 36 in a subset of 285 women (128 placebo, 157 denosumab) who had TBS values at baseline and ≥1 postbaseline visit. RESULTS: Baseline characteristics were comparable between treatment groups; mean (SD) lumbar spine BMD T-score was -2.79 (0.64), and mean (standard deviation [SD]) TBS was 1.200 (0.101) overall. In the placebo group, BMD and TBS increased by ≤0.2% or decreased from baseline at each visit. In the denosumab group, progressive increases from baseline at 12, 24, and 36 months were observed for BMD (5.7, 7.8, and 9.8%) and TBS (1.4, 1.9, and 2.4%). Percentage changes in TBS were statistically significant compared with baseline (p < 0.001) and placebo (p ≤ 0.014). TBS was largely unrelated to BMD, regardless of treatment, either at baseline or for annual changes from baseline (all r 2 ≤ 0.06). CONCLUSIONS: In postmenopausal women with osteoporosis, denosumab significantly improved TBS independently of BMD.

Treatment with denosumab reduces secondary fracture risk in women with postmenopausal osteoporosis.

OBJECTIVES: A history of prior fracture is one of the strongest predictors of a future fragility fracture. In FREEDOM, denosumab significantly reduced the risk of new vertebral, non-vertebral, and hip fractures. We carried out a post-hoc analysis of FREEDOM to characterize the efficacy of denosumab in preventing secondary fragility fractures in subjects with a prior fracture. METHODS: A total of 7808 women aged 60-90 years with a bone mineral density T-score of less than - 2.5 but not less than - 4.0 at either the lumbar spine or total hip were randomized to subcutaneous denosumab 60 mg or placebo every 6 months for 36 months. The anti-fracture efficacy of denosumab was analyzed by prior fracture status, to assess secondary fragility fracture, and by subject age, prior fracture site and history of prior osteoporosis medication use. RESULTS: A prior fragility fracture was reported for 45% of the overall study population. Compared with placebo, denosumab significantly reduced the risk of a secondary fragility fracture by 39% (incidence, 17.3% vs. 10.5%; p < 0.0001). Similar results were observed regardless of age or prior fracture site. In the overall population, denosumab significantly reduced the risk of a fragility fracture by 40% (13.3% vs. 8.0%; p < 0.0001), with similar results observed regardless of history of prior osteoporotic medication use. CONCLUSIONS: Denosumab reduced the risk of fragility fractures to a similar degree in all risk subgroups examined, including those with prior fragility fractures. Identifying and treating high-risk individuals could help to close the current care gap in secondary fracture prevention.

Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years.

UNLABELLED: Limited data exist on the efficacy of long-term therapies for osteoporosis. In osteoporotic postmenopausal women receiving denosumab for 7 years, nonvertebral fracture rates significantly decreased in years 4-7 versus years 1-3. This is the first demonstration of a further benefit on fracture outcomes with long-term therapy for osteoporosis. INTRODUCTION: This study aimed to evaluate whether denosumab treatment continued beyond 3 years is associated with a further reduction in nonvertebral fracture rates. METHODS: Participants who completed the 3-year placebo-controlled Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were invited to participate in an open-label extension. The present analysis includes 4,074 postmenopausal women with osteoporosis (n = 2,343 long-term; n = 1,731 cross-over) who enrolled in the extension, missed ≤1 dose during their first 3 years of denosumab treatment, and continued into the fourth year of treatment. Comparison of nonvertebral fracture rates during years 1-3 of denosumab with that of the fourth year and with the rate during years 4-7 was evaluated. RESULTS: For the combined group, the nonvertebral fracture rate per 100 participant-years was 2.15 for the first 3 years of denosumab treatment (referent) and 1.36 in the fourth year (rate ratio [RR] = 0.64; 95 % confidence interval (CI) = 0.48 to 0.85, p = 0.003). Comparable findings were observed in the groups separately and when nonvertebral fracture rates during years 1-3 were compared to years 4-7 in the long-term group (RR = 0.79; 95 % CI = 0.62 to 1.00, p = 0.046). Fracture rate reductions in year 4 were most prominent in subjects with persisting low hip bone mineral density (BMD). CONCLUSIONS: Denosumab treatment beyond 3 years was associated with a further reduction in nonvertebral fracture rate that persisted through 7 years of continuous denosumab administration. The degree to which denosumab further reduces nonvertebral fracture risk appears influenced by the hip bone density achieved with initial therapy.

Multimorbidity in women with and without osteoporosis: results from a large US retrospective cohort study 2004-2009.

UNLABELLED: To determine the incidence of comorbidities in women with and without osteoporosis, incidence rates per 1,000 person-years were calculated using electronic health records from an integrated healthcare system. The overall comorbidity burden and health service utilization were greater in women with osteoporosis than in the controls. INTRODUCTION: This retrospective cohort study describes the incidence of an array of comorbidities in women with and without osteoporosis (OP). METHODS: Using electronic health records from an integrated healthcare system, we identified 22,414 women aged 55-89 years with OP and 22,414 age-matched controls without OP. Incidence rates (IRs) per 1,000 person-years (P-Y) were calculated and 95% confidence intervals (CI) were estimated. RESULTS: Women with OP had significantly more comorbidities, medications, hospitalizations, and outpatient visits than the controls. Most cardiac comorbidity rates were 20-25% lower in the OP cohort than in the control cohort. Hypertension had the largest rate difference; the IR was 42.0 per 1,000 P-Y (95% CI 40.2-44.0) in the OP cohort compared to 94.0 (95% CI 90.7-97.4) in the control cohort. Rates for cerebrovascular disease were similar for both cohorts at 26 per 1,000 P-Y. Bronchitis, sinusitis, and cystitis were each 55 per 1,000 P-Y in the OP cohort, whereas they ranged from 28 to 34 per 1,000 P-Y in the controls. The OP cohort had decreased incidence of ovarian, uterine, colorectal, and liver cancers and increased incidence of lung cancer, breast cancer, and multiple myeloma, compared to the non-OP cohort. Falls, depression, vision, and musculoskeletal issues were higher for the OP cohort than the controls. CONCLUSIONS: This study demonstrates the high disease burden in women with OP. This knowledge may help guide the clinical management of this population and may aid in the interpretation of adverse events in randomized clinical trials of OP therapies.

Bone densitometry: the best way to detect osteoporosis and to monitor therapy.

The revolution in the field of osteoporosis has been aided and abetted by the advent of bone mass measurement technologies. As they become more widely applicable and more affordable, it is evident that we have the potential to discover the millions of individuals at risk for or with the disease. With effective therapies at hand, it is now possible to prevent and treat osteoporosis. There is every reason, therefore, to apply bone mass measurements as widely as possible to discover those subjects at risk for osteoporosis in a manner that is effective and affordable.

Effects of perfusate leucine concentration on the metabolism of valine by the isolated rat hindquarter.

Rates of oxidation of valine and release of alpha-ketoisovaleric acid by hindquarters from rats fed a 9% casein diet were measured at intervals over 90 minutes. The hindquarters were perfused with medium containing between 0.03 and 10 mmol/L L-leucine; concentrations of valine and isoleucine were kept constant at 0.2 and 0.1 mmol/L, respectively. The rate of oxidation of [1-14C]valine increased two to threefold when the perfusate contained 0.8 or 1.0 mmol/L leucine but was depressed by 50% when the leucine concentration was 10 mmol/L. The rate of release of alpha-ketoisovaleric acid from the hindquarter was affected little by perfusate leucine concentrations up to 1.0 mmol/L, but release was depressed when perfusate leucine concentration was increased to 10 mmol/L. The rate of release of alpha-ketoisocaproic acid increased with increasing perfusate leucine concentration, as did intracellular alpha-ketoisocaproic acid and leucine concentrations. These results indicate that valine oxidation by the isolated perfused hindquarter is stimulated by a high perfusate leucine concentration (1.0 mmol/L), suggesting that this response contributes to the depressed plasma and tissue valine pools of rats fed a high-leucine diet. An excessively high concentration of leucine (10 mmol/L) suppresses valine oxidation, presumably by competing with valine for transmination or transport.