The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study.

UNLABELLED: The FREEDOM study and its Extension provide long-term information about the effects of denosumab for the treatment of postmenopausal osteoporosis. Treatment for up to 8 years was associated with persistent reduction of bone turnover, continued increases in bone mineral density, low fracture incidence, and a favorable benefit/risk profile. INTRODUCTION: This study aims to report the results through year 5 of the FREEDOM Extension study, representing up to 8 years of continued denosumab treatment in postmenopausal women with osteoporosis. METHODS: Women who completed the 3-year FREEDOM study were eligible to enter the 7-year open-label FREEDOM Extension in which all participants are scheduled to receive denosumab, since placebo assignment was discontinued for ethical reasons. A total of 4550 women enrolled in the Extension (2343 long-term; 2207 cross-over). In this analysis, women in the long-term and cross-over groups received denosumab for up to 8 and 5 years, respectively. RESULTS: Throughout the Extension, sustained reduction of bone turnover markers (BTMs) was observed in both groups. In the long-term group, mean bone mineral density (BMD) continued to increase significantly at each time point measured, for cumulative 8-year gains of 18.4 and 8.3 % at the lumbar spine and total hip, respectively. In the cross-over group, mean BMD increased significantly from the Extension baseline for 5-year cumulative gains of 13.1 and 6.2 % at the lumbar spine and total hip, respectively. The yearly incidence of new vertebral and nonvertebral fractures remained low in both groups. The incidence of adverse and serious adverse events did not increase over time. Through Extension year 5, eight events of osteonecrosis of the jaw and two events of atypical femoral fracture were confirmed. CONCLUSIONS: Denosumab treatment for up to 8 years was associated with persistent reductions of BTMs, continued BMD gains, low fracture incidence, and a consistent safety profile.

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.

Design of the POSSIBLE UStrade mark Study: postmenopausal women's compliance and persistence with osteoporosis medications.

UNLABELLED: Failure to take prescribed medication is common. The POSSIBLE US study is evaluating the impact of physician and patient characteristics on patient-reported compliance and persistence with osteoporosis medications. We report our study design and the baseline characteristics of 4,994 postmenopausal women recruited from primary care physician offices in 33 states. INTRODUCTION: The Prospective Observational Scientific Study Investigating Bone Loss Experience (POSSIBLE US) is a longitudinal cohort study of osteoporosis therapy in primary care. METHODS: Between 2004 and 2007, 134 physicians (in 33 states) enrolled postmenopausal women initiating, changing, or continuing osteoporosis medications. After completing a baseline questionnaire, participants will provide data semi-annually for up to 3 years through 2008. Physicians provide patient data at baseline and routine follow-up visits. Participants from 23 sites also signed a release regarding administrative claims data for economic analyses and validation of self-reported data. BASELINE RESULTS: Four thousand nine hundred and ninety-four evaluable women were recruited from internal medicine (n = 1,784), family practice (n = 1,556), obstetrics/gynecology (n = 1,556), and from one rheumatology practice (n = 98). Mean participant age was 64.3 years (SD = 9.97); 89% were Caucasian; 59% had some college education. Sixty-three percent used a single osteoporosis agent, usually a bisphosphonate. For monotherapy patients, concordance between clinic- and patient-reported medication use was lowest for patients prescribed estrogen therapy (70%) or calcium/vitamin D (72%). Obstetrician/gynecologists enrolled younger women, who were more likely to use estrogen therapy than patients enrolled by other physicians. The 934 women (19%) prescribed only calcium/vitamin D were younger than women prescribed pharmacologic therapy. CONCLUSIONS: POSSIBLE US provides a unique foundation for evaluating longitudinal use of osteoporosis medications and related outcomes.

Exploration of multilocus effects in a highly polymorphic gene, the apolipoprotein (APOB) gene, in relation to plasma apoB levels.

A detailed exploration of all the polymorphisms in candidate genes is required to better characterize the relationship between gene variability and complex traits. We propose a novel strategy for investigating the association between a highly polymorphic gene and a phenotype, by combining a multilocus genotype analysis and an haplotype analysis. For the multilocus genotype analysis, a data mining tool--termed DICE (Detection of Informative Combined Effects)--was developed to identify the best subset of polymorphisms that are associated--individually or in combination--with the phenotype. For the haplotype analysis, we used our recently developed method of haplotype-phenotype association to determine the most informative and parsimonious haplotype model fitting the data. We illustrate this strategy by investigating the association between twelve polymorphisms of the APOB gene and plasma apoB levels in 1442 European subjects. After exploring all main effects and interactions between polymorphisms, DICE identified the N4311S polymorphism as the most informative polymorphism in relation to apoB levels. Haplotype analysis led to the same conclusion. Additionally, DICE identified the E4154K (EcoRI) and the T2488T (XbaI) polymorphisms as potentially interesting. This selection was not modified by inclusion of the common APOE polymorphism in the analysis.