Implementing a fracture liaison service open model of care utilizing a cloud-based tool.

PURPOSE: Although half of women and one-quarter of men aged 50 and older will sustain an acute low-trauma fracture, less than a quarter receive appropriate secondary fracture prevention. The goal of this quality improvement demonstration project was to implement a Fracture Liaison Service (FLS) focused on secondary prevention of an osteoporotic fracture in three open health care systems aided by a cloud-based tool. METHODS: The pre-post study design examined the proportion of men and women over age 50 who received appropriate assessment (bone mineral density, vitamin D levels) and treatment (calcium/vitamin D, pharmacologic therapy) in the six months following a recently diagnosed fracture. The pre-study (Pre FLS) included a retrospective chart review for baseline data (N = 344 patients) within each health care system. In the post-evaluation (Post FLS, N = 148 patients), the FLS coordinator from each health care system examined these parameters following enrollment and for 6 months following the recently diagnosed fracture. Data were managed in the cloud-based FLS application tool. RESULTS: Ninety-three participants completed the program. The FLS program increased the percentage of patients receiving bone mineral density testing from 21% at baseline to 93% (p < 0.001) Post FLS implementation. Assessments of vitamin D levels increased from 25 to 84% (p < 0.001). Patients prescribed calcium/vitamin D increased from 36% at baseline to 93% (p < 0.001) and those prescribed pharmacologic treatment for osteoporosis increased on average from 20 to 54% (p < 0.001) Post FLS. CONCLUSIONS: We conclude that the FLS model of care in an open health care system, assisted by a cloud-based tool, significantly improved assessment and/or treatment of patients with a recently diagnosed osteoporotic fracture. Future studies are necessary to determine if this model of care is scalable and if such programs result in prevention of fractures. Mini-Abstract: The goal was to implement a Fracture Liaison Service (FLS) focused on secondary prevention of an osteoporotic fracture in open health care systems aided by a cloud-based tool. This model significantly improved assessment and/or treatment of patients with a recently diagnosed fracture.

Vitamin D deficiency is associated with functional decline and falls in frail elderly women despite supplementation.

We examined the impact of daily supplementation on vitamin D deficiency, function, and falls in female long-term care residents. Initial vitamin D deficiency was associated with greater functional decline and increased fall risk despite guideline-recommended supplementation, highlighting the importance of preventing vitamin D deficiency in frail elderly. INTRODUCTION: Institute of Medicine (IOM) guidelines recommend 800 IU vitamin D daily for older adults and maintaining serum 25-hydroxyvitamin D [25(OH) D] above 20 ng/ml for optimal skeletal health. The adequacy of IOM guidelines for sustaining function and reducing falls in frail elderly is unknown. METHODS: Female long-term care residents aged ≥65 enrolled in an osteoporosis clinical trial were included in this analysis (n = 137). Participants were classified based on baseline 25(OH) D levels as deficient (<20 ng/ml, n = 26), insufficient (20-30 ng/ml, n = 40), or sufficient (>30 ng/ml, n = 71). Deficient women were provided initial vitamin D repletion (50,000 IU D3 weekly for 8 weeks). All were supplemented with 800 IU vitamin D3 daily for 24 months. Annual functional assessments included Activities of Daily Living (ADLs), Instrumental ADL (IADL), physical performance test (PPT), gait speed, cognition (SPMSQ), and mental health (PHQ-9). We used linear mixed models for analysis of functional measures and logistic regression for falls. RESULTS: Daily supplementation maintained 25(OH) D levels above 20 ng/ml in 95% of participants. All groups demonstrated functional decline. Women initially deficient had a greater decline in physical function at 12 (IADL -2.0 ± 0.4, PPT -3.1 ± 0.7, both p < 0.01) and 24 months (IADL -2.5 ± 0.6, ADL -2.5 ± 0.6, both p < 0.01), a larger increase in cognitive deficits at 12 months (1.7 ± 0.4: p = 0.01) and more fallers (88.5%, p = 0.04) compared to those sufficient at baseline, despite supplementation to sufficient levels. CONCLUSIONS: IOM guidelines may not be adequate for frail elderly. Further study of optimal 25(OH) D levels for maintaining function and preventing falls is needed.

Prevention of bone loss with risedronate in breast cancer survivors: a randomized, controlled clinical trial.

UNLABELLED: In postmenopausal women with low bone mass and hormone-receptor-positive breast cancer on an aromatase inhibitor, risedronate maintained skeletal health assessed by bone density and turnover markers. Women with the greatest decreases in bone turnover markers at 12 months had the greatest increases in bone density at 24 months. INTRODUCTION: Aromatase inhibitors (AIs), adjuvant endocrine therapy for postmenopausal women with hormone-receptor-positive breast cancer, are associated with bone loss and fractures. Our objectives were to determine if (1) oral bisphosphonate therapy can prevent bone loss in women on an AI and (2) early changes in bone turnover markers (BTM) can predict later changes in bone mineral density (BMD). METHODS: We conducted a 2-year double-blind, placebo-controlled, randomized trial in 109 postmenopausal women with low bone mass on an AI (anastrozole, letrozole, or exemestane) for hormone-receptor-positive breast cancer. Participants were randomized to once weekly risedronate 35 mg or placebo, and all received calcium plus vitamin D. The main outcome measures included BMD, BTM [carboxy-terminal collagen crosslinks (CTX) and N-terminal propeptide of type 1 procollagen (P1NP)], and safety. RESULTS: Eighty-seven percent completed 24 months. BMD increased more in the active treatment group compared to placebo with an adjusted difference at 24 months of 3.9 ± 0.7 percentage points at the spine and 3.2 ± 0.5 percentage points at the hip (both p < 0.05). The adjusted difference between the active treatment and placebo groups were 0.09 ± 0.04 nmol/LBCE for CTX and 23.3 ± 4.8 µg/mL for P1NP (both p < 0.05). Women with greater 12-month decreases in CTX and P1NP in the active treatment group had a greater 24-month increase in spinal BMD (p < 0.05). The oral therapy was safe and well tolerated. CONCLUSION: In postmenopausal women with low bone mass and breast cancer on an AI, the oral bisphosphonate risedronate maintained skeletal health.

Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial.

SUMMARY: Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. INTRODUCTION: Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. METHODS: The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score≤-2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score≤-1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. RESULTS: Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. CONCLUSIONS: This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.

The impact of an aromatase inhibitor on body composition and gonadal hormone levels in women with breast cancer.

Aromatase inhibitors (AIs) have become the standard adjuvant therapy of postmenopausal breast cancer survivors. AIs induce a reduction of bioavailable estrogens by inhibiting aromatase, which would be expected to induce alterations in body composition, more extensive than induced by menopause. The objectives are to examine the impact of AIs on (1) DXA-scan derived body composition and (2) gonadal hormone levels. This is a sub-analysis of a 2-year double-blind, placebo-controlled, randomized trial of 82 women with nonmetastatic breast cancer, newly menopausal following chemotherapy, who were randomized to risedronate (35 mg once weekly) versus placebo, and stratified for their usage of AI versus no AI. Outcomes included DXA-scan derived body composition and gonadal hormone levels. As a group, total body mass increased in women over 24 months. Women on AIs gained a significant amount of lean body mass compared to baseline as well as to no-AI users (P < 0.05). Women not on an AI gained total body fat compared to baseline and AI users (P < 0.05). Free testosterone significantly increased and sex hormone binding globulin (SHBG) significantly decreased in women on AIs compared to no AIs at 24 months (P < 0.01) while total estradiol and testosterone levels remained stable. Independent of AI usage, chemotherapy-induced postmenopausal breast cancer patients demonstrated an increase of total body mass. AI users demonstrated maintenance of total body fat, an increase in lean body mass and free testosterone levels, and a decrease in SHBG levels compared to no-AI users. The mechanisms and implications of these changes need to be studied further.

The effect of risedronate on hip structural geometry in chemotherapy-induced postmenopausal women with or without use of aromatase inhibitors: a 2-year trial.

INTRODUCTION: Osteoporosis is a major health problem for postmenopausal women. Adjuvant hormonal therapy with aromatase inhibitors (AIs) in postmenopausal breast cancer patients further worsens bone loss. Bisphosphonates are able to prevent AI-induced bone loss, but limited data exists on their effect on bone structure. Our objectives were to (1) examine the impact of AIs and no-AIs on hip structural geometry (HSA) of chemotherapy-induced postmenopausal women, and (2) determine if oral bisphosphonates could affect these changes. METHODS: This is a sub-analysis of a 2-year double-blind randomized trial of 67 women with nonmetastatic breast cancer, newly postmenopausal following chemotherapy (up to 8 years), who were randomized to risedronate, 35 mg once weekly (RIS) and placebo (PBO). Many women changed their cancer therapy from a no-AI to an AI during the trial. Outcomes were changes in Beck's HSA-derived BMD and structural parameters. RESULTS: Eighteen women did not receive adjuvant hormone therapy, while 41 women received other therapy and 8 received AIs at baseline distributed similarly between RIS and PBO. Women on AIs and PBO were found to have the lowest BMD and indices. RIS improved BMD and several HSA indices at the intertrochanteric site in women regardless of their hormonal therapy, but most improvement was observed in women who were not on AIs (all p< or =0.05 except buckling ratio). Changes at the narrow neck and femoral shaft were similar. CONCLUSION: The use of AIs appears to lead to lower HSA-derived BMD and hip structural indices as compared to women on no or non-AI therapy in chemotherapy-induced postmenopausal breast cancer patients. Preventive therapy with once weekly oral risedronate maintains structural, skeletal integrity independently of the use of or type of adjuvant therapy.

Evaluation of ability of biochemical markers of bone turnover to predict a response to increased doses of HRT.

Antiresorptive therapy is usually given in a fixed dose, and we hypothesized that some patients receiving standard doses of hormone replacement therapy (HRT) might benefit from a higher dose, particularly if their bone turnover decreases after increasing the dose of HRT. Eighty-eight women who had been receiving standard-dose (0.625 mg/day) conjugated equine estrogens (CEE) for at least one year were randomized to take either standard-dose (0.625 mg/day, n = 36) or high-dose (1.25 mg/day, n = 52) therapy. Subjects with a uterus were allowed to take either 10 mg of medroxyprogesterone cyclically or 5 mg daily, according to personal preference. Bone Mineral Density (BMD) and biochemical markers of bone turnover were followed for 2 years. Mean bone turnover decreased significantly (-4.1% to -19.1%) after 6 months of high-dose CEE. Decreases in serum BSAP (bone-specific alkaline phosphatase) and serum or urine NTX ( N-terminal telopeptide crosslink of type I collagen) on high-dose therapy were not predictive of an improvement in BMD, but a decrease in serum CrossLaps did predict an improvement in BMD. Mean change in BMD in subjects with a significant decrease in serum CrossLaps at the anteroposterior spine was 3.1% +/- 3.9% versus 1.2% +/- 2.9% for subjects with no significant change in CrossLaps, P < 0.02. There was, however, a wide range of changes in BMD in patients with or without a significant change in CTX on high-dose HRT, making it impossible to predict an improvement in BMD based on an individual's changes in turnover. Measuring of bone density and bone turnover with better precision might be more successful in guiding individual dosing of antiresorptive therapy.

Alendronate and estrogen effects in postmenopausal women with low bone mineral density. Alendronate/Estrogen Study Group.

The bisphosphonate alendronate and conjugated equine estrogens are both widely used for the treatment of postmenopausal osteoporosis. Acting by different mechanisms, these two agents decrease bone resorption and thereby increase or preserve bone mineral density (BMD). The comparative and combined effects of these medications have not been rigorously studied. This prospective, double blind, placebo-controlled, randomized clinical trial examined the effects of oral alendronate and conjugated estrogen, in combination and separately, on BMD, biochemical markers of bone turnover, safety, and tolerability in 425 hysterectomized postmenopausal women with low bone mass. In addition, bone biopsy with histomorphometry was performed in a subset of subjects. Treatment included placebo, alendronate (10 mg daily), conjugated equine estrogen (CEE; 0.625 mg daily), or alendronate (10 mg daily) plus CEE (0.625 mg daily) for 2 yr. All of the women received a supplement of 500 mg calcium daily. At 2 yr, placebo-treated patients showed a mean 0.6% loss in lumbar spine BMD, compared with mean increases in women receiving alendronate, CEE, and alendronate plus CEE of 6.0% (P < 0.001 vs. placebo), 6.0% (P < 0.001 vs. placebo), and 8.3% (P < 0.001 vs. placebo and CEE; P = 0.022 vs. alendronate), respectively. The corresponding changes in total proximal femur bone mineral density were +4.0%, +3.4%, +4.7%, and +0.3% for the alendronate, estrogen, alendronate plus estrogen, and placebo groups, respectively. Both alendronate and CEE significantly decreased biochemical markers of bone turnover, specifically urinary N-telopeptide of type I collagen and serum bone-specific alkaline phosphatase. The alendronate plus CEE combination produced slightly greater decreases in these markers than either treatment alone, but the mean absolute values remained within the normal premenopausal range. Alendronate, alone or in combination with CEE, was well tolerated. In the subset of patients who underwent bone biopsies, histomorphometry showed normal bone histology with the expected decrease in bone turnover, which was somewhat more pronounced in the combination group. Thus, alendronate and estrogen produced favorable effects on BMD. Combined use of alendronate and estrogen produced somewhat larger increases in BMD than either agent alone and was well tolerated.

Bone mineral densitometry substantially influences health-related behaviors of postmenopausal women.

Although bone mineral density measurements are helpful in predicting future risk for osteoporotic fractures, there is limited information available on how the results of bone densitometry influence a woman's use of therapeutic alternatives. To assess the role of bone mineral densitometry in influencing postmenopausal women to change health behaviors associated with osteoporosis, we prospectively followed, for an average of 2.9 years, 701 postmenopausal women over 50 years of age referred to an osteoporosis prevention program in a large metropolitan area. Assessments included bone mineral densitometry by dual-energy X-ray absorptiometry (with classification of skeletal health), medical history, use of hormone replacement therapy, calcium intake, caffeine intake, exercise, smoking habits, and fall precaution measures. Women classified at baseline with moderate low bone mass were twice as likely (33%), and women with severe low bone mass more than three times as likely (47%) to start hormone replacement therapy compared with women with a normal result (13%, P < 0.001). This was true regardless of whether they had taken hormone replacement therapy in the past. Below-normal BMD was a strong predictor of a woman's initiation of hormone replacement therapy (OR 4.2; 95% CI 2.7-6.4; P < 0.05) even after adjustment for age, education, history of osteoporosis or fracture, and medical condition related to osteoporosis. Women with moderate or severe low bone mass were also much more likely to start calcium supplements (81-90% versus 67%), increase dietary calcium (71-82% versus 60%), decrease use of caffeine (44-60% versus 34%), start exercising (61-76% versus 52%), and quit smoking (22-24% versus 11%) relative to their behaviors prior to testing (P < 0.01). In conclusion, postmenopausal women report that the results of bone densitometry substantially influence the decision to begin hormone replacement therapy and calcium supplements, increase dietary calcium, decrease caffeine, increase exercise, decrease smoking, and take precautions to prevent falls. More studies are needed to measure the long-term effects of this influence.

Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: a randomized clinical trial.

Although the antiresorptive agent alendronate has been shown to increase bone mineral density (BMD) at the hip and spine and decrease the incidence of osteoporotic fractures in older women, few data are available regarding early prediction of long-term response to therapy, particularly with regard to increases in hip BMD. Examining short-term changes in biochemical markers incorporates physiologic response with therapeutic compliance and should provide useful prognostic information for patients. The objective of this study was to examine whether early changes in biochemical markers of bone turnover predict long-term changes in hip BMD in elderly women. The study was a double-blind, placebo-controlled, randomized clinical trial which took place in a community-based academic hospital. One hundred and twenty community-dwelling, ambulatory women 65 years of age and older participated in the study. Intervention consisted of alendronate versus placebo for 2.5 years. All patients received appropriate calcium and vitamin D supplementation. The principal outcome measures included BMD of the hip (total hip, femoral neck, trochanter, and intertrochanter), spine (posteroanterior [PA] and lateral), total body, and radius. Biochemical markers of bone resorption included urinary N-telopeptide cross-linked collagen type I and free deoxypyridinoline; markers of bone formation included serum osteocalcin and bone-specific alkaline phosphatase. Long-term alendronate therapy was associated with increased BMD at the total hip (4.0%), femoral neck (3.1%), trochanter (5.5%), intertrochanter (3.8%), PA spine (7.8%), lateral spine (10.6%), total body (2.2%), and one-third distal radius (1.3%) in elderly women (all p < 0.01). In the placebo group, bone density increased 1.9-2.1% at the spine (p < 0.05) and remained stable at all other sites. At 6 months, there were significant decreases in all markers of bone turnover (-10% to -53%, p < 0.01) in women on alendronate. The changes in urinary cross-linked collagen at 6 months correlated with long-term bone density changes at the hip (r = -0.35, p < 0.01), trochanter (r = -0.36, p < 0.01), PA spine (r = -0.41, p < 0.01), and total body (r = -0.34, p < 0.05). At 6 months, patients with the greatest drop in urinary cross-linked collagen (65% or more) demonstrated the greatest gains in total hip, trochanteric, and vertebral bone density (all p < 0.05). A 30% decrease in urinary cross-linked collagen at 6 months predicted a bone density increase of 2.8-4.1% for the hip regions and 5.8-6.9% for the spine views at the 2.5-year time point (p < 0.05). There were no substantive associations between changes in biochemical markers and bone density in the placebo group. Alendronate therapy was associated with significant long-term gains in BMD at all clinically relevant sites, including the hip, in elderly women. Moreover, these improvements were associated with early decreases in biochemical markers of bone turnover. Early dynamic decreases in urinary cross-linked collagen can be used to monitor and predict long-term response to bisphosphonate therapy in elderly women. Future studies are needed to determine if early assessment improves long-term patient compliance or uncovers poor compliance, thereby aiding the physician in maximizing the benefits of therapy.