AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS-2020 UPDATE.

Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs). Methods: Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. Results: The Executive Summary of this 2020 updated guideline contains 52 recommendations: 21 Grade A (40%), 24 Grade B (46%), 7 Grade C (14%), and no Grade D (0%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 368 citations: 123 (33.5%) evidence level (EL) 1 (highest), 132 (36%) EL 2 (intermediate), 20 (5.5%) EL 3 (weak), and 93 (25%) EL 4 (lowest). New or updated topics in this CPG include: clarification of the diagnosis of osteoporosis, stratification of the patient according to high-risk and very-high-risk features, a new dual-action therapy option, and transitions from therapeutic options. Conclusion: This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of post-menopausal osteoporosis. Abbreviations: 25(OH)D = 25-hydroxyvitamin D; AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; AFF = atypical femoral fracture; ASBMR = American Society for Bone and Mineral Research; BEL = best evidence level; BMD = bone mineral density; BTM = bone turnover marker; CI = confidence interval; CPG = clinical practice guideline; CTX = C-terminal telopeptide type-I collagen; DXA = dual-energy X-ray absorptiometry; EL = evidence level; FDA = U.S. Food and Drug Administration; FRAX® = Fracture Risk Assessment Tool; GI = gastrointestinal; HORIZON = Health Outcomes and Reduced Incidence with Zoledronic acid ONce yearly Pivotal Fracture Trial (zoledronic acid and zoledronate are equivalent terms); ISCD = International Society for Clinical Densitometry; IU = international units; IV = intravenous; LSC = least significant change; NOF = National Osteoporosis Foundation; ONJ = osteonecrosis of the jaw; PINP = serum amino-terminal propeptide of type-I collagen; PTH = parathyroid hormone; R = recommendation; ROI = region of interest; RR = relative risk; SD = standard deviation; TBS = trabecular bone score; VFA = vertebral fracture assessment; WHO = World Health Organization.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS- 2020 UPDATE EXECUTIVE SUMMARY.

Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs). Methods: Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. Results: The Executive Summary of this 2020 updated guideline contains 52 recommendations: 21 Grade A (40%), 24 Grade B (46%), 7 Grade C (14%), and no Grade D (0%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 368 citations: 123 (33.5%) evidence level (EL) 1 (highest), 132 (36%) EL 2 (intermediate), 20 (5.5%) EL 3 (weak), and 93 (25%) EL 4 (lowest). New or updated topics in this CPG include: clarification of the diagnosis of osteoporosis, stratification of the patient according to high-risk and very-high-risk features, a new dual-action therapy option, and transitions from therapeutic options. Conclusion: This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of post-menopausal osteoporosis.

Proceedings of the 2017 Santa Fe Bone Symposium: Insights and Emerging Concepts in the Management of Osteoporosis.

The 18th Annual Santa Fe Bone Symposium was held on August 4-5, 2017, in Santa Fe, New Mexico, USA. The symposium convenes health-care providers and clinical researchers to present and discuss clinical applications of recent advances in research of skeletal diseases. The program includes lectures, oral presentations by endocrinology fellows, case-based panel discussions, and breakout sessions on topics of interest, with emphasis on participation and interaction of all participants. Topics included the evaluation and treatment of adult survivors with pediatric bone diseases, risk assessment and management of atypical femur fractures, nonpharmacologic strategies in the care of osteoporosis, and skeletal effects of parathyroid hormone with opportunities for therapeutic intervention. Management of skeletal complications of rheumatic diseases was discussed. Insights into sequential and combined use of antiresorptive agents were presented. Individualization of patient treatment decisions when clinical practice guidelines may not be applicable was covered. Challenges and opportunities with osteoporosis drug development were discussed. There was an update on progress of Bone Health TeleECHO (Bone Health Extension for Community Healthcare Outcomes), a teleconferencing strategy for sharing knowledge and expanding capacity to deliver best-practice skeletal health care.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS - 2016.

ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists AFF = atypical femur fracture ASBMR = American Society for Bone and Mineral Research BEL = best evidence level BMD = bone mineral density BTM = bone turnover marker CBC = complete blood count CI = confidence interval DXA = dual-energy X-ray absorptiometry EL = evidence level FDA = U.S. Food and Drug Administration FLEX = Fracture Intervention Trial (FIT) Long-term Extension FRAX® = Fracture Risk Assessment Tool GFR = glomerular filtration rate GI = gastrointestinal HORIZON = Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly IOF = International Osteoporosis Foundation ISCD = International Society for Clinical Densitometry IU = international units IV = intravenous LSC = least significant change NBHA = National Bone Health Alliance NOF = National Osteoporosis Foundation 25(OH)D = 25-hydroxy vitamin D ONJ = osteonecrosis of the jaw PINP = serum carboxy-terminal propeptide of type I collagen PTH = parathyroid hormone R = recommendation RANK = receptor activator of nuclear factor kappa-B RANKL = receptor activator of nuclear factor kappa-B ligand RCT = randomized controlled trial RR = relative risk S-CTX = serum C-terminal telopeptide SQ = subcutaneous VFA = vertebral fracture assessment WHO = World Health Organization.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS - 2016--EXECUTIVE SUMMARY.

ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists AFF = atypical femur fracture ASBMR = American Society for Bone and Mineral Research BEL = best evidence level BMD = bone mineral density BTM = bone turnover marker CBC = complete blood count CI = confidence interval DXA = dual-energy X-ray absorptiometry EL = evidence level FDA = U.S. Food and Drug Administration FLEX = Fracture Intervention Trial (FIT) Long-term Extension FRAX(®) = Fracture Risk Assessment Tool GFR = glomerular filtration rate GI = gastrointestinal HORIZON = Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly IOF = International Osteoporosis Foundation ISCD = International Society for Clinical Densitometry IU = international units IV = intravenous LSC = least significant change NBHA = National Bone Health Alliance NOF = National Osteoporosis Foundation 25(OH)D = 25-hydroxy vitamin D ONJ = osteonecrosis of the jaw PINP = serum carboxy-terminal propeptide of type I collagen PTH = parathyroid hormone R = recommendation RANK = receptor activator of nuclear factor kappa-B RANKL = receptor activator of nuclear factor kappa-B ligand RCT = randomized controlled trial RR = relative risk S-CTX = serum C-terminal telopeptide SQ = subcutaneous VFA = vertebral fracture assessment WHO = World Health Organization.

Bone mineral density in patients with alopecia areata treated with long-term intralesional corticosteroids.

BACKGROUND: Intralesional corticosteroid injections are a common treatment for patchy alopecia areata, the most prevalent subtype of this autoimmune hair disorder. To date, no studies have examined the potential adverse effects of this therapy on bone mineral density (BMD). METHODS: In this retrospective, cross-sectional case series, 18 patients with patchy alopecia areata treated at 4- to 8-week intervals with intralesional triamcinolone acetonide for at least 20 months were evaluated for BMD using dual-energy x-ray absorptiometry (DXA). Follow-up DXA measurements were obtained in those with abnormal findings. RESULTS: Nine out of 18 patients (50%) had abnormal DXA results. Patients with the following risk factors were more likely to have abnormal BMD: age older than 50 years, body mass index less than 18.5 kg/m2, lack of weight-bearing exercise, smoking history, postmenopausal status, past stress fracture, family history of osteopenia or osteoporosis, and a cumulative intralesional triamcinolone acetonide dose of greater than 500 mg. CONCLUSION: Patients with patchy alopecia areata who receive chronic intralesional triamcinolone acetonide therapy should be counseled on preventive measures for osteoporosis and monitored for effects on BMD.

The role of osteoanabolic agents in the management of patients with osteoporosis.

Reducing fracture risk is the objective of osteoporosis treatment. Bone-forming osteoporosis drugs increase bone mass, restore bone microarchitecture, and reduce fracture risk more effectively than oral bisphosphonates, providing strong justification for the use of these agents as the initial therapy or after anti-remodeling agents in patients at very high risk of fracture. At the end of a 12-to-24-month course of osteoanabolic therapy, transitioning to a potent anti-remodeling agent maintains and enhances the treatment benefit. This review describes the clinical applications of osteoanabolic therapy for osteoporosis.

History of etidronate.

Etidronate is a non-nitrogen-containing bisphosphonate. Because it binds with calcium and inhibits crystal formation and dissolution, it was considered by Procter & Gamble as an additive to toothpaste (to prevent build-up of tartar) and detergent (to bind calcium and increase sudsing in "hard" water). The first clinical use (1968) was for fibrodysplasia ossificans progressiva. The first approved clinical use (1977) was for treatment of Paget's disease of bone. Other approved indications are hypercalcemia of malignancy and heterotopic ossification, with a host of off-label uses (including fibrous dysplasia, periodontal disease, multiple myeloma, neuropathic arthropathy, pulmonary microlithiasis, diabetic retinopathy, bone metastases, melorheostosis, urinary stone disease, periodontal disease, etc.). Unique among bisphosphonates, etidronate (oral therapy) results in hyperphosphatemia, increased tubular reabsorption of phosphorus and increased levels of 1,25-dihydroxyvitamin D. The dose that reduces bone resorption is close to the dose that impairs mineralization; prolonged high-dose use can result in osteomalacia and bone fractures. Intermittent cyclic etidronate for osteoporosis resulted in favorable changes in bone density and histomorphometry (no mineralization defect) as well as a decrease in vertebral fracture rates in postmenopausal women with osteoporosis. Later studies showed similar effects in men with osteoporosis and patients with glucocorticoid-induced osteoporosis. Although its use for osteoporosis has given way to newer bisphosphonates and other agents, because of its unique properties, it remains the bisphosphonate of choice for treatment of heterotopic ossification.

Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use.

All therapies currently recommended for the management of osteoporosis act mainly to inhibit bone resorption and reduce bone remodeling. PTH and its analog, teriparatide [recombinant human PTH(1-34)], represent a new class of anabolic therapies for the treatment of severe osteoporosis, having the potential to improve skeletal microarchitecture. Significant reductions in both vertebral and appendicular fracture rates have been demonstrated in the phase III trial of teriparatide, involving elderly women with at least one prevalent vertebral fracture before the onset of therapy. However, there is as yet no evidence that the antifracture efficacy of PTH will be superior to the bisphosphonates, whereas cost-utility estimates suggest that teriparatide is significantly more expensive. Teriparatide should be considered as treatment for postmenopausal women and men with severe osteoporosis, as well as for patients with established glucocorticoid-induced osteoporosis who require long-term steroid treatment. Teriparatide should also be considered for the management of individuals at particularly high risk for fractures, including subjects who are younger than age 65 and who have particularly low bone mineral density measurements (T scores < or = 3.5). Teriparatide therapy is not recommended for more than 2 yr, based, in part, on the induction of osteosarcoma in a rat model of carcinogenicity. Total daily calcium intake from both supplements and dietary sources should be limited to 1500 mg together with adequate vitamin D intake (< or =1000 U/d). Monitoring of serum calcium may be safely limited to measurement after 1 month of treatment; mild hypercalcemia may be treated by withdrawing dietary calcium supplements, reducing the dosing frequency of PTH, or both. At present, concurrent therapy with antiresorptive therapy, particularly bisphosphonates, should be avoided, although sequential therapy with such agents may consolidate the beneficial effects upon the skeleton after PTH is discontinued.

Risk of severe gastrointestinal events in women treated with monthly ibandronate or weekly alendronate and risedronate.

BACKGROUND: Bisphosphonate (BP)-related gastrointestinal (GI) adverse events can lead to discontinuation of osteoporosis treatment. Irritation of the GI tract related to BPs may be worsened by more frequent administration. OBJECTIVE: To compare the number of women who experienced severe GI events within 3 months of starting once-monthly oral ibandronate with those starting once-weekly oral BP (alendronate or risedronate). METHODS: In a retrospective database study design, eligible women with a new prescription for monthly ibandronate were propensity-matched to women with a new weekly BP prescription. Patients had continuous health plan enrollment for 6 months prior to the index date and for 3 months after the index date. Women with previous intravenous BP treatment, Paget's disease, or oral BP treatment within the 6-month preindex period were excluded. Severe GI events (including acute events involving perforation or bleeding/perforation) within 3 months of treatment initiation were identified by ICD-9 and Current Procedural Terminology codes. A post hoc analysis assessed treatment discontinuation after severe GI events. GI-related healthcare utilization rates and costs were also compared. RESULTS: Of the 8608 patients per group, 45 (0.52%) who were receiving monthly ibandronate and 70 (0.81%) of those receiving weekly BP treatment experienced a severe GI event. Ibandronate patients had a 36% reduction in the risk of severe GI events compared with weekly BP users (OR 0.64, 95% CI 0.44 to 0.93). Significantly more women receiving a weekly BP discontinued treatment after a severe GI event compared with those receiving ibandronate (100% vs 55.6%; p < 0.001). Most healthcare utilization outcomes were not significantly different between the 2 groups; outpatient visits were significantly higher for ibandronate (p = 0.02). Costs were not significantly different between the 2 groups. CONCLUSIONS: Patients receiving monthly ibandronate therapy had a significantly reduced risk of severe GI events compared with those receiving weekly BP treatment. In addition, patients receiving a weekly BP were more likely to discontinue treatment after a severe GI event.

Western Osteoporosis Alliance Clinical Practice Series: Treat-to-Target for Osteoporosis.

Patients often start treatment to reduce fracture risk because of a bone mineral density T-score consistent with osteoporosis (≤ -2.5). Others with a T-score above -2.5 may be treated when there is a history of fragility fracture or when a fracture risk algorithm categorizes them as having a high risk for fracture. It is common to initiate therapy with a generic oral bisphosphonate, unless contraindicated, and continue therapy if the patient is responding as assessed by stability or an increase in bone mineral density. However, some patients may respond well to an oral bisphosphonate, yet remain with an unacceptably high risk for fracture. Recognition of this occurrence has led to the development of an alternative strategy: treat-to-target. This involves identifying a biological marker (treatment target) that represents an acceptable fracture risk and then initiating treatment with an agent likely to reach this target. If the patient is on a path to reaching the target with initial therapy, treatment is continued. If it appears the target will not be reached with initial therapy, treatment is changed to an agent more likely to achieve the goal.

Progression of efficacy with ibandronate: a paradigm for the development of new bisphosphonates.

While initial preclinical studies provide an important starting point for dose selection, they may not provide adequate information to identify the optimal dosage for an extended treatment regimen. Determining the best dose for use in an extended dosing regimen requires ongoing development, illustrated best with the bisphosphonate, ibandronate. As mandated for regulatory purposes, the daily oral regimen of ibandronate was proven effective in significantly reducing the rate of new vertebral fractures assessed prospectively, and nonvertebral fractures in a high-risk population, assessed retrospectively. Extended dosing regimens, namely monthly and quarterly intravenous formulations, were developed subsequently to improve the convenience and enhance persistence, while maintaining or increasing efficacy. The continuing and progressive evolution of data led to the understanding that extension of drug-free interval requires higher annual cumulative skeletal exposures (ACE), which were not simply numerical multipliers of the interval and daily dose. For ibandronate, this led to dose selection for the oral monthly 150 mg (ACE 10.8 mg) and intravenous quarterly 3 mg (ACE 12 mg) formulations that proved superior in increasing bone mineral density (BMD) compared with oral daily 2.5 mg (ACE 5.5 mg) ibandronate. Pooling data from clinical trials with high ACE regimens (monthly and quarterly) led to the evolution of statistical evidence for a reduction in clinical and nonvertebral fractures with ibandronate. The ibandronate story should serve as an important future paradigm for bisphosphonate development.

Diagnosis and Treatment of Osteoporosis Before and After Fracture: A Side-by-Side Analysis of Commercially Insured and Medicare Advantage Osteoporosis Patients.

BACKGROUND: Although treatment for osteoporosis is recommended by U.S. clinical guidelines, a lack of diagnosis and treatment is common among patients with osteoporotic fractures. OBJECTIVE: To determine the rates of osteoporosis diagnosis and treatment before and after various types of fractures. METHODS: This was a retrospective claims analysis using data from the Humana Medicare Advantage claims (Medicare group) and Optum Insight Clinformatics Data Mart commercial claims (Commercial group). Patients included in the study had a claim for a qualifying fracture occurring between January 2008 and December 2013 (the index fracture), were continuously enrolled in the health plan for ≥ 1 year before and after the index fracture, and were aged ≥ 65 years in the Medicare group or ≥ 50 years in the Commercial group at the time of the index fracture. Fragility fractures and osteoporosis diagnoses were identified from ICD-9-CM codes. Treatment for osteoporosis included oral and injectable therapies identified by National Drug Code numbers and Healthcare Common Procedure Coding System codes. Diagnosis and treatment rates were assessed during the 1-year periods before and after the index fracture. All analyses were conducted by fracture type (vertebral, hip, nonhip/nonvertebral [NHNV], and multiple), with stratification by age and sex. No comparisons were made between the Medicare and Commercial groups; rather, McNemar tests were used to compare prefracture versus postfracture diagnosis and treatment rates within each group. RESULTS: For inclusion in the Medicare group, 45,603 patients were identified, and 54,145 patients were identified for the Commercial group. In the prefracture period, the osteoporosis diagnosis rates ranged from 12.0% (NHNV) to 21.5% (vertebral) in the Medicare group and from 5.3% (NHNV) to 12.1% (vertebral) in the Commercial group. In the postfracture period, diagnosis rates significantly increased (P < 0.001)-and nearly doubled-for all fracture types but did not exceed 42.1% (vertebral) in the Medicare group and 27.7% (vertebral) in the Commercial group. Pre-index treatment rates were similarly low, ranging from 9.4% (hip) to 16.6% (vertebral) among Medicare patients, and 7.5% (NHNV) to 14.4% (vertebral) in Commercial patients. Osteoporosis treatment rates improved significantly in the postfracture year, ranging from 12.5% (NHNV) to 26.5% (vertebral) among Medicare patients, and 8.3% (NHNV) to 21.4% (vertebral) in Commercial patients. Larger increases in diagnosis rates and smaller increases in treatment rates were observed in stratified analyses of men and women and of different age groups, with women and older patients having higher overall rates of diagnosis and treatment before and after fracture. CONCLUSIONS: In men and women, osteoporosis diagnosis rates were low before the index fracture and improved substantially after the fracture, yet still remained low overall (under 50%). Osteoporosis treatment rates among patients experiencing a fracture were low before the index fracture and improved only minimally afterwards. DISCLOSURES: This study was funded by Merck & Co. Other than through the employer relationship disclosed here, Merck & Co. did not have a role in the study design, data collection, interpretation of the data, in writing of the manuscript, or in the decision to submit the manuscript for publication. Weaver is an employee of Merck & Co. Sajjan was an employee of Merck & Co. and owned stock in the company at the time of the study. Lewiecki has received consulting and/or speaker honoraria from Merck & Co., AbbVie, AgNovos Healthcare, Alexion Pharmaceuticals, Amgen, Eli Lilly and Company, Radius Health, Shire, and TheraNova, along with research grant support from Merck & Co., Amgen, and Eli Lilly and Company, and serves as a board member for the National Osteoporosis Foundation, the International Society for Clinical Densitometry, and the Osteoporosis Foundation of New Mexico. Harris has received consulting honoraria from Merck & Co., Alexion Pharmaceuticals, Amgen, Eli Lilly and Company, Gilead Sciences, Primus Pharmaceuticals, and Radius Health. Study concept and design were contributed by Weaver and Sajjan. Sajjan collected the data, and data interpretation was performed by all the authors. The manuscript was written and revised by Weaver, Lewiecki, and Harris.

Prevalence and Cost of Subsequent Fractures Among U.S. Patients with an Incident Fracture.

BACKGROUND: The prevalence and cost of subsequent fractures among patients with an incident fracture are not well defined. OBJECTIVE: To assess the prevalence of, and costs associated with, subsequent fractures in the year after an incident fracture. METHODS: This was a retrospective claims database analysis using data from Humana Medicare Advantage claims (Medicare group) and Optum Insight Clinformatics Data Mart commercial claims (commercial group). Patients included in the study had a claim for a qualifying fracture occurring between January 2008 and December 2013 (index fracture), were continuously enrolled in the health plan for ≥ 1 year before and after the index fracture, and were aged ≥ 65 years in the Medicare group or ≥ 50 years in the commercial group at the time of the index fracture. Subsequent fractures were identified by ICD-9-CM codes and were defined as the second fracture occurring ≥ 3 to ≤ 12 months after the index fracture (≥ 6 to ≤ 12 months for fractures at the same site as the index fracture). Rates of subsequent fractures were calculated as the number of patients who had a subsequent fracture divided by the total sample size. After propensity matching of demographic and clinical variables, we determined the total medical and pharmacy costs accrued within 1 year of the index fracture by patients with and without a subsequent fracture. Health care costs were compared between patients with and without a subsequent fracture using McNemar's test. RESULTS: A total of 45,603 patients were included in the Medicare group, and 54,145 patients were included in the commercial group. In the Medicare group, 7,604 (16.7%) patients experienced a subsequent fracture. The proportion of patients with a subsequent fracture was highest among patients with multiple index fractures (26.2%, n = 905), followed by those with hip (25.5%, n = 1,280) and vertebral (20.2%, n = 1,908) index fractures. In the commercial group, 6,256 (11.6%) patients experienced a subsequent fracture. The proportion of patients with a subsequent fracture paralleled those observed in the Medicare group: 24.5% (n = 808) in patients with multiple index fractures, 22.0% (n = 525) in those with hip fracture, and 14.5% (n = 841) in those with vertebral fracture. For vertebral, hip, and nonhip nonvertebral fractures, subsequent fractures were most frequently of the same type as the index fracture. The mean total health care cost (sum of medical and pharmacy costs) in the year following the incident fracture for the Medicare group was $27,844 and differed significantly between patients with and without a subsequent fracture ($34,897 vs. $20,790; P < 0.001). The mean total health care cost in the year following the incident fracture for the commercial group was $29,316 and also differed significantly between patients with and without a subsequent fracture ($39,501 vs. $19,131; P < 0.001). CONCLUSIONS: Among patients with an incident fracture, those who experienced a subsequent fracture in the following year had significantly higher health care costs than those who did not. A subsequent fracture is most likely to be of the same type as the initial fracture. DISCLOSURES: This study was funded by Merck & Co. Other than through the employer relationships disclosed here, Merck & Co did not have a role in the study design, data collection, interpretation of the data, in writing of the manuscript, or in the decision to submit the manuscript for publication. Weaver and Marvos are employees of Merck & Co. Sajjan was an employee of Merck & Co. and owned stock in the company at the time of the study. Lewiecki has received consulting and/or speaker honoraria from Merck, AbbVie, AgNovos Healthcare, Alexion Pharmaceuticals, Amgen, Eli Lilly and Company, Radius Health, Shire, and TheraNova. Lewiecki has received research grant support from Merck, Amgen, and Eli Lilly and Company and serves as a board member for the National Osteoporosis Foundation, the International Society for Clinical Densitometry, and the Osteoporosis Foundation of New Mexico. Harris has received consulting honoraria from Merck, Alexion Pharmaceuticals, Amgen, Eli Lilly and Company, Gilead Sciences, Primus Pharmaceuticals, and Radius Health. Study concept and design were contributed by Weave and Sajjan. Lewiecki collected the data, and data interpretation was performed by all the authors. The manuscript was written and revised by Weaver, Lewiecki, and Harris.

Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases.

OBJECTIVE: To characterize the relationships between adherence (complance and persistence) to bisphosphonate therapy and risk of specific fracture types in postmenopausal women. PATIENTS AND METHODS: Data were collected from 45 employers and 100 health plans in the continental United States from 2 claims databases during a 5-year period (January 1, 1999, through December 31, 2003). Claims from patients receiving a bisphosphonate prescription (alendronate or risedronate) were evaluated for 6 months before the Index prescription and during 24 months of follow-up to determine total, vertebral, and nonvertebral osteoporotic fractures, persistence (no gap in refills for >30 days during 24 months), and refill compliance (medication possession ratio > or = 0.80). RESULTS: The eligible cohort included 35,537 women (age, > or = 45 years) who received a bisphosphonate prescription. A subgroup with a specified diagnosis of postmenopausal osteoporosis was also evaluated. Forty-three percent were refill compliant, and 20% persisted with bisphosphonate therapy during the 24-month study period. Total, vertebral, nonvertebral, and hip fractures were significantly lower in refill-compliant and persistent patients, with relative risk reductions of 20% to 45%. The relationship between adherence and fracture risk remained significant after adjustment for baseline age, concomitant medications, and fracture history. There was a progressive relationship between refill compliance and fracture risk reduction, commencing at refill compliance rates of approximately 50% and becoming more pronounced at compliance rates of 75% and higher. CONCLUSIONS: Adherence to bisphosphonate therapy was associated with significantly fewer fractures at 24 months. Increasing refill compliance levels were associated with progressively lower fracture rates. These findings suggest that incremental changes in medication-taking habits could improve clinical outcomes of osteoporosis treatment.

Relationship Between Gastrointestinal Events and Compliance With Osteoporosis Therapy: An Administrative Claims Analysis of the US Managed Care Population.

PURPOSE: A large proportion of women with osteoporosis do not comply with current osteoporosis therapies, resulting in diminished therapeutic effect. Noncompliance may be due to the occurrence of gastrointestinal (GI) events during the course of therapy. The objective of this study was to estimate the rate of GI events among women taking oral bisphosphonates and to determine the association between GI events and compliance with bisphosphonate therapy. METHODS: This was a retrospective analysis of data from a US Medicare claims database (HUMANA). The study period was from January 2007 to June 2013. The index date was the date of the first oral bisphosphonate prescription (alendronate, ibandronate, or risedronate) occurring between January 2008 and June 2012. The pre- and postindex periods were the 1-year periods before and after the index date, respectively. The analysis included women 65 years of age and older who were naïve to all osteoporosis treatments before the index date. GI events included nausea/vomiting; dysphagia; esophagitis; esophageal reflux; esophageal, gastric, duodenal, and peptic ulcer; stricture, perforation, or hemorrhage of the esophagus; acute gastritis; and GI hemorrhage. GI events were assessed during the preindex period and at 3, 6, and 12 months in the postindex period. Compliance was defined as a medication possession ratio of ≥80%. The medication possession ratio was calculated as the total days׳ supply of bisphosphonate in the postindex period divided by 365 days. The association of postindex GI events with compliance was assessed using multivariate logistic regression. FINDINGS: The analysis included 37,886 women initiating oral bisphosphonate therapy. In the preindex year, 37.5% of the women experienced a GI event, and in the postindex year, 38.9% had a GI event. Patients with preindex GI events had numerically higher rates of postindex GI events than patients without preindex GI events (61.8% vs 25.1% at 12 months postindex). Patients who experienced postindex GI events were less likely to be compliant with bisphosphonate therapy, with odds of compliance of 0.76 (95% CI, 0.72-0.80) after 12 months. IMPLICATIONS: Among US women who were prescribed oral bisphosphonates, on-treatment GI events were associated with decreased compliance at 1 year.

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

UNLABELLED: 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.

Ibandronate produces significant, similar antifracture efficacy in North American and European women: new clinical findings from BONE.

OBJECTIVES: BONE (oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) determined whether less frequent dosing of ibandronate (dose-free interval > 2 months) provided similar antifracture efficacy to daily dosing. As osteoporosis medications must be effective across different populations, an additional objective of BONE was to investigate and report the effect of oral ibandronate in North American and European women, as described here. PATIENTS AND METHODS: BONE was a randomized, double-blind, placebo-controlled, fractureprevention study in 2946 postmenopausal women (age 55 years-80 years; > or = 5 years since menopause) with osteoporosis (low lumbar spine bone mineral density and one to four prevalent vertebral fractures [T4-L4]). Participants received daily calcium (500 mg) and vitamin D (400 IU) plus either placebo, oral daily ibandronate (2.5 mg) or oral intermittent ibandronate (20 mg every other day for 12 doses every 3 months). The efficacy and tolerability of ibandronate were assessed independently in both North American and European populations. RESULTS: Consistent, significant efficacy was observed in the North American (new vertebral fracture risk reduction: 60% and 54% with daily and intermittent ibandronate, respectively) and European patient populations (50% and 48%, respectively). Both ibandronate regimens also significantly reduced the incidence of new, worsening, and acute clinical, vertebral fractures. Daily and intermittent ibandronate significantly increased bone density at the spine in both North American (5.4% and 4.4% vs. baseline with daily and intermittent ibandronate, respectively) and European (7.1% and 6.3% vs. baseline, respectively) populations. Significant increases were also observed for total hip bone density (2.6% and 3.7% vs. baseline for daily, and 2.5% and 3.1% for intermittent; North American and European populations, respectively). Comparable, significant decreases in biochemical markers of bone turnover (reductions in urinary excretion of C-telopeptide levels of 53.5% and 67.1% vs. baseline for daily, and 50.0% and 53.8% for intermittent; North American and European populations, respectively) were also observed in both populations (p < 0.004 for all cited measurements in each ibandronate group vs. placebo). Oral ibandronate was well tolerated in both North American and European patients, with a safety profile similar to placebo. CONCLUSIONS: Oral ibandronate, administered daily or intermittently, effectively reduced vertebral fracture risk in North American and European women with postmenopausal osteoporosis. These results demonstrate the efficacy of ibandronate administered with extended dose-free intervals, regardless of patients' geographical origin. Research investigating other less frequent ibandronate regimens, such as once-monthly oral administration, is underway.

Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial.

The Multiple Outcomes of Raloxifene Evaluation trial studied 7705 postmenopausal women with osteoporosis randomized to placebo, or raloxifene 60 or 120 mg/d [JAMA 282(1999): 637]. This report assesses the efficacy of raloxifene on the long-term cumulative incidence new vertebral fractures through 4 yr. New vertebral fractures was assessed from radiographs taken at baseline, yr 2-4. The primary analysis was the cumulative incidence of new vertebral fractures through 4 yr. A posthoc analysis compared the vertebral fracture risk in yr 4 alone with that observed in the first 3 yr. The 4-yr cumulative relative risks (RR) for one or more new vertebral fractures were 0.64 [95% confidence interval (CI) 0.53, 0.76] with raloxifene 60 mg/d and 0.57 (95% CI 0.48, 0.69) with raloxifene 120 mg/d. In yr 4 alone, raloxifene 60 mg/d reduced the new vertebral fracture risk by 39% [RR 0.61 (95% CI 0.43, 0.88)], which was not found to be significantly different from the RR observed in the first 3 yr in both raloxifene groups, irrespective of prevalent fracture status. The nonvertebral fracture risk was not significantly reduced [RR 0.93 (95% CI 0.81, 1.06)]. The safety profile after 4 yr was similar to that observed after 3 yr. Raloxifene 60 and 120 mg/d through 4 yr decreased the cumulative risk of new vertebral fractures in postmenopausal women with osteoporosis. The decreased vertebral fracture risk in yr 4 alone was not different from that observed in the first 3 yr.

Classification algorithms for hip fracture prediction based on recursive partitioning methods.

This article presents 2 modifications to the classification and regression tree. The authors improved the robustness of a split in the test sample approach and developed a cost-saving classification algorithm by selecting noninferior to the optimum splits from variables with lower cost or being used in parent splits. The new algorithm was illustrated by 43 predictive variables for 5-year hip fracture previously documented in the Study of Osteoporotic Fractures. The authors generated the robust optimum classification rule without consideration of classification variable costs and then generated an alternative cost-saving rule with equivalent diagnostic utility. A 6-fold cross-validation study proved that the cost-saving alternative classification is statistically noninferior to the optimal one. Their modified classification and regression tree algorithm can be useful in clinical applications. A dual X-ray absorptiometry hip scan and information from clinical examinations can identify subjects with elevated 5-year hip fracture risk without loss of efficiency to more costly and complicated algorithms.