Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women : Postintervention Follow-up of a Randomized Clinical Trial.

BACKGROUND: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited. OBJECTIVE: To evaluate long-term health outcomes among postmenopausal women in the Women's Health Initiative CaD trial. DESIGN: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611). SETTING: A multicenter (n = 40) trial across the United States. PARTICIPANTS: 36 282 postmenopausal women with no history of breast or colorectal cancer. INTERVENTION: Random 1:1 assignment to 1000 mg of calcium carbonate (400 mg of elemental calcium) with 400 IU of vitamin D3 daily or placebo. MEASUREMENTS: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use. RESULTS: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality. LIMITATION: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled. CONCLUSION: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.

Potential endpoints for assessment of bone health in persons with neurofibromatosis type 1.

Neurofibromatosis type 1 is a genetic syndrome characterized by a wide variety of tumor and non-tumor manifestations. Bone-related issues, such as scoliosis, tibial dysplasia, and low bone mineral density, are a significant source of morbidity for this population with limited treatment options. Some of the challenges to developing such treatments include the lack of consensus regarding the optimal methods to assess bone health in neurofibromatosis type 1 and limited data regarding the natural history of these manifestations. In this review, the Functional Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration: (1) presents the available techniques for measuring overall bone health and metabolism in persons with neurofibromatosis type 1, (2) reviews data for use of each of these measures in the neurofibromatosis type 1 population, and (3) describes the strengths and limitations for each method as they might be used in clinical trials targeting neurofibromatosis type 1 bone manifestations. The Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration supports the development of a prospective, longitudinal natural history study focusing on the bone-related manifestations and relevant biomarkers of neurofibromatosis type 1. In addition, we suggest that the neurofibromatosis type 1 research community consider adding the less burdensome measurements of bone health as exploratory endpoints in ongoing or planned clinical trials for other neurofibromatosis type 1 manifestations to expand knowledge in the field.

Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials.

BACKGROUND: Uterine fibroids are common non-cancerous neoplasm that cause heavy menstrual bleeding and other signs. Linzagolix is an oral gonadotropin-releasing hormone receptor antagonist taken once per day that dose-dependently suppresses gonadal steroids and might reduce uterine-fibroid-associated signs. Two phase 3 trials were conducted to confirm the efficacy and safety of linzagolix at full-suppression (200 mg) and partial-suppression (100 mg) doses with or without hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate) compared with placebo for the treatment of symptomatic uterine fibroids. METHODS: PRIMROSE 1 and PRIMROSE 2 were identical 52-week, randomised, parallel, double-blind, placebo-controlled, phase 3 trials conducted at clinics in the USA (PRIMROSE 1) and Europe and the USA (PRIMROSE 2). Eligible women with uterine fibroid-associated heavy menstrual bleeding (menstrual blood loss >80 mL per cycle) were randomly assigned in a 1:1:1:1:1 ratio to one of five masked treatments: (1) placebo, (2) 100 mg linzagolix per day alone, (3) 100 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate), (4) 200 mg linzagolix per day alone, or (5) 200 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate). The primary endpoint was a response (menstrual blood loss ≤80 mL and ≥50% reduction from baseline) at 24 weeks in women who received at least one dose of treatment and did not meet any exclusion criteria based on predosing assessments. These trials are registered with ClinicalTrials.gov (NCT03070899 and NCT03070951). The trials have been completed. FINDINGS: Between May, 2017, and October, 2020, in PRIMROSE 1, 574 women were enrolled, of which 48 discontinued and 15 were excluded; therefore, 511 women were included in the full analysis set; and in PRIMROSE 2, 535 women were enrolled, of which 24 did not receive the study drug and ten women were excluded from the study, resulting in 501 women being included in the full analysis set. In both trials, a significantly higher proportion of women had a reduction in heavy menstrual bleeding in all linzagolix (with or without add-back therapy) treatment groups compared with the placebo group (p≤0·003). In PRIMROSE 1, the response rates were 56·4% (95% CI 45·8-66·6%) in the 100 mg group, 66·4% (56·6-75·2%) in the 100 mg plus add-back therapy group, 71·4% (61·8-79·8%) in the 200 mg group, and 75·5% (66·0-83·5%) in the 200 mg plus add-back therapy group, compared with 35·0% (25·8-45·0%) in the placebo group. In PRIMROSE 2, the response rates were 56·7% (46·3-66·7%) in the 100 mg group, 77·2% (67·8-85·0%) in the 100 mg plus add-back therapy group, 77·7% (68·4-85·3%) in the 200 mg group, and 93·9% (87·1-97·7%) in the 200 mg plus add-back therapy group, compared with 29·4% (20·8-39·3%) with placebo. The most common adverse events up to 24 weeks were hot flushes (35% of participants in PRIMROSE 1 and 32% in PRIMROSE 2 with linzagolix [200 mg] alone and 3-14% in all other groups). INTERPRETATION: Linzagolix (100 mg or 200 mg) with or without add-back therapy significantly reduced heavy menstrual bleeding. Partial suppression with once-per-day linzagolix (100 mg) without add-back therapy potentially provides a unique option for the chronic treatment of symptomatic uterine fibroids in women who cannot or do not want to take concomitant hormonal add-back therapy. FUNDING: ObsEva.

Elagolix for Heavy Menstrual Bleeding in Women with Uterine Fibroids.

BACKGROUND: Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding. METHODS: We conducted two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to evaluate the efficacy and safety of elagolix at a dose of 300 mg twice daily with hormonal "add-back" therapy (to replace reduced levels of endogenous hormones; in this case, estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) in women with fibroid-associated bleeding. An elagolix-alone group was included to assess the impact of add-back therapy on the hypoestrogenic effects of elagolix. The primary end point was menstrual blood loss of less than 80 ml during the final month of treatment and at least a 50% reduction in menstrual blood loss from baseline to the final month; missing data were imputed with the use of multiple imputation. RESULTS: A total of 412 women in UF-1 and 378 women in UF-2 underwent randomization, received elagolix or placebo, and were included in the analyses. Criteria for the primary end point were met in 68.5% of 206 women in UF-1 and in 76.5% of 189 women in UF-2 who received elagolix plus add-back therapy, as compared with 8.7% of 102 women and 10% of 94 women, respectively, who received placebo (P<0.001 for both trials). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2. Hot flushes (in both trials) and metrorrhagia (in UF-1) occurred significantly more commonly with elagolix plus add-back therapy than with placebo. Hypoestrogenic effects of elagolix, especially decreases in bone mineral density, were attenuated with add-back therapy. CONCLUSIONS: Elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. (Funded by AbbVie; Elaris UF-1 and Elaris UF-2 ClinicalTrials.gov numbers, NCT02654054 and NCT02691494.).

Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist.

BACKGROUND: Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies. METHODS: We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix - 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) - as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary. RESULTS: A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P=0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings. CONCLUSIONS: Both higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects. (Funded by AbbVie; Elaris EM-I and EM-II ClinicalTrials.gov numbers, NCT01620528 and NCT01931670 .).

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 2019 Santa Fe Bone Symposium: New Concepts in the Care of Osteoporosis and Rare Bone Diseases.

The 20th annual Santa Fe Bone Symposium was held August 9-10, 2019, in Santa Fe, New Mexico, USA. This is an annual meeting devoted to clinical applications of recent advances in skeletal research that impact the care of patients with osteoporosis, metabolic bone diseases, and inherited bone diseases. Participants included practicing and academic physicians, fellows, advanced practice providers, fracture liaison service (FLS) coordinators, clinical researchers, and bone density technologists. The symposium consisted of lectures, case presentations, and panel discussions, with an emphasis on learning through interaction of all attendees. Topics included new approaches in the use of anabolic agents for the treatment osteoporosis, a review of important events in skeletal health over the past year, new and emerging treatments for rare bone diseases, the use of genetic testing for bone diseases in clinical practice, medication-associated causes of osteoporosis, new concepts in the use of estrogen therapy for osteoporosis, new Official Positions of the International Society for Clinical Densitometry, skeletal consequences of bariatric surgery, and update on the progress and potential of Bone Health TeleECHO, a virtual community of practice using videoconferencing technology to link healthcare professionals for advancing the care of osteoporosis worldwide. Sessions on rare bone diseases were developed in collaboration with the Rare Bone Disease Alliance. Symposium premeetings included an FLS workshop by the National Osteoporosis Foundation and others devoted to the use of new therapeutic agents for the care of osteoporosis and related disorders.

Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program.

AIMS/HYPOTHESIS: An increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of these analyses was to identify reasons for the possibly different effects on fracture observed between CANVAS and CANVAS-R. METHODS: This study was an analysis of two highly similar trials, CANVAS and CANVAS-R, conducted in 10,142 individuals with type 2 diabetes and history or high risk of cardiovascular disease who received canagliflozin (pooled 100/300 mg once daily) or placebo. Outcomes assessed in this analysis were effects on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time. RESULTS: A total of 496 participants recorded ≥1 fracture event during follow-up (15.40 vs 11.93 per 1000 patient-years with canagliflozin vs placebo; HR 1.26 [95% CI 1.04, 1.52]). There was significant heterogeneity in the effects on fracture (p = 0.005) between CANVAS (n = 4330: HR 1.55 [95% CI 1.21, 1.97]) and CANVAS-R (n = 5812: HR 0.86 [95% CI 0.62, 1.19]). The between-study heterogeneity in fracture risk was not clearly explained by differences in baseline characteristics, interactions of randomised treatment with participant characteristics, dose effects, duration of follow-up, metabolic effects, adverse events related to falls or adverse events possibly causing falls. CONCLUSIONS/INTERPRETATION: There was no evidence to explain clearly the fracture risk observed in the CANVAS Program or the heterogeneity in fracture risk between the two studies. The recently reported null result for fracture in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggests that the observed association in CANVAS is likely to be a chance finding, although an unidentified fall-related mechanism remains a possibility. TRIAL REGISTRATION: ClinicalTrials.gov NCT01032629, NCT01989754.

ACUTE PHASE REACTIONS AFTER ZOLEDRONIC ACID INFUSION: PROTECTIVE ROLE OF 25-HYDROXYVITAMIN D AND PREVIOUS ORAL BISPHOSPHONATE THERAPY.

OBJECTIVE: The most common adverse reaction to zoledronic acid (ZOL) infusion is the acute phase reaction (APR), characterized by transient, usually mild, flu-like symptoms. Previous treatment with oral amino-bisphosphonates (BPs) was reported as an independent protective factor for APR, and an association between APR and 25-hydroxyvitamin D (25(OH)D) levels in BP-naïve patients treated with ZOL was identified. The aims of our study were to confirm this association and to see if it was different in patients previously treated with oral BPs compared with BP-naïve patients and to investigate the role of 25(OH)D for the time of APR onset. METHODS: We included 153 consecutive patients with postmenopausal osteoporosis undergoing their first ZOL infusion. Sixty-eight had been previously treated with oral BPs. Clinical, demographic, and serologic data were recorded. RESULTS: 25(OH)D levels were significantly lower in patients experiencing APR compared to patients without APR (26.3 ± 12.7 vs. 37.0 ± 13.5 ng/mL, respectively; P<.0001). Patients with 25(OH)D <30 ng/mL had a significantly higher risk of APR (odds ratio [OR] 4.2 [95% confidence interval [CI] 2.1-8.2]) occurring in 65%. APR was significantly less frequent in patients previously treated with oral BPs than in BP-naïve subjects (33.8% [23/68] vs 52.9% [45/85], P = .018), but only a weak association remained after correction for 25(OH)D (OR 0.5, 95% CI 0.3-1.1, P = .08). CONCLUSION: Higher baseline 25(OH)D levels appear to be protective for APR post-ZOL infusion. The role of previous treatment with oral BPs as an independent protective factor for APR should be evaluated in a larger cohort. ABBREVIATIONS: APR = acute phase reaction; BPs = amino-bisphosphonates; CI = confidence interval; 25(OH)D = 25-hydroxyvitamin D; OP = osteoporosis; OR = odds ratio; PTH = parathyroid hormone; ROC = receiver operating characteristic; ZOL = zoledronic acid.

Case-Based Review of Osteonecrosis of the Jaw (ONJ) and Application of the International Recommendations for Management From the International Task Force on ONJ.

Osteonecrosis of the jaw (ONJ) has been associated with antiresorptive therapy in both oncology and osteoporosis patients. This debilitating condition is very rare and advances in diagnosis and management may now effectively reduce the risk of its development and offer valuable treatment options for affected patients. This paper provides a case-based review of ONJ and application of the International Task Force on ONJ (referred to as the "Task Force") recommendations for the diagnosis and management of ONJ. The Task Force was supported by 14 international societies and achieved consensus from representatives of these multidisciplinary societies on key issues pertaining to the diagnosis and management of ONJ. The frequency of ONJ in oncology patients receiving oncology doses of bisphosphonate (BP) or denosumab is estimated at 1%-15%, and the frequency in the osteoporosis patient population receiving much lower doses of BP or denosumab is estimated at 0.001%-0.01%. Although the diagnosis of ONJ is primarily clinical, imaging may be helpful in confirming the diagnosis and staging. In those with multiple risk factors for ONJ for whom major invasive oral surgery is being planned, interruption of BP or denosumab therapy (in cancer patients) is advised, if possible, before surgery, until the surgical site heals. Major oral surgery in this context could include multiple extractions if surgical extractions are required, not simple forceps extractions. ONJ development may be reduced by optimizing oral hygiene and postoperatively using topical and systemic antibiotics as appropriate. Periodontal disease should be managed before starting oncology doses of BP or denosumab. Local debridement may be successful in disease unresponsive to conservative therapy. Successful surgical intervention has been reported in those with stage 3 disease; less severe disease is best managed conservatively. Teriparatide may be helpful in healing ONJ lesions and may be considered in osteoporosis patients at a high fracture risk in the absence of contraindications. Resumption of BP or denosumab therapy following healing of ONJ lesions is recommended, and there have not been reports of subsequent local recurrence.

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.

Combined Measures of Dynamic Bone Quality and Postural Balance--A Fracture Risk Assessment Approach in Osteoporosis.

We evaluated functional measures of neuromuscular integrity and bone's resistance to fracture as a combined tool in discriminating osteoporosis patients with and without fractures. Functional aspects of neuromuscular integrity were quantified with a noninvasive measure of static and dynamic functional postural stability (FPS), and fracture resistance was obtained with bone shock absorption in patients with osteoporosis aged 65-85 and compared our measures with dual-energy X-ray absorptiometry and Fracture Risk Assessment Tool (FRAX [World Health Organization Collaborating Center for Metabolic Bone Diseases, Sheffield, UK]) in women with osteoporosis, some with and some without vertebral fractures. Patients with vertebral fracture showed larger static FPS (postural sway excursion) in the mediolateral and anterior-posterior directions, suggesting poorer balance. Most of the variables of dynamic FPS showed significant differences between fracture and no-fracture groups (e.g., the fracture group took significantly longer during turning, implying poorer dynamic balance control). Also, compared with healthy control subjects, all 4 dynamic FPS responses for osteoporosis patients with and without fracture were significantly poorer, suggesting potential risk for falls. In summary, patients with osteoporosis who have vertebral fractures (compared with patients with similarly low bone mineral density and other nonfracture risk fractures) have not only lower bone shock absorption damping (ζ) but also increased postural imbalance.

Obesity, health-care utilization, and health-related quality of life after fracture in postmenopausal women: Global Longitudinal Study of Osteoporosis in Women (GLOW).

Fractures may be associated with higher morbidity in obese postmenopausal women than in nonobese women. We compared health-care utilization, functional status, and health-related quality of life (HRQL) in obese, nonobese, and underweight women with fractures. Information from the GLOW study, started in 2006, was collected at baseline and at 1, 2, and 3 years. In this subanalysis, self-reported incident clinical fractures, health-care utilization, HRQL, and functional status were recorded and examined. Women in GLOW (n = 60,393) were aged ≥55 years, from 723 physician practices at 17 sites in 10 countries. Complete data for fracture and body mass index were available for 90 underweight, 3,270 nonobese, and 941 obese women with one or more incident clinical fractures during the 3-year follow-up. The median hospital length of stay, adjusted for age, comorbidities, and fracture type, was significantly greater in obese than nonobese women (6 vs. 5 days, p = 0.017). Physical function and vitality score were significantly worse in obese than in nonobese women, both before and after fracture; but changes after fracture were similar across groups. Use of antiosteoporosis medication was significantly lower in obese than in nonobese or underweight women. In conclusion, obese women with fracture undergo a longer period of hospitalization for treatment and have poorer functional status and HRQL than nonobese women. Whether these differences translate into higher economic costs and adverse effects on longer-term outcomes remains to be established.

Low Testosterone Levels are Frequent in Patients with Acute Respiratory Failure and are Associated with Poor Outcomes.

OBJECTIVE: Low testosterone level is a common finding in critically ill patients with trauma, shock, and sepsis. However, its prevalence and outcomes in patients with primary acute respiratory failure is unknown; low testosterone could contribute to respiratory muscle weakness and further compromise ventilation in these patients. METHODS: We aimed to determine the prevalence, severity, and effects of hypotestosteronemia in patients with acute respiratory failure in a 16-bed single academic center medical intensive care unit (ICU). We studied 30 men who required mechanical ventilation for ≥24 hours for a primary diagnosis of acute respiratory failure. Blood samples were drawn on ICU day 1 and day 3 to measure serum levels of total and free testosterone. RESULTS: Hypotestosteronemia (level below the lower reference limit) was present on day 1 in 93.1% (total testosterone) and 76.7% (free testosterone) of patients and on day 3 in 94.4% (total testosterone) and 100% (free testosterone) of patients. Sex hormone-binding globulin, dehydroepiandrosterone sulfate, follicle-stimulating hormone, luteinizing hormone, and thyroid function levels were all within stated reference ranges. Total and free testosterone levels correlated inversely with ventilator days and ICU length of stay. CONCLUSION: Hypotestosteronemia is common in mechanically ventilated patients with primary acute respiratory failure and may contribute to longer ICU stay. Further studies are needed to determine the effect of testosterone replacement on short- and long-term outcomes in these patients.

Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBDs): What the Endocrinologist Needs to Know.

OBJECTIVE: Chronic kidney disease-mineral and bone disorders (CKD-MBDs) are a spectrum of abnormalities involving skeletal hormones, minerals, and bone turnover and mineralization. This paper focuses on what the endocrinologist should know about the assessment and management of skeletal and metabolic disorders in CKD-MBDs. METHODS: Relevant literature was reviewed to (1) define disturbances of minerals and hormones in the course of CKD; (2) identify the variable radiographic and histomorphometric changes of CKD-MBDs; (3) review the association among CKD-MBDs, vascular calcification, cardiovascular disease (CVD), and mortality; and (4) clarify issues in CKD-MBDs therapy. RESULTS: Assessment and treatment of CKD-MBDs is complicated by progressive changes in bone minerals and skeletal regulatory hormones as kidney function declines. CKD-MBDs are associated with fracture risk, and studies demonstrate that bone mineral density can be used to assess bone loss and fracture risk in these patients. Treatment of CKD-MBDs continues to evolve. Use of calcium, phosphate binders, vitamin D, vitamin D-receptor analogs, and drugs for osteoporosis and CKD-MBDs treatment are discussed in the context of safety and efficacy for patients with CKD. CONCLUSION: The association of CKD with bone disease, vascular calcification, CVD, and mortality mandates earlier recognition and treatment of CKD-MBDs. Osteoporosis as a distinct entity can be diagnosed and managed in CKD, although assessment of osteoporosis becomes challenging in late (stage 4 to 5) CKD. Diabetes is common in early (stage 1 to 3) CKD. In addition, 96% of all individuals identified as having CKD have early CKD. The endocrinologist is uniquely positioned to address and treat both diabetes and many of the metabolic and skeletal disorders associated with early CKD-MBDs, including osteoporosis.

An increased rate of falling leads to a rise in fracture risk in postmenopausal women with self-reported osteoarthritis: a prospective multinational cohort study (GLOW).

OBJECTIVES: Patients with osteoarthritis have increased bone mass but no decrease in fractures. The association between self-reported osteoarthritis and incident falls and fractures was studied in postmenopausal women. METHODS: The Global Longitudinal Study of Osteoporosis in Women is a prospective multinational cohort of 60,393 non-institutionalised women aged ≥55 years who had visited primary care practices within the previous 2 years. Questionnaires were mailed at yearly intervals. Patients were classified as having osteoarthritis if they answered yes to the question, 'Has a doctor or other health provider ever said that you had osteoarthritis or degenerative joint disease?', and this was validated against primary care records in a subsample. Information on incident falls, fractures and covariates was self-reported. Cox and Poisson models were used for incident fractures and number of falls, respectively, to compute hazard ratios (HRs) and rate ratios (RRs) for baseline osteoarthritis status. RESULTS: Of 51 386 women followed for a median of 2.9 years (interquartile range 2.1-3.0), 20 409 (40%) reported osteoarthritis. The adjusted HR for osteoarthritis predicting fracture was 1.21 (95% CI 1.13 to 1.30; p<0.0001) and the adjusted RR for falls was 1.24 (95% CI 1.22 to 1.26; p<0.0001). However, the association between osteoarthritis and fracture was not significant after adjustment for incident falls (HR 1.06 (95% CI 0.98 to 1.15; p=0.13)). CONCLUSIONS: Postmenopausal women with self-reported osteoarthritis have a 20% increased risk of fracture and experience 25% more falls than those without osteoarthritis. These data suggest that increased falls are the causal pathway of the association between osteoarthritis and fractures.

2013 International Society for Clinical Densitometry Position Development Conference: Task Force on Normative Databases.

Following the standard protocol for development of Official Positions for the International Society for Clinical Densitometry, the Expert Panel heard the report and recommendations from the Task Force on Normative Databases; using the RAND methodology, agreement was reached on the following statements: 1. Manufacturers should continue to use their own databases for the lumbar spine as the reference standard for T-scores. 2. Manufacturers should continue to use National Health and Nutrition Examination Survey III data as the reference standard for femoral neck and total hip T-scores. 3. If local reference data are available, they should be used to calculate only Z-scores but not T-scores. 4. A uniform Caucasian (non-race adjusted) female reference database should be used to calculate T-scores for men of all ethnic groups.