Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline.

BACKGROUND: Numerous studies demonstrate associations between serum concentrations of 25-hydroxyvitamin D (25[OH]D) and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases. Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population. The benefit-risk ratio of this increase in vitamin D use is not clear, and the optimal vitamin D intake and the role of testing for 25(OH)D for disease prevention remain uncertain. OBJECTIVE: To develop clinical guidelines for the use of vitamin D (cholecalciferol [vitamin D3] or ergocalciferol [vitamin D2]) to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing. METHODS: A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 14 clinically relevant questions related to the use of vitamin D and 25(OH)D testing to lower the risk of disease. The panel prioritized randomized placebo-controlled trials in general populations (without an established indication for vitamin D treatment or 25[OH]D testing), evaluating the effects of empiric vitamin D administration throughout the lifespan, as well as in select conditions (pregnancy and prediabetes). The panel defined "empiric supplementation" as vitamin D intake that (a) exceeds the Dietary Reference Intakes (DRI) and (b) is implemented without testing for 25(OH)D. Systematic reviews queried electronic databases for publications related to these 14 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and guide recommendations. The approach incorporated perspectives from a patient representative and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. The process to develop this clinical guideline did not use a risk assessment framework and was not designed to replace current DRI for vitamin D. RESULTS: The panel suggests empiric vitamin D supplementation for children and adolescents aged 1 to 18 years to prevent nutritional rickets and because of its potential to lower the risk of respiratory tract infections; for those aged 75 years and older because of its potential to lower the risk of mortality; for those who are pregnant because of its potential to lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age birth, and neonatal mortality; and for those with high-risk prediabetes because of its potential to reduce progression to diabetes. Because the vitamin D doses in the included clinical trials varied considerably and many trial participants were allowed to continue their own vitamin D-containing supplements, the optimal doses for empiric vitamin D supplementation remain unclear for the populations considered. For nonpregnant people older than 50 years for whom vitamin D is indicated, the panel suggests supplementation via daily administration of vitamin D, rather than intermittent use of high doses. The panel suggests against empiric vitamin D supplementation above the current DRI to lower the risk of disease in healthy adults younger than 75 years. No clinical trial evidence was found to support routine screening for 25(OH)D in the general population, nor in those with obesity or dark complexion, and there was no clear evidence defining the optimal target level of 25(OH)D required for disease prevention in the populations considered; thus, the panel suggests against routine 25(OH)D testing in all populations considered. The panel judged that, in most situations, empiric vitamin D supplementation is inexpensive, feasible, acceptable to both healthy individuals and health care professionals, and has no negative effect on health equity. CONCLUSION: The panel suggests empiric vitamin D for those aged 1 to 18 years and adults over 75 years of age, those who are pregnant, and those with high-risk prediabetes. Due to the scarcity of natural food sources rich in vitamin D, empiric supplementation can be achieved through a combination of fortified foods and supplements that contain vitamin D. Based on the absence of supportive clinical trial evidence, the panel suggests against routine 25(OH)D testing in the absence of established indications. These recommendations are not meant to replace the current DRIs for vitamin D, nor do they apply to people with established indications for vitamin D treatment or 25(OH)D testing. Further research is needed to determine optimal 25(OH)D levels for specific health benefits.

Updates on Osteoporosis in Men.

Osteoporosis is less common in men than women; however, the mortality rate associated with major fragility fractures is higher in men. The diagnosis of osteoporosis is established by measurement of bone mineral density or by the presence of a fragility fracture, especially spine or hip fracture. However, many men at high risk of fracture will not meet the T-score criteria for osteoporosis, so fracture risk calculation, with a tool such as FRAX, should be performed. Bone-active agents should be prescribed for men at high risk of fracture to decrease fracture risk, and therapy must be individualized.

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.

THE USE OF VITAMINS AND MINERALS IN SKELETAL HEALTH: AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND THE AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT.

ABBREVIATIONS: 25(OH)D = 25-hydroxyvitamin D; BMD = bone mineral density; CV = cardiovascular; GI = gastrointestinal; IOM = Institute of Medicine; PTH = parathyroid hormone; RCT = randomized controlled trial; αTF = α-tocopherol; ucOC = undercarboxylated osteocalcin; VKA = vitamin K antagonist; WHI = Women's Health Initiative.

Use of drug holidays in women taking bisphosphonates.

Bisphosphonates are the cornerstone of treatment for osteoporosis. These agents are generally safe and well-tolerated, but concerns have emerged about adverse effects related to long-term use, namely osteonecrosis of the jaw and atypical femur fractures. For most patients at moderate or high risk of fracture, the benefits of treatment far outweigh these serious but rare risks. Bisphosphonates accumulate in bone with some persistent protective effect after therapy is stopped, making it is reasonable to consider a "drug holiday." The duration of therapy and the length of the holiday should be based on clinical judgment.

Denosumab in osteoporosis.

INTRODUCTION: Denosumab is a fully human monoclonal antibody against the receptor activator of nuclear factor kappa-B ligand. It is an antiresorptive agent that reduces osteoclastogenesis. AREAS COVERED: This drug evaluation reviews denosumab for use in osteoporosis. Denosumab has been shown to improve bone mineral density (BMD) and to reduce the incidence of new vertebral, hip and nonvertebral fractures in postmenopausal women. It prevents bone loss and reduces vertebral fracture risk in men with nonmetastatic prostate cancer who are receiving androgen deprivation therapy. It has also been shown to improve BMD in men with osteoporosis unrelated to androgen deprivation therapy. Safety concerns include infections, cancer, skin reactions, cardiovascular disease, hypocalcemia, osteonecrosis of the jaw and atypical femur fractures. EXPERT OPINION: Although bisphosphonates are typically preferred as initial therapy for osteoporosis, denosumab could be used as initial therapy in select patients at high risk for fracture, including older patients who have difficulty with the dosing requirements of oral bisphosphonates, patients who are intolerant of or unresponsive to other therapies, and in those with impaired renal function. Additional data is needed to address issues regarding treatment duration and discontinuation, as well as to provide more information regarding denosumab's efficacy and safety.

Secondary osteoporosis: differential diagnosis and workup.

There are numerous causes of secondary osteoporosis including endocrine disorders, nutritional deficiencies, and other miscellaneous conditions and medications. It is essential to identify and address these factors to appropriately manage patients with osteoporosis. Failure to do so may result in further bone loss despite pharmacologic intervention for osteoporosis. The following diagnostic studies should be considered initially: complete blood count, complete metabolic panel, 25-hydroxyvitamin D level, testosterone level in men, and 24-hour urinary calcium, sodium, and creatinine. Further testing may be performed in selected patients depending on the clinical picture and results of the initial workup.

Postmenopausal osteoporosis.

PURPOSE OF REVIEW: The aim of this study is to provide a thorough updated review of the diagnosis and treatment of postmenopausal osteoporosis. RECENT FINDINGS: There have been several important findings in the field of postmenopausal osteoporosis over the past 1-2 years. Fewer morphometric vertebral fractures were found in women treated for 6 years with zoledronic acid compared with those who stopped treatment after 3 years. Longer duration of bisphosphonate therapy is associated with a higher risk of atypical femur fractures. Combination therapy with teriparatide and denosumab appears to increase bone mineral density to a greater extent than either therapy alone in postmenopausal women at high risk for fracture. There are several novel therapies under investigation for the treatment of osteoporosis, which are in various stages of development. Nonadherence to osteoporosis therapies continues to be a major problem in clinical practice. SUMMARY: There are numerous effective pharmacologic treatment options for postmenopausal osteoporosis. Bisphosphonate drug holidays continue to be an area of significant debate.

Bisphosphonate drug holiday: who, when and how long.

Bisphosphonates have been widely used in the treatment of osteoporosis with robust data from numerous placebo-controlled trials demonstrating efficacy in fracture risk reduction over 3-5 years of treatment. Although bisphosphonates are generally safe and well tolerated, concerns have emerged about adverse effects related to long-term use. For most patients with osteoporosis, the benefits of treatment outweigh the risks. Because these agents accumulate in bone with some persistent antifracture efficacy after therapy is stopped, it is reasonable to consider a 'drug holiday.' There is considerable controversy regarding the optimal duration of therapy and the length of the holiday, both of which should be based on individual assessments of risk and benefit.

Diagnosis and treatment of osteoporosis in older adults.

Osteoporosis in the elderly is a serious problem that is increasing as the population ages. Diagnosis is established by measurement of bone mineral density or by the presence of a fragility fracture, especially a spine or hip fracture. Bone-active agents should be prescribed for older patients with osteoporosis to decrease fracture risk. Nonskeletal risk factors for fracture and psychosocial impairment must be identified and managed, and therapy must be individualized.

Bisphosphonates in the treatment of osteoporosis.

Bisphosphonates are widely used in the treatment of osteoporosis to reduce fracture risk. Because of their long retention time in bone and uncommon side effects, questions have been raised about the optimal duration of therapy. Potential side effects appear to be rare and may not be causally related. Although there is no strong science to guide "drug holidays," there appears to be some lingering antifracture benefit when treatment is stopped, so some time off treatment should be offered to most patients on long-term bisphosphonate therapy. For most patients with osteoporosis, the benefits of treatment outweigh the risks.

The contribution of enteroinsular hormones to the pathogenesis of type 2 diabetes mellitus.

The gastrointestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), termed incretins, are essential regulators of normal glucose homeostasis. Research indicates that the incretin effect is impaired in type 2 diabetes, and this seems to be a consequence rather than a cause of type 2 diabetes. This review describes the defects in the incretin system seen in diabetic patients and discusses the potential roles of GIP and GLP-1 in the pathogenesis of type 2 diabetes. In addition, new information on clinical applications that exploit the enteroinsular axis to control blood glucose is discussed.

Long-term use of bisphosphonates in osteoporosis.

CONTEXT: Bisphosphonates have been widely used in the treatment of osteoporosis. Uncommon side effects have emerged in postapproval use. Because bisphosphonates accumulate in bone and are released for months or years after treatment is stopped, it is reasonable to consider the clinical question of how long to treat. OBJECTIVE: In this personal perspective, we review the pharmacology and mechanism of action of bisphosphonates and the clinical studies that support their efficacy. We then review the literature for longer-term studies and reports of possible side effects that were not seen in clinical trials. RESULTS: Bisphosphonates have demonstrated antifracture efficacy in randomized, placebo-controlled trials of 3 and 4 yr duration and have been widely used since the initial release of alendronate in 1995. For zoledronic acid and risedronate, an early effect (fractures reduced within 6-12 months of starting therapy) has been shown. A sustained effect for risedronate has been shown through 5 yr and suggested through 7 yr. Ten-year data with alendronate and 8 yr data with risedronate indicated good tolerability and safety; it is unlikely that longer-term studies will be done. Side effects that emerged in clinical trials include esophageal irritation with oral administration and acute phase response with iv treatment or high-dose oral therapy. Uncommon side effects that have been noted with wide clinical use include osteonecrosis of the jaw, musculoskeletal complaints, and atypical fractures. The numbers of events are small, and a clear cause-and-effect relationship between these events and bisphosphonate treatment has not been established. Because bisphosphonates accumulate in bone, they create a reservoir leading to continued release from bone for months or years after treatment is stopped. Studies with risedronate and alendronate suggest that if treatment is stopped after 3-5 yr, there is persisting antifracture efficacy, at least for 1-2 yr. CONCLUSIONS: Bisphosphonates are popular and effective for treatment of osteoporosis. Because they accumulate in bone and provide some residual antifracture reduction when treatment is stopped, we recommend a drug holiday after 5-10 yr of bisphosphonate treatment. The duration of treatment and length of the holiday are based on fracture risk and pharmacokinetics of the bisphosphonate used. Patients at mild risk might stop treatment after 5 yr and remain off as long as bone mineral density is stable and no fractures occur. Higher risk patients should be treated for 10 yr, have a holiday of no more than a year or two, and perhaps be on a nonbisphosphonate treatment during that time.

Triglyceride levels and not adipokine concentrations are closely related to severity of nonalcoholic fatty liver disease in an obesity surgery cohort.

Although nonalcoholic fatty liver disease (NAFLD) is frequent in obesity, the metabolic determinants of advanced liver disease remain unclear. Adipokines reflect inflammation and insulin resistance associated with obesity and may identify advanced NAFLD. At the time of obesity surgery, 142 consecutive patients underwent liver biopsy and had their preoperative demographic and clinical data obtained. Liver histology was scored by the NAFLD activity score, and patients subdivided into four groups. Concentrations of retinol-binding protein 4 (RBP4), adiponectin, tumor necrosis factor-alpha (TNF-alpha), and leptin were determined approximately 1 week prior to surgery and results were related to liver histology. The prevalence of no NAFLD was 30%, simple steatosis 23%, borderline nonalcoholic steatohepatitis (NASH) 28%, and definitive NASH 18%. Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS) prevalence were 39 and 75%, respectively, and did not differ across the four histological groups (P = NS). Triglyceride (TG) and alanine transaminase (ALT) levels, strongly associated with advanced stages of NAFLD and NASH (P = 0.04). TG levels >150 mg/dl, increased the likelihood of NASH 3.4-fold, whereas high-density lipoprotein (HDL) levels predicted no NAFLD (P < 0.01). Concentrations of TNF-alpha, leptin, and RBP4 did not differ among histological groups and thus did not identify NASH; however, there was a trend for adiponectin to be lower in NASH vs. no NAFLD (P = 0.061). In summary, both TG and ALT levels assist in identification of NASH in an obesity surgery cohort. These findings underscore the importance of fatty acid delivery mechanisms to NASH development in severely obese individuals.

Cytokeratin 18 fragment levels as a noninvasive biomarker for nonalcoholic steatohepatitis in bariatric surgery patients.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is extremely common among morbidly obese patients. We assessed the usefulness of plasma caspase-generated cytokeratin 18 (CK-18) fragments as a novel marker for NAFLD in a bariatric cohort. METHODS: The cohort consisted of 99 consecutive patients who underwent liver biopsy at the time of bariatric surgery. CK-18 levels were measured by using an enzyme-linked immunosorbent assay before and 6 months after surgery. Patients were subdivided into 4 histologic groups: not NAFLD (normal liver biopsy), nonalcoholic fatty liver (NAFL), borderline diagnosis, and definitive nonalcoholic steatohepatitis (NASH). RESULTS: CK-18 levels were significantly higher in subjects with NASH compared with those with not NAFLD, NAFL, or borderline diagnosis (median [25th quartile, 75th quartile], 389 U/L [275, 839] vs 196 U/L [158, 245], vs 217 U/L [154, 228], or vs 200 U/L [176, 274], respectively; P < .0001). CK-18 levels were significantly higher in subjects with moderate to severe fibrosis versus those with no or mild fibrosis (334.5 U/L [240.5, 896] vs 207 U/L [175, 275], respectively; P = .007). A significant decrease in CK-18 levels was observed in most patients 6 months postoperatively. The area under the receiver operating characteristic curve for NASH diagnosis was estimated to be 0.88 (95% confidence interval, 0.77-0.99). The values with the best combination of sensitivity and specificity were 252 U/L (sensitivity, 82%; specificity, 77%) and 275 U/L (sensitivity, 77%; specificity, 100%). CONCLUSIONS: These results support the potential utility of this test for diagnosis and staging of NAFLD before bariatric surgery.

Virilizing adrenal ganglioneuroma in a woman with subclinical Cushing syndrome.

OBJECTIVE: To describe a patient with a virilizing adrenal ganglioneuroma and subclinical Cushing syndrome. METHODS: Detailed clinical, laboratory, radiologic, and pathologic findings are presented, and the pertinent literature is reviewed. RESULTS: A 56-year-old postmenopausal woman was referred for evaluation of a 3.6- by 3.0-cm right adrenal mass, which had been diagnosed during a work-up for hirsutism. A bilateral oophorectomy done 2 months before the presentation failed to correct the elevated testosterone levels. On examination, she had severe hirsutism on her face, chest, back, and extremities, as well as male pattern baldness and clitoromegaly. Biochemical evaluation showed elevated total and free serum testosterone levels of 319 ng/dL (reference range, 20 to 70) and 78 pg/mL (reference range, 1 to 9), respectively, values in the adult male range. The serum dehydroepiandrosterone sulfate level was 117 microg/dL (reference range, 10 to 152), and the urine free cortisol was 10.4 microg/24 h (reference range, <45). A laparoscopic adrenalectomy revealed a 5.0-cm adrenal ganglioneuroma containing nests of adrenocortical cells. On the first day postoperatively, the serum cortisol level was <1.0 microg/dL. At 1 month after adrenalectomy, the total and free testosterone levels had declined to 16 ng/dL and 3.1 pg/mL, respectively. At 2 months postoperatively, normal results of a cosyntropin stimulation test (basal and peak cortisol levels of 13.6 and 20.0 microg/dL, respectively) indicated recovery of the hypothalamic-pituitary-adrenal axis. CONCLUSION: To our knowledge, this is the first case report of a virilizing adrenal ganglioneuroma with this unique pathologic finding and concomitant subclinical Cushing syndrome.

Virilizing ovarian Leydig cell tumor in a woman with subclinical Cushing syndrome.

OBJECTIVE: To report the case of a patient with a virilizing ovarian Leydig cell tumor and subclinical Cushing syndrome attributable to an adrenal adenoma. METHODS: Detailed clinical, laboratory, radiologic, and pathologic findings are presented, and the pertinent literature is reviewed. RESULTS: A 49-year-old woman was referred for evaluation of a left adrenal mass (3.0 by 2.4 cm), which had been diagnosed by computed tomographic scan 4 years previously during a work-up for hirsutism. On examination, she had central obesity, facial hirsutism, and male pattern baldness. Work-up showed elevated total and free testosterone levels of 196 ng/dL (reference range, 20 to 70) and 24 pg/mL (1 to 9), respectively. Other results (and reference ranges) were as follows: dehydroepiandrosterone sulfate, 7.5 microg/dL (10 to 221); corticotropin, 12 pg/mL (5 to 50); morning cortisol, 1.4 microg/dL after a 1-mg overnight dexamethasone suppression test; and urine free cortisol, 48.8 microg/24 h (20 to 100). The testosterone level decreased by 14% after a 2-day low-dose dexamethasone suppression test. Findings on transvaginal ovarian ultrasonography and a computed tomographic scan of the pelvis were normal. A laparoscopic adrenalectomy revealed an adrenal adenoma. On the first day postoperatively, the cortisol level was less than 1.0 microg/dL; however, the testosterone level remained elevated. At 6 months postoperatively, a normal result of a cosyntropin stimulation test indicated recovery of the hypothalamic-pituitary-adrenal axis. Bilateral oophorectomy revealed a 1.3-cm right ovarian Leydig cell tumor. Postoperatively, the testosterone level declined to less than 20 ng/dL. CONCLUSION: To our knowledge, this is the first case report of a virilizing ovarian Leydig cell tumor in a patient with subclinical Cushing syndrome.