2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: The objective is to update recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving >3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily. METHODS: An updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: For adults beginning or continuing >3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x-ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision-making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high-dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.

2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: The objective is to update recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving >3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily. METHODS: An updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: For adults beginning or continuing >3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x-ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision-making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high-dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.

Perspective: Design and Conduct of Human Nutrition Randomized Controlled Trials.

In the field of human nutrition, randomized controlled trials (RCTs) are considered the gold standard for establishing causal relations between exposure to nutrients, foods, or dietary patterns and prespecified outcome measures, such as body composition, biomarkers, or event rates. Evidence-based dietary guidance is frequently derived from systematic reviews and meta-analyses of these RCTs. Each decision made during the design and conduct of human nutrition RCTs will affect the utility and generalizability of the study results. Within the context of limited resources, the goal is to maximize the generalizability of the findings while producing the highest quality data and maintaining the highest levels of ethics and scientific integrity. The aim of this document is to discuss critical aspects of conducting human nutrition RCTs, including considerations for study design (parallel, crossover, factorial, cluster), institutional ethics approval (institutional review boards), recruitment and screening, intervention implementation, adherence and retention assessment, and statistical analyses considerations. Additional topics include distinguishing between efficacy and effectiveness, defining the research question(s), monitoring biomarker and outcome measures, and collecting and archiving data. Addressed are specific aspects of planning and conducting human nutrition RCTs, including types of interventions, inclusion/exclusion criteria, participant burden, randomization and blinding, trial initiation and monitoring, and the analysis plan.

Proton Pump Inhibitors, But Not H2-receptor Antagonists, Are Associated With Incident Fractures Among Kidney Transplant Recipients.

BACKGROUND: Fractures are a common and burdensome problem among kidney transplant recipients (KTRs). Proton pump inhibitors (PPIs) are frequently used after kidney transplantation and have been associated with increased fracture risk in the general population. This study aimed to determine whether PPI use is associated with incidence of major fractures in KTRs. METHODS: Using the Wisconsin Allograft Recipient Database, we identified 155 KTRs with a major fracture that occurred at least 12 months after transplantation. Controls were selected using incidence-density sampling. Use of PPIs and histamine 2-receptor antagonists (H2RA) during the year before the index date were identified. RESULTS: A total of 155 cases were matched to 685 controls. Within 1 year before the index date, 68% of cases and 52% of controls used a PPI, and 16% of cases and 11% of controls used an H2RA. PPI use was associated with higher incidence of major fractures in unadjusted analysis (odds ratio [OR], 2.4; 95% CI, 1.6-3.5) and in adjusted analyses controlling for demographic and transplant-related covariates and use of corticosteroids, bisphosphonates, vitamin D and calcium supplements (OR, 1.9; 95% CI, 1.2-3.1). H2RA use was not associated with incidence of major fractures in adjusted analyses (OR, 1.0; 95% CI, 0.5-1.8). The associations between PPI use and fractures remained similar in analyses limited to spine and hip fractures. CONCLUSIONS: Use of PPIs, but not H2RAs, is associated with a higher risk of major fractures among KTRs. Clinicians should individualize PPI use in KTRs, evaluating the risks and benefits of prescribing and continuing PPIs in KTRs.

Hypocalciuria as a Predictor of Reduced Intestinal Calcium Absorption.

Impaired intestinal calcium absorption contributes to osteoporosis, but its measurement is limited to research settings. We hypothesized that 24-hour urine calcium (24HUC) values could diagnose low fractional calcium absorption (FCA). We performed a post hoc analysis of clinical trial data to determine whether 24HUC predicted low FCA compared with the gold standard dual calcium isotope method. Two hundred thirty postmenopausal women <75 years old without osteoporosis underwent 445 FCA measurements using calcium isotopes (8 mg of oral 44Ca, 3 mg of intravenous 42Ca) and a 24-hour inpatient urine collection at 0 and 12 months. We determined subjects' total calcium intake via review of food diaries and supplements. Net calcium absorption (NCA) was total calcium intake × FCA. NCA and 24HUC values demonstrated a positive correlation (r = 0.34; 95% confidence interval, 0.25 to 0.42; P < 0.001). We calculated sensitivity, specificity, positive (PPV) and negative predictive value (NPV) for the ability of 24HUC thresholds to predict calcium malabsorption. When low calcium absorption was defined as <120 mg/d, a 24HUC value <150 mg demonstrated 65% sensitivity, 67% specificity, 31% PPV, and 89% NPV. When calcium malabsorption was defined as <100 mg/d, a 24HUC value <150 mg demonstrated 72% sensitivity, 65% specificity, 22% PPV, and 94% NPV. A 24HUC value <150 mg demonstrated a high NPV for calcium malabsorption. We suggest that 24HUC levels can exclude calcium malabsorption in postmenopausal women.

2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: To develop recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP). METHODS: We conducted a systematic review to synthesize the evidence for the benefits and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long-term (≥3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long-term GC treatment, as well as in special populations of long-term GC users. RESULTS: Because of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate-to-high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high-dose GC treatment, are also made. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions. Clinicians and patients should use a shared decision-making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: To develop recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP). METHODS: We conducted a systematic review to synthesize the evidence for the benefits and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long-term (≥3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long-term GC treatment, as well as in special populations of long-term GC users. RESULTS: Because of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate-to-high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high-dose GC treatment, are also made. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions. Clinicians and patients should use a shared decision-making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

An update on vitamin D for clinicians.

PURPOSE OF REVIEW: The clinical benefits of vitamin D therapy have received substantial attention over the past decade. Recently, several trials looked to clarify the optimal vitamin D dose or serum level needed to promote human health. The purpose of this review is to highlight selected studies published since January 2015. RECENT FINDINGS: Several recent trials challenge whether serum vitamin D levels at least 30 ng/ml promote human health. In postmenopausal women with 25-hydroxyvitamin D [25(OH)D] levels 21 ±â€Š3 ng/ml, high-dose vitamin D for 1 year increased calcium absorption by 1%, without changes in bone mineral density, physical function, or falls when compared with low-dose vitamin D and placebo. High-dose vitamin D increased risk of falling in 200 adults 78 ±â€Š5 years old with baseline 25(OH)D levels of ∼19 ±â€Š9 ng/ml. High-dose vitamin D in adults increased the number and duration of upper respiratory tract infections compared with placebo. Asthma patients achieving 25(OH)D levels more than 30 ng/ml during a trial experienced more respiratory infections than those not achieving such levels. SUMMARY: Recent studies are congruent with the Institute of Medicine's conclusion that humans are vitamin D replete when their serum 25(OH)D levels are at least 20 ng/ml. Higher levels seem to promote falls and respiratory infections.

Treatment of Vitamin D Insufficiency in Postmenopausal Women: A Randomized Clinical Trial.

IMPORTANCE: Experts debate optimal 25-hydroxyvitamin D (25[OH]D) levels for musculoskeletal health. OBJECTIVE: To compare the effects of placebo, low-dose cholecalciferol, and high-dose cholecalciferol on 1-year changes in total fractional calcium absorption, bone mineral density, Timed Up and Go and five sit-to-stand tests, and muscle mass in postmenopausal women with vitamin D insufficiency. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, placebo-controlled clinical trial was conducted at a single center in Madison, Wisconsin, from May 1, 2010, through July 31, 2013, and the final visit was completed on August 8, 2014. A total of 230 postmenopausal women 75 years or younger with baseline 25(OH)D levels of 14 through 27 ng/mL and no osteoporosis were studied. INTERVENTIONS: Three arms included daily white and twice monthly yellow placebo (n=76), daily 800 IU vitamin D3 and twice monthly yellow placebo (n=75), and daily white placebo and twice monthly 50,000 IU vitamin D3 (n=79). The high-dose vitamin D regimen achieved and maintained 25(OH)D levels≥30 ng/mL. MAIN OUTCOMES AND MEASURES: Outcome measures were 1-year change in total fractional calcium absorption using 2 stable isotopes, bone mineral density and muscle mass using dual energy x-ray absorptiometry, Timed Up and Go and five sit-to-stand tests, functional status (Health Assessment Questionnaire), and physical activity (Physical Activity Scale for the Elderly), with Benjamini-Hochberg correction of P values to control for the false discovery rate. RESULTS: After baseline absorption was controlled for, calcium absorption increased 1% (10 mg/d) in the high-dose arm but decreased 2% in the low-dose arm (P = .005 vs high-dose arm) and 1.3% in the placebo arm (P = .03 vs high-dose arm). We found no between-arm changes in spine, mean total-hip, mean femoral neck, or total-body bone mineral density, trabecular bone score, muscle mass, and Timed Up and Go or five sit-to-stand test scores. Likewise, we found no between-arm differences for numbers of falls, number of fallers, physical activity, or functional status. CONCLUSIONS AND RELEVANCE: High-dose cholecalciferol therapy increased calcium absorption, but the effect was small and did not translate into beneficial effects on bone mineral density, muscle function, muscle mass, or falls. We found no data to support experts' recommendations to maintain serum 25(OH)D levels of 30 ng/mL or higher in postmenopausal women. Instead, we found that low- and high-dose cholecalciferol were equivalent to placebo in their effects on bone and muscle outcomes in this cohort of postmenopausal women with 25(OH)D levels less than 30 ng/mL. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00933244.

Can a questionnaire predict vitamin D status in postmenopausal women?

OBJECTIVE: Our objective was to determine whether a questionnaire can identify individuals with vitamin D insufficiency (VDI). DESIGN: Women completed the Vitamin D & Sun (VIDSUN) questionnaire and we measured their serum 25-hydrocyvitamin D (25(OH)D) levels. We assessed the sensitivity and specificity of the questionnaire to identify VDI (25(OH)D level <50 nmol/l). SETTING: Clinical Research Unit, University of Wisconsin-Madison. SUBJECTS: Postmenopausal women. RESULTS: We recruited 609 postmenopausal women with a mean age of 61 (sd 6 years), of whom 113 (19%) had VDI. Women with VDI were more likely to be black (17% v. 2%, P < 0.001), heavier (BMI 33.0 (sd 7) kg/m2 v. 29.0 (sd 7) kg/m2, P < 0.001) and less likely to tan in the past year (49% v. 72%, P < 0.001), use sunscreen (57% v. 72%, P < 0.001) or report sun exposure in the last 3 months. They consumed less vitamin D from supplements (2.15 (sd 5.24) µg/d (86 (sd 210) IU/d) v. 4.55 (sd 8.48) µg/d (188 (sd 344) IU/d), P = 0.003). In logistic regression models, black race, BMI, suntan within the past year, sun exposure in the past 3 months, sunscreen use and supplemental vitamin D intake were the most useful questions to identify VDI. From these six items, a composite score of ≤ 2.25 demonstrated ≥89% sensitivity but ≤35% specificity for VDI. CONCLUSIONS: The VIDSUN questionnaire provides an initial tool to identify postmenopausal women at high or low risk of VDI. Existing studies suggest that inclusion of physical activity and TAG levels might improve the performance of the VIDSUN questionnaire.

Advances in the nutritional and pharmacological management of phenylketonuria.

PURPOSE OF REVIEW: The purpose is to discuss advances in the nutritional and pharmacological management of phenylketonuria (PKU). RECENT FINDINGS: Glycomacropeptide (GMP), a whey protein produced during cheese production, is a low-phenylalanine (phe) intact protein that represents a new dietary alternative to synthetic amino acids for people with PKU. Skeletal fragility is a long-term complication of PKU that based on murine research, appears to result from both genetic and nutritional factors. Skeletal fragility in murine PKU is attenuated with the GMP diet, compared with an amino acid diet, allowing greater radial bone growth. Pharmacologic therapy with tetrahydrobiopterin, acting as a molecular chaperone for phenylalanine hydroxylase, increases tolerance to dietary phe in some individuals. Large neutral amino acids inhibit phe transport across the intestinal mucosa and blood-brain barrier, and are most effective for individuals unable to comply with the low-phe diet. SUMMARY: Although a low-phe synthetic amino acid diet remains the mainstay of PKU management, new nutritional and pharmacological treatment options offer alternative approaches to maintain lifelong low phe concentrations. GMP medical foods provide an alternative to amino acid formula that may improve bone health, and tetrahydrobiopterin permits some individuals with PKU to increase tolerance to dietary phe. Further research is needed to characterize the long-term efficacy of these new approaches for PKU management.

High-dose vitamin D: helpful or harmful?

If the optimal serum 25(OH)D level for skeletal health is 30 ng/mL or greater, then vitamin D insufficiency is widespread, affecting about 75% of adults based on a recent survey of more than 20,000 Americans. However, after a comprehensive analysis of existing research studies, the Institute of Medicine recently concluded that nearly all individuals are vitamin D replete when their 25(OH)D levels are 20 ng/mL or greater. Furthermore, two recent publications challenge the belief that 25(OH)D levels greater than 30 ng/mL are optimal for bone health. In a randomized, placebo-controlled trial, high-dose, once-yearly vitamin D therapy increased the incidence of fractures and falls. The second study reported that high-dose vitamin D did not reduce levels of parathyroid hormone or bone resorption among adults with 25(OH)D levels less than 32 ng/mL at baseline. It is time to question whether serum 25(OH)D levels of 30 ng/mL or greater are necessary for all individuals.

The effect of physician workload on an educational intervention to increase vitamin D screening.

RATIONALE, AIMS AND OBJECTIVE: Changes in physician behavior are difficult to accomplish. We hypothesized measuring physicians' vitamin D levels would increase measurement of their patients' levels. METHODS: We recruited faculty via e-mail. We measured physicians' serum 25(OH)D levels and asked them to complete a questionnaire created to assess the risk of vitamin D deficiency. Physicians received their vitamin D test results by mail. We monitored physicians' vitamin D testing rate per 100 patient visits in the 12 weeks before and after receipt of their own vitamin D test result. RESULTS: Twenty-eight (22%) of 126 primary care physicians participated in the study; all were Caucasian and 17 (61%) were women. Gender, practic type, and year of graduation from medical school were similar in participants and non-participants. Over half of participants took a multivitamin and a third took a vitamin D supplement. Although 6 (21%) reported a recent fracture, only 1 physician carried a diagnosis of osteopenia or osteoporosis. At baseline, geriatricians ordered 14 vitamin D tests per 100 patient visits, while internists and family practitioners ordered substantially fewer tests (2 and <1 tests per 100 visits, respectively). After study participation, vitamin D testing rates increased significantly among family practitioners (rate ratio 3.27, 95% CI 1.29-8.33) and internists (rate ratio 3.19, 95% CI 1.12-9.07). Physicians with heavier clinic workloads were half as likely (rate ratio 0.50, 95% CI 0.32-0.76) as those with lighter clinic workloads to increase vitamin D testing rates. Surprisingly, physicians with hypovitaminosis D demonstrated no change in vitamin D testing rates. CONCLUSIONS: Physicians with low vitamin D testing rates were receptive to a personal intervention involving measurement of their own vitamin D levels. High workload appeared to attenuate this effect. These novel but preliminary observations require confirmation in future studies.

Vitamin D repletion does not alter urinary calcium excretion in healthy postmenopausal women.

OBJECTIVE: To evaluate, in a posthoc analysis of a previous study, whether vitamin D repletion in postmenopausal women with insufficient vitamin D increases urinary calcium excretion, as vitamin D therapy might contribute to hypercalciuria and calcium stones in susceptible individuals, and the effect of vitamin D on the risk of urolithiasis warrants attention. SUBJECTS AND METHODS: We recruited 18 women at > or =5 years after menopause who had vitamin D insufficiency (serum 25(OH)-vitamin D, 16-24 mg/dL). We excluded women with a history of urolithiasis and kidney disease. Women had one calcium absorption study when vitamin D-insufficient, received vitamin D therapy, and completed a second calcium absorption study when vitamin D-replete. We fed subjects meals that mirrored the nutrient composition from self-reported 7-day diet diaries. To measure calcium absorption, we collected urine for 24 h during both visits. RESULTS: We achieved vitamin D repletion in all women (25(OH)-vitamin D before and after treatment, 22 and 63 mg/dL, respectively; P < 0.001). The mean calcium intake was 832 mg/day. Residual urine specimens were available for 16 women, allowing a measurement of 24-h urinary calcium. Calcium excretion did not change after vitamin D therapy (212 before vs 195 mg/day after; P = 0.60). Of four women with hypercalciuria (>247 mg/day), calcium excretion decreased in three (377-312 mg/day, not significant). CONCLUSION: Vitamin D supplementation did not increase the urinary calcium excretion in healthy postmenopausal women. Many stone formers are at risk of premature bone loss, vitamin D insufficiency, or both. Based on the present results we suggest a study of patients with hypercalciuria and nephrolithiasis to determine the risks of vitamin D therapy.

Vitamin D and musculoskeletal health.

Vitamin D is critical for calcium homeostasis. Following cutaneous synthesis or ingestion, vitamin D is metabolized to 25(OH)D and then to the active form 1,25(OH)2D. Low serum vitamin D levels are common in the general population and cause a decline in calcium absorption, leading to low serum levels of ionized calcium, which in turn trigger the release of parathyroid hormone, promoting skeletal resorption and, eventually, bone loss or osteomalacia. Vitamin D deficiency is generally defined as a serum 25(OH)D concentration <25-37 nmol/l (<10-15 ng/ml), but the definition of the milder state of vitamin D insufficiency is controversial. Three recent meta-analyses concluded that vitamin D must be administered in combination with calcium in order to substantially reduce the risk of nonvertebral fracture in adults over the age of 50 years. Fracture protection is optimal when patient adherence to medication exceeds 80% and vitamin D doses exceed 700 IU/day. In addition to disordered calcium homeostasis, low vitamin D levels might have effects on cell proliferation and differentiation and immune function. Randomized, double-blind, placebo-controlled trials are needed to clarify whether vitamin D supplementation is beneficial in cancer, autoimmune disease and infection. This Review focuses on the pathophysiology, clinical correlates, evaluation and treatment of hypovitaminosis D.