Vitamin D and bisphosphonate therapy in systemic lupus erythematosus patients who receive glucocorticoids: are we offering the best care?

OBJECTIVE: This study aimed to evaluate management practices for glucocorticoid (GC)-induced osteoporosis (GIOP) in systemic lupus erythematosus (SLE) patients using 2017 American College of Rheumatology guidelines as a gold standard. METHODS: We conducted a retrospective cohort study using a clinical database from the years 2011 to 2016. SLE cases with >90 days continuous prednisone use at doses of ≥7.51 mg daily were identified. Osteoporosis risk factors were assessed via chart review. The Fracture Risk Assessment (FRAX) score was estimated for patients > 40 years of age. Vitamin D, bisphosphonate prescriptions, and osteoporotic (OP) fractures were ascertained through chart review. A classification tree was used to identify the key patient-related predictors of bisphosphonate prescription. RESULTS: A total of 203 SLE patients met the inclusion criteria. The recommended dose of vitamin D supplement was prescribed to 58.9% of patients < 40 years of age and 61.5% of patients ≥ 40 years of age. Among patients aged ≥ 40 years, 25% were prescribed bisphosphonates compared to 36% who met indications for bisphosphonates per the ACR guidelines. Another 10% were prescribed a bisphosphonate, despite not having indication per the ACR guidelines, which was considered as overtreatment. Among patients aged ≥ 40 years, older age and a higher FRAX score for major OP fracture and hip fracture predicted bisphosphonate prescription. In a classification tree analysis, patients with FRAX scores (for major OP fracture) of ≥ 23.5% predicted bisphosphonate prescription in this SLE population. Among patients who had OP fractures in the follow-up period, nine (6.50%) were inpatients receiving appropriate GIOP care versus 12 (13.6%) who were inpatients not receiving ACR-appropriate care (p = 0.098). CONCLUSIONS: In clinical practice, fewer SLE patients with or at risk for GIOP are prescribed vitamin D and bisphosphonates than recommended by the 2017 ACR guidelines. Also, in this study, another 10% were prescribed a bisphosphonate, despite not having an indication per the ACR guidelines. Patients were most likely to receive a bisphosphonate prescription if they had a major OP FRAX score of > 23.5%.

Low magnesium intake is associated with increased knee pain in subjects with radiographic knee osteoarthritis: data from the Osteoarthritis Initiative.

OBJECTIVE: As magnesium mediates bone and muscle metabolism, inflammation, and pain signaling, we aimed to evaluate whether magnesium intake is associated with knee pain and function in radiographic knee osteoarthritis (OA). METHODS: We investigated the associations between knee pain/function metrics and magnesium intake from food and supplements in 2548 Osteoarthritis Initiative cohort participants with prevalent radiographic knee OA (Kellgren-Lawrence score ≥2). Magnesium intake was assessed by Food Frequency Questionnaire (FFQ) at baseline. WOMAC and Knee Injury and Osteoarthritis Outcome Score (KOOS) scores were reported annually with total follow up of 48 months. Analyses used linear mixed models. RESULTS: Among participants with baseline radiographic knee OA the mean total magnesium intake was 309.9 mg/day (SD 132.6) for men, and 287.9 mg/day (SD 118.1) for women, with 68% of men and 44% of women below the estimated average requirement. Subjects with lower magnesium intake had worse knee OA pain and function scores, throughout the 48 months (P < 0.001). After adjustment for age, sex, race, body mass index (BMI), calorie intake, fiber intake, pain medication use, physical activity, renal insufficiency, smoking, and alcohol use, lower magnesium intake remained associated with worse pain and function outcomes (1.4 points higher WOMAC and 1.5 points lower KOOS scores for every 50 mg of daily magnesium intake, P < 0.05). Fiber intake was an effect modifier (P for interaction <0.05). The association between magnesium intake and knee pain and function scores was strongest among subjects with low fiber intake. CONCLUSION: Lower magnesium intake was associated with worse pain and function in knee OA, especially among individuals with low fiber intake.

High dairy protein intake is associated with greater bone strength parameters at the distal radius and tibia in older men: a cross-sectional study.

Dairy protein but not plant protein was associated with bone strength of the radius and tibia in older men. These results are consistent with previous results in women and support similar findings related to fracture outcomes. Bone strength differences were largely due to thickness and area of the bone cortex. INTRODUCTION: Our objective was to determine the association of protein intake by source (dairy, non-dairy animal, plant) with bone strength and bone microarchitecture among older men. METHODS: We used data from 1016 men (mean 84.3 years) who attended the Year 14 exam of the Osteoporotic Fractures in Men (MrOS) study, completed a food frequency questionnaire (500-5000 kcal/day), were not taking androgen or androgen agonists, and had high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the distal radius and distal or diaphyseal tibia. Protein was expressed as percentage of total energy intake (TEI); mean ± SD for TEI = 1548 ± 607 kcal/day and for total protein = 16.2 ± 2.9%TEI. We used linear regression with standardized HR-pQCT parameters as dependent variables and adjusted for age, limb length, center, education, race/ethnicity, marital status, smoking, alcohol intake, physical activity level, corticosteroids use, supplement use (calcium and vitamin D), and osteoporosis medications. RESULTS: Higher dairy protein intake was associated with higher estimated failure load at the distal radius and distal tibia [radius effect size = 0.17 (95% CI 0.07, 0.27), tibia effect size = 0.13 (95% CI 0.03, 0.23)], while higher non-dairy animal protein was associated with higher failure load at only the distal radius. Plant protein intake was not associated with failure load at any site. CONCLUSION: The association between protein intake and bone strength varied by source of protein. These results support a link between dairy protein intake and skeletal health, but an intervention study is needed to evaluate causality.

Antiepileptic drug use and rates of hip bone loss in older men: a prospective study.

OBJECTIVE: To test the hypotheses that older community dwelling men taking non-enzyme-inducing antiepileptic drugs (NEIAEDs) and those taking enzyme-inducing antiepileptic drugs (EIAEDs) have increased rates of hip bone loss. METHODS: We ascertained antiepileptic drug (AED) use (interviewer-administered questionnaire with verification of use by containers) and measured hip bone mineral density (BMD) (using dual energy x-ray absorptiometry) at baseline and an average of 4.6 years later in a cohort of 4,222 older community-dwelling men enrolled in the Osteoporotic Fractures in Men study. Men were categorized as nonusers (no AED use at either examination, n = 4060), NEIAED user (use of NEIAED only at either examination, n = 100), or EIAED user (use of EIAED only at either examination, n = 62). RESULTS: After adjustment for multiple potential confounders (age, race, clinic site, health status, pain interfering with work or activity, physical activity, smoking status, alcohol use, total calcium intake, diabetes, chronic kidney disease, vitamin D supplement use, bisphosphonate use, selective serotonin reuptake inhibitor use, inability to rise from a chair, body mass index, and baseline BMD), the average rate of decline in total hip BMD was -0.35%/year among nonusers compared with -0.53%/year among NEIAED users (p = 0.04) and -0.46%/year among EIAED users (p = 0.31). Multivariable adjusted rate of loss was -0.60%/year among men taking NEIAED at both examinations, -0.51%/year among men taking NEIAED at one examination only, and -0.35%/year among nonusers (p for trend = 0.03). Findings were similar at hip subregions. CONCLUSION: Use of non-enzyme-inducing antiepileptic drugs was independently associated with increased rates of hip bone loss in this cohort of older community-dwelling men.

Higher 1,25-dihydroxyvitamin D3 concentrations associated with lower fall rates in older community-dwelling women.

INTRODUCTION: The purpose of this study was to examine the relationships of vitamin D supplementation and serum concentrations of vitamin D metabolites and parathyroid hormone (PTH) with neuromuscular function and falls in older community-dwelling women. METHODS: We examined these relationships using a 4-year prospective multi-center study among 9,526 community-dwelling women enrolled in the Study of Osteoporotic Fractures (median age: 70 years; interquartile range: 67-75) and a subset of 389 women (97%) out of 400 who were randomly selected from the entire cohort for serum measures. Measurements included: vitamin D supplementation, serum 25-hydroxyvitamin D(3) [25(OH)D(3)], serum 1,25-dihydroxyvitamin D(3) [1,25(OH) (2)D(3)], and serum intact parathyroid hormone (iPTH); grip and quadriceps strength, chair-stand time, walking speed, reaction time, and balance-walk time (including changes in grip strength, chair-stand time, walking speed and balance-walk time over approximately 3.7 years); and incident fall rates (number of falls/woman-years). RESULTS: In 9,526 women, vitamin D supplementation was not associated with any measures of neuromuscular function, change in neuromuscular function, or fall rates (p>0.01 for all). In a subgroup of 389 women, there was a trend of higher 25(OH)D(3) concentration with slightly weaker grip strength (p=0.007), and women in the fourth quartile of 1,25(OH)(2)D(3) had a faster chair-stand time (p=0.017) than women in the first quartile; still, in general, concentrations of 25(OH)D(3), 1,25(OH)(2)D(3), and iPTH were not associated with either neuromuscular function or changes in neuromuscular function (p>0.05 for all). However, higher 1,25(OH)(2)D(3) concentration was associated with lower fall rates (p=0.039). CONCLUSIONS: Higher 1,25(OH)(2)D(3) concentration is associated with a lower fall risk in older community-dwelling women, but vitamin D supplementation, and 25(OH)D(3) and iPTH concentrations are not associated with either neuromuscular function or falls.

Low fractional calcium absorption increases the risk for hip fracture in women with low calcium intake. Study of Osteoporotic Fractures Research Group.

BACKGROUND: Decreased ability to absorb calcium with age limits adaptation to low calcium intake and is thought to lead to secondary hyperparathyroidism and increased risk for hip and other fractures. However, the associations between fractional calcium absorption, dietary calcium intake, and risk for fracture have never been studied. OBJECTIVE: To determine whether low fractional calcium absorption in women with low calcium intake increases the risk for subsequent hip and other nonspine fractures. DESIGN: Prospective cohort study. SETTING: Four clinical centers in Baltimore County, Maryland; Portland, Oregon; Minneapolis, Minnesota; and the Monongahela Valley, Pennsylvania. PARTICIPANTS: 5452 nonblack women 69 years of age or older participating in the fourth examination of the Study of Osteoporotic Fractures. MEASUREMENTS: Fractional calcium absorption was measured by using a 3-hour single isotope (45Ca) technique. Incident fractures were identified prospectively and were confirmed by radiographic report. RESULTS: During an average of 4.8 years, 729 women (13%) experienced at least one nonspine fracture; 153 of these women had hip fractures. After adjustment for age, women with lower fractional calcium absorption were at increased risk for hip fracture (relative risk per 1-SD [7.7%] decrease in fractional calcium absorption, 1.24 [95% CI, 1.05 to 1.48]). Women with low fractional calcium absorption and low calcium intake were at greatest risk for subsequent hip fracture; among women whose dietary calcium intake was less than 400 mg/d, those who had fractional calcium absorption at or below the median value of 32.3% had a 2.5-fold (CI, 1.29-fold to 4.69-fold) increase in risk for hip fracture compared with those who had greater absorption efficiency. Fractional calcium absorption was not related to risk for other nonspine fractures (relative risk per 1-SD [7.7%] decrease in fractional calcium absorption, 1.05 [CI, 0.96 to 1.14]). CONCLUSIONS: In elderly women, low fractional calcium absorption in the setting of low calcium intake increases the risk for hip fracture. Our findings support the hypothesis of type II osteoporosis, which postulates that decreased calcium absorption is an important risk factor for hip fracture in older persons.

Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators.

CONTEXT: Raloxifene hydrochloride, a selective estrogen receptor modulator, prevents bone loss in postmenopausal women, but whether it reduces fracture risk in these women is not known. OBJECTIVE: To determine the effect of raloxifene therapy on risk of vertebral and nonvertebral fractures. DESIGN: The Multiple Outcomes of Raloxifene Evaluation (MORE) study, a multicenter, randomized, blinded, placebo-controlled trial. SETTING AND PARTICIPANTS: A total of 7705 women aged 31 to 80 years in 25 countries who had been postmenopausal for at least 2 years and who met World Health Organization criteria for having osteoporosis. The study began in 1994 and had up to 36 months of follow-up for primary efficacy measurements and nonserious adverse events and up to 40 months of follow-up for serious adverse events. INTERVENTIONS: Participants were randomized to 60 mg/d or 120 mg/d of raloxifene or to identically appearing placebo pills; in addition, all women received supplemental calcium and cholecalciferol. MAIN OUTCOME MEASURES: Incident vertebral fracture was determined radiographically at baseline and at scheduled 24- and 36-month visits. Nonvertebral fracture was ascertained by interview at 6-month-interim visits. Bone mineral density was determined annually by dual-energy x-ray absorptiometry. RESULTS: At 36 months of the evaluable radiographs in 6828 women, 503 (7.4%) had at least 1 new vertebral fracture, including 10.1% of women receiving placebo, 6.6% of those receiving 60 mg/d of raloxifene, and 5.4% of those receiving 120 mg/d of raloxifene. Risk of vertebral fracture was reduced in both study groups receiving raloxifene (for 60-mg/d group: relative risk [RR], 0.7; 95% confidence interval [CI], 0.5-0.8; for 120-mg/d group: RR, 0.5; 95% CI, 0.4-0.7). Frequency of vertebral fracture was reduced both in women who did and did not have prevalent fracture. Risk of nonvertebral fracture for raloxifene vs placebo did not differ significantly (RR, 0.9; 95% CI, 0.8-1.1 for both raloxifene groups combined). Compared with placebo, raloxifene increased bone mineral density in the femoral neck by 2.1 % (60 mg) and 2.4% (120 mg) and in the spine by 2.6% (60 mg) and 2.7% (120 mg) P<0.001 for all comparisons). Women receiving raloxifene had increased risk of venous thromboembolus vs placebo (RR, 3.1; 95% CI, 1.5-6.2). Raloxifene did not cause vaginal bleeding or breast pain and was associated with a lower incidence of breast cancer. CONCLUSIONS: In postmenopausal women with osteoporosis, raloxifene increases bone mineral density in the spine and femoral neck and reduces risk of vertebral fracture.

Vitamin D receptor gene polymorphisms and the risk of fractures in older women. For the Study of Osteoporotic Fractures Research Group.

The association between vitamin D receptor gene polypmorphisms and bone mineral density is controversial. The relationship between vitamin D receptor genotype and risk of fracture is uncertain. To determine whether vitamin D receptor polymorphisms were associated with the risk of hip, vertebral, and other (nonhip, nonvertebral) fractures in elderly women, we conducted a case-cohort study within a prospective study of 9704 community-dwelling women aged 65 years and older. Vitamin D receptor allele and genotype frequencies in women who experienced first incident hip (n = 181), vertebral (n = 127), and other (n = 223) fractures were compared with those of control women selected randomly from the cohort. Average length of follow-up was 6.5, 3.7, and 5.4 years for women in hip, vertebral, and other fracture analyses, respectively. Vitamin D receptor polymorphisms were determined by polymerase chain reaction amplification of genomic DNA using TaqI and ApaI restriction site endonuclease digestion. All nonvertebral fractures were confirmed by X-ray reports; hip fractures were validated by review of X-ray films. Vertebral fractures were defined by morphometry using lateral spine radiography at baseline and an average of 3.7 years later. Allele or genotype frequencies did not differ between fracture cases and their respective controls. Vitamin D receptor genotype (defined by TaqI, ApaI, or the combination of TaqI and ApaI) was not significantly associated with the risk of hip, vertebral, or other fractures. For example, compared with the referent group of women with TT genotype, those with Tt and tt genotypes had similar age- and weight-adjusted risks of fracture at the hip (hazard ratios 0.9, 95% confidence interval [CI] 0.6-1.3, and 0.8, 95% CI 0.5-1.2, respectively), spine (odds ratios 1.1, 95% CI 0.7-1.8, and 0.7, 95% CI 0.4-1.3, respectively), or other skeletal site (hazard ratios 1.0, 95% CI 0. 7-1.4, and 1.0, 95% CI 0.7-1.5, respectively). These findings were not altered in additional analyses including those adjusted for and stratified by age, ethnic ancestry, calcaneal bone density, dietary calcium intake, use of calcium supplements, use of vitamin D supplements, and oral estrogen use. We conclude that Vitamin D receptor polymorphisms defined by TaqI and ApaI are not associated with the risk of fracture in older women. Our results suggest that determination of these vitamin D receptor polymorphisms is not a clinically useful test for the prediction of fracture risk in elderly women.

Depression, falls, and risk of fracture in older women. Study of Osteoporotic Fractures Research Group.

BACKGROUND: Previous studies have suggested that depression is associated with falls and with low bone density, but it is not known whether depression leads to an increased risk of fracture. SUBJECTS AND METHODS: We conducted a prospective cohort study in elderly white women who were recruited from population-based listings in the United States. At a second visit (1988-1990), 7414 participants completed the 15-item Geriatric Depression Scale and were considered depressed if they reported 6 or more symptoms of depression. We measured bone mineral density (BMD) in the spine and hip using dual energy x-ray absorptiometry at the second visit, and asked participants about incident falls (yes/no) at 4 follow-up visits. Nonvertebral fractures were ascertained for an average of 6 years following the depression measure, and verified radiologically. We determined incident vertebral fractures by comparing lateral spine films obtained at the first visit (1986-1988) with repeat films obtained an average of 3.7 years later (1991-1992). RESULTS: The prevalence of depression (Geriatric Depression Scale score > or = 6) was 6.3% (467/7414). We found no difference in mean BMD of the hip and lumbar spine in women with depression compared with those without depression. Women with depression were more likely to experience subsequent falls than women without depression (70% vs 59%; age-adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.3-1.9; P<.001), an association that persisted after adjusting for potential confounding variables (OR, 1.4; 95% CI, 1.1-1.8; P=.004). Women with depression had a 40% (age-adjusted hazard ratio [HR], 1.4; 95% CI, 1.2-1.7; P<.001) increased rate of nonvertebral fracture (124 fractures in 3805 woman-years of follow-up) compared with women without depression (1367 fractures in 59 503 woman-years of follow-up). This association remained strong after adjusting for potential confounding variables, including medication use and neuromuscular function (HR, 1.3; 95% CI, 1.1-1.6; P=.008). Further adjustment for subsequent falls appeared to explain part of this association (HR, 1.2; 95% CI, 1.0-1.5; P = .06). Women with depression were also more likely to suffer vertebral fractures than women without depression, adjusting for history of vertebral fracture, history of falling, arthritis, diabetes, steroid use, estrogen use, supplemental calcium use, cognitive function, and hip BMD (OR, 2.1; 95% CI, 1.4-3.2; P<.001). CONCLUSIONS: Depression is a significant risk factor for fracture in older women. The greater frequency of falls among individuals with depression partially explains this finding. Other mechanisms responsible for the association between depression and fracture remain to be determined.

Calcium intake and fracture risk: results from the study of osteoporotic fractures.

The relation between dietary calcium, calcium, and vitamin D supplements and the risk of fractures of the hip (n = 332), ankle (n = 210), proximal humerus (n = 241), wrist (n = 467), and vertebrae (n = 389) was investigated in a cohort study involving 9,704 US white women aged 65 years or older. Baseline assessments took place in 1986-1988 in four US metropolitan areas. Dietary calcium intake was assessed at baseline with a validated food frequency questionnaire. Data on new nonvertebral fractures were collected every 4 months during a mean of 6.6 years of follow-up; identification of new vertebral fractures was based on comparison of baseline and follow-up radiographs of the spine done a mean of 3.7 years apart. Results were adjusted for numerous potential confounders, including weight, physical activity, estrogen use, protein intake, and history of falls, osteoporosis, and fractures. There were no important associations between dietary calcium intake and the risk of any of the fractures studied. Current use of calcium supplements was associated with increased risk of hip (relative risk = 1.5, 95% confidence interval 1.1-2.0) and vertebral (relative risk = 1.4, 95% confidence interval 1.1-1.9) fractures; current use of Tums antacid tablets was associated with increased risk of fractures of the proximal humerus (relative risk = 1.7, 95% confidence interval 1.3-2.4). There was no evidence of a protective effect of vitamin D supplements. Although a true adverse effect of calcium supplements on fracture risk cannot be ruled out, it is more likely that our findings are due to inadequately controlled confounding by indications for use of supplements. In conclusion, this study did not find a substantial beneficial effect of calcium on fracture risk.