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The original version of this article, published on 21 March 2019, unfortunately contains some typos in Figs. 2, 3, 4, and Supplemental Fig. 1. The corrected figures are given below. [ABSTRACT FROM AUTHOR]

Patients treated with pharmacological agents to improve bone strength and reduce fracture risk may not achieve optimal skeletal benefit for reasons that include poor compliance and persistence, inadequate calcium and vitamin D intake, malabsorption, and medications or co-morbidities with adverse skeletal effects. Monitoring the effects of therapy can inform the patient and physician that the drug is having its expected skeletal response. Treatment is often monitored with serial bone mineral density (BMD) measurements using dual-energy X-ray absorptiometry or bone turnover markers (BTMs). Stable or increasing BMD is associated with reduced fracture risk in clinical trials, and is considered an indication of good response to therapy in individual patients outside of clinical trials. There are many differences between subjects in clinical trials and patients being treated in clinical practice. Thus, although defining a clinical practice patient as a “nonresponder” or “suboptimal responder” to treatment is problematic, a pragmatic approach would be to consider evaluation for contributing factors and possible changes in therapy in patients who have a statistically significant decrease in BMD, do not have the expected change in BTMs, or have a fracture. [ABSTRACT FROM AUTHOR]

Bisphosphonates (BPs) are well established as the leading drugs for the treatment of osteoporosis. There is new knowledge about how they work. The differences that exist among individual BPs in terms of mineral binding and biochemical actions may explain differences in their clinical behavior and effectiveness. The classical pharmacological effects of bisphosphonates (BPs) appear to be the result of two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts. There is new information about both properties. Mineral binding affinities differ among the clinically used BPs and may influence their differential distribution within bone, their biological potency, and their duration of action. The antiresorptive effects of the nitrogen-containing BPs (including alendronate, risedronate, ibandronate, and zoledronate) appear to result from their inhibition of the enzyme farnesyl pyrophosphate synthase (FPPS) in osteoclasts. FPPS is a key enzyme in the mevalonate pathway, which generates isoprenoid lipids utilized for the post-translational modification of small GTP-binding proteins that are essential for osteoclast function. Effects on other cellular targets, such as osteocytes, may also be important. BPs share several common properties as a drug class. However, as with other families of drugs, there are obvious chemical, biochemical, and pharmacological differences among the individual BPs. Each BP has a unique profile that may help to explain potential clinical differences among them, in terms of their speed and duration of action, and effects on fracture reduction. [ABSTRACT FROM AUTHOR]

One year after discontinuation of three year’s treatment with risedronate, BMD decreased at the lumbar spine and femoral neck and bone turnover markers returned to control group levels. Despite these changes, the risk of new morphometric vertebral fractures remained lower in previous risedronate patients compared with previous control patients. Differences in bisphosphonate pharmacology and pharmacokinetics could influence persistence or resolution of the effects once treatment is stopped. We investigated changes in intermediate markers—bone mineral density (BMD) and bone turnover markers (BTM)—and fracture risk after discontinuation of treatment with risedronate. Patients who received risedronate 5 mg daily ( N = 398) or placebo ( N = 361) during the VERT-NA study stopped therapy per protocol after 3 years but continued taking vitamin D (if levels at study entry were low) and calcium and were reassessed one year later. In the year off treatment, spine BMD decreased significantly, but remained higher than baseline ( p ≤ 0.001) and placebo ( p < 0.001), with similar findings at the femoral neck and trochanter. Urinary NTX and bone-specific alkaline phosphatase, which decreased significantly with treatment, were not significantly different from placebo after 1 year off treatment. Despite the changes in intermediate markers, the incidence of new morphometric vertebral fractures was 46% lower in the former risedronate group compared with the former placebo group (RR 0.54 [95% CI, 0.34, 0.86, p = 0.009]). Despite the apparent resolution of effect on BMD and BTM, the risk reduction of new vertebral fractures remained in the year after treatment with risedronate was stopped. [ABSTRACT FROM AUTHOR]

Randomized clinical trials have shown that risedronate and alendronate reduce fractures among women with osteoporosis. The aim of this observational study was to observe, in clinical practice, the incidence of hip and nonvertebral fractures among women in the year following initiation of once-a-week dosing of either risedronate or alendronate. Using records of health service utilization from July 2002 through September 2004, we created two cohorts: women (ages 65 and over) receiving risedronate (n = 12,215) or alendronate (n = 21,615). Cox proportional hazard modeling was used to compare the annual incidence of nonvertebral fractures and of hip fractures between cohorts, adjusting for potential differences in risk factors for fractures. There were 507 nonvertebral fractures and 109 hip fractures. Through one year of therapy, the incidence of nonvertebral fractures in the risedronate cohort (2.0%) was 18% lower (95% CI 2% – 32%) than in the alendronate cohort (2.3%). The incidence of hip fractures in the risedronate cohort (0.4%) was 43% lower (95% CI 13% – 63%) than in the alendronate cohort (0.6%). These results were consistent across a number of sensitivity analyses. Patients receiving risedronate have lower rates of hip and nonvertebral fractures during their first year of therapy than patients receiving alendronate. [ABSTRACT FROM AUTHOR]

The original version of this article, published on 21 March 2019, unfortunately contained a mistake. [ABSTRACT FROM AUTHOR]

Focuses on a patient who developed fatty deposits or benign symmetric lipomatosis while on the protease inhibitors indinavir, lamivudine, and zidovudine. The man's medical history, which includes HIV-1 infection; Episodes of herpes zoster, myalgia and weakness; The development of a `buffalo hump.'

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 .). [ABSTRACT FROM AUTHOR]

Summary: We compared self-perception of fracture risk with actual risk among 60,393 postmenopausal women aged ≥55 years, using data from the Global Longitudinal Study of Osteoporosis in Women (GLOW). Most postmenopausal women with risk factors failed to appreciate their actual risk for fracture. Improved education about osteoporosis risk factors is needed. Introduction: This study seeks to compare self-perception of fracture risk with actual risk among postmenopausal women using data from GLOW. Methods: GLOW is an international, observational, cohort study involving 723 physician practices in 17 sites in ten countries in Europe, North America, and Australia. Participants included 60,393 women ≥55 years attended by their physician during the previous 24 months. The sample was enriched so that two thirds were ≥65 years. Baseline surveys were mailed October 2006 to February 2008. Main outcome measures were self-perception of fracture risk in women with elevated risk vs women of the same age and frequency of risk factors for fragility fracture. Results: In the overall study population, 19% (10,951/58,434) of women rated their risk of fracture as a little/much higher than that of women of the same age; 46% (27,138/58,434) said it was similar; 35% (20,345/58,434) believed it to be a little/much lower. Among women whose actual risk was increased based on the presence of any one of seven risk factors for fracture, the proportion who recognized their increased risk ranged from 19% for smokers to 39% for current users of glucocorticoid medication. Only 33% (4,185/12,612) of those with ≥2 risk factors perceived themselves as being at higher risk. Among women reporting a diagnosis of osteopenia or osteoporosis, only 25% and 43%, respectively, thought their risk was increased. Conclusion: In this international, observational study, most postmenopausal women with risk factors failed to appreciate their actual risk for fracture. [ABSTRACT FROM AUTHOR]

We conducted a case–control study to examine osteonecrosis (ON) incidence, patient characteristics, and selected potential risk factors using two health record databases in the UK. Statistically significant risk factors for ON included systemic corticosteroid use, hospitalization, referral or specialist visit, bone fracture, any cancer, osteoporosis, connective tissue disease, and osteoarthritis. The purpose of this case–control study was to examine the incidence of osteonecrosis (ON), patient characteristics, and selected potential risk factors for ON using two health record databases in the UK: the General Practice Research Database and The Health Improvement Network. ON cases ( n = 792) were identified from 1989 to 2003 and individually matched (age, sex, and medical practice) up to six controls ( n = 4,660) with no record of ON. Possible risk factors were considered for inclusion based on a review of published literature. Annual incidence rates were computed, and a multivariable logistic regression model was derived to evaluate selected risk factors. ON of the hip represented the majority of cases (75.9%). Statistically significant risk factors for ON were systemic corticosteroid use in the previous 2 years, hospitalization, referral or specialist visit, bone fracture, any cancer, osteoporosis, connective tissue disease, and osteoarthritis within the past 5 years. Only 4.4% of ON cases were exposed to bisphosphonates within the previous 2 years. This study provides further perspective on the descriptive epidemiology of ON. Studies utilizing more recent data may further elucidate the understanding of ON key predictors. [ABSTRACT FROM AUTHOR]

The Global Longitudinal study of Osteoporosis in Women (GLOW) is a prospective cohort study involving 723 physicians and 60,393 women subjects ≥55 years. The data will provide insights into the management of fracture risk in older women over 5 years, patient experience with prevention and treatment, and distribution of risk among older women on an international basis. Data from cohort studies describing the distribution of osteoporosis-related fractures and risk factors are not directly comparable and do not compare regional differences in patterns of patient management and fracture outcomes. The GLOW is a prospective, multinational, observational cohort study. Practices typical of each region were identified through primary care networks organized for administrative, research, or educational purposes. Noninstitutionalized patients visiting each practice within the previous 2 years were eligible. Self-administered questionnaires were mailed, with 2:1 oversampling of women ≥65 years. Follow-up questionnaires will be sent at 12-month intervals for 5 years. A total of 723 physicians at 17 sites in ten countries agreed to participate. Baseline surveys were mailed (October 2006 to February 2008) to 140,416 subjects. After the exclusion of 3,265 women who were ineligible or had died, 60,393 agreed to participate. GLOW will provide contemporary information on patterns of management of fracture risk in older women over a 5-year period. The collection of data in a similar manner in ten countries will permit comparisons of patient experience with prevention and treatment and provide insights into the distribution of risk among older women on an international basis. [ABSTRACT FROM AUTHOR]

We determined the prevalence of left-right differences in hip bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) and the resultant consequence, namely: the frequency at which patients would be classified differently if lumbar spine and only one hip (rather than both hips) were measured. This was a retrospective DXA scan reanalysis of 3012 white women ≥50 yrs who had scans of both hips using Hologic DXA systems. The difference between left and right hips was considered significant if it exceeded the least significant change (LSC) for any of three hip subregions (total hip, femoral neck, trochanter). The number of women with osteoporosis in both hips, the left hip only, or the right hip only was determined by lowest T-score from total hip, femoral neck, or trochanter. Despite high left-right correlations of subregion BMD, significant left-right differences in BMD were common: the difference exceeded the LSC for 47% of women at total hip, 31% at femoral neck, and 56% at trochanter. Left-right differences in BMD that exceeded the LSC affected the percent agreement of left-right hip classification: for all women irrespective of spine status, there was 77% classification (diagnostic) agreement in hip pairs in which the left-right hip BMD difference exceeded the LSC versus 87% agreement in which LSC was not exceeded (significant difference in proportions, P<0.0001). The greatest risk of different classification would occur in women with normal spines as the diagnosis might be determined by hip T-scores. Using L1-4 lumbar spine T-scores, 1229 women were normal at the spine. Twenty-four (2%) were osteoporotic at both hips. However, 12 women (1%) were osteoporotic only in the left hip (significantly different from zero, P<0.001) and 11 (1%) only in the right hip (P<0.001); of these 23 women, the difference in BMD between the osteoporotic hip and the contralateral hip exceeded the LSC in 16 (70% of those with osteoporosis in only one hip). Using L1-4 lumbar spine T-scores, 1159 women were osteopenic at the spine. Of these, 126 (11%) were osteoporotic at both hips, 54 (5%) only in the left hip (P<0.001), and 42 (4%) only in the right hip (P<0.001); of these 96 women, the difference in BMD between the osteoporotic hip and the contralateral hip exceeded the LSC in 56 (58% of those with osteoporosis in only one hip). A statistically significant number of women with osteoporosis are potentially classified differently when scanning only one hip as a result of the high prevalence of left-right differences in BMD. Although the percentages are low, the total number of women affected may be large. From a public health perspective, the practice of scanning both hips could potentially identify more women with osteoporosis and may help prevent future hip fractures. [ABSTRACT FROM AUTHOR]

Context: Risedronate, a potent bisphosphonate, has been shown to be effective in the treatment of Paget disease of bone and other metabolic bone diseases but, to our knowledge, it has not been evaluated in the treatment of established postmenopausal osteoporosis.Objective: To test the efficacy and safety of daily treatment with risedronate to reduce the risk of vertebral and other fractures in postmenopausal women with established osteoporosis.Design, Setting, and Participants: Randomized, double-blind, placebo-controlled trial of 2458 ambulatory postmenopausal women younger than 85 years with at least 1 vertebral fracture at baseline who were enrolled at 1 of 110 centers in North America conducted between December 1993 and January 1998.Interventions: Subjects were randomly assigned to receive oral treatment for 3 years with risedronate (2.5 or 5 mg/d) or placebo. All subjects received calcium, 1000 mg/d. Vitamin D (cholecalciferol, up to 500 IU/d) was provided if baseline levels of 25-hydroxyvitamin D were low.Main Outcome Measures: Incidence of new vertebral fractures as detected by quantitative and semiquantitative assessments of radiographs; incidence of radiographically confirmed nonvertebral fractures and change from baseline in bone mineral density as determined by dual x-ray absorptiometry.Results: The 2.5 mg/d of risedronate arm was discontinued after 1 year; in the placebo and 5 mg/d of risedronate arms, 450 and 489 subjects, respectively, completed all 3 years of the trial. Treatment with 5 mg/d of risedronate, compared with placebo, decreased the cumulative incidence of new vertebral fractures by 41 % (95% confidence interval [CI], 18%-58%) over 3 years (11.3 % vs 16.3%; P= .003). A fracture reduction of 65% (95% CI, 38%-81 %) was observed after the first year (2.4% vs 6.4%; P<.001). The cumulative incidence of nonvertebral fractures over 3 years was reduced by 39% (95% CI, 6%-61 %) (5.2 % vs 8.4%; P = .02). Bone mineral density increased significantly compared with placebo at the lumbar spine (5.4% vs 1.1 %), femoral neck (1.6% vs -1.2%), femoral trochanter (3.3% vs -0.7%), and midshaft of the radius (0.2% vs -1.4%). Bone formed during risedronate treatment was histologically normal. The overall safety profile of risedronate, including gastrointestinal safety, was similar to that of placebo.Conclusions: These data suggest that risedronate therapy is effective and well tolerated in the treatment of women with established postmenopausal osteoporosis. [ABSTRACT FROM AUTHOR]

Purpose: To determine the efficacy and safety of cyclical etidronate for up to 7 years in the treatment of postmenopausal osteoporosis and to examine the effects of discontinuing treatment after 2 or 5 years of therapy.Patients and Methods: Patients were randomized at entry into the original study in 1986 to blinded treatment for 2 years with either a calcium (placebo) or an intermittent cyclical etidronate regimen, which most patients continued for a third year. Following this phase of the study, patients were enrolled into an open-label, follow-up study (years 4 and 5), during which all patients received cyclical etidronate treatment. In the present double-blind study (years 6 and 7), patients were rerandomized to receive intermittent cyclical therapy with either etidronate or placebo; all patients received calcium. The treatment regimen consisted of 400 mg/day etidronate or placebo for 14 days, followed by 76 days of elemental calcium (500 mg/day); this cycle was repeated approximately 4 times in each year. Of the 193 patients who continued in years 6 and 7 of the study, 93 were randomized to receive cyclical etidronate and 100 were randomized to receive calcium only. For purposes of efficacy analyses, patients were categorized by their total years of cumulative etidronate treatment (7, 5, 4, or 2 years). There were 51, 46, 42, and 54 patients in the 7-, 5-, 4-, and 2-year groups, respectively. Annual assessments included lumbar spine bone mineral density (BMD), as measured by densitometry, and vertebral radiographs.Results: The groups receiving cyclical etidronate during this 2-year study period (7- and 4-year groups) had statistically significant mean percent increases in spinal BMD of 1.8% and 2.2%, respectively (P < 0.05) at the week 104 observation time. The 5- and 2-year groups, which did not receive etidronate during this period, had mean values of 1.4% and 0.2%, respectively (not significant) at week 104. In the 7-, 5-, 4-, and 2-year groups, the increases in spinal BMD at the end of 7 years were 7.6%, 8.6%, 8.1%, and 3.9%, respectively; these values were statistically significant for all groups compared with original baseline (year 0) (P < 0.05). BMD of the femur and wrist was maintained throughout the 7-year period. The incidence and rate of vertebral fractures were lowest in patients with the longest exposure to etidronate. Etidronate was well tolerated during the study, with low incidences of gastrointestinal side effects and nonvertebral fractures.Conclusions: Long-term cyclical etidronate is a safe, effective, and well-tolerated treatment for postmenopausal osteoporosis. Bone mass is maintained for at least 2 years after treatment with etidronate is stopped; however, further gains in spinal bone mass are seen in patients who continue therapy. [ABSTRACT FROM AUTHOR]

Low trauma fractures are the cardinal manifestation of osteoporosis. Their occurrence supersedes bone mineral density in deciding whether specific therapy is warranted. We therefore disagree with the notion that a densitometric threshold for treatment should be applied to patients over age 50 who suffer low trauma distal radius fracture. [ABSTRACT FROM AUTHOR]