Antiresorptive Use Research Articles

Treatment for osteoporosis and risk of osteonecrosis of the jaw among female patients in the United Kingdom Clinical Practice Research Datalink.

Osteonecrosis of the jaw (ONJ) is a rare adverse effect of antiresorptive drug use; however, the magnitude of risk in osteoporosis patients has not been clearly described. We conducted a cohort study among cancer-free female patients aged 40-89 with, or at risk for, osteoporosis in United Kingdom Clinical Practice Research Datalink (CPRD) Aurum. We followed patients from first osteoporosis treatment until first of osteonecrosis diagnosis, age 90, record end, or other prespecified censoring event, and accumulated person-time by osteoporosis treatment. ONJ cases were selected from CPRD Aurum and linked Hospital Episode Statistics data using an algorithm and manual review. We estimated incidence rates (IR) of ONJ by current treatment type and post discontinuation. We conducted a nested case-control analysis to further describe risk by cumulative dose and duration of antiresorptive therapies. Among 467,654 eligible patients, there were 208 ONJ cases. IR among patients currently treated with antiresorptives (primarily alendronate) was 1.2 (95% confidence interval [CI] 1.0-1.4) per 10,000 person-years. Compared with past use of antiresorptives, odds ratios of ONJ were 3.0 (95% CI 1.5-5.7) after 2-3 years of treatment and 8.1 (95% CI 4.4-15) after 10 years. However, absolute risks remained low (~ 0.05% after 5 years and ~ 0.18% after 10 years) and elevated risks diminished to near zero within 6 to 9 months of discontinuation. Risk of ONJ increased after 2-3 years of treatment with antiresorptives; however, the absolute risk was low and returned to baseline shortly after treatment discontinuation.

The Risk of Medication-Related Osteonecrosis of the Jaw in Children: Guidance for Antiresorptive Use in Pediatric Patients

Antiresorptive targeted cancer therapies, such as denosumab and bisphosphonates, are used in adults, but their application in pediatric cancer is more recent. Side effects such as osteonecrosis of the jaw (ONJ) observed in adults have curtailed use of these medications in the pediatric population. This study assesses the frequency of ONJ, other side effects, and the indications for use of denosumab versus bisphosphonates in pediatric subjects. A retrospective cohort study of pediatric subjects who underwent bisphosphonate or denosumab therapy at our institution from 2007-2023 was conducted. Subjects aged ≥ 18years at therapy initiation were excluded. The independent variable was antiresorptive therapy divided into 2 groups, treatment with intravenous bisphosphonates or denosumab. Primary outcomes were development of bisphosphonate-related and denosumab-related ONJ. Secondary outcomes included additional side effects. ONJ risk factors, subject demographics, indications for use, timing, duration, and cumulative dose of antiresorptive therapy were abstracted. Univariate and bivariate statistics were computed to describe the sample and measure associations between antiresorptive therapy and outcomes. P values < .05 conferred statistical significance. The sample was composed of 178 subjects with a mean age of 11.7±6.1years. There were 14 (7.9%) and 164 (92.1%) subjects treated with denosumab and bisphosphonate therapies, respectively. There were 0 cases of ONJ across all subjects. The most common indication for treatment was adjuvant targeted therapy for aggressive tumors and malignancy (39.3%) followed by osteoporosis (14.6%). Subjects treated with denosumab had higher frequencies of hypercalcemia and severe bone pain than subjects treated with bisphosphonates, 28.6% versus 1.2% (P<.001) and 14.3% versus 0.00% (P<.001), respectively. While invasive dental procedures are ideally performed before antiresorptive treatment, our data suggest that bisphosphonates may be used safely in the pediatric population with low concern for ONJ. Our data also demonstrated bisphosphonates may have a more tolerable side effect profile than denosumab. If the perceived benefits are similar, we recommend using bisphosphonates as first-line therapy in children while reserving denosumab for refractory cases. Future studies will help determine long-term side effects and differences in efficacies of these medications.

The Incidence and Severity of Medication Related Osteonecrosis of the Jaws is Similar in Male and Female Mice

Medication related osteonecrosis of the jaws (MRONJ), a rare side-effect of antiresorptive medications, is described as exposed bone in the oral cavity that lasts for at least 8weeks. Most studies report a female predilection for MRONJ; these findings could be due to the increased use of antiresorptives in females, or due to inherent differences between male versus female patients. The purpose of this study was to measure and compare the incidence and severity of osteonecrosis of the jaws (ONJ) between male and female mice. We designed a randomized in-vivo animal study utilizing male and female mice treated with zoledronic acid (ZA). Experimental periodontitis was induced in 24 male and 24 female mice using a silk ligature following administration of saline or a potent bisphosphonate. After 8weeks, animals were evaluated radiographically and histologically. The independent variables were sex (male vs female) and treatment group (ZA vs saline control). Treatment was randomly assigned with balanced distribution between male and female animals. The main outcome variable was ONJ status coded as present or absent. ONJ was defined as present if there was histologic contact between the ligature and the alveolar bone. Secondary outcomes of interest were radiographic and histologic parameters. Statistical differences were analyzed using a two-way analysis of variance with Tukey's post hoc test using a P value of 0.05 for significance. The final sample was composed of 24 vehicle treated and 24ZA treated animals. In vehicle treated animals, 8% of female and 8% of male animals developed ONJ. In ZA treated animals, 83% of female and 92% of male animals developed ONJ. Sex was not associated with the risk (measured as incidence of disease) for developing ONJ or in the radiographic or histologic parameters that were assessed (P values >.1). Sex does not appear to affect the incidence of MRONJ or the severity of the disease as assessed by the radiographic and histologic parameters.

Trajectories of oral bisphosphonate use after hip fractures: a population-based cohort study

SummaryBisphosphonates prevent future hip fractures. However, we found that one in six patients with hip fractures had a delay in bisphosphonate initiation and another one-sixth discontinued treatment within 12 months after discharge. Our results highlight the need to address hesitancy in treatment initiation and continuous monitoring.PurposeSuboptimal antiresorptive use is not well understood. This study investigated trajectories of oral bisphosphonate use following first hip fractures and factors associated with different adherence and persistence trajectories.MethodsWe conducted a retrospective study of all patients aged ≥ 50 years dispensed two or more bisphosphonate prescriptions following first hip fracture in Victoria, Australia, from 2012 to 2017. Twelve-month trajectories of bisphosphonate use were categorized using group-based trajectory modeling. Factors associated with different trajectories compared to the persistent adherence trajectory were assessed using multivariate multinomial logistic regression.ResultsWe identified four patterns of oral bisphosphonate use in 1811 patients: persistent adherence (66%); delayed dispensing (17%); early discontinuation (9%); and late discontinuation (9%). Pre-admission bisphosphonate use was associated with a lower risk of delayed dispensing in both sexes (relative risk [RR] 0.28, 95% confidence interval [CI] 0.21–0.39). Older patients (≥\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\ge$$\\end{document} 85 years old versus 50–64 years old, RR 0.38, 95% CI 0.22–0.64) had a lower risk of delayed dispensing. Males with anxiety (RR 9.80, 95% CI 2.24–42.9) and females with previous falls had increased risk of early discontinuation (RR 1.80, 95% CI 1.16–2.78).ConclusionTwo-thirds of patients demonstrated good adherence to oral bisphosphonates over 12 months following hip fracture. Efforts to further increase post-discharge antiresorptive use should be sex-specific and address possible persistent uncertainty around delaying treatment initiation.

Antiresorptive Medications Prior to Stereotactic Body Radiotherapy for Spinal Metastasis are Associated with Reduced Incidence of Vertebral Body Compression Fracture.

Retrospective Cohort. Antiresorptive drugs are often given to minimize fracture risk for bone metastases, but data regarding optimal time or ability to reduce stereotactic body radiotherapy (SBRT)-induced fracture risk is limited. This study examines the association between antiresorptive use surrounding spinal SBRT and vertebral compression fracture (VCF) incidence to provide information regarding effectiveness and optimal timing of use. Patients treated with SBRT for spinal metastases at a single institution between 2009-2020 were included. Kaplan-Meier analysis was used to compare cumulative incidence of VCF for those taking antiresorptive drugs pre-SBRT, post-SBRT only, and none at all. Cox proportional hazards and Fine-Gray competing risk models were used to identify additional factors associated with VCF. Of the 234 patients (410 vertebrae) analyzed, 49 (20.9%) were taking bisphosphonates alone, 42 (17.9%) were taking denosumab alone, and 25 (10.7%) were taking both. Kaplan-Meier analysis revealed a statistically significant lower VCF incidence for patients initiating antiresorptive drugs before SBRT compared to those taking none at all (4% vs 12% at 1 year post-SBRT, P = .045; and 4% vs 23% at 2years, P = .008). On multivariate analysis, denosumab duration (HR: .87, P = .378) or dose (HR: 1.00, P = .644) as well as bisphosphonate duration (HR: .98, P= .739) or dose (HR: .99, P= .741) did not have statistical significance on VCF incidence. Initiating antiresorptive agents before SBRT may reduce the risk of treatment-induced VCF. Antiresorptive drugs are underutilized in patients with spine metastases and may represent a useful intervention to minimize toxicity and improve long-term outcomes.

Osteoporosis in hemophilia: what is its importance in clinical practice?

Introduction The relationship between severe hemophilia and osteoporosis has been well established in the literature. However, although the importance of its prevention in order to reduce the risk of bone fractures has been reported, the importance of its treatment in clinical practice has not been well analyzed. Areas covered In this paper a review of the available clinical and experimental information on osteoporosis in hemophilia has been performed, to better understand the relationship between hemophilia and osteoporosis. Prevention of osteoporosis in hemophilia should include primary hematological prophylaxis; a diet appropriate in calcium and vitamin D; a regular exercise program that includes aerobics, strength training and balance and flexibility activities; restriction of tobacco and alcohol use; and limitation of the duration of immobilization. Expert opinion Prevention of osteoporosis in hemophilic patients is paramount. However, it is noteworthy that there is only one publication on the treatment of osteoporosis in patients with hemophilia. Until further research is done on this topic, the existing recommendations for non-hemophilic patients should be followed. They include the use of antiresorptives (estrogens, selective estrogen receptor modulators, bisphosphonates, denosumab) and anabolic agents (teriparatide, abaloparatide, romosozumab). Further studies on the management of osteoporosis in patients with hemophilia are required.

The Effect of Immune-compromising Systemic Comorbidities on Outcome Measures for Deep Fascial Space Infections

Deep fascial space infections of the head and neck (H&N) region may result in significant patient morbidity as well as extended utilization of healthcare resources, particularly in the immunocompromised or those otherwise predisposed to infection. The purpose of this study was to evaluate the effect of systemic comorbidities and medications on outcome measures for deep fascial space infections in a tertiary care center over a 3-year period. The authors hypothesized that length of stay (LOS), readmission rate, and reoperation rate would be increased in patients with systemic comorbidities predisposing to infection.A retrospective chart review was performed for patients admitted to the sponsoring institution from January 2017 through December 2020. Cases were identified using an electronic medical record query for International Classification of Diseases (ICD-10) codes corresponding to diagnoses consistent with deep fascial space infections of the H&N region. Patients with an infection of 1 or more deep fascial spaces were included. Exclusion criteria were incomplete medical record, infections of superficial to the investing fascia, and intracranial abscesses.The analyzed variables included infection etiology; number of fascial spaces involved; medical comorbidities including human immunodeficiency virus (HIV), diabetes, active malignancy, H&N radiation, transplant history; and use of the following medications on admission: bisphosphonates, antiresorptives, biologics, tumor necrosis factor inhibitors, monoclonal antibodies, antimetabolites, and corticosteroids. The outcome measures studied were LOS, operation, reoperation, and readmission.Statistical analyses were performed using Qualtrics Stats iQ software. Bivariate analysis was performed using Chi-square test to evaluate the relationships between selected study variables. P < .05 was considered statistically significant.The initial query yielded 251 patients admitted with the included diagnoses. Of these 251 patients, 86 met the inclusion criteria. The mean number of spaces involved was 2.2±1.0 spaces. There were 18 patients (21.0%) with 1 or more of the defined comorbidities: 15 diabetes (17.4%), 3 HIV (3.5%), 2 H&N radiation (2.3%), 1 bisphosphonate (1.2%), 1 antiresorptive (1.2%), 2 biologics (2.3%), and 1 corticosteroid (1.2%). No patients included in the study had a history of transplant. Eighty-two patients (95.3%) underwent incision and drainage (I&D) under general anesthesia, and 1 patient (1.2%) underwent bedside incision and drainage under local anesthesia. Three patients (3.5%) received no surgical intervention and were treated with intravenous antibiotics alone. A total of 6 patients (7.0%) required reoperation. All 18 patients with identified comorbidities underwent I&D. The average length of stay for all patients was 3.3±2.4 days with a maximum LOS of 13 days; 6 (7.0%) patients required readmission.There was a strong statistically significant relationship between increased number of involved fascial spaces and LOS (P < .001). There was no significant relationship between any of the comorbidities and number of involved spaces, reoperation, or readmission. There was a strong statistically significant relationship between LOS and active malignancy (P = .01), H&N radiation (P < 0.001), bisphosphonate use (P = .01), and antiresorptive use (P = .01). There was no relationship between LOS and HIV, diabetes, and biologic or corticosteroid use.This study sought to identify predictors of outcome in patients with deep fascial space infections of the H&N region. The researchers found that an increased number of involved spaces, active malignancy, history of H&N radiation, and bisphosphonate/antiresorptive use are clinical indicators of LOS outcomes in patients with deep fascial space infections. However, these factors were not significantly associated with readmission or the need for reoperation.

Predictive factors of osteoradionecrosis necessitating segmental mandibulectomy: A descriptive study

The objective of this study was to assess characteristics of patients with mandibular osteoradionecrosis (ORN) of severity necessitating segmental mandibulectomy and osteocutaneous free flap reconstruction. This study is a retrospective review of patients who underwent free flap reconstruction of the mandible at the UCLA Medical Center between January 2016 and February 2020 secondary to ORN. Twenty-nine charts with detailed dental and medical records were identified. Hypertension was reported in 14 of 29 patients, diabetes in 2 of 29, osteoporosis in 2 of 29, antiresorptive use in 3 of 29, tobacco use in 15 of 29, and alcohol use in 19 of 29. Twenty-three patients initially had stage III-IV cancer. The median radiation dose was 68 Gy and median time to ORN was 5.2 years. Chemotherapy was given in 21 patients and 4 had previous mandibular surgery. Twelve of 29 patients had surgical procedures identified as the causative factor and 17 of 29 occurred spontaneously. Median decayed, missing, and filled teeth score was 17 and 17 of 29 patients had grade II-IV periodontitis. Periodontitis was present in 8 of 17 of spontaneous and 1 of 12 of surgery cases. Twenty-five of 29 cases occurred in the same oral sextant as the tumor. Severe ORN occurred at doses >60 Gy in most cases. Location of the primary tumor was predictive of site of ORN and only molars were involved when precipitated by tooth extraction. Risk of ORN persists indefinitely.

Anabolic treatments for osteoporosis in postmenopausal women.

Antiresorptive agents are generally recommended as first-line treatment for osteoporosis in postmenopausal women. These drugs suppress bone resorption but do not rebuild bone, limiting their efficacy. Antiresorptive use is further hampered by concerns over rare side effects, including atypical femoral fractures and osteonecrosis of the jaw. Anabolic treatments overcome limitations of antiresorptive treatment by stimulating new bone formation, reducing the risk of fracture with greater efficacy. This review summarises the latest trial data for the three anabolic agents currently available for the treatment of osteoporosis in postmenopausal women: teriparatide, abaloparatide, and romosozumab. Data from head-to-head studies comparing anabolic and antiresorptive treatments are reviewed. At present, anabolic treatments are generally reserved for use in patients with severe osteoporosis at very high fracture risk; the factors limiting their more widespread use are discussed together with how this may change in the future.

Change in Quantitative Ultrasound-assessed Speed of Sound as a Function of Age in Women and Men and Association With the Use of Antiresorptive Agents: The Canadian Multicentre Osteoporosis Study

Introduction: Five-year changes in multisite quantitative ultrasound-assessed speed of sound (SOS in m/s) were studied in a cohort of women and men. The impacts of antiresorptive therapies and menopausal status on SOS were also assessed. Methodology: Two SOS assessments, clinical assessments, and comprehensive questionnaires were completed 5 years apart on 509 women and 211 men. Age at first assessment was grouped into: <40 yr, 40–49 yr, 50–59 yr, 60–69 yr, 70–79 yr and 80+ yr. Mean rate of change in SOS at the distal radius and tibia were calculated for each age grouping by sex. SOS changes were stratified by antiresorptive use (yes, no) or menopausal status (premenopausal, postmenopausal, or bilateral oophorectomy). Results: Mean losses in SOS occurred over the 5 years in almost all age groupings. In women, mean losses in SOS for the <40 yr, 40–49 yr, 50–59 yr, 60–69 yr, 70–79 yr, and 80+ yr age groupings were −59, −83, −107, −92, −80 and −66 (p = 0.30; differences among age groupings) at the radius and −18, −16, −54, −1, −9 and 31 at the tibia (p < 0.05), respectively. In men, mean SOS losses were −101, −56, −69, −67, −83 and −127 at the radius (p = 0.61) and −46, −61, 0, −35, −29, and −26 at the tibia (p = 0.23). At the tibia, women prescribed antiresorptives had a mean increase in SOS (8.6 m/s) whereas untreated participants had a mean loss (−23.0; p < 0.001); there was no significant impact at the distal radius. There were no significant differences in change in SOS among menopausal groups (p > 0.26). Conclusions: Mean SOS generally declined over 5 years in all age groupings of both sexes. The consistent mean losses in SOS over the age spans investigated are coincident with increasing fracture risk. Women on antiresorptive therapy had increased mean SOS over the 5-year assessment period at the tibia, whereas untreated women had mean losses in SOS.

Medication-related osteonecrosis of the jaw. Implant presence-triggered osteonecrosis: Case series and literature review

PurposeThe aim of this study was to review the characteristics of ‘implant presence-triggered osteonecrosis’ (IPTO) in the literature and identify possible differences between IPTOs and ‘implant surgery-triggered osteonecrosis’ (ISTO). Materials and methodsReviews using PubMed and the Cochrane Database of Systematic Reviews were performed from 2009–2018; the focus was on medication-related osteonecrosis of the jaw (MRONJ) and dental implants. In addition, the hospital records of all patients presented in our department with IPTO were retrospectively reviewed. In both studies, the following data were collected: the number of patients with ISTO or IPTO, age, gender, location, stage of MRONJ, number of implants involved in MRONJ, the elapsed time between the placement of the implants and the development of MRONJ, applied treatment and the presence of mandibular fractures and progress. ResultsThe literature review provided 111 articles. Nine of the articles were selected for bibliographic review. The number of osteonecrosis cases was significantly higher in the IPTO group (74 cases) compared with the ISTO group (27 cases). The duration of the anti-resorptive treatment (oral and intravenous) was also longer in the IPTO group. In our centre, seven patients with IPTO were chosen; however, no patients with ISTO were selected. The significant differences between the patients in our series and the information collected in the literature for the IPTO group were the time of ingestion of alendronate, the elapsed time from the placement of the implants to the development of the MRONJ and the number of implants linked to the development of a complication. ConclusionsThe use of antiresorptives causes osteonecrosis in patients with implants that are subjected to functional loading, and this occurs at a higher frequency than what is observed after implant placement surgery.

Anti-osteoporosis Medication Use in a High Fracture-Risk Population: Contemporary Trends in Australian Residential Aged Care Facilities.

Osteoporotic fractures impose substantial morbidity and mortality among older adults. Undertreatment is an ongoing concern; treatment rates declined following reports of adverse effects of guideline-recommended bisphosphonates, but new antiresorptives have since become available. Our goal was to identify contemporary trends in osteoporosis treatment guideline adherence in a high fracture-risk population. We conducted a secondary data analysis using electronic health record data of adults aged ⩾65 years from 68 residential aged care facilities in Australia during 2014-2017 (n = 9094). Using medication administration data, we identified antiresorptive (bisphosphonates and denosumab) and vitamin D supplement use among residents with osteoporosis. Regression was used to evaluate temporal trends, and resident and facility characteristics associated with antiresorptive use and vitamin D use. In 2014, 34% of women and 42% of men with osteoporosis used antiresorptives; this decreased 8 percentage points by 2017. Antiresorptive use was higher among those with a history of fracture and lower in the last year of life. Denosumab use increased but did not substitute for the continued decline in bisphosphonate use. Vitamin D was consistently used by more than 60% of residents and was higher among those with fracture history. Greater attention to the treatment of osteoporosis treatment rates among this high fracture-risk population is warranted.

Advances and Unmet Needs in the Therapeutics of Bone Fragility.

The prevalence of fragility fractures increases as longevity increases the proportion of the elderly in the community. Until recently, the majority of studies have targeted women with osteoporosis defined as a bone mineral density (BMD) T score of < −2.5 SD, despite evidence that the population burden of fractures arises from women with osteopenia. Antiresorptive agents reduce vertebral and hip fracture risk by ~50 percent during 3 years but efficacy against non-vertebral fractures, 80% of all fractures in the community, is reported in few studies, and of those, the risk reduction is only 20–30%. Recent advances in the use of antiresorptives and anabolic agents has addressed some of these unmet needs. Zoledronic acid is now reported to reduce vertebral and non-vertebral fractures rates in women with osteopenia. Studies using teriparatide demonstrate better vertebral and clinical (symptomatic vertebral and non-vertebral) antifracture efficacy than risedronate. Abaloparatide, a peptide sharing amino acid sequences with teriparatide, reduces vertebral and non-vertebral fractures. Romosozumab, a monoclonal antibody suppressing sclerostin, reduces vertebral and non-vertebral fractures within a year of starting treatment, and does so more greatly than alendronate. Some recent studies signal undesirable effects of therapy but provide essential cautionary insights into long term management. Cessation of denosumab is associated with a rapid increase in bone remodeling and the uncommon but clinically important observation of increased multiple vertebral fractures suggesting the need to start alternative anti-resorptive therapy around the time of stopping denosumab. Antiresorptives like bisphosphonates and denosumab suppress remodeling but not completely. Antifracture efficacy may be limited, in part, as a consequence of continued unsuppressed remodeling, particularly in cortical bone. Bisphosphonates may not distribute in deeper cortical bone, so unbalanced intracortical remodeling continues to cause microstructural deterioration. In addition, suppressed remodeling may compromise the material composition by increasing matrix mineral density and glycosylation of collagen. As antiresorptive agents do not restore microstructural deterioration existing at the time of starting treatment, under some circumstances, anabolic therapy may be more appropriate first line treatment. Combining antiresorptive and anabolic therapy is an alternative but whether anti-fracture efficacy is greater than that achieved by either treatment alone is not known.

Antiresorptives: Safety Concerns-Clinical Perspective.

Antiresorptive drugs, such as amino-bisphosphonates and denosumab (Dmab), have dominated osteoporosis therapies for over 20 years. Since osteoporosis is a chronic disease, antifracture therapy could continue for the rest of a patient's life. Phase III clinical trials for antiresorptive drugs assessed relatively small patient populations for short durations and excluded up to 80% of patients who might seek osteoporosis therapy in clinical practice. Postmarketing reports based upon millions of patient-years and long-term (>5 years) clinical administration have associated some previously unknown, rare adverse events with antiresorptive use including osteonecrosis of the jaw (ONJ) and atypical femur fractures (AFFs). In the osteoporosis patient population, who receive much lower doses of bisphosphonate (BP) or Dmab, the incidence of ONJ is estimated at 0.001% to 0.01%, which is only slightly higher than that seen in the general population. AFFs are insufficiency or fissure transverse fractures originating on the lateral cortex of the subtrochanteric or diaphyseal region of the femur becoming oblique as they progress medially when complete. Incidence rates of AFF range from 1.8/100,000 per year with a 2-year BP exposure to 113/100,000 per year with BP exposure from 8 to 9.9 years. Most recent pathogenic hypotheses of these rare events will be discussed.

Bone Failure in Critical Illness.

The origin of systemic inflammatory response syndrome and multiple organ dysfunction syndrome is poorly understood but remains a fundamental concern in the ICU. This paper provides a critical appraisal on whether bone failure may represent an unrecognized component of systemic inflammatory response syndrome/multiple organ dysfunction syndrome. Search of the PubMed database and manual review of selected articles investigating bone pathophysiology in critical illness. Bone hyperresorption is highly prevalent among critically ill patients. Bone breakdown releases numerous systemically active cytokines and bone-sequestered toxins, with the capacity to fuel inflammatory hypercytokinaemia and metabolic toxaemia. Anti-resorptive medication inhibits bone break down and preadmission anti-resorptive use is associated with superior survival among critically ill patients. We propose that hyperresorptive bone failure is an unrecognised component of systemic inflammatory response syndrome/multiple organ dysfunction syndrome that is causal to critical illness progression. If this hypothesis is valid, bone preservative strategies could reduce the risk of osteoporosis/fractures among ICU survivors, as well as decreasing critical illness mortality.

Improvement of cancellous bone microstructure in patients on teriparatide following alendronate pretreatment

An increase in procollagen type I amino-terminal propeptide (PINP) early after teriparatide initiation was shown to correlate with increased lumbar spine areal BMD and is a good predictor of the anabolic response to teriparatide. Few data exist correlating PINP and bone microstructure, and no data exist in patients on teriparatide following prior potent antiresorptive treatment. This exploratory analysis aimed to investigate the effects of teriparatide on cancellous bone microstructure and correlations of bone markers with microstructure in alendronate-pretreated patients. This was a post hoc analysis of changes in bone markers and three-dimensional indices of bone microstructure in paired iliac crest biopsies from a prospective teriparatide treatment study in postmenopausal women with osteoporosis who were either treatment-naïve (TN, n=16) or alendronate-pretreated (ALN, n=29) at teriparatide initiation. Teriparatide (20μg/day) was given for 24months; biopsies were taken at baseline and endpoint, and serum concentrations of PINP and type 1 collagen cross-linked C-telopeptide (βCTX) were measured at intervals up to 24months. In the TN and ALN groups, respectively, mean (SD) increases in three-dimensional bone volume/tissue volume were 105 (356)% (P=0.039) and 55 (139)% (P<0.005) and trabecular thickness 30.4 (30)% (P<0.001) and 30.8 (53)% (P<0.001). No significant changes were observed in trabecular number or separation. In the ALN patients, 3-month change of neither PINP nor βCTX correlated with indices of cancellous bone microstructure. However, 12-month changes in biochemical bone markers correlated significantly with improvements in bone volume/tissue volume, r=0.502 (P<0.01) and r=0.378 (P<0.05), trabecular number, r=0.559 (P<0.01) and r=0.515 (P<0.01), and reduction of trabecular separation, r=−0.432 (P<0.05) and r=−0.530 (P<0.01), for PINP and βCTX, respectively. We conclude that cancellous bone microstructure improved with teriparatide therapy irrespective of prior antiresorptive use.

Bone lead (Pb) content at the tibia is associated with thinner distal tibia cortices and lower volumetric bone density in postmenopausal women

Conflicting evidence suggests that bone lead or blood lead may reduce areal bone mineral density (BMD). Little is known about how lead at either compartment affects bone structure. This study examined postmenopausal women (N=38, mean age 76±8, body mass index (BMI): 26.74±4.26kg/m2) within the Hamilton cohort of the Canadian Multicentre Osteoporosis Study (CaMos), measuring bone lead at 66% of the non-dominant leg and at the calcaneus using 109Cadmium X-ray fluorescence. Volumetric BMD and structural parameters were obtained from peripheral quantitative computed tomography images (200μm in-plane resolution, 2.3±0.5mm slice thickness) of the same 66% site and of the distal 4% site of the tibia length. Blood lead was measured using atomic absorption spectrometry and blood-to-bone lead partition coefficients (PBB, log ratio) were computed. Multivariable linear regression examined each of bone lead at the 66% tibia, calcaneus, blood lead and PBB as related to each of volumetric BMD and structural parameters, adjusting for age and BMI, diabetes or antiresorptive therapy. Regression coefficients were reported along with 95% confidence intervals. Higher amounts of bone lead at the tibia were associated with thinner distal tibia cortices (−0.972 (−1.882, −0.061) per 100μg Pb/g of bone mineral) and integral volumetric BMD (−3.05 (−6.05, −0.05) per μg Pb/g of bone mineral). A higher PBB was associated with larger trabecular separation (0.115 (0.053, 0.178)), lower trabecular volumetric BMD (−26.83 (−50.37, −3.29)) and trabecular number (−0.08 (−0.14, −0.02)), per 100μg Pb/g of bone mineral after adjusting for age and BMI, and remained significant while accounting for diabetes or use of antiresorptives. Total lead exposure activities related to bone lead at the calcaneus (8.29 (0.11, 16.48)) and remained significant after age and antiresorptives-adjustment. Lead accumulated in bone can have a mild insult on bone structure; but greater partitioning of lead in blood versus bone revealed more dramatic effects on both microstructure and volumetric BMD.

Long-term safety of antiresorptive treatment: bone material, matrix and mineralization aspects.

It is well established that long-term antiresorptive use is effective in the reduction of fracture risk in high bone turnover osteoporosis. Nevertheless, during recent years, concerns emerged that longer bone turnover reduction might favor the occurrence of fatigue fractures. However, the underlying mechanisms for both beneficial and suspected adverse effects are not fully understood yet. There is some evidence that their effects on the bone material characteristics have an important role. In principle, the composition and nanostructure of bone material, for example, collagen cross-links and mineral content and crystallinity, is highly dependent on tissue age. Bone turnover determines the age distribution of the bone structural units (BSUs) present in bone, which in turn is decisive for its intrinsic material properties. It is noteworthy that the effects of bone turnover reduction on bone material were observed to be dependent on the duration of the antiresorptive therapy. During the first 2-3 years, significant decreases in the heterogeneity of material properties such as mineralization of the BSUs have been observed. In the long term (5-10 years), the mineralization pattern reverts towards normal heterogeneity and degree of mineralization, with no signs of hypermineralization in the bone matrix. Nevertheless, it has been hypothesized that the occurrence of fatigue fractures (such as atypical femoral fractures) might be linked to a reduced ability of microdamage repair under antiresorptive therapy. The present article examines results from clinical studies after antiresorptive, in particular long-term, therapy with the aforementioned potentially positive or negative effects on bone material.

Commentary:Drug-Associated Atypical Femoral Fractures (DaAFFs): Balancing the Facts

The nitrogen-containing bisphosphonates (N-BPs), stable analogs of the naturally occurring pyrophosphate, are the most widely utilized drug class for osteoporosis and the first line of treatment in metastatic bone disease. They selectively bind bone mineral and are ingested by osteoclasts to impair their ability to resorb bone. Therefore, in conditions where bone resorption exceeds bone formation, N-BPs slow down the ongoing bone loss and, in doing so, reduce the risk of fracture in osteoporosis and skeletal-related events in metastatic cancer. Equally effective is denosumab, a fully human monoclonal antibody inhibiting the receptor activator of nuclear factor B ligand (RANKL), a protein essential for osteoclast development, activity, and survival. However, an unusual atraumatic or minimal-trauma fracture, the atypical femoral fracture (AFF), has been reported with increasing frequency in bisphosphonate users since the first case reports were published in 2005 and were recently reported in denosumab users. This fracture occurs between the lesser trochanter and the femoral condyles and has specific radiological features (1, 2). It also occurs in bisphosphonateor denosumabnaive individuals and in patients on weak non-bisphosphonate antiresorptive agents (3, 4). Despite its rarity, there is considerable concern among physicians and patients regarding the long-term use of bisphosphonates for fracture prevention. The first suggestions of an association of AFFs with bisphosphonates came from case reports and case series followed by observational studies that, while being hypothesis-generating, remain fraught with limitations. Because no ICD code is yet available for low-trauma AFF, certain studies have failed even to separate low-energy from high-energy fractures. The indication bias is inherent within most, if not all, such studies. Patients using antiresorptives are, by indication, at a high risk of fracture, which does not allow the attribution of AFFs to antiresorptive use as opposed to the pre-existing osteoporosis. Also, there is inconsistency of defining AFFs, and there is no radiographic adjudication for a good number of them. Furthermore, a Dutch cohort study over 11 years reported that AFFs occurred with the same frequency in non-bisphosphonate users (5). Other epidemiological studies from Europe and North America have had no access to radiographs, preventing the identification of features that are required to classify a fracture as atypical. These studies were thus performed on all subtrochanteric fractures. The outcomes, to no surprise, are at best contradictory. The rarity of AFFs prohibits the conduct of randomized safety trials that could potentially determine whether the risk of such fractures is increased in bisphosphonate or denosumab users. The only “prospective” evidence comes from the reanalysis of data from over 14 000 patients enrolled in the alendronate Fracture Intervention Trial (FIT), FIT Long-term Extension (FLEX), and the Zoledronic Acid Once Yearly (HORIZON) trials. There was no increase in subtrochanteric and femoral shaft fracture risk, or indeed the risk of any fracture, in bisphosphonatetreated patients compared with the placebo group (6). This analysis has nonetheless been rightly criticized for its lack of access to patient radiographs and the relatively short duration of bisphosphonate exposure. It was also underpowered, considering the rarity of these fractures. There is no apparent dose response between bisphosphonates and AFFs. This is highlighted in cancer patients with bone metastasis who are regularly treated with bisphosphonates or denosumab. The yearly amount of these potent antiresorptive medications prescribed could be up

Sequential use of antiresorptives in younger women

Dear Editor, We read with much interest the European guidance recently published by Kanis et al. [1]. We would like to congratulate the authors for the excellent work that summarizes the state of art concerning the diagnosis and management of osteoporosis. One important point, well highlighted in the guidance, concerns the combination and sequential treatments. Authors mention published studies on the use of inhibitors of resorption subsequent to anabolic treatment. The concatenation of treatments may also have some interest in women who, because of their younger age, are potential candidates to long-term treatment. Two variables, the gradation of the fracture phenotype with age and the particular profile of each drug, may favor some rational proposals. The Spanish Menopause Society (SMS) recently issued a clinical practice guideline [2], which included particular recommendations that, we think, might be of interest for the group of younger candidates to treatment. Vertebral, and not hip, fractures constitute themain threat for women less than 70–75 years. Moreover, younger women face many years of treatment once this is initiated. The reason is that whether there is already a treatment indication, the considerable impact of age as a risk factor imposes additional strength in the indication when women grow older. However, the long-term use of stronger antiresorptives, where bisphosphonates are the paradigm, is subjected to some debate. These considerations support the special value of selective estrogen receptor modulators (SERMs) in this age group. Both raloxifene and bazedoxifene are approved by the EuropeanMedicines Agency for use in osteoporosis. These compounds seem free of side effects associated with drastic reduction of resorption while protecting against vertebral fractures. Furthermore, SERMs provide sustained protection against invasive breast cancer [3], a disease that maintains a considerable share as a determinant of mortality in younger women [4]. This additional benefit has been taken as a variable contributing to improve the cost/benefit ratio of SERMs [5]. Finally, although neutral for cardiovascular disease, a post hoc analysis has suggested that raloxifene might reduce a risk for coronary heart disease in women at higher risk [6]. In consistence with those properties, SERMs have been considered as multi-target drugs. The European guidance rightly points out that one persistent side effect of SERMs is the increased risk for venous thromboembolic disease (VTED). It may be worth mentioning that VTED is an infrequent disorder that, interestingly, also increases with age [7]. In consequence, the absolute number of SERMs-induced cases should be lowered when the population being treated is younger. Taking the abovementioned arguments into consideration, the practice guideline of the (SMS) has recommended SERMs as an efficient option in younger women. A sequential concatenation has been suggested in which SERMs may be maintained for a certain number of years, up to the age in which hip fracture starts being a consistent threat. Then, SERMs may be replaced by a more powerful antiresorptive, with demonstrated efficacy against hip fracture. Individual profiles, side effects, compliance, or densitometric response may, obviously, operate as variables that should support treatment alternatives on a personalized basis. It should be stressed, A. Cano Hospital Universitario Dr. Peset, University of Valencia, Av Gaspar Aguilar, 90, 46017 Valencia, Spain