Nonvertebral Fractures Research Articles

Ibandronate in the Prevention of Vertebral and Nonvertebral Osteoporotic Fractures: A Systematic Review of Experimental and Observational Studies.

This study aims to evaluate ibandronate clinical effectiveness in the prevention of osteoporosis-related vertebral fractures (VFs) and nonvertebral fractures (NVFs) in the treatment of postmenopausal osteoporosis. This systematic review was conducted in accordance with the Centre for Reviews and Dissemination's guidance and reporting in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement 2020. A literature search was performed in PubMed and EMBASE since their inception until February 7, 2022. Randomized controlled trials (RCTs), meta-analysis, experimental, and observational studies evaluating adult patients treated with ibandronate and assessed to osteoporotic fractures prevention were included. The risk of bias was assessed according to study design. Data were analyzed using descriptive statistics. Eight references from 4 RCTs, 7 meta-analyses, and 6 observational studies were included. In RCTs, oral ibandronate was superior to placebo in the prevention of VF. However, the doses were lower than those approved. The meta-analyses confirmed these results and showed that adequate doses of oral ibandronate reduce the risk of NVF compared with insufficient doses. In observational studies, oral ibandronate (in approved doses) reduced the risk of VF compared with no treatment or risedronate or alendronate and the risk of NVF versus risedronate or alendronate; the risk of hip fractures was similar between ibandronate and other oral bisphosphonates. There is strong evidence that ibandronate reduces the risk of VF in postmenopausal osteoporosis. The available evidence further suggests that ibandronate may reduce the risk of NVF versus insufficient doses of ibandronate, as well as risedronate or alendronate.

Effect of denosumab treatment on bone mineral density and bone turnover markers in osteoporotic patients: real-life experience 2-year follow-up.

The long-term efficacy of anti-osteoclastic drugs in treatment of osteoporosis is well known. Denosumab, a novel human monoclonal antibody, is an anti-osteoclastic agent that has been shown to lead to reductions in vertebral, nonvertebral, and hip fracture risk in randomized and observational studies. Real-life data of this agent is increasing. In this study, we presented our real-life data about the 2-year follow-up of patients under denosumab treatment. Osteoporotic patients who were treated with at least one denosumab injection between 2014 and 2020years were included. Clinical and demographic data, bone turnover markers, and radiological reports (bone mineral densitometry (BMD), vertebral x-ray) were obtained from patient files retrospectively. A total of 305 patients (f/m: 275/30, 68.1 ± 11.05years) were included. The median injection number was 4 (1-10). Two hundred seventy-three patients (89.8%) were persistent on treatment at the 12th month; 175 patients (57.3%) were persistent at 24th month. Sixty-eight patients (22%) were not using denosumab anymore, 55 of the patients were not continuing by doctor desicion and 13 were not continuing due to patient-related causes. Median BMD levels significantly increased from 0.809 (0.2-1.601, IQR: 0.136) to 0.861 (0.517-1.607, IQR: 0.14) in L1-L4 and from 0.702 (0.349-0.997, IQR: 0.125) to 0.745 (0.508-1.008, IQR: 0.137) in femur area at the 24th month of treatment. An improvement of 8.04% in L1-L4 BMD and 4.5% in femur neck BMD levels at the 24th month of treatment was observed. There was a significant decrease in bone turnover markers at the 24th month of treatment. In our group of patients under denosumab treatment, 53% of persistence was found at 24months and associated with improvement in BMD levels without any significant side effects except one case with urticarial reaction. Denosumab leads to improvements in BMD levels and is a well-tolerated agent in a real-life setting comparable to results of randomized controlled studies in patients with different comorbidities.

EXTENSIVE EXPERTISE IN ENDOCRINOLOGY: Osteoporosis management.

Fractures occur in about half of older White women, and almost a third of older White men. However, 80% of the older individuals who have fractures do not meet the bone density definition of osteoporosis, suggesting that this definition is not an appropriate threshold for offering treatment. Fracture risk can be estimated based on clinical risk factors with or without bone density. A combination of calculated risk, fracture history, and bone density is used in treatment decisions. Medications available for reducing fracture risk act either to inhibit bone resorption or to promote bone formation. Romosozumab is unique in that it has both activities. Bisphosphonates are the most widely used interventions because of their efficacy, safety, and low cost. Continuous use of oral bisphosphonates for >5 years increases the risk of atypical femoral fractures, so is usually punctuated with drug holidays of 6-24 months. Denosumab is a further potent anti-resorptive agent given as 6-monthly s.c. injections. It is comparable to the bisphosphonates in efficacy and safety but has a rapid offset of effect after discontinuation so must be followed by an alternative drug, usually a bisphosphonate. Teriparatide stimulates both bone formation and resorption, substantially increases spine density, and reduces vertebral and non-vertebral fracture rates, though data for hip fractures are scant. Treatment is usually limited to 18-24 months, followed by the transition to an anti-resorptive. Romosozumab is given as monthly s.c. injections for 1 year, followed by an anti-resorptive. This sequence prevents more fractures than anti-resorptive therapy alone. Because of cost, anabolic drugs are usually reserved for those at very high fracture risk. 25-hydroxyvitamin D levels should be maintained above 30 nmol/L, using supplements if sunlight exposure is limited. Calcium intake has little effect on bone density and fracture risk but should be maintained above 500 mg/day using dietary sources.

P8.033: Teriparatide in Kidney Transplant Patients With Bisphosphonate-Resistent Osteoporosis

Introduction: Bisphosphonates increase Bone mineral density (BMD) by suppressing bone turnover inhibiting osteoclastic function with risk of inducing adynamic bone disease. Teriparatide is a fragment of the natural human parathyroid hormone (PTH) consisting of the first 34 amino acids counting from the N-terminus end of the natural PTH. Is anabolic drugs stimulate bone formation by increasing osteoblast activity and regulates both bone formation and resorption reducing the risk of vertebral and nonvertebral fractures. Arm: Teriparatide (Parathormone 1-34) treatment in renal trasplant patients with bisphosphonate-resistent osteoporosis.Metods: observational describe study of cases series of 10 kidney transplant patients with bone fragility without response to prolonged treatment with bisphosphonates (greater than 3 years). They were treated with daily subcutaneous injections of 20 microg teriparatide (PTH 1-34) by 18 months. All the patients had 6 months of bisphosphonate wash out. Measurements: we investigated bone turnover markers and effect of teriparatide over BMD of the femoral neck and lumbar spine as well also fractures, graft rejection, cardiovascular events, death and drug related adverse event. Results: 10 patients 9 women, mean age 64.4±14.15 years, BMI 24.3 ±2.64, etiology 3GMN, 3 PKD, 3 unknown, 1 NDBT, HD 9, preempive 1, transplant Time 10.12±5.21 years, 1 preemptive, 8 DBD and 1 LRD, Induction: 8 thymoglobulin, 2 basiliximab, Maintenance 5 belatacept/mycophenolate/MTP, 2 rapamune/mycophenolate/MTP, 3 tacrolimus/mycophenolate/MTP, 6 patients with fractures prior to treatment. Mean of treatment with bisphosphonates 4.1±1.79 years. It is observed at 18 months of treatment with 1-34 PTH increased levels of bone alkaline phosphatase (13.26 UI/L ± 5.75 vs 17.90 ± 7.28, p = 0.045), with NS changes in the rest of the analytes (Table 1) and increase of lumbar bone density of 11.27% (0.8816 gr/cm2 (TS-2.6) vs 0.9941 gr/cm2 (TS-1.38)) and femoral neck of 7.07% (0.6752 gr/cm2(TS-2.5) vs 0.7230 gr/cm2(TS-2.19)). 2 patients presented wrist fractures during treatment with low response(lumbar BMD) to treatment. No cardiovascular events, rejections, deaths were reported. Adverse Events: 1 patient presented hypotension during the first month of treatment. Conclusion: In this group of patients, and adequate response to teriparatide treatment was observed however our limitation were small number of patients and bone biopsy prior teriparatide treatment.

Association of Urinary Pentosidine Levels With the Risk of Fractures in Patients With Severe Osteoporosis: The Japanese Osteoporosis Intervention Trial-05 (JOINT-05).

ABSTRACTAssociations between urinary pentosidine, one of the advanced glycation end products in collagen, and the risk of fracture in patients with severe osteoporosis are unknown. In this study, we investigated whether the urinary pentosidine level is associated with the incidence of morphometric vertebral fracture and nonvertebral fracture using data of a randomized, controlled trial, JOINT‐05. JOINT‐05 enrolled Japanese women aged 75 years or older with primary osteoporosis. Patients were randomly assigned (1:1) to receive sequential therapy (teriparatide followed by alendronate) or monotherapy with alendronate for 120 weeks. Incidences of vertebral and nonvertebral fractures were assessed morphologically. During treatment, urinary levels of pentosidine and serum levels of bone turnover markers (osteocalcin, procollagen type I amino‐terminal propeptide, and tartrate‐resistant acid phosphatase 5b) were measured. A total of 967 patients with baseline pentosidine levels were included in the study. Of these, 137 had vertebral fractures, and 42 had nonvertebral fractures. The rate ratios for vertebral fracture for the second (30–39 pmol/mL), third (40–49 pmol/mL), and fourth quartile (≥50 pmol/mL) groups divided by pentosidine level compared with the first quartile (<30 pmol/mL) group were 1.65 (95% confidence interval [CI] 0.99–2.75, p = 0.06), 1.51 (95% CI 0.87–2.61, p = 0.14), and 1.69 (95% CI 1.01–2.83, p = 0.05), respectively. The corresponding rate ratios for nonvertebral fracture were 3.07 (95% CI 0.88–10.70, p = 0.08), 2.34 (95% CI 0.61–8.95, p = 0.22), and 3.95 (95% CI 1.14–13.67, p = 0.03), respectively. The association of the urinary pentosidine level with the incidence of nonvertebral fracture was the strongest among the biomarkers assessed in the study. In conclusion, the urinary pentosidine level was associated with the risk of fracture in patients with severe osteoporosis receiving teriparatide or alendronate. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Abdominal Aortic Calcification, Bone Mineral Density, and Fractures: ASystematic Review and Meta-analysis of Observational Studies.

Abdominal aortic calcification (AAC) has been inconsistently associated with skeletal health. We aimed to investigate the association of AAC with bone mineral density (BMD) and fracture risk by pooling the findings of observational studies. MEDLINE, EMBASE, Web of Science, and Google Scholar were searched (August 2021). All clinical studies that assessed the association between AAC and BMD or fracture were included. AAC was categorized into any/advanced (all higher reported groups) versus no/less advanced (lowest reported group). Pooled standardized mean differences (SMDs) and risk ratios (RRs) with 95% confidence intervals (CI) were determined for BMD and fracture, respectively, using random-effects models. Of 2192 articles screened, 86 (61553 participants) were included in the review, while 42 provided data for meta-analysis. AAC was associated with lower BMD at the total hip (SMD = -1.05 [95%CI: -1.47 to -0.63]; 16 studies), femoral neck (-0.25 [-0.46 to-0.04]; 10), and lumbar spine (-0.67 [-1.21 to -0.12]; 20). AAC was associated with a greater risk of any fracture (RR = 1.73 [95%CI: 1.48-2.02]; 27). AAC was also associated with vertebral, non-vertebral, and hip fractures. In dose-response analysis, the highest AAC group had greater risks of any, vertebral and non-vertebral fractures. AAC is associated with lower BMD and increased fracture risk at multiple sites, underscoring the potential importance of vascular disease on skeletal health. Detection of AAC at the time of BMD testing may provide clinicians with prognostic information about bone health to enhance osteoporosis screening programs and fracture risk prediction.

Role of Wnt signaling and sclerostin in bone and as therapeutic targets in skeletal disorders.

Wnt signaling is a key regulator of skeletal development and homeostasis; germinal mutations affecting genes encoding components, inhibitors, and enhancers of the Wnt pathways were shown to be responsible for the development of rare congenital metabolic bone disorders. Sclerostin is a bone tissue-specific inhibitor of the Wnt/β-catenin pathway, secreted by osteocytes, negatively regulating osteogenic differentiation and bone formation, and promoting osteoclastogenesis and bone resorption. Here, we reviewed current knowledge on the role of sclerostin and Wnt pathways in bone metabolism and skeletal disorders, and on the state of the art of therapy with sclerostin-neutralizing antibodies in low-bone-mass diseases. Various in vivo studies on animal models of human low-bone-mass diseases showed that targeting sclerostin to recover bone mass, restore bone strength, and prevent fragility fracture was safe and effective in osteoporosis, osteogenesis imperfecta, and osteoporosis pseudoglioma. Currently, only treatment with romosozumab, a humanized monoclonal anti-sclerostin antibody, has been approved in human clinical practice for the treatment of osteoporosis, showing a valuable capability to increase BMD at various skeletal sites and reduce the occurrence of new vertebral, non-vertebral, and hip fragility fractures in treated male and female osteoporotic patients. Preclinical studies demonstrated safety and efficacy of therapy with anti-sclerostin monoclonal antibodies in the preservation/restoration of bone mass and prevention of fragility fractures in low-bone-mass clinical phenotypes, other than osteoporosis, to be validated by clinical studies for their approved translation into prevalent clinical practice.

Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults

BackgroundVitamin D supplements are widely recommended for bone health in the general population, but data on whether they prevent fractures have been inconsistent.MethodsIn an ancillary study of the Vitamin D and Omega-3 Trial (VITAL), we tested whether supplemental vitamin D3 would result in a lower risk of fractures than placebo. VITAL was a two-by-two factorial, randomized, controlled trial that investigated whether supplemental vitamin D3 (2000 IU per day), n−3 fatty acids (1 g per day), or both would prevent cancer and cardiovascular disease in men 50 years of age or older and women 55 years of age or older in the United States. Participants were not recruited on the basis of vitamin D deficiency, low bone mass, or osteoporosis. Incident fractures were reported by participants on annual questionnaires and adjudicated by centralized medical-record review. The primary end points were incident total, nonvertebral, and hip fractures. Proportional-hazards models were used to estimate the treatment effect in intention-to-treat analyses.ResultsAmong 25,871 participants (50.6% women [13,085 of 25,871] and 20.2% Black [5106 of 25,304]), we confirmed 1991 incident fractures in 1551 participants over a median follow-up of 5.3 years. Supplemental vitamin D3, as compared with placebo, did not have a significant effect on total fractures (which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group; hazard ratio, 0.98; 95% confidence interval [CI], 0.89 to 1.08; P=0.70), nonvertebral fractures (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P=0.50), or hip fractures (hazard ratio, 1.01; 95% CI, 0.70 to 1.47; P=0.96). There was no modification of the treatment effect according to baseline characteristics, including age, sex, race or ethnic group, body-mass index, or serum 25-hydroxyvitamin D levels. There were no substantial between-group differences in adverse events as assessed in the parent trial.ConclusionsVitamin D3 supplementation did not result in a significantly lower risk of fractures than placebo among generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass, or osteoporosis. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; VITAL ClinicalTrials.gov number, NCT01704859.)

What is the impact of daily oral supplementation of vitamin D3 (cholecalciferol) plus calcium on the incidence of hip fracture in older people? A systematic review and meta-analysis.

Hip fractures have a huge impact in reducing the quality of life and increasing mortality. This review aims to assess the impact of daily oral supplementation of vitamin D3 plus calcium on the incidence of hip fracture in people over 65 years. PRISMA guidelines were followed and RCTs that evaluated the effectiveness of daily oral supplementation of vitamin D3 plus calcium in preventing hip fracture in adults over 65 years were included in the study. The databases such as Cochrane Library, Embase, Medline, PubMed, CINAHL, Web of Science and Scopus were searched from October 2019- January 2020.The Cochrane risk of bias tool was used to check the quality of the included studies. A meta-analysis with fixed effect model using Review Manager (Revman 5.3) was used to analyse the data. The meta-analysis of seven RCTs on vitamin D3 plus calcium supplementation and hip fracture (n= 12,620) identified odds ratio (OR) of 0.75; 95% Confidence interval (CI): 0.64, 0.87; p= .0003. Daily oral supplementation of 800 IU of Vitamin D3 plus 1200 mg of calcium was found more effective (n= 5676 participants; OR=0.69; 95% CI: 0.58, 0.82; p < .0001) than daily oral supplementation of 800 IU of Vitamin D3 plus 1000 mg of calcium (n= 6555,OR=1.08; 95% CI: 0.74, 1.56; p= .70) in reducing hip fracture. A meta-analysis of the seven RCTs to identify the incidence of non-vertebral fracture gave the OR of 0.80; 95% CI: 0.72, 0.89; p< .0001. A meta-analysis of three RCTs on femoral neck bone mineral density (BMD) (n= 483) gave a mean difference of 1.21; 95% CI: -0.79, 3.20; p= .24. Daily oral supplementation 800 IU of vitamin D3 plus 1200 mg of calcium reduces hip fracture and non-vertebral fracture in older people. Administering vitamin D3 and calcium supplements had no effect in increasing the femoral neck BMD. Even though it is evident from the review that optimal daily intake of vitamin D3 plus calcium supplementation help in the prevention of fracture, it is only one essential element in fracture prevention. Also, people who are on dietary supplements should be compliant with same for better result. Efforts to prevent bone loss and osteoporosis should begin from an early age. It includes maintaining a healthy lifestyle, optimal intake of calcium and vitamin D3, proper nutrition, adequate exposure to sunlight, exercise etc. Proper education on healthy lifestyle, avoiding risk factors like smoking, caffeine, alcohol and awareness of bone health should continue throughout life with emphasis during menopause when increased bone loss is expected.

To screen or not to screen for osteoporosis amongst post-menopausal women with one prior osteoporotic fracture in Greece.

Screening and linkage to care (SLTC) for osteoporosis is suboptimal in several settings. In Greece, it is estimated that only up to 8.6% of postmenopausal women are SLTC for osteoporosis, despite having suffered a previous fracture. This study aims to estimate the impact of comprehensive screening on future fracture burden amongst post-menopausal women aged 50-74, with one prior osteoporotic fracture, in Greece. We developed a cohort stochastic model, based on published epidemiological and clinical data, to assess impact of screening on future fracture burden in two scenarios: a current, assuming an 8.6% background SLTC, and a completely hypothetical, assuming 100% SLTC. Amongst a cohort of 50,000 post-menopausal women aged 50-74, with one prior osteoporotic fracture, applying the hypothetical versus the current scenario would result in a reduction in deaths (-0.6%) and fractures (-4.3%) over 10years. The hypothetical scenario leads to greater reductions in costs associated with vertebral (-8.1%) and hip (-5.5%) fractures, followed by other non-vertebral (-3.0%) and forearm (-2.5%) fractures. In the hypothetical scenario, treatment initiations and total screenings increased almost tenfold versus the current scenario, at an estimated direct incremental cost of 27.83€ per woman per year in the cohort. Our study adds to the existing evidence on the impact of screening to prevent fractures amongst post-menopausal women. Despite being based on a stochastic model, our study confirms findingsmost recently published in the literature. Our study models the positive public health impact of increasing SLTC levels amongst post-menopausal women with a prior osteoporotic fracture.

Effect of obesity on fragility fractures, BMD and vitamin D levels in postmenopausal women. Influence of type 2 diabetes mellitus

AimsTo see the effects of obesity on risk fracture, bone density (BMD), and vitamin D levels in a group of postmenopausal women, and consider how comorbid type 2 diabetes mellitus (T2DM) modifies them.Methods679 postmenopausal women were grouped into obese and non-obese. Obese women were grouped into those with T2DM and those without. 25(OH)-vitamin D, PTH and BMD were measured, and prevalent fragility fractures were gathered.ResultsObese women had higher prevalence of T2DM, than non-obese women. Levels of 25(OH)-vitamin D were lower and those of PTH higher in obese women, BMD values were higher in obese women. Diabetic-obese women had a higher prevalence of non-vertebral fractures than non-diabetic-obese. Multivariate logistic regression model showed association of fragility fractures with age, total hip BMD, BMI and T2DM. Obese women have higher BMD and lower 25(OH)-vitamin D values (and higher PTH) than non-obese, without diabetes.ConclusionsT2DM confers an increased risk of non-vertebral fractures in postmenopausal obese women.

Proposing a clinical algorithm for better diagnosis of hypophosphatasia in resource-limiting situations.

Early diagnosis of hypophosphatasia (HPP) is challenging. Here, we propose to broaden the diagnostic criteria of HPP by reviewing published data on BMD and fractures in HPP patients. Non-osteoporotic fractures and higher than normal lumbar BMD were recurrent in HPP patients and could be included as diagnostic criteria. HPP is a genetic disorder caused by autosomal recessive or dominant loss-of-function mutations in the ALPL gene that encodes for tissue-nonspecific alkaline phosphatase (TNSALP). Expressive genetic heterogeneity and varying severity of TNSALP deficiency lead to a wide-ranging presentation of skeletal diseases at different ages that coupled with HPP's rarity and limitation of biochemical and mutational studies present serious hurdles to early diagnosis and management of HPP. To widen the scope of HPP diagnosis, we assessed the possibility of areal bone mineral density (BMD) as an additional clinical feature of this disease. PubMed, Web of Science, and ScienceDirect were searched with the following keywords: ("Hypophosphatasia OR HPP") AND ("Bone Mineral Density OR BMD") AND "Human". Studies and case reports of subjects with age ≥ 18years and having BMD data were included. We pooled data from 25 publications comprising 356 subjects (90 males, 266 females). Only four studies had a control group. Biochemical hallmarks, pyridoxal 5'-phosphate (PLP) and phosphoethanolamine (PEA), were reported in fifteen and six studies, respectively. Twenty studies reported genetic data, nineteen studies reported non-vertebral fractures, all studies reported lumbar spine (LS) BMD, and nineteen reported non-vertebral BMD. Higher than normal and normal BMD at LS were reported in three and two studies, respectively. There was marked heterogeneity in BMD at the non-vertebral sites. Higher than normal or normal LS BMD in an adult with minimal or insufficient fractures, pseudofractures, non-healing fractures, fragility fractures, and stress fractures may be included in the diagnostic protocol of HPP. However, genetic testing is recommended for a definitive diagnosis.

Anemia is associated with increased risk of non-vertebral osteoporotic fractures in elderly men: the MrOS Sweden cohort

SummaryThis study includes 1005 men from the Gothenburg part of the Osteoporotic Fracture in Men Study (MrOS). Included are 66 men with anemia (hemoglobin < 130 g/L). The follow-up time was up to 16 years, and the main results are that anemia is associated with all fractures and non-vertebral osteoporotic fractures.IntroductionAnemia and osteoporotic fractures are conditions that are associated with increased morbidity and mortality. Clinical studies have suggested that anemia can be used as a predictor of future osteoporotic fractures.MethodMen from the Osteoporotic Fractures in Men Study (MrOS) Sweden, Gothenburg, with available hemoglobin (Hb) values (n = 1005, median age 75.3 years (SD 3.2)), were included in the current analyses. Of these, 66 suffered from anemia, defined as Hb < 130 g/L. Median follow-up time for fracture was 10.1 years and the longest follow-up time was 16.1 years.ResultsMen with anemia had, at baseline, experienced more falls and had a higher prevalence of diabetes, cancer, prostate cancer, hypertension, and stroke. Anemia was not statistically significantly associated with bone mineral density (BMD). Men with anemia had higher serum levels of fibroblast growth factor 23 (iFGF23) (p < 0.001) and phosphate (p = 0.001) and lower serum levels of testosterone (p < 0.001) and estradiol (p < 0.001). Moreover, men with anemia had an increased risk of any fracture (hazard ratio (HR) 1.97, 95% CI 1.28–3.02) and non-vertebral osteoporotic fracture (HR 2.15, 95% CI 1.18–3.93), after adjustment for age and total hip BMD, in 10 years. The risk for any fracture was increased in 10 and 16 years independently of falls, comorbidities, inflammation, and sex hormones. The age-adjusted risk of hip fracture was increased in men with anemia (HR 2.32, 95% CI 1.06–5.12), in 10 years, although this was no longer statistically significant after further adjustment for total hip BMD.ConclusionsAnemia is associated with an increased risk for any fracture and non-vertebral osteoporotic fracture in elderly men with a long follow-up time. The cause is probably multifactorial and our results support that anemia can be used as a predictor for future fracture.

Mechanism and efficacy of parathyroid hormone in osteoporosis

Background: Parathyroid hormone (PTH) and teriparatide, which is a PTH analog, are special options of osteoanabolic therapies for osteoporosis treatment. Their efficacy in improving the bone mineral density (BMD) and reducing fracture risk is considered to have a long-awaited justification.Current Concepts: PTH is an 84-amino acid polypeptide that plays a key role in the calcium homeostasis of the human body. It yields anabolic effects on the bone by intermittent injections. During the first 6 months of PTH treatment, bone formation increases rapidly and bone resorption rises gradually. PTH is believed to be maximally anabolic during the anabolic window. In the phase III trial of teriparatide, significant reductions in vertebral and non-vertebral fractures were identified. Teriparatide has been studied in drug-induced osteoporosis, postmenopausal women with osteoporosis, and men with osteoporosis. The data derived from clinical trials with teriparatide showed an increase of the BMD in the treatment group compared to that of the placebo. Selective advantages on fracture healing have been shown in some studies; however, consensus on the relationship between teriparatide and bone healing is unclear.Discussion and Conclusion: Teriparatide has been approved for osteoporosis treatment in various situations, including postmenopausal women, men with osteoporosis, and cases with glucocorticoid-induced osteoporosis. Additionally, it can be useful in high risk for fracture groups, if fractures persist despite bone resorption inhibitor therapy, and if bone resorption inhibitor administration is difficult and contraindicated.

1079-P: Effectiveness and Safety of Empagliflozin in Routine Care: Results from the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) Study

EMPRISE is a 5-year monitoring program that evaluates the effectiveness and safety of empagliflozin (EMPA) using Medicare and 2 U.S. commercial claims [2014-20 (2018 for Medicare) ]. We identified 190,226 patients ≥18 years with type 2 diabetes initiating EMPA or a dipeptidyl peptidase-4 inhibitors (DPP-4i) , and followed them up for heart failure hospitalization in primary (HHF-Specific) or any discharge positions (HHF-Broad) , a composite of myocardial infarction (MI) and stroke, and all-cause mortality (ACM) (Medicare only) . Safety outcomes were lower-limb amputations (LLA) , non-vertebral fractures, diabetic ketoacidosis (DKA) , acute kidney injury (AKI) , renal and bladder cancers (CA) . We estimated pooled HR (95% CI) after propensity score matching, adjusting for 143 baseline covariates. Compared to DPP4i, EMPA was associated with a reduced risk of HHF [HHF-Specific: 0.47 (0.41, 0.55) ; HHF-Broad: 0.67 (0.62, 0.72) ], a similar risk of the composite of MI or stroke [0.92 (0.84, 1.02) ], and a reduced risk of ACM [0.56 (0.46, 0.68) ]. EMPA was associated with a reduced risk of AKI [0.73 (0.68, 0.78) ], an increased risk of DKA [1.88 (1.51, 2.34) ], and a similar risk of LLA, fractures, and renal and bladder CA. Our findings support the cardiovascular effectiveness of EMPA in routine care with a safety profile in line with documented information. Disclosure P.T.Htoo: Employee; Johnson &amp; Johnson. S.Schneeweiss: Consultant; Aetion, Inc., Research Support; Boehringer Ingelheim International GmbH. E.Patorno: Research Support; Boehringer Ingelheim International GmbH, National Institutes of Health, Patient-Centered Outcomes Research Institute. H.Tesfaye: None. J.M.Paik: None. D.J.Wexler: Other Relationship; Elsevier, Novo Nordisk, UpToDate. M.Najafzadeh: None. R.Glynn: Research Support; Amarin Corporation, AstraZeneca, Kowa Pharmaceuticals America, Inc., Novartis AG, Pfizer Inc. A.Deruaz-luyet: Employee; Boehringer Ingelheim International GmbH, Other Relationship; IQVIA Inc., Sanofi. S.F.Fazeli farsani: Employee; Boehringer Ingelheim International GmbH. L.Koeneman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Fractures in type 2 diabetes confer excess mortality: The Dubbo osteoporosis epidemiology study.

Diabetes and fractures are both associated with increased mortality, however the effect of the combination is not well-established. We examined the mortality risk following all types of fractures in type 2 diabetes (T2D). In the Dubbo Osteoporosis Epidemiology Study (1989-2017), participants were grouped according to T2D and/or incident fracture. Study outcome was all-cause mortality. First incident radiological fragility fracture and incident T2D diagnosis were time-dependent variables. Cox's proportional hazards models quantified mortality risk associated with T2D and incident fracture overall, as well as by fracture site, T2D duration and T2D medication type. In 3618 participants (62% women), 272 had baseline and 179 developed T2D over median 13.0 years (IQR 8.2-19.6). 796 women (56 with T2D) and 240 men (25 with T2D) sustained a fracture. Compared to those without T2D or fracture, mortality risk increased progressively, in T2D without fracture, then no T2D with fracture, and was highest in those with T2D with fracture (adjusted hazard ratio (aHR) (95% CI) for women 2.62 (1.75-3.93) and men 2.61 (1.42-4.81)). Within T2D participants, incident fracture was associated with increased mortality (aHR for women 1.87 (1.10-3.16) and men 2.83 (1.41-5.68)), especially following hip/vertebral fractures in men (aHR 2.97 (1.29-6.83)) and non-hip non-vertebral fractures in women (aHR 2.42 (1.24-4.75)), and in T2D duration >5 years. Any fracture in T2D conferred significant excess mortality. Individuals with T2D should be carefully monitored post-fracture, especially if T2D >5 years. Optimising fracture prevention and post-fracture management in T2D is critical and warrants further studies.

The efficiency and safety of alendronate versus teriparatide for treatment glucocorticoid-induced osteoporosis: A meta-analysis and systematic review of randomized controlled trials.

Glucocorticoid-induced osteoporosis (GIOP) is the most common secondary osteoporosis, alendronate (ALE) and teriparatide (TPTD) are widely used in the treatment of GIOP. However, which of these two drugs has a better curative effect needs the support of evidence-based medicine. We searched PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar for randomized controlled trials of ALE and TPTD in the treatment of glucocorticoid-induced osteoporosis until February 2022. These patients included in the study took glucocorticoid doses greater than 7.5 mg/d for more than 3 months before treatment with ALE and TPTD. The risk ratio (RR) and its 95% confidence interval (CI) are used as the influence index of discontinuous data, and the standardized mean difference (SMD) and its 95% CI are used as the influence index of continuous data. A total of 4102 patients were enrolled in all 5 studies that met the admission criteria. We found that compared with ALE, TPTD could reduce the rate of new vertebral fracture (RR = 0.13, 95% CI: 0.05-0.34, P<0.00001). TPTD increased LS bone mineral density (BMD) (0.53, 95% CI 0.42-0.64, P<0.00001), TH BMD (0.17, 95% CI 0.05-0.28, P = 0.004) and FN BMD (0.17, 95% CI 0.05-0.29, P = 0.006) compared to ALE. However, there was no significant difference in the incidence of non-vertebral fracture and adverse events between the two groups. Compared with ALE, TPTD is an effective drug to reduce vertebral fracture risk in patients with GIOP. Furthermore, long-term use of TPTD can increase the bone mineral density of LS, FN, and TH.

Association between biologic therapy and fracture incidence in patients with selected rheumatic and autoimmune diseases: A systematic review and meta-analysis of randomized controlled trials

ObjectivesTo investigate the effect of biologic therapy on risk of fracture in selected rheumatic and autoimmune diseases. MethodsThe PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to June 4, 2021. Randomized clinical trials (RCTs) comparing biological disease-modifying antirheumatic drugs (bDMARDs) with non-bDMARDs or placebo in patients with five selected rheumatic and autoimmune diseases were included. Meta-analyses were conducted to calculate the odds ratio (OR) with 95 % confidence intervals (CIs) for major osteoporotic fracture, hip fracture, osteoporotic non-vertebral fracture, and total fracture. ResultsA total of 100 RCTs involving 51,413 participants fulfilled the inclusion criteria. In patients with psoriasis (Ps), and psoriatic arthritis (PsA), compared with placebo or non-bDMARDs therapy, the risk of major osteoporotic fracture (OR, 0.34 [95 %Cl, 0.15–0.76], p = 0.009), hip fracture (OR, 0.22 [95 %Cl, 0.05–0.89], p = 0.03), and osteoporotic non-vertebral fracture (OR, 0.26 [95 %Cl, 0.10–0.62], p = 0.003) were significantly decreased with the use of bDMARDs. In patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), systemic lupus erythematosus (SLE), and inflammatory bowel diseases (IBD), the risk of fracture were not changed with biologic treatment. ConclusionsThe existing evidence from RCTs indicated the use of bDMARDs was associated with a low risk of major osteoporotic fracture, hip fracture, and osteoporotic non-vertebral fracture in patients with Ps and PsA. There are still urgent needs for studies regarding the actions of biologic therapies on the risk of bone fractures in systemic inflammatory diseases.

Bone fragility in type 1 diabetes: new insights and future steps

Bone fragility is a recognised complication of type 1 diabetes.1 People with type 1 diabetes have lower bone mineral density (BMD) and greater fracture risk than individuals without diabetes (more than five times for hip fracture and two times for non-vertebral fractures).2 The mechanisms underlying the lower BMD and greater fracture risk in this population include absence of insulin, long diabetes duration, poor glycaemic control, oxidative stress, and impaired Wnt signalling.3,4 People with long-term type 1 diabetes with a low risk of cardiovascular complications also have low rates of osteoporosis and fractures,5 suggesting that bone fragility is associated with vascular complications.

When and how to stop denosumab therapy in a patient with osteoporosis.

Denosumab is a human monoclonal antibody that competitively inhibits the receptor activator of nuclear factor kappa B ligand which regulates osteoclast activity. It is an effective treatment for osteoporosis with a reduced cumulative rate of vertebral fractures, hip and nonvertebral fractures as well as an increase in bone mineral density. The benefits have been shown to be maintained when treatment is continued up to and likely after 10 years of therapy, but the effects are lost rapidly if treatment is discontinued abruptly. There are rare medical indications for discontinuation of treatment. Discontinuation of denosumab is often driven by concern about complications such as osteonecrosis of the jaw, atypical femoral fractures and hypocalcaemia, which remain rare events. Further studies are required to confirm safety and efficacy beyond 10 years of treatment, but it is likely that patients will have ongoing benefits from therapy beyond this. We aim to present a personal perspective of why and how denosumab should be discontinued in patients with osteoporosis.