The effect of romosozumab on bone mineral density depending on prior treatment: a prospective, multicentre cohort study in Switzerland.

This multicentre, prospective cohort study measured the effect of romosozumab for 12 months on bone mineral density, taking into account prior therapies. Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip. INTRODUCTION: In Switzerland, romosozumab is administered to high-risk osteoporosis patients. Our study aimed to assess the effect of romosozumab on bone mineral density (BMD), taking into account prior therapies. METHODS: This multicentre, prospective cohort study measured the effect of romosozumab for 12 months in patients in a nationwide Swiss osteoporosis registry. BMD and bone turnover marker (P1NP and CTX) changes were measured and compared between pre-treated and treatment naïve patients. RESULTS: Ninety-nine patients (92 women and 7 men, median age 71 years [65, 76]) were enrolled from January 2021 to December 2023. Among them, 22 had no prior treatment before romosozumab, while 77 had previous therapy (including 23 with a history of prior teriparatide therapy), with a median duration of 6 years [4, 11] of cumulative antiresorptive treatment. Over 12 months, romosozumab led to BMD changes of 10.3% [7.5, 15.5] at the lumbar spine, 3.1% [1.1, 5.8] at the total hip and 3.1% [0.5, 5.3] at the femoral neck, indicating notable variability. Significantly lower BMD responses were observed in pre-treated patients, with the duration of prior antiresorptive therapy inversely associated with BMD increases at the lumbar spine and hip. Other predictors of BMD changes at the total hip included baseline T-scores at the hip, body mass index and baseline CTX level, while the BMD response at the lumbar spine was associated with the lumbar spine T-score at baseline, age and baseline CTX level. CONCLUSION: Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip.

Fracture risk prediction in postmenopausal women with traditional and machine learning models in a nationwide, prospective cohort study in Switzerland with validation in the UK Biobank.

Fracture prediction is essential in managing patients with osteoporosis and is an integral component of many fracture prevention guidelines. We aimed to identify the most relevant clinical fracture risk factors in contemporary populations by training and validating short- and long-term fracture risk prediction models in 2 cohorts. We used traditional and machine learning survival models to predict risks of vertebral, hip, and any fractures on the basis of clinical risk factors, T-scores, and treatment history among participants in a nationwide Swiss Osteoporosis Registry (N = 5944 postmenopausal women, median follow-up of 4.1 yr between January 2015 and October 2022; a total of 1190 fractures during follow-up). The independent validation cohort comprised 5474 postmenopausal women from the UK Biobank with 290 incident fractures during follow-up. Uno's C-index and the time-dependent area under the receiver operating characteristics curve were calculated to evaluate the performance of different machine learning models (Random survival forest and eXtreme Gradient Boosting). In the independent validation set, the C-index was 0.74 [0.58, 0.86] for vertebral fractures, 0.83 [0.7, 0.94] for hip fractures, and 0.63 [0.58, 0.69] for any fractures at year 2, and these values further increased for longer estimations of up to 7 yr. In comparison, the 10-yr fracture probability calculated with FRAX Switzerland was 0.60 [0.55, 0.64] for major osteoporotic fractures and 0.62 [0.49, 0.74] for hip fractures. The most important variables identified with Shapley additive explanations values were age, T-scores, and prior fractures, while number of falls was an important predictor of hip fractures. Performances of both traditional and machine learning models showed similar C-indices. We conclude that fracture risk can be improved by including the lumbar spine T-score, trabecular bone score, numbers of falls and recent fractures, and treatment information has a significant impact on fracture prediction.

Fracture prediction is essential in managing patients with osteoporosis. We developed and validated traditional and machine learning models to predict short- and long-term fracture risk and identify the most relevant clinical fracture risk factors for vertebral, hip, and any fractures in contemporary populations. We used data from 5944 postmenopausal women in a Swiss Osteoporosis Registry and validated our findings with 5474 women from the UK Biobank. Our machine learning models performed well, with C-index values of 0.74 for vertebral fractures, 0.83 for hip fractures, and 0.63 for any fractures at year 2, and these values further increased for longer estimations of up to 7 years. In contrast, FRAX Switzerland had lower C-index values (0.60 for major fractures and 0.62 for hip fracture probabilities over 10 years). Key predictors identified included age, T-scores, prior fractures, and number of falls. We conclude that incorporating a broader range of clinical factors, as well as lumbar spine T-scores, fall history, recent fractures, and treatment information, can improve fracture risk assessments in osteoporosis management. Both traditional and machine learning models showed similar effectiveness in predicting fractures.

Comparison of anti-fracture effectiveness of zoledronate, ibandronate and alendronate versus denosumab in a registry-based cohort study.

This registry-based study of 3068 patients with osteoporosis compared the anti-fracture effectiveness of denosumab versus bisphosphonates. Denosumab was associated with significantly greater risk reduction than alendronate or ibandronate for vertebral and any fractures. No difference in fracture risk reduction was found between zoledronate and denosumab. PURPOSE: To analyse the fracture risk of patients with osteoporosis receiving bisphosphonates or denosumab in a real-world setting. METHODS: This registry-based cohort study evaluated patients taking denosumab, bisphosphonates or both sequentially. Fractures were analysed using rates, rate ratios and hazard ratios (HR), including both therapies as time-varying co-variates. Fracture risk hazards were adjusted (aHR) for baseline T-Scores and trabecular bone score (TBS) and were additionally analysed with inverse probability treatment weighting. RESULTS: A total of 3068 patients (89% female; median age at treatment onset, 69 years [63 to 76]) received denosumab (median duration 2.8 years, [2.2 to 4.7]), bisphosphonates (3.4 years, [2.1 to 5.7]) or both sequentially. Thus, 11,078 subject-years were assessed for bisphosphonates (41% alendronate, 36% ibandronate, 23% zoledronate) and 4216 for denosumab. Moreover, 48,375 subject-years were observed before treatment onset, in addition to 2593 years of drug holidays. A total of 1481 vertebral fractures (435 under therapy), 1508 non-vertebral fractures (499 under therapy) and 202 hip fractures (67 under therapy) occurred after age 50. The risks of vertebral, non-vertebral and hip fractures were significantly lower under all bisphosphonates, denosumab and drug holidays than before treatment onset (all p < 0.001). After adjusting for age, baseline T-scores and TBS, denosumab was associated with lower risk than alendronate or ibandronate for vertebral fractures (aHR 0.47 (0.35 to 0.64) and 0.70 [0.53 to 0.91], p < 0.001 and p = 0.009, respectively) and any fractures (aHR 0.62 [0.51 to 0.76] and 0.77 [0.64 to 0.92], p < 0.001 and p = 0.004). With propensity weighting, denosumab was associated with a lower hip fracture risk compared to alendronate (HR 0.54 [0.29 to 0.98], p = 0.044). No difference in fracture risk reduction (vertebral, non-vertebral or hip) was found between zoledronate and denosumab. CONCLUSIONS: When adjusting for disease severity, denosumab was associated with significantly greater risk reduction than alendronate and ibandronate for vertebral fractures. No difference in fracture risk reduction was found between zoledronate and denosumab.

Incidence of Atypical Femoral Fractures in Patients on Osteoporosis Therapy-A Registry-Based Cohort Study.

Atypical femoral fractures (AFFs) have been reported in patients taking bisphosphonates (BPs) for osteoporosis therapy but also in patients with no exposure to these drugs. In contrast, less is known about the incidence of AFFs in patients taking denosumab. This registry-based cohort study analyzed the incidence of AFFs in patients with suspected or confirmed osteoporosis who were included in the osteoporosis register of the Swiss Society of Rheumatology between January 2015 and September 2019. Statistical analyses included incidence rates, rate ratios, and hazard ratios for AFFs, and considered sequential therapies and drug holidays as time-dependent covariates. Among the 9956 subjects in the cohort, 53 had subtrochanteric or femoral shaft fractures. Ten fractures occurred under BP or denosumab treatment and two under teriparatide therapy. Five fractures were classified as AFFs based on the revised American Society of Bone and Mineral Research case definition of AFFs from 2014. Three AFFs occurred in women being treated with denosumab at the time of diagnosis, all with prior BP use (10, 7, and 1 years, respectively). One AFF developed in a woman receiving ibandronate and one arose in a woman receiving glucocorticoids rather than antiresorptive therapy. The incidence of AFFs per 10,000 observed patient-years was 7.1 in patients receiving denosumab and 0.9 in patients with BP-associated AFFs, yielding a rate ratio of 7.9 (95% confidence interval [CI] 0.63-413), p = 0.073. The risk of AFFs was not significantly higher in patients receiving denosumab therapy compared with BP therapy (hazard ratio = 7.07, 95% CI 0.74-68.01, p = 0.090). We conclude that the risk of AFFs is low in patients taking BPs, denosumab, or both sequentially. All three patients with AFFs under denosumab therapy had undergone prior BP therapy. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Effects of zoledronate on bone mineral density and bone turnover after long-term denosumab therapy: Observations in a real-world setting.

BACKGROUND: The rebound effect after denosumab discontinuation is lessened with subsequent zoledronate therapy. However, it is unclear whether this mitigation is sufficient after long-term denosumab treatment. OBJECTIVE: This retrospective observational study analysed bone mineral density (BMD) and bone turnover marker (BTM) changes after denosumab therapy according to treatment duration and subsequent zoledronate regimen. METHODS: We measured the outcomes of 282 women with postmenopausal osteoporosis who discontinued denosumab and received zoledronate 6 months later. In patients with longer denosumab therapy (≥5 years), BTMs were measured every 3 months and a second zoledronate infusion was administered if BTM levels increased by ≥2-fold. The BMD of all women was measured before denosumab therapy, at the last injection and 1 to 2 years after the first zoledronate. RESULTS: Bone loss after switching from denosumab to zoledronate was higher in patients with 10 ± 2 denosumab injections (n = 84) compared to 5 ± 2 injections (n = 144, p < 0.001 for lumbar spine and femoral neck), but there was no further increase with treatment durations of ≥15 ± 2 injections (n = 54, p = 0.35 and p = 0.20, respectively). BTMs in patients with ≥10 denosumab injections were elevated 6 months after zoledronate in some patients, but not all. Twenty-four women received a second zoledronate dose 6 months after the first one. BTMs in these patients were subsequently lower, but bone loss at both the lumbar spine and hip was comparable to that in patients with only one zoledronate dose (p = 0.37 for lumbar spine and p = 0.97 for femoral neck). CONCLUSIONS: Rebound-associated bone loss reached a plateau after denosumab treatment durations of 4-6 years, irrespective of the frequency of subsequent zoledronate therapy.

Risk Factors, Manifestation, and Awareness of Osteoporosis among Patients of Various Specialists in Switzerland: Results of a National Survey.

Osteoporosis is the most common chronic metabolic bone disease, known to be underdiagnosed and undertreated in parts of the Swiss population. Due to expected rise in new fragility fractures, adequate awareness of associated risk factors and diagnostic and therapeutic options will be essential for the management of osteoporosis. We therefore explored these aspects in a nationwide survey of Swiss specialists and their patients. A total of 262 physician questionnaires and 9065 patient questionnaires were analyzed, mainly from general practitioners (64.9%), followed by rheumatologists (16.8%), gynecologists (12.2%), and endocrinologists (6.1%). Around 20% of patients were under medication and/or had a medical condition increasing the risk of osteoporosis. Further risk factors, such as low consumption of calcium-rich foods, smoking, elevated alcohol intake, and insufficient physical activity, were present across regions and medical fields. 53.9% of patients did not take calcium/vitamin D supplements; 3.5% reported having fragility fractures, and 7.3% received treatment for osteoporosis. Only 38.5% of surveyed patients knew of the chronic nature of osteoporosis, indicating rather low awareness in this population. Despite generally perceived relevance of osteoporosis for daily practice, aspects of its prevention and management varied across regions and medical fields. Raising awareness among patients and physicians will be vital for addressing osteoporosis on a national scale.

Risk of Osteonecrosis of the Jaw Under Denosumab Compared to Bisphosphonates in Patients With Osteoporosis.

Osteonecrosis of the jaw (ONJ) is a rare but serious adverse event associated with antiresorptive treatment. There is little evidence regarding the incidence of ONJ among patients with osteoporosis who are treated with denosumab versus bisphosphonates (BPs). The aim of this study was to determine the risk of ONJ in a real-world population. Subjects who underwent at least one dual-energy X-ray absorptiometry (DXA) examination were included in the osteoporosis register of the Swiss Society of Rheumatology between January 1, 2015, and September 30, 2019. Statistical analyses included incidence rates, rate ratios, and hazard ratios for ONJ, considering sequential therapies and drug holidays as covariates. Among 9956 registered patients, 3068 (89% female, median age 69 years [63 to 76]) were treated with BPs or denosumab for a cumulative duration of 11,101 and 4236 patient-years, respectively. Seventeen cases of ONJ were identified: 12 in patients receiving denosumab at the time of ONJ diagnosis and 5 in patients receiving oral or intravenous BP therapy. The diagnosis of ONJ was confirmed by independent and blinded maxillofacial surgeons, using the American Association of Oral and Maxillofacial Surgeons case definition of ONJ. The incidence of ONJ per 10,000 observed patient-years was 28.3 in patients receiving denosumab and 4.5 in patients with BP-associated ONJ, yielding a rate ratio of 6.3 (95% confidence interval [CI] 2.1 to 22.8), p < 0.001. Nine of 12 patients who developed ONJ during denosumab treatment had been pretreated with BPs, but none of the 5 patients with BP-related ONJ had previously received denosumab. The risk of ONJ was higher in patients receiving denosumab therapy compared with BPs (hazard ratio 3.49, 95% CI 1.16 to 10.47, p = 0.026). Previous BP therapy before switching to denosumab may be an additional risk factor for ONJ development. © 2021 American Society for Bone and Mineral Research (ASBMR).

Are patterns of bone loss in anorexic and postmenopausal women similar? Preliminary results using high resolution peripheral computed tomography.

This study intended to compare bone density and architecture in three groups of women: young women with anorexia nervosa (AN), an age-matched control group of young women, and healthy late postmenopausal women. Three-dimensional peripheral quantitative high resolution computed-tomography (HR-pQCT) at the ultradistal radius, a technology providing measures of cortical and trabecular bone density and microarchitecture, was performed in the three cohorts. Thirty-six women with AN aged 18-30 years (mean duration of AN: 5.8 years), 83 healthy late postmenopausal women aged 70-81 as well as 30 age-matched healthy young women were assessed. The overall cortical and trabecular bone density (D100), the absolute thickness of the cortical bone (CTh), and the absolute number of trabecules per area (TbN) were significantly lower in AN patients compared with healthy young women. The absolute number of trabecules per area (TbN) in AN and postmenopausal women was similar, but significantly lower than in healthy young women. The comparison between AN patients and post-menopausal women is of interest because the latter reach bone peak mass around the middle of the fertile age span whereas the former usually lose bone before reaching optimal bone density and structure. This study shows that bone mineral density and bone compacta thickness in AN are lower than those in controls but still higher than those in postmenopause. Bone compacta density in AN is similar as in controls. However, bone inner structure in AN is degraded to a similar extent as in postmenopause. This last finding is particularly troubling.

Clinical value of prognostic instruments to identify patients with an increased risk for osteoporotic fractures: systematic review.

BACKGROUND: With the broad availability of effective medications, identifying individuals bearing a higher risk for osteoporotic fractures has become an issue of major concern in modern medicine. In recent years various prognostic instruments have become available showing conflicting results regarding estimated risks for individual patients. OBJECTIVE: To provide an overview of current evidence and of opportunities for further research. METHODOLOGY/PRINCIPAL FINDINGS: Systematic review: We identified studies describing the development of instruments and all subsequent validations in electronic databases and reference lists of included studies. We screened for inclusion, read full papers and extracted data on salient clinical features, performance characteristics and quality in duplicate. Searches retrieved 5,275 records of which full texts of 167 papers were obtained after screening titles and abstract. We included 35 studies enrolling a total of 609,969 patients (median 2546) reporting on 31 derivations and 12 validations after assessing full texts. Median follow-up time was 4.1 years (IQR 3 to 7.7). Only four studies validated an instrument that was developed by another group. None of the existing instruments was validated more than once. The five most frequent included variables in the final model were age, body mass index, bone mass index, past history of falls, and maternal history of fractures. The methodological quality of the studies was moderate. CONCLUSION: There is a plethora of evidence available studying the association of risk profiles and the development of osteoporotic fractures. The small number of out-of-sample validations, the large variety of study characteristics, outcomes and follow-up periods impedes from deriving robust summaries and from conclusions regarding the clinical performance of many tools. First and foremost, future activity in this field should aim at reaching a consensus among clinical experts in respect to the existing instruments. Then we call for careful validations and expedient adaptations for local circumstances of the most promising candidates.

Does weight gain induce cortical and trabecular bone regain in anorexia nervosa? A two-year prospective study.

This prospective study examines bone density and structure over a two-year time period in women with anorexia nervosa (AN) under weight gain treatment. Twenty-four women with AN were examined at baseline and at two annual follow-up examinations. In 9 AN patients BMI increased whereas in 15 it remained unchanged or decreased. Dual energy X-ray absorptiometry (DXA) was performed on the lumbar spine, the femoral neck and the whole hip and three-dimensional peripheral quantitative computer tomography (3D-pQCT) was performed on the ultradistal radius. ANOVAs for repeated measures were used to examine change over time in BMI and bone parameters. At baseline, patients with increased BMI had significantly higher bone density of femoral neck and total hip, and higher levels in all 3D-pQCT parameters of the ultradistal radius, compared to the group with unchanged or decreased BMI. The two groups did not differ at baseline in bone density of the spine. ANOVAs showed that bone density of the total hip increased significantly and that overall bone density (D100), the density of the trabecular area (D.Trab.) and the cortical thickness (C.Th.) in the ultradistal radius decreased significantly. Group x time interactions showed that changes over time were different in the two groups with regard to spine density and in the parameters D100, D.Trab. and C.Th. of the ultradistal radius. In the group with increased BMI the spine density dropped at the first follow-up whereas at the second follow-up it rose again to baseline. Patients with unchanged or decreased BMI showed a small but steady increase in spine density. The group changes of D100, D.Trab. and C.Th. of the ultradistal radius all followed the same pattern. Bone mineral density at all locations measured with both technologies (DXA and 3D-pQCT) did not vary according to BMI changes. The course of bone density and structure at different locations was different, and, despite weight increase, bone regain appeared to need different time periods.

Prediction of hip fracture risk by quantitative ultrasound in more than 7000 Swiss women > or =70 years of age: comparison of three technologically different bone ultrasound devices in the SEMOF study.

UNLABELLED: To compare the prediction of hip fracture risk of several bone ultrasounds (QUS), 7062 Swiss women > or =70 years of age were measured with three QUSs (two of the heel, one of the phalanges). Heel QUSs were both predictive of hip fracture risk, whereas the phalanges QUS was not. INTRODUCTION: As the number of hip fracture is expected to increase during these next decades, it is important to develop strategies to detect subjects at risk. Quantitative bone ultrasound (QUS), an ionizing radiation-free method, which is transportable, could be interesting for this purpose. MATERIALS AND METHODS: The Swiss Evaluation of the Methods of Measurement of Osteoporotic Fracture Risk (SEMOF) study is a multicenter cohort study, which compared three QUSs for the assessment of hip fracture risk in a sample of 7609 elderly ambulatory women > or =70 years of age. Two QUSs measured the heel (Achilles+; GE-Lunar and Sahara; Hologic), and one measured the heel (DBM Sonic 1200; IGEA). The Cox proportional hazards regression was used to estimate the hazard of the first hip fracture, adjusted for age, BMI, and center, and the area under the ROC curves were calculated to compare the devices and their parameters. RESULTS: From the 7609 women who were included in the study, 7062 women 75.2 +/- 3.1 (SD) years of age were prospectively followed for 2.9 +/- 0.8 years. Eighty women reported a hip fracture. A decrease by 1 SD of the QUS variables corresponded to an increase of the hip fracture risk from 2.3 (95% CI, 1.7, 3.1) to 2.6 (95% CI, 1.9, 3.4) for the three variables of Achilles+ and from 2.2 (95% CI, 1.7, 3.0) to 2.4 (95% CI, 1.8, 3.2) for the three variables of Sahara. Risk gradients did not differ significantly among the variables of the two heel QUS devices. On the other hand, the phalanges QUS (DBM Sonic 1200) was not predictive of hip fracture risk, with an adjusted hazard risk of 1.2 (95% CI, 0.9, 1.5), even after reanalysis of the digitalized data and using different cut-off levels (1700 or 1570 m/s). CONCLUSIONS: In this elderly women population, heel QUS devices were both predictive of hip fracture risk, whereas the phalanges QUS device was not.

Variation of cell and matrix morphologies in articular cartilage among locations in the adult human knee.

OBJECTIVE: Understanding of articular cartilage physiology, remodelling mechanisms, and evaluation of tissue engineering repair methods requires reference information regarding normal structural organization. Our goals were to examine the variation of cartilage cell and matrix morphology in different topographical areas of the adult human knee joint. METHODS: Osteochondral explants were acquired from seven distinct anatomical locations of the knee joints of deceased persons aged 20-40 years and prepared for analysis of cell, matrix and tissue morphology using confocal microscopy and unbiased stereological methods. Differences between locations were identified by statistical analysis. RESULTS: Medial femoral condyle cartilage had relatively high cell surface area per unit tissue volume in the superficial zone. In the transitional zone, meniscus-covered lateral tibia cartilage showed elevated chondrocyte densities compared to the rest of the knee while lateral femoral condyle cartilage exhibited particularly large chondrocytes. Statistical analyses indicated highly uniform morphology throughout the radial zone (lower 80% of cartilage thickness) in the knee, and strong similarities in cell and matrix morphologies among cartilage from the femoral condyles and also in the mediocentral tibial plateau. Throughout the adult human knee, the mean matrix volume per chondron was remarkably constant at approximately 224,000 microm(3), corresponding to approximately 4.6 x 10(6) chondrons per cm(3). CONCLUSIONS: The uniformity of matrix volume per chondron throughout the adult human knee suggests that cell-scale biophysical and metabolic constraints may place limitations on cartilage thickness, mechanical properties, and remodelling mechanisms. Data may also aid the evaluation of cartilage tissue engineering treatments in a site-specific manner. Results indicate that joint locations which perform similar biomechanical functions have similar cell and matrix morphologies; findings may therefore also provide clues to understanding conditions under which focal lesions leading to osteoarthritis may occur.

Phosphodiesterase isoenzyme families in human osteoarthritis chondrocytes--functional importance of phosphodiesterase 4.

We studied whether selective inhibitors of cyclic nucleotide hydrolysing phosphodiesterase (PDE) isoenzymes influence IL-1beta-induced nitric oxide (NO) release from human articular chondrocytes. In addition, the pattern of PDE isoenzymes contributing to cyclic nucleotide hydrolysis in human chondrocytes was characterized. Chondrocytes were isolated from human osteoarthritic cartilage and cultured in alginate beads. IL-1beta-induced chondrocyte products (nitric oxide and prostaglandin E(2)) were measured in culture supernatants after 48 h incubation time. PDE activities were assessed in chondrocyte lysates. Inducible nitric oxide synthase (iNOS) and PDE4A-D proteins were detected by immunoblotting. The selective PDE4 inhibitors Piclamilast and Roflumilast partially attenuated IL-1beta-induced NO production whereas selective inhibitors of PDE2 (EHNA), PDE3 (Motapizone) or PDE5 (Sildenafil) were inactive. Indomethacin reversed the reduction of IL-1beta-induced NO by PDE4 inhibitors. It was shown that autocrine prostaglandin E(2) (PGE(2)) enabled PDE4 inhibitors to reduce IL-1beta-induced NO in this experimental setting. Major PDE4 and PDE1 activities were identified in chondrocyte lysates whereas only minor activities of PDE2, 3 and 5 were found. IL-1beta and cyclic AMP-mimetics upregulated PDE4 activity and this was associated with an augmentation of PDE4B2 protein. Based on the view that nitric oxide contributes to cartilage degradation in osteoarthritis our study suggests that PDE4 inhibitors may have chondroprotective effects.