Erosive Progression by High-Resolution Peripheral Quantitative Computed Tomography and Conventional Radiography in Rheumatoid Arthritis.

OBJECTIVES: To investigate the diagnostic accuracy of high-resolution peripheral quantitative computed tomography (HR-pQCT) to assess erosive progression during one year compared to conventional radiography (CR) in rheumatoid arthritis (RA). METHODS: This prospective study included 359 patients with RA (disease duration ≥ 5 years) between March 2018 and October 2020. HR-pQCT and CR were obtained at inclusion and after one year. Erosive assessment was performed at two metacarpophalangeal joints of the dominant hand using HR-pQCT and progression was defined as an increase in erosion number ≥ 1 or an increase in erosive volume > least significant change. CR of hands, wrists, and feet were evaluated using Sharp/van der Heijde scores and erosive progression was defined as a 1.1-point increase in erosion score according to the smallest detectable change. RESULTS: In paired analyses (n = 310), erosive progression was identified in 30 patients using CR and in 40 patients using HR-pQCT. In the 40 patients with erosive progression on HR-pQCT, progression was not identified by CR in 33 patients. Adding HR-pQCT to CR doubled the proportion of patients identified with progression from 30 (10%) to 63 (20%) patients. Using CR as the reference, the sensitivity (% (95% CI)) of HR-pQCT for identifying erosive progression was 23.3 (9.9-42.3) and the specificity was 88.2 (83.8-91.7). CONCLUSION: A substantial proportion of patients with erosive progression are overlooked using CR only to monitor erosive progression. Adding high-resolution peripheral CT to CR doubles the proportion of patients, who may benefit from individualised therapy targeting erosive progression in RA.

Osteogenesis Imperfecta: Skeletal and Non-skeletal Challenges in Adulthood.

Osteogenesis imperfecta (OI) is a Mendelian connective tissue disorder associated with increased bone fragility and other clinical manifestations most commonly due to abnormalities in production, structure, or post-translational modification of type I collagen. Until recently, most research in OI has focused on the pediatric population and much less attention has been directed at the effects of OI in the adult population. This is a narrative review of the literature focusing on the skeletal as well as non-skeletal manifestations in adults with OI that may affect the aging individual. We found evidence to suggest that OI is a systemic disease which involves not only the skeleton, but also the cardiopulmonary and gastrointestinal system, soft tissues, tendons, muscle, and joints, hearing, eyesight, dental health, and women's health in OI and potentially adds negative affect to health-related quality of life. We aim to guide clinicians as well as draw attention to obvious knowledge gaps and the need for further research in adult OI.

Treatment Sequence for Osteoporosis.

BACKGROUND: Osteoporosis is a chronic progressive disease that requires lifelong monitoring and treatment. Sequencing from one treatment to another at different ages and stages of disease is an approach that can maximize benefits and avoid potential risks from long-term treatment with a single agent. OBJECTIVE: This article reviews clinical trial data in postmenopausal women that evaluate the effects of antiresorptive agents followed by other antiresorptives, osteoanabolic agents followed by antiresorptives, and antiresorptives followed by osteoanabolic medications. METHODS: Literature review and discussion. RESULTS: When medications are discontinued, in the absence of sequential therapy, bone turnover rates return to baseline or above baseline, and bone loss occurs. The rate of bone loss differs for different treatments, with a very slow decline after stopping bisphosphonates and a particularly rapid decline after stopping denosumab. Careful attention to osteoporosis medication transitions can mitigate bone density loss and its consequences. For women who remain at high risk, switching from bisphosphonates to the more potent antiresorptive, denosumab, will result in further improvement in bone mineral density (BMD). When indicated, stopping denosumab can be accomplished safely by transition to an adequate bisphosphonate regimen. For high- and very-high-risk patients, treating with osteoanabolic agents first, followed by antiresorptive agents, produces substantially larger BMD gains than the reverse treatment sequence, with the biggest differences seen for BMD of the hip. CONCLUSION: Awareness of the importance of treatment sequences can help improve osteoporosis care across the postmenopausal lifespan.

Bone Mineral Density Derived from Cardiac CT Scans: Using Contrast Enhanced Scans for Opportunistic Screening.

PURPOSE: Osteoporosis is under-diagnosed and often co-exists with other diseases. Very low bone mineral density (BMD) indicates risk of osteoporosis and opportunistic screening for low BMD in CT-scans has been suggested. In a non-contrast enhanced thoracic CT scan, the scan-field-of-view includes vertebrae enabling BMD estimation. However, many CT scans are obtained by administration of contrast material. If the impact of contrast enhancement on BMD measurements could be quantified, considerably more patients are eligible for screening. METHODS: This study investigated the impact of intravenous contrast on thoracic BMD measurements in cardiac CT scans pre- and post-contrast, including different contrast trigger levels of 130 and 180 Hounsfield units (HU). BMD was measured using quantitative CT with asynchronous calibration. RESULTS: In 195 participants undergoing cardiac CT (mean age 57±9 years, 37 % females) contrast increased mean thoracic BMD from 116±33 mg/cm3 (non-enhanced CT) to 130±38 mg/cm3 (contrast-enhanced CT) (p<0.001). Using clinical cut-off values for very low (<80 mg/cm3) and low BMD (<120 mg/cm3) showed that 24 % (47/195 participants) were misclassified when BMD was measured on contrast-enhanced CT-scans. Of the misclassified patients, 6 % (12/195 participants) were categorized as having low BMD despite having very low BMD on the non-enhanced images. Contrast-CT using a higher contrast trigger level showed a significant increase in BMD compared to the lower trigger level (119±32 vs. 135±40 mg/cm3, p<0.01). CONCLUSION: For patients undergoing cardiac CT, using contrast-enhanced images to assess BMD entails substantial overestimation. Contrast protocol trigger levels also affect BMD measurements. Adjusting for these factors is needed before contrast-enhanced images can be used clinically. MINI ABSTRACT: Osteoporosis is under-diagnosed. Contrast-enhanced CT made to examine other diseases might be utilized simultaneously for bone mineral density (BMD) screening. These scans, however, likely entails overestimation of BMD due to the effect of contrast. Adjusting for this effect is needed before contrast-enhanced images can be implemented clinically for BMD screening.

Development of a program theory for osteoporosis patient education in Denmark: a qualitative study based on realist evaluation.

BACKGROUND: Osteoporosis patient education is offered in many countries worldwide. When evaluating complex interventions like these, it is important to understand how and why the intervention leads to effects. This study aimed to develop a program theory of osteoporosis patient education in Danish municipalities with a focus on examining the mechanisms of change i.e. what is about the programs that generate change. METHODS: The program theory was developed in an iterative process. The initial draft was based on a previous published systematic review, and subsequently the draft was continually refined based on findings from observations (10 h during osteoporosis patient education) and interviews (individual interviews with six employees in municipalities and three health professionals at hospitals, as well as four focus group interviews with participants in patient education (in total 27 informants)). The transcribed interviews were analyzed using thematic analysis and with inspiration from realist evaluation the mechanisms as well as the contextual factors and outcomes were examined. RESULTS: Based on this qualitative study we developed a program theory of osteoporosis patient education and identified four mechanisms: motivation, recognizability, reassurance, and peer reflection. For each mechanism we examined how contextual factors activated the mechanism as well as which outcomes were achieved. For instance, the participants' motivation is activated when they meet in groups, and thereafter outcomes such as more physical activity may be achieved. Recognizability is activated by the participants' course of disease, which may lead to better ergonomic habits. Reassurance may result in more physical activity, and this mechanism is activated in newly diagnosed participants without previous fractures. Peer reflection is activated when the participants meet in groups, and the outcome healthier diet may be achieved. CONCLUSIONS: We developed a program theory and examined how and why osteoporosis patient education is likely to be effective. Understanding these prerequisites is important for future implementation and evaluation of osteoporosis patient education.

Genome-wide association study identifies genetic variants which predict the response of bone mineral density to teriparatide therapy.

OBJECTIVES: Teriparatide (TPTD) is an effective treatment for osteoporosis but the individual response to therapy is variable for reasons that are unclear. This study aimed to determine whether the response to TPTD might be influenced by genetic factors. METHODS: We searched for predictors of the response of bone mineral density (BMD) to TPTD using a two-stage genome-wide association study in 437 patients with osteoporosis from three referral centres. Demographic and clinical data including the response of BMD to treatment at the lumbar spine and hip were extracted from the medical records of each participant. RESULTS: Allelic variation at rs6430612 on chromosome 2, close to the CXCR4 gene was associated with the response of spine BMD to TPTD at a genome wide significant level (p=9.2×10-9 beta=-0.35 (-0.47 to -0.23)). The increase in BMD was almost twice as great in AA homozygotes at rs6430612 as compared with GG homozygotes with intermediate values in heterozygotes. The same variant was also associated with response of femoral neck and total hip BMD (p=0.007). An additional locus on chromosome 19 tagged by rs73056959 was associated with the response of femoral neck BMD to TPTD (p=3.5×10-9, beta=-1.61 (-2.14 to -1.07)). CONCLUSIONS: Genetic factors influence the response to TPTD at the lumbar spine and hip with a magnitude of effect that is clinically relevant. Further studies are required to identify the causal genetic variants and underlying mechanisms as well as to explore how genetic testing for these variants might be implemented in clinical practice.

Changes in RANKL and TRAcP 5b after discontinuation of denosumab suggest RANKL mediated formation of osteoclasts results in the increased bone resorption.

In patients discontinuing long-term denosumab, RANKL levels are high 6 months after the last denosumab injection. Nine and 12 months after the last denosumab injection RANKL levels are lower, but TRAcP 5b levels are higher, suggesting that accumulated RANKL increases the number of active osteoclasts. PURPOSE: The rapid increase in bone turnover occurring when discontinuing long-term treatment with denosumab (DMAB), an antibody that neutralizes receptor activator of nuclear factor kappa-B ligand (RANKL) is not fully understood. We aimed to investigate the mechanisms underlying the rebound activation of bone resorption by measuring tartrate-resistant acid phosphatase 5b (TRAcP 5b), RANKL, osteoprotegerin (OPG), C-terminal collagen crosslinks (CTX), and procollagen type I N-propeptide (P1NP) in patients discontinuing long-term DMAB. METHODS: Sixty-one patients with BMD T-score > - 2.5 at the spine and hip discontinuing long-term DMAB were randomized to treatment with zoledronate (ZOL) 6 months (6 M group, n = 20), 9 months (9 M group, n = 20) or 12 months after the last DMAB injection or when bone turnover was high (12 M group, n = 21). Bone turnover markers were measured immediately before initiation of ZOL treatment. RESULTS: We found higher CTX and PINP in the 9 M and 12 M groups compared to the 6 M group (p < 0.001). In the 6 M group, TRAcP 5b was lower and RANKL higher than in the other two groups (p < 0.001). TRAcP 5b correlated negatively with RANKL (R = - 0.54), and time since the last DMAB injection correlated positively with CTX (R = 0.56), PINP (R = 0.72), TRAcP 5b (R = 0.51) and negatively with RANKL (R = - 0.70) (p < 0.001 for all). We found no difference in OPG between groups. CONCLUSION: Following discontinuation of long-term DMAB, we find high levels of RANKL, which most likely result in an increase in the number of active osteoclasts (illustrated by TRAcP5b) causing an increased bone turnover.

Discontinuation of denosumab in men with prostate cancer.

In patients with non-metastatic prostate cancer, treated with radiation therapy and androgen deprivation therapy for 3 years and DMAB on average for 5 years, BMD was in the normal or osteopenic range. Discontinuation of DMAB led to a bone loss of 2-5%. In men with osteopenia, the bone loss was prevented by zoledronate. PURPOSE: Patients with prostate cancer receiving androgen deprivation therapy (ADT) are treated with denosumab (DMAB) to prevent fractures and preserve bone mass. We wanted to investigate the change in BMD in men with non-metastatic prostate cancer discontinuing DMAB. METHODS: We conducted a retrospective cohort study based on medical records from patients referred to the Department of Endocrinology from the Department of Urology, Aarhus University Hospital between June 1, 2018, and June 1, 2021. We retrieved information on biochemistry and DXA performed 0-6 months after the last DMAB injection and a second DXA performed approximately 12 months after the first. In case of a BMD T-score ≤ - 1 at the lumbar spine or total hip at the first DXA, the patients were treated with zoledronate. The primary endpoint was change in lumbar spine BMD. RESULTS: We included 50 patients with non-metastatic prostate cancer. The mean DMAB treatment duration was 5 ± 0.1 years. Among the patients treated with zoledronate (n = 9), BMD was maintained at the spine and femoral neck after a mean of 16 months. We found a significant decrease in BMD; - 4.9 ± 4.2%, - 1.9 ± 3.5%, and - 2.4 ± 3.6% at the spine, total hip, and femoral neck between the first and second DXA in the patients not treated with zoledronate (n = 24) (p ≤ 0.01 for all). One patient who did not receive ZOL sustained multiple fragility vertebral fractures after DMAB discontinuation. CONCLUSION: In men with non-metastatic prostate cancer, discontinuation of DMAB after stopping ADT led to an average bone loss of 2-5%. Zoledronate prevented bone loss in men with osteopenia.

The Effect of Effervescent and Buffered Alendronate Compared to Conventional Alendronate on Markers of Bone Turnover: A Randomized Non-inferiority Trial.

Buffered and effervescent alendronate (ALN-EFF) increases gastric pH and is reported to decrease the risk of gastrointestinal side effects compared to conventional formulations of alendronate (ALN). The clinical effectiveness of ALN-EFF, however, has not been investigated. This study aims to investigate if ALN-EFF is non-inferior to ALN in suppressing bone turnover markers (BTM). We conducted a 16-week prospective, randomized, open-label study comprising 64 postmenopausal women with BMD T-score < -1 naïve to osteoporosis treatment. Participants were randomized 1:1 to ALN or ALN-EFF. We collected blood samples at 0, 4, 8, and 16 weeks. Non-inferiority margin was determined as 12% (80% of efficacy retained), and an SD of 15% on change in CTx. CTx decreased by 58.2% ± 24.1% in the ALN group and by 46.9% ± 23.3% (CI - 38.42:- 55.35) in the ALN-EFF group (p = 0.08). The non-inferiority limit was 46.6%. With ALN-EFF the CI crosses the non-inferiority limit thus the test for non-inferiority was indeterminate. PINP decreased by 45.7 ± 22.6% in the ALN group and by 35.1 ± 20.7% in the ALN-EFF group (p = 0.07). Changes over time in the BTMs were not significantly different between the groups, p > 0.10 for both CTx and PINP. There was no difference in frequency of AEs or compliance between the two groups, but rate of discontinuation was lower with ALN-EFF. In conclusion, suppression of BTMs was not significantly different between the groups but formal non-inferiority could not be established.

Vitamin K supplementation and bone mineral density in dialysis: results of the double-blind, randomized, placebo-controlled RenaKvit trial.

BACKGROUND: Vitamin K deficiency is highly prevalent in patients on dialysis and may contribute to their low bone mineral density (BMD) and increased risk of fracture. This study investigated the effect of menaquinone-7 (MK-7) supplementation on BMD in patients on chronic dialysis. METHODS: In a multicentre, double-blind, placebo-controlled intervention trial, 123 patients on chronic dialysis were randomised to a daily oral supplement of either MK-7 360 µg or placebo for 2 years. BMD of the distal radius (1/3, mid, ultradistal and total), femoral neck, lumbar spine (L1-L4) and whole body was assessed by dual-energy X-ray absorptiometry. Serum levels of vitamin K1 and MK-7 and plasma levels of total osteocalcin, dephosphorylated-uncarboxylated matrix Gla protein and protein induced by vitamin K absence II were measured to assess vitamin K status. RESULTS: After 2 years, an accelerated BMD loss of the 1/3 distal radius was found with MK-7 supplementation {mean difference of changes relative to placebo -0.023 g/cm2 [95% confidence interval (CI) -0.039 to -0.008]}, whereas the decrease in lumbar spine BMD seen in the placebo group was prevented [mean difference of changes between groups 0.050 g/cm2 (95% CI 0.015-0.085)]. No significant effects were observed at the remaining skeletal sites. Vitamin K status strongly improved in MK-7-supplemented participants. CONCLUSION: Compared with placebo, an accelerated BMD loss of the 1/3 distal radius was found after 2 years of MK-7 supplementation, whereas a decline in lumbar spine BMD was prevented. As such, MK-7 supplementation might modify BMD site-specifically in patients on dialysis. In aggregate, our findings do not support MK-7 supplementation to preserve bone in patients on dialysis.

Denosumab Discontinuation.

PURPOSE OF REVIEW: To review the pathophysiology, the clinical consequences as well as way of mitigating the effects of denosumab discontinuation. RECENT FINDINGS: Treatment with denosumab (DMAB) is reversible and upon discontinuation there is a rapid increase in bone turnover and a subsequent bone loss. During this phase of high bone turnover, an increased risk of fractures has been reported. Therefore, treatment with DMAB could be considered life-long. However, side-effects may prompt the need for discontinuation and moreover, treatment with DMAB may have increased BMD to levels where continuing treatment does not provide further fracture risk reduction. Patients stopping DMAB should be offered subsequent antiresorptive treatment with an intense monitoring regimen during the initial year as most of the bone loss occurs within these initial 12 months. In this review, we evaluated the literature published over the past 1 to 3 years investigating DMAB withdrawal with focus on bone turnover markers, bone mineral density, and fracture risk and the transition to other anti-osteoporosis therapies. Furthermore, we summarized the current recommendations of international guidelines. In this review, we evaluated the literature published over the past 1 to 3 years investigating denosumab (DMAB) discontinuation and the transition to other anti-osteoporosis therapies. Additionally, we summarized the current recommendations of international guidelines.

Cerebral palsy and bisphosphonates - and what can be learned from other types of secondary osteoporosis in children: A scoping review.

AIM: We aimed to improve bone health management of children with cerebral palsy (CP) by reviewing studies investigating bisphosphonate therapy in children with CP and other types of secondary osteoporosis. METHODS: We included trials on bisphosphonate treatment reporting any direct bone measurement or fracture outcome. All studies of patients with CP were included. We also included all controlled trials of children with secondary bone fragility as well as observational studies with ≥20 participants or at least 3 years of follow-up. Studies were assessed according to PRISMA guidelines using the RoB2-tool and the Newcastle-Ottawa Scale. RESULTS: We reviewed 1104 studies and found 37 eligible. Some studies were sufficiently homogeneous to include in a meta-analysis, and we found a 1-year effect on lumbar spine bone mineral density (BMD) Z-score of +0.65 after oral and + 1.21 after intravenous bisphosphonates in children with secondary osteoporosis. Further, data on adverse events and post-treatment follow-up were reviewed. Limitations were heterogeneity and small size of the included studies. CONCLUSION: Meta-analysis consistently showed significant BMD increases with bisphosphonates in children with secondary osteoporosis. Direct evidence of the effect of bisphosphonates on reducing fractures is lacking. We found no reports of long-term adverse events yet longer studies are needed.

Asia-pacific consensus on osteoporotic fracture prevention in postmenopausal women with low bone mass or osteoporosis but no fragility fractures.

Postmenopausal women are at significant risk for osteoporotic fractures due to their rapid bone loss. Half of all postmenopausal women will get an osteoporosis-related fracture over their lifetime, with 25% developing a spine deformity and 15% developing a hip fracture. By 2050, more than half of all osteoporotic fractures will occur in Asia, with postmenopausal women being the most susceptible. Early management can halt or even reverse the progression of osteoporosis. Consequently, on October 31, 2020, the Taiwanese Osteoporosis Association hosted the Asia-Pacific (AP) Postmenopausal Osteoporotic Fracture Prevention (POFP) consensus meeting, which was supported by the Asian Federation of Osteoporosis Societies (AFOS) and the Asia Pacific Osteoporosis Foundation (APOF). International and domestic experts developed ten applicable statements for the prevention of osteoporotic fractures in postmenopausal women with low bone mass or osteoporosis but no fragility fractures in the AP region. The experts advocated, for example, that postmenopausal women with a high fracture risk be reimbursed for pharmaceutical therapy to prevent osteoporotic fractures. More clinical experience and data are required to modify intervention tactics.

Opportunities for biomineralization research using multiscale computed X-ray tomography as exemplified by bone imaging.

Biominerals typically have complex hierarchical structures traversing many length scales. This makes their structural characterization complicated, since it requires 3D techniques that can probe full specimens at down to nanometer-resolution, a combination that is difficult - if not impossible - to achieve simultaneously. One challenging example is bone, a mineralized tissue with a highly complex architecture that is replete with a network of cells. X-ray computed tomography techniques enable multiscale structural characterization through the combination of various equipment and emerge as promising tools for characterizing biominerals. Using bone as an example, we discuss how combining different X-ray imaging instruments allow characterizing bone structures from the nano- to the organ-scale. In particular, we compare and contrast human and rodent bone, emphasize the importance of the osteocyte lacuno-canalicular network in bone, and finally illustrate how combining synchrotron X-ray imaging with laboratory instrumentation for computed tomography is especially helpful for multiscale characterization of biominerals.

Diagnostic accuracy of high-resolution peripheral quantitative computed tomography and X-ray for classifying erosive rheumatoid arthritis.

OBJECTIVE: To investigate whether high-resolution peripheral quantitative CT (HR-pQCT) of two metacarpophalangeal (MCP) joints can more accurately classify patients as having erosive RA compared with conventional radiography (CR) of 44 joints in the hands, wrists and feet. METHODS: In this single-centre cross-sectional study, patients with established RA (disease duration ≥5 years) were investigated by HR-pQCT and CR. The second and third MCP joints of the dominant hand were assessed for erosions by HR-pQCT. CR of the hands, wrists and feet were scored according to the Sharp-van der Heijde (SHS) method. RESULTS: In total, 353 patients were included; 66 (18.7%) patients were classified as having non-erosive RA, and 287 (81.3%) had erosive RA by CR. The sensitivity and specificity (95% CI) of HR-pQCT for classifying patients as having erosive RA when standard CR of hands, wrists and feet was used as the reference was 89% (84, 92%) and 30% (20, 43%), respectively. Using HR-pQCT as the reference, the sensitivity and specificity of CR for classifying patients having erosive RA were 85% (80, 89%) and 38% (25, 52%), respectively. McNemar's χ2 test showed no significant difference between the sensitivities of patients classified as having erosive RA by HR-pQCT or by CR (2.14, P = 0.177). CONCLUSION: The diagnostic accuracy of HR-pQCT scanning of only two MCP joints and CR of 44 joints suggests the two modalities were comparable for classifying patients with established RA as having erosive disease. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT03429426).

Challenges in the diagnosis and management of glucocorticoid-induced osteoporosis in younger and older adults.

OBJECTIVE: Glucocorticoids constitute a considerable risk for developing osteoporosis in both younger and older adults. However, currently available bone imaging modalities and fracture-risk assessment tools do not adequately capture the dramatic changes in bone microarchitecture, heterogeneity of glucocorticoid exposure, the impact of chronic disease and other osteoporosis risk factors on the assessment of osteoporosis in these individuals. DESIGN: A narrative review is presented, following a systematic search of the literature from 2000 to 2021. RESULTS: Our current appreciation of glucocorticoid-induced osteoporosis (GIO) is focused on older populations, with limited evidence to guide the investigation, risk assessment and treatment in premenopausal women and men less than 50 years. The impact of the underlying chronic disease on secondary osteoporosis in these younger adults is also poorly understood. CONCLUSION: Through this narrative review, we provide a comprehensive overview of and recommendations for optimising the management of this common cause of secondary osteoporosis younger and older adults.

Romosozumab efficacy and safety in European patients enrolled in the FRAME trial.

In this post hoc analysis, we assessed romosozumab efficacy and safety in European patients enrolled in FRAME. Romosozumab treatment through 12 months, followed by denosumab for a further 24 months, resulted in early and sustained risk reduction for major fracture categories, associated with large gains in bone mineral density. INTRODUCTION: In the multinational FRAME phase 3 trial of romosozumab in postmenopausal women with osteoporosis, marked differences between clinical and non-vertebral fracture outcomes were observed among patients from Central and Southern America versus rest of world. This post hoc analysis assessed romosozumab efficacy and safety in European patients enrolled in the FRAME trial and extension study. METHODS: In FRAME (NCT01575834), patients were randomised 1:1 to romosozumab 210 mg or placebo monthly (QM) for 12 months, followed by open-label denosumab 60 mg Q6M to month 36, including a 12-month extension study. We report incidence of major fracture outcomes, bone mineral density (BMD) change from baseline and safety for European patients enrolled in FRAME. RESULTS: In FRAME, 3013/7180 (41.96%) patients were European; 1494 received romosozumab and 1519 received placebo. Through 12 months, romosozumab reduced fracture risk versus placebo for non-vertebral fracture (1.4% versus 3.0%; p = 0.004), clinical fracture (1.4% versus 3.6%; p < 0.001), new vertebral fracture (0.4% versus 2.1%; p < 0.001) and major osteoporotic fracture (0.9% versus 2.8%; p < 0.001), with results sustained through 36 months following transition to denosumab. Hip fractures were numerically reduced with romosozumab at month 12 (0.2% versus 0.6%; p = 0.092). Romosozumab increased BMD versus placebo at month 12; all patients in the romosozumab and placebo groups experienced further increases by month 36 after transition to denosumab. Adverse events were balanced between groups. CONCLUSIONS: Among European patients in FRAME, romosozumab resulted in early and sustained risk reduction for all major fracture categories, associated with large BMD gains that continued after transition to denosumab.

Romosozumab and antiresorptive treatment: the importance of treatment sequence.

To evaluate whether treatment sequence affects romosozumab response, this analysis reviewed studies where romosozumab was administered before or following an antiresorptive (alendronate or denosumab). Initial treatment with romosozumab followed by an antiresorptive resulted in larger increases in bone mineral density of both hip and spine compared with the reverse sequence. INTRODUCTION: Teriparatide followed by an antiresorptive increases bone mineral density (BMD) more than using an antiresorptive first. To evaluate whether treatment sequence affects romosozumab response, we reviewed randomized clinical trials where romosozumab was administered before (ARCH, FRAME) or following (STRUCTURE, Phase 2 extension) an antiresorptive (alendronate or denosumab, respectively). METHODS: We evaluated BMD percentage change for total hip (TH) and lumbar spine (LS) and response rates (BMD gains ≥ 3% and ≥ 6%) at years 1 and 2 (except STRUCTURE with only 1-year data available). RESULTS: With 1-year romosozumab initial therapy in ARCH and FRAME, TH BMD increased 6.2% and 6.0%, and LS BMD increased 13.7% and 13.1%, respectively. When romosozumab was administered for 1 year after alendronate (STRUCTURE) or denosumab (Phase 2 extension), TH BMD increased 2.9% and 0.9%, respectively, and LS BMD increased 9.8% and 5.3%, respectively. Over 2 years, TH and LS BMD increased 7.1% and 15.2% with romosozumab/alendronate, 8.5% and 16.6% with romosozumab/denosumab, and 3.8% and 11.5% with denosumab/romosozumab, respectively. A greater proportion of patients achieved BMD gains ≥ 6% when romosozumab was used first, particularly for TH, versus the reverse sequence (69% after romosozumab/denosumab; 15% after denosumab/romosozumab). CONCLUSION: In this study, larger mean BMD increases and greater BMD responder rates were achieved when romosozumab was used before, versus after, an antiresorptive agent. Since BMD on treatment is a strong surrogate for bone strength and fracture risk, this analysis supports the thesis that initial treatment with romosozumab followed by an antiresorptive will result in greater efficacy versus the reverse sequence.

Bone Turnover, Mineralization, and Volume Estimated by 18F-Sodium Fluoride PET/CT and Biomarkers in Chronic Kidney Disease: Mineral and Bone Disorder Compared with Bone Biopsy.

INTRODUCTION: Invasive bone biopsy to assess bone metabolism in patients with chronic kidney disease-mineral and bone disorder may be replaced by the noninvasive 18F-NaF PET/CT and biomarkers of bone metabolism. We aimed to compare parameters of bone turnover, mineralization, and volume assessed by bone biopsies with results derived from 18F-NaF PET/CT and biomarkers (bone-specific alkaline phosphatase, osteocalcin, fibroblast growth factor 23, and osteoprotegerin). METHODS: A cross-sectional study included 17 dialysis patients, and results from 18F-NaF PET/CT scans and the biomarkers were directly compared with the results of histomorphometric analyses of tetracycline double-labeled trans-iliac bone biopsies. RESULTS: Bone biopsies showed 40% high, 20% normal, and 40% low bone turnover. No biopsies had generalized abnormal mineralization, and the bone volume/total tissue volume was low in 80% and high in 7%. The pelvic skeletal plasma clearance (Ki) from 18F-NaF PET/CT correlated with bone turnover parameters obtained by bone biopsy (activation frequency: r = 0.82, p < 0.01; bone formation rate/bone surface: r = 0.81, p < 0.01), and Ki defined low turnover with high sensitivity (83%) and specificity (100%). CT-derived radiodensity correlated with bone volume, r = 0.82, p < 0.01. Of the biomarkers, only osteocalcin showed a correlation with turnover assessed by histomorphometry. CONCLUSION: In conclusion, 18F-NaF PET/CT may be applicable for noninvasive assessment of bone turnover and volume in CKD-MBD.

Component migration, bone mineral density changes, and bone turnover markers in cementless and cemented total knee arthroplasty: a prospective randomized RSA study in 53 patients with 2-year follow-up.

PURPOSE: Cementless tibial components migrate initially until osseointegration and preserve periprosthetic bone. Cemented tibial components are fixed from surgery but loose periprosthetic bone. Little is known about bone formation and resorption biomarkers in relation to component fixation and bone mineral density (BMD) changes of cementless and cemented total knee arthroplasty. We hypothesize a similar migration of cemented and cementless tibial components between 1- and 2-year follow-up indicating a stable long-term fixation. METHODS: In a prospective patient-blinded randomized study, we compared cementless (n = 27) and cemented (n = 26) tibial components with radiostereometry measured migration (MTPM = Maximum Total Point Motion: point of component that migrates the most) and changes in BMD and biochemical bone turnover markers (BTMs) until 24 months after surgery. RESULTS: The mean MTPM between 12 and 24 months were similar between groups with - 0.06 mm (95% CI - 0.23; 0.11) in the cementless group compared to 0.02 mm (95% CI - 0.07; 0.11) in the cemented group. However, there was a higher proportion of cementless components (16/25) than cemented components (7/24) with continuous migration (MTPM > 0.2 mm) (p = 0.02). In the medial and anterior region below the tibial components, the BMD increased by mean 1.8% and 7.4% for cementless components and decreased by mean 8.6% and 4.2% for cemented components until 24-month follow-up. In both groups, BTMs initially showed increased bone resorption (CTx) and bone formation (P1NP) followed by normalization to pre-operative levels at 6 months post-surgery. CONCLUSION: More cementless components than cemented components showed continues migration which suggest a higher risk of early revision. Bone turnover increased post-surgery in both groups, but did not explain the difference in change in periprosthetic BMD. LEVEL OF EVIDENCE: I.