A novel sequential treatment approach between denosumab and romosozumab in patients with severe osteoporosis.

In severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab is unclear. We utilised a novel overlapping strategy in three patients with very-high fracture risk despite long-term denosumab which led to greater bone density improvements than previously reported with standard approaches. Larger confirmatory prospective studies are needed. PURPOSE/INTRODUCTION: In patients with severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab has not been established. The ideal strategy would maximise gains in bone mineral density (BMD) with romosozumab and effectively mitigate the risk of rebound increased bone turnover when sequencing from denosumab. Limited studies exploring the sequence from denosumab to romosozumab report only modest-to-no improvement in BMD and inadequate suppression of rebound bone turnover. METHODS: We describe three patients with severe osteoporosis and multiple fragility fractures despite long-term denosumab. A novel overlapping sequential treatment approach was utilised to maximise therapeutic benefit given these patients had a very high fracture risk. Romosozumab was commenced 3 months after the last denosumab dose. Instead of waiting until completion of romosozumab, denosumab was recommenced 6 months after commencing romosozumab in response to rising bone turnover markers. RESULTS: Patients experienced a ~ 5-22% increase in lumbar spine BMD, and one patient had an 8% increase in total hip BMD after 12 months romosozumab. Serum bone turnover markers demonstrated an anabolic effect of romosozumab occurred despite overlapping treatment with denosumab. Recommencement of denosumab suppressed an increase in bone resorption in all cases. No new vertebral fractures occurred during this treatment. CONCLUSIONS: A novel overlapping sequential treatment approach between denosumab and romosozumab produced greater improvements in lumbar spine and hip BMD than previously reported with standard approaches. Larger prospective controlled studies are needed to confirm these findings and establish the optimal use of romosozumab in patients pre-treated with denosumab to maximise BMD gains and minimise fracture risk.

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.

An investigation of the differential therapeutic effects of romosozumab on postmenopausal osteoporosis patients with or without rheumatoid arthritis complications: a case-control study.

The impact of ROMO on the width of anabolic windows and the increase in BMD was reduced in the RA group compared to the non-RA group, and this reduction was associated with correlations to RA-related factors. PURPOSE: To investigate the effects of romosozumab (ROMO) in postmenopausal osteoporosis, with and without comorbid rheumatoid arthritis (RA). METHODS: In this retrospective, case-controlled, multicenter study, 171 postmenopausal patients who did not receive oral glucocorticoid, comprising 59 in the RA group and 121 in the non-RA group, received uninterrupted ROMO treatment for 12 months. Propensity score matching was employed to ensure comparability in clinical backgrounds, resulting in 41 patients in each group. Baseline characteristics were as follows: overall (mean age, 76.3 years; T-score of lumbar spine (LS), - 3.0; 45.1% were treatment-naive for osteoporosis); RA group (anti-cyclic citrullinated peptide antibody (ACPA) positivity, 80.5%; titer, 206.2 U/ml; clinical disease activity index (CDAI), 13.6; health assessment questionnaire disability index (HAQ-DI), 0.9). Bone mineral density (BMD) and serum bone turnover markers were monitored over a 12-month period. RESULTS: The rate of increase in the bone formation marker, PINP, and the rates of decrease in the bone resorption marker, TRACP-5b, exhibited a trend toward smaller changes in the RA group compared to the non-RA group, implying a smaller anabolic window. After 12 months, the RA group displayed lower BMD increases in the LS (9.1% vs. 12.6%; P = 0.013) and total hip (2.4% vs. 4.8%; P = 0.025) compared to the non-RA group. Multiple regression analysis in the all RA group (n = 59) for the association between RA-specific factors and 12-month BMD changes revealed negative correlations between ACPA titer and LS BMD and between HAQ-DI and femoral neck BMD. CONCLUSIONS: The efficacy of ROMO may be attenuated by RA-related factors.

Romosozumab in patients who experienced an on-study fracture: post hoc analyses of the FRAME and ARCH phase 3 trials.

Post hoc analysis of FRAME and ARCH revealed that on-study nonvertebral and vertebral fractures by Month 12 were less common in women initially treated with romosozumab versus placebo or alendronate. Recurrent fracture risk was also lower in romosozumab­treated patients, and there were no fracture­related complications. Results support continuing romosozumab treatment post­fracture. PURPOSE: Post hoc analysis evaluating efficacy and safety of romosozumab, administered in the immediate post­fracture period, in the FRAME and ARCH phase 3 trials. METHODS: In FRAME (NCT01575834) and ARCH (NCT01631214), postmenopausal women with osteoporosis were randomized 1:1 to romosozumab 210 mg monthly or comparator (FRAME, placebo; ARCH, alendronate 70 mg weekly) for 12 months, followed by antiresorptive therapy (FRAME, denosumab; ARCH, alendronate). In patients who experienced on-study nonvertebral or new/worsening vertebral fracture by Month 12, we report the following: fracture and treatment­emergent adverse event (TEAE) incidence through 36 months, bone mineral density changes (BMD), and romosozumab timing. Due to the sample sizes employed, meaningful statistical comparisons between treatments were not possible. RESULTS: Incidence of on-study nonvertebral and vertebral fractures by Month 12 was numerically lower in romosozumab- versus comparator-treated patients (FRAME, 1.6% and 0.5% versus 2.1% and 1.6%; ARCH, 3.4% and 3.3% versus 4.6% and 4.9%, respectively). In those who experienced on-study nonvertebral fracture by Month 12, recurrent nonvertebral and subsequent vertebral fracture incidences were numerically lower in patients initially treated with romosozumab versus comparator (FRAME, 3.6% [2/56] and 1.8% [1/56] versus 9.2% [7/76] and 3.9% [3/76]; ARCH, 10.0% [7/70] and 5.7% [4/70] versus 12.6% [12/95] and 8.4% [8/95], respectively). Among those with on-study vertebral fracture by Month 12, recurrent vertebral and subsequent nonvertebral fracture incidences were numerically lower with romosozumab versus comparator (FRAME, 0.0% [0/17] and 0.0% [0/17] versus 11.9% [7/59] and 8.5% [5/59]; ARCH, 9.0% [6/67] and 7.5% [5/67] versus 15.0% [15/100] and 16.0% [16/100], respectively). In patients with fracture by Month 12, no fracture­related complications were reported in romosozumab-treated patients. BMD gains were numerically greater with romosozumab than comparators. CONCLUSION: Data suggest support for the efficacy and safety of continuing romosozumab treatment following fracture. TRIAL REGISTRATIONS: NCT01575834; NCT01631214.

Current and Developing Pharmacologic Agents for Improving Skeletal Health in Adults with Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational processing of type I collagen. Drugs currently used to improve skeletal health in OI were initially developed to treat osteoporosis and clinical trials are ongoing to study their effectiveness in OI adults. Additionally, novel bone-protective agents are in preclinical studies and various phases of OI clinical trials. This review summarizes current knowledge on available pharmacologic agents and current drug trials involving OI participants. A PubMed online database search of all study types published in the English language using the terms "osteogenesis imperfecta," "OI," and "brittle bone disease" was performed in August 2022. Articles screened were restricted to adults. A ClinicalTrials.gov database search of all studies involving "osteogenesis imperfecta" was performed in August 2023. Although clinical trial data are limited, bisphosphonates and teriparatide may be useful in improving bone mineral density. As of yet, no clinical trials are available that adequately evaluate the usefulness of current therapies in reducing fracture risk. Several therapeutics, including teriparatide, setrusumab, anti-TGF-ß antibodies, and allogeneic stem cells, are being studied in clinical trials. Preclinical studies involving Dickkopf-1 antagonists present promising data in non-OI bone disease, and could be useful in OI. Research is ongoing to improve therapeutic options for adults with OI and clinical trials involving gene-editing may be possible in the coming decade.

Drug utilization pattern of romosozumab and other osteoporosis treatments in Japan, 2019-2021.

INTRODUCTION: Describe real-world treatment of osteoporosis and romosozumab treatment patterns in Japan. MATERIALS AND METHODS: Data for patients initiating romosozumab or other antiosteoporotic medications between March 01, 2018, and May 31, 2022, were extracted from the Medical Data Vision (MDV) and Japan Medical Data Center (JMDC) databases. Patients were categorized into four cohorts: those who newly initiated romosozumab within the first (MDV: n = 4782; JMDC: n = 2578) or second (MDV: n = 3888; JMDC: n = 2446) year after launch and those who initiated teriparatide (TPTD; MDV: n = 14,576; JMDC: n = 8259) or non-TPTD antiosteoporotic medications within the first year of romosozumab launch (MDV: n = 352,142; JMDC: n = 185,785). RESULTS: Mean age, sex, baseline cardiovascular history, comorbidities, and concomitant medications were similar across cohorts. In the MDV database, fracture history was higher in the romosozumab year-1 (59.3%), year-2 (64.1%), and TPTD (65.5%) cohorts versus the non-TPTD cohort (24.4%). Similar rates were identified in the JMDC database: romosozumab year-1 (64.7%), year-2 (66.6%), TPTD (67.5%), and non-TPTD (27.8%). Vertebral fractures were most common in all cohorts. 12-month romosozumab discontinuation varied between the year-1 and year-2 cohorts in MDV (62.4% and 58.8%) and JMDC (57.1% and 52.7%), whereas mean number of injections remained consistent (MDV: 9.7 and 9.8; JMDC: 7.3 and 7.8). Romosozumab persistence was lower in year-1 versus year-2 (MDV: 37.6% and 42.9%; JMDC: 41.2% and 47.3%). CONCLUSION: Patients initiating romosozumab and TPTD had a high fracture history. Given the dual effects of promoting bone formation and suppressing resorption, improving romosozumab adherence and persistence over time may be important for antiosteoporotic therapy.

Efficacy and safety of romosozumab: a meta-analysis of placebo-controlled trials.

INTRODUCTION: We aimed to comprehensively compile placebo-controlled trials on the efficacy and safety of romosozumab (210 mg, subcutaneously, once monthly) in postmenopausal women and men with osteoporosis. MATERIALS AND METHODS: PubMed, Google Scholar, and ClinicalTrials.gov were searched for relevant placebo-controlled trials (as of January 1, 2024). Percent change in bone mineral density (BMD), falls, fractures, and adverse events (AEs) after drug administration were collected. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were calculated. RESULTS: Six trials (7990 patients; follow-up period, 6-12 months) were included. Compared with placebo, romosozumab significantly increased lumbar spine BMD (MD = 12.69; 95% CI 11.10-14.29), total hip BMD (MD = 4.42; 95% CI 3.03-5.80), and femoral neck BMD (MD = 3.99; 95% CI 2.42-5.57) at 12 months. Romosozumab significantly decreased falls (RR = 0.80; 95% CI 0.68-0.93) and major osteoporotic fractures (RR = 0.37; 95% CI 0.25-0.54), but increased injection-site reactions (RR = 1.83; 95% CI 1.46-2.30) within 12 months. No significant differences were observed in other AEs (including cardiovascular AEs) within 12 months. CONCLUSION: Romosozumab treatment resulted in a significant BMD gain, reduced falls and major osteoporotic fractures. It was generally well-tolerated, including the cardiovascular aspects. However, clinicians should consider the occurrence of minor AEs (e.g., injection-site reactions).

Clinical effects of teriparatide, abaloparatide, and romosozumab in postmenopausal osteoporosis.

In the management of osteoporosis, anti-resorptive agents serve as a primary therapeutic approach. However, in cases where individuals exhibit an increased susceptibility to fractures, such as those characterized by severe low bone mass or a history of vertebral or hip fractures that markedly diminish life expectancy, the immediate reduction of fracture risk through the administration of osteoanabolic agents could be beneficial. Teriparatide, available in daily, once-weekly, or twice-weekly dosages, along with abaloparatide and romosozumab, constitutes a trio of such agents. Each of these medications is defined by unique characteristics, distinct efficacy profiles, and specific adverse effects. There is growing evidence to suggest that these agents have a superior effect on enhancing bone mineral density and reducing fracture incidence when compared to traditional bisphosphonate therapies. Nonetheless, their employment demands thorough consideration of clinical indications, which includes evaluating economic factors, the frequency of injections required, and the potential for adverse effects. The objective of this review is to consolidate the current evidence focusing primarily on the efficacy of these agents, with the goal of enhancing understanding and aiding in making more informed treatment decisions, particularly for those individuals who are at an elevated risk of fractures.

Effectiveness of romosozumab in patients with osteoporosis at high fracture risk: a Japanese real-world study.

INTRODUCTION: To describe the real-world use of romosozumab in Japan, we conducted a chart review of > 1000 Japanese patients with osteoporosis (OP) at high risk of fracture, across multiple medical institutions. MATERIALS AND METHODS: Treatment-naïve and prior OP-treatment patients who received romosozumab for 12 months followed by ≥ 6 months of sequential OP treatment were included. The primary objective described the baseline demographics and clinical characteristics; secondary objectives evaluated changes in bone mineral density (BMD) and bone turnover markers in all patients and effectiveness of romosozumab in a sub-group of treatment-naïve patients using the fracture risk assessment tool (FRAX®). RESULTS: Of the 1027 patients (92.4% female), 45.0% were treatment-naïve. The mean ± SD age of treatment-naïve versus prior OP-treatment patients was 76.8 ± 8.5 and 77.1 ± 8.5 years. The most frequent prior OP treatment was bisphosphonates (45.0%). Romosozumab treatment for 12 months increased BMD at the lumbar spine in all groups; the median percent change from baseline in lumbar spine BMD was higher in the treatment-naïve (13.4%) versus prior OP-treatment group (bisphosphonates [9.2%], teriparatide [11.3%], denosumab [DMAb, 4.5%]). DMAb, bisphosphonates, or teriparatide after romosozumab maintained the BMD gains at all skeletal sites at month 18 in treatment-naïve patients. Most treatment-naïve patients were at high risk of fracture, BMD increased consistently with romosozumab regardless of the baseline fracture risk assessed by FRAX. CONCLUSION: This large-scale, multicenter chart review provides clinically relevant insights into the profiles of patients initiating romosozumab, effectiveness of real-world romosozumab use, and sequential therapy in Japanese patients at high risk of fracture.

A practical approach for anabolic treatment of bone fragility with romosozumab.

BACKGROUND: Romosozumab, a fully humanized anti-sclerostin-antibody, is a bone-builder stimulating osteoblasts and inhibiting osteoclast by activation of the canonical Wnt-beta catenin signaling. This unique mechanism of action has the potential to address unmet needs in osteoporosis management. METHODS: The multifaceted practical clinical issues related to romosozumab are discussed, especially focusing on the rationale of employing a sclerostin inhibitor to target bone fragility as first line or second line treatment in post-menopausal osteoporosis and in males at increased risk of fractures. RESULTS: Four randomized clinical trials with several post-hoc analyses and more than ten observational studies have consistently demonstrated that romosozumab is effective in rapidly increasing bone mineral density (BMD) and decreasing risk of vertebral, non-vertebral and hip fractures in post-menopausal women at very-high risk of fractures. In male osteoporosis, only data on BMD are available. Noteworthy, romosozumab was shown to be more effective and rapid than teriparatide in improving BMD, bone structure and strength at the hip, especially in women already treated with anti-resorptive drugs. Interestingly, even if romosozumab displays best results in treatment-naïve patients, its favourable effects on BMD were observed even in women previously treated with teriparatide or denosumab, although to a lesser extent. CONCLUSIONS: Based on the available evidence, romosozumab could be proposed as ideal drug in several clinical settings, such as non-fractured post-menopausal women at very-high risk of fractures, patients with recent hip fracture, patients non responder to bisphosphonates and short-term denosumab therapy.

Australian clinicians' perceptions of patients with very high risk of fracture.

BACKGROUND: International osteoporosis guidelines have recommended treatment approaches based on fracture risk stratification, in particular, anabolic therapy for patients with very high risk (VHR) of fragility fracture. AIM: To summarise Australian clinicians' perceptions of patients at VHR of fracture. METHODS: Australian clinicians invited to educational webinars on anabolic treatments for osteoporosis were surveyed in March and April 2021 about a typical patient they had most recently seen and identified as at VHR of fracture. RESULTS: Of the 268 clinician attendees who were invited to complete the post-webinar surveys, 67 (25%) responded and permitted the publication of aggregated data. A typical patient perceived to have a VHR of fracture was a woman in her 80's, living at home, who had been diagnosed with osteoporosis between 5 and 10 years ago, and received treatment for 1-5 years' duration, most commonly denosumab. The patient frequently had a T-score below -3.0 SD (standard deviation), multiple fragility fractures and most commonly suffered a vertebral fracture in the past 12 months, whereas on an adequate regimen of osteoporosis medication. There was a mismatch between the patient being eligible for anabolic therapy (64.2%) and actually having been prescribed an anabolic treatment in the past (20.9%). CONCLUSIONS: Australian clinicians' perceptions of patients with a VHR of fracture and the use of anabolic agents appear to be heavily influenced by local reimbursement criteria. The mismatch between patients deemed eligible for reimbursed anabolic therapy and those prescribed an anabolic agent suggests treatment inertia.

Recommendations for the optimal use of bone forming agents in osteoporosis.

Bone forming agents, also known as anabolic therapies, are essential in managing osteoporosis, particularly for patients at very high-risk of fractures. Identifying candidates who will benefit the most from these treatments is crucial. For example, this group might include individuals with severe osteoporosis, multiple vertebral fractures, a recent fragility fracture or those unresponsive to antiresorptive treatments. Definitions of patients with a very high fracture risk vary across nations, are often based on fracture history, bone mineral density (BMD), and/or fracture risk calculated by FRAX® or other algorithms. However, for very high-risk patients, anabolic agents such as teriparatide, abaloparatide, or romosozumab are commonly recommended as first-line therapies due to their ability to stimulate new bone formation and improve bone microarchitecture, offering significant benefits in rapid fracture reduction over antiresorptive therapies. The cost-effectiveness of these agents is a critical consideration for decision-makers. Despite their higher costs, their effectiveness in significantly reducing fracture risk and improving quality of life can justify the investment, especially when long-term savings from reduced fracture rates and associated healthcare costs are considered. Additionally, after completing a course of anabolic therapy, transitioning to antiresorptive agents like bisphosphonates or denosumab is crucial to maintain the gains in bone density and minimize subsequent fracture risks. This sequential treatment approach ensures sustained protection and optimal resource utilization. In summary, the effective use of bone forming agents in osteoporosis requires a comprehensive strategy that includes accurate patient identification, consideration of cost-effectiveness, and implementation of appropriate sequential treatments, ultimately maximizing patient outcomes and healthcare efficiency.

Association between P1NP value and increases in bone mineral density in patients with postmenopausal osteoporosis treated with romosozumab.

OBJECTIVES: The present study aimed to investigate the effectiveness of treatment with romosozumab for 1 year and association between bone turnover markers and changes in bone mineral density (BMD) in patients with postmenopausal osteoporosis. METHODS: Participants were 53 treatment-naïve postmenopausal osteoporosis patients. Correlations of per cent changes (Δ) in lumbar (L) and total hip (TH) BMD 12 months after initiating romosozumab with baseline demographic factors and parameters of N-terminal propeptide of Type 1 collagen (P1NP) and tartrate-resistant acid phosphatase-5b at baseline and Months 1, 3, and 6 were assessed. Multiple regression analysis was performed on factors significantly correlated with ΔL-BMD and ΔTH-BMD at Month 12. RESULTS: ΔL-BMD and ΔTH-BMD at Month 12 were 17.5% and 8.1%, respectively. Multiple regression analysis revealed that a high P1NP value at Month 3 predicted large increases in L-BMD and TH-BMD at Month 12. High total amount of P1NP values from baseline to Month 6 was associated with large increases in L-BMD and TH-BMD at Month 12 and was most strongly correlated with the P1NP value at Month 3. CONCLUSIONS: A high P1NP value at Month 3 predicted large increases in both L-BMD and TH-BMD at Month 12 in postmenopausal osteoporosis patients treated with romosozumab.

Utilization of Romosozumab in Primary Care.

Objective: The objective of the study is to highlight the role and safety of romosozumab in patients at high risk of fractures in primary care. Data Sources: A systemic database search of PubMed/MEDLINE, ClinicalTrials.gov, and Cochrane Library was conducted for articles with keywords romosozumab, osteoporosis, and safety between inception and July 2022. Study Selection and Data Extraction: Phase 3 trials in patients with osteoporosis were included. Data results from these trials were utilized for assessment. Data Synthesis: Romosozumab decreased vertebral fracture incidence by 73% at 12 months (P < 0.001) in osteoporotic postmenopausal women compared with placebo. In an active-controlled fracture study in postmenopausal women with osteoporosis at high risk of fracture, a 48% lower risk of new vertebral fracture was observed at 24 months in the romosozumab-alendronate group (P < 0.001) compared with alendronate group. In a study comparing romosozumab with teriparatide in postmenopausal women with osteoporosis at high risk of fracture, 2.6% of the mean percentage change from baseline in the total hip (TH) areal bone mineral density (BMD) was observed with romosozumab, while teriparatide led -0.6% of change (P < 0.0001). Romosozumab significantly increased the mean percentage change from baseline in the lumbar spine (LS) and total hip (TH) BMD than placebo in men with osteoporosis (LS, 12.1% vs 1.2%; TH, 2.5% vs -0.5%; P < 0.001). Serious cardiovascular events were observed in the romosozumab compared with alendronate (2.5% vs 1.9%; odds ratio [OR] = 1.31; 95% confidence interval [CI] = 0.85-2.00) in postmenopausal women, and placebo (4.9% vs 2.5%) in men with osteoporosis. Relevance to Patient Care and Clinical Practice: This review discusses the role of romosozumab in patients with high fracture risk and its safety in primary care. Conclusions: Primary care physicians should consider romosozumab for patients at high fracture risk who are intolerant or have not responded to other pharmacological treatment. Further studies are needed to clarify the safety of cardiovascular events.

Romosozumab in osteoporosis: yesterday, today and tomorrow.

Osteoporosis is a systemic bone disease characterized by low bone mass, microarchitectural deterioration, increased bone fragility, and fracture susceptibility. It commonly occurs in older people, especially postmenopausal women. As global ageing increases, osteoporosis has become a global burden. There are a number of medications available for the treatment of osteoporosis, categorized as anabolic and anti-resorptive. Unfortunately, there is no drugs which have dual influence on bone, while all drugs have limitations and adverse events. Some serious adverse events include jaw osteonecrosis and atypical femoral fracture. Recently, a novel medication has appeared that challenges this pattern. Romosozumab is a novel drug monoclonal antibody to sclerostin encoded by the SOST gene. It has been used in Japan since 2019 and has achieved promising results in treating osteoporosis. However, it is also accompanied by some controversy. While it promotes rapid bone growth, it may cause serious adverse events such as cardiovascular diseases. There has been scepticism about the drug since its inception. Therefore, the present review comprehensively covered romosozumab from its inception to its clinical application, from animal studies to human studies, and from safety to cost. We hope to provide a better understanding of romosozumab for its clinical application.

Exploratory use of romosozumab for osteoporosis in a patient with Hajdu-Cheney syndrome: a case report.

Hajdu-Cheney syndrome (HCS) is an inherited skeletal disorder caused by mutations in the Notch homolog protein 2 gene (NOTCH2). Treatment of this rare disease is challenging because there are no established guidelines worldwide. Previous case reports using bisphosphonates, denosumab, or teriparatide suggested that curative treatment for HCS did not exist yet in terms of preventing the disease progression. Therefore, the efficacy of romosozumab for osteoporosis in patients with HCS needs to be evaluated. Herein, we report the case of a 43-year-old woman who had progressive acro-osteolysis and repeated fractures since the age of 29 years. Next-generation sequencing confirmed HCS with a mutation at nucleotide 6758G>A, leading to Trp2253Ter replacement in NOTCH2. Romosozumab treatment was initiated because she had already received bisphosphonate for more than 10 years at other hospitals. After 1 year of romosozumab treatment, the bone mineral density (BMD) increased by 10.2%, 6.3%, and 1.3%, with Z scores of -2.9, -1.6, and -1.2 at the lumbar spine, femoral neck, and total hip, respectively. In addition, C-telopeptide was suppressed by 26.4% (0.121 to 0.089 ng/mL), and procollagen type I N-terminal propeptide increased by 18.7% (25.2 to 29.9 ng/mL). This was the first report of romosozumab treatment in patient with osteoporosis and HCS in Korea. One year of romosozumab treatment provided substantial gains in BMD with maintaining the last acro-osteolytic status without deteriorating, representing a possible treatment option for HCS.

Romosozumab is associated with greater trabecular bone score improvement compared to denosumab in postmenopausal osteoporosis.

In this study, romosozumab demonstrated significantly greater improvement in trabecular bone score compared to denosumab therapy in postmenopausal women previously treated with antiresorptive agents. Notably, in patients previously treated with anti-resorptive agents, treatment with romosozumab resulted in similar increases in trabecular bone score compared to that of drug-naïve patients. PURPOSE: Romosozumab significantly increases bone mineral density (BMD) and rapidly reduces fracture risk. Whether romosozumab can improve the spinal trabecular bone score (TBS) as a bone quality indicator merits further investigation. METHODS: Data for postmenopausal women starting romosozumab or denosumab treatment at Severance Hospital, Korea, were analyzed. Romosozumab and denosumab groups were 1:1 matched using propensity scores, considering relevant covariates. Good responders were defined as those with TBS improvement of 5.8% or greater. RESULTS: Overall, 174 patients (romosozumab, n = 87; denosumab, n = 87) were analyzed. Matched groups did not differ in age (64 years), weight, height, previous fracture (38%), lumbar spine or femoral neck BMD (T-score, -3.4 and -2.6, respectively), or prior bisphosphonate or selective estrogen receptor modulator (SERM) exposure (50%). The romosozumab group exhibited a greater increase in lumbar spine BMD (15.2% vs. 6.9%, p < 0.001) and TBS (3.7% vs. 1.7%, p = 0.013) than the denosumab group. In patients transitioning from bisphosphonate or SERM, romosozumab users showed greater improvement in TBS compared to denosumab users (3.9% versus 0.8%, P = 0.006); the drug-naive group showed no significant difference (3.6% versus 2.7%, P = 0.472). The romosozumab group had a higher proportion of good responders than the denosumab group (33.3% vs. 18.4%, p = 0.024). Romosozumab therapy for 12 months resulted in 3.8-fold higher odds of a good response in TBS than denosumab after covariate adjustment (adjusted odds ratio 3.85, p = 0.002). CONCLUSION: Romosozumab could improve bone mass and bone quality, measured by TBS, in postmenopausal osteoporosis, particularly as a subsequent regimen in patients previously taking anti-resorptive agents.

Baseline serum PINP level is associated with the increase in hip bone mineral density seen with Romosozumab treatment in previously untreated women with osteoporosis.

Baseline serum PINP value was significantly and independently associated with the increased bone mineral density (≥ 3%) in both total hip and femoral necks by 12 months of romosozumab treatment in patients with treatment-naive postmenopausal osteoporosis. PURPOSE: Some patients fail to obtain a sufficiently increased hip bone mineral density (BMD) by romosozumab (ROMO) treatment. This study aimed to investigate the prognostic factor for increased hip BMD with ROMO in patients with treatment-naive postmenopausal osteoporosis. METHODS: This prospective, observational, and multicenter study included patients (n = 63: mean age, 72.6 years; T-scores of the lumbar spine [LS], - 3.3; total hip [TH], - 2.6; femoral neck [FN], - 3.3; serum type I procollagen N-terminal propeptide [PINP], 68.5 µg/L) treated by ROMO for 12 months. BMD and serum bone turnover markers were evaluated at each time point. A responder analysis was performed to assess the patient percentage, and both univariate and multivariate analyses were performed to investigate the factors associated with clinically significant increased BMD (≥ 3%) in both TH and FN. RESULTS: Percentage changes of BMD from baseline in the LS, TH, and FN areas were 17.5%, 4.9%, and 4.3%, respectively. In LS, 96.8% of patients achieved ≥ 6% increased LS-BMD, although 57.1% could not achieve ≥ 3% increased BMD in either TH or FN. Multiple regression analysis revealed that only the baseline PINP value was significantly and independently associated with ≥ 3% increased BMD in both TH and FN (p = 0.019, 95% confidence interval = 1.006-1.054). The optimal cut-off PINP value was 53.7 µg/L with 54.3% sensitivity and 92.3% specificity (area under the curve = 0.752). CONCLUSIONS: In a real-world setting, baseline PINP value was associated with the increased BMD of TH and FN by ROMO treatment in treatment-naive patients.

Nonresponder Considerations for Romosozumab Treatment.

Romosozumab can increase bone mineral density (BMD) in patients with osteoporosis, but some patients do not respond to it. This study aimed to identify risk factors for being a nonresponder to romosozumab treatment. This retrospective observational study included 92 patients. Romosozumab (210 mg) was subcutaneously administered to the participants every 4 weeks over 12 months. We excluded patients who previously underwent treatment for osteoporosis to assess the impact of romosozumab alone. We evaluated the proportion of patients who did not respond to romosozumab treatment to the lumbar spine and hip with increased BMD. Nonresponders were defined as those with a bone density change of < 3% after 12 months of treatment. We compared demographics and biochemical markers between responders and nonresponders. We found that 11.5% of patients were nonresponders at the lumbar spine, and 56.8% were nonresponders at the hip. A risk factor for nonresponse at the spine was low type I procollagen N-terminal propeptide (P1NP) values at 1 month. The cutoff value for P1NP at month 1 was 50 ng/ml. We found that 11.5% and 56.8% of patients experienced no significant improvement in the lumbar spine and hip BMD, respectively. Clinicians should use nonresponse risk factors to inform decisions about romosozumab treatment for patients with osteoporosis.

One-Year Romosozumab Treatment Followed by One-Year Denosumab Treatment for Osteoporosis in Patients on Hemodialysis: An Observational Study.

There is limited evidence on the use of romosozumab (ROMO) in the treatment of osteoporosis in patients on hemodialysis (HD); thus, we aimed to investigate this topic. This prospective, observational, single-center cohort study included 13 prior osteoporosis treatment-naïve patients on HD with osteoporosis. They first received ROMO once monthly for 12 months (210 mg; subcutaneously once every month). Thereafter, they received denosumab (DENO) for an additional 12 months (60 mg; subcutaneously once every 6 months). We examined the incidence of new fractures; treatment safety; and temporal changes in the bone mineral density (BMD), bone metabolism markers, and vascular calcification. No new cases of fractures were noted. The median one-year percentage changes (from the baseline) in the BMDs at the lumbar spine (LS), total hip (TH), and femoral neck (FN) were + 9.0%, + 2.5%, and + 4.7%, respectively. These changes were maintained for 24 months. The corresponding relative changes from the baseline to 24 months thereafter were + 14.9%, + 5.4%, and + 6.5%, respectively. The percentage changes in TH BMD and FN BMD were negatively correlated with baseline BMD. Coronary artery and thoracic aorta calcification scores increased slightly from baseline to 12 months thereafter. However, fatal events (cardiovascular disease-associated and all-cause deaths) did not occur during ROMO treatment. Effectiveness of ROMO was better in patients who had severe osteoporosis with low TH BMD, low FN BMD, and high tartrate-resistant acid phosphatase 5b level at ROMO initiation.