Baseline median levels of both PINP and β-CTX were low in STRUCTURE and the Phase 2 extension, consistent with prior alendronate and denosumab treatment, respectively 12, 28, 29. In FRAME , 19% of patients had a prior vertebral fracture and 22% had a previous nonvertebral fracture at baseline. In ARCH , 96% of women had a prevalent vertebral fracture, and 38% had a nonvertebral fracture at baseline. Serum levels of PINP and β-CTX were assessed at the start of the romosozumab period (at month 36) as the baseline/month 0 (before the first romosozumab dose) and at months 1, 3, 6, 9, and 12 during the romosozumab period. BMD at the lumbar spine and proximal femur was measured at baseline and at months 6 and 12. Women were randomly assigned to receive open-label subcutaneous romosozumab 210 mg monthly (218 patients) or daily subcutaneous teriparatide 20 µg (218 patients) for 12 months (Fig. 1).
In postmenopausal women
Furthermore, in individual patients, the total hip BMD level attained during or after treatment with alendronate, zoledronic acid, denosumab, or romosozumab is a major predictor of subsequent absolute risk of fracture and accordingly could serve as a treatment target for osteoporosis therapy 16–20. Although the study was too small to look at fracture outcomes, in postmenopausal women with osteoporosis at high risk of fracture previously treated with bisphosphonate therapy, 12 months of romosozumab resulted in statistically significant increases in BMD at the total hip, femoral neck and lumbar spine compared with teriparatide. At study completion (median exposure 33 months), relative risk reductions of 27% for clinical fractures, 19% for non-vertebral fractures and 38% for hip fractures were seen for the group initially treated with romosozumab relative to the group treated with alendronate alone.4 In postmenopausal women with osteoporosis at high risk of fracture, romosozumab treatment for 12 months followed by alendronate significantly reduced new vertebral, clinical and non-vertebral fractures compared with alendronate.
Romosozumab Treatment for Osteoporosis: Pharmacological Stimulation of Mechanical Strain-Related Bone Modeling
Treatment with romosozumab in the rare condition of pregnancy and lactation-induced osteoporosis has been reported in 1 case study, in which its use after 4 months of teriparatide was effective in increasing BMD without subsequent fracture . This concluded that BMD changes at the lumbar spine from 12 to 24 months were 2.5% in the ibandronate group and 5.4% in the denosumab group with comparably favorable trends of denosumab at the total hip and femoral neck. Patients were randomly assigned to received either ibandronate or denosumab for an additional 12 months after romosozumab treatment. Addressing the possible reduction in BMD gains resulting from previous denosumab treatment and minimizing the risk of increased bone turnover after discontinuing denosumab before transitioning to romosozumab is crucial.
Romosozumab
Patients should immediately report any oral symptoms such as dental mobility, pain or swelling or non-healing of sores or pus discharge during treatment with romosozumab. Patients under dental treatment, or who will undergo dental surgery (e.g. tooth extractions) whilst being treated with romosozumab should inform their doctor about their dental treatment and inform their dentist that they are receiving romosozumab. If an anaphylactic or other clinically significant allergic reaction occurs, appropriate therapy should be initiated and use of romosozumab should be discontinued. When determining whether to use romosozumab for an individual patient, the presence of risk factors for cardiovascular problems, including established cardiovascular disease, high blood pressure, high blood fat levels, diabetes, smoking or kidney problems, should be evaluated.
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. As we continue to gather data and refine our knowledge, we can better harness the potential of romosozumab to reduce the burden of osteoporosis, especially in high-risk populations. Clinical trials and real-world studies have provided insights into the practical implications of romosozumab therapy, emphasizing the challenge of pretreatment and its impact on BMD gains. Limited literature exists for the role of romosozumab in patients with glucocorticoid-induced osteoporosis, patients after spinal injury, lactation-induced osteoporosis, and patients with renal bone disease (chronic kidney disease CKD-mineral and bone disorder). Although further research with larger sample sizes is needed to better understand the efficacy and safety of subsequent romosozumab treatment courses, current evidence suggests romosozumab may have potential in osteoporosis management with treatment-cycling .
In the STRUCTURE trial, results showed that romosozumab resulted in BMD gains at the hip not observed in the teriparatide group (2.6% increase from baseline BMD in the romosozumab group and −0.6% in the teriparatide group) . Here, a phase III placebo-controlled double-blind study evaluated the safety and efficacy of romosozumab . Patients were ambulatory and aged 55 to 90 years with a BMD T-score of −2.5 or lower at the total hip, femoral neck, or lumbar spine. Given differing study designs, the figure is included as a visual representation of different treatment sequences explored in the studies rather than as a direct comparison of outcomes.
Data availability
No adjudicated events of osteonecrosis of the jaw or atypical femoral fracture daman game download were observed in the 12-month double-blind period. Additionally, 2 events consistent with osteonecrosis of the jaw occurred in the romosozumab group; however, in both cases, there were confounding factors potentially contributing to the event raising questions regarding causality. Overall adverse events and serious adverse events in the FRAME trial, including hyperostosis, cardiovascular events, osteoarthritis, and cancer, appeared balanced between the romosozumab and placebo groups . Those who had recently used other agents affecting bone metabolism, had low serum 25-hydroxyvitamin D concentration, or a history of other conditions affecting bone mass were excluded. Additionally, emerging evidence on the effectiveness of romosozumab in specific patient subgroups is investigated, including individuals with rheumatoid arthritis, nonweightbearing conditions, and end-stage kidney disease. Sclerostin, an antagonist of the Wnt-β-catenin pathway, binds to the Wnt LRP 5/6 coreceptors, leading to phosphorylation and ultimately degradation of β-catenin, thus inhibiting bone formation .
Total hip BMD gains
Two injections are given at the same time once a month for 12 months. This unique mechanism of action leads to a marked increase in BMD, greater than what is seen with oral alendronate or teriparatide.1,2 Romosozumab, a monoclonal antibody, is a potent bone anabolic agent (builds bone) that specifically targets and binds sclerostin. Guido Zavatta received fees for lectures from Abiogen Pharma and Bruno Farmaceutici.
Extending the Therapeutic Potential: Romosozumab in Osteoporosis Management
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. The effects of romosozumab on BMD in patients with RA and severe osteoporosis were compared to that of denosumab at 3 and 6 months in an open-label randomized study of 50 patients . Participants who received a second course of romosozumab following denosumab had a small increase in BMD at the lumbar spine but no improvement in BMD at the total hip.
Serum romosozumab levels were higher in these patients and, in addition, the dose was well-tolerated and results supported its use without dose adjustment in these patients. This demonstrated that in stages 1 to 3 of CKD, romosozumab resulted in greater BMD increases in comparison to alendronate and placebo with a similar safety profile between different levels of renal function. Other subgroups in which there is significant potential for the dual action of romosozumab to improve outcomes include groups with complex causes of low bone density. In the small group of participants, no new safety findings were reported in the second course of romosozumab with the adverse event profile comparable to that of a single course of treatment. This is in contrast to BMD loss after sequential therapy with denosumab followed by teriparatide .
- Interruption of romosozumab therapy should be considered, based on an individual benefit-risk assessment.
- Mukaddam et al describes off-label use in a 37 -year-old African American male with severe osteoporosis on hemodialysis after multiple rib fractures and T8 compression fracture.
- Most participants in these trials have been treatment naïve or have had minimal recent exposure to osteoporosis treatment.
- Unlike bisphosphonates and denosumab, which predominantly reduce bone resorption, and teriparatide, which predominantly increases bone formation, romosozumab both increases bone formation and reduces bone resorption.
- The introduction of the bone-forming agent romosozumab has led to a dramatic improvement in osteoporosis treatment.
Associated Data
An extension of a romosozumab phase 2 dose-finding study included a cohort of patients who received denosumab for 12 months followed by romosozumab for 12 months . Similarly, the ARCH study found that patients in the romosozumab-to-alendronate group had a 48% lower risk of new vertebral fractures over the 24 months in comparison to the alendronate-to-alendronate group . Also examining postmenopausal women, the ARCH study was a blinded phase III trial enrolling 4093 postmenopausal osteoporotic women with a fragility fracture, assigning them to either receive romosozumab or oral alendronate for 12 months followed by open-label alendronate in both groups . Currently, the Australian Pharmaceutical Benefits Scheme only subsidizes romosozumab treatment for high-risk patients whose osteoporosis has been refractory to antiresorptive treatment demonstrated by a further fracture on treatment. The effect of alendronate on remodeling suppression is near complete in cancellous bone of the spine, but much less prominent in cortical bone , leading to greater ultimate BMD gain at the total hip, with the sequence of romosozumab followed by denosumab in FRAME versus romosozumab followed by alendronate in ARCH .
Romosozumab is a monoclonal antibody that binds to sclerostin and exhibits both bone anabolic and antiresorptive effects through these mechanisms . Even on recognition, usually following a minimal trauma fracture, undertreatment remains widespread. The incidence of osteoporotic fractures is significant, with 50% of women and 22% of men older than age 50 years experiencing an osteoporotic fracture in their lifetime 1, 2. Adverse effects, comparative effectiveness with other osteoporotic agents, and challenges in sequential therapy are also discussed, providing insights for informed decision-making by physicians, particularly in the context of pre-treatment considerations.
Total hip BMD responder analysis
- BPatients received placebo during months 0–24, denosumab during months 24–36, and romosozumab during months 36–48; cumulative gains are relative to the month 24 baseline.
- In STRUCTURE, after patients stopped alendronate, mean BMD increased 9.8% with 1 year of romosozumab.
- The authors’ practice is to avoid romosozumab in patients who are intermediate or high risk for vascular events without appropriate mitigation.
- We have drawn conclusions about the effectiveness of romosozumab treatment as first therapy based on mean BMD changes; BMD changes have been shown to relate to fracture resistance in multiple but not all studies .
- Adverse effects, comparative effectiveness with other osteoporotic agents, and challenges in sequential therapy are also discussed, providing insights for informed decision-making by physicians, particularly in the context of pre-treatment considerations.
Similarly, outcomes of romosozumab in real-world clinical practice were investigated by Kobayakawa et al through a prospective multicenter observational cohort study in Japanese osteoporotic patients . Additionally, administration of osteoporosis medications before romosozumab had a blunting effect on BMD gains with romosozumab, consistent with previous studies . The study revealed that the treatment led to increases BMD at both the lumbar spine and the total femur. This is relevant because BMD gains in patients on teriparatide are typically seen at 18 to 24 months, later than this study’s endpoint.
Participants received romosozumab or placebo for 24 months followed by placebo or denosumab for 12 months. The efficacy and safety of a second romosozumab course is reported in a phase 2 dose-finding study of postmenopausal women . This study supports denosumab as an option for sequential therapy, although the optimal timing for denosumab initiation following romosozumab has yet to be determined. Cessation of denosumab and the immediate loss of inhibition of bone resorption may yield a rebound effect that impacts the actions of romosozumab, possibly accounting for a blunted response in BMD in those following this sequential therapy compared to naïve bone .
