Temporal patterns of osteoclast formation and activity following withdrawal of RANKL inhibition.

Rebound bone loss following denosumab discontinuation is an important clinical challenge. Current treatment strategies to prevent this fail to suppress the rise and overshoot in osteoclast-mediated bone resorption. In this study, we use a murine model of denosumab treatment and discontinuation to show the temporal changes in osteoclast formation and activity during RANKL inhibition and withdrawal. We show that the cellular processes that drive the formation of osteoclasts and subsequent bone resorption following withdrawal of RANKL inhibition precede the rebound bone loss. Furthermore, a rise in serum TRAP and RANKL levels is detected before markers of bone turnover used in current clinical practice. These mechanistic advances may provide insight into a more defined window of opportunity to intervene with sequential therapy following denosumab discontinuation.

Stopping denosumab, a medication commonly used to improve bone mass by blocking formation of bone resorbing osteoclasts, leads to a rebound loss in the bone which was gained during treatment. Current strategies to prevent this bone loss fail in most cases as they are unable to prevent the rise and overshoot in bone resorption by osteoclasts. Thie stems from an incomplete understanding of how osteoclasts behave during denosumab treatment and after treatment is discontinued. We use a mouse model of this phenomenon to show how osteoclast formation and activity changes throughout this process. We show that increases in the processes that drive the formation of osteoclasts can be detected in the circulation before bone loss occurs. These findings could therefore provide insight into a targeted 'window of opportunity' to intervene and prevent the rebound bone loss following stopping denosumab in patients.

Multi-Targeting DKK1 and LRP6 Prevents Bone Loss and Improves Fracture Resistance in Multiple Myeloma.

An imbalance between bone resorption and bone formation underlies the devastating osteolytic lesions and subsequent fractures seen in more than 90% of multiple myeloma (MM) patients. Currently, Wnt-targeted therapeutic agents that prevent soluble antagonists of the Wnt signaling pathway, sclerostin (SOST) and dickkopf-1 (DKK1), have been shown to prevent bone loss and improve bone strength in preclinical models of MM. In this study, we show increasing Wnt signaling via a novel anti-low-density lipoprotein receptor-related protein 6 (LRP6) antibody, which potentiates Wnt1-class ligand signaling through binding the Wnt receptor LRP6, prevented the development of myeloma-induced bone loss primarily through preventing bone resorption. When combined with an agent targeting the soluble Wnt antagonist DKK1, we showed more robust improvements in bone structure than anti-LRP6 treatment alone. Micro-computed tomography (µCT) analysis demonstrated substantial increases in trabecular bone volume in naïve mice given the anti-LRP6/DKK1 combination treatment strategy compared to control agents. Mice injected with 5TGM1eGFP murine myeloma cells had significant reductions in trabecular bone volume compared to naïve controls. The anti-LRP6/DKK1 combination strategy significantly improved bone volume in 5TGM1-bearing mice by 111%, which was also superior to anti-LRP6 single treatment; with similar bone structural changes observed within L4 lumbar vertebrae. Consequently, this combination strategy significantly improved resistance to fracture in lumbar vertebrae in 5TGM1-bearing mice compared to their controls, providing greater protection against fracture compared to anti-LRP6 antibody alone. Interestingly, these improvements in bone volume were primarily due to reduced bone resorption, with significant reductions in osteoclast numbers and osteoclast surface per bone surface demonstrated in 5TGM1-bearing mice treated with the anti-LRP6/DKK1 combination strategy. Importantly, Wnt stimulation with either single or combined Wnt-targeted agents did not exacerbate tumor activity. This work provides a novel approach of targeting both membrane-bound and soluble Wnt pathway components to provide superior skeletal outcomes in patients with multiple myeloma and other bone destructive cancers. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Hearing the Veteran's Voice in Congestive Heart Failure Readmissions.

PURPOSE/OBJECTIVE: Our purpose was to examine congestive heart failure (CHF) readmissions from the veterans' perspective. The use of health care provider interventions, such as standardized education materials, home telehealth, and a CHF clinic, was able to reduce readmissions rates from 35% to 23%. Our objective was to use input from the veterans to fine-tune our efforts and achieve readmission rates for patients with CHF below the national average of 21%. We wanted to identify factors that result in CHF readmissions, including disease education, self-care management, and barriers to self-care. This study was directed toward answering two questions: 1. What is the veteran's explanation for readmission? 2. According to the veteran, what are the barriers to following their treatment regimen? PRIMARY PRACTICE SETTING: It was a rural 84-bed Veterans Health Administration hospital in the Western United States. FINDINGS: Before this study, our efforts to reduce CHF readmissions were one-sided, all from the health care professionals' viewpoint. We wanted to hear what the veteran had to say; so, we interviewed 25 veterans. Four veterans were excluded due to issues with their consents. Ninety percent (n = 19/21) responded that they knew their CHF was worse by a change in their breathing (shortness of breath). They identified 48 signs/symptoms that indicated worsening CHF. Weight gain was noted as an indication of worsening CHF symptoms (n = 6/48) in 12.5% of the responses. Twenty-five percent (n = 12/48) of the veterans stated they recognized the early symptoms of worsening CHF. Thirty-eight percent (n = 8/21) of the veterans stated they had early symptoms of worsening CHF, but only two of them contacted their doctor. It is interesting to note that only 29% (n = 6/21) of the veterans recognized weight gain as a sign of worsening CHF and all of these veterans listed other symptoms (such as shortness of breath) along with weight gain. Weighing on a daily basis was practiced by only 30% of the group (n = 7/21); all but two of the veterans had no problems with weighing themselves. More than 71% of the veterans responded that they had no problems following their diet or taking their medications. More than half of the veterans did not need help with meals, transportation, or daily grooming/dressing/toileting. CONCLUSIONS: We were concerned about the evident delays in seeking medical care for worsening CHF. All veterans who did need help with the activities of daily living, medications, or diet had their needs met through their support systems. They did not perceive any barriers to seeking care. However, there remain many unanswered questions. Does the patient understand their discharge education and know how to use this information from daily weights or recognition of early symptoms, to indicate their need for urgent and emergency medical interventions? Or is it a problem that the education is not sufficient? Is it a question of the burden of care from multiple comorbid conditions or of taking too many medications? Do social issues drive readmissions? These questions are further explored in a second study, which is in the data analysis stage. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: There are three key findings from our study. 1. Veterans think in terms of symptoms that increase the impact of CHF on their life. 2. The relationship between daily weight and controlling CHF is not clear to veterans. 3. Hospital discharge instructions should clearly associate symptoms that are associated with worsening CHF.