Severe osteoporosis treatment: anabolic therapy options

The world's population is aging rapidly, with increasing prevalence of many chronic diseases that are more common in older people. Osteopenia and osteoporosis are two chronic conditions often diagnosed in frail older patients, and both seem to be a significant public health burden. In Russia, osteoporosis (in accordance with the criteria of the World Health Organization) was detected in 33.8% of women and 26.9% of men aged 50 and over. Every minute in the country, 7 vertebral fractures happen, and every 5 minutes — a fracture of the proximal femur occurs. According to the latest data, about 34 million people in Russia are at high risk of developing low-energy fractures. The use of anabolic therapy in older patients with severe osteoporosis can achieve optimal results in the accumulation of bone mineral density and significantly reduce the risk of repeated low-energy fractures.

A call for research on soft tissue manipulation (STM) as a bone anabolic therapy

Individuals with osteoporosis, i.e., low bone mass, are at enhanced risk for fracture, disability, and death. Hospitalizations for osteoporotic fractures exceed those for heart attack, stroke, and breast cancer. Osteoporosis rates are predicted to increase due to an aging global population yet there are limited pharmacological treatment options for osteoporosis, particularly for long-term management of this chronic condition. Moreover, the drug development pipeline is relatively bereft of new strategies and drug candidates, creating an urgent need for developing new therapeutic strategies for treating osteoporosis. In this mini-review, we speculate about the potential for non-invasive soft tissue manipulation (STM) to exert anabolic effects on the skeleton that may provide therapeutic benefit for individuals with low bone mass. Our rationale is premised on work by us and others showing that STM leads to decreased levels of chemokines and pro-inflammatory cytokines (such as Interleukin (IL)-3, IL-6, and IL-8) known to restrict the differentiation and/or activity of bone-forming osteoblasts. However, there are no published studies examining whether STM impacts bone mass, potentially limiting the widespread use of this non-invasive and non-pharmacological intervention in the worldwide treatment of patients with osteoporosis, individuals with low bone mass due to being bed-ridden or otherwise mobility-limited, and persons subjected to spaceflight-related bone loss.

POS1488-HPR CAN A SPECIALIST NURSE LEAD A COMPREHENSIVE OSTEOPOROSIS SERVICE WITH REMOTE SUPERVISION – AN INNOVATIVE CONCEPT

Background:Specialist services traditionally rely on a consultant to lead a multidisciplinary team and provide patient facing activities. However, demand outstrips the limited expertise available and therefore significant delays occur in treatment pathways. There is an urgent need to expand the skill set of the employed workforce and think ‘outside the box’. A service run by clinical nurse specialists (CNS) can be an effective solution. CNS are already an integral part of multidisciplinary teams caring for a diverse range of patients including those with chronic conditions such as osteoporosis.Objectives:We designed an innovative osteoporosis service with patients consulting only a metabolic bone CNS with a consultant rheumatologist providing remote oversight. The aim of the project was to improve the efficiency of the service by eliminating consultant appointments and reducing unnecessary hospital visits while continuing to deliver a high-quality and safe service.Methods:A new pathway was implemented where a consultant rheumatologist and a CNS virtually triaged post menopausal women over the age of 65 into the service. A dedicated proforma provided the template for the CNS to undertake new patient telephone consultation. Relevant investigations were requested during the telephone clinic and treatment related information was despatched to help with shared decision making. All patients were then reviewed in a Rheumatologist-CNS virtual MDT. An appropriate parenteral treatment option was agreed and confirmed to each individual. The CNS worked through a safety checklist and provided further advice and support to the patient as necessary. Using the database, we compared the timelines for the patient journey to the conventional pathway, obtained the number of consultant follow-up appointments saved by implementing this service, and calculated total savings.Results:In the pilot phase, 116 patients were triaged into the new service. The patient cohort was a combination of new referrals and patients taken from the consultants’ waiting lists. The mean age of the participants was 78 years (65-93). The median time: from referral to virtual triage was 20 days (0-308); from triage to new patient CNS telephone consultation was 20 days (0-137); and from virtual MDT to treatment authorisation was zero days (0-331 days). 45 patients had anabolic therapy commenced via home care. The remainder had anti resorptive therapy. No patient requested face-to-face review. Only one patient fed back that they would’ve preferred to see the consultant once. 116 new patient consultant appointments were saved and the median delay in treatment commencement was reduced from 84 to 38 days.Conclusion:To our knowledge, this is the first successful example of an innovative service wholly provided by CNS for commencing parenteral anti-osteoporotic therapy with only remote consultant supervision. Our service redesign has significantly improved the efficiency of the parenteral osteoporosis pathway with reduction in treatment delay and a more streamlined patient journey. A nurse-delivered osteoporosis treatment pathway is highly effective, safe and provides an innovative solution to address thinly stretched health care resources for people with chronic conditions.Disclosure of Interests:None declared

Diminishing value from multiple serial bone densitometry in women receiving anti-resorptive medication for osteoporosis

Background The value of serial bone mineral density (BMD) monitoring while on osteoporosis therapy is controversial. Objective We determined the percentage of women classified as suboptimal-responders to therapy with anti-resorptive medications according to two definitions of serial BMD change. Design Cohort study using administrative databases. Setting Single-payer government health system in Manitoba, Canada. Patients Post-menopausal women aged 40 years or older receiving anti-resorptive medications and having 3 sequential BMD measures. Women stopping or switching therapies were excluded. Methods The percentage of women whose spine or hip BMD decreased significantly during the first or second interval of monitoring by BMD was determined. Suboptimal-responder status was defined as BMD decrease during both monitoring intervals or BMD decreased from baseline to final BMD. Results There were 1369 women in the analytic cohort. Mean BMD monitoring intervals were 3.0(0.8) and 3.2(0.8) years respectively. In the first interval, 3.2% and 6.5% of women had a decrease in spine or hip BMD; 8.0% and 16.9% had decreases in the second monitoring interval, but only 1.4% showed repeated losses in both intervals. Considering the entire treatment interval, only 3.2% and 7.4% showed BMD loss at spine or hip. Limitations Results may not apply to situations of poor adherence to anti-resorptive medication or anabolic therapy use. Interpretation Among women highly adherent to anti-resorptive therapy for osteoporosis, a very small percentage sustained BMD losses on repeated measures. The value of multiple serial BMD monitoring to detect persistent suboptimal-responders should be questioned.

LOXL2 promotes aggrecan and gender-specific anabolic differences to TMJ cartilage

In the United States, 5–12% of adults have at least one symptom of temporomandibular joint (TMJ) disorders, including TMJ osteoarthritis (TMJ-OA). However, there is no chondroprotective agent that is approved for clinical application. We showed that LOXL2 is elevated in the regenerative response during fracture healing in mice and has a critical role in chondrogenic differentiation. Indeed, LOXL2 is an anabolic effector that attenuates pro-inflammatory signaling in OA cartilage of the TMJ and knee joint, induces chondroprotective and regenerative responses, and attenuates NF-kB signaling. The specific goal of the study was to evaluate if adenoviral delivery of LOXL2 is anabolic to human and mouse TMJ condylar cartilage in vivo and evaluate the protective and anabolic effect on cartilage-specific factors. We employed two different models to assess TMJ-OA. In one model, clinical TMJ-OA cartilage from 5 different samples in TMJ-OA cartilage plugs were implanted subcutaneously in nude mice. Adenovirus LOXL2 -treated implants showed higher mRNA levels of LOXL2, ACAN, and other anabolic genes compared to the adenovirus-Empty-treated implants. Further characterization by RNA-seq analysis showed LOXL2 promotes proteoglycan networks and extracellular matrix in human TMJ-OA cartilage implants in vivo. In order to evaluate if LOXL2-induced functional and sex-linked differences, both male and female four-month-old chondrodysplasia (Cho/+) mice, which develop progressive TMJ-OA due to a point mutation in the Col11a1 gene, were subjected to intraperitoneal injection with Adv-RFP-LOXL2 every 2 weeks for 12 weeks. The data showed that adenovirus delivery of LOXL2 upregulated LOXL2 and aggrecan (Acan), whereas MMP13 expression was slightly downregulated. The fold change expression of Acan and Runx2 induced by Adv-RFP-LOXL2 was higher in females compared to males. Interestingly, Adv-RFP-LOXL2 injection significantly increased Rankl expression in male but there was no change in females, whereas VegfB gene expression was increased in females, but not in males, as compared to those injected with Adv-RFP-Empty in respective groups. Our findings indicate that LOXL2 can induce specifically the expression of Acan and other anabolic genes in two preclinical models in vivo. Further, LOXL2 has beneficial functions in human TMJ-OA cartilage implants and promotes gender-specific anabolic responses in Cho/+ mice with progressive TMJ-OA, suggesting its merit for further study as an anabolic therapy for TMJ-OA.

Targeting actin-bundling protein L-plastin as an anabolic therapy for bone loss

The actin-bundling protein L-plastin (LPL) mediates the resorption activity of osteoclasts, but its therapeutic potential in pathological bone loss remains unexplored. Here, we report that LPL knockout mice show increased bone mass and cortical thickness with more mononuclear tartrate-resistant acid phosphatase–positive cells, osteoblasts, CD31hiEmcnhi endothelial vessels, and fewer multinuclear osteoclasts in the bone marrow and periosteum. LPL deletion impeded preosteoclasts fusion by inhibiting filopodia formation and increased the number of preosteoclasts, which release platelet-derived growth factor-BB to promote CD31hiEmcnhi vessel growth and bone formation. LPL expression is regulated by the phosphatidylinositol 3-kinase/AKT/specific protein 1 axis in response to receptor activator of nuclear factor–κB ligand. Furthermore, we identified an LPL inhibitor, oroxylin A, that could maintain bone mass in ovariectomy-induced osteoporosis and accelerate bone fracture healing in mice. In conclusion, we showed that LPL regulates osteoclasts fusion, and targeting LPL serves as a novel anabolic therapy for pathological bone loss.