Primary osteoporosis is closely linked to hormone deficiency, which disrupts the balance of bone remodeling. It affects postmenopausal women but also significantly impacts older men. Estrogen can promote the production of osteoprotegerin, a decoy receptor for RANKL, thereby preventing RANKL from activating osteoclasts. Furthermore, estrogen promotes osteoblast survival and function via activation of the Wnt signaling pathway. Likewise, androgens play a critical role in bone metabolism, primarily through their conversion to estrogen in men. Estrogen deficiency accelerates bone resorption through a rise in pro-inflammatory cytokines (IL-1, IL-6, TNF-α) and RANKL, which promote osteoclastogenesis. In the classic genomic pathway, estrogen binds to estrogen receptors in the cytoplasm, forming a complex that migrates to the nucleus and binds to estrogen response elements on DNA, regulating gene transcription. Androgens can be defined as high-affinity ligands for the androgen receptor; their combination can serve as a ligand-inducible transcription factor. Hormone replacement therapy has shown promise but comes with associated risks and side effects. In contrast, the non-genomic pathway involves rapid signaling cascades initiated at the cell membrane, influencing cellular functions without directly altering gene expression. Therefore, the ligand-independent actions and rapid signaling pathways of estrogen and androgen receptors can be harnessed to develop new drugs that provide bone protection without the side effects of traditional hormone therapies. To manage primary osteoporosis, other pharmacological treatments (bisphosphonates, teriparatide, RANKL inhibitors, sclerostin inhibitors, SERMs, and calcitonin salmon) can ameliorate osteoporosis and improve BMD via actions on different pathways. Non-pharmacological treatments include nutritional support and exercise, as well as the dietary intake of antioxidants and natural products. The current study reviews the processes of bone remodeling, hormone actions, hormone receptor status, and therapeutic targets of primary osteoporosis. However, many detailed cellular and molecular mechanisms underlying primary osteoporosis seem complicated and unexplored and warrant further investigation. 

Primary Osteoporosis Induced by Androgen and Estrogen Deficiency: The Molecular and Cellular Perspective on Pathophysiological Mechanisms and Treatments

Since vertebral fragility fractures (VFFs) might increase the risk of subsequent fractures, we evaluated the incidence rate and the refracture risk of subsequent vertebral and non-vertebral fragility fractures (nVFFs) in untreated patients with a previous VFF.We systematically searched PubMed, Embase, and Cochrane Library up to February 2022 for randomized clinical trials (RCTs) that analyzed the occurrence of subsequent fractures in untreated patients with prior VFFs. Two authors independently extracted data and appraised the risk of bias in the selected studies. Primary outcomes were subsequent VFFs, while secondary outcomes were further nVFFs. The outcome of refracture within ≥ 2 years after the index fracture was measured as (i) rate, expressed per 100 person-years (PYs), and (ii) risk, expressed in percentage.Forty RCTs met our inclusion criteria, ranging from medium to high quality. Among untreated patients with prior VFFs, the rate of subsequent VFFs and nVFFs was 12 [95% confidence interval (CI) 9-16] and 6 (95% CI 5-8%) per 100 PYs, respectively. The higher the number of previous VFFs, the higher the incidence. Moreover, the risk of VFFs and nVFFs increased within 2 (16.6% and 8%) and 4 years (35.1% and 17.4%) based on the index VFF.The highest risk of subsequent VFFs or nVFFs was already detected within 2 years following the initial VFF. Thus, prompt interventions should be designed to improve the detection and treatment of VFFs, aiming to reduce the risk of future FFs and properly implement secondary preventive measures. 

Refracture following vertebral fragility fracture when bone fragility is not recognized: summarizing findings from comparator arms of randomized clinical trials.

Abstract Previous parathyroid hormone (PTH)‐related peptides (PTHrPs) cannot be used to prevent implant loosening in osteoporosis patients due to the catabolic effect of local sustained release. A novel PTHrP (PTHrP‐2) that can be used locally to promote osseointegration of macroporous titanium alloy scaffold (mTAS) and counteract implant slippage in osteoporosis patients is designed. In vitro, PTHrP‐2 enhances the proliferation, adhesion, and osteogenic differentiation of bone marrow‐derived mesenchymal stem cells (BMSCs) within the mTAS. Further, it promotes proliferation, migration, angiogenesis‐related protein expression, and angiogenesis in human umbilical vein endothelial cells (HUVECs). Compared to PTH(1–34), PTHrP‐2 can partially weaken the osteoclast differentiation of RAW 264.7 cells. Even in an oxidative stress microenvironment, PTHrP‐2 safeguards the proliferation and migration of BMSCs and HUVECs, reduces reactive oxygen species generation and mitochondrial damage, and partially preserves the angiogenesis of HUVECs. In the Sprague–Dawley (SD) rat osteoporosis model, the therapeutic benefits of PTHrP‐2‐releasing mTAS (mTAS P2 ) and ordinary mTAS implanted for 12 weeks via micro‐CT, sequential fluorescent labeling, and histology are compared. The results demonstrate that mTAS P2 exhibits high bone growth rate, without osteophyte formation. Consequently, PTHrP‐2 exhibits unique local synthesis properties and holds the potential for assisting the osseointegration of alloy implants in osteoporosis patients. 

A Novel PTH-Related Peptide Combined with 3d Printed Macroporous Titanium Alloy Scaffold Enhances Osteoporotic Osseointegration.

Abaloparatide (ABL) significantly increases bone mineral density in men with osteoporosis similar to what was reported in postmenopausal women with osteoporosis. The cost effectiveness of sequential treatment with ABL followed by alendronate (ALN) in men at high fracture risk was compared to relevant alternative treatments. A Markov-based microsimulation model based on a lifetime US healthcare decision maker perspective was developed to evaluate the cost (expressed in US$2021) per quality-adjusted life-years (QALYs) gained of sequential ABL/ALN. Comparators were sequential treatment unbranded teriparatide (TPTD)/ALN, generic ALN monotherapy, and no treatment. Discount rates of 3% were used. Consistent with practice guidelines, patients received 18 months of ABL or TPTD followed by ALN for 5 years, or 5 years of ALN monotherapy. Analyses were conducted in high-risk men aged over 50 years defined as having a bone mineral density T-score ≤−2.5 and a recent fracture. Time-specific risk of subsequent fracture after a recent fracture, incremental costs up to 5 years following fractures, real-world medication adherence, and mostly US men-specific data were included in the model. One-way and probabilistic sensitivity analyses were conducted to assess the robustness of results. Over the full age range, sequential ABL/ALN led to more QALYs for lower costs than sequential unbranded TPTD/ALN, while no treatment was dominated (more QALYs, lower costs) by ALN monotherapy. The costs per QALY gained of sequential ABL/ALN were lower than the US threshold of US$150,000 versus generic ALN monotherapy. The probabilities that sequential ABL/ALN was cost effective compared to ALN monotherapy were estimated at 51% in men aged 50 years and between 88 and 90% in those aged ≥ 60 years. Sequential therapy using ABL/ALN may be cost effective compared with generic ALN monotherapy in US men aged ≥ 50 years at high fracture risk, especially in those aged ≥ 60 years. Unbranded TPTD/ALN and no treatment were dominated interventions (less QALY, more costs) compared with ABL/ALN or ALN monotherapy. 

/pdf/cost-effectiveness-of-sequential-abaloparatide-alendronate-1ynkapo7.pdf

Cost-Effectiveness of Sequential Abaloparatide/Alendronate in Men at High Risk of Fractures in the United States

Abstract Postmenopausal osteoporosis (PMOP) affects hundreds of millions of elderly women worldwide. The imbalance between osteoblast‐mediated bone formation and osteoclast‐mediated bone resorption is the key factor in the progression of PMOP. Recently, exosomal circRNAs have been considered as critical regulators in physiological and pathological progress. However, their roles in PMOP still require further exploration. Herein, we identified that the expression ofexosomalcircFAM63B significantly increased in PMOP patients and is closely related to bone density. We further demonstrated that circFAM63B inhibits osteogenic differentiation of BMSCs and bone formation in OVX mice by using a combination of in vitro and in vivoexperiment strategies. Mechanistically, circFAM63B promotes HMGA2 expression by inhibiting miR‐578, thereby suppressing bone repair. Our study proved that exosomal circFAM63B suppresses the bone regeneration of postmenopausal osteoporosis by regulating the miR‐578/HMGA2 axis, which may provide new insights into the pathogenesis and development of PMOP. Knocking down exosomal circFAM63Bcould be regarded as a new strategy for the treatment of PMOP. This article is protected by copyright. All rights reserved. 

Exosomal circFAM63Bsuppresses bone regeneration of postmenopausal osteoporosis via regulating miR‐578/HMGA2 axis

Five strategies were recommended by the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) guidelines for the treatment of postmenopausal osteoporosis (PMO) patients with a very high fracture risk. We aimed to assess their cost-effectiveness in the United States (US).A microsimulation Markov model was created to compare the cost-effectiveness of five treatment strategies, including zoledronate, denosumab, abaloparatide, teriparatide, and romosozumab in PMO patients with a recent fracture from the healthcare perspective of the US. The data used in the model were obtained from published studies or online resources. Base-case analysis, one-way deterministic sensitivity analysis (DSA) and probability sensitivity analysis (PSA) were conducted for 65-, 70-, 75-, and 80-year-old patients.In base case, at 65 years, zoledronate was the cheapest strategy. The incremental cost-effectiveness ratios (ICER, which represent incremental costs per QALY gained) of denosumab, teriparatide, abaloparatide, and romosozumab against zoledronate were $13,020/QALY (quality-adjusted years), $477,331 /QALY, $176,287/QALY, and $98,953/QALY, respectively. Under a willing-to-pay (WTP, which means the highest price a consumer will pay for one unit of a good of service) threshold of $150,000/QALY, denosumab and romosozumab were cost-effective against zoledronate. The PSA results showed that denosumab was the most cost-effective option with WTP thresholds of $50,000/QALY, $100,000/QALY and $150,000/QALY. The results were similar in other age groups. The DSA results indicated that the most common parameters that have important influence on the outcome were drug persistence, incidence of adverse events, the efficacy of drugs on hip fractures and the cost of the drug.Among PMO patients with a very high fracture risk in the US, zoledronate is the cheapest strategy and denosumab is the most cost-effective choice among these five strategies. 

/pdf/cost-effectiveness-analysis-of-five-drugs-for-treating-28m1ll3v.pdf

Cost-effectiveness analysis of five drugs for treating postmenopausal women in the United States with osteoporosis and a very high fracture risk

Development and validation of explainable machine learning models for female hip osteoporosis using electronic health records.

Economic evaluation of four treatment strategies for postmenopausal patients with osteoporosis and a recent fracture in mainland China: a cost-effectiveness analysis

Purpose Fragility fractures, the most serious complication of osteoporosis, affect life quality and increase medical expenses and economic burden. Strategies to identify populations with very low bone mineral density (T-scores <-3), indicating very high fracture risk according to the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE), are necessary to achieve acceptable fracture risk levels. In this study, the characteristics of persons with T-scores <−3 were analyzed in the Chinese population to identify risk factors and develop a nomogram for very low bone mineral density (T-scores <-3) identification. Materials and Methods We conducted a cross-sectional study using the datasets of the Health Improvement Program of Bone (HOPE), with 602 men aged ≥50 years and 482 postmenopausal women. Bone mineral density (BMD) was measured using dual energy X-ray absorptiometry (DXA). Data on clinical risk factors, including age, sex, weight, height, previous fracture, parental hip fracture history, smoking, alcohol intake >3 units/day, glucocorticoid use, rheumatoid arthritis, and secondary osteoporosis were collected. A multivariate logistic regression to evaluate the relationship between the clinical risk factors and very low BMD (T-scores <-3) was conducted. Parameter estimates of the final model were then used to construct a nomogram. Results Sixty-three of 1084 participants (5.8%) had BMD T-score <−3. In multivariable regression analysis, age (odds ratio [OR] = 1.068, 95% confidence interval [CI]: 1.037–1.099) and weight (OR = 0.863, 95% CI: 0.830–0.897) were significant factors that were associated with very low BMD (T-scores <-3). These variables were the factors considered in developing the nomogram. The area under the receiver operating characteristic (ROC) curve for the model was 0.861. The cut-off value of the ROC curve was 0.080. Conclusion The nomogram can effectively assist clinicians to identify persons with very low BMD (T-scores <-3) and very high fracture risk in the Chinese population.

https://www.dovepress.com/getfile.php?fileID=78056

Development of a Nomogram for Predicting Very Low Bone Mineral Density (T-Scores <−3) in the Chinese Population

The Association Between Two Different Non-invasive Advanced Glycation End Products and Osteoporosis in the Non-diabetic Population: A Cross-Sectional Study.

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