Open research questions in Bone health and osteoporosis research

What the literature leaves open

• However, the efficacy of denosumab combined with either ELD or native vitamin D plus calcium in postmenopausal Chinese women with osteoporosis has not been established.

  Comparison of Efficacy and Safety of Denosumab with Eldecalcitol or Native Vitamin D in Postmenopausal Chinese Women with Osteoporosis (ESCORT): A Randomized Controlled Trial · 2026 · DOI

• A significant number of patients were not investigated or treated for osteoporosis despite the GP considering the fracture minimal trauma: only 44 of these 76 (57.

  Investigation and treatment rates following minimal trauma fracture: results of a primary care physician survey · 2026 · DOI

• Introduction/Purpose: Aging is associated with declines in muscle strength, lean mass, and bone mineral density (BMD), yet sex-specific lower-body trajectories and their interrelationships across the adult lifespan remain incompletely characterized.

  Lower-Body Strength, Lean Mass, and Bone Mineral Density Across the Adult Lifespan: Age- and Sex-Related Associations · 2026 · DOI

• Potential Implementation strategies Offer a first consultation post treatment Not necessarily a GP. A suitably trained recommendation face to face member of staff e.g. practice nurse or careco-ordinator who can advise on the care pathway, lifestyle matters and signpost to appropriate support Increase clinicians’ Request training via Primary Care Networks knowledge/understanding of osteoporosis or Federations Use commercial providers e.g. RedWhale for continuous personal development Make training proportional e.g.

  “I have no idea who does the bone thing” A qualitative exploration of older women and healthcare professionals’ experiences to guide improvements in osteoporosis care. · 2026 · DOI

• Strengths of this study include its randomized, multicenter design and the inclusion of long-term Dmab users, with or without prior BP exposure, as well as homogeneous BMD T-score targets. Nevertheless, the study also has some limita- tions. One of the major limitations is the small sample size, partly due to recruitment difficulties in some centers, which reduces the robustness of the statistical analysis. However, the observed effect size was larger than anticipated, sug- gesting that a smaller sample size (approximately 10–12 patients per group) could potentially provide adequate sta- tistical power. Furthermore, since CTX measurements were performed across different centers, a given CTX threshold for intervention may correspond to different levels of bone resorption. However, this variability likely reflects routine clinical practice.

  Preventing post-denosumab bone loss with zoledronate: a 2-year randomized trial in post-menopausal women without and with pre-exposure to bisphosphonates · 2026 · DOI

• Abstract Background Muscle fatty infiltration (MFI) is a hallmark of skeletal muscle degeneration, yet its independent associations with musculoskeletal disorders remain debated.

  The Relationship between Muscle Fatty Infiltration and Musculoskeletal Health: An Imaging-Based Population Study · 2026 · DOI

• Antiresorptive and anabolic therapies for osteoporosis have demonstrated efficacy and safety in mild to moderate stages of CKD, but there are limited data to guide the use of these drugs in CKD stages 4-5.

  Management of Osteoporosis and Low Bone Mass in Kidney Disease · 2026 · DOI

• Abstract Romosozumab is known to markedly increase areal bone mineral density (aBMD) at the lumbar spine and proximal femur assessed by dual-energy X-ray absorptiometry (DXA), however, its effects on peripheral volumetric BMD (vBMD) and bone microarchitecture measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) remain incompletely characterized in postmenopausal women at very high fracture risk.

  Differential Effects of Romosozumab Across Central and Peripheral Skeletal Sites: A Prospective DXA and HR-pQCT Study in High-Risk Postmenopausal Osteoporosis · 2026 · DOI

• Although improvements in lumbar spine and femoral neck BMD were observed, the study was limited by a small sample size, high attrition rate, and absence of fracture out- comes, substantially limiting external validity.

  Management of osteoporosis in older men: a systematic review of randomized trials of pharmacological and non-pharmacological strategies · 2026 · DOI

• First, most included studies were retrospective and observational, and there was substantial heterogeneity across imaging protocols, VBQ definitions, HU mea- surement techniques, and muscle assessment methods. Muscle metrics were particularly heterogeneous, which may explain the weaker and more variable associations observed for muscle size than fat infiltration. Second, causality could not be inferred from the reported cor- relations. Finally, while publication bias was not de- tected for the primary VBQ–HU analysis, the number of studies was insufficient for robust bias assessment in the secondary analyses.

  Magnetic resonance imaging-derived vertebral bone quality correlates with computed tomography-derived bone density and paraspinal muscle degeneration: a systematic review and meta-analysis · 2026 · DOI

• This nationwide registry-based matched case–control study benefits from complete population coverage and precise individual-level linkage across Danish health reg- istries. The 1:3 matching on age, sex, T2D onset date, and weighted CCI improved comparability between cases and controls while reducing confounding by overall comorbid- ity burden. Fracture status was analysed using conditional logistic regression, and medication exposure was based on redeemed prescriptions with a minimum one-year history to increase the likelihood of sustained treatment. Several limitations should however be considered. Matching included weighted CCI, which incorporates car- diovascular conditions and may have resulted in partial overmatching, potentially attenuating associations between CVD and fracture. However, specific CVD subtypes were analysed separately, and any attenuation would likely bias results towards the null. Because people with CVD recorded before their first documented T2D diagnosis were excluded, the findings may not be generalizable to people with pre-existing cardiovascular disease before T2D onset. This restriction was applied to ensure a consistent temporal sequence in which T2D preceded CVD exposure. The study relied on ICD and ATC codes from nationwide registers. Therefore, individual events could not be adjudi- cated, diagnoses could not be clinically standardized beyond registry coding, and misclassification of CVD exposures, comorbidities, medication exposure, or fracture outcomes cannot be excluded. Clinically silent or radiographically detected vertebral fractures not registered as clinical diag- noses would not be captured. Although Danish health reg- istries provide high-quality nationwide data, reliance on Fracture coding did not permit differentiation between low- and high-trauma events, and misclassification of fracture site cannot be excluded. The lack of information on trauma severity and fall history limits interpretation of whether observed associations reflect skeletal fragility, fall- related mechanisms, or both. The absence of significant associations for MOF may partly reflect the lower number of MOF events and reduced statistical power in these sec- ondary analyses. Furthermore, because fall history, trauma severity, physical function, and frailty were not directly mea- sured, the present data cannot determine whether observed associations are mediated by fall-related pathways, skeletal fragility, or both. We did not perform separate analyses of non-MOF fractures, as this was not a predefined outcome; however, such analyses may provide further insight into whether associations for any fracture are driven by fractures outside the MOF category. Medication analyses are susceptible to confounding by indication, as dispensing patterns reflect disease sever- ity and frailty. Polypharmacy, cumulative treatment bur- den, dose–response relationships, and detailed duration of therapy were not assessed. Although exposure required ≥ 2 prescriptions within 365 days to reduce misclassification during the initiation phase, redeemed prescriptions do not guarantee adherence, and some exposure misclassification is inevitable. Such misclassification is likely non-differen- tial and may bias associations towards the null.

  Cardiovascular Disease and Fracture Risk in People with Type 2 Diabetes: A Nationwide Matched Case–Control Study · 2026 · DOI

• Future research should investigate how psychostimulants affect acquisition of peak bone mass, stability of bone min- eral density (BMD) when used through mid/late-life, par- ticularly in women, and fracture healing.

  Stimulant Medications and Bone Health · 2026 · DOI

• This narrative review has many strengths, including a comprehensive review of relevant literature, inclusion and synthesis of studies with diverse experimental designs and occasionally contradictory findings, and a critical appraisal of the available literature. The manuscript also has some limitations. For example, a more limited scope may have provided a more focused, concise review. However, by evaluating the current body of literature across the lifes- pan, the review helps to identify areas in need of further investigation.

  Stimulant Medications and Bone Health · 2026 · DOI

• It remains unclear whether this difference persists over time or improves with longer follow-up or sequential therapy. Whether this reflects GC exposure itself or the underlying autoimmune or inflammatory background remains uncertain and warrants further investigation.

  Impact of oral glucocorticoids on the effectiveness of romosozumab: the multicenter OASIS cohort study · 2026 · DOI

• This study significantly contributes to the field of osteoporotic fracture management through several notable strengths. First, its comprehensive coverage extends beyond hip fractures and involves the examination of multiple fracture sites. This broader perspective enhances our understanding of osteoporotic injuries across diverse populations. Second, the multicentre design ensures generalizability by reflecting variations in healthcare practices across different settings within Malaysia. Consequently, findings from multiple centres provide insights relevant to real-world scenarios. Third, the study robustly evaluated specialised care frameworks by comparing standard tertiary care hospitals with accredited fracture liaison service (FLS) hospitals. These comparisons inform clinical practice and guide policy decisions. Finally, assessing various outcome measures, including patient mortality, mobility, and independence rates, contributes significantly to evidence-based decision-making. Despite its strengths, the study has several limitations. First, while the retrospective design of this study presents inherent challenges such as reliance on existing documentation and variability in record quality, we took several proactive steps to ensure the integrity of our findings. Incomplete records and inconsistent documentation practices, particularly within STC hospitals, were anticipated and addressed through rigorous data validation processes. Notably, a higher proportion of missing entries was observed in STC settings (e.g., 97.7% lacked documented fracture history compared to 15.6% in FLS). To mitigate this, we quantified missing data for each variable and presented it transparently in the results tables. Dual independent data extraction and cross-referencing with discharge summaries were employed to minimize abstraction errors. Furthermore, outcome comparisons were limited to variables with consistent reporting across sites, and sensitivity ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT ARTICLE IN PRESS analyses—excluding variables with high missingness—confirmed the robustness of our overall conclusions. In addition, due to the nature of retrospective data, patient-reported outcomes such as mobility confidence, functional independence (e.g., Barthel Index), satisfaction with care, and follow-up experiences could not be systematically captured. While this represents a limitation, it also highlights a valuable opportunity for future research. These outcomes are increasingly recognized as essential for evaluating recovery from the patient’s perspective and informing allied health and rehabilitation services. We recommend that future prospective studies incorporate standardized patient-reported outcome measures to provide a more comprehensive and patient-centered evaluation of postfracture care. Third, variability in treatment protocols across different centres could affect outcome comparability between the standard care and FLS groups. This variability is evident in several key findings: First, the preferred anti-osteoporosis medication (AOM) differs, with Denosumab being the most prescribed agent in the FLS setting, while Fosamax is predominantly used in STC hospitals. Second, there is a clear difference in the diagnostic workup protocol, demonstrated by the dramatically higher rate of Bone Mineral Density (BMD) testing in FLS (40.8%) compared to STC settings (2.3%). These examples illustrate systemic differences in care pathways and highlight the need for standardizing protocols or explicitly accounting for these variations to strengthen future study validity.

  Comparative outcomes of osteoporotic fracture management between tertiary hospitals and fracture liaison services in Malaysia · 2026 · DOI

• This review has several limitations. First, the broad scope of this narrative review enables a comprehensive synthesis across multiple interconnected domains but limits focused, quantitative pooling typical of a conventional systematic review with meta-analysis. Second, the evidence for next-generation biologics (exosomes, NELL-1, and gene therapy) is predominantly preclinical, with uncertain clinical translation; accordingly, all related recommendations are rated as very low certainty under the GRADE framework. Third, the heterogeneity of study designs, patient populations, fusion techniques, and outcome measures across the included pharma- Dong-Ju Lim et al. Bone quality and fusion enhancers Asian Spine J. April 24, 2026 [Epub ahead of print]: 1-14 Table 6.

  Bone quality, biology, and next-generation enhancers for spinal fusion in osteoporosis: a comprehensive narrative review with systematic search methodology · 2026 · DOI

• Several limitations should be considered. First, as this study focused on biomarker exploration, the model was not directly ®, leaving compared with the clinical gold standard FRAX its incremental value within existing frameworks to be clarified. Second, the cohort mainly comprised Han Chinese postmenopausal women from Northwestern China, limiting generalizability to other ethnic or regional populations. Third, the retrospective design relying on electronic medical records did not capture dynamic lifestyle factors such as falls, diet, or physical activity, potentially omitting relevant predictors. Finally, model validation was restricted to internal and local external datasets, lacking multicentric prospective confirmation. Future studies should incorporate perform multi-population prospective validations, in realdynamic variables, and evaluate integration with FRAX world clinical settings.

  Osteoporotic fractures prediction in Chinese postmenopausal women: a machine learning-based multi-dimensional approach · 2026 · DOI

• Despite the fact that periarticular osteoporosis and erosions are known as radiographic hallmarks of RA, there is a lack of data on the relationship between forearm bone loss and radiographic damage.

  The relation between joint erosion and forearm bone mineral density in female patients with Rheumatoid Arthritis · 2018 · DOI

• Current guidelines recommend screening women by age 65 years, but because no guidelines for screening intervals exist, decisions are made on the basis of clinical judgment alone.

  Osteoporosis Prevention, Screening, and Treatment: A Review · 2014 · DOI

• Certain devices may allow to estimate the likelihood of osteoporosis, but very limited evidence exists supporting QUS use during the initiation or monitoring of osteoporosis treatment.

  Quantitative ultrasound for the detection and management of osteoporosis · 2009 · DOI

• There is little known regarding whether alveolar bone loss (ABL) of the mandible detected on panoramic radiographs is a potentially accurate screening tool for osteoporosis in comparison with MCW.

  Diagnostic efficacy of alveolar bone loss of the mandible for identifying postmenopausal women with femoral osteoporosis · 2007 · DOI

• These guidelines contain 36 specific recommendations, mainly in the areas of diagnosis and been assisted by having a wide cross-section of interests, including patients, in the guideline development group; by extensive consultation; and by the inclusion of good practice points in areas where hard evidence is lacking.

  Evidence-based osteoporosis · 2004 · DOI

• Although women were fairly knowledgeable about some aspects of OP, gaps in knowledge were identified in relation to hereditary links, bone density scans, hormone replacement therapy (HRT), vitamin D, and specific exercise.

  "I NEVER REALISED HOW LITTLE I KNEW!": A PILOT STUDY OF OSTEOPOROSIS KNOWLEDGE, BELIEFS, AND BEHAVIOURS · 2002 · DOI

• The subjects were classified into 3 groups of genotypes: A = PXPX (homozygote for the PX haplotype); B = PXPx, PXpx (the heterozygotes for the PX haplotype); C = PxPx, Pxpx, pxpx (genotypes that are lacking the PX haplotype).

  Bone Mineral Density is Associated with Estrogen Receptor Gene Polymorphism in Men · 2002 · DOI

• Examining the relation between PvuII and XbaI restriction fragment length polymorphism (RFLPs) at the estrogen receptor (ER alpha) gene and BMD, in women or men, have yielded conflicting results.

  Bone Mineral Density is Associated with Estrogen Receptor Gene Polymorphism in Men · 2002 · DOI

Most-cited papers in Bone health and osteoporosis research

• Risk Factors for Hip Fracture in White Women · New England Journal of Medicine · 1995 · 2,663 citations
• Effects of Risedronate Treatment on Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis<SUBTITLE>A Randomized Controlled Trial</SUBTITLE> · JAMA · 1999 · 1,908 citations
• Effect of Alendronate on Risk of Fracture in Women With Low Bone Density but Without Vertebral Fractures<SUBTITLE>Results From the Fracture Intervention Trial</SUBTITLE> · JAMA · 1998 · 1,802 citations
• Risk of New Vertebral Fracture in the Year Following a Fracture · JAMA · 2001 · 1,496 citations
• Mortality Risk Associated With Low-Trauma Osteoporotic Fracture and Subsequent Fracture in Men and Women · JAMA · 2009 · 1,463 citations
• 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary · Canadian Medical Association Journal · 2010 · 858 citations
• Optimizing Bone Health in Children and Adolescents · PEDIATRICS · 2014 · 427 citations
• Undertreatment of Osteoporosis in Men With Hip Fracture · Archives of Internal Medicine · 2002 · 294 citations
• Depression, Falls, and Risk of Fracture in Older Women · Archives of Internal Medicine · 1999 · 267 citations
• Compliance With Osteoporosis Medications · Archives of Internal Medicine · 2005 · 256 citations

Most recent work

• Calcium isotope ratio (δ44/42Ca) reflects kidney function and calcium excretion but not bone mineral density or bone turnover: a cross-sectional study · Osteoporosis International · 2026
• Osteoporotic fractures prediction in Chinese postmenopausal women: a machine learning-based multi-dimensional approach · Frontiers in Endocrinology · 2026
• Impact of oral glucocorticoids on the effectiveness of romosozumab: the multicenter OASIS cohort study · Osteoporosis International · 2026
• A HYBRID MACHINE LEARNING MODEL OPTIMIZED BY CHAOTIC DUNG BEETLE ALGORITHM FOR EXPLAINABLE OSTEOPOROSIS RISK PREDICTION · Journal of Mechanics in Medicine and Biology · 2026
• Chronic Alcohol Consumption Reprograms Osteoclast Lineage Communications to Promote Osteoclastogenesis · Biology · 2026
• Machine learning-based risk predictive model for postoperative refractures in patients with osteoporotic vertebral compression fractures: a systematic review and critical appraisal · BMC Musculoskeletal Disorders · 2026
• Genetic prediction of blood cell reactivity and its potential causal influence on bone continuity and density disorders · Animal Models and Experimental Medicine · 2026
• Association between low-carbohydrate-diet score and osteoporosis in hypertensive patients: a cross-sectional study · Annals of Human Biology · 2026
• PBMGA—python-based bone material grouping and anisotropy, a software tool to automatically assign advanced material properties · Medical Engineering & Physics · 2026
• Xianling Gubao capsule alleviates osteoporosis: Modulation of gut-bone axis and Wnt signaling · World Journal of Orthopedics · 2026

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