Bone metabolism in diabetes: a clinician's guide to understanding the bone-glucose interplay.

Skeletal fragility is an increasingly recognised, but poorly understood, complication of both type 1 and type 2 diabetes. Fracture risk varies according to skeletal site and diabetes-related characteristics. Post-fracture outcomes, including mortality risk, are worse in those with diabetes, placing these people at significant risk. Each fracture therefore represents a sentinel event that warrants targeted management. However, diabetes is a very heterogeneous condition with complex interactions between multiple co-existing, and highly correlated, factors that preclude a clear assessment of the independent clinical markers and pathophysiological drivers for diabetic osteopathy. Additionally, fracture risk calculators and routinely used clinical bone measurements generally underestimate fracture risk in people with diabetes. In the absence of dedicated prospective studies including detailed bone and metabolic characteristics, optimal management centres around selecting treatments that minimise skeletal and metabolic harm. This review summarises the clinical landscape of diabetic osteopathy and outlines the interplay between metabolic and skeletal health. The underlying pathophysiology of skeletal fragility in diabetes and a rationale for considering a diabetes-based paradigm in assessing and managing diabetic bone disease will be discussed.

Sex-differential testosterone response to long-term weight loss.

OBJECTIVES: Obesity-associated gonadal dysfunction is a common comorbidity in patients seeking weight loss interventions. We examined the incremental effect of weight loss on gonadal axes in men and women over 3 years. Changes in sex hormones were compared between dietary intervention (Diet) and bariatric procedures: Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) and laparoscopic adjustable gastric banding (LAGB). Additional analysis assessed changes in corticotropic, somatotropic and thyroid axes after weight loss interventions. METHODS: This prospective, observational study included 61 adults with Body Mass Index >30 kg/m2, mean age 51 (SD = 11) years. Endocrine parameters were measured at baseline and at 6 timepoints over 36-months. RESULTS: For each 1 kg of weight lost, between baseline and 36 months, total testosterone increased by 0.6% (95% CI: 0.2%, 1.0%, p = 0.002) in males and decreased by 0.8% (95% CI: -1.4%, -0.3%, p = 0.003) in females. These changes remained statistically significant when controlled for age and for menopausal status in females. At 36 months, in comparison with Diet, RYGB women had lower total testosterone by 54% (95% CI: -90%, -17%, p = 0.004), reduced free androgen index (FAI) by 65% (95% CI; -114%, -17%, p = 0.009) while SG had reduced FAI by 39% (95% CI; -77%, 0%, p = 0.05). No such differences between groups were noted for male subjects. Adrenocorticotropic hormone declined by 0.3% (95% CI: 0.0, -0.5%, p = 0.05), insulin-like growth factor-1 increased by 0.4% (95% CI; 0.2%, 0.7%, p = 0.005), without such thyrotrophin change for each 1 kg of weight loss, for entire cohort, over 36 months. CONCLUSIONS: The testosterone changes observed in this study were proportional to the amount of weight loss. In females, reduction in androgens was independent of age and menopausal status and more pronounced after bariatric procedures. This study finding warrants further clinical research to explore an impact of androgen reduction on functional and cognitive status in postmenopausal women. The observed changes in pituitary hormones may contribute to the metabolic benefits of bariatric surgery.

Establishing consensus recommendations for long-term osteoporosis care for patients who have attended an Australian fracture liaison service: a Delphi study.

Coordinating healthcare activities between fracture liaison services (FLS) and primary care is challenging. Using a Delphi technique, we developed 34 consensus statements to support improved care coordination across this healthcare transition. PURPOSE: Evidence supporting an optimal coordination strategy between fracture liaison services (FLS) and primary care is lacking. This study aimed to develop consensus statements to support consistency and benchmarking of clinical practice to improve coordination of care for patients transitioning from FLS to primary care following an osteoporotic fracture. METHODS: A Delphi technique was used to develop consensus among a panel of experts, including FLS clinicians (medical and non-medical), general practitioners (GPs), and consumers. RESULTS: Results of a preparatory questionnaire (n = 33) informed the development of 34 statements for review by expert panellists over two Delphi rounds (n = 25 and n = 19, respectively). The majority of participants were from New South Wales (82%), employed as FLS clinicians (78.8%) and working in metropolitan centres (60.6%). Consensus was achieved for 24/34 statements in round one and 8/10 statements in round two. All statements concerning patient education, communication, and the GP-patient relationship achieved consensus. Expert opinions diverged in some areas of clinician roles and responsibilities and long-term monitoring and management recommendations. CONCLUSION: We found clear consensus among experts in many key areas of FLS integration with primary care. While experts agreed that primary care is the most appropriate setting for long-term osteoporosis care, overall confidence in primary care systems to achieve this was low. The role of (and responsibility for) adherence monitoring in a resource-limited setting remains to be defined.

Fracture risk assessment in the presence of competing risk of death.

PURPOSE: To identify the optimal statistical approach for predicting the risk of fragility fractures in the presence of competing event of death. METHODS: We used real-world data from the Dubbo Osteoporosis Epidemiology Study that has monitored 3035 elderly participants for bone health and mortality. Fragility fractures were ascertained radiologically. Mortality was confirmed by the State Registry. We considered four statistical models for predicting fracture risk: (i) conventional Cox's proportional hazard model, (ii) cause-specific model, (iii) Fine-Gray sub-distribution model, and (iv) multistate model. These models were fitted and validated in the development (60% of the original sample) and validation (40%) subsets, respectively. The model performance was assessed by discrimination and calibration analyses. RESULTS: During a median follow-up of 11.3 years (IQR: 7.2, 16.2), 628 individuals (34.5%) in the development cohort fractured, and 630 (34.6%) died without a fracture. Neither the discrimination nor the 5-year prediction performance was significantly different among the models, though the conventional model tended to overestimate fracture risk (calibration-in-the-large index = - 0.24; 95% CI: - 0.43, - 0.06). For 10-year risk prediction, the multistate model (calibration-in-the-large index = - 0.05; 95% CI: - 0.20, 0.10) outperformed the cause-specific (- 0.23; - 0.30, - 0.08), Fine-Gray (- 0.31; - 0.46, - 0.16), and conventional model (- 0.54; - 0.70, - 0.39) which significantly overestimated fracture risk. CONCLUSION: Adjustment for competing risk of death has minimum impact on the short-term prediction of fracture. However, the multistate model yields the most accurate prediction of long-term fracture risk and should be considered for predictive research in the elderly, who are also at high mortality risk. Fracture risk assessment might be compromised by the competing event of death. This study, using real-world data found a multistate model was superior to the current competing risk methods in fracture risk assessment. A multistate model is considered an optimal statistical method for predictive research in the elderly.

A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. CONCLUSIONS: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.

Multimorbidity clusters potentially superior to individual diseases for stratifying fracture risk in older people: a nationwide cohort study.

RATIONALE: Comorbidities are common in fracture patients, but the interaction between fracture and comorbidities remains unclear. This study aimed to define specific multimorbidity clusters in older adults and quantify the association between the multimorbidity clusters and fracture risk. METHODS: This nationwide cohort study includes 1.7 million adults in Denmark aged ≥50 years who were followed from 2001 through 2014 for an incident low-trauma fracture. Chronic diseases and fractures were identified from the Danish National Hospital Discharge Register. Latent class analysis and Cox's regression were conducted to define the clusters and quantify fracture risk, respectively. RESULTS: The study included 793 815 men (age: 64 ± 10) and 873 524 women (65.5 ± 11), with a third having ≥1 chronic disease. The pre-existent chronic diseases grouped individuals into low-multimorbidity (80.3% in men, 83.6% in women), cardiovascular (12.5%, 10.6%), malignant (4.1%, 3.8%), diabetic (2.4%, 2.0%) and hepatic clusters (0.7%, men only). These clusters distinguished individuals with advanced, complex, or late-stage disease from those having earlier-stage disease. During a median follow-up of 14 years (IQR: 6.5, 14), 95 372 men and 212 498 women sustained an incident fracture. The presence of multimorbidity was associated with a significantly greater risk of fracture, independent of age and sex. Importantly, the multimorbidity clusters had the highest discriminative performance in assessing fracture risk, whereas the strength of their association with fracture risk equalled or exceeded that of both the individual chronic diseases most prevalent in each cluster and of counts-based comorbidity indices. CONCLUSIONS: Future fracture prevention strategies should take comorbidities into account. Multimorbidity clusters may provide greater insight into fracture risk than individual diseases or counts-based comorbidity indices.

The association between multimorbidity and osteoporosis investigation and treatment in high-risk fracture patients in Australia: A prospective cohort study.

BACKGROUND: Multimorbidity is common among fracture patients. However, its association with osteoporosis investigation and treatment to prevent future fractures is unclear. This limited knowledge impedes optimal patient care. This study investigated the association between multimorbidity and osteoporosis investigation and treatment in persons at high risk following an osteoporotic fracture. METHODS AND FINDINGS: The Sax Institute's 45 and Up Study is a prospective population-based cohort of 267,153 people in New South Wales, Australia, recruited between 2005 and 2009. This analysis followed up participants until 2017 for a median of 6 years (IQR: 4 to 8). Questionnaire data were linked to hospital admissions (Admitted Patients Data Collection (APDC)), emergency presentations (Emergency Department Data Collection (EDDC)), Pharmaceutical Benefits Scheme (PBS), and Medicare Benefits Schedule (MBS). Data were linked by the Centre for Health Record Linkage and stored in a secured computing environment. Fractures were identified from APDC and EDDC, Charlson Comorbidity Index (CCI) from APDC, Dual-energy X-ray absorptiometry (DXA) investigation from MBS, and osteoporosis treatment from PBS. Out of 25,280 persons with index fracture, 10,540 were classified as high-risk based on 10-year Garvan Fracture Risk (age, sex, weight, prior fracture and falls) threshold ≥20%. The association of CCI with likelihood of investigation and treatment initiation was determined by logistic regression adjusted for education, socioeconomic and lifestyle factors). The high-risk females and males averaged 77 ± 10 and 86 ± 5 years, respectively; >40% had a CCI ≥2. Only 17% of females and 7% of males received a DXA referral, and 22% of females and 14% males received osteoporosis medication following fracture. A higher CCI was associated with a lower probability of being investigated [adjusted OR, females: 0.73 (95% CI, 0.61 to 0.87) and 0.43 (95% CI, 0.30 to 0.62); males: 0.47 (95% CI, 0.33 to 0.68) and 0.52 (0.31 to 0.85) for CCI: 2 to 3, and ≥4 versus 0 to 1, respectively] and of receiving osteoporosis medication [adjusted OR, females: 0.85 (95% CI, 0.74 to 0.98) and 0.78 (95% CI, 0.61 to 0.99); males: 0.75 (95% CI, 0.59 to 0.94) and 0.37 (95% CI, 0.23 to 0.53) for CCI: 2 to 3, and ≥4 versus 0 to 1, respectively]. The cohort is relatively healthy; therefore, the impact of multimorbidity on osteoporosis management may have been underestimated. CONCLUSIONS: Multimorbidity contributed significantly to osteoporosis treatment gap. This suggests that fracture risk is either underestimated or underprioritized in the context of multimorbidity and highlights the need for extra vigilance and improved fracture care in this setting.

Exploring barriers and opportunities to improve osteoporosis care across the acute-to-primary care interface: a qualitative study.

This qualitative study interviewed general practitioners, patients, and FLS clinicians and identified key challenges facing stakeholders seeking to improve post-fracture osteoporosis care. Local policies and care pathways as an initial strategy may address information and service delivery issues across the acute-primary care divide. INTRODUCTION: Fracture liaison services (FLS) can be effective for secondary fracture prevention, but long-term adherence to therapies remains suboptimal. Few studies have explored how services manage the transition between tertiary and primary post-fracture care. This study mapped service processes and factors influencing integration of post-clinic care, identifying barriers, supports, and opportunities for seamless healthcare. METHODS: Qualitative descriptive study using semi-structured interviews with FLS stakeholders at two metropolitan hospitals in New South Wales (NSW) and surrounding general practices. RESULTS: Seven FLS clinicians, 11 general practitioners (GPs), and seven patients were interviewed. Six key themes emerged on the transition of patient care from tertiary to primary care (PC). Interprofessional communication issues and role ambiguity posed threats to seamless care. Delayed, absent, inaccessible, or poor-quality communication frustrated GPs, while FLS clinicians lacked confidence in existing communication systems and desired bidirectional communication with PC. GPs were confident managing osteoporosis, but FLS clinicians had limited confidence that patients would discuss osteoporosis with their GP and that GPs would action recommendations. Effective PC follow-up required a positive GP-patient relationship and that patients perceived a need to engage with PC. Patient understanding of osteoporosis (influenced by patient education, knowledge, beliefs, and health behaviours) affected PC attendance. Limited public awareness of osteoporosis and healthcare policy deficits contributed to care gaps. CONCLUSION: Key challenges were identified facing stakeholders seeking to improving post-clinic osteoporosis care. Development and implementation of local, integrated acute-community policies and care pathways as an initial intervention may address information and service delivery issues across the acute-PC divide.

Factors associated with fragility fractures in type 2 diabetes: An analysis of the randomised controlled Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

AIMS: Fracture risk is elevated in some type 2 diabetes patients. Bone fragility may be associated with more clinically severe type 2 diabetes, although prospective studies are lacking. It is unknown which diabetes-related characteristics are independently associated with fracture risk. In this post-hoc analysis of fracture data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial (ISRCTN#64783481), we hypothesised that diabetic microvascular complications are associated with bone fragility. MATERIALS AND METHODS: The FIELD trial randomly assigned 9795 type 2 diabetes participants (aged 50-75 years) to receive oral co-micronised fenofibrate 200 mg (n = 4895) or placebo (n = 4900) daily for a median of 5 years. We used Cox proportional hazards models to identify baseline sex-specific diabetes-related parameters independently associated with incident fractures. RESULTS: Over 49,470 person-years, 137/6138 men experienced 141 fractures and 143/3657 women experienced 145 fractures; incidence rates for the first fracture of 4∙4 (95% CI 3∙8-5∙2) and 7∙7 per 1000 person-years (95% CI 6∙5-9∙1), respectively. Fenofibrate had no effect on fracture outcomes. In men, baseline macrovascular disease (HR 1∙52, 95% CI 1∙05-2∙21, p = 0∙03), insulin use (HR 1∙62, HR 1∙03-2∙55, p = 0∙03), and HDL-cholesterol (HR 2∙20, 95% CI 1∙11-4∙36, p = 0∙02) were independently associated with fracture. In women, independent risk factors included baseline peripheral neuropathy (HR 2∙04, 95% CI 1∙16-3∙59, p = 0∙01) and insulin use (HR 1∙55, 95% CI 1∙02-2∙33, p = 0∙04). CONCLUSIONS: Insulin use and sex-specific complications (in men, macrovascular disease; in women, neuropathy) are independently associated with fragility fractures in adults with type 2 diabetes.

The role of community pharmacists in delivering interventions for osteoporosis: A systematic review.

BACKGROUND: Osteoporosis is a major public health concern, given that disease prevalence is expected to substantially increase due to the aging population. Community pharmacists can play a key role in the identification and management of chronic diseases. OBJECTIVES: The purpose of this systematic review was to present an overview of the literature on the role of community pharmacists in providing osteoporosis interventions to patients. The secondary objective was to assess the impact of these interventions on patient outcomes. METHODS: A literature search was conducted in Embase, CINAHL, Scopus, MEDLINE, and Web of Science from database inception to March 2021. The search was limited to human studies in the English language. Primary studies were included if they described or assessed a patient-directed osteoporosis intervention conducted by community pharmacists. The following data were extracted and tabulated: citation, study location, study design, subject, number of participants, nature of intervention, classification of intervention, outcome measures, measurement methods, findings, and effect. Risk of bias was assessed using the Cochrane Risk of Bias tool for randomized trials (RoB 2) and Risk of Bias in Non-randomized Studies (ROBINS-I). RESULTS: Twenty-one studies were included in this review. The main interventions were education, screening, and medication management. Nineteen of these studies reported patient outcomes, all yielding positive outcomes. Outcomes included increased physician follow-up, risk factor reduction, increased osteoporosis knowledge, increased medication adherence, identification of medication-related problems, and positive patient-reported experience measures (PREMs). Three studies were considered to have a moderate risk of bias, whereas the remaining 18 studies had a high risk of bias. CONCLUSION: There is some evidence that pharmacist-led osteoporosis interventions have a positive impact on patient outcomes. More high-quality studies using objective outcome measures are needed to determine whether this translates into clinical outcomes such as decreased hospitalization and fractures.