Impact of osteoporosis and osteoporosis medications on fracture healing: a narrative review.

Antiresorptive medications do not negatively affect fracture healing in humans. Teriparatide may decrease time to fracture healing. Romosozumab has not shown a beneficial effect on human fracture healing. BACKGROUND: Fracture healing is a complex process. Uncertainty exists over the influence of osteoporosis and the medications used to treat it on fracture healing. METHODS: Narrative review authored by the members of the Fracture Working Group of the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF), on behalf of the IOF and the Société Internationale de Chirurgie Orthopédique et de Traumatologie (SICOT). RESULTS: Fracture healing is a multistep process. Most fractures heal through a combination of intramembranous and endochondral ossification. Radiographic imaging is important for evaluating fracture healing and for detecting delayed or non-union. The presence of callus formation, bridging trabeculae, and a decrease in the size of the fracture line over time are indicative of healing. Imaging must be combined with clinical parameters and patient-reported outcomes. Animal data support a negative effect of osteoporosis on fracture healing; however, clinical data do not appear to corroborate with this. Evidence does not support a delay in the initiation of antiresorptive therapy following acute fragility fractures. There is no reason for suspension of osteoporosis medication at the time of fracture if the person is already on treatment. Teriparatide treatment may shorten fracture healing time at certain sites such as distal radius; however, it does not prevent non-union or influence union rate. The positive effect on fracture healing that romosozumab has demonstrated in animals has not been observed in humans. CONCLUSION: Overall, there appears to be no deleterious effect of osteoporosis medications on fracture healing. The benefit of treating osteoporosis and the urgent necessity to mitigate imminent refracture risk after a fracture should be given prime consideration. It is imperative that new radiological and biological markers of fracture healing be identified. It is also important to synthesize clinical and basic science methodologies to assess fracture healing, so that a convergence of the two frameworks can be achieved.

Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX. INTRODUCTION: The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD). METHODS: We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted ß-coefficients. RESULTS: A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination. CONCLUSION: A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.

Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan.

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. INTRODUCTION: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. METHODS: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. RESULTS: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed. CONCLUSIONS: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).

Post-fracture care programs for prevention of subsequent fragility fractures: a literature assessment of current trends.

Post-fracture care (PFC) programs evaluate and manage patients with a minimal trauma or fragility fracture to prevent subsequent fractures. We conducted a literature review to understand current trends in PFC publications, evaluate key characteristics of PFC programs, and assess their clinical effectiveness, geographic variations, and cost-effectiveness. We performed a search for peer-reviewed articles published between January 2003 and December 2020 listed in PubMed or Google Scholar. We categorized identified articles into 4 non-mutually exclusive PFC subtopics based on keywords and abstract content: PFC Types, PFC Effectiveness/Success, PFC Geography, and PFC Economics. The literature search identified 784 eligible articles. Most articles fit into multiple PFC subtopics (PFC Types, 597; PFC Effectiveness/Success, 579; PFC Geography, 255; and PFC Economics, 98). The number of publications describing how PFC programs can improve osteoporosis treatment rates has markedly increased since 2003; however, publication gaps remain, including low numbers of publications from some countries with reported high rates of osteoporosis and/or hip fractures. Fracture liaison services and geriatric/orthogeriatric services were the most common models of PFC programs, and both were shown to be cost-effective. We identified a need to expand and refine PFC programs and to standardize patient identification and reporting on quality improvement measures. Although there is an increasing awareness of the importance of PFC programs, publication gaps remain in most countries. Improvements in established PFC programs and implementation of new PFC programs are still needed to enhance equitable patient care to prevent occurrence of subsequent fractures.

In community-dwelling women frailty is associated with imminent risk of osteoporotic fractures.

Frailty reflects an accelerated health decline. Frailty is a consequence of fracture and contributes to fracture. Greater frailty was associated with higher fracture risk. Frail women were at immediate risk (within 24 months) of a hip or major fracture. Fracture prevention could be improved by considering frailty status. INTRODUCTION: Frailty encompasses the functional decline in multiple systems, particularly the musculoskeletal system. Frailty can be a consequence of and contribute to fracture, leading to a cycle of further fractures and greater frailty. This study investigates this association, specifically time frames for risk, associated fracture types, and how grade of frailty affects risk. METHODS: The study is performed in the OPRA cohort of 1044, 75-year-old women. A frailty index was created at baseline and 5 and 10 years. Women were categorized as frail or nonfrail and in quartiles (Q1 least frail; Q4 most frail). Fracture risk was assessed over short (1 and 2 years) and long terms (5 and 10 years). Fracture risk was defined for any fracture, major osteoporotic fractures (MOFs), and hip and vertebral fracture, using models including bone mineral density (BMD) and death as a competing risk. RESULTS: For women aged 75, frailty was associated with higher risk of fracture within 2 years (Hip SHRadj. 3.16 (1.34-7.47)) and MOF (2 years SHRadj. 1.88 (1.12-3.16)). The increased risk continued for up to 5 years (Hip SHRadj. 2.02 (1.07-3.82)); (MOF SHRadj. 1.43 (0.99-2.05)). Grade of frailty was associated with increased 10-year probability of fracture (p = 0.03). Frailty predicted fracture independently of BMD. For women aged 80, frailty was similarly associated with fracture. CONCLUSION: Frail elderly women are at immediate risk of fracture, regardless of bone density and continue to be at risk over subsequent years compared to identically aged nonfrail women. Incorporating regular frailty assessment into fracture management could improve identification of women at high fracture risk.

Cost-effectiveness of romosozumab for the treatment of postmenopausal women with severe osteoporosis at high risk of fracture in Sweden.

Romosozumab is a novel bone-building drug that reduces fracture risk. This health economic analysis indicates that sequential romosozumab-to-alendronate can be a cost-effective treatment option for postmenopausal women with severe osteoporosis at high risk of fracture. PURPOSE: To estimate the cost-effectiveness of sequential treatment with romosozumab followed by alendronate ("romosozumab-to-alendronate") compared with alendronate alone in patients with severe osteoporosis at high risk of fracture in Sweden. METHODS: A microsimulation model with a Markov structure was used to simulate fractures, costs, and quality-adjusted life years (QALYs), for women treated with romosozumab-to-alendronate or alendronate alone. Patients aged 74 years with a recent major osteoporotic fracture (MOF) were followed from the start of treatment until the age of 100 years or death. Treatment with romosozumab for 12 months was followed by alendronate for up to 48 months or alendronate alone with a maximum treatment duration of 60 months. The analysis had a societal perspective. Efficacy of romosozumab and alendronate were derived from phase III randomized controlled trials. Resource use and unit costs were collected from the literature. Cost-effectiveness was estimated using incremental cost-effectiveness ratio (ICER) with QALYs as effectiveness measures. RESULTS: The base case analysis showed that sequential romosozumab-to-alendronate treatment was associated with 0.089 additional QALYs at an additional cost of €3002 compared to alendronate alone, resulting in an ICER of €33,732. At a Swedish reference willingness-to-pay per QALY of €60,000, romosozumab-to-alendronate had a 97.9% probability of being cost-effective against alendronate alone. The results were most sensitive to time horizon, persistence assumptions, patient age, and treatment efficacy. CONCLUSION: The results of this study indicate that sequential romosozumab-to-alendronate can be a cost-effective treatment option for postmenopausal women with severe osteoporosis at high risk of fracture.

Vertebral fracture: epidemiology, impact and use of DXA vertebral fracture assessment in fracture liaison services.

Vertebral fractures are independent risk factors for vertebral and nonvertebral fractures. Since vertebral fractures are often missed, the relatively new introduction of vertebral fracture assessment (VFA) for imaging of the lateral spine during DXA-measurement of the spine and hips may contribute to detect vertebral fractures. We advocate performing a VFA in all patients with a recent fracture visiting a fracture liaison service (FLS). Fracture liaison services (FLS) are important service models for delivering secondary fracture prevention for older adults presenting with a fragility fracture. While commonly age, clinical risk factors (including fracture site and number of prior fracture) and BMD play a crucial role in determining fracture risk and indications for treatment with antiosteoporosis medications, prevalent vertebral fractures usually remain undetected. However, vertebral fractures are important independent risk factors for future vertebral and nonvertebral fractures. A development of the DXA technology, vertebral fracture assessment (VFA), allows for assessment of the lateral spine during the regular DXA bone mineral density measurement of the lumbar spine and hips. Recent approaches to the stratification of antiosteoporosis medication type according to baseline fracture risk, and differences by age in the indication for treatment by prior fracture mean that additional information from VFA may influence initiation and type of treatment. Furthermore, knowledge of baseline vertebral fractures allows reliable definition of incident vertebral fracture events during treatment, which may modify the approach to therapy. In this manuscript, we will discuss the epidemiology and clinical significance of vertebral fractures, the different methods of detecting vertebral fractures, and the rationale for, and implications of, use of VFA routinely in FLS. • Vertebral fracture assessment is a tool available on modern DXA instruments and has proven ability to detect vertebral fractures, the majority of which occur without a fall and without the signs and symptoms of an acute fracture. • Most osteoporosis guidelines internationally suggest that treatment with antiosteoporosis medications should be considered for older individuals (e.g., 65 years +) with a recent low trauma fracture without the need for DXA. • Younger individuals postfracture may be risk-assessed on the basis of FRAX® probability including DXA and associated treatment thresholds. • Future fracture risk is markedly influenced by both site, number, severity, and recency of prior fracture; awareness of baseline vertebral fractures facilitates definition of true incident vertebral fracture events occurring during antiosteoporosis treatment. • Detection of previously clinically silent vertebral fractures, defining site of prior fracture, might alter treatment decisions in younger or older FLS patients, consistent with recent IOF-ESCEO guidance on baseline-risk-stratified therapy, and provides a reliable baseline from which to define new, potentially therapy-altering, vertebral fracture events.

Suppressed immune profile in children with combined type 1 diabetes and celiac disease.

Children diagnosed with a combination of type 1 diabetes (T1D) and celiac disease (CD) show a dysregulated T helper type 1 (Th1)/Th17 response. Besides the cellular involvement, several soluble immune markers are involved in the autoimmune process of both T1D and CD. Only few studies have examined the peripheral pattern of different cytokines, chemokines and acute-phase proteins (APP) in children with combined T1D and CD. To our knowledge, no studies have evaluated the serum levels of adipocytokines and matrix metalloproteinases (MMPs) in this context. The purpose of the present study was to acquire more knowledge and to gain deeper understanding regarding the peripheral immunoregulatory milieu in children with both T1D and CD. The study included children diagnosed with both T1D and CD (n = 18), children with T1D (n = 27) or CD (n = 16) and reference children (n = 42). Sera were collected and analysis of 28 immune markers (cytokines, chemokines, APPs, adipocytokines and MMPs) was performed using the Luminex technique. The major findings showed that children with a double diagnosis had lower serum levels of interleukin (IL)-22, monocyte chemoattractant protein (MIP)-1α, monocyte chemoattractant protein (MCP)-1, procalcitonin, fibrinogen, visfatin and matrix metalloproteinase (MMP)-2. These results indicate a suppressed immune profile in children with combined T1D and CD, including Th17 cytokines, chemokines, APPs, adipocytokines and MMPs. We conclude that, besides cytokines and chemokines, other immune markers, e.g. APPs, adipocytokines and MMPs, are of importance for further investigations to elucidate the heterogeneous immune processes present in patients diagnosed with T1D in combination with CD.

Real-world effectiveness of osteoporosis treatment in the oldest old.

We studied effectiveness of osteoporosis treatment in women older than 80 years, who often are not included in clinical trials. Treatments were as effective on bone density and fractures as in younger women. INTRODUCTION: To study real-world effectiveness of osteoporosis treatment on BMD and fractures in the oldest old women (≥ 80 years) compared with women (60-79 years) in the clinical setting using Swedish health register data. METHODS: National registers and data from DXA machines were used to study effectiveness of all available osteoporosis treatments in women 60-79 and ≥ 80 years using three approaches: (1) Total Hip BMD change up to 8 years after treatment start; (2) fracture incidence where patients served as their own controls, comparing the first 3 months after treatment start with the subsequent 12 months; and (3) comparison of fracture incidence post-fracture in women ≥ 80 years treated with osteoporosis treatment or calcium/vitamin D. RESULTS: Analysis 1: Total Hip BMD increased by up to 6.7% and 7.7% in women 60-79 and ≥ 80 years old, respectively. The mean increase in BMD was 1.1%-units per year in both age groups. Analysis 2: Relative to the 3-month baseline, fracture incidence decreased during the subsequent 12 months of treatment. Incidence rate ratios were estimated at 0.65, 0.74, 0.29, and 0.81 for any, hip, vertebral, and non-hip-non-vertebral fracture, respectively. Analysis 3: A 24-month incidence of any fracture in women ≥ 80 years given post-fracture osteoporosis treatment was lower (HR = 0.78) than in women given calcium/vitamin D, but treatment allocation was not random, with lower mortality (HR = 0.51) in patients receiving OP treatment. CONCLUSIONS: Osteoporosis medication in women > 80 years in clinical practice likely works, and the magnitude of effect is similar to what was estimated in younger women. The choice between osteoporosis treatment and calcium/vitamin D after fracture in women ≥ 80 years is not random but appears associated with the patient's health status and presence of vertebral fractures, rather than the known risk profile of sustaining a fracture at a high age.

A patient-level key performance indicator set to measure the effectiveness of fracture liaison services and guide quality improvement: a position paper of the IOF Capture the Fracture Working Group, National Osteoporosis Foundation and Fragility Fracture Network.

The International Osteoporosis Foundation (IOF) Capture the Fracture® Campaign with the Fragility Fracture Network (FFN) and National Osteoporosis Foundation (NOF) has developed eleven patient-level key performance indicators (KPIs) for fracture liaison services (FLSs) to guide quality improvement. INTRODUCTION: Fracture Liaison Services (FLSs) are recommended worldwide to reduce fracture risk after a sentinel fracture. Given not every FLS is automatically effective, the IOF Capture the Fracture working group has developed and implemented the Best Practice Framework to assess the organisational components of an FLS. We have now developed a complimentary KPI set that extends this assessment of performance to the patient level. METHODS: The Capture the Fracture working group in collaboration with the Fragility Fracture Network Secondary Fragility Fracture Special Interest Group and National Osteoporosis Foundation adapted existing metrics from the UK-based Fracture Liaison Service Database Audit to develop a patient-level KPI set for FLSs. RESULTS: Eleven KPIs were selected. The proportion of patients: with non-spinal fractures; with spine fractures (detected clinically and radiologically); assessed for fracture risk within 12 weeks of sentinel fracture; having DXA assessment within 12 weeks of sentinel fracture; having falls risk assessment; recommended anti-osteoporosis medication; commenced of strength and balance exercise intervention within 16 weeks of sentinel fracture; monitored within 16 weeks of sentinel fracture; started anti-osteoporosis medication within 16 weeks of sentinel fracture; prescribed anti-osteoporosis medication 52 weeks after sentinel fracture. The final KPI measures data completeness for each of the other KPIs. For these indicators, levels of achievement were set at the < 50%, 50-80% and > 80% levels except for treatment recommendation where a level of 50% was used. CONCLUSION: This KPI set compliments the existing Best Practice Framework to support FLSs to examine their own performance using patient-level data. By using this KPI set for local quality improvement cycles, FLSs will be able to efficiently realise the full potential of secondary fracture prevention and improved clinical outcomes for their local populations.

Low bone mineral density is associated with hypogonadism and cranial irradiation in male childhood cancer survivors.

We investigated if bone mineral density was related to testosterone deficiency and/or previous cancer treatment in men who were childhood cancer survivors. Men with untreated testosterone deficiency or previous treatment with cranial irradiation were at increased risk of impaired bone health. Prevention of osteoporosis should be considered in their follow-up. INTRODUCTION: Childhood cancer survivors (CCS) are at increased risk of hypogonadism. Reduced bone mineral density (BMD) has been reported in CCS but it is unclear whether this is due to hypogonadism or a direct effect of cancer therapy. This study investigated BMD in CCS, and association with hypogonadism, previous treatment and cancer type. METHODS: Investigation of 125 CCS (median age 33.7 at inclusion; 9.6 at diagnosis) and 125 age-matched population controls. Serum testosterone and luteinizing hormone were assayed and BMD at total hip and lumbar spine L1-L4 measured. The mean difference in BMD (g/cm2; 95% CI) between CCS and controls was analysed. Odds ratios (OR; 95% CI) for low BMD were also calculated. RESULTS: Overall, BMD in the CCS cohort did not significantly differ from controls. However, compared with eugonadal CCS, the CCS with untreated hypogonadism had lower BMD at the hip (mean difference - 0.139 (- 0.210; - 0.067); p < 0.001) and spine (- 0.102 (- 0.174; - 0.030); p = 0.006). They also had a higher risk of low hip BMD (OR 4.1 (1.3; 14); p = 0.018). CCS treated with cranial irradiation also had lower BMD (hip - 0.076 (- 0.133; - 0.019); p = 0.009; spine - 0.071 (- 0.124; - 0.018); p = 0.009) compared with controls. The latter associations remained statistically significant after adjustment for hypogonadism. CONCLUSIONS: CCS with hypogonadism or previously treated with cranial irradiation are at increased risk of impaired bone health. Prevention of osteoporosis should be considered as an important part in future follow-up of these men.

Kidney function and its association to imminent, short- and long-term fracture risk-a longitudinal study in older women.

Reduced kidney function is associated with an increased fracture risk, although the relationship between an age-related decline and fractures needs further investigation. We followed kidney function and fracture risk for 10 years. A mild-moderate decline in kidney function was associated with fracture, but not in advanced age. INTRODUCTION: With age, kidney function declines. Though well known that chronic kidney disease is associated with increased fracture risk, the extent to which the typical age-related decline contributes is unclear. In the OPRA cohort, a longitudinal study of older non-selected women, we investigated the association between kidney function and fracture. METHODS: Cystatin C-based kidney function estimates were available at age 75 (n = 981) and 80 (n = 685). Women were categorized by kidney function: normal (CKD stages 1 and 2), mild-moderate (3a), poor (3b-5), and imminent, short- and long-term fracture risk investigated. BMD measurements and kidney function for risk prediction were also evaluated; women were categorized by both reduced kidney function (stages 3-5) and osteoporosis status. RESULTS: In the short term, 2-3 years, mild-moderate kidney dysfunction was associated with the highest risk increase: osteoporotic fractures (2 years HRadj 2.21, 95% CI 1.27-3.87) and also up to 5 years (between 75 and 80 years) (HRadj 1.51, 1.04-2.18). Hip fracture risk was similarly increased. This association was not observed from age 80 nor for women with poorest kidney function. Reduced kidney function was associated with higher risk even without osteoporosis (osteoporotic fracture; HRadj 1.66, 1.08-2.54); risk increased by having both osteoporosis and reduced function (HRadj 2.53, 1.52-4.23). CONCLUSION: Older women with mild-moderate reduction of kidney function are at increased risk of fractures, but not those with the worst function. Our findings furthermore confirm the value of osteoporosis assessment and it is possible that in this age group, age-related decline of kidney function has limited contribution compared with BMD.

Correction to: Progression of frailty and prevalence of osteoporosis in a community cohort of older women-a 10-year longitudinal study.

The Open Access license, which previously read.

Risk of imminent fracture following a previous fracture in a Swedish database study.

This study examined the imminent risk of a future fracture within 1 and 2 years following a first fracture in women aged 50 years and older and assessed independent factors associated with risk of subsequent fractures. The study highlights the need to intervene rapidly after a fracture to prevent further fractures. INTRODUCTION: This study aims to determine the imminent risk of subsequent fractures within 1 and 2 years following a first fracture and to assess independent factors associated with subsequent fractures. METHODS: Retrospective, observational cohort study of women aged ≥ 50 years with a fragility fracture was identified from Swedish national registers. Clinical/demographic characteristics at the time of index fracture and cumulative fracture incidences up to 12 and 24 months following index fracture were calculated. Risk factors for subsequent fracture were identified using multivariate regression analysis. RESULTS: Two hundred forty-two thousand one hundred eight women (mean [SD] age 74 [12.5] years) were included. The cumulative subsequent fracture incidence at 12 months was 7.1% (95% confidence interval [CI], 6.9-7.2) and at 24 months was 12.0% (95% CI, 11.8-12.1). The rate of subsequent fractures was highest in the first month (~ 15 fractures per 1000 patient-years) and remained steady between 4 and 24 months (~ 5 fractures/1000 patient-years). Higher age was an independent risk factor for imminent subsequent fractures (at 24 months, sub-distribution hazard ratio [HR], 3.07; p < 0.001 for women 80-89 years [reference 50-59 years]). Index vertebral fracture was a strong independent risk factor for subsequent fracture (sub-distribution HR, 2.72 versus hip fracture; p < 0.001 over 12 months; HR, 2.23; p < 0.001 over 24 months). CONCLUSIONS: Our findings highlight the need to intervene rapidly after any fragility fracture in postmenopausal women. The occurrence of a fragility fracture provides healthcare systems with a unique opportunity to intervene to reduce the increased risk of subsequent fractures.

Diagnosis and management of bone fragility in diabetes: an emerging challenge.

Fragility fractures are increasingly recognized as a complication of both type 1 and type 2 diabetes, with fracture risk that increases with disease duration and poor glycemic control. Yet the identification and management of fracture risk in these patients remains challenging. This review explores the clinical characteristics of bone fragility in adults with diabetes and highlights recent studies that have evaluated bone mineral density (BMD), bone microstructure and material properties, biochemical markers, and fracture prediction algorithms (i.e., FRAX) in these patients. It further reviews the impact of diabetes drugs on bone as well as the efficacy of osteoporosis treatments in this population. We finally propose an algorithm for the identification and management of diabetic patients at increased fracture risk.

Progression of frailty and prevalence of osteoporosis in a community cohort of older women-a 10-year longitudinal study.

In community dwelling, 75-year-old women followed 10 years, a frailty index was created at each of three visits. Frailty score increased by ~ 6-7% annually. A higher frailty score was equivalent to being 5-10 years chronologically older. Frailty was associated with low bone density and higher risk of dying. INTRODUCTION: To understand the distribution of frailty among a population-based sample of older community-dwelling women, progression over 10 years, and association with mortality and osteoporosis. METHODS: The study is performed in a cohort designed to investigate osteoporosis. The OPRA cohort consists of 75-year-old women, n = 1044 at baseline, and follow-up at age 80 and 85. A frailty index (scored from 0.0-1.0) based on deficits in health across multiple domains was created at all time-points; outcomes were mortality up to 15 years and femoral neck bone density. RESULTS: At baseline, the proportion least frail, i.e., most robust (FI 0.0-0.1) constituted 48%, dropping to 25 and 14% at age 80 and 85. On average, over 10 years, the annual linear frailty score progression was approximately 6-7%. Among the least frail, 11% remained robust over 10 years. A higher frailty score was equivalent to being 5 to 10 years older. Mortality was substantially higher in the highest quartile compared to the lowest based on baseline frailty score; after 10 years, 48.7% had died vs 17.2% (p = 1.7 × 10-14). Mortality risk over the first 5 years was highest in the frailest (Q4 vs Q1; HRunadj 3.26 [1.86-5.73]; p < 0.001) and continued to be elevated at 10 years (HRunadj 3.58 [2.55-5.03]; p < 0.001). Frailty was associated with BMD after adjusting for BMI (overall p = 0.006; Q1 vs Q4 p = 0.003). CONCLUSIONS: The frailty index was highly predictive of mortality showing a threefold increased risk of death in the frailest both in a shorter and longer perspective. Only one in ten older women escaped progression after 10 years. Frailty and osteoporosis were associated.

A health economic simulation model for the clinical management of osteoporosis.

The objective was to estimate the burden of osteoporosis in Sweden based on current clinical practice and the cost-effectiveness of improvements in the management of osteoporosis over the clinical management compared to current clinical practice. Results showed that better compliance to treatment guidelines is associated with better projected outcomes and cost-savings. INTRODUCTION: The purpose of this study is to estimate the burden of osteoporosis in Sweden based on current clinical practice and the cost-effectiveness of improvements in the management of osteoporosis over the clinical management compared to current clinical practice. METHODS: The analysis was carried out using a model that simulates the individual patients considered for pharmacological treatment during 1 year and their projected osteoporosis treatment pathway, quality-adjusted life years (QALYs) and costs over their remaining lifetime. All patients regardless of treatment or no treatment were simulated. Information on current management of osteoporosis in terms of patient characteristics and treatment patterns were derived from a Swedish osteoporosis research database based on national registers and patient records. Current (standard) clinical management was compared with alternative scenarios mirroring Swedish treatment guidelines. RESULTS: The national burden in terms of lost QALYs was estimated at 14,993 QALYs and the total economic cost at €776M. Scenario analyses showed that 382-3864 QALYs could be gained at a cost/QALY ranging from cost-saving to €31368, depending on the scenario. The margin of investment, i.e. the maximum amount that could be invested in the healthcare system to achieve these improvements up to the limit of the willingness to pay/QALY, was estimated at €199M on a population level (€3,634/patient). CONCLUSIONS: The analysis showed that better compliance to treatment guidelines is associated with better projected outcomes and cost-savings. From a cost-effectiveness perspective, there is also considerable room for investment to achieve these improvements in the management of osteoporosis.

Reduced kidney function is associated with BMD, bone loss and markers of mineral homeostasis in older women: a 10-year longitudinal study.

Kidney function decreases with age; however, the long-term influence on bone density (BMD) in older women already at risk of osteoporosis is unknown. We followed kidney function and bone loss for 10 years. Declining kidney function was adversely associated with bone loss and mineral homeostasis in old women, though it attenuated with advanced aging. INTRODUCTION: Existing studies do not fully address the relationship between kidney function and bone metabolism with advanced aging in Caucasian women. This study describes the association between kidney function, BMD, bone loss and bone metabolism in older women and provides a review of the available literature for context. METHODS: We studied participants from the OPRA cohort with follow-up after 5 and 10 years. Using plasma cystatin C (cysC), estimated glomerular function rate (eGFR) was evaluated at age 75 (n = 981), 80 (n = 685) and 85 (n = 365). Women were stratified into "normal" function (CKD stages 1-2), "intermediate" (stage 3a) and "poor" (stages 3b-5), and outcome measures-BMD, bone loss and markers of mineral homeostasis-were compared. RESULTS: Femoral neck (FN) BMD positively associated with kidney function at 75 years old ([Formula: see text] = 0.001, p = 0.028) and 80 years old ([Formula: see text] = 0.001, p = 0.001), although with small effect size. Prevalence of osteoporosis (FN T-score ≤ - 2.5) did not differ with kidney function. Measured at age 75, women with poor kidney function had higher annual percentage bone loss over 5 years compared to those with normal function (2.3%, 95% CI 1.8-2.8 versus 1.3%, 95% CI 1.1-1.5, p = 0.007), although not when measured from age 80 or 85. Additionally, markers of mineral homeostasis (PTH, phosphate, vitamin D, calcium), CRP and osteocalcin differed by kidney function. CONCLUSIONS: In old women, kidney function is associated with BMD, bone loss and altered mineral homeostasis; probably, a relationship attenuated in the very elderly.

Risk of low bone mineral density in testicular germ cell cancer survivors: association with hypogonadism and treatment modality.

The cure rate of testicular cancer exceeds 95%, but testicular cancer survivors (TCS) are at increased risk of hypogonadism (HG). It has been suggested that TCS have reduced bone mineral density (BMD), but it is unclear whether this is related to HG or a direct effect of cancer therapy. The aim of this study was to evaluate whether TCS have decreased BMD, and if BMD is related to HG and/or the cancer treatment given. We investigated 91 TCS (mean age at diagnosis: 31 years; mean 9.3 years follow-up) and equal number of age matched controls (mean age at inclusion 40.3 years and 41.2 years, respectively). Total testosterone and LH were measured. BMD was determined using dual-energy X-ray absorptiometry (DXA). Low BMD (LBD) was defined as Z-score <-1. Compared to eugonadal TCS, both TCS with untreated HG (mean difference: -0.063 g/cm2 ; 95% CI: -0.122; -0.004 p = 0.037) and TCS receiving androgen replacement (mean difference -0.085 g/cm2 ; 95% CI: -0.168; -0.003; p = 0.043) presented with statistically significantly 6-8% lower hip BMD. At the spine, L1-L4, an 8% difference reached the level of statistical significance only for those with untreated HG (mean difference: -0.097 g/cm2 ; 95% CI: -0.179; -0.014; p = 0.022). TCS with untreated HG had significantly increased OR for spine L1-L4 LBD (OR = 4.1; 95% CI: 1.3; 13; p = 0.020). The associations between the treatment given and BMD were statistically non-significant, both with and without adjustment for HG. In conclusion, TCS with HG are at increased risk of impaired bone health. Prevention of osteoporosis should be considered as an important part in future follow up of these men.

Hip fracture, mortality risk, and cause of death over two decades.

UNLABELLED: Men and women with hip fracture have higher short-term mortality. This study investigated mortality risk over two decades post-fracture; excess mortality remained high in women up to 10 years and in men up to 20 years. Cardiovascular disease (CVD) and pneumonia were leading causes of death with a long-term doubling of risk. INTRODUCTION: Hip fractures are associated with increased mortality, particularly short term. In this study with a two-decade follow-up, we examined mortality and cause of death compared to the background population. METHODS: We followed 1013 hip fracture patients and 2026 matched community controls for 22 years. Mortality, excess mortality, and cause of death were analyzed and stratified for age and sex. Hazard ratio (HR) was estimated by Cox regression. A competing risk model was fitted to estimate HR for common causes of death (CVD, cancer, pneumonia) in the short and long term (>1 year). RESULTS: For both sexes and at all ages, mortality was higher in hip fracture patients across the observation period with men losing most life years (p < 0.001). Mortality risk was higher for up to 15 years (women (risk ratio (RR) 1.9 [95 % confidence interval (CI) 1.7-2.1]); men (RR 2.8 [2.2-3.5])) and until end of follow-up ((RR 1.8 [1.6-2.0]); (RR 2.7 [2.1-3.3])). Excess mortality by time intervals, censored for the first year, was evident in women (<80 years, up to 10 years; >80 years, for 5 years) and in men <80 years throughout. CVD and pneumonia were predominant causes of death in men and women with an associated higher risk in all age groups. Pneumonia caused excess mortality in men over the entire observation period. CONCLUSION: In a remaining lifetime perspective, all-cause and excess mortality after hip fracture was higher even over two decades of follow-up. CVD and pneumonia reduce life expectancy for the remaining lifetime and highlights the need to further improve post-fracture management.