Growth hormone and testosterone delay vertebral fractures in boys with muscular dystrophy on chronic glucocorticoids.

Glucocorticoid use in Duchenne and Becker muscular dystrophy prolongs ambulation but cause significant skeletal toxicity. Our analysis has immediate clinical implications, suggesting that growth hormone and testosterone have a stronger effect prior to first and subsequent vertebral fracture, respectively, relative to bisphosphonates alone in children with dystrophinopathies on chronic glucocorticoids. PURPOSE: Glucocorticoids prolong ambulation in boys with Duchenne muscular dystrophy; however, they have significant endocrine side effects. We assessed the impact of growth hormone (GH), testosterone, and/or zoledronic acid (ZA) on vertebral fracture (VF) incidence in patients with dystrophinopathies on chronic glucocorticoids. METHODS: We conducted a longitudinal retrospective review of 27 males with muscular dystrophy. Accelerated failure time (AFT) models were used to estimate the relative time to VF while on GH, testosterone, and/or ZA compared to ZA alone. Results are reported as failure time ratio, where >1 indicates prolonged time versus <1 indicates shorter time to next VF. RESULTS: The prevalence of growth impairment was 96% (52% utilized GH), pubertal delay was 86% (72% utilized testosterone), and low trauma fractures were 87% (72% utilized ZA). Multivariable analysis of the AFT models showed that participants on either GH or testosterone treatment relative to ZA alone experienced prolonged time to next VF (1.253, P<0.001), with GH being the significant contributor when analyzed independently from testosterone (1.229, P<0.001). Use of ZA with GH or testosterone relative to ZA alone resulted in prolonged time to next VF (1.171, P<0.001), with testosterone being a significant contributor (1.130, P=0.033). CONCLUSION: GH and testosterone each decreased VF risk in patients independent of or in combination with ZA, respectively.

Bone health status evaluation in men by means of REMS technology.

BACKGROUND: Osteoporosis in males is largely under-diagnosed and under-treated, with most of the diagnosis confirmed only after an osteoporotic fracture. Therefore, there is an urgent need for highly accurate and precise technologies capable of identifying osteoporosis earlier, thereby avoiding complications from fragility fractures. AIMS: This study aimed to evaluate the diagnostic accuracy and precision of the non-ionizing technology Radiofrequency Echographic Multi Spectrometry (REMS) for the diagnosis of osteoporosis in a male population in comparison with conventional Dual-energy X-ray Absorptiometry (DXA). METHODS: A cohort of 603 Caucasian males aged between 30 and 90 years were involved in the study. All the enrolled patients underwent lumbar and femoral scans with both DXA and REMS. The diagnostic agreement between REMS and DXA-measured BMD was expressed by Pearson correlation coefficient and Bland-Altman method. The accuracy of the diagnostic classification was evaluated by the assessment of sensitivity and specificity considering DXA as reference. RESULTS: A significant correlation between REMS- and DXA-measured T-score values (r = 0.91, p < 0.0001) for lumbar spine and for femoral neck (r = 0.90, p < 0.0001) documented the substantial equivalence of the two measurement techniques. Bland-Altman outcomes showed that the average difference in T-score measurement is very close to zero (-0.06 ± 0.60 g/cm2 for lumbar spine and - 0.07 ± 0.44 g/cm2 for femoral neck) confirming the agreement between the two techniques. Furthermore, REMS resulted an effective technique to discriminate osteoporotic patients from the non-osteoporotic ones on both lumbar spine (sensitivity = 90.1%, specificity = 93.6%) and femoral neck (sensitivity = 90.9%, specificity = 94.6%). Precision yielded RMS-CV = 0.40% for spine and RMS-CV = 0.34% for femur. CONCLUSION: REMS, is a reliable technology for the diagnosis of osteoporosis also in men. This evidence corroborates its high diagnostic performance already observed in previous studies involving female populations.

Osteoid osteoma appearing after bony fracture in a girl with osteogenesis imperfecta.

Osteoid osteoma (OO) is a common, benign bone tumor. However, there are no case reports of OO associated with osteogenesis imperfecta (OI), or pathological fractures in OO. A 3-year-old girl with OI sustained a complete right tibial diaphyseal fracture. Bony fusion was completed after 4 months of conservative therapy; nevertheless, 18 months later spontaneous pain appeared at the fracture site, without any cause. Plain radiographs showed a newly apparent, rounded area of translucency 1 cm in diameter, just overlapping the previous fracture. Images obtained using three-dimensional time-resolved contrast-enhanced magnetic resonance angiography showed strong central enhancement in the early phase, with an apparent nidus, suggesting the diagnosis of OO. Nineteen months after the first fracture, while skipping, the patient refractured her tibial diaphysis at the site of the previous fracture. This is a very rare case of OO, apparently co-existing with OI and leading to a bony fracture. In our case, the combination of bone fragility in OI and a recent fracture at the site of the OO may have caused the re-fracture.

Risk factors associated with prevalent vertebral fractures in Duchenne muscular dystrophy.

Patients with Duchenne muscular dystrophy (DMD) have a high fracture burden due to progressive myopathy and steroid-induced osteoporosis. This study in males with DMD showed that markers of systemic glucocorticoid exposure including shorter stature, greater bone age delay, and lower lumbar spine bone mineral density were associated with spine fragility. INTRODUCTION: Fragility  fractures are frequent in DMD. The purpose of this study was to identify clinical factors associated with prevalent vertebral fractures (VF) in boys, teens/young adults with Duchenne muscular dystrophy (DMD). METHODS: This was a cross-sectional study of males aged 4-25 years with DMD. VF were evaluated using the modified Genant semi-quantitative method on T4-L4 lateral spine radiographs. Areal bone mineral density (aBMD) was measured at the lumbar spine (LS) and used to estimate volumetric BMD (vBMD). Clinical factors were analyzed for their association with the Spinal Deformity Index (SDI, the sum of the Genant grades). RESULTS: Sixty participants were enrolled (mean age 11.5 years, range 5.4-19.5). Nineteen participants (32%) had a total of 67 VF; 23/67 VF (34%) were moderate or severe. Participants with VF were shorter (mean height Z-score ± standard deviation: - 3.1 ± 1.4 vs. - 1.8 ± 1.4, p = 0.001), had longer glucocorticoid exposure (mean duration 6.0 ± 3.3 vs. 3.9 ± 3.3 years, p = 0.027), greater bone age (BA) delay (mean BA to chronological age difference - 3.2 ± 3.4 vs. - 1.3 ± 1.2 years, p = 0.035), and lower LSaBMD Z-scores (mean - 3.0 ± 1.0 vs. - 2.2 ± 1.2, p = 0.023). There was no difference in LSvBMD Z-scores. Multivariable Poisson regression showed that every 0.1 mg/kg/day increment in average glucocorticoid daily dose was associated with a 1.4-fold SDI increase (95% confidence interval: 1.1-1.7, p = 0.013). Greater BA delay (p < 0.001), higher weight Z-score (p = 0.004), decreased height Z-score (p = 0.025), and lower LSvBMD Z-score (p = 0.025) were also associated with SDI increase. CONCLUSION: Readily measurable clinical variables were associated with prevalent VF in males with glucocorticoid-treated DMD. These variables may be useful to identify candidates for primary osteoporosis prevention after glucocorticoid initiation.

Relationship Between Plasma Homocysteine and Bone Density, Lean Mass, Muscle Strength and Physical Function in 1480 Middle-Aged and Older Adults: Data from NHANES.

Hyperhomocysteinemia induces oxidative stress and chronic inflammation (both of which are catabolic to bone and muscle); thus, we examined the association between homocysteine and body composition and physical function in middle-aged and older adults. Data from the National Health and Nutrition Examination Survey was used to build regression models. Plasma homocysteine (fluorescence immunoassay) was used as the exposure and bone mineral density (BMD; dual-energy X-ray absorptiometry; DXA), lean mass (DXA), knee extensor strength (isokinetic dynamometer; newtons) and gait speed (m/s) were used as outcomes. Regression models were adjusted for confounders (age, sex, race/Hispanic origin, height, fat mass %, physical activity, smoking status, alcohol intakes, cardiovascular disease, diabetes, cancer and vitamin B12). All models accounted for complex survey design by using sampling weights provided by NHANES. 1480 adults (median age: 64 years [IQR: 56, 73]; 50.3% men) were included. In multivariable models, homocysteine was inversely associated with knee extensor strength (ß = 0.98, 95% CI 0.96, 0.99, p = 0.012) and gait speed (ß = 0.85, 95% CI 0.78, 0.94, p = 0.003) and borderline inversely associated with femur BMD (ß = 0.84, 95% CI 0.69, 1.03, p = 0.086). In the sub-group analysis of older adults (≥ 65 years), homocysteine was inversely associated with gait speed and femur BMD (p < 0.05) and the slope for knee extensor strength and whole-body BMD were in the same direction. No significant associations were observed between homocysteine and total or appendicular lean mass in the full or sub-group analysis. We found inverse associations between plasma homocysteine and muscle strength/physical function, and borderline significant inverse associations for femur BMD.

Trabecular Bone Score as an Index of Bone Fragility in Patients with Acromegaly: A Systematic Review and Meta-Analysis.

BACKGROUND: Acromegaly is characterized by impaired bone quality and increased fracture risk. However, due to the pathophysiology of acromegalic osteopathy, bone mineral density (BMD) does not represent a reliable predictor for fragility fractures in this setting. Trabecular bone score (TBS) has been recently evaluated as an alternative index of skeletal fragility in acromegalic patients. However, no conclusive data are still available in this regard. METHODS: PubMed/Medline, EMBASE, Cochrane Library, Ovid, and CINAHL databases were systematically searched until June 2022 for studies reporting data either about the comparison of TBS values between acromegalic patients and non-acromegalic controls or about the relationship - within acromegalic patients - between TBS values and fracture risk. Effect sizes were pooled through a random-effect model. RESULTS: Eight studies were eligible for inclusion in the meta-analysis, encompassing 336 acromegalic patients and 490 non-acromegalic controls. Overall, TBS was significantly lower in acromegalic patients compared to controls (-0.089, 95% CI: [-0.111, -0.067], p < 0.01), irrespective of acromegaly disease activity and gonadal status. With respect to fracture risk, TBS was significantly lower in acromegalic patients with vertebral fractures than in those without (-0.099, 95% CI: [-0.166, -0.032], p < 0.01). CONCLUSION: In this meta-analysis, we specifically assessed the role of TBS as an index of bone quality and fracture risk in patients with acromegaly. Our results support the notion that TBS could be of value in the assessment and management of skeletal fragility in acromegalic patients, especially in light of the poor information provided in this setting by BMD.

Serum phosphate is associated with increased risk of bone fragility fractures in hemodialysis patients.

BACKGROUND: Bone fragility fractures are associated with high morbidity and mortality. This study analysed the association between the current biochemical parameters of CKD-MBD and bone fragility fractures in the COSMOS project. METHODS: COSMOS is a 3-year, multicentre, open cohort, prospective, observational study carried out in 6797 hemodialysis patients (227 centres from 20 European countries). The association of bone fragility fractures (outcome) with serum calcium, phosphate and PTH (exposure), was assessed using Standard Cox proportional hazards regression and Cox proportional hazards regression for recurrent events. Additional analyses were performed considering all-cause mortality as a competitive event for bone fragility fracture occurrence. Multivariable models were used in all strategies, with the fully adjusted model including a total of 24 variables. RESULTS: During a median follow-up of 24 months 252 (4%) patients experienced at least one bone fragility fracture (incident bone fragility fracture rate 28.5 per 1000 patient-years). In the fractured and non-fractured patients, the percentage of men was 43.7% and 61.4%, mean age 68.1 and 63.8 years and a haemodialysis vintage of 55.9 and 38.3 months respectively. Baseline serum phosphate > 6.1 mg/dL (reference value 4.3-6.1 mg/dL) was significantly associated with a higher bone fragility fracture risk in both regression models (HR: 1.53[95%CI: 1.10-2.13] and HR: 1.44[95%CI: 1.02-2.05]. The significant association persisted after competitive risk analysis (subHR: 1.42[95%CI: 1.02-1.98]) but the finding was not confirmed when serum phosphate was considered as a continuous variable. Baseline serum calcium showed no association with bone fragility fracture risk in any regression model. Baseline serum PTH > 800 pg/mL was significantly associated with a higher bone fragility fracture risk in both regression models, but the association disappeared after a competitive risk analysis. CONCLUSIONS: Hyperphosphatemia was independently and consistently associated with an increased bone fracture risk, suggesting serum phosphate could be a novel risk factor for bone fractures in hemodialysis patients.

Validation of the clinical consensus recommendations on the management of fracture risk in postmenopausal women with type 2 diabetes.

BACKGROUND AND AIMS: Bone fragility is recognized as a complication of type 2 diabetes (T2D). However, the fracture risk in T2D is underestimated using the classical assessment tools. An expert panel suggested the diagnostic approaches for the detection of T2D patients worthy of bone-active treatment. The aim of the study was to apply these algorithms to a cohort of T2D women to validate them in clinical practice. METHODS AND RESULTS: The presence of T2D-specific fracture risk factors (T2D ≥ 10 years, ≥1 T2D complications, insulin or thiazolidinedione use, poor glycaemic control) was assessed at baseline in 107 postmenopausal T2D women. In all patients at baseline and in 34 patients after a median follow-up of 60.2 months we retrospectively evaluated bone mineral density and clinical and morphometric vertebral fractures. No patient was treated with bone-active drug. Following the protocols, 34 (31.8%) and 73 (68.2%) patients would have been pharmacologically and conservatively treated, respectively. Among 49 patients without both clinical fractures and major T2D-related risk factors, who would have been, therefore, conservatively followed-up without vertebral fracture assessment, only one showed a prevalent vertebral fracture (sensitivity 90%, negative predictive value 98%). The two patients who experienced an incident fracture would have been pharmacologically treated at baseline. CONCLUSIONS: The clinical consensus recommendations showed a very good sensitivity in identifying T2D postmenopausal women at high fracture risk. Among those with treatment indication as many as 13% of patients experienced an incident fracture, and, conversely, among those without treatment indication no incident fractures were observed.

Ipsilateral Periprosthetic Fractures above and below the Knee Associated with Navigation Tracker Pin and Bone Fragility.

We report a case of ipsilateral periprosthetic fractures above and below the knee that occurred at different times due to navigation tracker pin and bone fragility. A 66-year-old Japanese woman with rheumatoid arthritis (RA) underwent a total knee arthroplasty. Four months post-surgery, a periprosthetic fracture above the knee at the navigation pin hole was detected. She underwent osteosynthesis and could walk independently, but she developed an ipsilateral tibial component fracture. Conservative treatment with a splint was followed by bone union. Patients with RA treated with oral steroids tend to develop ipsilateral periprosthetic fractures around the knee due to bone fragility.

Effect of non-enzymatic glycation on collagen nanoscale mechanisms in diabetic and age-related bone fragility.

Age and diabetes have long been known to induce an oxidative reaction between glucose and collagen, leading to the accumulation of advanced glycation end-products (AGEs) cross-links in collagenous tissues. More recently, AGEs content has been related to loss of bone quality, independent of bone mass, and increased fracture risk with aging and diabetes. Loss of bone quality is mostly attributed to changes in material properties, structural organization, or cellular remodeling. Though all these factors play a role in bone fragility disease, some common recurring patterns can be found between diabetic and age-related bone fragility. The main pattern we will discuss in this viewpoint is the increase of fibrillar collagen stiffness and loss of collagen-induced plasticity with AGE accumulation. This study focused on recent related experimental studies and discusses the correlation between fluorescent AGEs content at the molecular and fibrillar scales, collagen deformation mechanisms at the nanoscale, and resistance to bone fracture at the macroscale.

Bone biopsy findings in patients receiving long-term bisphosphonate therapy for glucocorticoid-induced osteoporosis.

INTRODUCTION: Bisphosphonates (BPs) have been shown to reduce the incidence of vertebral fractures during the first year or two of glucocorticoid (GC) treatments and are therefore recommended as a first-line treatment for GC-induced osteoporosis (GIO). However, there are theoretical concerns about the long-term use of BPs in low-turnover osteoporosis caused by chronic GC therapy. MATERIALS AND METHODS: We analyzed the trabecular microarchitecture, bone metabolism, and material strength of iliac crest bone biopsy samples from 10 female patients with rheumatoid arthritis who received an average of 6.7 years of BP therapy for GIO (GIOBP group), compared with those of 10 age- and bone mineral density (BMD)-matched non-rheumatoid arthritis postmenopausal women (reference group). RESULTS: Patients in the GIOBP group had a significantly greater fracture severity index, as calculated from the number and the extent of vertebral fractures compared with the reference patients. Micro-computed tomography analysis showed that the degree of mineralization and trabecular microarchitecture were significantly lower in the GIOBP group than in the reference patients. Patients in the GIOBP group exhibited lower bone contact stiffness, determined by micro-indentation testing, than in the reference group. The contact stiffness of the bone was negatively correlated with the fracture severity index and the daily prednisolone dosage. Immunohistochemistry and serum bone turnover markers showed decreased osteoclastic activity, impaired mineralization, and an increased fraction of empty lacunae in the GIOBP group. CONCLUSION: Our findings indicate that patients receiving long-term BP for GIO are still at high risk for fragility fractures because of poor bone quality.

MicroRNA and Diabetic Bone Disease.

PURPOSE OF REVIEW: The incidence of diabetes is increasing worldwide. Diabetes mellitus is characterized by hyperglycemia, which in the long-term damages the function of many organs including the eyes, the vasculature, the nervous system, and the kidneys, thereby imposing an important cause of morbidity for affected individuals. More recently, increased bone fragility was also noted in patients with diabetes. While patients with type 1 diabetes mellitus (T1DM) have low bone mass and a 6-fold risk for hip fractures, patients with type 2 diabetes mellitus (T2DM) have an increased bone mass, yet still display a 2-fold elevated risk for hip fractures. Although the underlying mechanisms are just beginning to be unraveled, it is clear that diagnostic tools are lacking to identify patients at risk for fracture, especially in the case of T2DM, in which classical tools to diagnose osteoporosis such as dual X-ray absorptiometry have limitations. Thus, new biomarkers are urgently needed to help identify patients with diabetes who are at risk to fracture. RECENT FINDINGS: Previously, microRNAs have received great attention not only for being involved in the pathogenesis of various chronic diseases, including osteoporosis, but also for their value as biomarkers. Here, we summarize the current knowledge on microRNAs and their role in diabetic bone disease and highlight recent studies on miRNAs as biomarkers to predict bone fragility in T1DM and T2DM. Finally, we discuss future directions and challenges for their use as prognostic markers.

Augmentation in fragility fractures, bone of contention: a systematic review.

BACKGROUND: Osteoporosis is a complex multifactorial disease characterized by reduced bone mass and microarchitectural deterioration of bone tissue linked to an increase of fracture risk. Fragility fractures occur in osteoporotic subjects due to low-energy trauma. Osteoporotic patients are a challenge regarding the correct surgical planning, as it can include fixation augmentation techniques to reach a more stable anchorage of the implant, possibly lowering re-intervention rate and in-hospital stay. METHODS: The PubMed database and the Google Scholar search engine were used to identify articles on all augmentation techniques and their association with fragility fractures until January 2022. In total, we selected 40 articles that included studies focusing on humerus, hip, spine, and tibia. RESULTS: Literature review showed a quantity of materials that can be used for reconstruction of bone defects in fragility fractures in different anatomic locations, with good results over the stability and strength of the implant anchorage, when compared to non-augmented fractures. CONCLUSION: Nowadays there are no recommendations and no consensus about the use of augmentation techniques in osteoporotic fractures. Our literature review points at implementing the use of bone augmentation techniques with a specific indication for elderly patients with comminuted fractures and poor bone quality.

Use of the 95-degree angled blade plate with biological and mechanical augmentation to treat proximal femur non-unions: a case series.

BACKGROUND: Intertrochanteric and subtrochanteric non-union are rare but challenging complications. In the present study, we investigate the use of a 95° blade, in association with biological and mechanical augmentation, in the management of intertrochanteric and subtrochanteric femoral non-unions. METHODS: Between October 2015 and February 2021, a retrospective cohort study was conducted at our institution to investigate the use of a 95° blade, in association with biological and mechanical augmentation, in the management of intertrochanteric and subtrochanteric femoral non-unions, following the mechanical failure of the first device. All the patients underwent a clinical and radiographic follow-up at 6 weeks, 3, 6, 9, 12 and 18 months; at each follow-up, a plain radiograph of the femur was performed and patients were assessed using Harris Hip Score (HHS) and the Short Form-12 (SF-12) questionnaire. RESULTS: From October 2015 and February 2021, 40 proximal femur non-unions were managed at our Institution. Fifteen patients out of forty (37.5%) met the inclusion criteria. The main data of the study are summarized in Table 1; patients' mean was 57 years old (range 19-83); 10 males and 5 females were included in the study. All the patients completely healed clinically and radiologically at an average of 6.1 months (range 4-13). All these patients returned to their pre-injury mobility status. During an average follow-up period of 25 months (range 8-60), the observed complications included wound dehiscence, which was treated with a superficial surgical debridement, a below-the-knee deep vein thrombosis, and a blade plate failure 3 months after the first revision surgery. CONCLUSIONS: This study shows the treatment of inter-and sub-trochanteric non-unions with a 95° blade plate, medial strut allograft, and bone autograft obtained with RIA system, together with a varus malalignment correction, leads to a high percentage of bone healing, with a low incidence of complications and good clinical outcome.

Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside.

Mild hypercortisolism is defined as biochemical evidence of abnormal cortisol secretion without the classical detectable manifestations of overt Cushing's syndrome and, above all, lacking catabolic characteristics such as central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Mild hypercortisolism is frequently discovered in patients with adrenal incidentalomas, with a prevalence ranging between 5 and 50%. This high variability is mainly due to the different criteria used for defining this condition. This subtle cortisol excess has also been described in patients with incidentally discovered pituitary tumors with an estimated prevalence of 5%. To date, the mechanisms responsible for the pathogenesis of mild hypercortisolism of pituitary origin are still not well clarified. At variance, recent advances have been made in understanding the genetic background of bilateral and unilateral adrenal adenomas causing mild hypercortisolism. Some recent data suggest that the clinical effects of glucocorticoid (GC) exposure on peripheral tissues are determined not only by the amount of the adrenal GC production but also by the peripheral GC metabolism and by the GC sensitivity. Indeed, in subjects with normal cortisol secretion, the combined estimate of cortisol secretion, cortisone-to-cortisol peripheral activation by the 11 beta-hydroxysteroid dehydrogenase enzyme and GC receptor sensitizing variants have been suggested to be associated with the presence of hypertension, diabetes and bone fragility, which are three well-known consequences of hypercortisolism. This review focuses on the pathophysiologic mechanism underlying both the different sources of mild hypercortisolism and their clinical consequences (bone fragility, arterial hypertension, subclinical atherosclerosis, cardiovascular remodeling, dyslipidemia, glucose metabolism impairment, visceral adiposity, infections, muscle damage, mood disorders and coagulation).

Management of bone fragility in type 2 diabetes: Perspective from an interdisciplinary expert panel.

AIM: Bone fragility is increasingly recognized as a relevant complication of type 2 diabetes (T2D) and diabetic patients with fragility fractures have higher mortality rates than non diabetic individuals or diabetic patients without fractures. However, current diagnostic approaches for fracture risk stratification, such as bone mineral density measurement or the use of risk assessment algorithms, largely underestimate fracture risk in T2D patients. A multidisciplinary expert panel was established in order to in order to formulate clinical consensus recommendations on bone health assessment and management of fracture risk in patients with T2D. DATA SYNTHESIS: The following key questions were addressed: a) which are the risk factors for bone fragility in T2D?, b) which diagnostic procedures can be currently used to stratify fracture risk in T2D patients?, c) which are the effects of antidiabetic treatments on bone?, and d) how to prevent and treat bone fragility in T2D patients? Based on the available data members of this panel suggest that the stratification of fracture risk in patients with diabetes should firstly rely on the presence of a previous fragility fracture and on the individual risk profile, with the inclusion of T2D-specific risk factors (namely T2D duration above 10 yrs, presence of chronic T2D complications, use of insulin or thiazolidinediones and persistent HbA1c levels above 8% for at least 1 year). Two independent diagnostic approaches were then suggested in the presence or the absence of a prevalent fragility fracture, respectively. CONCLUSIONS: Clinical trials in T2D patients at risk for fragility fractures are needed to determine the efficacy and safety of available antiresorptive and anabolic agents in this specific setting.

Part 2: When Should Bisphosphonates Be Used in Children with Chronic Illness Osteoporosis?

PURPOSE OF REVIEW: Part 1 of this review on secondary osteoporosis of childhood was devoted to understanding which children should undergo bone health monitoring, when to label a child with osteoporosis in this setting, and how best to monitor in order to identify early, rather than late, signs of bone fragility. In Part 2 of this review, we discuss the next critical step in deciding which children require bisphosphonate therapy. This involves distinguishing which children have the potential to undergo "medication-unassisted" recovery from secondary osteoporosis, obviating the need for bisphosphonate administration, from those who require anti-resorptive therapy in order to recover from osteoporosis. RECENT FINDINGS: Unlike children with primary osteoporosis such as osteogenesis imperfecta, where the potential for recovery from osteoporosis without medical therapy is limited, many children with secondary osteoporosis can undergo complete recovery in the absence of bisphosphonate intervention. Over the last decade, natural history studies have unveiled the spectrum of this recovery, which spans overt deterioration (i.e., incident vertebral and non-vertebral fractures and declines in bone mineral density (BMD)), to spectacular reclamation of BMD, and complete restoration of normal vertebral dimensions after spine fractures. The fact that reshaping of vertebral bodies following fractures is growth-dependent underscores the need to identify and treat those at risk for permanent vertebral deformity in a timely fashion. The decision to treat a child with a bisphosphonate hinges on distinguishing bone fragility from typical childhood fractures, and determining the potential for medication-unassisted recovery following an osteoporotic fragility fracture. While improvements in BMD are a well-known sign of recovery, restitution of bone structure is also a key indicator of recuperation, one that is unique to childhood, and that plays a pivotal role in the decision to intervene or not.

Poor bone matrix quality: What can be done about it?

PURPOSE OF THE REVIEW: Bone's ability to withstand load resisting fracture and adapting to it highly depends on the quality of its matrix and its regulators. This review focuses on the contribution of bone quality to fracture resistance and possible therapeutic targets for skeletal fragility in aging and disease. RECENT FINDINGS: The highly organized, hierarchical composite structure of bone extracellular matrix together with its (re)modeling mechanisms and microdamage dynamics determines its stiffness, strength, and toughness. Aging and disease affect the biological processes regulating bone quality, thus resulting in defective extracellular matrix and bone fragility. Targeted therapies are being developed to restore bone's mechanical integrity. However, their current limitations include low tissue selectivity and adverse side effects. Biological and mechanical insights into the mechanisms controlling bone quality, together with advances in drug delivery and studies in animal models, will accelerate the development and translation to clinical application of effective targeted-therapeutics for bone fragility.

Part I: Which Child with a Chronic Disease Needs Bone Health Monitoring?

PURPOSE OF THE REVIEW: Underlying conditions which adversely affect skeletal strength are one of the most common reasons for consultations in pediatric bone health clinics. The diseases most frequently linked to fragility fractures include leukemia and other cancers, inflammatory disorders, neuromuscular disease, and those treated with osteotoxic drugs (particularly glucocorticoids). The decision to treat a child with secondary osteoporosis is challenged by the fact that fractures are frequent in childhood, even in the absence of risk factors. Furthermore, some children have the potential for medication-unassisted recovery from osteoporosis, obviating the need for bisphosphonate therapy. RECENT FINDINGS: Over the last decade, there have been important advances in our understanding of the skeletal phenotypes, fracture frequencies, and risk factors for bone fragility in children with underlying disorders. With improved knowledge about the importance of fracture characteristics in at-risk children, there has been a shift away from a bone mineral density (BMD)-centric definition of osteoporosis in childhood, to a fracture-focused approach. As a result, attention is now drawn to the early identification of fragility fractures, which includes asymptomatic vertebral collapse. Furthermore, even a single, long bone fracture can represent a major osteoporotic event in an at-risk child. Fundamental biological principles of bone strength development, and the ways in which these go awry in chronic illnesses, form the basis for monitoring and diagnosis of osteoporosis in children with underlying conditions. Overall, the goal of monitoring is to identify early, rather than late, signs of osteoporosis in children with limited potential to undergo medication-unassisted recovery. These are the children who should undergo bisphosphonate therapy, as discussed in part 1 (monitoring and diagnosis) and part 2 (recovery and the decision to treat) of this review.

Finite Element Assessment of Bone Fragility from Clinical Images.

PURPOSE OF REVIEW: We re-evaluated clinical applications of image-to-FE models to understand if clinical advantages are already evident, which proposals are promising, and which questions are still open. RECENT FINDINGS: CT-to-FE is useful in longitudinal treatment evaluation and groups discrimination. In metastatic lesions, CT-to-FE strength alone accurately predicts impending femoral fractures. In osteoporosis, strength from CT-to-FE or DXA-to-FE predicts incident fractures similarly to DXA-aBMD. Coupling loads and strength (possibly in dynamic models) may improve prediction. One promising MRI-to-FE workflow may now be tested on clinical data. Evidence of artificial intelligence usefulness is appearing. CT-to-FE is already clinical in opportunistic CT screening for osteoporosis, and risk of metastasis-related impending fractures. Short-term keys to improve image-to-FE in osteoporosis may be coupling FE with fall risk estimates, pool FE results with other parameters through robust artificial intelligence approaches, and increase reproducibility and cross-validation of models. Modeling bone modifications over time and bone fracture mechanics are still open issues.