Osteoporosis is a skeletal disorder with enhanced bone fragility, usually affecting the elderly. It is very rare in children and young adults and the definition is not only based on a low BMD (a
Z
...-score < − 2.0 in growing children and a
Z
-score ≤ − 2.0 or a
T
-score ≤ − 2.5 in young adults) but also on the occurrence of fragility fractures and/or the existence of underlying chronic diseases or secondary factors such as use of glucocorticoids. In the absence of a known chronic disease, fragility fractures and low BMD should prompt extensive screening for secondary causes, which can be found in up to 90% of cases. When fragility fractures occur in childhood or young adulthood without an evident secondary cause, investigations should explore the possibility of an underlying monogenetic bone disease, where bone fragility is caused by a single variant in a gene that has a major role in the skeleton. Several monogenic forms relate to type I collagen, but other forms also exist. Loss-of-function variants in
LRP5
and
WNT1
may lead to early-onset osteoporosis. The X-chromosomal osteoporosis caused by
PLS3
gene mutations affects especially males. Another recently discovered form relates to disturbed sphingolipid metabolism due to
SGMS2
mutations, underscoring the complexity of molecular pathology in monogenic early-onset osteoporosis. Management of young patients consists of treatment of secondary factors, optimizing lifestyle factors including calcium and vitamin D and physical exercise. Treatment with bone-active medication should be discussed on a personalized basis, considering the severity of osteoporosis and underlying disease versus the absence of evidence on anti-fracture efficacy and potential harmful effects in pregnancy.
Antiresorptive therapy significantly reduces fracture risk in patients with benign bone disease and skeletal-related events (SREs) in patients with bone metastases (BM). Osteonecrosis of the jaw ...(ONJ) is a rare but severe condition manifested as necrotic bone lesion or lesions of the jaws. ONJ has been linked to the use of potent antiresorptive agents, termed medication-related ONJ (MRONJ).
We aimed to identify the differences various aspects of MRONJ among distinct patient categories and provide recommendations on how to mitigate the risk and optimally manage MRONJ in each of them.
A working group of the European Calcified Tissue Society (ECTS) and 2 experts performed an updated detailed review of existing literature on MRONJ incidence, characteristics, and treatment applied in bone diseases with variable severity of skeletal insult, ranging from osteoporosis to prevention of cancer treatment-induced bone loss and SREs in cancer patients with BM.
The risk for MRONJ is much higher in patients with advanced malignancies compared to those with benign bone diseases because of the higher doses and more frequent administration of antiresorptive agents in individuals with compromised general health, along with coadministration of other medications that predispose to MRONJ. The overall risk for MRONJ is considerably lower than the benefits in all categories of patients.
The risk for MRONJ largely depends on the underlying bone disease and the relevant antiresorptive regimen applied. Physicians and dentists should keep in mind that the benefits of antiresorptive therapy far outweigh the risk for MRONJ development.
The optimal duration of osteoporosis treatment is controversial. As opposed to bisphosphonates, denosumab does not incorporate into bone matrix and bone turnover is not suppressed after its ...cessation. Recent reports imply that denosumab discontinuation may lead to an increased risk of multiple vertebral fractures.
The European Calcified Tissue Society (ECTS) formed a working group to perform a systematic review of existing literature on the effects of stopping denosumab and provide advice on management.
Data from phase 2 and 3 clinical trials underscore a rapid decrease of bone mineral density (BMD) and a steep increase in bone turnover markers (BTMs) after discontinuation of denosumab. Clinical case series report multiple vertebral fractures after discontinuation of denosumab and a renewed analysis of FREEDOM and FREEDOM Extension Trial suggests, albeit does not prove, that the risk of multiple vertebral fractures may be increased when denosumab is stopped due to a rebound increase in bone resorption.
There appears to be an increased risk of multiple vertebral fractures after discontinuation of denosumab although strong evidence for such an effect and for measures to prevent the occurring bone loss is lacking. Clinicians and patients should be aware of this potential risk. Based on available data, a re-evaluation should be performed after 5years of denosumab treatment. Patients considered at high fracture risk should either continue denosumab therapy for up to 10years or be switched to an alternative treatment. For patients at low risk, a decision to discontinue denosumab could be made after 5years, but bisphosphonate therapy should be considered to reduce or prevent the rebound increase in bone turnover. However, since the optimal bisphosphonate regimen post-denosumab is currently unknown continuation of denosumab can also be considered until results from ongoing trials become available. Based on current data, denosumab should not be stopped without considering alternative treatment in order to prevent rapid BMD loss and a potential rebound in vertebral fracture risk.
•Discontinuation of denosumab treatment potentially leads to a high risk of multiple vertebral fractures•Patients at high fracture risk should either continue denosumab therapy or be switched to an alternative treatment•Treatment with denosumab should not be stopped without considering an alternative (antiresorptive) treatment
Abstract
Context
Atypical femur fractures (AFFs) are serious adverse events associated with bisphosphonates and often show poor healing.
Evidence acquisition
We performed a systematic review to ...evaluate effects of teriparatide, raloxifene, and denosumab on healing and occurrence of AFF.
Evidence synthesis
We retrieved 910 references and reviewed 67 papers, including 31 case reports, 9 retrospective and 3 prospective studies on teriparatide. There were no RCTs. We pooled data on fracture union (n = 98 AFFs on teriparatide) and found that radiological healing occurred within 6 months of teriparatide in 13 of 30 (43%) conservatively managed incomplete AFFs, 9 of 10 (90%) incomplete AFFs with surgical intervention, and 44 of 58 (75%) complete AFFs. In 9 of 30 (30%) nonoperated incomplete AFFs, no union was achieved after 12 months and 4 (13%) fractures became complete on teriparatide. Eight patients had new AFFs during or after teriparatide. AFF on denosumab was reported in 22 patients, including 11 patients treated for bone metastases and 8 without bisphosphonate exposure. Denosumab after AFF was associated with recurrent incomplete AFFs in 1 patient and 2 patients of contralateral complete AFF. Eight patients had used raloxifene before AFF occurred, including 1 bisphosphonate-naïve patient.
Conclusions
There is no evidence-based indication in patients with AFF for teriparatide apart from reducing the risk of typical fragility fractures, although observational data suggest that teriparatide might result in faster healing of surgically treated AFFs. Awaiting further evidence, we formulate recommendations for treatment after an AFF based on expert opinion.
Mineral and bone disease is omnipresent in patients with chronic kidney disease (CKD) and leads to a diverse range of clinical manifestations, including bone pain and fractures. The accumulation of ...traditional clinical risk factors, in addition to those related to CKD, enhances the risk of comorbidity and mortality. Despite significant advances in understanding bone disease in CKD, most clinical and biochemical targets used in clinical practice remain controversial, resulting in an undermanagement of bone fragility. Vitamin D supplementation is widely used, but only a few studies have shown beneficial effects and a reduced risk of fracture and mortality. The achievement of serum levels of 25-hydroxyvitamin D is recommended for CKD patients to reduce a high parathyroid hormone level, which is associated with skeletal fractures. Optimal control of parathyroid hormone also improves bone mineralization and lowers circulating bone biomarkers such as alkaline phosphatase and cross-linked collagen type I peptide. The potential value of more recent biomarkers such as sclerostin and fibroblast growth factor 23, as surrogates for bone fragility, is an encouraging new direction in clinical research but is far from being firmly established. This article reviews the literature related to the pathophysiological role of various mineral and biochemical factors involved in renal osteodystrophy. To better understand bone fragility in CKD, new information related to the impact of disturbances of mineral metabolism on bone strength is urgently needed. The combined expertise of clinicians from various medical disciplines appears crucial for the most successful prevention of fractures in these patients.
Abstract
Background
Accumulation of advanced glycation end-products (AGEs) in tissues has been linked to various age-related disease phenotypes. Therefore, we investigated the potential relationship ...between skin AGE accumulation and frailty.
Methods
A cross-sectional analysis was performed on 2 521 participants from the Rotterdam Study. Skin AGEs were assessed as skin autofluorescence (SAF) using the AGE reader™. We used 2 approaches to define frailty. Fried’s criteria, including weight loss, weakness, slow gait speed, exhaustion, and low physical activity, were used to define physical frailty (presence of ≥3 components) and prefrailty (presence of ≤2 components). Rockwood’s concept, including 38 deficits from physical and psychosocial health domains, was used to calculate the frailty index (score 0–1). Multinomial logistic and multivariate linear regression were used with SAF as exposure and physical frailty (ordinal) and frailty index (continuous) as outcome adjusting for age, sex, diabetes, renal function, socioeconomic status, and smoking status.
Results
The mean SAF was 2.39 ± 0.49 arbitrary units and the median age was 74.2 (14.0) years. Regarding physical frailty, 96 persons (4%) were frail and 1 221 (48%) were prefrail. Skin autofluorescence was associated with both being prefrail (odds ratio 95% confidence interval = 1.29 1.07–1.56) and frail (1.87 1.20–2.90) compared with nonfrail. Regarding the frailty index, the median value was 0.14 (0.10–0.19) and higher SAF was also associated with a higher frailty index (coefficient, B = 0.017 (0.011–0.023).
Conclusions
Higher skin AGEs are associated with both physical frailty and frailty index. Longitudinal studies are needed to evaluate the causality and the potential of SAF as a biomarker to screen frailty.
We aimed to assess whether individuals with type 2 diabetes (T2D) have increased risk of vertebral fractures (VFs) and to estimate nonvertebral fracture and mortality risk among individuals with both ...prevalent T2D and VFs.
A systematic PubMed search was performed to identify studies that investigated the relationship between T2D and VFs. Cohorts providing individual participant data (IPD) were also included. Estimates from published summary data and IPD cohorts were pooled in a random-effects meta-analysis. Multivariate Cox regression models were used to estimate nonvertebral fracture and mortality risk among individuals with T2D and VFs.
Across 15 studies comprising 852,705 men and women, individuals with T2D had lower risk of prevalent (odds ratio OR 0.84 95% CI 0.74-0.95;
= 0.0%;
= 0.54) but increased risk of incident VFs (OR 1.35 95% CI 1.27-1.44;
= 0.6%;
= 0.43). In the IPD cohorts (
= 19,820), risk of nonvertebral fractures was higher in those with both T2D and VFs compared with those without T2D or VFs (hazard ratio HR 2.42 95% CI 1.86-3.15) or with VFs (HR 1.73 95% CI 1.32-2.27) or T2D (HR 1.94 95% CI 1.46-2.59) alone. Individuals with both T2D and VFs had increased mortality compared with individuals without T2D and VFs (HR 2.11 95% CI 1.72-2.59) or with VFs alone (HR 1.84 95% CI 1.49-2.28) and borderline increased compared with individuals with T2D alone (HR 1.23 95% CI 0.99-1.52).
Based on our findings, individuals with T2D should be systematically assessed for presence of VFs, and, as in individuals without T2D, their presence constitutes an indication to start osteoporosis treatment for the prevention of future fractures.
The association between metabolic syndrome (MS) and bone health remains unclear. We aimed to study the association between MS and hip bone geometry (HBG), femoral neck bone mineral density (FN-BMD), ...and the risk of osteoporosis and incident fractures. Data of 2040 women and 1510 men participants in the third visit (1997-1999) of the Rotterdam Study (RSI-3), a prospective population based cohort, were available (mean follow-up 6.7 years). MS was defined according to the recent harmonized definition. HBG parameters were measured at the third round visit whereas FN-BMD was assessed at the third round and 5 years later. Incident fractures were identified from medical registry data. After correcting for age, body mass index (BMI), lifestyle factors and medication use, individuals with MS had lower bone width (β = -0.054, P = 0.003), lower cortical buckling ratio (β = -0.81, P = 0.003) and lower odds of having osteoporosis (odds ratio =0.56, P = 0.007) in women but not in men. Similarly, MS was associated with higher FN-BMD only in women (β = 0.028, P=0.001). In the analyses of MS components, the glucose component (unrelated to diabetes status) was positively associated with FN-BMD in both genders (β = 0.016, P = 0.01 for women and β = 0.022, P = 0.004 for men). In men, waist circumference was inversely associated with FN-BMD (β = -0.03, P = 0.004). No association was observed with fracture risk in either sex. In conclusion, women with MS had higher FN-BMD independent of BMI. The glucose component of MS was associated with high FN-BMD in both genders, highlighting the need to preserve glycemic control to prevent skeletal complications.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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