The first clinical use of bisphosphonates was in Paget's disease of bone (PDB) when disodium etidronate was found to be effective at suppressing metabolic activity of the disease. Subsequently, PDB ...became a testing ground for many bisphosphonates using changes in alkaline phosphatase (ALP) as the primary outcome measure in clinical trials. Bisphosphonates are now considered to be the treatment of choice for PDB since they are highly effective at suppressing the elevations in bone turnover that are characteristic of the disease. Short term studies have shown that treatment with alendronate and risedronate can promote formation of lamellar bone in affected sites and improve x-ray appearances in some patients. Bisphosphonates have also been shown to improve bone pain in PDB and within the bisphosphonates, zoledronic acid (ZA) is most likely to give a favourable pain response. Many patients with PDB do not have pain however, even when there is increased metabolic activity and more research is needed to find out why this is the case. The effects of bisphosphonates on complications of PDB such as deformity, pathological fractures and deafness have not been adequately studied since most clinical trials have been short term and have not collected information on these important outcomes. The PRISM and PRISM-EZ studies investigated the long-term effects of bisphosphonates in patients with established PDB using a treat-to-target approach and showed that intensive bisphosphonate therapy aimed at normalising ALP was no more effective than symptom directed treatment with bisphosphonates at preventing complications of PDB. The Zoledronate in the Prevention of Paget's Disease (ZiPP) trial, which is currently in progress, seeks to determine whether early intervention with this potent bisphosphonate might be effective in preventing disease progression. Should the ZiPP study yield positive results, genetic testing coupled to prophylactic bisphosphonate therapy might represent a new indication for these highly effective inhibitors of bone resorption in future years.
•Bisphosphonates have been widely used in the treatment of Paget’s disease of bone•Bisphosphonates are the treatment of choice for bone pain caused by increased metabolic activity of the disease•Bisphosphonates can normalise bone remodelling, but it remains uncertain if they can alter the natural history of the disease
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
Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Twin and family studies have shown that the heritability ...of bone mineral density (BMD) and other determinants of fracture risk-such as ultrasound properties of bone, skeletal geometry, and bone turnover-is high, although heritability of fracture is modest. Many different genetic variants of modest effect size are likely to contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Linkage studies in rare Mendelian bone diseases have identified several previously unknown genes that play key roles in regulating bone mass and bone turnover. In many instances, subtle polymorphisms in these genes have also been found to regulate BMD in the general population. Although there has been extensive progress in identifying the genetic variants that regulate susceptibility to osteoporosis, most of the genes and genetic variants that regulate bone mass and susceptibility to osteoporosis remain to be discovered.
Osteogenesis imperfecta (OI) is the term used to describe a group of rare inherited skeletal disorders characterized by a greatly increased risk of fragility fractures (1). Mutations in several genes ...can cause OI but the condition is most commonly caused by mutations of
or
resulting in the production of collagen which is abnormal or present in reduced amounts. Fractures in OI are particularly common during childhood but the elevated fracture risk continues throughout life. Bone mineral density (BMD) can be reduced in OI but the magnitude of increase in fracture risk is far greater than can be accounted for by low BMD, highlighting that a key mechanism of bone fragility is reduced bone quality due to defects of bone matrix and mineralization. A multidisciplinary approach is needed to optimize management of OI, with input from physicians, orthopedic surgeons, physiotherapists, occupational therapists, and other allied health professionals. Orthopedic surgery plays a key role both in the fixation of fractures and in the correction of limb deformities. Bisphosphonates have been widely used in the treatment of children and adults with OI. Although there is good evidence that they increase BMD, it is uncertain to what extent they reduce fracture risk. Clinical trials of bone anabolic drugs such as teriparatide and inhibitors of sclerostin have also been studied; although they increase BMD, studies of these agents have not been powered to look at fracture endpoints. Various other treatment modalities including denosumab, and cell therapy have been explored but haven't gained acceptance in routine clinical practice. There have been huge advances in understanding the pathogenesis of OI but these have not been accompanied by advances in treatment. This signals need for well-designed clinical trials with fracture endpoints in OI, both with existing agents and with the newer therapeutic agents that are now starting to emerge.
Genetics of osteoporosis Ralston, Stuart H.
Annals of the New York Academy of Sciences,
April 2010, Letnik:
1192, Številka:
1
Journal Article
Recenzirano
Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and an increased risk of fragility fractures. Twin and family studies have shown that the ...heritability of bone mineral density and other determinants of fracture risk, such as ultrasound properties of bone, skeletal geometry, and bone turnover, is high, although heritability of fracture is modest. Many different genetic variants contribute to the regulation of these phenotypes. Most are common variants of small effect size, but there is evidence that rare variants of large effect size also contribute in some individuals. Many of the genes that regulate susceptibility to osteoporosis have been identified through studies of rare bone diseases, but genome‐wide association studies have also been successful in identifying genes that predispose to osteoporosis. Although there has been extensive progress in this area over the past 10 years, most of the genetic variants that regulate susceptibility to osteoporosis remain to be discovered.
Vertebroplasty is commonly used to treat painful, osteoporotic vertebral compression fractures.
In this multicenter trial, we randomly assigned 131 patients who had one to three painful osteoporotic ...vertebral compression fractures to undergo either vertebroplasty or a simulated procedure without cement (control group). The primary outcomes were scores on the modified Roland-Morris Disability Questionnaire (RDQ) (on a scale of 0 to 23, with higher scores indicating greater disability) and patients' ratings of average pain intensity during the preceding 24 hours at 1 month (on a scale of 0 to 10, with higher scores indicating more severe pain). Patients were allowed to cross over to the other study group after 1 month.
All patients underwent the assigned intervention (68 vertebroplasties and 63 simulated procedures). The baseline characteristics were similar in the two groups. At 1 month, there was no significant difference between the vertebroplasty group and the control group in either the RDQ score (difference, 0.7; 95% confidence interval CI, -1.3 to 2.8; P=0.49) or the pain rating (difference, 0.7; 95% CI, -0.3 to 1.7; P=0.19). Both groups had immediate improvement in disability and pain scores after the intervention. Although the two groups did not differ significantly on any secondary outcome measure at 1 month, there was a trend toward a higher rate of clinically meaningful improvement in pain (a 30% decrease from baseline) in the vertebroplasty group (64% vs. 48%, P=0.06). At 3 months, there was a higher crossover rate in the control group than in the vertebroplasty group (51% vs. 13%, P<0.001) corrected. There was one serious adverse event in each group.
Improvements in pain and pain-related disability associated with osteoporotic compression fractures in patients treated with vertebroplasty were similar to the improvements in a control group. (ClinicalTrials.gov number, NCT00068822.)
Some rheumatic diseases are associated with stroke. Less is known about associations with stroke subtypes or stroke risk by age. We quantified the association between stroke, its subtypes, and ...rheumatic diseases and identified when stroke risk is greatest.
Searches of EMBASE (from 1980) and MEDLINE (from inception) to end 2014 and manual search of reference lists for studies of stroke and stroke subtypes in rheumatic diseases as well as studies measuring cerebrovascular disease from magnetic resonance imaging.
Prior published meta-analyses and new pooled analyses of any stroke in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, gout, and psoriasis show an excess risk of stroke over the general population with odds ratio (OR) ranging from 1.51 (95% confidence interval: 1.39-1.62) to 2.13 (1.53-2.98). New meta-analyses of stroke subtypes in rheumatoid arthritis ischemic: OR, 1.64 (1.32-2.05); hemorrhagic: OR, 1.68 (1.11-2.53) and systemic lupus erythematosus ischemic: OR, 2.11 (1.66-2.67); hemorrhagic: OR, 1.82 (1.07-3.09) show an excess risk of stroke over the general population. Stroke risk across rheumatic diseases is highest in those aged <50 years OR, 1.79 (1.46-2.20) and reduces relatively with ageing >65 years: OR, 1.14 (0.94-1.38); difference P<0.007. Inflammatory arthropathies conveyed higher stroke risk than noninflammatory diseases (OR, 1.3, 1.2-1.3). It was not possible to adjust ORs for risk factors or treatments.
Risk of any stroke is higher in most rheumatic diseases than in the general population, particularly <50 years. Rheumatoid arthritis and systemic lupus erythematosus increase ischemic and hemorrhagic stroke risk by 60% to 100% relative to the general population.
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