We searched Medline and PubMed for articles published between 2000 and 2010. We used the search terms “osteoporosis” in combination with “treatment”, “RANK ligand”, “denosumab”, “cathepsin K”, “odanacatib”, “saracatinib”, “calcium-sensing receptor”, “calcilytic”, “sclerostin”, and “dickkopf-1”. We largely selected original papers and reviews published in the past 5 years, but did not exclude commonly referenced and important older publications. We also searched the ClinicalTrials.gov database
New HorizonsOsteoporosis: now and the future
Introduction
Osteoporosis is an emerging medical and socioeconomic threat characterised by a systemic impairment of bone mass, strength, and microarchitecture, which increases the propensity of fragility fractures (figure 1).1 Bone-mineral density (BMD) can be assessed with dual x-ray absorptiometry (DXA), and osteoporosis is defined by a T score of less than 2·5, ie, more than 2·5 standard deviations below the average of a young adult. About 40% of white postmenopausal women are affected by osteoporosis and, with an ageing population, this number is expected to steadily increase in the near future.2, 3, 4 The lifetime fracture risk of a patient with osteoporosis is as high as 40%, and fractures most commonly occur in the spine, hip, or wrist (figure 1), but other bones such as the trochanter, humerus, or ribs can also be affected. From a patient's perspective, a fracture and the subsequent loss of mobility and autonomy often represent a major drop in quality of life. Additionally, osteoporotic fractures of the hip and spine carry a 12-month excess mortality of up to 20%, because they require hospitalisation and they have subsequently enhanced risk of other complications, such as pneumonia or thromboembolic disease due to chronic immobilisation (panel 1).5
A high index of suspicion is needed for early diagnosis of osteosporosis because elderly patients can concurrently have other comorbidities that receive more attention, such as cardiovascular diseases or cancer. Because bone loss occurs insidiously and is initially asymptomatic, osteoporosis is often only diagnosed after the first clinical fracture has occurred.6, 7 Consequently, the aim of therapy is usually prevention of further fractures. Early assessment of an individual's risk of osteoporosis is therefore important to prevent the first fracture. National and international guidelines have been implemented to address the challenge of screening for osteoporosis in an evidence-based and cost-effective manner.8, 9, 10 Several risk factors, such as age, low body-mass index, previous fragility fractures, a family history of fractures, the use of glucocorticoids, and active cigarette smoking have to be taken into account.11 The measurement of BMD by DXA is a valid method to diagnose osteoporosis and to predict the risk of fracture.12 New decision-making methods, such as the fracture-risk assessment tool (FRAX), have integrated clinical risk factors with DXA-based BMD to predict an individual's 10-year risk of sustaining a hip fracture as well as the 10-year probability of having a major osteoporotic fracture, defined as clinical spine, forearm, hip, or shoulder fracture.6 Panel 2 shows an example of how to use BMD and clinical risk factors within the FRAX model to guide decisions for osteoporosis treatment. Although the baseline characteristics of all three patients are similar with regards to body-mass index and BMD, their risk profiles and ensuing risk of having a fracture in the next 10 years varies greatly. This model underlines the importance of considering additional individual risk factors and comorbidities in osteoporosis management.
Although DXA is widely available and has been commonly used for clinical phase-3 studies, it has some limitations. As an area-based measure of bone mineral, DXA does not allow assessment of bone geometry, neither does it distinguish between cortical bone, the outer shell, and trabecular bone, the spongy inner part, which are important determinants of bone strength and loss at different rates. Advances in imaging techniques with high-resolution peripheral CT that yield volumetric bone-density data might allow better prediction of bone strength and thus fracture risk, if indices such as intracortical porosity are taken into account.13 Whether these novel techniques will be useful in daily practice remains to be seen.
Section snippets
Current therapies
In addition to lifestyle modifications (cessation of smoking, reduction of alcohol consumption, and increased physical activity), vitamin D and calcium supplementation is recommended as baseline treatment in every patient with osteoporosis. The efficacy of specific osteoporosis drugs has only been shown if these supplements were concurrently given. Use of vitamin D as a drug has had a renaissance because vitamin-D deficiency is highly prevalent and associated with various adverse extraskeletal
Recent developments in bone biology
In the past decade, the pathogenesis of osteoporosis has been linked to tissue, cellular, and molecular processes (figure 1). Master signals that integrate various endocrine, neuroendocrine, inflammatory, and mechanical stimuli have been defined. At the cellular level, communication and coupling between the main bone-cell types, the bone-forming osteoblasts and the bone-degrading osteoclasts, constitute the smallest functional unit (figure 1). Several key molecules coordinate activities of
Denosumab
The prominent role of RANKL in osteoclastogenesis has made it a prime target in diseases characterised by excessive bone loss (table 3). Initially, a chimeric OPG-Fc fusion protein was used to antagonise RANKL.52 However, the formation of neutralising antibodies against OPG after administration of the fusion protein, and its potential cross-reactivity with tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL),53 led to a new strategy; the development of denosumab, a fully human
Conclusion
With multiple novel antiosteoporotic compounds in advanced clinical trials, the number of available drugs will increase considerably in the coming years. Present antiresorptive treatments are effective, but some are limited by side-effects, concurrent comorbidities, and inadequate long-term compliance. Many of the new drugs combine efficacy with convenient administration that might translate into better adherence. However, conventional antiresorptives such as aminobisphosphonates and denosumab
Search strategy and criteria
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Cited by (2010)
Mitigation of inflammatory bowel disease-related osteoporosis by oxyberberine: Insights into the RANKL/NF-κB signaling pathway
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2024, Trends in Food Science and Technology