NIHR Oxford Musculoskeletal Biomedical Research Centre

UNLABELLED: This report describes the epidemiology, burden, and treatment of osteoporosis in the 27 countries of the European Union (EU27). INTRODUCTION: Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased risk of fragility fractures which represent the main clinical consequence of the disease. Fragility fractures are associated with substantial pain and suffering, disability and even death for affected patients and substantial costs to society. The aim of this report was to characterize the burden of osteoporosis in the EU27 in 2010 and beyond. METHODS: The literature on fracture incidence and costs of fractures in the EU27 was reviewed and incorporated into a model estimating the clinical and economic burden of osteoporotic fractures in 2010. RESULTS: Twenty-two million women and 5.5 million men were estimated to have osteoporosis; and 3.5 million new fragility fractures were sustained, comprising 610,000 hip fractures, 520,000 vertebral fractures, 560,000 forearm fractures and 1,800,000 other fractures (i.e. fractures of the pelvis, rib, humerus, tibia, fibula, clavicle, scapula, sternum and other femoral fractures). The economic burden of incident and prior fragility fractures was estimated at <euro> 37 billion. Incident fractures represented 66 % of this cost, long-term fracture care 29 % and pharmacological prevention 5 %. Previous and incident fractures also accounted for 1,180,000 quality-adjusted life years lost during 2010. The costs are expected to increase by 25 % in 2025. The majority of individuals who have sustained an osteoporosis-related fracture or who are at high risk of fracture are untreated and the number of patients on treatment is declining. CONCLUSIONS: In spite of the high social and economic cost of osteoporosis, a substantial treatment gap and projected increase of the economic burden driven by the aging populations, the use of pharmacological interventions to prevent fractures has decreased in recent years, suggesting that a change in healthcare policy is warranted.

Guidance is provided in a European setting on the assessment and treatment of postmenopausal women at risk from fractures due to osteoporosis. Introduction The International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis published guidance for the diagnosis and management of osteoporosis in 2013. This manuscript updates these in a European setting. Methods Systematic reviews were updated.

BACKGROUND: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. METHODS AND FINDINGS: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). CONCLUSIONS: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.

BACKGROUND: Sarcopenia is increasingly recognized as a correlate of ageing and is associated with increased likelihood of adverse outcomes including falls, fractures, frailty and mortality. Several tools have been recommended to assess muscle mass, muscle strength and physical performance in clinical trials. Whilst these tools have proven to be accurate and reliable in investigational settings, many are not easily applied to daily practice. METHODS: This paper is based on literature reviews performed by members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group on frailty and sarcopenia. Face-to-face meetings were afterwards organized for the whole group to make amendments and discuss further recommendations. RESULTS: This paper proposes some user-friendly and inexpensive methods that can be used to assess sarcopenia in real-life settings. Healthcare providers, particularly in primary care, should consider an assessment of sarcopenia in individuals at increased risk; suggested tools for assessing risk include the Red Flag Method, the SARC-F questionnaire, the SMI method or different prediction equations. Management of sarcopenia should primarily be patient centered and involve the combination of both resistance and endurance based activity programmes with or without dietary interventions. Development of a number of pharmacological interventions is also in progress. CONCLUSIONS: Assessment of sarcopenia in individuals with risk factors, symptoms and/or conditions exposing them to the risk of disability will become particularly important in the near future.

This report provides an overview and a comparison of the burden and management of fragility fractures in the largest five countries of the European Union plus Sweden (EU6). In 2017, new fragility fractures in the EU6 are estimated at 2.7 million with an associated annual cost of €37.5 billion and a loss of 1.0 million quality-adjusted life years. INTRODUCTION: Osteoporosis is characterized by reduced bone mass and strength, which increases the risk of fragility fractures, which in turn, represent the main consequence of the disease. This report provides an overview and a comparison of the burden and management of fragility fractures in the largest five EU countries and Sweden (designated the EU6). METHODS: A series of metrics describing the burden and management of fragility fractures were defined by a scientific steering committee. A working group performed the data collection and analysis. Data were collected from current literature, available retrospective data and public sources. Different methods were applied (e.g. standard statistics and health economic modelling), where appropriate, to perform the analysis for each metric. RESULTS: Total fragility fractures in the EU6 are estimated to increase from 2.7 million in 2017 to 3.3 million in 2030; a 23% increase. The resulting annual fracture-related costs (€37.5 billion in 2017) are expected to increase by 27%. An estimated 1.0 million quality-adjusted life years (QALYs) were lost in 2017 due to fragility fractures. The current disability-adjusted life years (DALYs) per 1000 individuals age 50 years or more were estimated at 21 years, which is higher than the estimates for stroke or chronic obstructive pulmonary disease. The treatment gap (percentage of eligible individuals not receiving treatment with osteoporosis drugs) in the EU6 is estimated to be 73% for women and 63% for men; an increase of 17% since 2010. If all patients who fracture in the EU6 were enrolled into fracture liaison services, at least 19,000 fractures every year might be avoided. CONCLUSIONS: Fracture-related burden is expected to increase over the coming decades. Given the substantial treatment gap and proven cost-effectiveness of fracture prevention schemes such as fracture liaison services, urgent action is needed to ensure that all individuals at high risk of fragility fracture are appropriately assessed and treated.

UNLABELLED: This report describes epidemiology, burden, and treatment of osteoporosis in each of the 27 countries of the European Union (EU27). INTRODUCTION: In 2010, 22 million women and 5.5 million men were estimated to have osteoporosis in the EU; and 3.5 million new fragility fractures were sustained, comprising 620,000 hip fractures, 520,000 vertebral fractures, 560,000 forearm fractures and 1,800,000 other fractures. The economic burden of incident and prior fragility fractures was estimated at € 37 billion. Previous and incident fractures also accounted for 1,180,000 quality-adjusted life years lost during 2010. The costs are expected to increase by 25 % in 2025. The majority of individuals who have sustained an osteoporosis-related fracture or who are at high risk of fracture are untreated and the number of patients on treatment is declining. The aim of this report was to characterize the burden of osteoporosis in each of the EU27 countries in 2010 and beyond. METHODS: The data on fracture incidence and costs of fractures in the EU27 were taken from a concurrent publication in this journal (Osteoporosis in the European Union: Medical Management, Epidemiology and Economic Burden) and country specific information extracted. RESULTS: The clinical and economic burden of osteoporotic fractures in 2010 is given for each of the 27 countries of the EU. The costs are expected to increase on average by 25 % in 2025. The majority of individuals who have sustained an osteoporosis-related fracture or who are at high risk of fracture are untreated and the number of patients on treatment is declining. CONCLUSIONS: In spite of the high cost of osteoporosis, a substantial treatment gap and projected increase of the economic burden driven by aging populations, the use of pharmacological prevention of osteoporosis has decreased in recent years, suggesting that a change in healthcare policy concerning the disease is warranted.

BACKGROUND: All proposed definitions of sarcopenia include the measurement of muscle mass, but the techniques and threshold values used vary. Indeed, the literature does not establish consensus on the best technique for measuring lean body mass. Thus, the objective measurement of sarcopenia is hampered by limitations intrinsic to assessment tools. The aim of this study was to review the methods to assess muscle mass and to reach consensus on the development of a reference standard. METHODS: Literature reviews were performed by members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis working group on frailty and sarcopenia. Face-to-face meetings were organized for the whole group to make amendments and discuss further recommendations. RESULTS: A wide range of techniques can be used to assess muscle mass. Cost, availability, and ease of use can determine whether the techniques are better suited to clinical practice or are more useful for research. No one technique subserves all requirements but dual energy X-ray absorptiometry could be considered as a reference standard (but not a gold standard) for measuring muscle lean body mass. CONCLUSIONS: Based on the feasibility, accuracy, safety, and low cost, dual energy X-ray absorptiometry can be considered as the reference standard for measuring muscle mass.

OBJECTIVES: The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) sought to revisit the 2014 algorithm recommendations for knee osteoarthritis (OA), in light of recent efficacy and safety evidence, in order to develop an updated stepwise algorithm that provides practical guidance for the prescribing physician that is applicable in Europe and internationally. METHODS: Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process, a summary of evidence document for each intervention in OA was provided to all members of an ESCEO working group, who were required to evaluate and vote on the strength of recommendation for each intervention. Based on the evidence collected, and on the strength of recommendations afforded by consensus of the working group, the final algorithm was constructed. RESULTS: An algorithm for management of knee OA comprising a stepwise approach and incorporating consensus on 15 treatment recommendations was prepared by the ESCEO working group. Both "strong" and "weak" recommendations were afforded to different interventions. The algorithm highlights the continued importance of non-pharmacological interventions throughout the management of OA. Benefits and limitations of different pharmacological treatments are explored in this article, with particular emphasis on safety issues highlighted by recent literature analyses. CONCLUSIONS: The updated ESCEO stepwise algorithm, developed by consensus from clinical experts in OA and informed by available evidence for the benefits and harms of various treatments, provides practical, current guidance that will enable clinicians to deliver patient-centric care in OA practice.

Therapeutic targets have been defined for axial and peripheral spondyloarthritis (SpA) in 2012, but the evidence for these recommendations was only of indirect nature. These recommendations were re-evaluated in light of new insights. Based on the results of a systematic literature review and expert opinion, a task force of rheumatologists, dermatologists, patients and a health professional developed an update of the 2012 recommendations. These underwent intensive discussions, on site voting and subsequent anonymous electronic voting on levels of agreement with each item. A set of 5 overarching principles and 11 recommendations were developed and voted on. Some items were present in the previous recommendations, while others were significantly changed or newly formulated. The 2017 task force arrived at a single set of recommendations for axial and peripheral SpA, including psoriatic arthritis (PsA). The most exhaustive discussions related to whether PsA should be assessed using unidimensional composite scores for its different domains or multidimensional scores that comprise multiple domains. This question was not resolved and constitutes an important research agenda. There was broad agreement, now better supported by data than in 2012, that remission/inactive disease and, alternatively, low/minimal disease activity are the principal targets for the treatment of PsA. As instruments to assess the patients on the path to the target, the Ankylosing Spondylitis Disease Activity Score (ASDAS) for axial SpA and the Disease Activity index for PSoriatic Arthritis (DAPSA) and Minimal Disease Activity (MDA) for PsA were recommended, although not supported by all. Shared decision-making between the clinician and the patient was seen as pivotal to the process. The task force defined the treatment target for SpA as remission or low disease activity and developed a large research agenda to further advance the field.

This systematic review summarizes the effect of combined exercise and nutrition intervention on muscle mass and muscle function. A total of 37 RCTs were identified. Results indicate that physical exercise has a positive impact on muscle mass and muscle function in subjects aged 65 years and older. However, any interactive effect of dietary supplementation appears to be limited. INTRODUCTION: In 2013, Denison et al. conducted a systematic review including 17 randomized controlled trials (RCTs) to explore the effect of combined exercise and nutrition intervention to improve muscle mass, muscle strength, or physical performance in older people. They concluded that further studies were needed to provide evidence upon which public health and clinical recommendations could be based. The purpose of the present work was to update the prior systematic review and include studies published up to October 2015. METHODS: Using the electronic databases MEDLINE and EMBASE, we identified RCTs which assessed the combined effect of exercise training and nutritional supplementation on muscle strength, muscle mass, or physical performance in subjects aged 60 years and over. Study selection and data extraction were performed by two independent reviewers. RESULTS: The search strategy identified 21 additional RCTs giving a total of 37 RCTs. Studies were heterogeneous in terms of protocols for physical exercise and dietary supplementation (proteins, essential amino acids, creatine, β-hydroxy-β-methylbuthyrate, vitamin D, multi-nutrients, or other). In 79% of the studies (27/34 RCTs), muscle mass increased with exercise but an additional effect of nutrition was only found in 8 RCTs (23.5%). Muscle strength increased in 82.8% of the studies (29/35 RCTs) following exercise intervention, and dietary supplementation showed additional benefits in only a small number of studies (8/35 RCTS, 22.8%). Finally, the majority of studies showed an increase of physical performance following exercise intervention (26/28 RCTs, 92.8%) but interaction with nutrition supplementation was only found in 14.3% of these studies (4/28 RCTs). CONCLUSION: Physical exercise has a positive impact on muscle mass and muscle function in healthy subjects aged 60 years and older. The biggest effect of exercise intervention, of any type, has been seen on physical performance (gait speed, chair rising test, balance, SPPB test, etc.). We observed huge variations in regard to the dietary supplementation protocols. Based on the included studies, mainly performed on well-nourished subjects, the interactive effect of dietary supplementation on muscle function appears limited.

OBJECTIVE: Studies of previous cohorts have demonstrated an association between a status of overweight/obesity and the presence of knee and hand osteoarthritis (OA). However, no data on the effect of these factors on the OA burden are available. The aim of the present study was to analyze the effect of being overweight or obese on the incidence of routinely diagnosed knee, hip, and hand OA. METHODS: The study was conducted in a population-based cohort using primary care records from the Sistema d'Informació per al Desenvolupament de l'Investigació en Atenció Primària database (>5.5 million subjects, covering >80% of the population of Catalonia, Spain). Participants were subjects ages ≥40 years who were without a diagnosis of OA on January 1, 2006 and had available body mass index (BMI) data. All subjects were followed up from January 1, 2006 to December 31, 2010 or to the time of loss to follow-up or death. Measures included the World Health Organization categories of BMI (exposure), and incident clinical diagnoses of knee, hip, or hand OA according to International Classification of Diseases, Tenth Revision codes. RESULTS: In total, 1,764,061 subjects were observed for a median follow-up period of 4.45 years (interquartile range 4.19-4.98 years). Incidence rates (per 1,000 person-years at risk) of knee, hip, and hand OA were 3.7 (99% confidence interval [99% CI] 3.6-3.8), 1.7 (99% CI 1.7-1.8), and 2.6 (99% CI 2.5-2.7), respectively, among subjects in the normal weight category, and 19.5 (99% CI 19.1-19.9), 3.8 (99% CI 3.7-4.0), and 4.0 (99% CI 3.9-4.2), respectively, in those with a classification of grade II obesity. Compared to subjects with normal weight, being overweight or obese increased the risk of OA at all 3 joint sites, especially at the knee. A status of overweight, grade I obesity, and grade II obesity increased the risk of knee OA by a factor of 2-fold, 3.1-fold, and 4.7-fold, respectively. CONCLUSION: Being overweight or obese increases the risk of hand, hip, and knee OA, with the greatest risk in the knee, and this occurs on a dose-response gradient of increasing BMI.

BACKGROUND: Despite treatment according to the current management recommendations, a significant proportion of patients with rheumatoid arthritis (RA) remain symptomatic. These patients can be considered to have 'difficult-to-treat RA'. However, uniform terminology and an appropriate definition are lacking. OBJECTIVE: Development of EULAR recommendations for the comprehensive management of difficult-to-treat rheumatoid arthritis" aims to create recommendations for this underserved patient group. Herein, we present the definition of difficult-to-treat RA, as the first step. METHODS: The Steering Committee drafted a definition with suggested terminology based on an international survey among rheumatologists. This was discussed and amended by the Task Force, including rheumatologists, nurses, health professionals and patients, at a face-to-face meeting until sufficient agreement was reached (assessed through voting). RESULTS: The following three criteria were agreed by all Task Force members as mandatory elements of the definition of difficult-to-treat RA: (1) Treatment according to European League Against Rheumatism (EULAR) recommendation and failure of ≥2 biological disease-modifying antirheumatic drugs (DMARDs)/targeted synthetic DMARDs (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated); (2) presence of at least one of the following: at least moderate disease activity; signs and/or symptoms suggestive of active disease; inability to taper glucocorticoid treatment; rapid radiographic progression; RA symptoms that are causing a reduction in quality of life; and (3) the management of signs and/or symptoms is perceived as problematic by the rheumatologist and/or the patient. CONCLUSIONS: The proposed EULAR definition for difficult-to-treat RA can be used in clinical practice, clinical trials and can form a basis for future research.

OBJECTIVES: Existing practice guidelines for osteoarthritis (OA) analyze the evidence behind each proposed treatment but do not prioritize the interventions in a given sequence. The objective was to develop a treatment algorithm recommendation that is easier to interpret for the prescribing physician based on the available evidence and that is applicable in Europe and internationally. The knee was used as the model OA joint. METHODS: ESCEO assembled a task force of 13 international experts (rheumatologists, clinical epidemiologists, and clinical scientists). Existing guidelines were reviewed; all interventions listed and recent evidence were retrieved using established databases. A first schematic flow chart with treatment prioritization was discussed in a 1-day meeting and shaped to the treatment algorithm. Fine-tuning occurred by electronic communication and three consultation rounds until consensus. RESULTS: Basic principles consist of the need for a combined pharmacological and non-pharmacological treatment with a core set of initial measures, including information access/education, weight loss if overweight, and an appropriate exercise program. Four multimodal steps are then established. Step 1 consists of background therapy, either non-pharmacological (referral to a physical therapist for re-alignment treatment if needed and sequential introduction of further physical interventions initially and at any time thereafter) or pharmacological. The latter consists of chronic Symptomatic Slow-Acting Drugs for OA (e.g., prescription glucosamine sulfate and/or chondroitin sulfate) with paracetamol at-need; topical NSAIDs are added in the still symptomatic patient. Step 2 consists of the advanced pharmacological management in the persistent symptomatic patient and is centered on the use of oral COX-2 selective or non-selective NSAIDs, chosen based on concomitant risk factors, with intra-articular corticosteroids or hyaluronate for further symptom relief if insufficient. In Step 3, the last pharmacological attempts before surgery are represented by weak opioids and other central analgesics. Finally, Step 4 consists of end-stage disease management and surgery, with classical opioids as a difficult-to-manage alternative when surgery is contraindicated. CONCLUSIONS: The proposed treatment algorithm may represent a new framework for the development of future guidelines for the management of OA, more easily accessible to physicians.

UNLABELLED: The International Osteoporosis Foundation (IOF) Capture the Fracture Campaign aims to support implementation of Fracture Liaison Services (FLS) throughout the world. INTRODUCTION: FLS have been shown to close the ubiquitous secondary fracture prevention care gap, ensuring that fragility fracture sufferers receive appropriate assessment and intervention to reduce future fracture risk. METHODS: Capture the Fracture has developed internationally endorsed standards for best practice, will facilitate change at the national level to drive adoption of FLS and increase awareness of the challenges and opportunities presented by secondary fracture prevention to key stakeholders. The Best Practice Framework (BPF) sets an international benchmark for FLS, which defines essential and aspirational elements of service delivery. RESULTS: The BPF has been reviewed by leading experts from many countries and subject to beta-testing to ensure that it is internationally relevant and fit-for-purpose. The BPF will also serve as a measurement tool for IOF to award 'Capture the Fracture Best Practice Recognition' to celebrate successful FLS worldwide and drive service development in areas of unmet need. The Capture the Fracture website will provide a suite of resources related to FLS and secondary fracture prevention, which will be updated as new materials become available. A mentoring programme will enable those in the early stages of development of FLS to learn from colleagues elsewhere that have achieved Best Practice Recognition. A grant programme is in development to aid clinical systems which require financial assistance to establish FLS in their localities. CONCLUSION: Nearly half a billion people will reach retirement age during the next 20 years. IOF has developed Capture the Fracture because this is the single most important thing that can be done to directly improve patient care, of both women and men, and reduce the spiralling fracture-related care costs worldwide.

It is well recognized that poor muscle function and poor physical performance are strong predictors of clinically relevant adverse events in older people. Given the large number of approaches to measure muscle function and physical performance, clinicians often struggle to choose a tool that is appropriate and validated for the population of older people they deal with. In this paper, an overview of different methods available and applicable in clinical settings is proposed. This paper is based on literature reviews performed by members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group on frailty and sarcopenia. Face-to-face meetings were organized afterwards where the whole group could amend and discuss the recommendations further. Several characteristics should be considered when choosing a tool: (1) purpose of the assessment (intervention, screening, diagnosis); (2) patient characteristics (population, settings, functional ability, etc.); (3) psychometric properties of the tool (test-retest reliability, inter-rater reliability, responsiveness, floor and ceiling effects, etc.); (4) applicability of the tool in clinical settings (overall cost, time required for the examination, level of training, equipment, patient acceptance, etc.); (5) prognostic reliability for relevant clinical outcomes. Based on these criteria and the available evidence, the expert group advises the use of grip strength to measure muscle strength and the use of 4-m gait speed or the Short Physical Performance Battery test to measure physical performance in daily practice. The tools proposed are relevant for the assessment of muscle weakness and physical performance. Subjects with low values should receive additional diagnostic workups to achieve a full diagnosis of the underlying condition responsible (sarcopenia, frailty or other).

The profound effects of the bisphosphonates on calcium metabolism were discovered over 30 years ago, and they are now well established as the major drugs used for the treatment of bone diseases associated with excessive resorption. Their principal uses are for Paget disease of bone, myeloma, bone metastases, and osteoporosis in adults, but there has been increasing and successful application in pediatric bone diseases, notably osteogenesis imperfecta. Bisphosphonates are structural analogues of inorganic pyrophosphate but are resistant to enzymatic and chemical breakdown. Bisphosphonates inhibit bone resorption by selective adsorption to mineral surfaces and subsequent internalization by bone-resorbing osteoclasts where they interfere with various biochemical processes. The simpler, non–nitrogen-containing bisphosphonates (eg, clodronate and etidronate) can be metabolically incorporated into nonhydrolysable analogues of adenosine triphosphate (ATP) that may inhibit ATP-dependent intracellular enzymes. In contrast, the more potent, nitrogen-containing bisphosphonates (eg, pamidronate, alendronate, risedronate, ibandronate, and zoledronate) inhibit a key enzyme, farnesyl pyrophosphate synthase, in the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small guanosine triphosphate (GTP)-binding proteins (which are also GTPases) such as Rab, Rho, and Rac. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity. The recently elucidated crystal structure of farnesyl diphosphate reveals how bisphosphonates bind to and inhibit at the active site via their critical nitrogen atoms. Although bisphosphonates are now established as an important class of drugs for the treatment of many bone diseases, there is new knowledge about how they work and the subtle but potentially important differences that exist between individual bisphosphonates. Understanding these may help to explain differences in potency, onset and duration of action, and clinical effectiveness.

IL-6, leukemia inhibitory factor (LIF), and oncostatin M (OSM) are IL-6-type cytokines that stimulate osteoclast formation and function. In the present study, the resorptive effects of these agents and their regulation of receptor activator of NF-kappaB ligand (RANKL), RANK, and osteoprotegerin (OPG) were studied in neonatal mouse calvaria. When tested separately, neither human (h) IL-6 nor the human soluble IL-6R (shIL-6R) stimulated bone resorption, but when hIL-6 and the shIL-6R were combined, significant stimulation of both mineral and matrix release from bone explants was noted. Semiquantitative RT-PCR showed that hIL-6 plus shIL-6R enhanced the expression of RANKL and OPG in calvarial bones, but decreased RANK expression. Human LIF, hOSM, and mouse OSM (mOSM) also stimulated 45Ca release and enhanced the mRNA expression of RANKL and OPG in mouse calvaria, but had no effect on the expression of RANK. In agreement with the RT-PCR analyses, ELISA measurements showed that both hIL-6 plus shIL-6R and mOSM increased RANKL and OPG proteins. 1,25-Dihydroxyvitamin D3 (D3) also increased the RANKL protein level, but decreased the protein level of OPG. OPG inhibited 45Ca release stimulated by RANKL, hIL-6 plus shIL-6R, hLIF, hOSM, mOSM, and D3. An Ab neutralizing mouse gp130 inhibited 45Ca release induced by hIL-6 plus shIL-6R. These experiments demonstrated stimulation of calvarial bone resorption and regulation of mRNA and protein expression of RANKL and OPG by D3 and IL-6 family cytokines as well as regulation of RANK expression in preosteoclasts/osteoclasts of mouse calvaria by D3 and hIL-6 plus shIL-6R.

A summation analysis of more than 70 individual kinematic studies involving normal knees and 33 different designs of total knee arthroplasty (TKA) was done with the objective of analyzing implant design variables that affect knee kinematics. Eight hundred eleven knees (733 subjects) were analyzed either during the stance phase of gait or a deep knee bend maneuver while under fluoroscopic surveillance. Fluoroscopic videotapes then were downloaded onto a workstation computer and anteroposterior (AP) femorotibial translational patterns were determined using an automated three-dimensional model fitting technique. The highest magnitude of translation was found in the normal and ACL-retaining TKA groups. Paradoxical anterior femoral translation during deep flexion was most commonly observed in PCL-retaining TKA. Substantial variability in kinematic patterns was observed in all groups. The least variability during gait was observed in mobile-bearing TKA designs, whereas posterior-stabilized TKA designs (fixed or mobile-bearing) showed the least variability during a deep knee bend. A medial pivot kinematic pattern was observed in only 55% of knees during deep knee flexion. Kinematic patterns of fixed versus mobile-bearing designs were similar with the exception of mobile-bearing TKA during gait in which femorotibial contact remained relatively stationary with minimal AP femorotibial translation.

AIMS: Preliminary studies have suggested that there is an increase in adipocytic tissue in osteoporotic (OP) bone, supporting in vitro evidence for a switch in differentiation of stromal cells from the osteoblastic to the adipocytic lineage. To investigate this the variation of the ratio of adipose tissue to haemopoietic/stromal tissue in OP bone was measured. METHODS: The ratio of adipocytic to haemopoietic/stromal tissue (A/H) was measured by semi-automated image analysis in iliac crest biopsies from 127 patients with osteoporosis (84 female patients, 48 male patients; mean age, 55 years; range, 5-80). Fourteen patients with normal histomorphometric data (nine women; five men; mean age, 48 years; range 21-70) acted as controls. RESULTS: The ratio of A/H was higher in OP bone than in the normal controls (OP mean 43.06% v normal mean 22.4%; p < 0.001). Multiple regression analysis showed that 98.5% of the variability in the A/H ratio was the result of age and several measures of bone formation, including cancellous wall thickness, osteoid volume, cancellous thickness, cortical wall thickness, cancellous apposition rate, and bone formation rate, together with cancellous separation (each significant at p < 0.001). Those with the greatest effect on the A/H ratio (in decreasing order) were cancellous apposition rate, osteoid volume, and age. CONCLUSIONS: Cancellous apposition rate, osteoid volume, and age were associated with the increase in the proportion of adipose tissue present in OP bone. Of these, cancellous apposition rate reflects osteoblast activity, indicating that the increase in the volume of adipose tissue in osteoporosis is associated with reduced bone formation, supporting the postulated switch in differentiation of stromal cells from the osteoblastic to the adipocytic pathway in osteoporosis.

The discovery and development of the bisphosphonates (BPs) as a major class of drugs for the treatment of bone diseases has been a fascinating journey that is still not over. In clinical medicine, several BPs are established as the treatments of choice for various diseases of excessive bone resorption, including Paget's disease of bone, myeloma and bone metastases, and osteoporosis. Bisphosphonates are chemically stable analogues of inorganic pyrophosphate, and are resistant to breakdown by enzymatic hydrolysis. Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of the bone-resorbing osteoclasts. Bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes. Bisphosphonates can be classified into at least two groups with different molecular modes of action. The simpler non-nitrogen-containing bisphosphonates (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolyzable analogues of adenosine triphosphate (ATP) that may inhibit ATP-dependent intracellular enzymes. The more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate, and zoledronate) are not metabolized in this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small GTP-binding proteins (which are also GTPases) such as rab, rho, and rac. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explain the loss of osteoclast activity and induction of apoptosis. The key target for bisphosphonates is farnesyl pyrophosphate synthase (FPPS) within osteoclasts, and the recently elucidated crystal structure of this enzyme reveals how BPs bind to and inhibit at the active site via their critical N atoms. In conclusion, bisphosphonates are now established as an important class of drugs for the treatment of many bone diseases, and their mode of action is being unraveled. As a result their full therapeutic potential is gradually being realized.