History of etidronate.

Etidronate is a non-nitrogen-containing bisphosphonate. Because it binds with calcium and inhibits crystal formation and dissolution, it was considered by Procter & Gamble as an additive to toothpaste (to prevent build-up of tartar) and detergent (to bind calcium and increase sudsing in "hard" water). The first clinical use (1968) was for fibrodysplasia ossificans progressiva. The first approved clinical use (1977) was for treatment of Paget's disease of bone. Other approved indications are hypercalcemia of malignancy and heterotopic ossification, with a host of off-label uses (including fibrous dysplasia, periodontal disease, multiple myeloma, neuropathic arthropathy, pulmonary microlithiasis, diabetic retinopathy, bone metastases, melorheostosis, urinary stone disease, periodontal disease, etc.). Unique among bisphosphonates, etidronate (oral therapy) results in hyperphosphatemia, increased tubular reabsorption of phosphorus and increased levels of 1,25-dihydroxyvitamin D. The dose that reduces bone resorption is close to the dose that impairs mineralization; prolonged high-dose use can result in osteomalacia and bone fractures. Intermittent cyclic etidronate for osteoporosis resulted in favorable changes in bone density and histomorphometry (no mineralization defect) as well as a decrease in vertebral fracture rates in postmenopausal women with osteoporosis. Later studies showed similar effects in men with osteoporosis and patients with glucocorticoid-induced osteoporosis. Although its use for osteoporosis has given way to newer bisphosphonates and other agents, because of its unique properties, it remains the bisphosphonate of choice for treatment of heterotopic ossification.

Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial.

OBJECTIVE: To evaluate the efficacy of denosumab in suppressing joint destruction when added to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy in patients with rheumatoid arthritis (RA). METHODS: This was a multi-centre, randomised, double-blind, parallel-group, placebo-controlled phase 3 study in Japan. Patients with RA aged ≥20 years receiving csDMARDs were randomly assigned (1:1:1) to denosumab 60 mg every 3 months (Q3M), denosumab 60 mg every 6 months (Q6M) or placebo. The change in the modified total Sharp score (mTSS) and effect on bone mineral density (BMD) at 12 months was evaluated. RESULTS: In total, 654 patients received the trial drugs. Denosumab groups showed significantly less progression of joint destruction. The mean changes in the mTSS at 12 months were 1.49 (95% CI 0.99 to 1.99) in the placebo group, 0.99 (95% CI 0.49 to 1.49) in the Q6M group (p=0.0235) and 0.72 (95% CI 0.41 to 1.03) in the Q3M group (p=0.0055). The mean changes in bone erosion score were 0.98 (95% CI 0.65 to 1.31) in the placebo group, 0.51 (95% CI 0.22 to 0.80) in the Q6M group (p=0.0104) and 0.22 (95% CI 0.09 to 0.34) in the Q3M group (p=0.0001). No significant between-group difference was observed in the joint space narrowing score. The per cent change in lumbar spine (L1-L4) BMD in the placebo, Q6M and Q3M groups were -1.03%, 3.99% (p<0.0001) and 4.88% (p<0.0001). No major differences were observed among safety profiles. CONCLUSIONS: Denosumab inhibits the progression of joint destruction, increases BMD and is well tolerated in patients with RA taking csDMARD.

Development and Reliability of the OMERACT Thumb Base Osteoarthritis Magnetic Resonance Imaging Scoring System.

OBJECTIVE: To develop the Outcome Measures in Rheumatology (OMERACT) thumb base osteoarthritis (OA) magnetic resonance imaging (MRI) scoring system (TOMS) for the assessment of inflammatory and structural abnormalities in this hand OA subset, and test its cross-sectional reliability. METHODS: Included features and their scaling were agreed upon by members of the OMERACT MRI Task Force using the Hand OA MRI scoring system as a template. A reliability exercise was performed in which 3 readers participated, using a preliminary atlas with examples to facilitate reading. Each reader independently scored a set of 20 MRI (coronal and axial T1- and T2-weighted fat-suppressed images, of which 5 included T1-weighted fat-suppressed post-Gadolinium images). Intra- and inter-reader reliability were assessed using ICC, percentage exact agreement (PEA), and percentage close agreement (PCA). RESULTS: The TOMS assessed the first carpometacarpal (CMC-1) and scaphotrapeziotrapezoid (STT) joints for synovitis, subchondral bone defects (including erosions, cysts, and bone attrition), osteophytes, cartilage, and bone marrow lesions on a 0-3 scale (normal to severe). Subluxation was evaluated only in the CMC-1 joint (absent/present). Reliability of scoring for both joints was comparable. Interreader ICC were good for all features (0.77-0.99 and 0.74-0.96 for CMC-1 and STT joints, respectively). Intrareader reliability analyses gave similar results. PCA was ≥ 65% for all features. PEA was low to moderate, with better performance for subchondral bone defects, subluxation, and bone marrow lesions. CONCLUSION: A thumb base OA MRI scoring system has been developed. The OMERACT TOMS demonstrated good intrareader and interreader reliability. Longitudinal studies are warranted to investigate reliability of change scores and responsiveness.

The Longitudinal Reliability and Responsiveness of the OMERACT Hand Osteoarthritis Magnetic Resonance Imaging Scoring System (HOAMRIS).

OBJECTIVE: To evaluate the interreader reliability of change scores and the responsiveness of the OMERACT Hand Osteoarthritis (OA) Magnetic Resonance Image (MRI) Scoring System (HOAMRIS). METHODS: Paired MRI (baseline and 5-yr followup) from 20 patients with hand OA were scored with known time sequence by 3 readers according to the HOAMRIS: Synovitis, erosive damage, cysts, osteophytes, cartilage space loss, malalignment, and bone marrow lesions (BML; 0-3 scales with 0.5 increments for synovitis, erosive damage, and BML). Interreader reliability for status and change scores were assessed by intraclass correlation coefficients (ICC), percentage exact agreement and percentage close agreement (PEA/PCA), and smallest detectable change (SDC). Responsiveness was assessed by standardized response means (SRM). RESULTS: Cross-sectional interreader ICC were good to very good (≥ 0.74) for all features except synovitis, cysts, and malalignment (ICC 0.50-0.58). The range of change values was small, leading to low ICC for change scores. The SDC values for sum scores (total range 0-24) varied between 1.97-3.05 (except 1.08 for malalignment). For status scores, PEA/PCA on scores in individual joints across the readers were 8.1-50.0 and 43.8-78.1, respectively. Similarly, PEA/PCA for change scores were 20.6-63.8 and 66.3-93.1, respectively. All features except cysts and BML demonstrated good responsiveness with higher SRM for sum scores (range 0.46-1.62) than for scores in individual joints (range 0.24-0.73). CONCLUSION: Good to very good interreader ICC values were found for cross-sectional readings, whereas the longitudinal reliability was lower because of a smaller range of change scores. All features, except cysts and BML, showed good responsiveness.

The OMERACT MRI in Arthritis Working Group - Update on Status and Future Research Priorities.

OBJECTIVE: To provide an update on the status and future research priorities of the Outcome Measures in Rheumatology (OMERACT) magnetic resonance imaging (MRI) in arthritis working group. METHODS: A summary is provided of the activities of the group within rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA), and its research priorities. RESULTS: The OMERACT RA MRI score (RAMRIS) evaluating bone erosion, bone edema (osteitis), and synovitis is now the standard method of quantifying articular pathology in RA trials. Cartilage loss is another important part of joint damage, and at the OMERACT 12 conference, we provided longitudinal data demonstrating reliability and sensitivity to change of the RAMRIS JSN component score, supporting its use in future clinical trials. The MRI group has previously developed a PsA MRI score (PsAMRIS). At OMERACT 12, PsAMRIS was evaluated in a randomized placebo-controlled trial of patients with PsA, demonstrating the responsiveness and discriminatory ability of applying the PsAMRIS to hands and feet. A hand OA MRI score (HOAMRIS) was introduced at OMERACT 11, and has subsequently been further validated. At OMERACT 12, good cross-sectional interreader reliability, but variable reliability of change scores, were reported. Potential future research areas were identified at the MRI session at OMERACT 12 including assessment of tenosynovitis in RA and enthesitis in PsA and focusing on alternative MRI techniques. CONCLUSION: MRI has been further developed and validated as an outcome measure in RA, PsA, and OA. The group will continue its efforts to optimize the value of MRI as a robust biomarker in rheumatology clinical trials.

Reduced Bone Density and Vertebral Fractures in Smokers. Men and COPD Patients at Increased Risk.

RATIONALE: Former smoking history and chronic obstructive pulmonary disease (COPD) are potential risk factors for osteoporosis and fractures. Under existing guidelines for osteoporosis screening, women are included but men are not, and only current smoking is considered. OBJECTIVES: To demonstrate the impact of COPD and smoking history on the risk of osteoporosis and vertebral fracture in men and women. METHODS: Characteristics of participants with low volumetric bone mineral density (vBMD) were identified and related to COPD and other risk factors. We tested associations of sex and COPD with both vBMD and fractures adjusting for age, race, body mass index (BMI), smoking, and glucocorticoid use. MEASUREMENTS AND MAIN RESULTS: vBMD by calibrated quantitative computed tomography (QCT), visually scored vertebral fractures, and severity of lung disease were determined from chest CT scans of 3,321 current and ex-smokers in the COPDGene study. Low vBMD as a surrogate for osteoporosis was calculated from young adult normal values. Male smokers had a small but significantly greater risk of low vBMD (2.5 SD below young adult mean by calibrated QCT) and more fractures than female smokers. Low vBMD was present in 58% of all subjects, was more frequent in those with worse COPD, and rose to 84% among subjects with very severe COPD. Vertebral fractures were present in 37% of all subjects and were associated with lower vBMD at each Global Initiative for Chronic Obstructive Lung Disease stage of severity. Vertebral fractures were most common in the midthoracic region. COPD and especially emphysema were associated with both low vBMD and vertebral fractures after adjustment for steroid use, age, pack-years of smoking, current smoking, and exacerbations. Airway disease was associated with higher bone density after adjustment for other variables. Calibrated QCT identified more subjects with abnormal values than the standard dual-energy X-ray absorptiometry in a subset of subjects and correlated well with prevalent fractures. CONCLUSIONS: Male smokers, with or without COPD, have a significant risk of low vBMD and vertebral fractures. COPD was associated with low vBMD after adjusting for race, sex, BMI, smoking, steroid use, exacerbations, and age. Screening for low vBMD by using QCT in men and women who are smokers will increase opportunities to identify and treat osteoporosis in this at-risk population.

Longterm safety, efficacy, and inhibition of structural damage progression over 5 years of treatment with abatacept in patients with rheumatoid arthritis in the abatacept in inadequate responders to methotrexate trial.

OBJECTIVE: Evaluate the safety and efficacy of longterm abatacept (ABA) treatment over 5 years in methotrexate (MTX)-refractory patients with rheumatoid arthritis (RA). METHODS: Patients from the 1-year, double-blind Abatacept in Inadequate Responders to Methotrexate (AIM) study (NCT00048568) received open-label ABA (∼10 mg/kg) in the longterm extension (LTE). Safety was assessed for patients who received ≥ 1 ABA dose, and efficacy for patients randomized to ABA and treated in the LTE. Radiographs were evaluated for changes in Genant-modified Sharp scores. RESULTS: Out of 652 patients, 539 entered the LTE (ABA, n = 378; placebo, n = 161). At Year 5, 72.4% were ongoing; discontinuation rates declined over time. Incidence rates of serious adverse events, serious infections, malignancies, and autoimmune events were 13.87, 2.84, 1.45, and 0.99 events/100 patient-years exposure, respectively. American College of Rheumatology 20 response was 82.3% (n = 373) and 83.6% (n = 268) at years 1 and 5, respectively. Disease Activity Score 28 C-reactive protein (DAS28-CRP) < 2.6 and ≤ 3.2 were achieved by 25.4% and 44.1% of patients at Year 1 (n = 370), and 33.7% and 54.7% at Year 5 (n = 267), respectively. Mean changes in DAS28-CRP and Health Assessment Questionnaire-Disability Index at Year 1 [-2.83 (n = 365) and -0.68 (n = 369)] were maintained at Year 5 [-3.14 (n = 264) and -0.77 (n = 271)] for patients continuing treatment. Of them, 59.5% (n = 291) and 45.1% (n = 235) remained free from radiographic progression at years 1 and 5, respectively. CONCLUSION: In MTX-refractory patients with RA, longterm ABA treatment was well tolerated and provided consistent safety and sustained efficacy, with high patient retention. Radiographic progression continued to be inhibited with ongoing treatment.

MRI of bone marrow abnormalities in hematological malignancies.

Magnetic resonance imaging (MRI) is essential for evaluating bone marrow. Bone marrow undergoes constant modification and its appearance on MRI changes in response. Knowledge of the types of changes and their origins is essential for analysis of MRI findings of bone marrow infiltration with hematological malignancies. This pictorial review describes the MRI pulse sequences used for imaging of bone marrow, and illustrates bone marrow changes due hematological malignancies, including changes following treatment.

Update on research and future directions of the OMERACT MRI inflammatory arthritis group.

The OMERACT Magnetic Resonance Imaging (MRI) Task Force has developed and evolved the psoriatic arthritis MRI score (PsAMRIS) over the last few years, and at OMERACT 10, presented longitudinal evaluation by multiple readers, using PsA datasets obtained from extremity MRI magnets. Further evaluation of this score will require more PsA imaging datasets. As well, due to improved image resolution since the development of the original rheumatoid arthritis MRI scoring system (RAMRIS), the Task Force has worked on semiquantitative assessment of joint space narrowing, and developed a reliable method as a potential RAMRIS addendum, although responsiveness will need to be evaluated. One of the strengths of MRI is the ability to detect subclinical synovitis, so the group worked on obtaining low disease activity/clinical remission datasets from a number of international centers and presented cross-sectional findings. Subsequent longitudinal evaluation of this unique resource will be a major continuing focus for the group.

Long-term safety, efficacy and inhibition of radiographic progression with abatacept treatment in patients with rheumatoid arthritis and an inadequate response to methotrexate: 3-year results from the AIM trial.

OBJECTIVE: To evaluate abatacept treatment over 3 years in patients with rheumatoid arthritis (RA) refractory to methotrexate (MTX). METHODS: Patients randomised to abatacept or placebo (+MTX) during the 1-year double-blind period of the Abatacept in Inadequate responders to Methotrexate (AIM) trial received open-label abatacept (+MTX) in the long-term extension (LTE). Safety was assessed for patients who received ≥ 1 dose of abatacept, regardless of randomisation group. Efficacy was assessed for patients randomised to abatacept who entered the LTE. RESULTS: 433 and 219 patients were randomised and treated with abatacept or placebo, respectively; 378 and 161 entered the LTE. At year 3, 440/539 patients were ongoing. No unexpected safety events were observed in the LTE. By year 3, incidence rates of adverse event and serious adverse events were 249.8/100 and 15.1/100 patient-years, respectively. Incidence rates were generally stable over time. At year 3, 84.8%, 63.4% and 37.5% of patients achieved American College of Rheumatology (ACR) criteria of 20, 50 and 70, respectively, compared with 82.3%, 54.3% and 32.4% of patients at year 1. Mean changes in Genant-modified Sharp scores were reduced progressively over 3 years, with significantly greater inhibition during year 3 compared with year 2 (p=0.022 for total score). CONCLUSION: In MTX-inadequate responders with RA, abatacept provided consistent safety and sustained efficacy over 3 years. The data suggest an increasing inhibitory disease-modifying effect on radiographic progression.

Bazedoxifene: a new selective estrogen receptor modulator for postmenopausal osteoporosis.

An ongoing need for safe and effective pharmacological therapies exists for postmenopausal osteoporosis, which imposes a significant burden on both women and the health-care system. Bazedoxifene is a novel selective estrogen receptor modulator with a unique tissue-selectivity profile. In phase 3 clinical trials of nearly 10,000 postmenopausal women, bazedoxifene was shown to significantly reduce the risk of new vertebral fracture versus placebo, with favourable effects on bone mineral density, bone turnover markers and the lipid profile. Moreover, in a subgroup of women at increased risk of fracture, bazedoxifene significantly decreased non-vertebral fracture risk versus both placebo and raloxifene. Bazedoxifene has been shown to be safe and well tolerated, with no evidence of endometrial or breast stimulation. These data suggest that bazedoxifene may offer significant clinical benefit for postmenopausal women with or at risk of developing osteoporosis, which may subsequently lessen the medical and economic burden of this disease.

Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures.

Animal experiments show a dramatic improvement in skeletal repair by teriparatide. We tested the hypothesis that recombinant teriparatide, at the 20 microg dose normally used for osteoporosis treatment or higher, would accelerate fracture repair in humans. Postmenopausal women (45 to 85 years of age) who had sustained a dorsally angulated distal radial fracture in need of closed reduction but no surgery were randomly assigned to 8 weeks of once-daily injections of placebo (n = 34) or teriparatide 20 microg (n = 34) or teriparatide 40 microg (n = 34) within 10 days of fracture. Hypotheses were tested sequentially, beginning with the teriparatide 40 microg versus placebo comparison, using a gatekeeping strategy. The estimated median time from fracture to first radiographic evidence of complete cortical bridging in three of four cortices was 9.1, 7.4, and 8.8 weeks for placebo and teriparatide 20 microg and 40 microg, respectively (overall p = .015). There was no significant difference between the teriparatide 40 microg versus placebo groups (p = .523). In post hoc analyses, there was no significant difference between teriparatide 40 microg versus 20 microg (p = .053); however, the time to healing was shorter in teriparatide 20 microg than placebo (p = .006). The primary hypothesis that teriparatide 40 microg would shorten the time to cortical bridging was not supported. The shortened time to healing for teriparatide 20 microg compared with placebo still may suggest that fracture repair can be accelerated by teriparatide, but this result should be interpreted with caution and warrants further study.

Occupation-related squatting, kneeling, and heavy lifting and the knee joint: a magnetic resonance imaging-based study in men.

OBJECTIVE: We examined the relation between occupational exposures to frequent squatting/kneeling and/or heavy lifting with cartilage morphology, based on magnetic resonance imaging (MRI), at the tibiofemoral and patellofemoral joints in men and determined which compartments are most affected. METHODS: We evaluated 192 men with symptomatic knee osteoarthritis (OA). The more symptomatic knee was imaged using MRI. Cartilage was scored using the Whole Organ MRI Score semiquantitative method at the medial and lateral tibiofemoral joint and patellofemoral joint. Occupational exposures to frequent squatting, kneeling, and/or heavy lifting were assessed using a validated questionnaire. RESULTS: Among the 192 men [mean (+/- standard deviation) age 69 +/- 9 yrs, body mass index (BMI) 30.8 +/- 4.7 kg/m(2)], those reporting occupational exposure to squatting/kneeling alone, heavy lifting alone, both squatting/kneeling and heavy lifting, or none of these activities numbered 7, 40, 47, and 98, respectively. Compared with men with no occupational exposure to these activities, and following adjustment for age, BMI, and history of knee injury or surgery, we found that men reporting occupational exposures to both squatting/kneeling and heavy lifting had a modest increased risk for worse cartilage morphology scores at the patellofemoral joint [odds ratio (OR) 1.8, 95% confidence interval (CI) 1.1 to 3.2] and medial tibiofemoral joint (OR 1.6, 95% CI 0.9, 3.0), although the latter did not reach statistical significance. CONCLUSION: Men with frequent occupational squatting/kneeling and heavy lifting have a greater likelihood for worse cartilage morphology scores at the patellofemoral joint. These findings add support to the important role of biomechanical loading on the pathogenesis of knee OA, particularly patellofemoral OA.

Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial.

In this 3-yr, randomized, double-blind, placebo- and active-controlled study, healthy postmenopausal women with osteoporosis (55-85 yr of age) were treated with bazedoxifene 20 or 40 mg/d, raloxifene 60 mg/d, or placebo. The primary endpoint was incidence of new vertebral fractures after 36 mo; secondary endpoints included nonvertebral fractures, BMD, and bone turnover markers. Among 6847 subjects in the intent-to-treat population, the incidence of new vertebral fractures was significantly lower (p < 0.05) with bazedoxifene 20 mg (2.3%), bazedoxifene 40 mg (2.5%), and raloxifene 60 mg (2.3%) compared with placebo (4.1%), with relative risk reductions of 42%, 37%, and 42%, respectively. The treatment effect was similar among subjects with or without prevalent vertebral fracture (p = 0.89 for treatment by baseline fracture status interaction). The incidence of nonvertebral fractures with bazedoxifene or raloxifene was not significantly different from placebo. In a posthoc analysis of a subgroup of women at higher fracture risk (femoral neck T-score or=1 moderate or severe vertebral fracture or multiple mild vertebral fractures; n = 1772), bazedoxifene 20 mg showed a 50% and 44% reduction in nonvertebral fracture risk relative to placebo (p = 0.02) and raloxifene 60 mg (p = 0.05), respectively. Bazedoxifene significantly improved BMD and reduced bone marker levels (p < 0.001 versus placebo). The incidence of vasodilatation, leg cramps, and venous thromboembolic events was higher with bazedoxifene and raloxifene compared with placebo. In conclusion, bazedoxifene significantly reduced the risk of new vertebral fracture in postmenopausal women with osteoporosis and decreased the risk of nonvertebral fracture in subjects at higher fracture risk.

Advanced imaging of bone macrostructure and microstructure in bone fragility and fracture repair.

Research into the molecular and cellular pathways focusing on bone fragility and fracture-healing has led to new potential treatments to aid in fracture-healing. This research has focused on physical as well as biological modes of treatment. As new products and methods are derived, it is essential to develop effective and sensitive noninvasive means by which early changes in the fracture repair process can be detected. Specialized noninvasive and/or nondestructive techniques can provide structural information about local and systemic skeletal health, the propensity to fracture, and the pathophysiology of bone fragility. The methods available to quantitatively assess macrostructure include computed tomography and, particularly, volumetric quantitative computed tomography. Methods for assessing microstructure of trabecular bone include high-resolution computed tomography, microquantitative computed tomography, high-resolution magnetic resonance imaging, and micromagnetic resonance imaging. These new techniques help to illustrate the process of fracture-healing by defining the skeletal response to innovative therapies and assessing biomechanical relationships. This review presents perspectives on the advanced imaging modalities that are currently available and on recent developments that may improve the detection and understanding of bone fragility and fracture-healing.

Histomorphometric and microCT analysis of bone biopsies from postmenopausal osteoporotic women treated with strontium ranelate.

UNLABELLED: Strontium ranelate is a new anti-osteoporotic treatment. On bone biopsies collected from humans receiving long-term treatment over 5 yr, it has been shown that strontium ranelate has good bone safety and better results than placebo on 3D microarchitecture. Hence, these effects may explain the decreased fracture rate. INTRODUCTION: Strontium ranelate's mode of action involving dissociation of bone formation and resorption was shown in preclinical studies and could explain its antifracture efficacy in humans. MATERIALS AND METHODS: One hundred forty-one transiliac bone biopsies were obtained from 133 postmenopausal osteoporotic women: 49 biopsies after 1-5 yr of 2 g/d strontium ranelate and 92 biopsies at baseline or after 1-5 yr of placebo. RESULTS AND CONCLUSIONS: Histomorphometry provided a 2D demonstration of the bone safety of strontium ranelate, with significantly higher mineral apposition rate (MAR) in cancellous bone (+9% versus control, p = 0.019) and borderline higher in cortical bone (+10%, p = 0.056). Osteoblast surfaces were significantly higher (+38% versus control, p = 0.047). 3D analysis of 3-yr biopsies with treatment (20 biopsies) and placebo (21 biopsies) using microCT showed significant changes in microarchitecture with, in the strontium ranelate group, higher cortical thickness (+18%, p = 0.008) and trabecular number (+14%, p = 0.05), and lower structure model index (-22%, p = 0.01) and trabecular separation (-16%, p = 0.04), with no change in cortical porosity. The changes in 3D microarchitecture may enhance bone biomechanical competence and explain the decreased fracture rate with strontium ranelate.

A selective p38 alpha mitogen-activated protein kinase inhibitor reverses cartilage and bone destruction in mice with collagen-induced arthritis.

Destruction of cartilage and bone is a poorly managed hallmark of human rheumatoid arthritis (RA). p38 Mitogen-activated protein kinase (MAPK) has been shown to regulate key proinflammatory pathways in RA, including tumor necrosis factor alpha, interleukin (IL)-1beta, and cyclooxygenase-2, as well as the process of osteoclast differentiation. Therefore, we evaluated whether a p38alpha MAPK inhibitor, indole-5-carboxamide (SD-282), could modulate cartilage and bone destruction in a mouse model of RA induced with bovine type II collagen [collagen-induced arthritis (CIA)]. In mice with early disease, SD-282 treatment significantly improved clinical severity scores, reduced bone and cartilage loss, and reduced mRNA levels of proinflammatory genes in paw tissue, including IL-1beta, IL-6, and cyclooxygenase-2. Notably, SD-282 treatment of mice with advanced disease resulted in significant improvement in clinical severity scoring and paw swelling, a reversal in bone and cartilage destruction as assessed by histology, bone volume fraction and thickness, and three-dimensional image analysis. These changes were accompanied by reduced osteoclast number and lowered levels of serum cartilage oligomeric matrix protein, a marker of cartilage breakdown. Thus, in a model of experimental arthritis associated with significant osteolysis, p38alpha MAPK inhibition not only attenuates disease progression but also reverses cartilage and bone destruction in mice with advanced CIA disease.

Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34.

Mice heterozygous for targeted disruption of Pthrp exhibit, by 3 months of age, diminished bone volume and skeletal microarchitectural changes indicative of advanced osteoporosis. Impaired bone formation arising from decreased BM precursor cell recruitment and increased apoptotic death of osteoblastic cells was identified as the underlying mechanism for low bone mass. The osteoporotic phenotype was recapitulated in mice with osteoblast-specific targeted disruption of Pthrp, generated using Cre-LoxP technology, and defective bone formation was reaffirmed as the underlying etiology. Daily administration of the 1-34 amino-terminal fragment of parathyroid hormone (PTH 1-34) to Pthrp+/- mice resulted in profound improvement in all parameters of skeletal microarchitecture, surpassing the improvement observed in treated WT littermates. These findings establish a pivotal role for osteoblast-derived PTH-related protein (PTHrP) as a potent endogenous bone anabolic factor that potentiates bone formation by altering osteoblast recruitment and survival and whose level of expression in the bone microenvironment influences the therapeutic efficacy of exogenous PTH 1-34.

Bone marrow lesions in the knee are associated with increased local bone density.

OBJECTIVE: Bone marrow lesions are associated with pain and compartment-specific progression of joint space narrowing in patients with knee osteoarthritis (OA). Bone marrow lesions occur in regions under increased loading, and excess loading produces increased bone mineral density (BMD). The ratio of BMD in the medial tibial plateau compared with that in the lateral tibial plateau (M:L BMD ratio) reflects loading in the knee. Therefore, we hypothesized that a higher M:L BMD ratio would be associated with medial bone marrow lesions, and that lower ratios would be associated with lateral bone marrow lesions. METHODS: Participants in the Framingham Osteoarthritis Study underwent magnetic resonance imaging (MRI), measurement of bone mineral density (BMD), and knee radiography between 2002 and 2004. MRI was used to define medial and lateral bone marrow lesions in the medial and lateral tibiofemoral compartments, respectively. We performed a logistic regression analysis with medial bone marrow lesions as the outcome, testing M:L BMD ratio groups as predictor variables. We adjusted for age, sex, body mass index, and systemic BMD, using generalized estimating equations to adjust for correlations between knees. An identical analysis evaluating lateral bone marrow lesions was performed. RESULTS: Medial bone marrow lesions were strongly associated with a high M:L BMD ratio. The odds ratios (ORs) for prevalent medial bone marrow lesions, for the lowest to the highest quartile of M:L BMD ratios, were 1.0 (referent), 1.3, 5.0, and infinity (P for trend < 0.0001). Lateral bone marrow lesions were strongly associated with low M:L BMD ratios (the ORs for prevalent lateral bone marrow lesions, for the highest to the lowest quartile, were 1.0 [referent], 3.0, 26.8, and 54.0 [P for trend < 0.0001]). CONCLUSION: Medial bone marrow lesions occur in knees with relatively higher local medial tibial bone density, and lateral bone marrow lesions occur in knees with relatively higher lateral tibial bone density, supporting the hypothesis that local BMD reflects loading within the knee. Our findings emphasize the importance of loading in the pathophysiology of OA.

The effects of teriparatide on the incidence of back pain in postmenopausal women with osteoporosis.

OBJECTIVES: Back pain is a major cause of suffering, disability, and cost. The risk of developing back pain was assessed following treatment with teriparatide [rh(PTH 1-34)] in postmenopausal women with osteoporosis. RESEARCH DESIGN AND METHODS: A secondary analysis of back pain findings from the global, multi-site Fracture Prevention Trial was conducted where postmenopausal women with prevalent vertebral fractures were administered teriparatide 20 microg (n = 541) or placebo (n = 544) for a median of 19 months. Treatment-emergent back pain data were collected during adverse event monitoring, and spine radiographs were obtained at baseline and study endpoint. MAIN OUTCOME MEASURES: The risk of back pain stratified by severity of new or worsening back pain and the risk of back pain associated with both number and severity of new vertebral fractures. RESULTS: Women randomized to teriparatide 20 microg had a 31% reduced relative risk of moderate or severe back pain (16.5% vs. 11.5%, P = 0.016) and a 57% reduced risk of severe back pain (5.2% vs. 2.2%, P = 0.011). Compared with placebo, teriparatide-treated patients experienced reduced relative risk of developing back pain associated with findings of: one or more new vertebral fractures by 83% (6.5% vs. 1.1%, P < 0.001), two or more new vertebral fractures by 91% (2.5% vs. 0.20%, P = 0.004), and one or more new moderate or severe vertebral fractures by 100% (5.1% vs. 0.0%, P < 0.001). CONCLUSIONS: Teriparatide-treated women had reduced risk for moderate or severe back pain, severe back pain, and back pain associated with vertebral fractures. The mechanism of the back pain reduction likely includes the reduction both in severity and number of new vertebral fractures.