Johan Halse

Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis: Results from 394 patients in the Oslo County rheumatoid arthritis register

OBJECTIVE To examine the bone mineral density (BMD), frequency of osteoporosis, and risk factors for BMD reduction in a representative population of female rheumatoid arthritis (RA) patients ages 20-70 years. METHODS BMD in the femoral neck, total hip, and spine L2-4 (anterior-posterior view) was measured in 394 RA patients recruited from a validated county RA register (completeness 85%) comprising 721 women ages 20-70 years. BMD was measured with dual-energy x-ray absorptiometry, and age-specific values were compared with pooled values from a European/US population of healthy subjects free from earlier fractures, chronic diseases, and medications influencing bone metabolism. A multiple linear regression model was used to determine individual predictors of BMD. RESULTS No statistically significant differences were found in demographic, disease activity, disease severity, or health status parameters between the RA register patients in whom BMD was measured and the remaining register patients. Femoral neck BMD was significantly reduced by 4.2% in the age group 50-59 years, and by 5.0% in those ages 60-70 years. For BMD in the total hip, the significant reductions were 3.7%, 6.0%, and 8.5% in the age groups 40-49 years, 50-59 years, and 60-70 years, respectively. No significant reduction in spine L2-4 BMD was found. A 2-fold increased frequency of osteoporosis was observed in all 4 age groups of RA patients compared with the reference population, ranging from 0% to 28.6% in the femoral neck, 0% to 29.9% in the total hip, and 1.8% to 31.5% in the spine. Predictors of reduced BMD were as follows: at the femoral neck, older age, low body weight, current use of corticosteroids, greater physical disability (as measured by the modified Health Assessment Questionnaire [M-HAQ]), and presence of rheumatoid factor; at the total hip, older age, low weight, current use of corticosteroids, and higher M-HAQ disability score; and at the lumbar spine, older age, low weight, and current use of corticosteroids. CONCLUSION Register-based prevalence data on BMD reduction in female RA patients ages 20-70 years are presented for the first time in this report, which demonstrates a 2-fold increase in osteoporosis in this representative population.

Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure

In a substudy of the HORIZON pivotal fracture trial, in which yearly intravenous zoledronic acid 5 mg was found to significantly reduce risk of various fracture types in patients with postmenopausal osteoporosis, 152 patients underwent bone biopsy. Zoledronic acid reduced bone turnover by 63% and preserved bone structure and volume, with evidence of ongoing bone remodeling in 99% of biopsies obtained.

Sustained Nonvertebral Fragility Fracture Risk Reduction After Discontinuation of Teriparatide Treatment

A follow‐up in 1262 women was conducted after the discontinuation of teriparatide. The hazard ratio for combined teriparatide group (20 and 40 μg) for the 50‐month period after baseline was 0.57 (p = 0.002), suggesting a sustained effect in reducing the risk of nonvertebral fragility fracture.

Reduced bone mineral density in male rheumatoid arthritis patients: Frequencies and associations with demographic and disease variables in ninety-four patients in the Oslo county rheumatoid arthritis register

OBJECTIVE To examine reductions in bone mineral density (BMD) and factors associated with reduced BMD in 94 male rheumatoid arthritis (RA) registry patients ages 20-70 years. METHODS Dual-energy x-ray absorptiometry was used to measure BMD in the anteroposterior lumbar spine at L2-LA, the femoral neck, and the total hip, and clinical data were collected. The patients were recruited from a validated county RA registry (completeness 85%) comprising 192 men ages 20-70 years. Age-specific BMD values were compared with a pooled healthy European/United States population. Bivariate and multivariate analyses were performed to determine demographic and disease-related associations with BMD and reduced bone mass (Z score of < or =1 SD below the mean value in controls). RESULTS A statistically significant BMD reduction was found only for the oldest age group (60-70 years): 5.2% reduction in the femoral neck and 6.9% in the total hip. No BMD reduction was found at L2-L4. The proportions (95% confidence intervals) of RA patients with Z scores of < or =1 SD below control (16% expected) were 30.9% (21.6-40.2) for L2-L4, 30.8% (95% CI 21.3-40.3) for the femoral neck, and 33.0% (95% CI 23.3-42.7) for the total hip. Disease activity and severity measures were, in general, not associated with BMD or reduced bone mass. CONCLUSION A 2-fold statistically significant increased frequency of patients with reduced bone mass (Z score of < or =1 SD below control; 16% expected) was found for both the spine and the hip. The only significant reduction in BMD by age group was for the hip in patients who were ages 60-70 years, with no reduction in L2-LA BMD. Multivariate analyses did not reveal consistent associations between reduced BMD and demographic or disease variables.

Self reported non-vertebral fractures in rheumatoid arthritis and population based controls: incidence and relationship with bone mineral density and clinical variables

Objective: To compare the incidence of self reported non-vertebral fractures after RA diagnosis between female patients with RA and control subjects, and to explore possible associations between non-vertebral fractures and bone mineral density (BMD), disease, and demographic factors. Methods: 249 women (mean age 63.0 years) recruited from a county register of patients with RA and population controls (n = 249) randomly selected after matching for age, sex, and residential area were studied. Data on previous non-vertebral fractures were obtained from a detailed questionnaire, and BMD was measured at the hip and spine. Results: 53 (21.3%) patients with RA had had 67 fractures after RA diagnosis, the corresponding numbers for controls were 50 (20.1%) and 60 (odds ratio (OR) for paired variables for overall fracture history 1.09, 95% CI 0.67 to 1.77). The overall fracture rates per 100 patient-years were 1.62 and 1.45, respectively, but self reported hip fractures were increased in RA (10 v 2, OR 9.0, 95% CI 1.2 to 394.5). Patients with a positive fracture history had longer disease duration, were more likely to have at least one deformed joint, and had lower age and weight adjusted BMD than those with no fracture history. In logistic regression analysis, fracture history was independently related to BMD only. Conclusions: With the probable exception of hip fractures, non-vertebral fractures do not seem to be a substantial burden in RA. Similar independent relationships between levels of BMD and fracture history were found in patients with RA and in population based controls.

Data driven attempt to create a clinical algorithm for identification of women with rheumatoid arthritis at high risk of osteoporosis

OBJECTIVES To examine relations between osteoporosis and low bone mass and demographic and clinical variables in patients with rheumatoid arthritis (RA), in an attempt to develop a data driven clinical tool for identification of patients at high risk of osteoporosis. METHODS All patients were recruited from a county based register and were examined cross sectionally with a variety of clinical and health status measures as well as bone density measures (anteroposterior spine L2-4, total hip, and femoral neck). Associations between osteoporosis (T score ⩽−2.5SD) and low bone mass (T score ⩽−1SD), on the one hand, and demographic and clinical measures, on the other, were examined bivariately and by logistic regression analyses. RESULTS 394 patients with a mean age of 54.8 years were examined. The percentages having osteoporosis/low bone mass were 16.8/45.8, 14.7/54.5 and 14.7/55.5 in spine L2-4, total hip, and femoral neck, respectively. Osteoporosis and low bone mass were bivariately related to age, body mass index (BMI), disease duration, disease process measures, presence of deformed joints, physical disability, current use of corticosteroids, and history of non-vertebral fracture. In multivariate analyses, age >60 years, low BMI, and current use of corticosteroids were consistently related to osteoporosis and to low bone mass at all sites. The presence of deformed joints was associated with osteoporosis at the total hip, and a history of previous non-vertebral fracture with osteoporosis at the femoral neck. The Modified Health Assessment Questionnaire (MHAQ) ⩾1.5 and non-vertebral fracture were also independently associated with low bone mass at the hip. The logistic regression analyses models could, however, only predict osteoporosis with a sensitivity of about 50–60% and a specificity of 80–90% at the various measurement sites, and low bone mass with a sensitivity and specificity of about 70%. CONCLUSION Consideration of demographic and disease markers may be of some help in predicting presence of osteoporosis or low bone mass, but a combination of markers cannot be used as a clinical tool with sufficient sensitivity and specificity for the identification of osteoporosis or low bone mass in patients with RA.

Clinical decision rules in rheumatoid arthritis: do they identify patients at high risk for osteoporosis? Testing clinical criteria in a population based cohort of patients with rheumatoid arthritis recruited from the Oslo Rheumatoid Arthritis Register

Background: Preliminary clinical criteria based on age, inflammation, and immobility have been proposed to identify which patients with rheumatoid arthritis (RA) should be examined by dual energy x ray absorptiometry (DXA) to diagnose osteoporosis. The three item criteria have not been evaluated in male patients with RA or in the entire female RA population. Objectives: (1) To test the proposed criteria in a cohort of men and women thought to be representative of the entire underlying RA population. (2) To develop clinical decision rules, which could be applied to all patients with RA irrespective of corticosteroid use. Methods: Clinical and demographic data were collected from a total of 287 representative patients with RA (235 (82%) women, 52 (18%) men, age range 25.3–73.1 years) from the Oslo RA register (completeness 85%). Bone mineral density (BMD) was measured in spine L2–4 (anterior-posterior view) and femoral neck by DXA. The criteria were applied and sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Results: Mean age (SD) for the women and men with RA was 56.8 (11.0) years and 61.5 (10.2) years; disease duration was 15.5 (9.5) years and 14.7 (8.6) years. Of the women 163 (69%) were postmenopausal. One hundred and seventeen (50%) women and 28 (54%) men fulfilled the three item criteria. For the diagnosis of osteoporosis (T score ≤−2.5) using the original three item criteria sensitivity in women and men was 74% and 67%, specificity 57% and 50%, PPV 32% and 29% and NPV 89% and 83%, and including weight and ever use of corticosteroids in a five item criteria sensitivity increased to 82% and 83%, specificity decreased to 45% and 45%, PPV was 29% and 31%, and NPV was 90% and 90% respectively. Conclusion: The novel five item criteria (age, weight, inflammation, immobility, and ever use of corticosteroids) are a more accurate tool to identify patients with RA and osteoporosis than the original three item criteria (age, inflammation, and immobility). The clinical decision rules have an acceptable sensitivity and provide a practical tool for the doctor to identify patients with RA who should have a DXA measurement performed.

Incidence of vertebral deformities in 255 female rheumatoid arthritis patients measured by morphometric X-ray absorptiometry

To date, no studies have been published on incident deformities in patients with rheumatoid arthritis (RA). Morphometric X-ray absorptiometry (MXA) is an alternative to conventional X-rays for identifying vertebral deformities. The aim of the present study was to describe the incidence of vertebral deformities in 255 female RA patients measured by MXA, and the relationship between incident deformities and clinical and demographic variables. MXA is still under evaluation for its ability to identify deformities, so we explored four different cut-off thresholds including fixed percentage reduction and the principle of least significant change (LSC). MXA (T4–L4) and BMD (L2–L4 and total hip; Lunar Expert) were performed on 255 patients (mean age 54.3, range 29.2–70.8 years) at baseline and after a mean period of 2.3 years. MXA scans were analyzed pairwise by the same trained technician, and incident deformities calculated applying LSC with a 99.9% and 99.99% confidence limit, and a fixed reduction of 20% and 25% for anterior, middle or posterior heights. Long term precision (%CV) of height measurements for all vertebrae combined (T4–L4) were 4.8, 4.8 and 4.4, respectively. Frequency and distribution of incident deformities varied from 39 deformities in 33 patients (fixed 20% reduction) to 17 deformities in 15 patients (fixed 25% reduction), and quality control analyses revealed a high number of presumed false deformities. Incidence per 100 patient years varied from 2.9 to 6.7 deformities according to method, and was comparable to those obtained from intervention studies in corticosteroid-induced osteoporosis. Patients with incident deformities were significantly older, had lower BMD, higher disability and more often a previous non-vertebral fractures than those without incident deformities Incident deformities by MXA need further evaluation in secondary osteoporosis. It seems, however, that older patients with previous limb fractures and low BMD are especially prone to this complication.

Bisphosphonate treatment of osteoporosis and other skeletal diseases

BACKGROUND Bisphosphonates are antiresorptive drugs widely used to treat osteoporosis. They are also used to treat hereditary skeletal diseases with systemic or local defects, and as a supplement in treatment of cancer. This paper provides an overview of pharmacokinetics, mode of action, and clinical effects. MATERIAL AND METHODS Literature was retrieved through a non-systematic search in Pubmed/Medline. RESULTS Bisphosphonates are derivates of pyrophosphate which bind to hydroxyapatite with high affinity. Aminobisphosphonates inhibit an enzyme in the mevalonate pathway, thereby inducing apoptosis and inhibiting osteoclast activity. A reduced incidence of vertebral and hip fractures has been shown for alendronate, risedronate and zoledronate, while ibandronate has been shown to only reduce vertebral fracture. Reduced mortality was observed in a study where patients with recent hip fracture were treated with zoledronic acid. Intravenous bisphosphonates improve compliance and are relatively simple to use. Bisphosphonates reduce the risk for skeletal complications and bone pain in breast cancer, myelomatosis and prostate cancer. They are also effective in the treatment of Pagets disease and bone marrow edema. Gastrointestinal adverse effects are relatively frequent with peroral bisphosphonates, while acute phase reactions with influenza-like symptoms are common with intravenous bisphosphonates. INTERPRETATION Aminobisphoshonates are effective in the treatment of osteoporosis and in other bone diseases, and as an adjuvance in the treatment of cancer.

The Use of Bone Biopsies in the Diagnosis of Male Osteoporosis

Publisher Summary The incidence of fractures is higher in men than women from adolescence through mid life. This difference is ascribed to a difference in high energy fractures between the two genders. After 50 years, however, the incidence of fractures increases with aging in men as well as women, but the age-adjusted incidence of both hip and vertebral fractures in men is about half of that in women. Another important difference pertaining to osteoporosis pathogenesis between males and females is the higher prevalence of secondary osteoporosis in men. While around 20% of osteoporotic women exhibit other diseases causing bone loss and fracture, the prevalence of secondary osteoporosis in men has been cited to be 40–50% in most studies. This chapter aims to review how bone biopsies have helped us understand the differences in bone remodeling between males and females that are responsible for the different bone loss patterns in the two sexes; review the role of bone biopsies in the elucidation of possible secondary causes in male osteoporosis; and finally review possible new information on bone quality, which can be gained from studies of bone biopsies.