Gorm Thamsborg

Effect of Intermittent Cyclical Etidronate Therapy on Bone Mass and Fracture Rate in Women with Postmenopausal Osteoporosis

Progressive bone loss in osteoporosis results from bone resorption in excess of bone formation. We conducted a double-blind study in 66 women with postmenopausal osteoporosis of therapy with etidronate, a diphosphonate compound that reduces bone resorption by inhibiting osteoclastic activity. The patients were randomly assigned in equal numbers to receive oral etidronate (400 mg per day) or placebo for 2 weeks, followed by a 13-week period in which no drugs were given. This sequence was repeated 10 times, for a total of 150 weeks. Daily oral supplementation with calcium and vitamin D was given throughout the study to both groups. Vertebral bone mineral content was measured by dual-photon absorptiometry; spinal radiographs were assessed to identify new vertebral fractures. Vertebral bone mineral content increased significantly (P less than 0.01) after 150 weeks of etidronate therapy (5.3 percent; 95 percent confidence interval, 2.0 to 8.6; n = 20) but decreased with placebo (-2.7 percent; 95 percent confidence interval, -7.3 to 1.9; n = 20). The difference between groups was 8.0 percentage points (P less than 0.01; 95 percent confidence interval, 2.4 to 13.6). The rates of fracture were significantly different for the period from week 60 to week 150 between the etidronate and placebo groups (6 vs. 54 fractures per 100 patient-years; P = 0.023). No adverse clinical, biochemical, or bone histomorphometric effects of treatment were observed. We conclude that at the end of nearly three years, etidronate therapy for postmenopausal osteoporosis results in significant increases in vertebral bone mineral content and, after approximately one year of treatment, a significant decrease in the rate of new vertebral fractures.

Responsiveness of the Ankylosing Spondylitis Disease Activity Score (ASDAS) and clinical and MRI measures of disease activity in a 1-year follow-up study of patients with axial spondyloarthritis treated with tumour necrosis factor α inhibitors

Objectives To investigate construct validity and responsiveness of the novel ankylosing spondylitis (AS) disease activity score (ASDAS) in patients with spondyloarthritis (SpA). Methods In a 46-week prospective longitudinal multicentre study of 60 patients with SpA (80% men, median age 40 years (range 21–62)) treated with tumour necrosis factor α (TNFα) inhibitors (infliximab, n=41; etanercept, n=13; adalimumab, n=6), the responsiveness of ASDAS, conventional clinical measures of disease activity and treatment response and the Berlin MRI sacroiliac joint (SIJ) and lumbar spine inflammation scores were compared. Results After 22 weeks, 58.3% of the patients were clinical responders (50% or 20 mm reduction in the Bath AS Disease Activity Index (BASDAI)). At baseline, clinical responders had significantly higher median (range) ASDAS than non-responders (4.15 (1.98–6.04) vs 2.99 (2.05–6.19), p=0.008). Changes in ASDAS correlated with changes in clinical measures of disease activity (including BASDAI (ρ=0.76) and C-reactive protein (CRP) (0.79)), MRI SIJ inflammation (0.46) and MRI total inflammation scores (0.34). Patients with higher BASDAI or Assessment of SpondyloArthritis International Society (ASAS) responses obtained more profound reductions in ASDAS. ASDAS had the highest responsiveness with an effect size of 2.04 and a standardised response mean of 1.45, whereas BASDAI (effect size 1.86; standardised response mean 1.36) and CRP (effect size 0.63; standardised response mean 0.70) were less responsive. Linear regression showed that a change in BASDAI of 20 mm or 50% corresponded to a change in ASDAS of 1.38 and 1.95, respectively. Conclusion ASDAS demonstrates construct validity and high responsiveness during treatment with TNFα inhibitors in patients with SpA. The proposed thresholds for disease activity and treatment response need further validation. Trial registration number NCT00133315.

ASDAS, BASDAI and different treatment responses and their relation to biomarkers of inflammation, cartilage and bone turnover in patients with axial spondyloarthritis treated with TNFα inhibitors

Objectives To investigate the relation between ankylosing spondylitis disease activity score (ASDAS), Bath ankylosing spondylitis disease activity index (BASDAI) and treatment response and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), YKL-40), angiogenesis (vascular endothelial growth factor (VEGF)), cartilage (C-terminal crosslinking telopeptide of type II collagen (CTX-II), matrix metalloproteinase-3 (MMP-3), total aggrecan, cartilage oligomeric matrix protein) and bone (C-terminal crosslinking telopeptide of type I collagen, osteocalcin) turnover in 60 patients with axial spondyloarthritis initiating tumour necrosis factor alpha (TNFα) inhibitor therapy. Methods ASDAS (CRP-based), BASDAI and biomarkers were determined before and seven times during 46 weeks of TNFα inhibitor therapy. Results Very high ASDAS were associated with high levels of inflammatory biomarkers, while high BASDAI were not related to any biomarkers. Mixed modeling demonstrated significant longitudinal associations between ASDAS and IL-6, VEGF, MMP-3 and osteocalcin and between BASDAI and CRP, IL-6 and VEGF. Major improvement in ASDAS was associated with larger percentage decreases in biomarkers of inflammation, angiogenesis, MMP-3 and increases in aggrecan and osteocalcin. BASDAI response was associated with larger decreases in CRP and IL-6. Biomarkers with moderate/high differences in responsiveness for major versus no/clinically important improvement in ASDAS were CRP, IL-6, VEGF, aggrecan and osteocalcin, and VEGF and CTX-II for BASDAI response versus non-response. Conclusion Levels and changes of 10 biomarkers in patients with axial spondyloarthritis during anti-TNFα therapy were documented. Construct validity and responsiveness of IL-6, VEGF, MMP-3, total aggrecan and osteocalcin were demonstrated. ASDAS was more associated with these biomarkers than BASDAI, and may better reflect the inflammatory disease processes. ClinicalTrials.gov identifier NCT00133315.

Radiographic progression is associated with resolution of systemic inflammation in patients with axial spondylarthritis treated with tumor necrosis factor α inhibitors: a study of radiographic progression, inflammation on magnetic resonance imaging, and circulating biomarkers of inflammation, angiogenesis, and cartilage and bone turnover.

OBJECTIVE To investigate the relationship of circulating biomarkers of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and YKL-40), angiogenesis (vascular endothelial growth factor), cartilage turnover (C-terminal crosslinking telopeptide of type II collagen [CTX-II], total aggrecan, matrix metalloproteinase 3 [MMP-3], and cartilage oligomeric matrix protein [COMP]), and bone turnover (CTX-I and osteocalcin) to inflammation on magnetic resonance imaging (MRI) and radiographic progression in patients with axial spondylarthritis (SpA) beginning tumor necrosis factor α (TNFα) inhibitor therapy. METHODS MRIs were evaluated according to the Berlin sacroiliac (SI) joint and spine inflammation scoring method at baseline, week 22, and week 46. Radiographs were evaluated using the modified Stoke Ankylosing Spondylitis Spine Score at baseline and week 46. Patients with new syndesmophytes were identified. Biomarker levels in patients were compared to levels in healthy subjects. RESULTS Higher pretreatment MRI inflammation scores for SI joints and/or lumbar spine were associated with higher baseline CTX-II levels, but not with higher levels of biomarkers of inflammation and bone turnover. During treatment with TNFα inhibitors, a decrease in MRI inflammation scores from baseline to week 22 was associated with larger percentage decreases in and a normalization of CRP and IL-6 levels as compared to an increase or no change in MRI scores. Development of new syndesmophytes was associated with larger percentage decreases in CRP and IL-6 levels and an increase in osteocalcin level, and with normalization of CRP and IL-6 levels from baseline to week 22. Persistent systemic inflammation was associated with radiographic nonprogression. CONCLUSION Our findings indicate that inflammation on baseline MRI is associated with higher CTX-II levels. Radiographic progression is associated with decreased systemic inflammation, as assessed by IL-6 and CRP levels and MRI, supporting the notion of a link between the resolution of inflammation and new bone formation in SpA patients during anti-TNFα therapy.

Quantitation of urinary hydroxypyridinium cross-links from collagen by high-performance liquid chromatography

Pyridinoline and deoxypyridinoline are intermolecular cross-links in mature collagen in bone and cartilage. The urinary excretion of the two compounds correlates well to bone turnover. A fast, sensitive, and accurate isocratic ion-pairing reverse-phase high-performance liquid chromatography method for measurement of pyridinoline and deoxypyridinoline in urine has been established. Intra- and inter-assay precision were 5-7% and 12-14%, respectively. Recovery for pyridinoline was 97.4% and for deoxypyridinoline 94.3%. The detection limit was 0.4 pmol. Pyridinoline:creatinine and deoxypyridinoline: creatinine ratios in healthy subjects, were 38.8 nmol:mmol and 13.0 nmol:mmol, respectively. Increased values of both cross-links were observed in children, in the age group 20-29 in both sexes, and in post-menopausal women.

Acute effects of nasal salmon calcitonin on calcium and bone metabolism

SummaryEffects of a single dose of 200 IU of nasal salmon calcitonin (SCT) on calcium metabolism and biochemical markers of bone turnover were investigated in 12 healthy male volunteers in a randomized, placebo-controlled, crossover design. The nasal spray was given in the morning, and subsequently blood and urine samples were collected for 26 hours. There was a significant decrease in serum ionized calcium with a nadir 4 hours after administration of nasal SCT accompanied by a significant increase in serum parathyroid hormone (P = 0.01) and serum calcitriol (P = 0.04). Nasal SCT did not reduce urinary hydroxyproline/creatinine. Urinary deoxypyridinoline/creatinine was lowered significantly 2 hours after administration of nasal SCT and throughout the first 24 hours, but remained unchanged for the last 2 hours. On a 24-hour basis, urinary deoxypyridinoline/creatinine decreased from 14.1 (3.5) nmol/mmol to 11.7 (3.2) nmol/mmol after nasal SCT (P = 0.04). Nasal SCT did not change the serum levels of alkaline phosphatase, osteocalcin, and the carboxyterminal propeptide of type 1 procollagen. The results indicate that nasal SCT given as a single dose provokes a modest decrease in bone resorption lasting several hours, but leaves bone formation unaffected.

The effect of different doses of nasal salmon calcitonin on plasma cyclic AMP and serum ionized calcium

SummaryTo investigate the effect of low doses of intranasal salmon calcitonin on plasma cyclic AMP (cAMP) and serum ionized calcium, 40 healthy postmenopausal women were randomized to receive a single dose of either placebo or 50, 100, or 200 IU of salmon calcitonin as a nasal spray. Blood samples were collected throughout an 8-hour period. None of the doses could provoke detectable hypocalcemia, whereas 100 and 200 IU of salmon calcitonin were associated with an increase in plasma cAMP after 15 minutes. Measurable plasma levels of salmon calcitonin were demonstrated in all active treatment groups, and the calculated areas under the curves showed a dose-dependent increase.

Course of Magnetic Resonance Imaging-Detected Inflammation and Structural Lesions in the Sacroiliac Joints of Patients in the Randomized, Double-Blind, Placebo-Controlled Danish Multicenter Study of Adalimumab in Spondyloarthritis, as Assessed by the Berlin and Spondyloarthritis Research Consortium of Canada Methods.

To investigate changes in magnetic resonance imaging (MRI)–assessed inflammation and structural lesions in the sacroiliac (SI) joints during treatment with adalimumab versus placebo.

Course of MRI Inflammation and Structural Lesions in the Sacroiliac Joints in a Randomized Double‐blind Placebo‐controlled Trial of Adalimumab in Patients with Axial Spondyloarthritis as Assessed by the Berlin and SPARCC Methods (the DANISH Study)

To investigate changes in magnetic resonance imaging (MRI)–assessed inflammation and structural lesions in the sacroiliac (SI) joints during treatment with adalimumab versus placebo.

Lack of effect of nasal salmon calcitonin on cell-mediated immunity

The calcium lowering hormone, calcitonin, also affects the immune system. The effect of nasal salmon calcitonin on lymphocyte transformation tests and on serum-ionised calcium was investigated in a randomised, double-blind and placebo-controlled study including 24 healthy adult volunteers. The participants received a single dose of either 200 IU of nasal salmon calcitonin or nasal placebo in the morning and measurements were done before and 3 h after administration of the spray. Nasal salmon calcitonin exerted a significant hypocalcemic effect, but did not interfere with antigen- or mitogen-induced expansion of T-lymphocytes. It is unlikely that nasal salmon calcitonin affects cell-mediated immunity in healthy subjects.