Claus Christiansen

Acidification of the Osteoclastic Resorption Compartment Provides Insight into the Coupling of Bone Formation to Bone Resorption

Patients with defective osteoclastic acidification have increased numbers of osteoclasts, with decreased resorption, but bone formation that remains unchanged. We demonstrate that osteoclast survival is increased when acidification is impaired, and that impairment of acidification results in inhibition of bone resorption without inhibition of bone formation. We investigated the role of acidification in human osteoclastic resorption and life span in vitro using inhibitors of chloride channels (NS5818/NS3696), the proton pump (bafilomycin) and cathepsin K. We found that bafilomycin and NS5818 dose dependently inhibited acidification of the osteoclastic resorption compartment and bone resorption. Inhibition of bone resorption by inhibition of acidification, but not cathepsin K inhibition, augmented osteoclast survival, which resulted in a 150 to 300% increase in osteoclasts compared to controls. We investigated the effect of inhibition of osteoclastic acidification in vivo by using the rat ovariectomy model with twice daily oral dosing of NS3696 at 50 mg/kg for 6 weeks. We observed a 60% decrease in resorption (DPYR), increased tartrate-resistant acid phosphatase levels, and no effect on bone formation evaluated by osteocalcin. We speculate that attenuated acidification inhibits dissolution of the inorganic phase of bone and results in an increased number of nonresorbing osteoclasts that are responsible for the coupling to normal bone formation. Thus, we suggest that acidification is essential for normal bone remodeling and that attenuated acidification leads to uncoupling with decreased bone resorption and unaffected bone formation.

Influence of food intake on the bioavailability and efficacy of oral calcitonin

AIMS To investigate the influence of food intake on the bioavailability and pharmacodynamic effects of salmon calcitonin (sCT). METHODS A single-blind, randomized, partly placebo-controlled study was conducted in 36 healthy postmenopausal female volunteers aged 62-74 years. The influence of food intake on oral dosing with 0.8 mg of sCT at 22.00 h was evaluated for a (i) predose meal at 18.00 h, (ii) predose meal at 20.00 h, (iii) predose meal at 21.00 h, (iv) postdose meal at 22.10 h, (v) no meal, and (vi) meal at 20.00 h and placebo at 22.00 h. Study biomarkers were plasma sCT levels and changes in the bone resorption marker CTX-I (C-terminal telopeptide of collagen type I). RESULTS The predose meal at 18.00 and 21.00 h significantly decreased relative oral bioavailability of sCT to 26% [95% confidence interval (CI) 0.09, 0.73 and 0.09, 0.75, P= 0.009 and P= 0.01]. The meal consumed 10 min after dosing decreased the oral bioavailability of sCT to 59% (95% CI 0.21, 1.68), although nonsignificant (P= 0.48). This decreased bioavailability led to lower relative suppression of serum CTX-I, with an AUC of the 4-h efficacy response of -91%-x-hours for those receiving a meal at 18.00 h, compared with -238%-x-hours for fasting subjects. The Dunnett-adjusted difference between these two treatment sequences was 147%-x-hours (95% CI 68, 225) (P= 0.0003). The AUC was comparable among fasting subjects and those consuming a meal 10 min after dosing. CONCLUSIONS Postprandial dosing may limit the bioavailability of orally administered sCT. Maximal benefit can be achieved by dosing at least 10 min prior to meal time.

A Variational Method for Automatic Localization of the most Pathological ROI in the Knee Cartilage

Osteoarthritis (OA) is a degenerative joint disease characterized by degradation of the articular cartilage, and is a major cause of disability. At present, there is no cure for OA and currently available treatments are directed towards relief of symptoms. Recently it was shown that cartilage homogeneity visualized by MRI and representing the biochemical changes undergoing in the cartilage is a potential marker for early detection of knee OA. In this paper based on homogeneity we present an automatic technique, embedded in a variational framework, for localization of a region of interest in the knee cartilage that best indicates where the pathology of the disease is dominant. The technique is evaluated on 283 knee MR scans. We show that OA affects certain areas of the cartilage more distinctly, and these are more towards the peripheral region of the cartilage. We propose that this region in the cartilage corresponds anatomically to the area covered by the meniscus in healthy subjects. This finding may provide valuable clues in the pathology and the etiology of OA and thereby may improve treatment efficacy. Moreover our method is generic and may be applied to other organs as well.

Recent advances in photon absorptiometric techniques for measurement of bone mass

Publisher Summary The development of methods for measuring bone mineral content (BMC) of the skeleton has revolutionized the study of osteoporosis in the past 25 years. The first few methods graded the degree of bone loss from simple radiographs of the lumbar spine and the femoral neck, but the poor precision of these techniques led to a method for measuring bone mass by the absorption of monoenergetic photons. This chapter discusses different studies to assess different photon absorptiometric techniques that are used to diagnose osteoporosis and estimate changes during treatment for bone loss. In these studies, Bone mineral BMC in the forearms was measured with single-photon absorptiometry (SPA) and corrected for fat. The studies demonstrate that the spinal scanner has both systematic and random errors. The reduction of bone mass in the patients with vertebral fractures is universal, and there are no signs of a preferential spinal bone loss. There is a large overlap between the bone mass in normal subjects than that in patients with osteoporotic fractures, but the bone mass measurements in the forearm have a higher diagnostic specificity for identifying patients with vertebral fractures than have spinal bone mass measurements.