The role of busulfan in bone marrow transplantation

High-dose busulfan is an important component in many conditioning protocols for hematopoietic stem cell transplantation (HSCT) or bone marrow transplantation (BMT) in both adults and children. During the past 12y several studies have reported the wide inter-invidual variability in busulfan disposition. Age, disease status, hepatic function, circadian rhythmicity, drug interactions and bioavailability, were identified as factors contributing to the high inter-individual variability found in busulfan disposition. Traditionally, a standard busulfan dose of 4mg/kg/d for four days is used in most BMT/HSCT protocols. Many investigations have pointed out the pharmacodynamic relationship between a high busulfan systemic exposure and the occurrence of BMT related toxicity including hepatic veno-occlusive disease (VOD), interstitial pneumonia and alopecia in adult patients. However, studies in young patients have shown a high rate of graft failure and subsequently relapse which most probably is due to the low systemic exposure despite the standard dose schedule. In children and infants VOD was not observed with the standard doses. Increasing interest for the drug and new modification strategies for children led to higher rate of VOD and CNS toxicity when busulfans was administered according to the body surface area. More pharmacodynamic studies are required to establish the relation between the systemic exposure to busulfan and the therapeutic efficacy, especially in young children undergoing BMT or HSCT. In the present time an accurate and effective busulfan plasma level monitoring combined with dose adjustment based on the known pharmacological parameters may improve the clinical outcome for patients undergoing BMT.     

Analysis of the bone metabolism by quantitative computer tomography and clinical chemistry in a primate model (Callithrix jacchus)

Background Common marmosets are widely used as experimental primates; however, little is still known about their bone physiology. Therefore, the aim of our study was to analyse body weight, age and bone‐specific blood parameters in relation to morphological bone parameters. Methods Fifty‐eight common marmosets were analysed for blood calcium (Ca), inorganic phosphor (P_i), alkaline phosphatase (AP) and 17‐β‐estradiol (E2). The examination of bone parameters was undertaken in the lumbar spine by computer tomography. Results There was a correlation between bone mineral density (BMD) and body weight, trabecular area ratio and polar moment as well as between BMD and AP or Ca (only males), whereas there were no correlations between BMD and age, P_i or E2 in all analysed genders. Conclusions Our data support the assumption that the common marmoset is a reliable primate model to study changes in bone metabolism because of the similarity of our results to humans.     

Raman spectroscopy predicts the link between claw keratin and bone collagen structure in a rodent model of oestrogen deficiency

Osteoporosis is a common disease characterised by reduced bone mass and an increased risk of fragility fractures. Low bone mineral density is known to significantly increase the risk of osteoporotic fractures, however, the majority of non-traumatic fractures occur in individuals with a bone mineral density too high to be classified as osteoporotic. Therefore, there is an urgent need to investigate aspects of bone health, other than bone mass, that can predict the risk of fracture. Here, we successfully predicted association between bone collagen and nail keratin in relation to bone loss due to oestrogen deficiency using Raman spectroscopy. Raman signal signature successfully discriminated between ovariectomised rats and their sham controls with a high degree of accuracy for the bone (sensitivity 89%, specificity 91%) and claw tissue (sensitivity 89%, specificity 82%). When tested in an independent set of claw samples the classifier gave 92% sensitivity and 85% specificity. Comparison of the spectral changes occurring in the bone tissue with the changes occurring in the keratin showed a number of common features that could be attributed to common changes in the structure of bone collagen and claw keratin. This study established that systemic oestrogen deficiency mediates parallel structural changes in both the claw (primarily keratin) and bone proteins (primarily collagen). This strengthens the hypothesis that nail keratin can act as a surrogate marker of bone protein status where systemic processes induce changes.