Fox, Paul Edward; (1997) The biochemistry of metabolic bone disease: Investigation and experimental treatment. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Far from being an inert support for the soft tissues, bone is one of the principal organs of calcium homeostasis, undergoing constant turnover regulated by a number of systemic hormones and paracrine factors. Any disruption to the rate or turnover or the degree to which bone formation and resorption are linked, may lead to a 'metabolic bone disease'. This thesis examines the use of biochemical markers in the diagnosis and assessment of treatment of some of these disorders. From basic work on the adjustment of serum total calcium to account for protein binding, the newer biomarkers of bone turnover are considered. The use of acidified urine in a collagen crosslink immunoassay is validated, as is a new immunoextraction assay for 1,25-dihydroxy vitamin D. Two osteocalcin immunoassays, directed towards different sites of the molecule, are used to indicate circulating C-terminal osteocalcin fragments. The use of serum tartrate-resistant acid phosphatase as a marker of bone resorption is shown to be promising, but limited by current assay technology. A number of the markers were used clinically; to monitor the response to different therapies in fibrous dysplasia, and to compare privational and tumour induced osteomalacia. An atypical case of humoral hypercalcaemia of malignancy with elevated osteoblastic activity is also described. In a larger population, urinary excretion of free deoxypyridinoline and the N-telopeptide of type I collagen were used to investigate the pathogenesis of bone loss in women approaching the menopause. Bone loss during this period, apparently clinically significant in some individuals, is better indicated by the collagen telopeptide marker. The possible use of markers to target therapy in osteoporosis is examined. Serum bone-specific alkaline phosphatase was found to be the best pre-treatment indicator of response to bisphosphonate therapy. The use of bone biomarkers is discussed in the context of these experimental studies. Due to problems inherent with urinary markers, the need for a simple serum marker of bone resorption is highlighted. However it is pointed out that although several serum formation markers exist, their application lacks subtlety due to incomplete understanding of the different aspects of osteoblast function they represent.

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