Biochemical Markers Of Bone Metabolism In Children
With Osteogenesis Imperfecta (OI).

Frank Rauch, Rose Travers, Francis H. Glorieux
Genetics Unit, Shriners Hospital and McGill University, Montreal, Canada.

Biochemical bone markers are systemic indicators of bone metabolism, which are schematically classified as reflecting either 'formation' or 'resorption'. A growing number of such markers can be quantified with commercial assays in blood or urine samples. Many of these parameters arise during various stages of collagen metabolism, others are non-collagenous molecules released from bone cells. Over the last 10 years a variety of studies have evaluated sets of bone markers in patients with OI. Results have been variable. Normal or decreased bone formation and decreased, normal or increased markers of bone resorption have been reported. Part of the discrepant findings may be due to difficulties in recruiting adequate control groups of healthy children. Differences between centers in patient classification and treatment management might also contribute to variations between studies. To interpret the results of biochemical bone markers in a rational way, it may be helpful to remember what determines the blood and urine levels of these molecules.

Like any other substance produced in the body, the serum levels of biochemical markers of bone metabolism are influenced by production rate and clearance rate. Very little is known about the clearance rates of commonly used markers of bone metabolism, and the results of bone markers are commonly assumed to mainly reflect their rates of production. The production of biochemical bone markers per unit bone mass is determined by two factors: First, the bone surface area that is available to osteoblasts and osteoclasts. Second, the rate of bone turnover per unit surface area. As shown by iliac crest histomorphometry, the rates of bone formation and resorption per unit surface area are clearly increased in OI types I, III and IV. Surface area per unit bone mass is increased as well, because trabeculae are thinner and cortical porosity is increased. Therefore, the turnover of the available bone is markedly increased in OI. However, at the same time bone mass is very much decreased. Thus, two pathological abnormalities - increased bone turnover and decreased bone mass - will 'neutralize' each other and values for serum bone markers may be close to normal or even decreased.

Many bone resorption markers are collagen degradation products, which are quantified in the urine. Urinary markers are more variable than serum parameters, because they additionally depend on glomerular filtration rate and tubular reabsorption. As the urinary concentration of any substance is influenced by water diuresis, the results for urinary markers of bone resorption are usually related to urinary creatinine levels. This introduces an additional source of analytical and interpretational errors. The amount of creatinine excreted in the urine is directly related to muscle mass, and in fact, creatinine excretion has been used to estimate total body muscle mass. As muscle mass is clearly decreased in severe OI, creatinine excretion is low, resulting in an increased ratio between urinary resorption markers and urinary creatinine. Thus, urine markers related to creatinine excretion may be elevated, while serum markers at the same time may be normal or low.

These considerations highlight the difficulties surrounding attempts to elucidate the pathogenesis of OI by quantifying molecules in serum and urine. Biochemical bone markers might be more useful in the short-term monitoring of therapeutic interventions.

Reference: Proceedings of the 7th International Conference on Osteogenesis Imperfecta. Montreal, Canada, 1999.