**3.1.1 Bone turnover**

30 Chronic Kidney Disease

ALP) is a colorimetric assay that is routinely used in clinical laboratories in automated machines. The enzyme is found throughout the body in the form of isoenzymes that are unique to the tissue of origin. Highest concentrations are found in the liver and bone, but the enzyme is also present in the intestines, placenta, kidneys, and leukocytes (Iba K et al. 2004). Specific ALP isoenzymes to identify the tissue source can be determined after fractionation and heat inactivation, but these procedures are not widely available in clinical laboratories. Bone-specific ALP (b-ALP) is measured with an immunoradiometric assay. Elevated levels of t-ALP are generally due to an abnormal liver function, an increased bone activity, or bone metastases. Levels are normally higher in children with growing bones than in adults, and often are increased after fracture. In addition, t-ALP and b-ALP can be elevated in both primary and secondary HPT, osteomalacia, and in the presence of bone metastasis and Paget's disease. In patients with CKD–MBD alkaline phosphatise may be used as an adjunct test, but if values are high, then liver function tests should be checked. t-ALP could reasonably be used as a routine test to follow response to therapy. The more expensive testing for b-ALP can be used when the clinical situation is more ambiguous. Testing for t-ALP is inexpensive and therefore may be helpful for following patients' response to therapy or determining bone turnover status when the interpretation of PTH is unclear. The use of b-ALP, an indicator of bone source, may provide additional and more

specific information, although it is not readily available (Iba K et al. 2004).

Disorders of mineral metabolism are also associated with abnormal bone structure. It has been shown that the gold standard test for bone quality is its ability to resist fracture under strain. In animal models, this resistance can be directly tested with three-point bending mechanical tests. Bone quality is impaired in CKD, as the prevalence of hip fracture is increased in dialysis patients compared with the general population in all age groups. Dialysis patients in their forties have a relative risk of hip fracture that is 80-fold higher than that of age-matched and sex-matched control subjects. Furthermore, hip fracture in dialysis patients is associated with a doubling of the mortality observed in hip fractures in nondialysis patients (Coco M and Rush H., 2000; Alem et al., 2000). It has been shown that risk factors for hip fracture in CKD patients include age, gender, duration of dialysis, and presence of peripheral vascular disease. There are also analyses that found race, gender, duration of dialysis, and low or very high PTH levels as risk factors for hip fracture. It has been reported that both hip and lumbar-spine fractures occur independent of gender and race in CKD patients. Other risk factors for abnormal bone identified in studies from the general population are also common in CKD, including smoking, sedentary lifestyle, and hypogonadism (Alem et al., 2000). These factors are likely to increase the risk of bone fragility and fractures in CKD but have not been well evaluated. Extremes of bone turnover found in patients with CKD have significant impact on fragility and are likely additive to bone abnormalities commonly found in the aging and sedentary general population

Bone biopsy is performed to understand the pathophysiology and course of bone disease, to relate histological findings to clinical symptoms of pain and fracture, and to determine

**3. CKD – MBD and bone abnormalities** 

(Vassalotti et al., 2008; Melamed et al., 2008).

**3.1 Classification of renal osteodystrophy by bone biopsy** 

In CKD patients a spectrum of bone formation rates varies from abnormally low to very high. Other measurements that help to define a low or high turnover (such as eroded surfaces, number of osteoclasts, fibrosis, or woven bone) tend to be associated with the bone-formation rate as measured by tetracycline labeling. This is the most definite dynamic measurement, hence it was chosen to represent bone turnover. It should be noted that an improvement of a bone biopsy cannot be determined on the basis of a simple change in the bone-formation rate, because the restoration of normal bone may require either an increase or a decrease in bone turnover, depending on the starting point (Melsen and Moselkilde, 1978).

### **3.1.2 Bone mineralization**

It is a parameter which reflects the amount of unmineralized osteoid. Mineralization is measured by the osteoid maturation time or by mineralization lag time, both of which depend heavily on the osteoid width as well as on the distance between tetracycline labels. The classic disease with an abnormality of mineralization is osteomalacia, in which the bone-formation rate is low and the osteoid volume is high. Some patients have a modest increase in osteoid, which is a result of high bone formation rates. They do not have osteomalacia because the mineralization lag time remains normal. The overall mineralization, however, is not normal because unmineralized osteoid is increased.
