Use of Currently Available Diagnostic and Therapeutic Tools in the Investigation and Treatment of Disorders of Bone and Calcium Metabolism

In the past decade considerable advances have been made in both the investigation and treatment of various disorders of bone and calcium metabolism. The progress in investigative techniques has taken place in many different directions including biochemical evaluation, parathyroid imaging and bone densitometric measurement. Advances have also taken place in therapeutics with, in particular, the introduction into clinical practice of the bisphosphonates. These drugs are potent inhibitors of bone resorption and are therefore potentially useful in conditions where bone resorption is increased such as in most cases of hypercalcaemia, Paget's disease of bone and some cases of osteoporosis. Accurate evaluation of serum parathyroid hormone (PTH) concentrations and parathyroid hormone-like activity by use of indirect biochemical indices such as nephrogenous cyclic adenosine monophosphate (NcAMP) and renal tubular threshold for phosphate reabsorption (TmPO4), led to the discovery that in many instances cancer-associated hypercalcaemia is due to the production by the tumour of a factor with PTH-like activity. This, in turn, led to the identification of this factor as PTH-related protein (PTHrP), a peptide with significant structural homology to PTH itself. It has generally become apparent that PTHrP driven hypercalcaemia is more common in the presence of squamous cancer whereas hypercalcaemia due to direct invasion of bone by lytic metastases is more common in conditions such as myeloma. Traditionally breast cancer-associated hypercalcaemia has been considered to be due to direct metastatic invasion of bone, though more recent evidence suggests that humoral factors, such as PTHrP, may also play a significant role. A retrospective analysis of 20 patients with breast cancer-associated hypercalcaemia was carried out (chapter 3.1). This study indicated that on the basis of elevated levels of urinary cAMP (UcAMP) excretion and/or depressed TmP04 (in the presence of undetectable serum PTH), hypercalcaemia associated with the presence of a PTH-like factor was present in between 45- 60% patients. Recent evidence has suggested a number of potential physiological roles for PTHrP. One such example is in the active transfer of calcium into milk in the breast and the active transfer of calcium from mother to fetus in pregnancy by an action at the placenta. In the physiological situation, where PTHrP and PTH concentrations are likely to be within the normal reference range, it is unlikely that measurement of UcAMP, NcAMP or TmPO4 will give accurate indication of plasma PTHrP concentrations. In this context direct measurement of PTHrP is essential. A prospective study of 10 normal women through pregnancy (chapter 3.2) showed that plasma PTHrP concentrations rise throughout pregnancy reaching their highest concentration around term. Thereafter levels continue to rise into the puerperium. PTHrP levels during pregnancy correlated closely with serum alkaline phosphatase (ALP) concentrations suggesting a placental source to this PTHrP. Post-partum, however, it is likely that the continued rise in PTHrP was due to the onset of lactation and production of PTHrP by the breast. As expected, concentrations of NcAMP did not change significantly during the period of study. The importance of the vitamin D/PTH axis has been known for a number of years. The availability of precise and accurate biochemical assays for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) (the principal active metabolite of vitamin D3 in man) and intact PTH(l-84) has allowed detailed investigation of their inter-relationship in vivo. 1,25(OH)2D3 and other active metabolites of vitamin D3 such as 1alpha-hydroxycholecalciferol (alfacalcidol) have recently been used therapeutically in the treatment of hypocalcaemia (including that associated with hypoparathyroidism), osteoporosis and renal osteodystrophy. Recent evidence has suggested an advantage in using these drugs by intravenous routes such that significant PTH suppression may be achieved though not at the expense of the development of hypercalcaemia. The acute (first 24hours) effect of intravenous administration of alfacalcidol upon serum concentrations of 1,25(OH)2D3, PTH and osteocalcin was studied prospectively in 6 normal males, 6 patients with primary hyperparathyroidism (PHPT) and 6 women with osteoporosis (chapter 3.3). Significant increases in serum concentrations of l,25(OH)2D3 were seen in each group 2-3 hours after administration of alfacalcidol. The increase in 1,25(OH)2D3 observed was greatest in those patients with PHPT. In the first 24 hours after administration, suppression of PTH concentrations or elevations in serum concentration of osteocalcin were not observed. This would suggest that changes normally seen in the longer term with these parameters are effected via changes in hormone synthesis rather than secretion. (Abstract shortened by ProQuest.)