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There are many causes of hypercalcaemia, all of which are characterised by abnormalities in the transport of calcium across gut, bone, kidney or a combination of these. It is possible to separate the relative importance of these factors in individual patients which not only help the clinician to understand the pathogenesis of hypercalcaemla but should also influence the therapeutic priorities.

A variety of agents are known to stimulate resorption of bone, some of which may be involved in the pathogenesis of disorders associated with bone loss. Several drugs used in clinical practice act principally by inhibiting bone resorption. The mechanisms of action of these factors are reviewed.

The two most commonly used biochemical markers of bone turnover are the serum alkaline phosphatase and the urinary excretion of peptide-bound hydroxyproline, both of which are increased in Paget's disease. Serum alkaline phosphatase is assumed to be derived from osteoblasts during the process of bone formation, whereas small peptides containing hydroxyproline are excreted in the urine following the degradation of bone collagen. The alkaline phosphatase is probably the more useful measurement for diagnosis and for following response to treatment, whereas hydroxyproline, although very sensitive, presents technical difficulties in collection and measurement. Several other biochemical changes in Paget's disease indicate abnormal bone metabolism. These include increased urinary excretion of hydroxylysine and its glycosides derived from collagen, as well as the release into the circulation and subsequent urinary excretion of fragments of pro-collagen indicative of increased collagen formation. Proteins specific to bone, such as osteocalcin, are increased in serum, bone, such as osteocalcin, are increased in serum, as are various enzymes possibly derived from bone cells, including acid phosphatase and proline imino-peptidase. Treatment of Paget's disease results in a fall in urinary hydroxyproline before alkaline phosphatase. This indicates that drug treatment, whether with diphosphonates, calcitonin or mithramycin, has a primary action to inhibit bone resorption, with a subsequent adaptive reduction in bone formation rate.

Small doses of 24,25-dihdyroxy-vitamin D3 (24,25 (OH)2D3; 2μg daily) given by mouth increased plasma levels of 24,25(OH)2D3 several-fold in normal subjects and in patients with metabolic bone disease. When oral treatment was stopped, or following the intravenous administration of 24,25(OH)2D3, plasma disappearance of 24,25(OH)2D3, was slow ( t 1 2 approx. 16 days). This suggests that the endogenous production rate of 24,25(OH)2D3 is similar to that of 1,25(OH)2D3 (less than 2μg daily) but that its metabolic clearance is much slower. The slow metabolic clearance of 24,25(OH)2D3 may explain why plasma levels of this metabolite are about 100 times higher than those of 1,25(OH)2D3.

The main features of Paget's disease are described, together with the indications for medical treatment. A brief summary is given of the drugs available for treatment of Paget's disease with particular emphasis on sodium etidronate (EHDP, ethylidene-1-hydroxy-1, 1-diphosphonate). Sodium etidronate, given at doses between 5 and 20 mg per kilogram per day for 3-6 months, causes a progressive reduction in the biochemical abnormalities (raised plasma alkaline phosphatase and urinary hydroxyproline) and in the histological abnormalities of bone. Clinical symptoms also improve. The usual dose is 5 mg per kilogram body weight per day to be given for not longer than 6 months. Higher doses (10 and 20 mg per kilogram per day) may cause impairment of normal bone mineralisation and should be given for short periods only (1-3 months). Sodium etidronate also has a limited place in the treatment of certain disorders of ectopic calcification, notably heterotopic ossification after spinal cord injury or hip surgery. At the present time there is insufficient evidence to justify its use in the treatment of renal stones or in osteoporosis other than that due to immobilisation after spinal cord injury.

The effects of small doses of 1,24,25 trihydroxyvitamin D3 (1,24,25(OH)3D3; 1–10 μg daily by mouth) on intestinal absorption of calcium were measured in 3 normal subjects (5 studies) and 8 patients with disorders of mineral metabolism. No significant change in calcium absorption (assessed on a total body counter by the retention at 7 days of oral 47Ca) was observed after 4 days of treatment in normal subjects or in patients with chronic renal failure. Similarly, 1,24,25(OH)3D3 at 2μg daily for 4 days had no effect on net intestinal calcium absorption assessed by metabolic balance in a patient with idiopathic hypercalciuria. In contrast, an increase in plasma calcium was noted in an anephric hypoparathyroid patient after 40 days of continuous treatment with 1,24,25(OH)3D3 at 10μg daily. These results suggest that 1,24,25(OH)3D3 is much less potent than 1,25-dihydroxycholecalciferol in stimulating the absorption of calcium from the gut and further suggest that the biological effects of 24,25-dihydroxyvitamin D3 in man are not mediated by its conversion to 1,24,25(OH)3D3.