Biochemical Indices Of Bone Resorption Research Articles

Strontium ranelate: a novel mode of action optimizing bone formation and resorption

Strontium ranelate has been shown to decrease the risk of fractures in postmenopausal women. Its efficacy in clinical studies results from its unique mode of action, on both bone resorption and bone formation. Pharmacological studies in animals have shown that strontium ranelate decreases bone resorption and increases bone formation, resulting in increased bone mass. In ovariectomized rats, strontium ranelate prevented the reduction in bone mineral content and the decrease in trabecular bone volume induced by estrogen deficiency. In this model, strontium ranelate decreased bone resorption, whereas bone formation was maintained at a high level as documented by plasma biochemical markers and histomorphometric indices of bone formation. In the model of osteopenia induced by hind-limb immobilization in rats, strontium ranelate reduced histomorphometric parameters of bone resorption and partially prevented long-bone loss, as assessed by bone mineral content, bone volume, and biochemical indices of bone resorption. In intact mice, strontium ranelate increased bone formation and vertebral bone mass. In intact growing rats, strontium ranelate increased the bone trabecular volume without alteration of mineralization. The unique mode of action of strontium ranelate on bone formation and resorption was supported by in vitro studies. In rat calvaria culture systems and rat osteoblastic cell cultures, strontium ranelate enhanced preosteoblastic cell replication and increased collagen synthesis by osteoblasts. Moreover, strontium ranelate decreased bone resorption in organ cultures and decreased the resorbing activity of isolated mouse osteoclasts. The assessment of bone markers in a clinical trial [Spinal Osteoporosis Therapeutic Intervention (SOTI)] supports the mode of action of strontium ranelate: bone alkaline phosphatase levels increased and C-telopeptide of type I collagen levels decreased in treated patients compared with the placebo group at all time points. Thus, pharmacological and clinical studies suggest that strontium ranelate optimizes bone resorption and bone formation, resulting in increased bone mass, which may be of great value in the treatment of osteoporosis.

Optimizing bone metabolism in osteoporosis: insight into the pharmacologic profile of strontium ranelate.

Strontium ranelate (SR) is currently being developed for the treatment of osteoporosis. Pharmacologic studies in animal models have shown that its efficacy on bone mass is based on its original mode of action on bone formation and bone resorption. In normal mice, SR increased bone formation and vertebral bone mass. In normal rats, SR increased bone mass and the mechanical properties of vertebral, humeral and femoral bones, associated with increased femoral shaft diameter. Vertebral bone mineral density and bone strength were also increased by SR, whereas stiffness was not altered, underlining that the improvement in bone strength occurs without inducing defective bone mineralization. In normal adult monkey alveolar bone, SR decreased bone resorption and increased bone. In ovariectomized (OVX) rats, SR limited the reduction in bone mineral content and the decrease in trabecular bone volume induced by estrogen deficiency, by inhibiting bone resorption while maintaining bone formation. Curative treatment with SR also partially restored bone mass in OVX rats. In the model of hind limb immobilization in rats, SR reduced bone resorption and partially limited long bone loss, as assessed by bone mineral content, bone volume, and histomorphometric and biochemical indices of bone resorption. The unique mode of action of SR on bone formation and resorption is also supported by in vitro studies. In calvaria culture systems and osteoblastic cell cultures, SR enhanced the replication of preosteoblastic cells and consequently increased collagen synthesis. Moreover, SR inhibited the bone-resorbing activity of isolated mouse osteoclasts and devreased osteoclast differentiation markers in chicken bone marrow cultures. Altogether, these pharmacologic results suggest that SR optimizes bone metabolism by decreasing bone resorption and promoting bone formation, which may be of potential value in the treatment of osteoporosis.

Prophylactic effects of 1,24,25-trihydroxyvitamin D3 on ovariectomy-induced cancellous bone loss in the rat.

Vitamin D metabolites can prevent estrogen depletion-induced bone loss in ovariectomized (OVX) rats. In this study, we investigated the bone-sparing effects of oral 1alpha,24R,25-trihydroxyvitamin D3 (1,24,25(OH)3D3) in a wide dose range in aged OVX rats. Fifty-three female Fischer-344 rats (6 months old, 170 g BW) were either ovariectomized or sham-operated (SHAM). Eight rats served as baseline controls. Groups of OVX rats (n = 7-8 each) received vehicle alone or graded oral doses of 1,24,25(OH)3D3 (0.05, 0.1, 0.2, and 0.3 microg/kg BW/day), starting five days after surgery. Urine and blood samples were collected one, two, three, and four months after surgery. Serum samples were analyzed for total calcium and alkaline phosphatase. Calcium, hydroxyproline, and collagen crosslinks (HPLC) were determined in urine. After fluorochrome double labeling, the rats were sacrificed four months postsurgery and the first lumbar vertebrae and the proximal tibiae were processed undecalcified for bone histomorphometry. Ovariectomy induced a 28% and a 69% reduction in vertebral and tibial cancellous bone area, respectively. Osteopenia in OVX rats was associated with increased histomorphometric and biochemical indices of bone turnover. The administration of 1,24,25(OH)3D3 to OVX rats dose-dependently increased vertebral and tibial cancellous bone mass, serum calcium, and urinary calcium excretion, and reduced histomorphometric and biochemical indices of bone resorption. 1,24,25(OH)3D3 at doses of 0. 2 and 0.3 microg/kg/day produced strong anabolic effects, especially on vertebral cancellous bone in OVX rats, and increased mineral apposition rate and wall width of completed remodeling units relative to vehicle-treated OVX rats. Even at high doses, 1,24, 25(OH)3D3 did not impair bone mineralization. We conclude that oral administration of 1,24,25(OH)3D3 can effectively prevent estrogen depletion-induced cancellous bone osteopenia in the aged OVX rat model. The therapeutic window for 1,24,25(OH)3D3 in OVX rats, however, is also narrow, comparable to that for calcitriol.

Continuous and cyclical clodronate therapies and bone density in postmenopausal bone loss

To evaluate the effectiveness of different clodronate regimens in postmenopausal osteoporosis. In groups of 20, 60 women were randomly assigned to one of three treatments: oral calcium, 1000 mg/day; oral calcium plus oral clodronate, 400 mg/day; oral calcium plus oral clodronate, 400 mg/day for 30 days, followed by a 60-day period of calcium supplement alone. This last regimen was repeated four times in the 12-month study period. Patients who received calcium alone showed a decline in spinal bone mass, both after 6 and 12 months (P < .03 and P < .005, respectively); femoral density in this group also decreased after 6 and 12 months (P < .002 and P < .05, respectively). On the other hand, both clodronate-treated groups had increased levels of lumbar bone mass compared with controls, both after 6 and 12 months of therapy. However, at the end of the study, patients treated with cyclical clodronate had higher spinal bone mass compared with those treated continuously (3.32 +/- 0.71 versus 0.43 +/- 0.89%, P < .02). After 6 months, femoral bone density was significantly higher both in subjects treated with clodronate, both cyclically and continuously (P < .01), compared with controls. Continuous clodronate treatment resulted in a clear fall in biochemical indices of bone resorption, together with a consequent decrease in osteocalcin at 6 (P < .02) and 12 months (P < .003) and a significant increase in parathyroid hormone after 12 months (P < .001) of therapy. One-year treatment with clodronate induces a gain in bone mass, especially in the spine. The continuous regimen does not result in any further benefit in lumbar bone density over the cyclical one, probably because of a greater suppression of bone turnover.

Urinary collagen crosslink excretion: a better index of bone resorption than hydroxyproline in Paget's disease of bone?

The 24 h urinary excretion of the collagen degradation products pyridinoline (Pyr) and deoxypyridinoline (Dpyr) have been proposed as specific and quantitative indices of bone resorption. We compared the value of the urinary excretion of Pyr and Dpyr to that of hydroxyproline (OHP) in 11 patients with Paget's disease of bone before and during treatment with inhibitors of bone resorption, during admission to a metabolic ward and maintenance on a gelatin-free diet. Pyr and Dpyr excretion rates were significantly correlated with those of OHP (r = 0.81 and 0.77, respectively, P < 0.001; n = 106). The rate and degree of suppression of bone resorption were monitored in 6 of the patients similarly treated with intravenous dimethyl-APD at a dose of 4 mg/day for 10 days, by daily measurements of the 24 h urinary excretion of Pyr, Dpyr and OHP. Treatment with dimethyl-APD resulted in a decrease in the three indices of bone resorption. The percentage change from baseline values was similar for the three indices, although changes in Dpyr appeared to follow more closely those of OHP. Our findings suggest that Pyr and Dpyr are useful and specific indices of bone resorption in Paget's disease of bone. They appear to confer no advantage, however, over the traditional determination of the urinary excretion of OHP, in the monitoring of response to treatment of such patients with inhibitors of bone resorption. Further studies are required to establish the value of these new biochemical indices of bone resorption, possibly in more subtle disorders of bone metabolism such as osteoporosis.

Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of bone resorption.

We studied bone biopsies from 26 patients with myelomatosis with apparently normal skeletal metabolism. Quantitative histomorphometric measurements suggested that skeletal disease was progressive despite normocalcaemia and normal urinary excretion rates of calcium and hydroxyproline. When biopsies were divided according to the involvement of marrow by plasma cells, bone resorption--as judged by the eroded surface--increased significantly the greater plasma cell burden. Osteoclasts were frequent with moderate tumour burdens, but there was no further increase in the number of osteoclasts when plasma cell infiltration increased by more than 50% of bone marrow. Contrary to expectation, the numbers of osteoblasts and bone formation rates were increased with bone biopsies with moderate tumour burden, but were markedly lower when plasma cell infiltration occupied more than 50% of bone marrow, due to a decreased functional capacity of osteoblasts. We conclude that skeletal bone disease in myeloma is commonly progressive despite apparently stable bone disease as judged by biochemical measurements. The major mechanism of bone loss in myelomatosis is increased osteoclastic resorption but decreased bone formation contributes to bone loss with heavy plasma cell burdens. Urinary excretion of calcium and hydroxyproline provide insensitive indices of bone resorption in myelomatosis.

Biochemical assessment of bone loss in patients on long-term thyroid hormone treatment

To test conditions under which thyroid hormone might be deleterious to bone, we studied a group of 58 patients who had undergone thyroidectomy because of thyroid cancer 1 to 21 years previously and were treated with steady doses of exogenous thyroid hormone. Vertebral bone density (BMD Z-score) was significantly reduced and biochemical indices of bone resorption (urinary hydroxyproline and plasma tartrate-resistant acid phosphatase activity) and of osteoblastic activity (plasma osteocalcin and bone isoenzyme of serum alkaline phosphatase) as well as the calculated prevalence of bone resorption relative to osteoblastic activity (HBP) were significantly increased in thyroid hormone-treated post-menopausal women but not in men and premenopausal women. The HBP as well as the biochemical indices of bone remodeling were significantly negatively correlated with serum TSH levels. In treated patients, BMD Z-score was significantly dependent on the HBP, menopausal state, duration of treatment and serum TSH levels. In conclusion, the further increase in bone resorption by thyroid hormone is predisposed by menopausal changes in bone turnover. The simultaneous evaluation of biochemical indices of bone resorption and formation improves the assessment of bone loss in patients treated with thyroid hormone in a suppressive dose.

LONG‐TERM EFFECTS OF PARENTERAL DICHLOROMETHYLENE BISPHOSPHONATE (CL2MBP) ON BONE DISEASE OF MYELOMA PATIENTS TREATED WITH CHEMOTHERAPY

Data on the long-term treatment of myeloma bone disease with bisphosphonates are scanty. In a prospective pilot trial we evaluated the effect of long-term parenteral administration of dichloromethylene bisphosphonate (Clodronate), in addition to standard chemotherapy, in 30 patients with active myeloma bone disease. Patients were treated with a mean of 4 courses (range 2-8) of Clodronate: 300 mg/day i.v. for seven days followed by 100 mg/day i.m. for 10 days, administered at a mean interval of 4 months (range 3-6). The median follow-up was 24 months (range 8-36). Clodronate reduced bone pain rapidly and significantly, and reduced the mean values of the biochemical indices of bone resorption to within normal limits; these effects were maintained throughout the follow-up. In three hypercalcemic episodes serum calcium became normal after 2-5 days of treatment with Clodronate. No toxic or side effects were noticed. The occurrence of skeletal morbidity in patients treated with Clodronate was compared with that observed in the control group of myeloma patients (p less than 0.001) in severe bone pain as well as in the incidence of new osteolytic lesions and pathological fractures (p less than 0.001). Supportive Clodronate therapy contributes significantly in controlling the progression of myeloma bone disease.

Treatment of painful bone lesions and hypercalcemia

The control of myeloma bone disease has been an important therapeutic problem. Bisphosphonates are potentially active for the control of myeloma bone resorption. Although several studies proved the efficacy of short-term bisphosphonate treatment in inhibiting myeloma bone destruction, data on the long-term efficacy are scanty. We present the results of a prospective pilot study for the evaluation of long-term parenteral administration of dichloromethylene bisphosphonate (Clodronate) in 30 patients with active myeloma bone disease. Patients were treated with a mean of 4 courses (range 2-8) of Clodronate: 300 mg/d i.v. for 7 days followed by 100 mg/d i.m. for 10 d, administered at a mean interval of 4 months. The median follow-up was 24 months (range 8-36). Clodronate reduced bone pain rapidly and significantly, and reduced the mean values of the biochemical indices of bone resorption to within normal limits. The occurrence of skeletal morbidity in patients treated with Clodronate was compared with that observed in the control group of myeloma patients treated with chemotherapy only: Clodronate provided a significant (p less than 0.001) reduction in severe bone pain as well as in the incidence of new osteolytic lesions and pathological fractures. The results of this prospective pilot trial indicate that supportive long-term treatment with parenteral Clodronate can contribute significantly to controlling the progression of myeloma bone disease.

Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling.

To test the hypothesis that the reduction in gonadal function can lead to bone mass loss, a group of 12 men who had undergone bilateral orchidectomy at the age of 28.2 +/- 6.8 yr was evaluated. A progressive loss of the lumbar bone density was observed as a function of time after orchidectomy. Both the biochemical indices of bone resorption (urinary hydroxyproline/creatinine ratio and plasma tartrate-resistant acid phosphatase) and bone formation (serum osteocalcin and bone isoenzyme of alkaline phosphatase) were significantly increased in the patients compared with healthy controls. A positive correlation was found between urinary hydroxyproline excretion and percent change in spinal bone mineral density per yr. Because of this increase in the biochemically indicated bone resorption, nine of the patients were studied again after 1-3 yr and were thereafter treated with intranasal calcitonin. Urinary hydroxyproline excretion normalized after 3 months of treatment, and a significant decrease, but not to normal levels, was also observed in the mean values for the other biochemical indices of bone remodeling. Thus, testosterone deficiency, like estrogen deficiency, is associated with accelerated bone loss. The increase in osteoresorption was partially corrected by calcitonin treatment.

A new way to induce oestrogen-deficiency osteopaenia in the rat: comparison of the effects of surgical ovariectomy and administration of the LHRH agonist buserelin on bone resorption and composition

Prolonged administration of LHRH agonist suppresses pituitary gonadotrophin secretion, thereby lowering blood oestrogen. This study was undertaken to compare the osteopaenic effects of bilateral ovariectomy and chronic administration of the LHRH agonist, buserelin, in the rat. Four groups of animals which had their skeletons labelled with 45Ca were studied for 4 weeks. Group 1 underwent a sham-ovariectomy, group 2 were surgically ovariectomized, group 3 were given buserelin by daily s.c. injection and group 4 were given a continuous infusion of buserelin by osmotic minipump. Plasma concentrations of oestradiol were measured weekly. Bone resorption was assessed by measuring the urinary excretion of 45Ca and hydroxyproline and determining bone 45Ca content. Ovariectomy and buserelin treatments lowered blood oestradiol, increased biochemical indices of bone resorption and decreased femur and total body calcium and 45Ca values. The degree of oesteopaenia elicited by ovariectomy and buserelin treatment was similar. Bone responses to s.c. buserelin and to continuous buserelin infusion were alike. We attribute evidence of increases in bone resorption and induction of osteopaenia with buserelin treatment to hypo-oestrogenism. We have shown for the first time by bone analysis that buserelin induces osteopaenia as effectively as bilateral ovariectomy. This appears to be the first demonstration in the rat that long-term administration of LHRH agonist influences bone. Administration of buserelin provides a new way of inducing oestrogen-deficiency osteopaenia in the rat without removing the ovaries.

Bone demineralization, biochemical indices of bone remodeling, and estrogen replacement therapy in adults with Turner's syndrome.

The study centered on a controversy about whether long-term estrogen replacement therapy may ameliorate the osteoporosis seen in patients with Turner's syndrome. This study comprised 26 adult patients with Turner's syndrome (9 treated and 17 untreated or insufficiently treated) and 12 adult women with pure gonadal dysgenesis (8 untreated and 4 treated). A low bone density below -2 standard deviations from the age- and sex-matched predicted normal mean was documented by dual-photon absorptiometry of the lumbar spine in all the untreated and insufficiently treated patients, but only in 6 treated patients. The biochemical indices of bone resorption (urinary hydroxyproline excretion and plasma tartrate-resistant acid phosphatase activity), as well as osteoblastic function (serum osteocalcin and bone alkaline phosphatase isoenzyme), were significantly increased in untreated and insufficiently treated patients compared with treated patients. A significant negative correlation was found between biochemically documented osteoresorption and spinal bone mineral density corrected for age of the patients. Significant positive correlations were found between serum osteocalcin and bone alkaline phosphatase isoenzyme and between biochemical indices of bone resorption and formation. Although in the patients there was an evidence of a high bone remodeling rate, the rate of bone mass loss seemed to be low, comparable with that seen in oophorectomized women who had already passed their accelerated phase of bone loss. The results indicate that long-term hormonal replacement therapy is justified in gonadal dysgenesis, regardless of the karyotype of the patient, to prevent further bone mass loss.

The application of plasma tartrate-resistant acid phosphatase to assess changes in bone resorption in response to artificial menopause and its treatment with estrogen or norethisterone

Plasma tartrate-resistant acid phosphatase (TR ACP), urinary hydroxyproline excretion (UH), serum osteocalcin, and bone alkaline phosphatase isozyme were determined in a prospective study in 31 women who had undergone bilateral ovariectomy (OOX). Nine patients were followed up for 1 year without treatment and for the following 3 years when on mestranol (M) substitution. On the basis of UH, 22 patients were identified as having increased bone resorption (BR) within 3 months of OOX. Subsequently, 11 patients were treated with transdermal estradiol (E2) and 11 patients with norethisterone (norethindrone, NE). In untreated patients, the biochemical indices of BR peaked 3-6 months following OOX and biochemical indices of bone formation (BF) continued to increase from 3 until 12 months. The substitution with both E2 or M resulted in normalization in serum and urinary calcium, serum phosphate, renal threshold phosphate concentration (TmPO4/GRF), and biochemical indices of BR within 4 months of treatment. Biochemical indices of BF normalized within 6 months of treatment. In the M-treated group, these effects continued for 3 years of the follow-up. The hormonal substitution had a protective effect on cortical and lumbar spine bone mass. A significant decrease, but not to normal values, in biochemical indices of BR and a persistent elevation in indices of BF were found in NE-treated patients. Unlike E2, NE does not depress osteoblastic function. There is strong evidence supporting the utility of measurements of TR ACP in plasma in examination of women who had ovariectomies and in assessement of the efficacy of treatment.

Prospective trial of ossein-hydroxyapatite compound in surgically induced postmenopausal women

Women with increased bone resorption induced by bilateral oophorectomy 1–5 years previously (of a total of 48 women in the study, 20 were controls, and 28 were the treatment group) were studied during a 3 year follow-up. The osseinhydroxyapatite compound (OHC) treatment provided 1.6 g calcium, 0.74 g phosphorus and 1.94 g noncollagen peptides a day. Biochemical indices of bone remodeling (urinary hydroxyproline/creatinine and calcium/creatinine ratios, bone alkaline phosphatase isoenzyme in serum and plasma tartrate resistant acid phosphatase) decreased significantly in both treatment and control groups compared with their baseline values. Biochemical indices were significantly lower in the treatment group compared to the controls after the first year, but in only half the patients after three years. By the third year these responders had significantly higher cortical area than controls. In an additional 13 women a transient response to OHC was followed by an accelerated bone loss and a return to the control values of the biochemical indices of bone resorption. In the poor responders an estrogen/progesterone substitution resulted within 6 months in a complete normalization in the biochemical parameters and in no further cortical bone loss. The results confirm a heterogeneous pattern of bone mass loss in menopause and indicate that OHC treatment is of value in preventing cortical bone loss in a portion of at-risk postmenopausal women, provided that the efficacy of the treatment is monitored.

Bone turnover in spinal osteoporosis.

We have investigated biochemical indices of bone formation and bone resorption: serum alkaline phosphatase (sAP) plasma bone Gla protein (pBGP), fasting urinary hydroxyproline corrected for creatinine (FuHP/Cr), and fasting urinary calcium corrected for creatinine (FuCa/Cr) in 43 postmenopausal women with spinal fractures. Furthermore, histomorphometric indices of bone resorption and bone formation, as well as whole body retention (WBR) of 99m-technetium-diphosphonate (99mTc-DP), were determined. The results are compared to pre- and postmenopausal normal subjects. The results showed that indices of bone formation were mutually correlated except for sAP vs. WBR. sAP, WBR, and pBGP increased with age. sAP and WBR were not different between osteoporotics and age-matched controls, while pBGP and probably histological indices of bone formation were lower in osteoporotics than in age-matched controls. pBGP--and to a lesser extent sAP--were significantly correlated with all histological parameters reflecting bone formation. Finally, biochemical indices of bone resorption were high in osteoporotic patients and poorly correlated with histological bone resorption. The discrepancy between biochemical markers of bone formation may be related to the low sensitivity of sAP and WBR. Conversely, pBGP, sAP, and WBR may reflect different aspects of osteoblastic activity and bone mineralization. Finally, our data suggest that bone turnover increases with aging and that osteoporotic patients have higher bone resorption and probably lower bone formation than age-matched controls.

Bone loss and biochemical indices of bone remodeling in surgically induced postmenopausal women

In a cross-sectional study in 214 women who had undergone bilateral oophorectomy up to 12 years previously, the maximal rate of bone loss, as judged by radiogrammetry of the metacarpals and by dual-photon absorptiometry of the lumbar spine, coincided with the peak of the dissociation between urinary hydroxyproline excretion and/or plasma tartrate resistant acid phosphatase activity and the activity of bone isoenzyme of serum alkaline phosphatase. A significant negative correlation was found between the prevalence of the biochemical indices of bone resorption relative to bone formation and/or biochemical indices of bone resorption and the change in the metacarpal cortical area per year. The prevalence of bone resorption relative to bone formation was evident even 12 years after oophorectomy, indicating continuous imbalance of bone remodeling in the patients. Accordingly, the rates of 2.8% cortical and 8% trabecular bone loss per year on the first year after oophorectomy decreased exponentially but did not become asymptotic with the slow phase of bone loss in healthy women up to 12 years after oophorectomy.

Generalised increase in bone resorption in carcinoma of the prostate.

Several indirect biochemical indices of bone resorption are increased in patients with carcinoma of the prostate and skeletal metastases. We have examined histological indices of bone resorption in biopsies from affected patients. Bone-forming surfaces and active osteoblast numbers were increased in skeletal sites adjacent to tumour tissue and indices of bone resorption were significantly increased at sites adjacent to tumour. Contrary to expectation, indices of bone resorption were also increased in bone distant from skeletal metastases. These findings suggest that prostatic cancer induces generalised loss of trabecular bone which may minimise disturbances in plasma calcium homeostasis but could contribute to morbidity.

Relative contribution of humoral and metastatic factors to the pathogenesis of hypercalcaemia in malignancy.

Some relations between metastatic bone disease and calcium homoeostasis were determined in a consecutive series of 81 patients with solid malignant tumours attending for radionuclide bone scans. Biochemical evaluation showed that bone resorption from metastatic disease was generally not enough to account for hypercalcaemia. While skeletal metastases were present in about half of the patients who developed hypercalcaemia, biochemical indices of bone resorption in these subjects were greatly increased and disproportionate to the extent of metastatic disease detected by the bone scans. Furthermore, a reduced renal phosphate threshold and increased tubular calcium reabsorption were generally observed in hypercalcaemic patients when compared with their normocalcaemic counterparts. These findings suggest that in most cases malignancy associated hypercalcaemia may be caused by the release of a humoral factor by tumour tissue which exhibits "parathyroid-hormone-like" activity with regard to bone resorption, renal phosphate threshold, and renal calcium handling. It may be postulated that this putative humoral mediator predisposes to hypercalcaemia both by stimulating generalised osteolysis and in most cases also by impairing the renal excretion of the resultant increase in filtered calcium load. While hypercalcaemia may arise as a result of metastatic bone disease alone, these data indicate that this may be the exception rather than the rule. Hence the term "metastatic hypercalcaemia" should probably be reserved for patients with extensive skeletal tumour disease in whom biochemical evaluation fails to yield evidence of an underlying humorally mediated cause.