Metabolic balance studies in patients with Paget's disease receiving salmon calcitonin over long periods.

Metabolic balance and calcium kinetic studies were performed in four patients with Paget''s disease before treatment with salmon calcitonin and during the early and late stages of the treatment, which lasted 9 to 19 months, A significant decrease in bone turnover and 24-hour urine hydroxyproline and serum alkaline phosphatase values was observed in all patients. In contrast, the calcium, phosphorus and magnesium balances did not change significantly. In agreement with this, the partial body calcium, measured by in vivo neutron activation analysis, did not change. Intestinal calcium absorption increased initially, but returned to baseline levels 9 to 19 months after the study began. During the initial period there was a small, significant, but transient decrease in tubular reabsorption of phosphorus; this was accompanied by a significant decrease in serum phosphorus values--probably a direct effect of calcitonin rather than evidence of secondary hyperparathyroidism. Administration of salmon calcitonin to patients with Paget''s disease decreases bone turnover without affecting calcium and phosphorus balances.     

Chronic treatment of Paget's disease of bone with synthetic human calcitonin.

Twelve patients with Paget''s disease of bone were treated with synthetic human calcitonin for seven to 26 months (mean 15.3 months). This group included six patients who had previous therapy. Eleven of the 12 patients experienced relief of the symptoms associated with Paget''s disease. The initial therapy of synthetic human calcitonin 0.5-1.0 mg subcutaneously was administered daily until the alkaline phosphatase had declined to a plateau response; the dose was then decreased to thrice weekly. The major biochemical findings were a 47 percent fall in serum alkaline phosphatase and a comparable decline in 24-hour urinary hydroxyproline. Two subjects discontinued therapy because of side effects; persistent nausea and vomiting in one and a cutaneous allergic reaction in the other. Other side effects were minor. Preliminary results suggest that some patients will maintain the same biochemical response on the reduced dose but that this is not predictable by pre-treatment data. We conclude that synthetic human calcitonin is a safe and effective treatment for Paget''s disease of bone. Preliminary results suggest that the dose and frequency of administration of this agent must be individualized.     

Paget's Disease in a 5-year-old: Acute Response to Human Calcitonin

A five-year-old boy presented with a three-and-a-half-year history of repeated bone fractures and progressive bone deformity. The excretion of hydroxyproline in the urine was greatly increased, and serum alkaline phosphatase and acid phosphatase levels were very high. These abnormalities together with the findings on bone histology and radiology suggested a diagnosis of juvenile Paget''s disease. Human calcitonin reduced the bone turnover as evidenced by an immediate and sustained fall in urine hydroxyproline excretion, while calcium and phosphate balance became more positive. This treatment is therefore being continued on an outpatient basis.     

Glucagon in the Treatment of Paget's Disease of Bone

Glucagon given by intravenous infusion at a dosage of 0·2 to 0·8 mg/hour to four patients with Paget''s disease of bone resulted in a dramatic fall in plasma alkaline phosphatase. This was associated with a fall in 24-hour urinary calcium and in total urinary hydroxyproline excretion and a marked relief of bone pain.Glucagon may induce these changes by three possible mechanisms: (1) by stimulating release of calcitonin; (2) by a direct action of the hormone on bone; and (3) by stimulation of certain bone pyrophosphatases, thus altering the local mechanisms controlling the rate of bone formation and resorption.     

Treatment of Paget's Disease of Bone with Mithramycin

We report data from three patients with severe Paget''s disease of bone who were treated with mithramycin.Mithramycin infusion resulted in a fall in plasma calcium, phosphate, alkaline phosphatase, and urinary hydroxyproline excretion. There was an improvement in calcium and phosphorus balance in two of the three subjects studied. A pronounced or complete relief of bone pain occurred in all three.We suggest that mithramycin exerts its beneficial effect in Paget''s disease of bone by stimulating parathyroid hormone release. The parathyroid hormone released has a predominantly anabolic action on bone since its catabolic action is blocked by mithramycin, which inhibits bone resorption.     

Effect of calcitonin treatment on deafness due to Paget's disease of bone.

Seventeen patients with Paget''s disease of the skull and deafness were followed for nine to 18 months. Patients who received calcitonin treatment showed less deterioration in hearing than untreated patients. Calcitonin treatment may retard the progression of deafness in Paget''s disease, and further studies are indicated.     

PAGET'S DISEASE—Changes Occurring Following Treatment with Newer Hormonal Agents

From experience in six cases the anabolic steroid hormones, especially long-acting testosterone and estrogen preparations, are the treatment of choice in Paget''s disease, as in postmenopausal osteoporosis. Details of the management of three patients over a period of four years are presented.Roughly 4 per cent of the population, mostly persons over 40, show some evidence of Paget''s disease. Only a small number of them, however, have severe manifestations requiring treatment, such as pain, howing or fracture of the bones, pressure on nerves or heart failure. In rare cases malignant changes occur in the involved bone.Since the cause of Paget''s disease is not known, treatment in the past has been largely empirical. Reifenstein and Albright had advocated the therapeutic use of calcium, vitamin D and ascorbic acid, and, in postmenopausal women, administration of estrogens; but with fractures or immobilization, intake of calcium-containing foods, such as milk, must be restricted to avoid dangerous piling up of calcium and kidney stones, and fluids must be forced. In recent years anabolic steroid hormones, principally oral androgens and estrogens, have been employed by Gordan and others to promote bone repair, lessen bone pain and decrease urinary excretion of calcium. While these hormones probably do not arrest the disease, they seem to stabilize it and bring relief of symptoms.More recently, Albright and Henneman demonstrated that very large doses of corticotropin (ACTH) or cortisone resulted in immediate cessation of bone pain, decrease in urinary excretion of calcium and histologic evidence of regression of the disease process. The large doses required, however, also produce dangerous side effects, such as psychosis and osteoporosis, indicating that such treatment probably should not be continued over long periods.     

Renal Effects of Calcitonin

Porcine calcitonin in a slow-release gelatin vehicle was given by intramuscular injection to 10 patients—four with primary hyperparathyroidism, four with Paget''s disease, and two with carcinoma of the breast and hypercalcaemia. All cases showed a fall in serum calcium with an immediate rise in urine calcium. All except three patients with primary hyperparathyroidism showed a fall in serum phosphorus, but an immediate rise in urine phosphorus occurred in all cases. Urine hydroxyproline output fell in three patients with severe Paget''s disease. Urine sodium rose in all cases, but the effects on potassium, magnesium, water, and pH were not appreciably different from results obtained in four control subjects who were given the gelatin vehicle alone.The data suggest that calcitonin caused a decrease in the tubular resorption of calcium and phosphorus. The hypocalcaemic effect appeared to be due to a decrease in bone resorption in the patients with Paget''s disease but in the remaining cases could be accounted for in part or entirely by the rise in urine calcium.     

Paget's disease of bone: early and late responses to three different modes of treatment with aminohydroxypropylidene bisphosphonate (APD).

Early and late responses to treatment with either oral (600 mg/day) or intravenous (20 mg/day) (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (aminohydroxypropylidene bisphosphonate; APD) were studied in 142 patients with Paget''s disease of bone who had not previously been treated with bisphosphonate. The efficacy of three therapeutic regimens was compared: (a) oral aminohydroxypropylidene bisphosphonate given continuously until six months after the serum alkaline phosphatase activity had returned to normal (long term); (b) oral aminohydroxypropylidene bisphosphonate given until urinary hydroxyproline excretion had returned to normal (short term); (c) intravenous aminohydroxypropylidene bisphosphonate for 10 days. With either oral or intravenous treatment the decrease in urinary hydroxyproline excretion was rapid and always preceded the fall in serum alkaline phosphatase activity. Normal urinary hydroxyproline excretion is essential for return of the serum alkaline phosphatase activity to normal. Complete biochemical remission, defined as return of the serum alkaline phosphatase activity to normal, was obtained in 129 patients (91%). The median duration of remission as assessed by actuarial analysis was 2.7 years. This study found no difference in the long term among the three modes of treatment, suggesting that for most patients with Paget''s disease a short course of intravenous aminohydroxypropylidene bisphosphonate will produce longlasting, complete remission without need for maintenance treatment.     

Urinary excretion of pyridinium crosslinks: a new marker of bone resorption in metabolic bone disease

The pyridinium derivatives hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) are intermolecular crosslinking compounds of collagen which are only present in its mature form. Contrasting to the wide distribution of type I and II rollagens, HP and LP are absent from skin, ligament and fascia, and their major sources are bone and cartilage. Using a specific HPLC assay, we have determined the 24-h excretion of HP and LP crosslinks in normal adults of both sexes, in patients with primary hyperparathyroidism and in patients with Paget's disease of bone before and after intravenous treatment with aminopropylidene bisphosphonate (APB). Mean adult normal values were 33 ± 13 pmol/μmol creatinine for HP and 6.3 ± 3.4 pmol/μmol creatinine for LP. In women, menopause induced a 2–3-fold increase of HP and LP reflecting the well documented postmenopausal increase of bone turnover. In the urine of patients with primary hyperparathyroidism and of patients with active Paget's disease of bone, urinary crosslinks were significantly higher than in age-matched controls, with a mean 3- and 12-fold increase, respectively. Urinary excretion of hydroxyproline is a well recognized but poorly sensitive marker of bone turnover, reflecting resorption. In the same patients, the effect of menopause and disease state on hydroxyproline excretion was much less dramatic than on HP and LP. During intravenous APB treatment of pagetic patients, there was an early decrease of HP and LP, which was significant after 24 h and reached 62% at 4 days, contrasting with a late and milder decrease of urinary hydroxyproline. Because APB is a potent inhibitor of resorption which does not have a direct short-term effect on bone formation, these data also indicate that urinary excretion of HP and LP reflect only coilagen degradation occurring during osteoclastic resorption and not the degradation of newly synthesized collagen. We conclude that urinary HP and LP excretion represents the firs sensitive and specific marker of bone resorption. Its use should be valuable in the clinical investigation of metabolic bone diseases, especially osteoporosis.     

Urinary excretion of glycosaminoglycans in patients with postmenopausal osteoporosis.

The organic bone matrix contains glycosaminoglycans (GAG) of which the precise function and importance in bone mineralisation are still unclear. We examined 85 persons--35 healthy women (25 premenopausal [preMP] mean aged 40.7 years; 10 menopausal [MP] mean aged 59.3 years) and 50 patients with postmenopausal osteoporosis [PMOP] at a mean age 60.4 years. The dynamic of urinary excretion of GAG was measured in 24-hour collected urine by precipitation with cetylpyridinum chloride and spectrophotometry at 560 nm, corrected for the level of excretion of creatinine. There was a significant increase in GAG excretion in patients with PMOP compared with healthy persons (8.25 mg/g and 9.53 mg/g vs 24.11 mg/g; p < 0.0001). A significant positive correlation was established between GAG and calcium urinary excretion and a negative one between GAG and serum estradiol levels. During the treatment with calcitonin the excretion of GAG was decreased which can be used for monitoring the changes of bone metabolism.     

Renal Calculi

The pathogenesis of renal calculi is reviewed in general terms followed by the results of investigation of 439 patients with renal calculi studied by the author at Toronto General Hospital over a 13-year period. Abnormalities of probable pathogenetic significance were encountered in 76% of patients. Idiopathic hypercalciuria was encountered in 42% of patients, primary hyperparathyroidism in 11%, urinary infection in 8% and miscellaneous disorders in 8%. The incidence of uric acid stones and cystinuria was 5% and 2% respectively. In the remaining 24% of patients in whom no definite abnormalities were encountered the mean urinary magnesium excretion was less than normal. Of 180 patients with idiopathic hypercalciuria, only 24 were females. In the diagnosis of hyperparathyroidism, the importance of detecting minimal degrees of hypercalcemia is stressed; attention is also drawn to the new observation that the upper limit of normal for serum calcium is slightly lower in females than in males. The efficacy of various measures advocated for the prevention of renal calculi is also reviewed. In the author''s experience the administration of thiazides has been particularly effective in the prevention of calcium stones. Thiazides cause a sustained reduction in urinary calcium excretion and increase in urinary magnesium excretion. These agents also appear to affect the skeleton by diminishing bone resorption and slowing down bone turnover.     

Bone loss in response to long-term glucocorticoid therapy

A number of studies have shown that an excess of glucocorticoids induces osteoporosis, but the mechanism(s) and the time course of the reduction of bone mass remain uncertain. In order to clarify this issue we carried out a longitudinal clinical and histomorphometric study of patients requiring long-term glucocorticoid treatment.In 23 patients (9 men, 10 post- and 4 premenopausal women) biochemical and bone histomorphometric investigations were carried out before and during treatment with 10–25 mg/day of prednisone. Histomorphometric analysis of bone biopsies of the iliac crest showed that the decrease of TBV (up to −27%, P < 0.001) occurs predominantly within the first 5–7 months of treatment; during the subsequent stages, which include observations after 12 months of treatment, only minor changes were observed. Therefore trabecular bone loss can be satisfactorily described by a negative exponential function. None of the other histomorphometric parameters (osteoid surfaces, resorption surfaces, etc.) showed significant changes. However, the histological features of the bone biopsies during steroid therapy, showing a virtual lack of osteoblastic activity, ruled out an increase of bone resorption. Moreover, the dynamic study of the bone formation by double tetracycline labelling showed, in a small subgroup of patients, a decrease of the apposition rates (from 0.763 ± 0.053 to 0.305 ± 0.074 μ/day (mean ± SE) after treatment).No significant changes, at any time during steroid treatment, were observed in serum alkaline phosphatase, 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone or urinary calcium excretion. Serum calcium increased significantly within the first 1–2 months of therapy and then it returned to baseline. Urinary hydroxyproline excretion decreased significantly within the first 1–2 months and continued to fall throughout the treatment.Thus, both biochemical and histological findings suggest that long-term glucocorticoid therapy causes a reduction of bone turnover, that the bone loss occurs predominantly within the first 6 months of treatment and that patients with lower bone mass have a lower rate of bone loss.     

Development and significance of antibodies to salmon calcitonin in patients with Paget's disease on long-term treatment.

Sixteen consecutive patients in one unit were studied during long-term treatment of Paget''s disease of bone with salmon calcitonin. Eleven patients developed detectable antibody titres at some time during treatment. In one patient with a high antibody titre evidence of resistance to treatment emerged two years after the development of antibodies, but no other patient showed evidence of resistance. The clinical and biochemical response could be maintained in the absence of an acute calcium-lowering effect of calcitonin. Although antibodies often develop during treatment with heterologous calcitonin, they are only rarely the cause of clinical resistance.     

Comparison between perindopril and nifedipine in hypertensive and normotensive diabetic patients with microalbuminuria. Melbourne Diabetic Nephropathy Study Group.

OBJECTIVE--To compare the efficacy of angiotensin converting enzyme inhibition with calcium antagonism in diabetic patients with microalbuminuria. DESIGN--Randomised study of diabetic patients with microalbuminuria treated with perindopril or nifedipine for 12 months and monitored for one or three months after stopping treatment depending on whether they were hypertensive or normotensive. Patients were randomised separately according to whether they were hypertensive or normotensive. SETTING--Diabetic clinics in three university teaching hospitals. PATIENTS--50 diabetic patients with persistent microalbuminuria. In all, 43 completed the study: 30 were normotensive and 13 hypertensive; 19 had type I diabetes and 24 had type II diabetes. INTERVENTIONS--For 12 months 20 patients were given perindopril 2-8 mg daily and 23 were given nifedipine 20-80 mg daily. MAIN OUTCOME MEASURES--Albumin excretion rate, blood pressure, and glomerular filtration rate. RESULTS--Both perindopril and nifedipine significantly reduced mean blood pressure. During treatment there was no significant difference between those treated with perindopril and those treated with nifedipine with respect to albuminuria or mean blood pressure. Stopping treatment with both drugs was associated with a sustained increase in albuminuria and mean blood pressure. There was a significant correlation between mean blood pressure and albuminuria and also between the reduction in mean blood pressure and the decrease in albuminuria during treatment with both drugs. In hypertensive patients both drugs caused significant decreases in mean blood pressure and albuminuria. In normotensive patients there was no significant reduction in albuminuria with either regimen. CONCLUSIONS--In diabetic patients with microalbuminuria blood pressure seems to be an important determinant of urinary albumin excretion. Perindopril and nifedipine have similar effects on urinary albumin excretion, both preventing increases in albuminuria in normotensive patients and decreasing albuminuria in hypertensive patients.     

Thyrotoxicosis and hypercalcaemia: response to antithyroid drugs and salmon calcitonin.

Four patients with thyrotoxicosis, hypercalcaemia and metabolic bone disease are described. One of them had a 'hot nodule', T3 toxicosis and a parathyroid tumour and another had thin bones, subperiosteal cortical bone erosions and complete dysphagia. Hypercalcaemia persisted during treatment with antithyroid drugs in two patients, both of whom had hyperparathyroidism. The administration of salmon calcitonin to these two patients before starting antithyroid treatment produced an immediate and sustained fall in serum calcium and urinary hydroxyproline levels. Calcitonin administration should be of value in the early management of hypercalcaemic patients.     

Mithramycin therapy in Paget's disease

Nine patients with symptomatic Paget''s disease were treated with mithramycin in doses of 15 μg/kg/day for 10 days. All but one had considerable symptomatic improvement and, in some, pain relief was dramatic after only a few days. A progressive decrease in serum alkaline phosphatase levels and urinary hydroxyproline excretion was seen at the same time. Bone scans with technetium-99m stannous polyphosphate were performed in six patients and were grossly abnormal in all, showing increased uptake in areas approximately co-extensive with the radiological changes. In five cases improvement in the scans was seen during therapy. In those cases in which the scans had not returned to normal by the end of therapy the improvement continued and was associated with a further decrease in serum alkaline phosphatase levels. We suggest that mithramycin is effective therapy for Paget''s disease and, in the dose used, is safe.     

Malabsorption Syndrome in Paget's Disease of Bone

Of eight patients with Paget''s disease one had diarrhoea, steatorrhoea, impaired xylose absorption, and macrocytic anaemia due to folic acid deficiency, while another had diarrhoea and very low xylose absorption. In both patients jejunal biopsy was normal, and they responded to folic acid therapy with considerable increase in xylose absorption. Low xylose excretion was seen in three more patients, one of whom also had steatorrhoea. Thus malabsorption may be a systemic complication of Paget''s disease of bone, possibly due either to secondary folate deficiency or to relative ischaemia of the bowel.     

Effect of Actinomycin D on Paget's Disease of Bone

Four patients with active Paget''s disease were treated with the RNA inhibitor actinomycin D. Three were clinically improved after treatment; the fourth had multiple collapsed vertebrae and showed no symptomatic improvement. Striking changes took place in urinary calcium and hydroxyproline, in serum alkaline phosphatase, and to a less extent in serum calcium and phosphate. These studies are continuing and are being compared with the effects of mithramycin.     

Paradoxical acute hypercalcemic effect of salmon calcitonin in patients having Paget's disease of bone after treatment with dichloromethylene diphosphonate

The hypocalcemia following administration of calcitonin may be an index to disease activity in Paget's disease of bone. Therefore, we assessed the effect of a single injection of 100 MRC units of salmon calcitonin (SCT) on plasma calcium in 28 patients with active Paget's disease before and after 6 months of treatment with dichloromethylene diphosphonate (Cl2MDP) at a dose of 400 mg/day (3 patients), 800 mg/day (8 patients), 1.600 mg/day (9 patients) or 2.600 mg/day (8 patients). The mean SCT-induced hypocalcemia was reduced by Cl2MDP and there was a significant positive correlation between the decrease of serum calcium induced by SCT and bone resorption evaluated by the number of osteoclasts on bone biopsy taken in pagetic iliac crest. After Cl2MCP treatment, 5 patients manifested a paradoxical hypercalcemic response to SCT injection ranging from +0.3 mg/dl to +0.5 mg/dl, which was sustained over the 9 hours following injection. As these patients had a dramatic inhibition of bone resorption induced by Cl2 MDP, it is suggested that the hypercalcemic response to SCT might reflect persistence or exaggeration of the early hypercalcemic effect of CT which reportedly precedes the hypocalcemic response to SCT.