Paget's disease in New Zealand: is it changing?
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Adult↗
Biomedical subjects
H K Ibbertson
Publications and source records attributed to H K Ibbertson.
Evidence for secular change in Paget's disease.
Death certification data has shown that death rates due to Paget's disease of bone and osteosarcoma in older people (assumed to be attributable to Paget's) declined in the latter part of the 19th and in the early 20th century, suggesting that there may be a secular trend toward less severe disease. We have reviewed a 21 year experience in a clinic specializing in Paget's disease. Data from all 1041 patients attending the clinic in this period were reviewed. Despite an increase in the susceptible population and an increased rate of referral to the clinic over this time (p = 0.012), there was a fall in the absolute numbers of patients referred with severe disease, as judged by the initial plasma alkaline phosphatase activity at presentation. In the years 1973-1978 the initial plasma alkaline phosphatase was > 500 U/L in an average of 22 new patients per year and > 1000 U/L in 12 per year. In the years 1988-1993, the figures were 12 and 3 per year, respectively. During this period, there were no other facilities offering scintigraphy or intravenous treatment for Paget's disease in the Auckland region, making it unlikely that patients with severe disease were being seen and treated elsewhere. The average age of newly referred patients rose steadily from a mean 62 years, in 1971-1973 to 71 years in 1991-1993 (p < 0.001). 534 subjects had scintiscans (52%) from which the extent of skeletal involvement was calculated. Skeletal involvement showed a significant negative correlation with year of birth (p < 0.01) but not with age or year of presentation. The proportion of patients with > 20% skeletal involvement had fallen by a third in the cohort born after 1926, compared to the cohort born before 1915. Our data demonstrate that, on average, newly referred patients with Paget's disease have less severe disease and are significantly older at diagnosis than was the case two decades ago.
Aged↗
Osteomalacia after pamidronate for Paget's disease.
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Diphosphonates↗
The effect of long- and short-term corticosteroids on plasma calcitonin and parathyroid hormone levels.
The role of calcitonin and parathyroid hormone (PTH) in corticosteroid-induced osteoporosis is controversial. We therefore measured plasma calcitonin and PTH levels in 34 adults receiving chronic pharmacological corticosteroids for obstructive airways disease, and in controls matched for age, sex, menopause, and disease. In addition, the acute effect of a 7-day course of 15 mg prednisolone daily on fasting and calcium-stimulated calcitonin was studied in 10 normal male volunteers. There was no difference in calcitonin and PTH levels in the corticosteroid-treated patients when compared with controls. The corrected serum calcium was significantly higher in the steroid-treated patients (patients mean 2.40 (SEM 0.01) mmol/liter; controls mean 2.33 (SEM 0.01) mmol/liter; P < 0.001). The short course of corticosteroids in volunteers did not alter basal or stimulated calcitonin, PTH, or calcium levels. These results suggest that neither calcitonin deficiency nor PTH excess is a feature of corticosteroid-induced osteoporosis.
Adult↗
Determinants of clinical outcome and survival in acromegaly.
OBJECTIVE: The extent to which treatment modifies the excess in morbidity and mortality in acromegaly remains uncertain. This study investigates the determinants of final outcome following therapy for acromegaly. DESIGN: A retrospective analysis of patients treated at the Departments of Endocrinology and Neurosurgery, Auckland Hospital, New Zealand. PATIENTS: One hundred and fifty-one patients (63 females and 88 males) with acromegaly or gigantism treated between the years 1964 and 1989. The mean duration of follow-up was 12 years (median 11 years). MEASUREMENTS: Patients had their age, estimated duration of symptoms preceding diagnosis, serum GH at diagnosis, presence of diabetes mellitus, cardiovascular disease, hypertension and/or osteoarthritis at diagnosis and the last known serum GH documented. The final outcome at the time of study was graded under three classes: dead (n = 32), those with major complications (n = 47) and those with minor/no complications (n = 67). RESULTS: The mean age at diagnosis of acromegaly was 41 years and the average estimated duration of symptoms prior to diagnosis was 7 years, with older patients showing longer duration of symptoms preceding diagnosis (P = 0.0002). Final outcome (dead, alive with major complications, alive and well) was significantly worse in those with older age at diagnosis (P = 0.008), longer duration of symptoms before diagnosis (P = 0.03) and higher GH at last follow-up (P = 0.0001). In multivariate analysis, survival was significantly influenced by the last known GH (P = 0.0001), presence of hypertension (P = 0.02) or cardiac disease (P = 0.03) at diagnosis, and duration of symptoms prior to diagnosis (P = 0.04). Survival in the acromegalic group, irrespective of treatment, was reduced by an average of 10 years compared with the non-acromegalic population. CONCLUSIONS: Acromegaly has a significant adverse effect on well-being and survival. The predominant determinant of outcome is the final serum GH level following treatment.
Acromegaly↗
The acromegalic rosary.
Palpable enlargement of the costochondral junctions on the anterolateral chest wall was detected in 26 of 27 patients with acromegaly. In a further study three doctors wearing eyemasks examined a further 13 acromegalic patients and 12 control subjects; costochondral enlargement was detected with a sensitivity of 77% and specificity of 86%. It was not found in normal subjects in the absence of previous chest injury. The presence and extent of costochondral enlargement was unrelated to the duration of active or cured acromegaly, the initial or present growth hormone concentrations, or other clinical features of growth hormone excess. Costochondral enlargement is a common clinical sign in acromegaly and can serve as a biological marker of previous or current growth hormone excess.
Acromegaly↗
Previous pet ownership and Paget's disease.
The relationship between pet ownership and Paget's disease (PD) of bone was investigated in 112 patients with PD who were matched with a similar number of community-based controls. There was a significantly increased frequency of dog ownership by patients with PD aged less than 60 years. Multivariate logistic regression analysis revealed that there was a significant age-related increase in risk of PD associated with past or present ownership of either dogs or cats, with younger patients having the greatest risk. These results suggest that slow virus infection of osteoclasts by paramyxoviruses acquired from pets may contribute to the development of Paget's disease in the younger patient.
Age Factors↗
Effects of aminobisphosphonate infusion on biochemical indices of bone metabolism in rheumatoid arthritis.
In a phase 1 study, seven patients with classical rheumatoid arthritis were treated with intravenous 3-amino-1-hydroxypropylidene-1-1-bisphosphonate (APD). Following this treatment, bone resorption as measured by fasting urine calcium/creatinine and hydroxyproline/creatinine ratios, was reduced. This was sustained for 6 months in only three patients. Elevations of these ratios often coincided with flares of active arthritis in the remaining four patients. Bone turnover as measured by serum osteocalcin levels was reduced in all patients but serum alkaline phosphatase levels remained unchanged. There was no consistent improvement in clinical indices of disease activity.
Adult↗
Insulin-like growth factor 1 and bone turnover in glucocorticoid-treated and control subjects.
The role of the growth hormone-somatomedin axis in the genesis of steroid osteoporosis has been studied by measuring circulating insulin-like growth factor 1 (IGF-1) levels in asthmatic subjects either receiving or not receiving therapy with oral glucocorticoids. There was no difference in IGF-1 levels between the two groups (60.6 micrograms/l (95% confidence interval 47.3-77.8) in the control subjects vs 69.1 micrograms/l (49.3-96.9) in the steroid-treated group). IGF-1 declined with age in the control subjects but not in those taking steroids. When IGF-1 levels were correlated with biochemical indices of bone turnover, a significant relationship was found with urine hydroxyproline in the control subjects (r = 0.55, P less than 0.02) but not in those taking steroids. It is concluded that glucocorticoid therapy does not alter mean circulating levels of IGF-1 but that the growth hormone-somatomedin axis may influence bone turnover in normal subjects. Interference by glucocorticoids with the normal regulation of IGF-1 and its influence on bone turnover is suggested.
Adult↗
Two-year follow-up of biphosphonate (APD) treatment in steroid osteoporosis.
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Diphosphonates↗
Prevention of steroid-induced osteoporosis with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD).
In a prospective, randomised, placebo-controlled trial comparing the effect of (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) (150 mg/day) plus calcium (1 g/day) with that of calcium alone on the bone mass of patients receiving long-term glucocorticoid therapy, the mean metacarpal cortical area in patients receiving APD increased by 1.2% between 0 and 6 months (p less than 0.06) and then remained stable between 6 and 12 months. In contrast, this index progressively declined in the placebo group (p less than 0.05 at 12 months). The two groups differed significantly in the changes at both 6 and 12 months (p less than 0.01). Mean vertebral mineral density, as measured by quantitative computed tomography, increased by 19.6% over 12 months in the APD group (p less than 0.02) but showed a non-significant decline of 8.8% in controls. The differences between the changes were again significant (p less than 0.005). Biochemical indices and bone histomorphometry indicated a reduction in bone resorption and bone formation but there was no evidence of osteomalacia. APD may thus prevent bone loss in glucocorticoid-treated patients over a year.
Calcium↗
Aminobisphosphonate inhibition of interleukin-1-induced bone resorption in mouse calvariae.
Interleukin-1 (IL-1) is probably an important lymphokine mediator of inflammation and bone resorption. IL-1 derived from mononuclear cells, a melanoma cell line (MM96 cells), and recombinant human IL-1 (rHuIL-1 beta) increased in vitro bone resorption, as measured by the release of 45Ca from cultured mouse calvariae. The 50% maximum active resorption was observed with 0.125 ng/ml or approximately 10(-11) M rHuIL-1 beta. The resorptive action of IL-1 was not entirely dependent on prostaglandin mediation, since its effect was evident when prostaglandin synthesis was inhibited in the cultures by indomethacin. IL-1-induced resorption has been shown to be inhibited by 10(-5) M 3-amino-1-hydroxypropylidene-1-1-bisphosphonate (APD). This inhibition was partially reversed by increasing doses of IL-1. In vitro toxicity studies showed that at concentrations of 10(-4) M, APD inhibited the growth of cultured MM96, murine myelomonocytic P388D1, and rat osteosarcoma UMR 106 cells, but not other mast and lymphoid cell lines. These in vitro observations may have relevance to the use of APD in bone and joint diseases in which inflammation and bone resorption are prominent.
Animals↗
Treatment of metastatic prostate carcinoma with the depot LRH analog Zoladex.
A long-acting LRH agonist (ICI 118630, Zoladex) was given by monthly subcutaneous injection to 25 patients with previously untreated symptomatic advanced prostatic carcinoma. The medication was well tolerated with the only side effect being hot flushes in 15 patients. Subjective improvement occurred in 22 patients, and disease remission or stabilization judged by objective criteria was seen in 21 and 18 patients from the total group at 3 and 6 months of treatment, respectively. Twelve of 18 patients followed for 1 year were still in objective remission/stabilization. Prostate volume measured by ultrasound decreased by a mean value of 75% and urine flow increased significantly. There were significant falls in serum testosterone and gonadotrophin levels and significant although lesser reductions in serum androstenedione and dehydroepiandrosterone. These changes were accompanied by significant reductions in serum acid and alkaline phosphatase and a rise in serum osteocalcin. Four patients (16%) experienced an initial tumor flare. Although only a small number of patients were studied, Zoladex appeared to be a well-tolerated agent for treatment of prostatic carcinoma, with an initial clinical response similar to that seen with standard endocrine therapy.
Adult↗
Zoladex treatment of symptomatic prostatic carcinoma.
The depot LH-RH agonist Zoladex was used to treat 38 patients with previously untreated symptomatic stage D2 prostate carcinoma. Side effects were minimal and patient acceptability excellent, although temporary tumor flare occurred in 11% of patients. Eighty-four percent experienced subjective improvement and 87% had objective evidence of initial disease stabilization or remission lasting 3 months. Serum levels of gonadotrophin and free testosterone as well as androgens of adrenal origin fell significantly with treatment. Long-term survival to date appears at least as good as that described for conventional endocrine therapy.
Buserelin↗
Corticosteroids and osteoporosis.
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Adrenal Cortex Hormones↗
Evidence for decreased tubular reabsorption of calcium in glucocorticoid-treated asthmatics.
Fasting urine calcium excretion was measured in 15 asthmatic patients receiving long-term glucocorticoid therapy (steroid group) and in age- and sex-matched asthmatics not receiving these drugs. In the steroid group, the mean urinary calcium/creatinine ratio and the mean calcium excretion per liter of glomerular filtrate (CaE) were both approximately twice the control values (p less than 0.005). When CaE was plotted as a function of serum calcium it more often exceeded the mean normal value in the steroid-treated patients than in the controls (p less than 0.05), suggesting a reduction in tubular calcium reabsorption. Calculation of the tubular maximum for calcium reabsorption confirmed a significant reduction in the glucocorticoid-treated patients (p less than 0.005). It is concluded that glucocorticoid drugs probably inhibit the tubular reabsorption of calcium and that this is likely to contribute to the development of osteoporosis in patients receiving this treatment.
Asthma↗
Radiological assessment of Paget's disease of bone after treatment with the bisphosphonates EHDP and APD.
The effects of therapy on the osteolytic bone lesions of Paget's disease have been assessed from serial bone radiographs. Changes in the rate of progression of lytic "wedge" lesions were measured and alterations in the texture of lytic "blade" lesions were graded on an empirical scale. Useful matching was possible using standard radiographs, although special care was needed to avoid artefacts from suboptimal positioning, magnification and variation in exposure. Serial radiographs were obtained of 57 lytic blade lesions in 54 patients receiving treatment with the bisphosphonate 1-hydroxyethylidene-1, 1-bisphosphonate (EHDP) and of 20 lesions in 20 patients treated with oral or intravenous 3-amino-1-hydroxypropylidene-1, 1-bisphosphonate (APD). Treatment with EHDP was associated with a significant deterioration in bone texture in 50% of lytic blade lesions, and with healing in only 20%. Deterioration was accompanied by an increase in local bone pain in 17% of these patients. In contrast, significant healing was observed in 17 of 20 lytic lesions (eight wedge, nine blade) within 6 months of beginning a course of intravenous or oral APD. In four of eight patients the progression of a lytic tibial wedge was arrested and in the remaining four the direction of wedge movement was reversed. In two patients the wedge had almost completely "filled in", making measurement difficult. Bone healing was usually accompanied by pain relief, reduction in skin temperature and rapid suppression of the urine hydroxyproline (uHP) into the normal range. However, in four patients who received intravenous APD, repair of lytic bone lesions was observed despite persisting elevation of uHP. These improvements with APD were sustained at 12 months, although in one patient whose biochemical indices were restored to normal the resorption front showed further progression, despite initial temporary reversal. The trends apparent in these short-term studies were also seen in four patients in whom wedge velocities were measured over periods of 6-10 years. These results confirm that after treatment of Paget's disease, bone healing or deterioration can be accurately assessed from serial standard radiographs. Reproducible matching is best achieved by ensuring that all radiographs are taken by the same radiographer. Minor alterations in radiological bone texture provide an important index of drug effect which is not always apparent from measurement of biochemical and other indices.
Aged↗
Bone mineral content in Polynesian and white New Zealand women.
The forearm bone mineral content of Polynesian and European women in New Zealand was measured to assess whether the inter-racial differences found in other populations also occurred in these two groups. The bone mineral content of the nondominant distal radius and ulna was measured by single photon absorptiometry in 123 European and 80 Polynesian women. The mean values were about 20% higher in Polynesians than in Europeans. The reason for this difference in bone mineral content is unknown but the findings do show that high bone density is not confined to African races and that inter-racial differences in bone mineral content may be more common than has been thought hitherto.
Adolescent↗