Tartrate-resistant acid phosphatase (TRAP) activity in serum: potential use in assessing bone resorption in patients with multiple myeloma

We measured serum tartrate-resistant acid phosphatase (TRAP) activity in 120 healthy subjects and 35 patients with multiple myeloma as well as urinary hydroxyproline excretion in the myeloma patients. Young subjects (0-18 years) showed higher TRAP levels (ANOVA p less than 0.01) compared with the other age classes due to the more active bone remodelling processes associated with growth. Myeloma patients with bone lytic lesions (MM+) showed higher serum TRAP values than controls (p less than 0.01). Hydroxyproline excretion was higher in MM+ patients but the difference between patients with and without bone lesions was not statistically significant. Our data suggest that serum TRAP activity may be a suitable, simple biochemical test to assess bone turnover in patients with multiple myeloma but that its clinical usefulness as a marker of bone resorption needs further evaluation.     

Zinc supplementation increases bone alkaline phosphatase in healthy men.

Zinc takes part in the metabolism of bone as a constituent of the matrix and as an activator of several metallo-enzymes. Animal in vitro and in vivo studies strongly suggest that zinc supplementation could stimulate bone formation and inhibit bone resorption but data in humans remain rare. The biological effects of 50 mg zinc given orally as gluconate in 20 healthy male volunteers were investigated in a 12 weeks double-blind placebo-controlled randomized trial. To investigate bone turnover, total alkaline phosphatases activity (ALP), bone specific alkaline phosphatase activity (BAPE) and BAP mass (BAP-M) concentration were measured as parameters of bone formation while urine calcium and C-terminal collagen peptide were determined as parameters of bone resorption. Samples were obtained in fasting subjects at baseline and after 6 and 12 weeks. In zinc treated subjects, a significant increase was observed at least after 12 weeks in total ALP (p < 0.01), BAP-M (p < 0.05) and BAP-E (p < 0.02). These parameters did not significantly change in the placebo group. Urine zinc/creatinine ratio significantly increased after 6 (p < 0.03) and 12 weeks (p < 0.04) in the zinc-treated group and was significantly different from the placebo group (p < 0.002). There was no significant effect of zinc supplementation on parameters of bone resorption. In conclusion, zinc supplementation at supraphysiological doses increased parameters of bone formation in healthy men while parameters of bone resorption remained unchanged.     

Mechanism of malignant hypercalcaemia in carcinoma of the breast.

To investigate the mechanisms of hypercalcaemia in carcinoma of the breast, 22 patients with hypercalcaemia due to metastatic carcinoma were studied and the findings compared with those obtained in normal subjects and patients with benign and malignant breast disease without hypercalcaemia. As expected, patients with metastases of bone showed biochemical evidence of increased bone resorption. Whereas all patients with hypercalcaemia had skeletal metastases, not all patients with skeletal metastases had hypercalcaemia despite considerable degrees of bone resorption. The presence of hypercalcaemia was associated with a significant increase in renal tubular reabsorption of calcium (p less than 0.001) and decreased reabsorption of phosphate (p less than 0.001) despite adequate rehydration of patients. These studies suggest that increased renal tubular reabsorption of calcium, possibly mediated by a humoral factor with activity similar to that of parathyroid hormone, contributes appreciably to the hypercalcaemia of malignant breast disease.     

What happens to defaulters from a diabetic clinic?

The annual rate at which patients defaulted from follow up at the Wolverhampton diabetic clinic between 1971 and 1981 was 4.1% overall and 3.5% in white patients. In 1982 a study was started to discover what happened to white patients, born after 1919, who defaulted from the hospital clinic. There were 162 defaulters, of whom 19 had died. Of the remaining 143 patients, 19 were attending another hospital diabetic clinic, 22 had moved out of the area, and 28 refused to participate in the study. Seventy four agreed to participate: 39 were treated with diet, 15 with oral hypoglycaemic agents, and 20 with insulin. They were matched for sex, age, treatment, and duration of diabetes with patients attending the clinic. Non-insulin dependent defaulters were significantly more overweight at diagnosis (40% v 25%; p less than 0.05) and remained more obese. They developed significantly higher diastolic blood pressure (94 v 86 mm Hg; p less than 0.02) and higher haemoglobin A1 (HbA1) concentrations (11.7% v 8.4%; p less than 0.01). They had significantly more neuropathy at reassessment (15 v 6 out of 54; p less than 0.05) and a greater incidence of new retinopathy (p less than 0.02), which correlated with their higher diastolic blood pressures (p less than 0.01) and HbA1 concentration (p less than 0.02). In defaulters who were treated with insulin only the prevalence of neuropathy was significantly different from that in controls (p less than 0.05). Defaulters received minimal medical supervision and suffered greater morbidity than regular attenders at the clinic.     

Association of a synthetic bone graft and bone marrow cells as a composite biomaterial

Porous calcium phosphates have osteoconductive properties. The aim of this study was to obtain synthetic calcium phosphate bone graft substitute. X-ray diffraction was employed to investigate the formation of the beta-tricalcium phosphate (β-TCP) phase. We evaluated the effects of bone marrow on the osteoconductivity and mechanical properties of synthetic bone graft (SG). SG cylinders loaded with bone marrow (SGBM) and SG alone were implanted into rabbits femoral condyle bone defects. Histological examinations revealed the resorption of the SG, trabecular bone with osteoblasts and osteoid substance around the implants, and colonization inside the porous β-TCP by newly formed bone. Histomorphometry conducted after three months revealed the osteoid surface to be higher in SGBM than SG (p < 0.05). The compressive strengths of SG and SGBM were significantly higher than the anatomic control at all time periods. The elastic modulus of SBG and SGBM became weaker after implantation. The present results indicate that gB-TCP is a good matrix for bone marrow, which contributes osteoinductive properties in an orthotopic. The composite biomaterial may be useful in reconstructive bone surgery.     

Plasma monomeric calcitonin as a marker of disease activity in multiple myeloma patients with osteolysis.

Circulating monomeric human calcitonin (hCT-M), parathyroid hormone, osteocalcin, alkaline phosphatase, urinary hydroxyproline, corrected serum calcium and inorganic phosphate were measured in 49 multiple myeloma patients and 49 matched controls. In patients with Durie-Salmon stage III disease hCT-M levels (16.9 +/- 5.8 ng/l, mean +/- SD) were significantly higher than controls and stage I patients (P less than 0.01), and correlated directly with corrected serum calcium (r = 0.74; P less than 0.001). In the same subgroup 14 of 15 patients had plasma hCT-M concentrations higher than the mean + 2SD of the controls. The calcium infusion test induced an increase of hCT-M in normocalcemic patients which was significantly greater in patients with advanced disease than in either controls or stage I patients. These findings suggest that hCT-M may be a biochemical index of bone resorption and disease activity in myeloma patients with osteolysis. In fact, its plasma concentrations were elevated in a large proportion (93%) of patients with severe bone involvement, and correlated directly with serum calcium. Moreover, our findings suggest the presence of a calcitonin-dependent calcium homeostatic mechanism, that protects against hypercalcemia due to tumor osteolysis.     

Prolonged increase in dietary phosphate intake alters bone mineralization in adult male rats

Excessive intake of dietary phosphate without the company of calcium causes serum parathyroid hormone (s-PTH) concentration to rise. We investigated the effect of a modest but prolonged increase in dietary intake of inorganic phosphate on the bone quantitative factors of mature male rats. Twenty Wistar rats were divided into two groups and fed a high-phosphate diet (1.2% phosphate) or a control diet (0.6% phosphate) for 8 weeks. In the beginning and at the end of the study period, femur and lumbar bone mineral density (BMD), bone mineral content and area were measured using DXA, s-PTH was analyzed from the blood sample, and after sacrifice, right femur was cut loose and processed into paraffin cuts. Bone diameter, inner diameter and cortical width was measured from the hematoxylin- and eosin-dyed femur cuts. Tibias were degraded and calcium and phosphate content was analyzed by inductively coupled plasma-mass spectrometer. Femoral BMD increased significantly more in the control group than in the phosphate group (P=.005). Lumbar BMD values decreased in both groups, and the fall was greater in the control group (P=.007). The phosphate group had significantly higher s-PTH values (P=.0135). Femoral histomorphometric values or tibial mineral contents did not differ between groups. In conclusion, increase in dietary phosphate intake caused s-PTH to rise and hindered mineral deposition into cortical bone, leading to lower BMD. The effect on trabecular bone was opposing as mineral loss was less in the lumbar spine of phosphate group animals. These results are in concurrence with the data stating that skeletal response to PTH is complex and site dependent.     

Elevated frequencies of 6-thioguanine-resistant lymphocytes in multiple sclerosis patients treated with cyclophosphamide: a prospective study

An autoradiographic assay for 6-thioguanine-resistant (TGr) lymphocytes was used to determine the frequency of in vivo derived variant T lymphocytes in peripheral blood from multiple sclerosis (MS) patients treated with monthly intravenous infusions of 750 mg/m2 of cyclophosphamide (CP). To analyze the time-course of response to CP, the MS patients were studied prospectively. Samples were obtained from the patients before the beginning of CP therapy, 4-5 times during the course of treatment, and, finally, 2 or 3 months after the completion of therapy. 2 weeks after the first CP infusion, the variant frequencies (Vfs) of the MS patients were significantly increased (p less than 0.05) above their pre-treatment values, but by 4 weeks following the first CP infusion the Vfs had fallen to normal or near-normal levels. After subsequent treatments, the frequencies of variant TGr cells were again higher than pre-treatment Vfs. However, within 7-13 weeks after the cessation of CP therapy, the Vfs of all subjects had returned to normal levels. The transient nature of the response indicates rapid in vivo selection against CP-induced TGr mutant cells. The mean pre-treatment Vf of the 4 MS patients who were cigarette smokers was 6.56 X 10(-6) which was significantly greater (p less than 0.05) than the mean Vf (1.52 X 10(-6) of the 4 MS patients who were non-smokers. The mean Vf from 8 assays of healthy non-smokers was 1.92 X 10(-6).     

Protective effect of breast feeding against infection.

OBJECTIVE--To assess the relations between breast feeding and infant illness in the first two years of life with particular reference to gastrointestinal disease. DESIGN--Prospective observational study of mothers and babies followed up for 24 months after birth. SETTING--Community setting in Dundee. PATIENTS--750 pairs of mothers and infants, 76 of whom were excluded because the babies were preterm (less than 38 weeks), low birth weight (less than 2500 g), or treated in special care for more than 48 hours. Of the remaining cohort of 674, 618 were followed up for two years. INTERVENTIONS--Detailed observations of infant feeding and illness were made at two weeks, and one, two, three, four, five, six, nine, 12, 15, 18, 21, and 24 months by health visitors. MAIN OUTCOME MEASURE--The prevalence of gastrointestinal disease in infants during follow up. RESULTS--After confounding variables were corrected for babies who were breast fed for 13 weeks or more (227) had significantly less gastrointestinal illness than those who were bottle fed from birth (267) at ages 0-13 weeks (p less than 0.01; 95% confidence interval for reduction in incidence 6.6% to 16.8%), 14-26 weeks (p less than 0.01), 27-39 weeks (p less than 0.05), and 40-52 weeks (p less than 0.05). This reduction in illness was found whether or not supplements were introduced before 13 weeks, was maintained beyond the period of breast feeding itself, and was accompanied by a reduction in the rate of hospital admission. By contrast, babies who were breast fed for less than 13 weeks (180) had rates of gastrointestinal illness similar to those observed in bottle fed babies. Smaller reductions in the rates of respiratory illness were observed at ages 0-13 and 40-52 weeks (p less than 0.05) in babies who were breast fed for more than 13 weeks. There was no consistent protective effect of breast feeding against ear, eye, mouth, or skin infections, infantile colic, eczema, or nappy rash. CONCLUSION--Breast feeding during the first 13 weeks of life confers protection against gastrointestinal illness that persists beyond the period of breast feeding itself.     

Incorporation of excess gadolinium into human bone from medical contrast agents

We find anomalously high gadolinium (Gd) concentrations in the femoral head bones of patients exposed to chelated Gd, commonly used as a contrast agent for medical imaging. Gd is introduced in chelated form to protect patients from exposure to toxic free Gd(3+), a calcium antagonist which disrupts cellular processes. Recent studies suggest Gd chelates break down in vivo, and Gd accumulation in tissue is linked to medical conditions such as nephrogenic systemic fibrosis (NSF), acute kidney failure, and in some cases death. We measure Gd and other rare earth element (REE) concentrations in 35 femoral heads by solution based ICP-MS. Gd concentrations in patients with documented exposure to Gd-based contrast agents (n = 13: Gd DTPA-BMA (Omniscan) n = 6; Gd HP-DO3A (Prohance) n = 5; unknown type n = 4) are significantly higher (p < 0.001) than the control group (n = 17). We use our control group to establish the 'natural' background level of Gd in human bone (cortical 95% CI: 0.023, 0.041 nmol/g; trabecular 95% CI: 0.054, 0.107 nmol/g). A control group outlier reveals the occurrence of individuals with high concentrations of all REEs, including Gd. Because of this, we calculate Gd anomalies from the concentrations of adjacent REEs and normalize to the control group mean to isolate Gd input from contrast agents. Normalized Gd anomalies, (Gd/Gd*)(N), for exposed patients range up to >800 times the 'natural' level (95% CI: 124, 460). Our data confirm that Gd, introduced in chelated form, incorporates into bone and is retained for more than 8 years. No difference was observed in bone Gd concentrations and anomalies between patients dosed with Gd DTPA-BMA (Omniscan; n = 6) and Gd HP-DO3A (Prohance; n = 5). Osteoporotic fracture patients exposed to Gd have significantly lower Gd concentrations than osteoarthritis patients (p < 0.001). This indicates different mechanisms of metal incorporation and/or retention in osteoporotic bone tissues, and may signal an increased risk of endogenous Gd release for patients with increased rates of bone resorption (e.g. osteoporosis patients and menopausal, pregnant, and lactating women) who are exposed to Gd-based contrast agents.     

Effect of alendronate on osteoclast differentiation and bone volume in transplanted bone.

Alendronate, one of the bisphosphonates, is known to have an inhibitory effect on bone resorption. The purpose of this study was to investigate the effects of alendronate on ectopic bone graft resorption and to determine the optimal dose in the mouse. The grafted bone in the control group disappeared due to resorption by osteoclasts within 5 weeks. In the experimental groups, the area of bone tissue decreased by only 20-40% at 5 weeks post-operatively. At 8 and 9 weeks after surgery, the decreased area of bone structure was significantly less in all the 10(-4) M injected alendronate-immersed groups than in the 10(-4) M non-injected alendronate-immersed. At 9 weeks after surgery, the number of osteoclasts were significantly less in the 10(-4) M injected alendronate-treated groups than in the 10(-4) M non-injected alendronate-treated groups. These results suggest that alendronate inhibits resorption of ectopic bone graft at concentrations of 10(-4) and 10(-6) M.     

Bone metabolism in patients with primary hyperparathyroidism before and after surgery

Primary hyperparathyroidism (PHPT) is accompanied with a reduced bone mineral density (BMD) and an increased risk of fracture. Surgery is the only option for cure. It is hypothesized that in patients with PHPT bone metabolism normalizes after parathyroidectomy (PTX) and that BMD gradually increases. Fifty-two patients with PHPT who underwent surgery were prospectively followed for 1 year. Biochemical analyses were performed at baseline and 1, 4, 7 days; 6 weeks; and 3, 6, and 12 months, and BMD before and one year after surgery. Parathyroid hormone (PTH), calcium, and the bone resorption marker dropped immediately, but transiently after PTX, bone formation decreased more slowly. Osteoprotegerin (OPG) as well as cathepsin K did not show significant changes. BMD of the lumbar spine, but not of the femoral neck, increased significantly within one year after surgery. Moderate correlations existed between the changes of total calcium, ionized calcium, as well as bone-specific alkaline phosphatase and changes of the lumbar BMD. Patients who needed postoperative supplementation with calcium and vitamin D had significantly higher PTH levels. Some gender-specific differences in patients with PHPT were observed. In patients with PHPT, males appear to be more severely affected than females. Within the first year after PTX, bone metabolism normalized, and BMD of the lumbar spine increased. Patients who needed a supplementation with calcium and vitamin D after PTX preoperatively had higher serum levels of PTH.     

Decreasing of residual alveolar ridge height in complete denture wearers. A five year follow up study

The resorption of the residual alveolar ridges is a chronic and continuous process of bone remodeling. The aim of this study was to analyse the rate of residual ridge resorption at different sites in the both jaws in complete denture wearers, through a five-year period of denture wearing. Residual ridge changes were measured on successive lateral cephalograms at 5 measurement points of the maxilla and the mandible. The first lateral radiograph was obtained at the delivery of complete dentures. The second lateral cephalogram was obtained after five years of denture wearing. Measurements were performed using a calibrated grid. The results of this study showed the existence of a significant alveolar ridge resorption at all five measurement points of the maxilla and the mandible. The observed variables, such as body mass index and the night time denture wearing had no significant influence on the rate of residual alveolar ridge resorption (p > 0.05). The duration of edentulousness had a significant influence on the rate of residual ridge resorption with significantly higher amounts of alveolar bone height decrease in those patients who had lost the last remaining teeth more recently.     

Postoperative morphine requirements of free TRAM and DIEP flaps

In a review of the charts of 158 patients who had undergone breast reconstruction with free transverse rectus abdominis musculocutaneous (TRAM) or deep inferior epigastric perforator (DIEP) flaps and who were treated for postoperative pain with morphine administered by a patient-controlled analgesia pump, the total dose of morphine administered during hospitalization for the flap transfer was measured. Patients whose treatment was supplemented by other intravenous narcotics were excluded from the study. The mean amount of morphine per kilogram required by patients who had reconstruction with DIEP flaps (0.74 mg/kg, n = 26) was found to be significantly less than the amount required by patients who had reconstruction with TRAM flaps (1.65 mg/kg; n = 132; p < 0.001). DIEP flap patients also remained in the hospital less time (mean, 4.73 days) than did free TRAM flap patients (mean, 5.21 days; p = 0.026), but the difference was less than one full hospital day. It was concluded that the use of the DIEP flap does reduce the patient requirement for postoperative pain medication and therefore presumably reduces postoperative pain. It may also slightly shorten hospital stay.     

Influence of thyroid function on serum bone Gla protein

The serum BGP level was assayed in patients with hyperthyroidism (untreated and remittent cases) and hypothyroidism. The mean serum BGP concentration was 9.7 +/- 0.90 ng/ml in 30 patients with untreated hyperthyroidism which was significantly higher than the 2.7 +/- 0.38 ng/ml in 15 remittent patients and 1.3 +/- 0.31 ng/ml in 13 patients with hypothyroidism (p less than 0.001, p less than 0.001). Serum BGP had a significant positive correlation with the concentrations of free triiodothyronine and alkaline phosphatase in the serum, while it had a significant negative correlation with serum PTH. In the patients with hypothyroidism, serum BGP increased significantly in parallel with increases in serum free triiodothyronine with thyroxine therapy. In the patients with hyperthyroidism, serum free triiodothyronine decreased significantly after the first month of methimazole treatment, and fluctuated within the normal range after two months. Serum alkaline phosphatase and BGP did not show significant changes during the first six months of treatment, although they were eventually reduced significantly at the end of one year. These results suggest that thyroid hormone directly stimulates the synthesis and secretion of BGP in existent osteoblasts and also acts on the bone remodeling cycle, therapy accelerating the rate of bone formation; the latter action may occur over a long period.     

Effect of isolation of periosteum and dura on the healing of rabbit calvarial inlay bone grafts

Little is understood about the role of the recipient site in the revascularization and incorporation of autogenous inlay bone grafts in the craniofacial skeleton. Clinical experience demonstrates that secondary complex cranial vault reconstruction performed with scarred avascular dura or poor soft-tissue coverage may undergo significant resorption, thus compromising the aesthetic outcome. This study was designed to determine the effect of isolating autogenous orthotopic inlay calvarial bone grafts from the surrounding dura and/or periosteum on graft revascularization, healing, and volume maintenance in the adult rabbit. Adult rabbits were randomized into four groups (n = 10 per group); in each rabbit, the authors created a circular, 15-mm in diameter, full-thickness cranial defect followed by reconstruction with an autogenous calvarial bone graft, which was replaced orthotopically and held with microplate fixation. Silicone sheeting (0.5 mm thickness) was used to isolate the dura (group II), the periosteum (group II), or both dura and periosteum (group IV) from the graft interface. No silicone was placed in group I. Animals were killed 10 weeks postoperatively, and calvaria were harvested to assess graft surface area, morphology, quantitative histology, fluorochrome staining, and revascularization. Grafts isolated from both the dura and periosteum exhibited significant decreases in total bone (cortical and trabecular) surface area, blood vessel count, and interface healing compared with nonisolated control grafts. Isolation of either the dura or periosteum significantly (p < 0.05) decreased blood vessel count but had no significant effect on interface healing. Isolation of the dura alone was associated with a significant (p < 0.05) decrease in graft cross-sectional surface area and dural cortical thickness compared with nonisolated control grafts, but this effect was not observed when the periosteum alone was isolated. Quantitative histology performed 10 weeks after surgery indicated that graft isolation was associated with increased marrow fibrosis and necrosis compared with nonisolated controls; it also demonstrated evidence of increased activity in bone remodeling (osteoblast and osteocyte count, new trabecular bone, and surface resorption). Triple fluorochrome staining suggested increased bone turnover in the nonisolated grafts compared with isolated grafts at 1 and 5 weeks postoperatively. This study demonstrates that isolating a rabbit calvarial inlay autogenous bone graft from the dura and/or periosteum results in significantly (p < 0.05) decreased revascularization, interface healing, and cross-sectional areas of amount of mature bone compared with nonisolated control grafts 10 weeks after surgery. At this time point, histologic examination demonstrates a paradoxical increase in bone remodeling in isolated bone grafts compared with controls. It is possible that the inhibition of revascularization results in a delayed onset of the remodeling phase of graft incorporation. However, in the model studied, it is not known whether the quantitative histologic and morphometric parameters measured in these isolated grafts exhibit a "catch-up" phenomenon at time points beyond 10 weeks after surgery. The results of this study emphasize the importance of a healthy recipient site in the healing and incorporation of calvarial bone grafts but stress the need for further investigation at later time points.     

Decreased levels of ionized calcium one year after hemithyroidectomy: importance of reduced thyroid hormones

BACKGROUND: Previously we have found reduced levels of total serum calcium and 1,25(OH)2D3 despite an unaltered stimulated parathyroid hormone (PTH) secretion 1 year after hemithyroidectomy. The present study was undertaken to elucidate the possible relationship between calcium homeostasis, thyroid hormones and bone resorption in a group of 45 consecutive patients subjected to hemithyroidectomy because of a solitary nodule. All patients had free T4 and T3 levels within normal range preoperatively. METHODS: Thyroid hormones, bone mineral and biochemical variables known to reflect calcium homeostasis were studied. Patients were divided into three separate groups depending on their pre- and postoperative thyroid hormone status. RESULTS: One year postoperatively, serum levels of free T4 were decreased and that of thyrotropin (TSH) increased in the entire group of patients. The concentration of ionized calcium was reduced from 1.25 +/- 0.05 to 1.22 +/- 0.04 (p < 0.001) despite an unaltered PTH value (2.8 +/- 1.0 vs. 3.1 +/- 1.5, p = 0.50). A significant reduction in C-terminal telopeptide type 1 collagen (1CTP) indicated decreased bone resorption 1 year after surgery (p < 0.05). Subgroup analysis showed that a reduction in ionized calcium was seen only among patients with a postoperative decrease in free T4. Patients with subclinical hyperthyroidism preoperatively presented the lowest postoperative levels of ionized calcium, significantly reduced levels of 1CTP and increased levels of phosphate and creatinine. Multiple linear regression analysis showed that age (p < 0.05) and postoperatively changed serum levels of TSH (p < 0.05), creatinine (p < 0.05), phosphate (p < 0.001) and FT4 (p < 0.01) were independently associated with altered levels of ionized calcium. CONCLUSION: We conclude that the reduction in ionized calcium 1 year after hemithyroidectomy was not due to PTH deficiency. Instead our results suggest that the reduced effects of thyroid hormones on bone and kidney function is essential.     

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.     

Bone fracture in elderly female with primary hyperparathyroidism: relationship among renal function, vitamin D status and fracture risk

Among 12 aged postmenopausal females with primary hyperparathyroidism, 5 had no bone fracture and 7 had fractures. Both serum 1,25 (OH)2D levels and creatinine clearance values in patients with fracture were significantly lower than those without fracture (p less than 0.025). In addition, significant positive correlation was observed between serum 1,25 (OH)2D levels and creatinine clearance values (p less than 0.05). These data suggest that decreased serum 1,25 (OH)2D level due to renal dysfunction may causally correlate to bone fracture in postmenopausal primary hyperparathyroidism.     

Phase II study of recombinant interferon alpha-C in patients with metastatic renal cell carcinoma

Recombinant interferon alpha-C is a new strain of the alpha interferon family. It was given to 33 patients with measurable metastatic renal cell carcinoma of whom 31 were evaluable. Protocol consisted of 3 million U/d for 2 weeks, then 3 million U/m2 every other day until progression. No complete response was observed. Three patients (9.7%) had partial response for a mean duration of 5.6 months and eight patients (25.8%) were stabilized for a mean of 4.3 months. Responsive sites were mainly lung, bone, and kidney, while side effects were generally mild. better results were observed in previously nephrectomized patients who had not received chemotherapy or hormonotherapy for recurrent or metastatic disease (p less than 0.05), and also in patients with a brief disease-free interval and short delay from presenting symptoms of the primary tumor until interferon treatment (p less than 0.05). Median survival was significantly longer in responders than in progressors (p less than 0.05). We suggest that the efficacy of recombinant interferon alpha-C in a low-dose regime versus other types of interferon as first-line therapy for inoperable, metastatic, or locally recurrent renal cell carcinoma should be investigated in a prospective, controlled, randomized study.