A preoperative decolonization protocol for staphylococcus aureus prevents orthopaedic infections.

UNLABELLED: Staphylococcus aureus (S. aureus) is an independent risk factor for orthopaedic surgical site infection (SSI). To determine whether a preoperative decolonization protocol reduces S. aureus SSIs, we conducted a prospective observational study of patients undergoing elective total joint arthroplasty (TJA) at our institution, with two control groups. The concurrent control group comprised patients of surgeons who did not participate in the intervention study. The preintervention control group comprised patients of participating surgeons who had undergone elective TJA during the year before the study. Patients in the intervention group were screened preoperatively for S. aureus by nasal swab cultures. S. aureus carriers were decolonized with mupirocin ointment to the nares twice daily and chlorhexidine bath once daily for 5 days before surgery. All 164 of 636 participants (26%) who tested positive completed the decolonization protocol without adverse events and had no postoperative S. aureus SSIs at 1-year followup. In contrast, 1330 concurrent control patients had 12 S. aureus infections. If these infections had occurred in the 26% of patients expected to be nasal carriers of S. aureus at a given time, the infection rate would have been 3.5% (12 of 345) in the control group. In addition, the overall infection rate of the participating surgeons, including nonstaphylococcal infections, decreased from 2.6% during the preintervention period to 1.5% during the intervention period, translating to an adjusted economic gain of $231,741 for the hospital. The data suggest a preoperative decolonization protocol reduces S. aureus SSIs in patients undergoing TJA. LEVEL OF EVIDENCE: Level II, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis.

Treatment effects on bone quality and remodeling was assessed in postmenopausal women with osteoporosis treated with oral alendronate. One transiliac bone biopsy was obtained from 231 women at either 24 mo (n = 11) or 36 mo (n = 120) from the start of treatment with alendronate at doses of between 5 and 20 mg/d, or placebo. 64 biopsies at 24 mo (31 from the placebo group and 33 alendronate-treated patients) and 95 biopsies at 36 mo (40 from the placebo group and 55 alendronate-treated patients) provided adequate cancellous tissue, and were analyzed by histomorphometry. Mineral apposition rate was unaffected by treatment. At 24 and 36 mo, osteoid thickness, volume, and surface significantly decreased. At each of the doses studied, mineralizing surface and activation frequency significantly decreased at each time point (e.g., -92% and -87%, respectively, for the 10 mg daily dose after 2 yr). These diminutions were of the same magnitude for each dose at 24 mo, and for the two highest doses at 36 mo. A significant increase in wall thickness accompanied by a reduction in erosion depth was detected in biopsies obtained at 24 mo. These findings confirm that mineralization is normal, and trabecular bone turnover markedly decreased in patients receiving long-term dosing with alendronate. The findings also suggest that the observed increases in bone mineral density could result both from a reduction in the remodeling space due to a decreased activation frequency and a possible trend to a positive bone balance. In addition, further studies focused on a possible increase in the degree of mineralization of bone are required.

Effects of a synthetic peptide of a parathyroid hormone-related protein on calcium homeostasis, renal tubular calcium reabsorption, and bone metabolism in vivo and in vitro in rodents.

A synthetic peptide corresponding to the first 34 amino acids of the parathyroid hormone-related protein (PTH-rP) produced by a human tumor associated with hypercalcemia was examined for skeletal and renal effects on calcium metabolism in vivo and in vitro. These effects were compared with those of human parathyroid hormone (1-34), hPTH (1-34). Equal doses of PTH-rP(1-34) and hPTH(1-34) produced equivalent stimulation of adenylate cyclase in vitro in bone cells and kidney cells and tubules. Subcutaneous injection of PTH-rP(1-34) in mice caused a significant dose-related increase in blood ionized calcium similar to that seen with hPTH(1-34) at equivalent doses. Repeated injections of equal doses of both peptides caused sustained hypercalcemia which was significantly greater in PTH-rP(1-34)-treated mice, although each induced comparable increases in histomorphometric indices of osteoclastic bone resorption. PTH-rP(1-34) and hPTH(1-34) also caused similar increases in bone resorption when incubated with fetal rat long bones in organ culture. Infusion of either peptide into thyroparathyroidectomized rats suppressed urinary calcium excretion and increased urinary excretion of cyclic AMP. PTH-rP appears to have similar effects to those of PTH on the skeleton, the kidney, and overall calcium homeostasis.

TRAIL-induced apoptosis in U-1242 MG glioma cells.

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induces apoptosis in U-1242 MG cells. To investigate the molecular events involved in this process, we studied the effects of TRAIL on the localization within membrane fractions of molecules critical to the extrinsic apoptotic pathway. We report here that death receptor-5 (DR5), tumor necrosis factor receptor-1 (TNF-R1), and Fas receptor (FasR) are all located in the caveolin-1-enriched membrane fractions, and TRAIL caused the translocation of DR5, FasR, and TNF-R1 to the caveolar fractions. Caspase-8 is mainly located outside of caveolae, but TRAIL caused it to redistribute to the caveolin-1-enriched fractions where it was cleaved. Within 6 hours, the cleaved caspase-8 appeared in the high-density, noncaveolin fractions. Using confocal microscopy, we found that DR5, caspase-8, and caveolin-1 became progressively concentrated in blebs of plasmalemma as they formed in response to TRAIL. Our results provide the first evidence for the caveolar localization of TNF-R1 and DR5 and the coordinated redistribution among membrane fractions of several death receptors in response to TRAIL. We propose that the coordinated movement of these molecules among membrane compartments is probably an important component of the mechanisms regulating and initiating the extrinsic apoptotic pathway in human glioma cells.

Effects of interferon and gangliosides on growth of cultured human glioma and fetal brain cells.

Human beta-interferon (IFN) induced an antiviral state in two fetal brain and six glioma cell lines. The growth-inhibitory effect of IFN was most pronounced on three glioblastoma lines and least on fetal brain and oligodendroglioma cells; IFN growth inhibition of one schwannoma and one anaplastic cell line was intermediate between the two other groups. Thus, the growth-inhibitory effect of IFN generally correlated with the degree of anaplasia of the tissue from which the cells were derived. IFN (1000 units/ml) had to be present for 24 to 48 hr to have a significant inhibitory effect on growth of glioblastoma (12-18) cells. However, growth inhibition of 12-18 cells exposed to IFN for 3 days persisted for 3 weeks. Both sialic acid-N-acetylgalactosamine ganglioside and a mixture of normal human brain gangliosides (50 microM) inhibited growth of fetal brain (CHII) but not glioblastoma 12-18 cells. However, preincubation of cells with either sialic acid-N-acetylgalactosamine or a mixture of gangliosides did not augment the growth-inhibitory effects of IFN on either CHII or 12-18. These results indicate that gangliosides and IFN may be operating through different mechanisms to cause growth inhibition.

Age and TP53 mutation frequency in childhood malignant gliomas: results in a multi-institutional cohort.

Malignant astrocytoma is one of the most deadly primary central nervous system tumors. Although significant progress has been made in understanding the molecular pathways that lead to the development of these tumors in adults, comparatively little analysis has been done in childhood astrocytomas, which are less common and have a more favorable prognosis. Our previous studies of an institutional cohort of children with malignant gliomas suggested the existence of distinct molecular pathways of tumorigenesis in younger versus older children, based on the finding of a high frequency of TP53 mutations in tumors from children >3 years of age at diagnosis, compared with those from younger children. In the current study, the association between TP53 mutations and age was examined in greater detail using the multi-institutional group of children enrolled in Children's Cancer Group Study 945, the largest cohort of childhood high-grade gliomas analyzed to date. Seventy-seven tumors with centrally reviewed diagnoses of anaplastic astrocytoma or glioblastoma multiforme had sufficient archival histopathological material for microdissection-based genotyping. Sections were examined histologically, and topographic targets that contained malignant tissue were isolated by microdissection and subjected to PCR-based amplification and sequencing of TP53 exons 5-8. Twenty-six tumors (33.8%) had mutations in those exons. Mutations were observed in 2 of 17 tumors (11.8%) from children <3 years of age at diagnosis versus 24 of 60 tumors (40%) from older children, a difference that was statistically significant (P = 0.04), in agreement with our previous results. Whereas malignant gliomas in older children have a frequency of mutations comparable to tumors that arise in young adults, those from children <3 years old do not. The association between age and frequency of TP53 mutations among pediatric malignant gliomas indicates the probable existence of two distinct pathways of molecular tumorigenesis in younger versus older children.

Gangliosides inhibit platelet-derived growth-factor-stimulated increases in intracellular calcium in Swiss 3T3 cells.

Individual Swiss 3T3 cells stimulated by platelet-derived growth factor delivered by means of a picopump device respond with a brisk, large, and sustained increase in intracellular calcium concentration ([Ca2+]i). Preincubation of cells with either GM1 or GT1b gangliosides inhibited the proportion of responding cells and caused a dose-related diminution in the magnitude of the increase in [Ca2+]i. This effect of ganglioside is probably part of the mechanism through which gangliosides exert their biological effects, including inhibition of platelet-derived growth-factor-induced mitogenesis.

Phospholipase A2 activities with a plasmalogen substrate in brain and in neural tumor cells: a sensitive and specific assay using pyrenesulfonyl-labeled plasmenylethanolamine.

We have developed a new assay method for phospholipase A2 (EC 3.1.1.4.), towards ethanolamine plasmalogen using pyrenesulfonyl-labeled plasmenylethanolamine as the substrate. This procedure is sensitive to about 3 pmol/ml per min and is absolutely specific for plasmalogen. In this method, the product of phospholipase A2, pyrenesulfonyl-labeled lysoplasmalogen, is hydrolyzed to aldehyde and labeled glycerophosphoethanolamine with hydrochloric acid exposure, and after TLC separation, the pyrenesulfonyl-glycerophosphoethanolamine is quantitated spectrofluorometrically. The excitation and emission wave lengths were 340 and 376 nm, respectively. The activity of bovine brain homogenate was 44.1 +/- 6.47 pmol/min per mg protein (n = 3). Among bovine brain subcellular fractions, the distribution and specific activity of the enzymes were highest in cytosol (38.7 +/- 1.58% and 102.6 +/- 16.2 pmol/min per mg protein, n = 3). The activities of neural tumor cells, PC12 pheochromocytoma, Neuro2A and SKNSH neuroblastoma and U1242MG glioblastoma, were 34.4 +/- 6.83 (n = 5), 7.05 +/- 0.97 (n = 4), 5.25 +/- 1.69 (n = 5), and 9.68 +/- 1.35 (n = 4), pmol/min per mg protein (M +/- S.E.M.), respectively.

A comparative study of the glycolipids of human, bird and fish testes and of human sperm.

The glycolipids of human testis and sperm have been compared. Both adult testis and the sperm exhibited remarkably complex, but generally similar, patterns of glycolipids. In particular, both contained appreciable amounts of the sulfogalactosylmonoalkylmonoacylglycerol, recently shown to be the principal glycolipid of the testis and sperm of a number of animals. In contrast, immature (prebuteral) human testis did not contain this compound. To extend knowledge on the possible distribution of sulfogalactosylmonoalkylmonoacylglycerol in the testes of other chordates, we have also analysed the glycolipids of the testes of a number of birds and fish. None of the testes from these species contained the above compound. Instead, sulfogalactosylceramide was found to be a major glycolipid of the testis of mature fowl, duck and skate-fish and sulfogalactosylglucosylceramide of the testis of mature salmon and trout. Immature duck testis contained only a trace of sulfogalactosylceramide. These studies reveal intriguing differences between the sulfatides of various chordates, lend support to the concept that sulfatides increase markedly in testis at a specific stage of spermatogenesis and suggest an important role for sulfatides in testicular and spermatozoal function.

Randomized phase III trial in childhood high-grade astrocytoma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day regimen. Childrens Cancer Group.

PURPOSE: In a previous randomized trial, the addition of adjuvant chemotherapy to postoperative radiotherapy proved beneficial in the treatment of childhood high-grade astrocytomas. The present study tests the hypothesis that an eight-drug adjuvant chemotherapy regimen would improve survival in such children compared with the three-drug regimen of the prior study. PATIENTS AND METHODS: Between April 1985 and May 1990, patients between the ages of 18 months and 21 years with newly diagnosed high-grade astrocytomas were eligible for this study, as determined by the treating institution's histopathologic diagnosis. Treatment consisted of postoperative local-field radiotherapy and adjuvant chemotherapy, either lomustine (CCNU), vincristine, and prednisone (control regimen) or eight-drugs-in-1-day chemotherapy (experimental regimen). Two cycles of postoperative preirradiation chemotherapy were administered in the experimental regimen. Patients were evaluated radiographically every 3 months after irradiation. RESULTS: Eighty-five eligible patients were randomized to the control regimen and 87 to the experimental regimen. The progression-free survival (PFS) and overall survival (OS) at 5 years were 33% (SE = 5%) and 36% (SE = 6%), respectively. There was no statistical difference in outcome between the two chemotherapy regimens. In patients with confirmed diagnoses of anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM), anaplastic astrocytoma, greater than 90% resection, and nonmidline tumor location were characteristics predictive of an improved PFS. There was a difference in toxicity between the two chemotherapeutic regimens, with greater myelosuppression and hearing loss in the experimental regimen. Tumor recurrence occurred primarily within the primary tumor site. CONCLUSIONS: There is no benefit to the treatment of high-grade astrocytomas in children with eight-drugs-in-1-day chemotherapy compared with CCNU, vincristine, and prednisone. Extent of tumor resection and histopathologic diagnosis are significant prognostic variables. The overall outcome for children with high-grade astrocytomas remains poor.

Pilot study of high-dose thiotepa and etoposide with autologous bone marrow rescue in children and young adults with recurrent CNS tumors. The Children's Cancer Group.

PURPOSE: This study was designed to determine the toxicity, radiographic response rate, and outcome following high-dose thiotepa, etoposide, and autologous bone marrow rescue (ABMR) for young patients with recurrent malignant brain tumors. METHODS: Eligibility criteria required adequate renal, hepatic, and pulmonary function, and no bone marrow infiltration. Thiotepa 300 mg/m2 and etoposide 500 mg/ m2 were infused on 3 consecutive days, and autologous bone marrow was infused 72 hours following chemotherapy. RESULTS: Forty-five patients with recurrent high-grade brain tumors, aged 8 months to 36 years (median, 8 years), were treated. Seven patients (16%) died of treatment-related toxicities within 56 days of marrow reinfusion. Delayed platelet engraftment occurred in 44% of patients who survived beyond day 56. Of 35 patients with radiographically measurable disease who survived at least 28 days following ABMR, there were two complete responses (CRs) and six partial responses (PRs), for an overall response (CRs plus PRs) rate of 23% (SE = 7%). Objective responses were observed in four of 14 assessable patients with high-grade glioma and in two of six with primitive neuroectodermal tumors (PNETs)/ medulloblastoma. Survival was significantly improved in patients treated with minimal residual disease (P < .0005). Five of 18 patients (28%) with high-grade gliomas remain free of disease at 39+, 44+, 49+, 52+, and 59+ months post-ABMR. CONCLUSION: The combination of high-dose thiotepa and etoposide has activity against a variety of recurrent childhood brain tumors. These results merit further evaluation in children and young adults with both recurrent and newly diagnosed high-grade brain tumors.

Over-representation of PPARgamma sequence variants in sporadic cases of glioblastoma multiforme: preliminary evidence for common low penetrance modifiers for brain tumour risk in the general population.

PPARgamma, the gamma isoform of a family of peroxisome proliferator activated receptors, plays a key role in adipocyte differentiation. Recently, its broad expression in multiple tissues and several epithelial cancers has been shown. Further, somatic loss of function mutations in PPARgamma have been found in primary colorectal carcinomas. We sought to determine if somatic high penetrance mutations in this gene might also play a role in glioblastoma multiforme (GBM). We also examined this gene to determine if common low penetrance polymorphic alleles might lend low level susceptibility to GBM in the general population. No somatic high penetrance mutations were detected in 96 sporadic GBMs. However, polymorphic alleles at codons 12 and 449 were significantly over-represented among the 27 unrelated American patients with sporadic GBM compared to 80 race matched controls. While nine (33%) were heterozygous for the P12A variant, c.34C/G (cytosine to guanine change at nucleotide 34), 12 (15%) controls were heterozygous for P12A (p<0.05). Similarly, 13 of 26 (50%) glioblastoma patients compared to 10 of 80 (12%) normal controls were found to have the heterozygous H449H polymorphism (p<0.001). The over-representation of H449H in glioblastoma patients was confirmed with a second validation set of American patients. When both American series were combined, polymorphic H449H was over-represented among cases versus controls (p<0.001) and there was a similar trend (p=0.07) for P12A. The precise mechanism for this association is unknown but these PPARgamma polymorphisms may be acting in a low penetrance predisposing manner. However, these associations were not found in a German population, possibly arguing that if these variants are in linkage disequilibrium with a third locus, then this effect is relatively new, after the settlement of the American colonies.

Phalangeal bone density and hip fracture risk.

OBJECTIVE: To assess the long-term predictive usefulness of radiographic absorptiometry measurements of phalangeal bone density for hip fracture risk. METHODS: Participants were members of the First National Health and Nutrition Examination Survey Epidemiologic Follow Up Study cohort. Subjects were followed up for a maximum of 16 years. The First National Health and Nutrition Examination Survey data were obtained from a nationally representative sample of non-institutionalized civilians. A cohort of 3481 white and black subjects (1559 white women) aged 45 through 74 years at baseline (1971-1975) were observed through 1987. Ninety-eight percent of the original cohort completed the study. Hospital records and death certificates were used to identify a total of 72 hip fracture cases. Phalangeal bone density at baseline was measured using photodensitometry (PD), and later reanalyzed by radiographic absorptiometry (RA), a newer, more sophisticated technique. RESULTS: Results were evaluated to determine the relative risk for hip fracture per 1-SD decrease in bone density, after controlling for age at baseline, race, gender, weight, and previous fractures. Both RA and PD measurements showed a significant inverse relationship to hip fracture risk, with RA density measurements showing a slightly higher adjusted relative risk per 1-SD density decrease than PD measurements. For RA bone density, the relative risk for all subjects was 1.81 (95% confidence interval, 1.34-2.44) compared with 1.57 (95% confidence interval, 1.19-2.07) for PD bone density after adjusting for age at baseline, race, gender, weight, and previous fractures. Results for white women were essentially the same as those for all subjects for RA bone density and PD bone density. CONCLUSIONS: Phalangeal bone density determined from standard hand x-ray films is a significant predictor of future hip fracture risk. Availability of a valid method to assess fracture risk using conventional radiographs will expand the ability to identify individuals with osteoporosis.

Effect of alendronate on limited-activity days and bed-disability days caused by back pain in postmenopausal women with existing vertebral fractures. Fracture Intervention Trial Research Group.

BACKGROUND: Women with new vertebral fractures have an increased risk of back pain and functional limitation because of back pain. Alendronate sodium treatment reduces the risk of new vertebral fracture by 50% in postmenopausal women with osteoporosis. OBJECTIVE: To determine the effect of alendronate therapy on days affected by back pain in postmenopausal women with existing vertebral fractures. DESIGN: Three-year, placebo-controlled, randomized, double-blind study. SETTING: Fifteen university-based research clinics in the United States. PARTICIPANTS: A total of 2027 postmenopausal women aged 55 to 81 years with low femoral neck bone density and a preexisting vertebral fracture. INTERVENTION: Alendronate sodium (5 mg/d for 2 years and 10 mg/d for the third year) or placebo. MAIN OUTCOME MEASURES: Occurrence and severity of back pain, number of days with back pain, and number of days of bed rest or limited activity because of back pain during 3 years of follow-up. RESULTS: Irrespective of treatment assignment, women with new, clinically recognized vertebral fractures during follow-up had an increased risk of days of bed disability and days of limited activity because of back pain after the fracture. Women receiving alendronate reported an average of 3.2 fewer days of bed rest (P = .001) and 11.4 fewer days of limited activity (not including days of bed rest) because of back pain (P = .04) during follow-up than those receiving placebo. In the alendronate group, relative to the placebo group, there was a reduced risk of 1 or more bed-rest days (relative risk, 0.68; 95% confidence interval, 0.53-0.87), of 7 or more bed-rest days (0.44; 0.30-0.64), and of 7 or more limited-activity days (0.87; 0.76-0.99). There were no statistically significant differences between treatment groups in the frequency of days of back pain or increases in back-related disability between baseline and study end. CONCLUSION: In postmenopausal women with preexisting vertebral fracture, alendronate therapy for 3 years reduced the number of days of bed disability and days of limited activity caused by back pain.

In vivo effects of human recombinant transforming growth factor beta on bone turnover in normal mice.

Reports of the effects of TGF-beta on bone cells are conflicting and controversial. Different cell culture and organ culture models for both osteoblasts and osteoclasts have given different responses. In some the effects are dependent on prostaglandin synthesis, and in others they are prostaglandin independent. To determine the effects of TGF-beta on osteoblasts and osteoclasts in vivo and the role of prostaglandins in mediating these effects, we injected 2.5-5 micrograms TGF-beta into the subcutaneous tissue overlying the calvariae of normal mice for 2-5 days anc compared the morphologic responses in underlying calvarial bone with those in mice injected caused a marked increase in periosteal thickness (fivefold) and cellularity, morphologic changes in osteoblasts, and new mineralized bone formation. These effects were localized to the site of injection and were partially inhibited by concomitant indomethacin treatment. There was a parallel increase in osteoclast numbers in adjacent marrow spaces, and the osteoclasts formed were unusually large. In contrast, no increase in the numbers of osteoclasts was seen in indomethacin-treat animals. These data show that TGF-beta has powerful effects on local bone cell function in vivo and that these effects may be mediated, in part, by prostaglandin generation.

Inhibition of bone resorption by inorganic phosphate is mediated by both reduced osteoclast formation and decreased activity of mature osteoclasts.

High concentrations of inorganic phosphate (Pi) are known to inhibit bone resorption, although the mechanism(s) underlying this effect is unclear. To investigate whether Pi can inhibit the formation of osteoclasts we studied the effects of changes in Pi concentration between 1 and 4 mM on osteoclast-like cell formation in 1 week cultures of mouse bone marrow. Osteoclast-like cells were identified by multinuclearity, positive staining for tartrate-resistant acid phosphatase (TRAP), and contraction in response to calcitonin. Increasing concentrations of Pi inhibited formation of these cells in a dose-dependent manner. To study effects of Pi on the bone-resorbing activity of mature osteoclasts we isolated osteoclasts from calcium-deficient egg-laying hens or rat pups and incubated them on sperm whale dentine slices. High Pi concentrations markedly reduced both the number of resorption pits formed per dentine slice and the mean area of each pit in both avian and mammalian systems. These data indicate that high concentrations of Pi act on bone directly, both to inhibit generation of new osteoclasts from their precursor cells and to inhibit bone resorption by mature osteoclasts. These effects of extracellular Pi concentration may play an important modulatory role on bone turnover in vivo and have potential importance in several disease states in which Pi metabolism is perturbed.

Bisphosphonate effects and the bone remodeling transient.

Published randomized clinical trial data for alendronate, given at a dose of 10 mg/day, were fitted by a computer algorithm to the currently accepted model of the bone remodeling process. The purpose was to determine how much of the reported improvement in lumbar spine bone density could be attributed to the inevitable remodeling transient and how much might represent positive bone balance. Very good fits to the clinical data were easily obtained, indicating the general validity of current syntheses of bone remodeling biology. The best fit was provided by simulations produced by combinations of 36-38% suppression of remodeling activation and positive remodeling balance ranging from 1.1 to 1.4% per year. Whole body bone biomarker changes would have suggested both a slightly greater degree of suppression and a higher baseline level of remodeling than could be provided by any of the simulations if they were to fit the clinical data. Either regional skeletal heterogeneity or lack of a one-to-one quantitative relationship between remodeling changes and biomarker changes may explain the discrepancies between the two approaches.

Forskolin augments the effects of calcitonin on cytoplasmic spreading of isolated rat osteoclasts and plasma calcium levels in the rat.

Recently we have shown that forskolin acts synergistically with calcitonin on stimulation of cyclic AMP (cAMP) production in isolated rat osteoclasts and now show that forskolin also augments later physiological responses to calcitonin. The sensitivity of calcitonin inhibition of cytoplasmic spreading in isolated rat osteoclasts was increased 3.5-fold by simultaneous treatment with 10(-7) M forskolin, which alone had no effect on the response. In weanling rats the threshold of the hypocalcemic response to salmon calcitonin was reduced fivefold by simultaneous treatment with 200 micrograms/kg forskolin i.v., which alone did not influence the plasma calcium. These results provide further evidence that calcitonin-induced inhibition of osteoclast function is mediated by elevation of cAMP levels and suggest that forskolin could be used to augment the therapeutic effects of calcitonin.

Aminohexane diphosphonate in the treatment of Paget's disease of bone.

We studied the effects of the intravenous or oral administration of aminohexane diphosphonate (AHDP) in 42 patients with active Paget's disease of bone. Treatment of mouth (400 mg daily for 1 month) or intravenously (25 mg or 50 mg daily for 5 days) induced marked suppression of biochemical indices of disease activity. Urinary excretion of hydroxyproline fell to 39 and 42% of pretreatment values (oral and IV treatments respectively), and was followed by a similar decrease in the serum activity of alkaline phosphatase. In both groups of patients, disease activity remained suppressed for the 6 months of followup, and pain improved in 34 out of 37 patients who had bone pain attributed to Paget's disease. Both biopsies indicated that osteoblast and osteoclast numbers decreased with no adverse effects on mineralization. Neither regime was associated with significant side effects. We conclude that short courses of AHDP provide a promising treatment for the long-term control of Paget's disease.

Low body mass index is an important risk factor for low bone mass and increased bone loss in early postmenopausal women. Early Postmenopausal Intervention Cohort (EPIC) study group.

Thinness (low percentage of body fat, low body mass index [BMI], or low body weight) was evaluated as a risk factor for low bone mineral density (BMD) or increased bone loss in a randomized trial of alendronate for prevention of osteoporosis in recently postmenopausal women with normal bone mass (n = 1609). The 2-year data from the placebo group were used (n = 417). Percentage of body fat, BMI, and body weight were correlated with baseline BMD (r = -0. 13 to -0.43, p < 0.01) and 2-year bone loss (r = -0.14 to -0.19, p < 0.01). Women in the lowest tertiles of percentage of body fat or BMI had up to 12% lower BMD at baseline and a more than 2-fold higher 2-year bone loss as compared with women in the highest tertiles (p