Association between telemedicine use and diabetes risk factor assessment and control in a primary care network.

PURPOSE: Our study examined whether telemedicine use in primary care is associated with risk factor assessment and control for patients with diabetes mellitus. METHODS: This was a retrospective, 1:1 propensity score matched cohort study conducted in a primary care network between February 2020 and December 2020. Participants included patients with diabetes mellitus, ages 18 to 75. Exposure of interest was any telemedicine visit. We determined whether hemoglobin A1c (HbA1c), blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) were assessed for each patient. For each risk factor, we also determined whether the risk factor was controlled when they were assessed (i.e., last HbA1c < 8.0%, BP < 130/80 mmHg, LDL-C < 100 mg/dL). RESULTS: After 1:1 propensity score matching, we identified 1,824 patients with diabetes during the study period. Telemedicine use was associated with a lower proportion of patients with all three risk factors assessed (162/912 [18%], versus 408/912 [45%], p < 0.001). However, when individual risk factors were assessed, telemedicine use did not impact risk factor control. When compared with patients with in-person visit only, the odds ratio (OR) for HbA1c < 8% was 1.04 (95% CI 0.74 to 1.46, p = 0.23) for patients with any telemedicine visit. Similarly, the OR for BP < 130/80 mmHg was 1.08 (95% CI 0.85-1.36 p = 0.53), and the OR for LDL-C < 100 mg/dL was 1.14 (95% CI 0.76-1.72, p = 0.52). CONCLUSIONS: Telemedicine use was associated with gaps in risk factor assessment for patients with diabetes during the COVID-19 pandemic, but had limited impact on whether risk factors were controlled.

Determinants of imminent fracture risk in postmenopausal women with osteoporosis.

In elderly women with osteoporosis, prior fracture, low BMD, impaired physical functioning, poorer general health, and recent falls were all direct predictors of imminent (in next year) fracture risk. Prior fracture, older age, worse health, impaired cognitive functioning, and recent falls indirectly increased imminent risk by reducing physical functioning/general health. INTRODUCTION: This study was designed to examine determinants of imminent risk of osteoporotic fracture (i.e., next 1-2 years) in postmenopausal women. METHODS: This retrospective cohort study used data from Caucasian women age 65 or older with osteoporosis who participated in the observational Study of Osteoporotic Fractures (SOF). We examined potential direct and indirect predictors of hip and nonvertebral fractures in 1-year follow-up intervals including anthropometric measures, bone mineral density (T-score), fracture since age 50, physical function, cognition, medical conditions, recent (past year) falls, and lifestyle factors. Clinically related variables were grouped into constructs via factor analysis. These constructs and selected individual variables were incorporated into a theoretical structural equation model to evaluate factors that influence imminent risk. RESULTS: Among 2261 patients, 19.4% had a nonvertebral fracture and 5.5% had a hip fracture within 1 year of a study visit between 1992 and 2008. Prior fracture, lower T-scores, lower physical functioning, and recent falls all directly increased 1-year risk of nonvertebral fracture. For both nonvertebral and hip fractures, prior fracture and recent falls influenced risk indirectly through general health, while cognition influenced risk via physical functioning. Age influenced both physical functioning and general health. CONCLUSIONS: Several established risk factors for 10-year fracture risk also played a role in predicting imminent risk of fracture (e.g., T-scores, prior fracture), as did falls, cognition, physical functioning, and general health. Fracture risk assessments should also consider falls and fall risk factors as well as established bone-related risk factors in assessing imminent fracture risk.

A single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of romosozumab.

This phase 2 study evaluated the efficacy and safety of transitioning to zoledronate following romosozumab treatment in postmenopausal women with low bone mass. A single dose of 5 mg zoledronate generally maintained the robust BMD gains accrued with romosozumab treatment and was well tolerated. INTRODUCTION: Follow-on therapy with an antiresorptive agent is necessary to maintain the skeletal benefits of romosozumab therapy. We evaluated the use of zoledronate following romosozumab treatment. METHODS: This phase 2, dose-finding study enrolled postmenopausal women with low bone mineral density (BMD). Subjects who received various romosozumab doses or placebo from months 0-24 were rerandomized to denosumab (60 mg SC Q6M) or placebo for 12 months, followed by open-label romosozumab (210 mg QM) for 12 months. At month 48, subjects who had received active treatment for 48 months were assigned to no further active treatment and all other subjects were assigned to zoledronate 5 mg IV. Efficacy (BMD, P1NP, and ß-CTX) and safety were evaluated for 24 months, up to month 72. RESULTS: A total of 141 subjects entered the month 48-72 period, with 51 in the no further active treatment group and 90 in the zoledronate group. In subjects receiving no further active treatment, lumbar spine (LS) BMD decreased by 10.8% from months 48-72 but remained 4.2% above the original baseline. In subjects receiving zoledronate, LS BMD was maintained (percentage changes: - 0.8% from months 48-72; 12.8% from months 0-72). Similar patterns were observed for proximal femur BMD in both groups. With no further active treatment, P1NP and ß-CTX decreased but remained above baseline at month 72. Following zoledronate, P1NP and ß-CTX levels initially decreased but approached baseline by month 72. No new safety signals were observed. CONCLUSION: A zoledronate follow-on regimen can maintain robust BMD gains achieved with romosozumab treatment.

Risk of subsequent fracture after prior fracture among older women.

Among 377,561 female Medicare beneficiaries who sustained a fracture, 10% had another fracture within 1 year, 18% within 2 years, and 31% within 5 years. Timely management to reduce risk of subsequent fracture is warranted following all nontraumatic fractures, including nonhip nonvertebral fractures, in older women. INTRODUCTION: Prior fracture is a strong predictor of subsequent fracture; however, postfracture treatment rates are low. Quantifying imminent (12-24 month) risk of subsequent fracture in older women may clarify the need for early postfracture management. METHODS: This retrospective cohort study used Medicare administrative claims data. Women ≥ 65 years who sustained a clinical fracture (clinical vertebral and nonvertebral fracture; index date) and were continuously enrolled for 1-year pre-index and ≥ 1-year (≥  2 or ≥ 5 years for outcomes at those time points) post-index were included. Cumulative incidence of subsequent fracture was calculated from 30 days post-index to 1, 2, and 5 years post-index. For appendicular fractures, only those requiring hospitalization or surgical repair were counted. Death was considered a competing risk. RESULTS: Among 377,561 women (210,621 and 10,969 for 2- and 5-year outcomes), cumulative risk of subsequent fracture was 10%, 18%, and 31% at 1, 2, and 5 years post-index, respectively. Among women age 65-74 years with initial clinical vertebral, hip, pelvis, femur, or clavicle fractures and all women ≥ 75 years regardless of initial fracture site (except ankle and tibia/fibula), 7-14% fractured again within 1 year depending on initial fracture site; risk rose to 15-26% within 2 years and 28-42% within 5 years. Risk of subsequent hip fracture exceeded 3% within 5 years in all women studied, except those < 75 years with an initial tibia/fibula or ankle fracture. CONCLUSIONS: We observed a high and early risk of subsequent fracture following a broad array of initial fractures. Timely management with consideration of pharmacotherapy is warranted in older women following all fracture types evaluated.

Bone mineral density gains with a second 12-month course of romosozumab therapy following placebo or denosumab.

Romosozumab is a therapy that stimulates bone formation and reduces bone resorption. In this study of postmenopausal women with low BMD, a second course of romosozumab following a period off treatment or on denosumab increased or maintained BMD, respectively, and was well tolerated, providing insight into treatment sequence options. INTRODUCTION: In patients with high fracture risk, therapies that stimulate bone formation provide rapid BMD gains; currently available agents, parathyroid hormone receptor agonists, are limited to a 2-year lifetime exposure and generally used for a single treatment course. However, for long-term osteoporosis management, a second treatment course may be appropriate. Romosozumab, a therapy with the dual effect of increasing bone formation and decreasing bone resorption, reduces fracture risk within 12 months. Here, we report efficacy and safety of a second romosozumab course. METHODS: In this phase 2, dose-finding study, postmenopausal women with low bone mass (T-score ≤ - 2.0 and ≥ - 3.5) received romosozumab or placebo (month 0-24) followed by placebo or denosumab (month 24-36); participants then received a year of romosozumab (month 36-48). RESULTS: Of 167 participants who entered the month 36-48 period, 35 had been initially randomized to romosozumab 210 mg monthly. In participants who received romosozumab 210 mg monthly followed by placebo, a second romosozumab course (n = 19) increased BMD by amounts similar to their initial treatment (month 0-12) at the lumbar spine (12.4%; 12.0%, respectively) and total hip (6.0%; 5.5%, respectively). Following denosumab, a second romosozumab course (n = 16) increased BMD at the lumbar spine (2.3%) and maintained BMD at the total hip. Safety profiles were similar between first and second romosozumab courses. CONCLUSIONS: After 12 months off-treatment, a second romosozumab course again led to rapid and large BMD gains. Following denosumab, BMD gains with romosozumab were smaller than with initial treatment. No new safety findings were observed during the second course.

Predictors of near-term fracture in osteoporotic women aged ≥65 years, based on data from the study of osteoporotic fractures.

Using data from the Study of Osteoporotic Fractures (SOF), several clinical characteristics predictive of near-term (1-year) risk of hip and non-vertebral fracture among elderly osteoporotic women were identified, and a subset of those for hip fracture was incorporated into a risk assessment tool. Additional research is needed to validate study findings. INTRODUCTION: While several risk factors are known to contribute to long-term fracture risk in women with osteoporosis, factors predicting fracture risk over a shorter time horizon, such as over a 1-year period, are less well-established. METHODS: We utilized a repeated-observations design and data from the Study of Osteoporotic Fractures to identify factors contributing to near-term risk of hip fracture and any non-vertebral fracture, respectively, among osteoporotic women aged ≥65 years. Potential predictors of hip fracture and any non-vertebral fracture over the 1-year period subsequent to each qualifying SOF exam were examined using multivariable frailty models. Because the discriminative ability of the hip fracture model was acceptable, a corresponding risk-prediction tool was also developed. RESULTS: Study population included 2499 women with osteoporosis, who contributed 6811 observations. Incidence of fracture in the 1-year period subsequent to each exam was 2.2% for hip fracture and 6.6% for any non-vertebral fracture. Independent predictors of hip fracture included low total hip T-score, prior fracture, and risk factors for falls (multivariable model c-statistic = 0.71 (95% CI 0.67-0.76)). Independent predictors of any non-vertebral fracture included age, total hip T-score, prior falls, prior fracture, walking speed, Parkinson's disease or stroke, and smoking (multivariable model c-statistic = 0.62 (0.59-0.65)). CONCLUSIONS: Several clinical characteristics predictive of hip and non-vertebral fracture within a 1-year follow-up period among elderly women with osteoporosis were identified, and a subset of those for hip fracture was incorporated into a risk assessment tool. Assessment of these risk factors may help guide osteoporosis treatment choices by identifying patients in whom there is urgency to treat. Additional research is needed to validate the findings of this study and the accuracy of the risk assessment tool.

Comorbidity indices for clinical trials: adaptation of two existing indices for use with the FREEDOM trial in women with postmenopausal osteoporosis.

UNLABELLED: Two comorbidity indices were adapted for use in the FREEDOM trial and significantly correlated with the number of medications and impaired health status at baseline. The indices have applications for the analysis of clinical trial data and would allow for the appropriate adjustment of comorbidities when evaluating clinical trial outcomes. INTRODUCTION: The purpose of this study is to adapt two published comorbidity indices for use with the FREEDOM clinical trial evaluating postmenopausal women with osteoporosis. METHODS: FREEDOM enrolled women aged 60-90 years with a bone mineral density T-score <-2.5 at the lumbar spine or total hip and ≥-4.0 at both sites. Comorbidity indices were calculated using methods described by Sangha (Arthritis Rheum 49:156-163, 2003) and Wolfe (J Rheumatol 37:305-315, 2010) following modification. The adapted Sangha index included 12 conditions with a summary score of 0-12; the adapted Wolfe index included 7 conditions with a weighted summary score of 0-8. Higher scores indicated greater comorbidity. A panel of clinicians independently reviewed subjects' medical histories using a systematic process based on Medical Dictionary for Regulatory Activities (MedDRA) preferred terms to map specified comorbid conditions. Spearman correlations between the adapted indices and baseline subject characteristics expected to be associated with comorbidities were examined. RESULTS: Of the 7808 subjects in this study, 74 % had ≥1 comorbidities based on the adapted Sangha or Wolfe comorbidity indices. The mean (SD) adapted Sangha and Wolfe comorbidity indices were 1.4 (1.2) and 1.4 (1.3), respectively. Both indices correlated positively with age, body mass index, and the number of medications (r = 0.54 to 0.55) at baseline and inversely correlated with health-related quality of life (r = -0.22 to -0.30) (all P < 0.0001). Further, when either the adapted Sangha or Wolfe index was included as a covariate for assessing mortality over 36 months in the FREEDOM population, the hazard ratio of the comorbidity index indicated that the mortality risk increased by 27 or 28 %, respectively, for each unit increase in the adapted index (both P < 0.0001). CONCLUSIONS: Our work suggests these comorbidity indices may be adapted for use with clinical trial data, thereby allowing for the appropriate adjustment and reporting of covariates in the evaluation of clinical trial outcomes in an osteoporotic population.

Teriparatide treatment patterns in osteoporosis and subsequent fracture events: a US claims analysis.

UNLABELLED: The objective of this study was to describe the risk of fragility-related fractures in the 2 years following teriparatide initiation. In an administrative claims analysis of over 11,407 patients, approximately one in eight patients had a new or recurrent fragility-related fracture in the 2 years following teriparatide initiation. INTRODUCTION: The objective of this study was to describe the risk of fragility-related fractures in the 2 years following the initiation of teriparatide in a real-world setting. METHODS: This retrospective study used data from the 2002 to 2011 MarketScan® Commercial and Medicare Supplemental Databases to identify patients 50 years and older with a diagnosis of osteoporosis (ICD-9-CM code 733.0x) who were initiating teriparatide. Patients were required to have continuous medical and pharmacy benefit coverage for the 12 months prior to and 24 months following teriparatide initiation (index event). Teriparatide treatment patterns (persistence and adherence) were described, as was the use of antiresorptive therapy. The primary study outcome was the presence of a new or recurring fragility fracture following the initiation of teriparatide. RESULTS: A total of 11,407 patients met the study criteria (mean age = 69.5, standard deviation = 10.6 years; 92.0% female). One in four (25.6%) patients had fragility fracture claims in the year prior to teriparatide initiation, of which 64.0% were on existing antiresorptive therapy. Overall, 13.4% (n = 1527) of patients had a new or recurrent fracture during the 2-year follow-up period. Forty-eight percent of patients on teriparatide treatment were considered persistent; fragility fractures were more common among patients nonpersistent with teriparatide (15.2%) than among those persistent with teriparatide (11.4%). A higher fracture rate (35.7%) was observed in the cohort with previous fragility fracture then those without pre-index fractures (24%). CONCLUSION: More than 13.4% of patients had new or recurrent fragility-related fractures during the 2 years following the initiation of teriparatide; these fractures were more in common in patients with pre-existing fractures and the patients who were nonpersistent with teriparatide.

Infections in postmenopausal women with osteoporosis treated with denosumab or placebo: coincidence or causal association?

UNLABELLED: Serious adverse events of infections that occurred in subjects receiving denosumab or placebo in the Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were examined in detail. Serious adverse events of infections in denosumab subjects had heterogeneous etiology, with no clear clinical pattern to suggest a relationship to time or duration of exposure to denosumab. INTRODUCTION: Denosumab reduces the risk for new vertebral, hip, and nonvertebral fractures compared with placebo. In the pivotal phase 3 fracture trial (FREEDOM), the overall safety profile and incidence of adverse events including adverse events of infections were similar between groups. Serious adverse events of erysipelas and cellulitis were more frequent in denosumab-treated subjects. In this report, we further evaluate the details of infectious events in FREEDOM to better understand if RANKL inhibition with denosumab influences infection risk. METHODS: FREEDOM was an international multicenter, randomized, double-blind, placebo-controlled study in postmenopausal women with osteoporosis randomly assigned to receive placebo (n = 3,906) or denosumab 60 mg every 6 months (n = 3,902). The incidence of adverse events and serious adverse events categorized within the Medical Dictionary for Regulatory Activities system organ class, "Infections and Infestations," was compared between the placebo and denosumab groups by body systems and preferred terms. The temporal relationship between occurrence of serious adverse events of infections of interest and administration of denosumab was explored. RESULTS: Serious adverse events of infections involving the gastrointestinal system, renal and urinary system, ear, and endocarditis were numerically higher in the denosumab group compared with placebo, but the number of events was small. No relationship was observed between serious adverse events of infections and timing of administration or duration of exposure to denosumab. CONCLUSIONS: Serious adverse events of infections that occurred with denosumab treatment had heterogeneous etiology, with no clear clinical pattern to suggest a relationship to time or duration of exposure to denosumab.

Effects of 17 beta-estradiol on calcitonin secretion and content in a human medullary thyroid carcinoma cell line.

The presence of a direct estrogen effect on calcitonin secretion is controversial. Because most of the data available were obtained from complex in vivo systems, we chose an in vitro approach to assess the problem. Using a human C cell carcinoma cell line (TT cells) with well-documented estrogen receptors, we investigated the effect of 17 beta-estradiol (E2) on basal and stimulated calcitonin secretion, on calcitonin content, and on total cellular protein. After short (30 and 180 minutes) and long-term (24 h to 6 days) incubation of the cells with different concentrations of E2 (from 0.01 to 100 nM) we observed no stimulatory but a transient dose-dependent inhibitory effect on CT secretion and content. The nadir of the effect on CT secretion appeared at 24 h, demonstrating a reduction to 80.5 +/- 7.8% of control at 1 nM and to 59.1 +/- 15% of control at 100 nM E2. After 72 h, the CT levels of the E2-exposed groups returned to control levels. The acute stimulation of the cells with TPA plus forskolin after preincubation with E2 up to 6 days showed no difference in the increment of CT release compared to the control groups. Additionally, E2 had a dose-dependent stimulatory effect on cell protein content. The data demonstrate the absence of a direct stimulatory effect of E2 on CT secretion, revealing a dose-dependent inhibitory effect on CT secretion and content.

Regulation of calcitonin gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat.

High calcium leads to the secretion of calcitonin, and the administration of 1,25-dihydroxyvitamin D3 leads to a decreased transcription of the calcitonin gene. We now report the effect of chronic hypercalcemia, hypocalcemia, and vitamin D deficiency on calcitonin gene expression in vivo in the rat. Hypercalcemia was created by calcium infusions for 6 h, a high-calcium diet given to weanling rats for 3 weeks, and the transplantation of the Walker carcinosarcoma 256 cell line. Despite serum calcium as high as 22 mg/dl, there was no difference in calcitonin mRNA levels among these rats. The control genes studied, actin and somatostatin, which is specific for C cells in the thyroparathyroid tissue, also did not differ among the different groups of rats. Injected 1,25-(OH)2D3 decreased calcitonin mRNA levels at 6 h, as previously reported. Hypocalcemia, created by feeding diets deficient in calcium and vitamin D to weanling rats for 3 weeks, had no effect on calcitonin mRNA levels, in contrast to the large increases in PTH mRNA levels. These results demonstrate that calcitonin gene expression in vivo in the rat is regulated by administered 1,25-(OH)2D3 but not by changes in serum calcium.

In vitro detection of neutralizing antibodies after treatment of Paget's disease of bone with nasal salmon calcitonin.

To elucidate the biologic relevance of circulating sCT antibodies, an in vitro bioassay system for the detection of neutralizing antibodies was developed utilizing the human breast carcinoma cell line T47D. We reasoned that the inhibition of the dose-dependent cAMP response to sCT in the T47D assay system by anti-sCT antibodies could be used to determine the in vivo relevance of these antibodies. In this report the clinical course of nine patients with Paget's disease of bone treated with intranasal sCT was correlated with the presence of 125I-sCT binding and neutralizing antibodies. Of these seven patients, four were found to have neutralizing antibodies; the appearance of the antibodies coincided with the development of resistance. One of these patients was subsequently treated with human calcitonin and revealed a good response to the treatment. There was no clinical resistance observed in the three patients with 125I-sCT binding antibodies but no neutralizing antibodies; no resistance was observed in two patients without 125I-sCT binding or neutralizing antibodies. We conclude that this new technique to determine the biologic relevance of circulating anti-sCT antibodies may be an useful adjunct for determining the cause of resistance in patients treated with sCT.

Differential effects of 1,25-dihydroxyvitamin D3 on cell proliferation and calcitonin gene expression.

1,25-Dihydroxyvitamin D3 (1,25D3) inhibits cell growth and induces differentiation in many cell systems by inhibition of c-myc gene expression. In the human medullary thyroid carcinoma cell line (TT), c-myc gene expression appears to be closely related to cell proliferation and differentiation. TT cells are also a well known target system for 1,25D3, which inhibits calcitonin (CT) gene expression in these cells. So far, no direct cis-acting vitamin D-responsive element could be identified in the promoter region of the CT gene. We, therefore, investigated potential indirect mechanisms of 1,25D3-mediated CT gene expression by examining the hormone's effects on proliferation. In contrast to its well established antiproliferative action in other cell systems, addition of 1,25D3 to TT cells led to a 2.3-fold stimulation of DNA synthesis, which was maximal after 48 h and was preceded by a 4.8-fold increase in c-myc gene expression. c-Myc antisense DNA oligomers abolished the proliferative effect of 1,25D3, but not the latter's inhibition of CT gene expression. Here we present evidence that activation of c-myc gene expression mediates 1,25D3-stimulated TT cell proliferation, but not the 1,25D3-induced inhibition of CT gene expression.

Seasonal variation of biochemical indexes of bone turnover: results of a population-based study.

Biochemical markers of bone turnover have been shown to provide valuable information for the diagnosis and monitoring of metabolic bone disease. However, these dynamic indexes are influenced by a number of factors that need to be clearly identified to improve their clinical usefulness. To evaluate the contributions of anthropometric, life style, and environmental variables on bone turnover, biochemical markers of bone metabolism were determined in a population-based sample of 580 adults, aged 50-81 yr (297 men and 283 women). Subjects were recruited during 14 consecutive months within the framework of the European Vertebral Osteoporosis Study. Serum total and bone-specific alkaline phosphatase (S-BAP), serum C-terminal propeptide of type I collagen, and serum osteocalcin (S-OC) were measured as bone formation markers. Urinary total pyridinoline and deoxypyridinoline were included as bone resorption indexes. In females, serum levels of 25-hydroxyvitamin D3 were significantly higher (P < 0.01) in summer (May-September) than in winter (October-April), whereas no significant differences were found in males. In both sexes, no seasonal changes were seen in serum PTH. In males, serum total alkaline phosphatase (P < 0.01), S-BAP (P < 0.001), and S-OC (P < 0.05) were significantly higher in winter than in summer. During the same period, females had higher values of S-BAP (P < 0.05), S-OC (P < 0.01), and urinary pyridinoline and deoxypyridinoline (P < 0.001, respectively). Univariate analyses of the effects of life style habits on markers of bone metabolism revealed that in females, regular alcohol consumption and current smoking led to a suppression of markers of bone turnover, whereas in males, only alcohol intake was associated with such changes. In contrast, physical activity was associated with higher levels of bone formation markers and reduced levels of bone resorption indexes in both sexes. As shown by multivariate regression analyses, seasonal variations accounted for more of the variability in most biomarkers (up to 12%) than any of the other anthropometric or life style factors except age. This effect may be attributed to subclinical vitamin D deficiency during the winter period, which is common in countries of the northern hemisphere. We conclude that seasonal variation contributes significantly to the biological variability of bone turnover and needs consideration when interpreting the results of bone marker measurements.

A case of neuroendocrine oncogenic osteomalacia associated with a PHEX and fibroblast growth factor-23 expressing sinusidal malignant schwannoma.

Oncogenic osteomalacia is a rare paraneoplastic syndrome that is characterized biochemically by hypophosphatemia and low plasma 1,25-dihydroxyvitamin D3, and clinically by osteomalacia, pseudofractures, bone pain, fatigue, and muscle weakness. We present a patient with a malignant schwannoma as the underlying cause of this disorder. A permanent cell line (HMS-97) derived from this tumor showed evidence of neuroendocrine differentiation by immunohistochemistry and of neurosecretory activity by electron microscopy. The cell line did express PHEX (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) and FGF-23 (fibroblast growth factor-23) transcripts on northern hybridization; however, none of the known mutations from the related mendelian disorders of X-linked hypophosphatemic rickets or autosomal-dominant hypophosphatemic rickets could be detected. Tumor cell (HMS-97)-derived conditioned medium did not inhibit phosphate transport in a standard opossum kidney cell assay and in animal experiments. The medium also showed no PTH1- or PTH2-receptor-stimulating bioactivity. HMS-97 cells might be useful for further studies that aim to determine the genetic mechanism that leads to the observed PHEX and FGF-23 expression, both of which might have a direct role in the pathogenesis of oncogenic osteomalacia. In addition, these cells might be a useful tool for the investigation of neuroendocrine Schwann cell function and autoimmune peripheral nerve disease.

Formation of neutralizing antibodies after treatment with human calcitonin.

PURPOSE: Calcitonin is used for the treatment of Paget's disease of bone, hypercalcemia, and postmenopausal osteoporosis. The formation of antibodies against heterologous calcitonins, such as salmon calcitonin (sCT), has been described frequently. Neutralizing effects of these antibodies have been demonstrated in many cases. As far as antibody formation against human calcitonin (hCT) is concerned, only a single case has been reported in the literature; however, investigations concerning the biologic activity of the antibodies were not performed. We have now assessed the sera of 33 patients treated with hCT for postmenopausal osteoporosis for a period of at least 12 months to evaluate the occurrence of hCT-binding and hCT-neutralizing antibodies. PATIENTS AND METHODS: Binding antibodies were detected by incubation of patient sera with 125I-labeled hCT; neutralizing activity was assessed in an in vitro bioassay that measured the impairment of the hCT-induced cyclic adenosine monophosphate (cAMP) formation in the human breast cancer cell line T47D. RESULTS: Prior to hCT treatment, none of the patients showed evidence of the presence of either binding or neutralizing antibodies. During the course of treatment, binding antibodies occurred in a single patient. These antibodies had a neutralizing activity characterized by 15% impairment of cAMP formation after 6 months and 27% impairment after 12 months of treatment compared with pretreatment control values. The neutralizing effect observed in this particular patient was comparatively mild compared with the effects seen after the formation of neutralizing antibodies against sCT, so major clinical sequelae were not expected in this patient. This may be due to the lower antigenicity of hCT as compared with sCT. CONCLUSION: Although antibody formation against hCT is a rare phenomenon, we nonetheless recommend monitoring of postmenopausal osteoporosis patients treated with sCT or hCT for neutralizing antibody formation in order to evaluate the therapeutic effect of treatment.

Multiple endocrine neoplasia type 2. Clinical features and screening.

Prospective screening programs have changed the presenting clinical features of MEN 2, the association of medullary thyroid carcinoma, pheochromocytoma, and parathyroid disease. Currently, all manifestations of MEN 2 syndrome can be diagnosed at an early stage. Gene carrier status can be identified by characterization of specific mutations. Prospective screening for early medullary thyroid carcinoma by calcitonin testing and for pheochromocytoma by several techniques routinely permits identification of early manifestations.

Changing concepts in the management of hereditary and sporadic medullary thyroid carcinoma.

Recent linkage of the gene for multiple endocrine neoplasia type 2A and 2B to the centromeric region of chromosome 10 has provided new insight into the causes of medullary thyroid carcinoma and has provided tools to diagnose gene carriers status for this syndrome with greater than 90% certainty. This review focuses on how these advances influence the clinical management of both sporadic and hereditary medullary thyroid carcinoma and discusses how tests based on the genetic linkage studies will aid in the early diagnosis and treatment of this syndrome. In addition, the authors have focused on several controversial management questions regarding the type and extent of surgery for this thyroid tumor, the management of the patient with metastatic disease, and the approach to management of other manifestations of multiple endocrine neoplasia types 2A and 2B. This review attempts to provide a balanced overview of these complex issues.

Elevated thrombomodulin plasma levels as a result of endothelial involvement in plasmodium falciparum malaria.

We used thrombomodulin (TM) to assess the participation of the vascular endothelium in human Plasmodium falciparum (P.F.) malaria. Before therapy TM plasma levels were elevated in P.F. malaria and fell to normal values during therapy. Parasitemia, TNF alpha, elastase and TAT levels correlated directly with TM. Elevated TM levels can not be explained by increased synthesis, since incubating HUVEC with pretherapy serum of patients with P.F. malaria, but not reconvalescence serum, suppressed TM transcription. This was partially prevented by adding a TNF alpha neutralizing antibody to patient serum before incubation with HUVEC. However, TNF alpha does not release TM from cultured HUVEC in vitro. Coincubation of HUVEC with pretherapy serum together with neutrophils resulted in endothelial cell destruction, which could be partly prevented by a TNF alpha neutralizing antibody. Hence the increase of TM during P.F. malaria might reflect the concerted action of cytokines and neutrophils on HUVEC.