Joan C. Lo

The metabolic syndrome and chronic kidney disease.

Purpose of reviewThe metabolic syndrome is a constellation of physical and laboratory abnormalities including hypertension, hyperglycemia, hyperlipidemia and abdominal obesity. Over the past decade, the metabolic syndrome has emerged as a critically important risk factor for cardiovascular disease. Recent findingsA large population-based cross-sectional analysis (the National Health and Nutrition Evaluation Survey III) found that the presence of the metabolic syndrome was associated with chronic kidney disease, defined as an estimated glomerular filtration rate of less than 60 ml/min per 1.73 m2 and was also associated with proteinuria. More recently, a prospective cohort study found that the presence of the metabolic syndrome was associated with incident chronic kidney disease by the same definition, even when excluding individuals with diabetes mellitus and hypertension. More studies are required to determine whether the relationship between the metabolic syndrome and chronic kidney disease is mainly mediated by hyperglycemia (with insulin resistance) and hypertension, or other metabolic or hemodynamic factors. SummaryThe metabolic syndrome is associated with chronic kidney disease. Efforts aimed at determining the mechanisms underlying this association and strategies for the prevention of chronic kidney disease (or slowing the progression of chronic kidney disease) in affected patients should be research priorities in the future.

Metabolic Syndrome and the Risk for Chronic Kidney Disease among Nondiabetic Adults

The metabolic syndrome is a risk factor for the development of diabetes and cardiovascular disease; however, no prospective studies have examined the metabolic syndrome as a risk factor for chronic kidney disease (CKD). A total of 10,096 nondiabetic participants who were in the Atherosclerosis Risk in Communities study and had normal baseline kidney function composed the study cohort. The metabolic syndrome was defined according to recent guidelines from the National Cholesterol Education Program. Incident CKD was defined as an estimated GFR (eGFR) <60 ml/min per 1.73 m2 at study year 9 among those with an eGFR > or =60 ml/min per 1.73 m2 at baseline. After 9 yr of follow-up, 691 (7%) participants developed CKD. The multivariable adjusted odds ratio (OR) of developing CKD in participants with the metabolic syndrome was 1.43 (95% confidence interval [CI], 1.18 to 1.73). Compared with participants with no traits of the metabolic syndrome, those with one, two, three, four, or five traits of the metabolic syndrome had OR of CKD of 1.13 (95% CI, 0.89 to 1.45), 1.53 (95% CI, 1.18 to 1.98), 1.75 (95% CI, 1.32 to 2.33), 1.84 (95% CI, 1.27 to 2.67), and 2.45 (95% CI, 1.32 to 4.54), respectively. After adjusting for the subsequent development of diabetes and hypertension during the 9 yr of follow-up, the OR of incident CKD among participants with the metabolic syndrome was 1.24 (95% CI, 1.01 to 1.51). The metabolic syndrome is independently associated with an increased risk for incident CKD in nondiabetic adults.

Persistence with weekly alendronate therapy among postmenopausal women

IntroductionAlthough clinical trials indicate that oral bisphosphonates reduce osteoporotic fracture risk, compliance with bisphosphonate therapy in practice is suboptimal, with 1-year discontinuation rates exceeding 50%.MethodsWe conducted a retrospective cohort study among female members of a large integrated health care delivery system (Kaiser Permanente of Northern California), age 45 years and older, to determine their persistence with weekly alendronate (defined as continuous use, allowing for a refill gap of 60 days), predictors of discontinuation, and subsequent osteoporosis therapy. We also examined the effect of varying the refill gap from 30 to 120 days on the discontinuation rate. From 2002 through 2003, we identified 13,455 women (age 68.8±10.4 years) who initiated weekly oral alendronate therapy.ResultsUsing a 60-day refill gap, the 1-year discontinuation rate was 49.6% [95% confidence interval (CI) 48.8–50.4%]; this increased to 58.0% (CI 57.2–58.8%) with a 30-day gap and decreased to 42.2% (CI 41.1–43.0%) with a 120-day gap. Among those who discontinued therapy, about one-third restarted alendronate or another osteoporosis drug within 6 months. Baseline factors associated with alendronate discontinuation included prior bone mineral density testing [adjusted odds ratio (OR) 0.64, CI 0.60–0.69], prior postmenopausal hormone therapy (OR 0.78, CI 0.73–0.84), prior high-dose oral glucocorticoid therapy (OR 1.26, CI 1.05–1.51), prior gastrointestinal diagnoses (OR 1.21, CI 1.09–1.36), and high number of therapeutic classes of prescriptions filled in the prior year (OR 1.21, CI 1.10–1.32), although the final model had limited explanatory power.ConclusionsWe conclude that apparent discontinuation rates are high within 1 year after treatment initiation, although a subset of women appears to restart bisphosphonate or other osteoporosis therapy. Because intermittent use and/or poor adherence is common, discontinuation rates based on data from administrative databases are sensitive to the refill gap length. In addition, we identified no clinical factors highly predictive of discontinuation.

Intravenous Bisphosphonate-Related Osteonecrosis of the Jaw: Bone Scintigraphy as an Early Indicator

PURPOSE Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is recognized as a serious complication among patients receiving bisphosphonate therapy. However, methods for early detection and identification of patients at risk for osteonecrosis of the jaw (ONJ) need further investigation. The purpose of this study was to characterize BRONJ among patients receiving intravenous bisphosphonates and to examine bone scintigraphy findings that preceded manifestation of frank ONJ. MATERIALS AND METHODS We identified all known cases of BRONJ (defined according to 2006 American Association of Oral and Maxillofacial Surgeons criteria) diagnosed between January 2004 and September 2008 among patients who received intravenous bisphosphonate therapy (IVBP). The medical records were abstracted, and the clinical and radiographic features of BRONJ and relevant comorbidities were characterized. Technetium Tc 99 bone scintigrams were systematically reviewed among the subset of patients who received these imaging studies for oncologic care and imaging findings were correlated with the temporal development of ONJ. RESULTS We identified 59 cases of intravenous BRONJ (median age, 61.4 +/- 10.7 years; 57.6% female), of whom 44.1% had breast cancer, 33.9% had multiple myeloma, and the remainder had metastatic prostate cancer (15.3%) or other cancers (6.8%). One third (32.2%) of the cohort was diabetic. In addition to IVBP, the vast majority (86.4%) had also received prior systemic glucocorticoid therapy. The median cumulative number of IVBP doses was 25 (interquartile range, 16-39) at the time of BRONJ diagnosis. Half of the patients had prior invasive dental procedures; ONJ developed spontaneously in 27.1%, and in the remainder ONJ developed in the setting of periodontal disease (10.1%) or local trauma (8.4%). Most patients presented with painful stage 2 disease involving the mandible (75%), and Actinomyces was present in more than 77% of available histologic specimens. During the median follow-up of 1.5 years, 15 patients (25.4%) regressed to a less severe stage, with healing in 6 patients; 16 (27.1%) worsened; and the remainder stayed within the same stage, but in almost half of these patients, the extent of involvement progressed. Of the 38 patients who had 99Tc bone scintigraphy, 35 had bone scans before development of BRONJ, and among these patients, 23 (67.5%) had positive tracer uptake in areas that subsequently developed BRONJ. CONCLUSIONS In this study bone scintigraphy showed positive tracer uptake before the development of BRONJ in almost 66% of patients who had these scans before clinical evidence of frank osteonecrosis. BRONJ subsequently developed in the areas identified on scintigraphy in these patients. Further studies should explore the role of bone scintigraphy in the detection of early subclinical BRONJ.

Lactation Intensity and Postpartum Maternal Glucose Tolerance and Insulin Resistance in Women With Recent GDM: The SWIFT cohort

OBJECTIVE To examine the association between breastfeeding intensity in relation to maternal blood glucose and insulin and glucose intolerance based on the postpartum 2-h 75-g oral glucose tolerance test (OGTT) results at 6–9 weeks after a pregnancy with gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS We selected 522 participants enrolled into the Study of Women, Infant Feeding, and Type 2 Diabetes (SWIFT), a prospective observational cohort study of Kaiser Permanente Northern California members diagnosed with GDM using the 3-h 100-g OGTT by the Carpenter and Coustan criteria. Women were classified as normal, prediabetes, or diabetes according to American Diabetes Association criteria based on the postpartum 2-h 75-g OGTT results. RESULTS Compared with exclusive or mostly formula feeding (>17 oz formula per 24 h), exclusive breastfeeding and mostly breastfeeding (≤6 oz formula per 24 h) groups, respectively, had lower adjusted mean (95% CI) group differences in fasting plasma glucose (mg/dL) of −4.3 (−7.4 to −1.3) and −5.0 (−8.5 to −1.4), in fasting insulin (μU/mL) of −6.3 (−10.1 to −2.4) and −7.5 (−11.9 to −3.0), and in 2-h insulin of −21.4 (−41.0 to −1.7) and −36.5 (−59.3 to −13.7) (all P < 0.05). Exclusive or mostly breastfeeding groups had lower prevalence of diabetes or prediabetes (P = 0.02). CONCLUSIONS Higher intensity of lactation was associated with improved fasting glucose and lower insulin levels at 6–9 weeks’ postpartum. Lactation may have favorable effects on glucose metabolism and insulin sensitivity that may reduce diabetes risk after GDM pregnancy.

Radiographic findings in bisphosphonate-treated patients with stage 0 disease in the absence of bone exposure.

PURPOSE Radiographic features in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) are well described, but less is known in bisphosphonate-exposed individuals with stage 0 disease (clinical symptoms without exposed necrotic bone) considered at risk for BRONJ. We sought to characterize radiographic findings in a subgroup of patients with concerning clinical symptoms and bisphosphonate exposure to identify imaging features that may presage development of BRONJ. MATERIALS AND METHODS A dental symptom survey was returned by 8,572 Kaiser Permanente Health Plan members receiving chronic oral bisphosphonate therapy, and 1,005 patients reporting pertinent dental symptoms or complications after dental procedures were examined. Those without BRONJ but with concerning symptoms were referred for clinical evaluation, including imaging. Among the subset who received maxillofacial imaging, we identified those with stage 0 disease and abnormal radiographic features. RESULTS There were a total of 30 patients without exposed bone but with concerning symptoms who received maxillofacial imaging (panoramic radiography or computed tomography) in the context of clinical care. Among these 30 patients, 10 had stage 0 disease with similar radiographic features of regional or diffuse osteosclerosis in clinically symptomatic areas, most with extension beyond the involved site. Other findings in these 10 patients included density confluence of cortical and cancellous bone, prominence of the inferior alveolar nerve canal, markedly thickened and sclerotic lamina dura, uniform periradicular radiolucencies, cortical disruption, lack of bone fill after extraction, and a persisting alveolar socket. None had exposed bone develop during 1-year follow-up. The remaining 20 patients had normal or localized radiographic findings consistent with odontogenic pathology. CONCLUSION In 10 of 30 symptomatic patients referred for clinical evaluation and imaging, a consistent finding was conspicuous osteosclerosis in clinically symptomatic areas characteristic of stage 0 disease. These data support the need to better understand radiographic features associated with bisphosphonate exposure and to determine whether osteosclerosis is a specific finding indicative of the risk for progression to BRONJ.

Prehypertension and Hypertension in Community-Based Pediatric Practice

OBJECTIVE: To examine the prevalence of prehypertension and hypertension among children receiving well-child care in community-based practices. METHODS: Children aged 3 to 17 years with measurements of height, weight, and blood pressure (BP) obtained at an initial (index) well-child visit between July 2007 and December 2009 were included in this retrospective cohort study across 3 large, integrated health care delivery systems. Index BP classification was based on the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents: normal BP, <90th percentile; prehypertension, 90th to 94th percentile; hypertension, 3 BP measurements ≥95th percentile (index and 2 subsequent consecutive visits). RESULTS: The cohort included 199 513 children (24.3% aged 3–5 years, 34.5% aged 6–11 years, and 41.2% aged 12–17 years) with substantial racial/ethnic diversity (35.9% white, 7.8% black, 17.6% Hispanic, 11.7% Asian/Pacific Islander, and 27.0% other/unknown race). At the index visit, 81.9% of participants were normotensive, 12.7% had prehypertension, and 5.4% had a BP in the hypertension range (≥95th percentile). Of the 10 848 children with an index hypertensive BP level, 3.8% of those with a follow-up BP measurement had confirmed hypertension (estimated 0.3% prevalence). Increasing age and BMI were significantly associated with prehypertension and confirmed hypertension (P < .001 for trend). Among racial/ethnic groups, blacks and Asians had the highest prevalence of hypertension. CONCLUSIONS: The prevalence of hypertension in this community-based study is lower than previously reported from school-based studies. With the size and diversity of this cohort, these results suggest the prevalence of hypertension in children may actually be lower than previously reported.

Increased Prevalence of Gestational Diabetes Mellitus Among Women With Diagnosed Polycystic Ovary Syndrome: A population-based study

Gestational diabetes mellitus (GDM), defined as carbohydrate intolerance at onset of pregnancy (or first recognition), affects ∼4–7% of pregnancies overall (1–6). Common risk factors include nonwhite race/ethnicity, older age, obesity, and prior GDM (3–7). Other conditions predisposing to glucose intolerance might also increase the risk of GDM. Polycystic ovary syndrome (PCOS) is a reproductive condition characterized by chronic anovulation, insulin resistance, and androgen excess (8–10). Affected women have an increased risk of glucose intolerance and type 2 diabetes (11–14). Some, but not all, studies suggest the risk of GDM is higher among PCOS versus non-PCOS women (15–18), and several studies note an increased prevalence of polycystic ovarian morphology and symptoms in women with prior GDM (19–21). This study examines the prevalence and association of PCOS and GDM among a large multiethnic population of pregnant women in northern California. Kaiser Permanente of Northern California (KPNC) is a large integrated health care delivery system providing comprehensive medical care for >3,000,000 members in northern California. There are 14 delivery hospitals with >30,000 births/year. Comprehensive health plan databases of all hospitalizations, ambulatory visits, and laboratory tests are available and linked by unique patient identifiers (22). This study was approved by the KPNC Institutional Review Board. As previously described (1), we used hospitalization databases to identify third trimester pregnancies between 1 January 2002 and 31 December 2004 …

Antipsychotic Medication Use Among Children and Risk of Diabetes Mellitus

OBJECTIVE: To assess whether the risk of incident diabetes was increased with the use of second-generation antipsychotics (SGAs) in a large diverse cohort of children. METHODS: A retrospective study was conducted by using the administrative databases of 3 health plans participating in the Health Maintenance Organization Research Network. Children 5 to 18 years of age who initiated SGA therapy between January 2001 and December 2008 and 2 comparison groups, namely, nonusers of psychotropic drugs and users of antidepressant medications, were identified. Diagnoses from inpatient and outpatient records, pharmacy dispensings, and outpatient laboratory results were used to identify incident cases of diabetes. RESULTS: The crude incidence rate of diabetes for the SGA-exposed cohort was 3.23 cases per 1000 person-years (95% confidence interval [CI]: 1.67–5.65), compared with 0.76 cases per 1000 person-years (95% CI: 0.49–1.12) among nonusers of psychotropic medications and 1.86 cases per 1000 person-years (95% CI: 1.12–2.90) among antidepressant users. The risk of incident diabetes was significantly increased among SGA users (unadjusted incidence rate ratio: 4.24 [95% CI: 1.95–8.72]) in comparison with nonusers of psychotropic medications but was not significantly increased in comparison with antidepressant medication users (unadjusted incidence rate ratio: 1.74 [95% CI: 0.77–3.78]). CONCLUSIONS: Although we found a potentially fourfold increased rate of diabetes among children exposed to SGAs, the findings were inconsistent and depended on the comparison group and the outcome definition.

Atypical femur fractures among breast cancer and multiple myeloma patients receiving intravenous bisphosphonate therapy

PURPOSE Atypical femur fractures represent a potential complication of chronic oral bisphosphonate therapy in women with osteoporosis, but the risk of atypical femur fractures among cancer patients receiving intravenous bisphosphonates at higher cumulative doses remains unclear. We examined femur fractures occurring in cancer patients treated with intravenous bisphosphonates (IVBP) to determine whether a subset may be atypical fractures. METHODS Between 2005 and 2010, we identified patients with known IVBP therapy for multiple myeloma or metastatic breast cancer, who subsequently sustained a femur fracture based on hospitalization, oncology, pharmacy and chemotherapy visit records. Radiographs were examined by an orthopedic surgeon to determine anatomic fracture site and pattern. An atypical fracture was defined as a transverse or short oblique fracture occurring below the lesser trochanter with evidence of focal hypertrophy of the lateral cortex and absence of biopsy-proven malignancy or radiation therapy at the fracture site. RESULTS A total of 62 patients with breast cancer (N=39) or multiple myeloma (N=23) with femur fracture and prior IVBP treatment for bone malignancy were identified. There were 30 proximal hip, 18 subtrochanteric and 14 femoral shaft fractures. Intraoperative bone samples were sent in 29 of 58 fracture cases undergoing operative repair, with 76% positive for malignancy. Six cases (4 breast cancer, 2 multiple myeloma) of atypical femur fracture were identified, two with negative intraoperative pathology and four with no bone biopsy samples sent. Five of the six patients with atypical fracture had bilateral femur findings, including two with transverse fracture in the contralateral femur and three with focal hypertrophy of the contralateral cortex. Two atypical fracture cases also experienced osteonecrosis of the jaw compared to 3 in the remaining cohort (33% vs. 5%, p=0.07). Patients with atypical fracture received more IVBP (median 55 vs. 15 doses) and zoledronic acid (32 vs. 12 doses) and had longer treatment duration (median 5.9 vs. 1.6 years) compared to patients without atypical fracture (all p≤0.01). CONCLUSIONS Among 62 patients who received IVBP for skeletal malignancy and experienced a femur fracture, we identified six cases of atypical fracture. While fractures in this population are often assumed to be pathologic, prospective studies investigating fracture pattern, microscopic bone pathology and pharmacologic exposures should be conducted to further examine the association of IVBP and atypical femur fractures.