Progression of atypical femur stress fracture after discontinuation of bisphosphonate therapy.

Atypical femur fracture (AFF) is an uncommon complication of long-term bisphosphonate use, but the risk declines substantially after treatment cessation. We report a case of a 70-year-old woman with osteopenia treated with alendronate for 9 years who presented with right mid-thigh pain and radiographic findings of focal lateral cortical thickening in the right mid-femur and lateral cortex irregularity in the proximal-mid left femur. Alendronate was discontinued, but she remained on estrogen for menopausal symptoms. Four years later, a horizontal linear translucent defect was seen in the right mid-femur area of cortical hypertrophy, consistent with an incomplete AFF. The patient underwent prophylactic intramedullary rodding of the right femur and estrogen was discontinued. Three years later (7 years after initial presentation), the cortical irregularities in the left femur were more prominent and three small horizontal linear translucent defects were now evident, consistent with early incomplete atypical fracture development. The patient also suffered a wrist fracture. She was treated with teriparatide for 1.5 years with resolution of the translucent defects in the left but not the right femur, although abnormal thickening of the lateral cortex persisted in both femurs. Our case demonstrates incomplete atypical femur fracture progression in a patient with long-term bisphosphonate exposure, even after treatment cessation. These findings highlight the importance of follow-up for patients who develop diaphyseal femur stress fractures and the potential for early healing with anabolic therapy. This case also demonstrates the challenge in managing older patients with incomplete AFF at risk for progression to complete AFF and osteoporotic fracture.

Atypical femur fracture incidence in women increases with duration of bisphosphonate exposure.

In a northern California population of older women who were treated with oral bisphosphonate drugs, the incidence of atypical femur fracture, a rare complication of treatment, increased with longer duration of bisphosphonate exposure. These findings align with those previously reported in an independent southern California population. INTRODUCTION: The age-adjusted incidence of atypical femur fracture (AFF) reported in southern California increased with bisphosphonate (BP) exposure, ranging up to 113 per 100,000 person-years for 8-10-year exposure. This study examines the incidence of AFF in a northern California population. METHODS: Women age 45-89 years who initiated oral BP during 2002-2014 in Kaiser Permanente Northern California were followed for AFF outcome, defined by a primarily transverse diaphyseal femur fracture through both cortices, with focal periosteal/endosteal hypertrophy, minimal trauma, and minimal/no comminution. Total BP exposure was determined from dispensed prescriptions. The incidence of AFF, calculated for 2-year BP categories ranging from < 2 to > 10 years, was age-adjusted using the 2000 US Census. RESULTS: Among 94,542 women, 107 experienced an AFF during or < 1 year after BP cessation (mean exposure 6.6 ± 3.0 years and total days' supply 5.7 ± 2.8 years at AFF). A strong relationship between AFF incidence and increasing BP exposure was seen, more than doubling for each 2-year category until 8-10 years. Among women with 2- to < 4-year BP, the crude and age-adjusted incidence was 18 and 9 per 100,000 person-years but increased over 2- and 5-fold for women with 4- to < 6- and 6- to < 8-year BP, respectively. For those receiving ≥ 8-year BP, the crude and age-adjusted incidence peaked at 196 and 112 per 100,000 person-years exposure. CONCLUSION: Incidence of AFF increases markedly after 4-6 years of BP. These trends align with southern California and confirm a strong BP duration-related risk of this rare but serious event.

Applying ethnic-specific bone mineral density T-scores to Chinese women in the USA.

Caucasian reference data are used to classify bone mineral density in US women of all races. However, use of Chinese American reference data yields lower osteoporosis prevalence in Chinese women. The reduction in osteoporosis labeling may be relevant for younger Chinese women at low fracture risk. INTRODUCTION: Caucasian reference data are used for osteoporosis classification in US postmenopausal women regardless of race, including Asians who tend to have lower bone mineral density (BMD) than women of white race. This study examines BMD classification by ethnic T-scores for Chinese women. METHODS: Using BMD data in a Northern California healthcare population, Chinese women aged 50-79 years were compared to age-matched white women (1:5 ratio), with femoral neck (FN), total hip (TH), and lumbar spine (LS) T-scores calculated using Caucasian versus Chinese American reference data. RESULTS: Comparing 4039 Chinese and 20,195 white women (44.8 % age 50-59 years, 37.5 % age 60-69 years, 17.7 % age 70-79 years), Chinese women had lower BMD T-scores at the FN, TH, and LS (median T-score 0.29-0.72 units lower across age groups, p < 0.001) using Caucasian reference data. Using Chinese American BMD reference data resulted in an average +0.47, +0.36, and +0.48 units higher FN, TH, and LS T-scores, respectively, reducing the prevalence of osteoporosis (T-score ≤ -2.5) in Chinese women at the FN (16.7 to 6.6 %), TH (9.8 to 3.2 %), and LS (23.2 to 8.9 %); osteoporosis prevalence at any one of three sites fell from 29.6 to 12.6 % (22.4 to 8.1 % for age 50-64 years and 43.2 to 21.0 % for age 65-79 years). CONCLUSION: Use of Chinese American BMD reference data yields higher (ethnic) T-scores by 0.4-0.5 units, with a large proportion of Chinese women reclassified from osteoporosis to osteopenia. The reduction in osteoporosis labeling with ethnic T-scores may be relevant for younger Chinese women at low fracture risk.

Racial/ethnic differences in hip and diaphyseal femur fractures.

UNLABELLED: Contemporary femur fracture rates were examined in northern California women and compared by race/ethnicity. During 2006-2012, hip fracture rates declined, but diaphyseal fracture rates increased, especially in Asians. Women with diaphyseal fracture were younger and more likely to be bisphosphonate-treated. These disparities in femur fracture should be further examined. INTRODUCTION: The epidemiology of diaphyseal femur fracture differs from proximal femur (hip) fracture, although few studies have examined demographic variations in the current era. This study examines contemporary differences in low-energy femur fracture by race/ethnicity in a large, diverse integrated health-care delivery system. METHODS: The incidence of hip and diaphyseal fracture in northern California women aged ≥50 years old during 2006-2012 was examined. Hip (femoral neck and pertrochanteric) fractures were classified by hospital diagnosis codes, while diaphyseal (subtrochanteric and femoral shaft) fractures were further adjudicated based on radiologic findings. Demographic and clinical data were obtained from health plan databases. Fracture incidence was examined over time and by race/ethnicity. RESULTS: There were 10,648 (97.3 %) hip and 300 (2.7 %) diaphyseal fractures among 10,493 women. The age-adjusted incidence of hip fracture fell from 281 to 240 per 100,000 women and was highest for white women. However, diaphyseal fracture rates increased over time, with a significant upward trend in Asians (9 to 27 per 100,000) who also had the highest rate of diaphyseal fracture. Women with diaphyseal fracture were younger than women with hip fracture, more likely to be of Asian race and to have received bisphosphonate drugs. Women with longer bisphosphonate treatment duration were also more likely to have a diaphyseal fracture, especially younger Asian women. CONCLUSION: During 2006 to 2012, hip fracture rates declined, but diaphyseal fracture rates increased, particularly among Asian women. The association of diaphyseal fracture and bisphosphonate therapy should be further investigated with examination of fracture pattern.

Proposed pathogenesis for atypical femoral fractures: lessons from materials research.

Atypical femoral fractures (AFFs) have been well defined clinically and epidemiologically. Less clear are the underlying mechanisms responsible. This commentary points out the likely sources of decreased resistance to fracture using lessons from bone material studies and biomechanics. We hypothesize that the key element in the cascade of events leading to failure of the largest and strongest bone in the human body is long-term suppression of normal bone turnover caused by exposure to potent anti-remodeling agents, most notably the bisphosphonates (BPs). Suppressed bone turnover produces changes in bone that alter its material quality and these changes could lead to adverse effects on its mechanical function. At the submicroscopic [<1 µm] level of collagen fibrils, suppression of bone turnover allows continued addition of non-enzymatic cross links that can reduce collagen's plasticity and this in turn contributes to reduced bone toughness. Further, adverse changes in hydroxyapatite crystalline structure and composition can occur, perhaps increasing collagen's brittleness. At the microscopic level [~1-500 µm] of the bone-matrix structure, suppressed bone turnover allows full mineralization of cortical bone osteons and results in a microstructure of bone that is more homogeneous. Both brittleness and loss of heterogeneity allow greater progression of microscopic cracks that can occur with usual physical activity; in crack mechanical terms, normal mechanisms that dissipate crack tip growth energy are greatly reduced and crack progression is less impeded. Further, the targeted repair of cracks by newly activated BMUs appears to be preferentially suppressed by BPs. We further hypothesize that it is not necessary to have accumulation of many cracks to produce an AFF, just one that progresses - one that is not stopped by bone's several protective mechanisms and is allowed to penetrate through a homogeneous environment. The remarkable straight transverse fracture line is an indicator of the slow progression of a "mother crack" and the failure of usual mechanisms to bridge or deflect the crack. Research in AFF mechanisms has been focused at the organ level, describing the clinical presentation and radiologic appearance. Although today we have not yet connected all the dots in the pathophysiology of BP-induced AFF, recent advances in measuring bone mechanical qualities at the submicroscopic and tissue levels allow us to explain how spontaneous catastrophic failure of the femur can occur.

Performance of FRAX in a cohort of community-dwelling, ambulatory older men: the Osteoporotic Fractures in Men (MrOS) study.

UNLABELLED: We evaluated performance of FRAX in older men who participated in the Osteoporotic Fractures in Men (MrOS) study. INTRODUCTION: FRAX has been extensively studied in women, but there are few studies of its performance in men. METHODS: FRAX estimates for 10-year hip fracture and major osteoporotic fracture (MOF; either hip, clinical spine, forearm, or shoulder) were calculated from data obtained from MrOS participants and compared to observed 10-year fracture cumulative incidence calculated using product limit estimate methods, accounting for competing mortality risk. RESULTS: Five thousand eight hundred ninety-one men were followed for an average of 8.4 years. Without bone mineral density (BMD) in the FRAX model, the mean 10-year predicted fracture probabilities for hip and MOF were 3.5% and 8.9%, respectively; addition of BMD to the calculations reduced these estimates to 2.3% and 7.6%. Using FRAX without BMD, predicted quintile probabilities closely estimated cumulative incidence of hip fracture (range of observed to predicted ratios 0.9-1.1). However, with BMD in the FRAX calculation, observed to predicted hip fracture probabilities were not close to unity and varied markedly across quintiles of predicted probability. For MOF, FRAX without BMD overestimated observed cumulative incidence (range of observed to predicted ratios 0.7-0.9) and addition of BMD did not improve this discrepancy (range of observed to predicted ratios 0.7-1.1). Addition of BMD to the calculation had mixed effects on the discriminatory performance of FRAX, depending on the analysis tool applied. CONCLUSION: Among this cohort of community-dwelling older men, the FRAX risk calculator without BMD was well calibrated to hip fracture but less well to MOF.

The impact of subtrochanteric fracture criteria on hip fracture classification.

SUMMARY: Hospital diagnosis codes are useful for assessing hip fracture rates in large populations. However, these codes do not reliably differentiate hip fractures that occur in the subtrochanteric region. Identification of subtrochanteric fractures requires review of radiographic images to distinguish these fractures from the more commonly occurring trochanteric fractures. PURPOSE: This study examines the accuracy of coded hospital diagnoses for hip fracture compared to fracture site verification based on operative and radiologic data. The variability in subtrochanteric fracture assignment was also examined using different anatomic criteria. METHODS: This retrospective study includes female members of Kaiser Permanente Northern California age 60 years and older with nontraumatic hip fracture during 2007-2008. Anatomic site was verified by operative and radiologic records, including radiographic image review for fractures occurring in the subtrochanteric region. Two different criteria were compared for subtrochanteric fracture. RESULTS: We identified 2,824 women with incident hip fracture during the 2-year period. The average age was 82.9 ± 8.2 years and 15% were non-White. International Classification of Diseases, Ninth Revision (ICD-9) coding was accurate for femoral neck and trochanteric fractures (>90% confirmed by operative/radiologic reports), compared to only 26% for subtrochanteric fractures using the Orthopedic Trauma Association (OTA) criteria for subtrochanteric fracture. Using OTA classification, 1.3% of hip fractures were assigned as subtrochanteric compared to 4.2% when the criteria were broadened to include the lesser trochanter. Both femoral neck and pertrochanteric fracture rates increased exponentially with age, while age-related rates in subtrochanteric fracture differed by diagnostic classification method; the broader criteria including the lesser trochanter produced age-related trends that mirrored femoral neck and pertrochanteric fractures. CONCLUSION: Unlike femoral neck and pertrochanteric fractures, epidemiologic studies of subtrochanteric fractures cannot rely on ICD-9 codes alone. Review of radiologic images using OTA criteria is required for identification of subtrochanteric fractures occurring below the lesser trochanter.

Updated fracture incidence rates for the US version of FRAX.

UNLABELLED: On the basis of updated fracture and mortality data, we recommend that the base population values used in the US version of FRAX be revised. The impact of suggested changes is likely to be a lowering of 10-year fracture probabilities. INTRODUCTION: Evaluation of results produced by the US version of FRAX indicates that this tool overestimates the likelihood of major osteoporotic fracture. In an attempt to correct this, we updated underlying fracture and mortality rates for the model. METHODS: We used US hospital discharge data from 2006 to calculate annual age- and sex-specific hip fracture rates and age-specific ratios to estimate clinical vertebral fracture rates. To estimate the incidence of any one of four major osteoporotic fractures, we first summed these newly derived hip and vertebral fracture estimates with Olmsted County, MN, wrist and upper humerus fracture rates, and then applied 10-20% discounts for overlap. RESULTS: Compared with rates used in the current FRAX tool, 2006 hip fracture rates are about 16% lower, with greatest reductions observed among those below age 65 years; major osteoporotic fracture rates are about one quarter lower, with similar reductions across all ages. CONCLUSIONS: We recommend revising the US-FRAX by updating current base population values for hip fracture and major osteoporotic fracture. The impact of these revisions on FRAX is likely to be lowering of 10-year fracture probabilities, but more precise estimates of the impact of these changes will be available after these new rates are incorporated into the FRAX tool.

Cost-effectiveness of bisphosphonate therapies for women with postmenopausal osteoporosis: implications of improved persistence with less frequently administered oral bisphosphonates.

OBJECTIVE: Studies have shown that weekly bisphosphonate dosing results in improved persistence compared to daily dosing among patients with postmenopausal osteoporosis, yet more than 50% of patients discontinue therapy within a year. An oral, less frequent administration bisphosphonate provides an opportunity to improve persistence, a parameter not well modeled in previous cost-effectiveness analyses of osteoporosis therapies. RESEARCH DESIGN AND METHODS: We developed a Markov model to estimate the effect of improved persistence on the cost-effectiveness of bisphosphonates among postmenopausal women with established osteoporosis (vertebral fracture and bone mineral density T-score

Persistence with weekly alendronate therapy among postmenopausal women.

INTRODUCTION: Although 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%. METHODS: We 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. RESULTS: Using 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. CONCLUSIONS: We 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.

Outcomes of a disease-management program for patients with recent osteoporotic fracture.

INTRODUCTION: The purpose of this study was to evaluate outcomes of a disease-management program designed to increase rates of bone-mineral-density (BMD) testing and initiation of osteoporosis medication among patients with a recent osteoporotic fracture. STUDY DESIGN: We identified 744 consecutive patients aged>or=55 years who were seen at either of 2 of 14 Kaiser Permanente medical facilities in Northern California (KPNC) after sustaining a fracture of the hip, spine, wrist, or humerus between April 2003 and May 2004. These patients were invited to participate in a study of the Fragile Fracture Management Program, whose protocol used fracture-risk assessment tools to determine treatment recommendations. Postfracture care of study participants was compared with usual postfracture care received by osteoporotic-fracture patients at 12 other KPNC facilities. RESULTS: Of the 744 patients who were invited to participate in the study, 293 (39%) agreed to participate, and 169 (23%) completed the evaluation. Of these 169 patients (127 women, 42 men), 65 (51%) of the women and 7 (17%) of the men qualified for drug treatment; of these 72 patients, 6 (86%) of the men and 41 (63%) of the women accepted the offered treatment. At the two study locations, rates of care (BMD testing or prescribing osteoporosis medication) were about twice as high as rates of usual postfracture care observed at 12 other medical centers in KPNC. CONCLUSIONS: Compared with patients who received usual care for osteoporotic fracture, patients participating in a postfracture disease management program had substantially higher rates of medical attention given for osteoporosis; however, the overall yield of the program was low. This low uptake rate was related to factors not previously appreciated: many patients refused participation in the program; a high proportion of younger women-and men of all ages-did not qualify for treatment; and treatment was refused by one in three study-qualified women and by one in seven study-qualified men. Additional efforts are needed to overcome patient barriers to improved osteoporosis evaluation, treatment and participation in postfracture programs.

Endogenous hormones and bone turnover markers in pre- and perimenopausal women: SWAN.

We tested the hypothesis that higher serum osteocalcin and urinary N-telopeptide of type I collagen (NTx) concentrations would be found in women with increasing cycle irregularity or increased follicle stimulating hormone concentrations. We studied 2,375 pre- and early perimenopausal women from the Study of Women's Health Across the Nation (SWAN), aged 42-52 years, who self-identified their race/ethnic origin as African-American (28.3%), Caucasian (49.4%), Japanese (10.5%) or Chinese (11.8%). Outcome measures were serum osteocalcin, a measure of bone formation, and NTx, a measure of bone resorption. The explanatory variables were menopausal status, based on self-reported regularity of menstrual bleeding, and circulating endogenous hormone concentrations including estradiol (E(2)), testosterone (T), sex hormone binding globulin (SHBG) and follicle stimulating hormone (FSH) concentrations. Additionally, we evaluated the association of the bone turnover markers with the Free Androgen Index (FAI) and the Free Estradiol Index (FEI), ratios of total testosterone and estradiol concentrations to SHBG, respectively. Higher FSH concentrations were associated with higher NTx concentrations ( beta=0.003, partial r2=2.1%, p<0.0001), both before and after adjusting for other covariates (total explained variability of 9%). Higher FSH concentrations were also associated with higher osteocalcin concentrations ( beta=-0.216, partial r2=4.1%, p<0.0001, total explained variability of 15.4%). There were no significant associations of the bone turnover markers with other endogenous hormones, following adjustment for covariates. Mean osteocalcin and NTx values were not significantly different in premenopausal women compared to early perimenopausal women. In these pre- and early perimenopausal women, higher FSH concentrations, but not other serum reproductive hormone concentrations, are positively associated with greater bone turnover prior to the last menstrual period.

The association of endogenous hormone concentrations and bone mineral density measures in pre- and perimenopausal women of four ethnic groups: SWAN.

We evaluated bone mineral density (BMD), hormone concentrations and menstrual cycle status to test the hypothesis that greater variations in reproductive hormones and menstrual bleeding patterns in mid-aged women might engender an environment permissive for less bone. We studied 2336 women, aged 42-52 years, from the Study of Women's Health Across the Nation (SWAN) who self-identified as African-American (28.2%), Caucasian (49.9%), Japanese (10.5%) or Chinese (11.4%). Outcome measures were lumbar spine, femoral neck and total hip BMD by dual-energy X-ray densitometry (DXA). Explanatory variables were estradiol, testosterone, sex hormone binding globulin (SHBG) and follicle stimulating hormone (FSH) from serum collected in the early follicular phase of the menstrual cycle or menstrual status [premenopausal (menses in the 3 months prior to study entry without change in regularity) or early perimenopause (menstrual bleeding in the 3 months prior to study entry but some change in the regularity of cycles)]. Total testosterone and estradiol concentrations were indexed to SHBG for the Free Androgen Index (FAI) and the Free Estradiol Index (FEI). Serum logFSH concentrations were inversely correlated with BMD (r = -10 for lumbar spine [95% confidence interval (CI): -0.13, -0.06] and r = -0.08 for femoral neck (95% CI: -0.11, -0.05). Lumbar spine BMD values were approximately 0.5% lower for each successive FSH quartile. There were no significant associations of BMD with serum estradiol, total testosterone, FEI or FAI, respectively, after adjusting for covariates. BMD tended to be lower (p values = 0.009 to 0.06, depending upon the skeletal site) in women classified as perimenopausal versus premenopausal, after adjusting for covariates. Serum FSH but not serum estradiol, testosterone or SHBG were significantly associated with BMD in a multiethnic population of women classified as pre- versus perimenopausal, supporting the hypothesis that alterations in hormone environment are associated with BMD differences prior to the final menstrual period.

Oral contraceptives and bone mineral density in white and black women in CARDIA. Coronary Risk Development in Young Adults.

To examine whether exposure to oral contraceptives (OCs) is associated with bone mineral density (BMD) in young women, we studied, cross-sectionally and longitudinally, 216 white and 260 black women enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Spine, hip and whole body BMDs were measured by dual-energy X-ray absorptiometry (DXA) when the women were aged 25-37 years, and whole body BMD was remeasured in 369 of the women 3 years later. A comprehensive history of OC use, including dose of ethinyl estradiol (estrogen) and duration of use, was determined from an interviewer-administered questionnaire. After adjustment for other relevant variables, we found that cumulative estrogen from OCs (mg) explained 4.0% of the variation in spine BMD ( p = 0.024) among white women, but did not explain any of the variance in BMD in black women. Cumulative OC estrogen was associated with a decreased risk for low bone density (lowest quartile) at the spine, hip and whole body in white women. The odds ratios (95% CIs) comparing women in the highest quartile of cumulative OC estrogen with those in the lowest quartile were, at the spine: 0.08 (0.02, 0.46); at the hip: 0.23 (0.06, 0.87); and at the whole body: 0.37 (0.11, 1.26). OC exposure was not related to low bone density in black women. OCs did not predict longitudinal changes in whole body BMD in either race. These results suggest that exposure to the estrogen from OCs during the premenopausal years may have a small beneficial effect on the skeleton in white women. Benefit is proportional to the cumulative estrogen exposure, suggesting that previous cross-sectional studies that considered OC use as a dichotomous variable may have lacked the power to detect an association.

Timing of estrogen replacement therapy for optimal osteoporosis prevention.

To determine whether estrogen initiated at age 60 yr or later reduces rates of bone loss and fracture incidence, we performed a prospective cohort study of 6910 nonosteoporotic women, 65 yr of age or older. Estrogen use, medical history, lifestyle, and anthropometric data were obtained by questionnaire, interview and examination. We identified five patterns of estrogen use: never users (67%); past early users (started under age 60 yr with no current use; 23%); past late users (started at age 60 or later with no current use; 2%); current early users (started under age 60 yr with use both at baseline and 6 yr later; 6.7%); and current late users (started at age 60 or later with use at baseline and 6 yr later; 1.5%). Bone mineral density was measured at the total hip twice, an average of 3.5 yr apart, and at the calcaneus, an average of 5.7 yr apart. Incident nonspine fractures were validated by radiographic report. Bone mineral density was significantly higher among current users, compared with never and past users. The annual rate of hip bone loss was significantly lower in current early users (-0.22%/yr) and current late users (-0.35%/yr) in comparison with never users (-0.6%/yr), past early users (-0.6%/yr), and past late users (-0.72%/yr). During an average of 11.0 yr of follow-up, 1953 nonspine fractures were confirmed. The multiple-adjusted relative risk of nonspine fracture was 0.63 (95% confidence interval 0.51-0.78) among current early users and 0.75 (0.50-1.12) among current late users, compared with never users. Early initiation and long-term continuation of estrogen is associated with a reduction in the risk of nonspine fractures, and initiation at or after age 60 yr with long-term continuation may also be associated with a reduced fracture risk.

Reversal by medical treatment of endometrial hyperplasia caused by estrogen replacement therapy.

OBJECTIVE: Endometrial hyperplasia, an entity considered a precursor to endometrial carcinoma, frequently develops in women receiving unopposed estrogens. Progestins used concomitantly with estrogens can largely prevent endometrial hyperplasia and carcinoma. However, the ability of progestins to reverse endometrial hyperplasia induced by estrogens is less well recognized. The purpose of this study was to assess the medical reversal rate of endometrial hyperplasia that develops in women receiving unopposed estrogen replacement therapy (ERT). DESIGN: Review of recent literature (1990-2000). RESULTS: Based on four large series, more than 90% of endometrial hyperplasia caused by ERT can be reversed by medical treatment. Discontinuation of estrogen and oral administration of 10 mg/day of medroxyprogesterone acetate continuously for 6 weeks or cyclically for 3 months (2 weeks of each month) are the two regimens most widely used. Other progestins also have been shown to be effective. CONCLUSIONS: Progestins are highly successful in reversing endometrial hyperplasia caused by ERT.

Low-dosage esterified estrogens opposed by progestin at 6-month intervals.

OBJECTIVE: To estimate incidence of endometrial hyperplasia, vaginal bleeding, and menopausal symptoms in women who changed from standard monthly cyclic hormone replacement therapy (HRT) to half-strength estrogen opposed by medroxyprogesterone acetate (MPA) at 6-month intervals. METHODS: We identified 138 women aged 55-75 years who had regularly used HRT at a standard dosage (equivalent to 0.625 mg conjugated estrogen) opposed by cyclic monthly MPA. Each subject's HRT regimen was changed to 0.3 mg/day esterified estrogens (Estratab; Solvay Pharmaceuticals, Marietta, GA) combined with 14-day courses of MPA, 10 mg/day, every 6 months. Endometrial biopsy was repeated after 1 year of the new regimen. Any vaginal bleeding was reported in each patient's daily diary. Menopause symptoms were evaluated using the Greene Menopause Symptom Index. RESULTS: Among 125 women who had biopsy after 1 year of the new regimen, endometrial hyperplasia was found in two (1.6%, 95% confidence interval 0.3%, 6.2%). Of the 125 women, 44% had scheduled bleeding, and 9.4% had unscheduled bleeding. Relative to baseline vasomotor score (range 0-6), an increase of at least 2 U was reported by 20% of subjects at 6 months and by 17% of subjects at 12 months. CONCLUSION: Most women aged at least 55 years can safely switch their HRT regimen from standard dosage HRT to low-dosage estrogen opposed by MPA at 6-month intervals. Moreover, this new HRT regimen causes little vaginal bleeding while maintaining adequate control of menopausal symptoms.

Postmenopausal hormonal support: discontinuation of raloxifene versus estrogen.

OBJECTIVE: To determine possible differences in continuation among women initiating treatment with the selective estrogen receptor modulator raloxifene, versus those initiating treatment with estrogen-containing regimens. DESIGN: A pharmacy prescription database search for refill patterns. The study subjects were members of Kaiser Foundation Health Plan, a large health maintenance organization; 1,394 women age >or=60 years who filled index prescriptions for either raloxifene (n = 331) or systemic estrogens (n = 1,063) between April 1998 and March 1999. The main outcome measure was discontinuation based on prescription refill patterns through December 2000. RESULTS: At 24 months, the probabilities of discontinuing were 56% for women starting raloxifene compared to 72% for women starting estrogens. The likelihood of discontinuation was significantly less among women starting raloxifene than among those starting estrogen (hazard ratio = 0.75; 95% confidence interval = 0.64-0.88). Adjustments for age and prescriber specialty did not affect the risk. CONCLUSIONS: We conclude that discontinuation of estrogen by women well beyond the age of menopause is high; more than two-thirds discontinue within 2 years of starting. Women starting therapy with raloxifene are 25% percent less likely to discontinue their medication than those starting estrogen, providing some promise that long-term benefits of raloxifene may be more easily achieved than those of estrogen.

Initiation of osteoporosis treatment after bone mineral density testing.

The aim of the study was to describe initiation of osteoporosis drug therapy after bone mineral density (BMD) testing and to determine any association with BMD test results obtained, physician factors, or both. The setting was the Kaiser Foundation Health Plan (KFHP), a large health maintenance organization (HMO) in Northern California. Data were collected from bone densitometry centers at four KFHP medical centers sites in Sacramento, San Rafael, Fresno, and Oakland. We identified 17,290 women aged > or = 45 years who had BMD testing between January 1, 1997 and June 30, 1999. After excluding those for whom any osteoporosis drugs were prescribed in the year before testing, 8020 women were available for analysis. Using logistic regression, we examined the association between BMD diagnosis (i.e., osteoporosis or osteopenia versus normal) and initiation of drug therapy, for osteoporosis (including hormone replacement therapy (HRT), alendronate, etidronate, raloxifene and calcitonin) within 6 months after the test. Among the 8020 women, 1934 (24%) filled a prescription for an osteoporosis drug within 6 months after BMD testing. Compared with women who had a normal BMD test result, women diagnosed with osteopenia were nearly 4 times more likely (OR = 3.7; CI = 3.0-4.4), and women diagnosed with osteoporosis were 15 times more likely (OR = 15.0; CI = 12.5-18.1), to fill a prescription for an osteoporosis drug within 6 months after BMD testing. Women with high exposure to corticosteroid agents were twice as likely (OR = 2.1; CI = 1.7-2.7) to start osteoporosis drug therapy compared with women who were not similarly exposed; women diagnosed with recent osteoporotic fractures were 50% more likely (OR = 1.5; CI = 1.2-1.9) to begin therapy than women without such fractures. Despite the strong association between BMD and initiating treatment, nearly half the osteoporotic women did not initiate treatment. In addition, we found that age strongly influenced choice of osteoporotic drug. Compared with osteoporotic women aged 45-54 years, women aged 55-64 years who started drug therapy were 40% more likely (OR = 1.4; CI = 1.0-2.2) and women aged > or = 65 years were twice as likely (OR = 2.0; CI = 1.4-2.8) to start non-HRT drugs. BMD test results indicating osteoporosis were thus strongly associated with increased likelihood of beginning drug therapy, and half of such women initiated therapy. Drug initiation was also associated with other factors, including age, use of corticosteroid agents, recent fracture, and physician characteristics. However, these factors showed much weaker associations than those found for BMD. Health care providers must consider whether test results will influence treatment decisions, and our data indicate that results of BMD testing do influence management decisions regarding osteoporosis drug use for women.

Prevalence and determinants of osteoporosis drug prescription among patients with high exposure to glucocorticoid drugs.

OBJECTIVE: To investigate use of osteoporosis drugs among patients with high exposure to glucocorticoid drugs. STUDY DESIGN: Retrospective review of pharmacy records. METHODS: We identified patients aged > or = 20 years who received prescriptions for > or = 2 g of prednisone (or equivalent) during any 12-month period between January 1, 1998, and December 31, 1999, and who initiated use of osteoporosis-specific drugs (alendronate sodium, etidronate disodium, and calcitonin) during that period. RESULTS: Among 8807 patients who met study criteria, 772 (8.8%) received prescriptions for osteoporosis drugs. Prevalence of osteoporosis drug prescriptions increased linearly during the study and differed markedly by patient sex, age, and exposure to glucocorticoid drugs. Osteoporosis drugs were prescribed for 16.3% of women aged > or = 65 years, for 6.1% of women aged < 50 years, for 6.5% of men aged > or = 65 years, and for 2.2% of men aged < 50 years. Higher glucocorticoid exposure was also associated with higher rate of osteoporosis drug prescription (11.2% of patients exposed to > 4 g/y and 5.6% exposed to 2 to 3 g/y received such therapies). Osteoporosis drugs were 50% more likely to be prescribed by clinicians who prescribed glucocorticoid drugs to > 18 patients than by providers who prescribed glucocorticoid drugs to < 4 patients. CONCLUSIONS: Despite ready availability of bone-specific osteoporosis drugs, few patients with high exposure to glucocorticoid drugs received such therapy. Likelihood of an osteoporosis drug being prescribed for such patients strongly depends on patient sex, age, and exposure to glucocorticoid drugs and on level of practitioner experience in prescribing glucocorticoid drugs.