Kevin Wolter

Recovery of bone mineral density in adolescents following the use of depot medroxyprogesterone acetate contraceptive injections

BACKGROUND Depot medroxyprogesterone acetate (DMPA) is a highly effective progestin-only contraceptive that is widely used by adolescents. We investigated bone mineral density (BMD) changes in female adolescents during and following use of this method. STUDY DESIGN A multicenter, prospective, non-randomized observational study in 98 healthy female adolescents aged 12-18 years who initiated DMPA intramuscular injections for contraception and provided BMD data for up to 240 weeks while receiving DMPA and for up to 300 weeks after DMPA cessation. BMD at the lumbar spine (LS), total hip (TH) and femoral neck (FN) was assessed by dual-energy X-ray absorptiometry. A mixed model analysis of variance was used to examine BMD changes. RESULTS At the time of their final DMPA injection, participants had mean BMD declines from baseline of 2.7% (LS), 4.1% (TH) and 3.9% (FN) (p<.001 at all three sites). Within 60 weeks of discontinuation of DMPA, mean LS BMD had returned to baseline levels, and 240 weeks after DMPA discontinuation, the mean LS BMD was 4.7% above baseline. Mean TH and FN BMD values recovered to baseline values more slowly: 240 weeks and 180 weeks, respectively, after the last DMPA injection. CONCLUSIONS BMD loss in female adolescents receiving DMPA for contraception is substantially or fully reversible in most girls following discontinuation of DMPA, with faster recovery at the LS than at the hip.

Subcutaneous DMPA vs. intramuscular DMPA: a 2-year randomized study of contraceptive efficacy and bone mineral density

BACKGROUND A formulation of depot medroxyprogesterone acetate (DMPA) has been developed that allows subcutaneous injection (104 mg/0.65 mL; DMPA-SC) and achieves highly effective contraception with a similar tolerability profile to intramuscular DMPA (150 mg/mL; DMPA-IM). STUDY DESIGN This randomized, evaluator-blinded study was designed to compare efficacy, safety, and user satisfaction in women receiving DMPA-SC (n=266) or DMPA-IM (n=268) for 2 years with an option to continue for a third year. The primary objectives were to evaluate bone mineral density (BMD) changes and contraceptive efficacy after 2 years. RESULTS A total of 225 women completed the first 2 years of this study (DMPA-SC, n=116; DMPA-IM, n=109). After 2 years of DMPA use, BMD loss was marginally smaller in the DMPA-SC group than in the DMPA-IM group at both the total hip (-3.3% and -3.6%, respectively) and lumbar spine (-4.3% and -5.0%, respectively). In those women who received DMPA during the third year, there were no statistically significant differences in BMD loss between DMPA-SC and DMPA-IM groups at the end of Year 3. Recovery of BMD was observed in the small subpopulation of women who had discontinued DMPA-SC or DMPA-IM after the second year. The 2-year treatment-failure cumulative pregnancy rate was 0% in the DMPA-SC group and 0.8% (95% confidence interval, 0.00-2.37%) in the DMPA-IM group (life-table method). Adverse events were similar in the two groups except that injection site reactions were more common in the DMPA-SC group. CONCLUSION DMPA-SC is an effective and well-tolerated contraceptive option, providing comparable efficacy and BMD safety to DMPA-IM.

Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture.

OBJECTIVE: Depot medroxyprogesterone acetate (DMPA) reversibly reduces bone mineral density. To estimate the extent to which DMPA might increase fracture risk, we undertook a retrospective cohort study of fractures in DMPA users and users of non-DMPA contraceptives, using the General Practice Research Database. METHODS: Eligible women were aged younger than 50 years at the qualifying first contraceptive prescription. The DMPA users were classified by DMPA exposure (cumulative and time of last dose) based on prescription records. All incident fractures were included; fracture incidence and risk factors before starting contraceptive use (DMPA or other) also were estimated. RESULTS: We identified 11,822 fractures in 312,395 women during 1,722,356 person-years of follow-up. Before contraceptive use started, DMPA users had higher fracture risk than nonusers (incidence rate ratio 1.28, 95% confidence interval [CI] 1.07–1.53). After DMPA started, crude fracture incidence was 9.1 per 1,000 person-years for DMPA users and 7.3 for nonusers (crude incidence rate ratio 1.23, 95% CI 1.16–1.30). Fracture risk in DMPA users did not increase after starting DMPA (incidence rate ratio after or before 1.08, 95% CI 0.92–1.26). There was little confounding by age or other factors that could be measured. Fracture incidence was 9.4 per 1,000 person-years in low-exposure DMPA users, and 7.8 per 1,000 in high-exposure DMPA users. The DMPA users had higher fracture risk than nonusers at the start of contraceptive use, with no discernible induction period. CONCLUSION: Although DMPA users experienced more fractures than nonusers, this association may be the result of confounding by a pre-existing higher risk for fractures in women who chose DMPA for contraception. LEVEL OF EVIDENCE: II

A double-blind, randomized, placebo-controlled trial of a diazepam auto-injector administered by caregivers to patients with epilepsy who require intermittent intervention for acute repetitive seizures

A diazepam auto‐injector (AI) has been developed for intramuscular administration to treat acute repetitive seizures (ARS). The objective of this study was to evaluate the efficacy and safety of the diazepam AI when administered by caregivers to control an episode of ARS (ClinicalTrials.gov identifier NCT00319501).

Clinical cure rates in subjects treated with azithromycin for community-acquired respiratory tract infections caused by azithromycin-susceptible or azithromycin-resistant Streptococcus pneumoniae: analysis of Phase 3 clinical trial data

BACKGROUND Community-acquired respiratory tract infections (CARTI) are commonly caused by Streptococcus pneumoniae (SPN) and empirically treated with azithromycin. This study assessed clinical cure rates in azithromycin-treated subjects with CARTI caused by azithromycin-susceptible (Azi-S) or azithromycin-resistant (Azi-R) SPN. METHODS 1127 subjects with CARTI (402 acute otitis media, 309 community-acquired pneumonia, 255 acute bacterial exacerbations of chronic bronchitis and 161 acute bacterial sinusitis) in 13 Phase 3 clinical trials (1993-2007) had a confirmed pathogen, received azithromycin and were assessed for clinical cure/failure. 34.4% of subjects (388/1127) had a positive culture for SPN; 33.4% (376/1127) had Azi-S or Azi-R SPN. RESULTS 28.9% (112/388) of subjects with SPN had Azi-R SPN: 35.7% (40/112) were low-level Azi-R SPN (LLAR; MIC 2-8 mg/L), while 64.3% (72/112) were high-level Azi-R SPN (HLAR; MIC ≥16 mg/L). Among Azi-S and Azi-R SPN CARTI subjects, clinical cure rates were: 86.2% (324/376) overall; 89.4% (236/264) for subjects with Azi-S SPN; 78.6% (88/112) for subjects with Azi-R SPN (P = 0.003, versus Azi-S); 77.5% (31/40) for subjects with LLAR SPN (P < 0.001); and 79.2% (57/72) for subjects with HLAR SPN (P = 0.122). CONCLUSIONS Clinical cure rates in CARTI subjects treated with azithromycin were higher for Azi-S SPN (89.4%) versus Azi-R SPN (78.6%; P = 0.003). However, cure rates were not different for subjects infected with LLAR-SPN versus HLAR-SPN. At the observed prevalence of Azi-R SPN of 28.9%, an additional 3.1 clinical failures would be predicted, as a consequence of azithromycin resistance (LLAR and HLAR), per 100 subjects treated empirically with azithromycin.

Safety and effectiveness of long-term treatment with diazepam auto-injector administered by caregivers in an outpatient setting for the treatment of acute repetitive seizures

Part 1 of this phase III study was a randomized, double‐blind, parallel‐group, placebo‐controlled, multicenter study of caregiver administered diazepam auto‐injector (AI) in subjects with acute repetitive seizures (ARS) and demonstrated that diazepam AI was well‐tolerated and significantly more effective than placebo AI in delaying the time to next seizure or rescue. Part 2 of this study, presented herein, was an open‐label continuation to assess the long‐term safety and effectiveness of diazepam AI for the treatment of ARS.

Biopsychosocial variables associated with substantial bone mineral density loss during the use of depot medroxyprogesterone acetate in adolescents: adolescents who lost 5% or more from baseline vs. those who lost less than 5%

BACKGROUND It is unclear why some adolescents experience substantial bone mineral density (BMD) loss, while others experience a minimal decrease during depot medroxyprogesterone acetate (DMPA) use. We examined biopsychosocial factors in adolescents who experienced ≥5% BMD loss from baseline compared with adolescents who experienced <5% BMD loss during DMPA use. STUDY DESIGN A multicenter, prospective, nonrandomized study of 181 female adolescents who initiated DMPA for contraception was conducted. BMD (by dual-energy X-ray absorptiometry) and serum estradiol were measured at initiation and every 6 months for 240 weeks of DMPA use. RESULTS Half of participants experienced BMD loss of ≥5% from baseline at the hip, and a quarter experienced BMD loss of ≥5% at the lumbar spine (BMD substantial losers, SL). Hip and lumbar spine BMD-SL received a significantly greater number of DMPA injections than non-SL (p<.001). Decreased estradiol levels did not statistically differ between BMD loss subgroups. Hip BMD-SL had significantly lower baseline body mass index (BMI) than non-SL (p=.002), and there was an inverse relationship between weight gain and degree of BMD loss. Mean calcium intake was significantly lower (p<.05) in hip BMD-SL, and reported alcohol use was significantly higher (p<.05) in lumbar spine BMD-SL compared with non-SL. CONCLUSIONS BMD loss of ≥5% was more common at the hip than at the lumbar spine among adolescents using DMPA. Decreased serum estradiol levels did not correlate with magnitude of BMD loss. Lower BMI and calcium intake and greater alcohol use were associated with greater BMD loss in adolescents using DMPA.

Effects of 5 years of treatment with lasofoxifene on incidence of breast cancer in older women.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #11 The Postmenopausal Evaluation and Risk-reduction with Lasofoxifene (PEARL) Trial evaluated the effects of 5 years of a new potent SERM on the incidence of estrogen receptor positive (ER+) breast cancer (BC) (co-primary endpoints, invasive alone and invasive plus ductal carcinoma in situ [DCIS] together). 8556 women ages 5980 with femoral neck or spine T-score ≤ –2.5 and > –4.5 were enrolled in 32 countries. Women were randomly assigned to receive 0.25 mg/d or 0.5 mg/d of lasofoxifene (LASO), or placebo (PBO). BC events were ascertained through annual clinical breast exam and mammographic screening and adjudicated by physician oncologists and a BC pathologist blinded to treatment assignment. 77% of women completed 5 years of follow-up and 62–64% remained on study medication until planned trial closure. ITT analyses were conducted using Cox Proportional Hazards models. The protocol-defined primary analysis for all ER+ BCs compared each of the LASO groups to PBO. In the PBO group, 21 women developed invasive or non-invasive ER+ BC (17.3/10,000 person-years (P-Y)) compared to 10 in the LASO 0.25 mg/d group (9.0/10,000 P-Y; HR=0.52, 95%CI 0.25–1.08) and 5 in the 0.5 mg/d LASO group (3.3/10,000 P-Y; HR=0.19, 95% CI 0.07–0.56). For all invasive BCs (ER+ve and ve), 20 women in the PBO group were affected (16.4/10,000) compared to 16 in the LASO 0.25 mg/d group (13.2/10,000 P-Y; HR=0.79, 95%CI 0.41–1.52) and 3 in the 0.5 mg/d LASO group (2.5/10,000 P-Y; HR=0.15, 95% CI 0.04–0.50). For total BC, 24 women in the PBO group were affected (19.8/10,000 P-Y) compared to 20 in the LASO 0.25 mg/d group (16.4/10,000 P-Y; HR=0.82, 95%CI 0.45–1.49) and 5 in the 0.5 mg/d LASO group (4.1/10,000 P-Y; HR=0.21, 95% CI 0.08–0.55). Too few cases of DCIS occurred to determine effects of LASO on noninvasive breast tumors. No significant differences among treatment groups were observed for breast density. LASO also reduced the incidence of vertebral (primary at 3 years) and nonvertebral clinical fractures (co-primary at 5-years). LASO increased risk of venous thromboembolic events, but not stroke, endometrial cancer or endometrial hyperplasia and decreased risk of major coronary events at 0.5 mg/d. Endometrial hypertrophy, uterine polyps, and fibroids were more common with LASO while hypertension and hyperlipidemia was less frequent compared to PBO. We conclude that LASO reduces the incidence of ER+ BC and appears to have a favorable benefit-risk profile for prevention of clinical fractures in postmenopausal women with osteoporosis. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 11.

Comment on journal review of ‘Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture’

We thank Dr Curry for an accurate summary1 of our study entitled ‘Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture’.2 Nevertheless, we do not recommend more selective use of depot medroxyprogesterone acetate (DMPA) on account of fracture risk, as we believe that this recommendation would reduce access to an effective, safe contraceptive without actually reducing fracture risk. As we reported, in those subjects with at least 6 months of pre-DMPA medical history (176 pre-treatment fractures …