Coen Netelenbos

Randomized, double-blind, placebo- controlled study of the effects of raloxifene and conjugated equine estrogen on plasma homocysteine levels in healthy postmenopausal women

OBJECTIVE To investigate the long-term effects of raloxifene on fasting plasma homocysteine levels in postmenopausal women compared with conjugated equine estrogen (CEE). DESIGN Randomized, double-blind, placebo-controlled study. SETTING Outpatient department of a university hospital. PATIENT(S) Fifty-two hysterectomized, healthy postmenopausal women. INTERVENTION(S) Oral raloxifene in two dosages (60 mg/d [n=13] and 150 mg/d [n=13]), oral CEE (0.625 mg/d [n=13], and placebo (n=13) were given for 24 months. MAIN OUTCOME MEASURE(S) Fasting plasma homocysteine concentrations. RESULT(S) Plasma homocysteine levels were not altered in the placebo group. After 12 months, a significant reduction versus baseline in the mean plasma homocysteine level (-16%) was found only in the raloxifene 150-mg group. The mean change in plasma homocysteine levels within this group also was significantly different from the changes versus baseline found in the placebo group (+2%) and the raloxifene 60-mg group (-2%), but not different from those found in the CEE group (-8%). After 24 months, plasma homocysteine levels were decreased significantly in the raloxifene 150-mg and CEE groups compared with both baseline (-13% and -10%, respectively) and placebo values (-15% and -11%, respectively). No significant change in plasma homocysteine levels was observed in the raloxifene 60-mg group. CONCLUSION(S) Raloxifene has a favorable, dose-related effect on plasma homocysteine levels in postmenopausal women.

Bone mineral density and markers of bone turnover in young adult survivors of childhood lymphoblastic leukaemia

In order to determine if a serious disease like childhood acute lymphoblastic leukaemia (ALL) and the treatment necessary to cure the patients has long term effects on bone mass, we assessed bone mineral density (BMD) and several parameters involved in bone formation in a group of young adult survivors of ALL.

Postmenopausal Oral 17β-Estradiol Continuously Combined with Dydrogesterone Reduces Fasting Serum Homocysteine Levels

OBJECTIVE To investigate the effects of oral 17beta-estradiol administration continuously combined with dydrogesterone on fasting serum total homocysteine levels in postmenopausal women. DESIGN Randomized, double-blind study. SETTING Gynecologic outpatient department of a university hospital. PATIENT(S) One hundred thirty-five healthy, nonhysterectomized postmenopausal women. INTERVENTION(S) Oral micronized 17beta-estradiol (2 mg/d) continuously combined with one of four dosages of dydrogesterone (2.5 mg [n = 41], 5 mg [n = 38], 10 mg [n = 37], or 15 mg [n = 19]) was given for 6 months. MAIN OUTCOME MEASURE(S) Fasting serum total homocysteine concentrations. RESULT(S) The mean fasting serum total homocysteine concentrations in the overall study population decreased significantly (by 13.5%) after the first 3 months of treatment and remained unchanged thereafter. No influence of dydrogesterone dosage was found. The greatest reduction in total homocysteine concentration was obtained in women with the highest baseline levels. CONCLUSION(S) Continuously combined hormone replacement therapy lowers fasting serum total homocysteine levels significantly in postmenopausal women. This decrease may be one of the mechanisms that underlie the cardioprotective effects of postmenopausal hormone replacement therapy.

Raloxifene treatment enhances brain activation during recognition of familiar items: a pharmacological fMRI study in healthy elderly males

Raloxifene is a selective estrogen receptor modulator that may delay the onset of mild cognitive impairment in elderly women. Effects of raloxifene treatment on mental performance in males remain to be investigated. In a previous functional magnetic resonance imaging (fMRI) study, we showed that raloxifene treatment enhanced brain activation in elderly males during encoding of new information (faces) into memory. The current study used fMRI in the same group of subjects to screen for effects of raloxifene treatment on brain function during face recognition. Healthy elderly males (n=28; mean age 63.6 years, SD 2.4) were scanned at baseline and after 3 months of treatment with either raloxifene 120 mg (n=14) or placebo (n=14) in a randomized, double-blind, placebo-controlled study design. Functional data were analyzed in an event-related fashion with respect to correct hits and correct rejections using FSL software. Performance data were analyzed with respect to recognition accuracy, latency, and response bias. Functional effects of treatment were found on brain activation related to correct hits only. When compared to placebo treatment, raloxifene treatment enhanced brain activation in the left posterior parahippocampal area (Z=3.9) and right inferior prefrontal cortex (Z=3.5). Recognition accuracy scores remained stable in the raloxifene group, whereas the placebo group showed a small but significant decrease in accuracy scores (p=0.02). No significant effects were found on response bias or latency. In conclusion, raloxifene treatment affects brain function during memory performance in a way that may reflect increased arousal during initial encoding, with downstream effects on brain function during retrieval of information. Behaviorally, such neurofunctional effects may actively block decreased memory performance as a result of context-dependency. The validity of these predictions can be tested in large-scale clinical trials.

Two-step gonadotropin-releasing hormone agonist treatment of uterine leiomyomas: Standard-dose therapy followed by reduced-dose therapy

OBJECTIVE Gonadotropin-releasing hormone agonist-induced partial pituitary suppression with low-grade estrogen production may be useful in long-term treatment of uterine leiomyomas. STUDY DESIGN Twenty-seven women with uterine leiomyomas were treated with a standard dose of triptorelin for 8 weeks. Patients were then randomized to use 100, 20, or 5 micrograms of triptorelin until week 26. Uterine and myoma size, pituitary-ovarian function, bone metabolism, and bone mineral density were monitored. RESULTS During standard treatment uterine size was reduced to 67.1% of baseline. During randomized treatment uterine size was further reduced to 57.8% of baseline. There were no differences in overall volume reduction among the groups. Luteinizing hormone and estradiol levels were restored in a dose-dependent way. Bone mineral density decreased significantly in the highest-dose group at week 26. CONCLUSIONS This study shows that the beneficial effects of initial high-dose agonist treatment on uterine leiomyomas can be preserved by continued low-dose treatment. Bone mineral density does not seem to change during reduced-dose agonist treatment.

Osteoporosis: intervention options.

Osteoporosis is a systemic progressive disease with important clinical complications because of the fractures that arise and cause major morbidity in especially the aging postmenopausal women. Because of the relative not complex procedure of diagnosis and prediction the most important question to answer: is treatment possible? There are now a variety of treatments available for the management of osteoporosis. The inhibitors of bone resorption, which include calcium, the vitamin Ds, bisphosphonates, calcitonins and gonadal steroids have been variously shown to prevent bone loss or to reduce fractures. On the other hand bone formation stimulating agents as fluorides and in the near future parathyroid hormone and analogues must be considered also. However, randomized clinical trials with fractures as clinical endpoints are only few in number and not present for every suggested treatment. During the last 3 years it has become clear that besides estrogen, bisphosphonates and now perhaps the selective estrogen receptor modulators also show a good alternative as intervention option of postmenopausal osteoporosis. At this moment sodium fluoride is not the first choice in treatment of osteoporosis in general practice.

Raloxifene treatment increases plasma levels of β-endorphin in postmenopausal women: a randomized, placebo-controlled study

OBJECTIVE To evaluate the effect of the selective estrogen receptor modulator raloxifene hydrochloride (Evista, Eli Lilly and Company, Indianapolis, IN) on plasma levels of beta-endorphin, and to determine whether beta-endorphin levels and menopausal symptoms are related. DESIGN A randomized, double-blind, placebo-controlled pilot study. SETTING Endocrinology outpatient department. PATIENT(S) Forty postmenopausal women. INTERVENTION(S) The women received raloxifene, 60 mg/d, or placebo for 3 months. A questionnaire on climacteric symptoms was administered before and after treatment. MAIN OUTCOME MEASURE(S) Circulating levels of beta-endorphin, climacteric symptom score, and correlation with beta-endorphin levels. RESULT(S) Raloxifene treatment significantly increased levels of beta-endorphin and did not significantly affect climacteric symptoms, with the exception of worsening vasomotor symptoms. No significant relation was seen between plasma levels of beta-endorphin and climacteric symptoms. CONCLUSION(S) Raloxifene modulates plasma levels of beta-endorphin without concomitantly relieving climacteric symptoms, as seen with hormone replacement therapy.

Hyperparathyroidism following irradiation of benign diseases of the head and neck

In a series of 73 consecutive patients with hyperparathyroidism (HPT) eight patients gave a history of irradiation of head and neck because of benign diseases. The average interval between irradiation and definite diagnosis was 34 years. Intermittent hypercalcaemia was found in three patients. Microscopic examination of pathologic parathyroid glands of three patients showed a predominance of oxyphil cells. Thyroid abnormalities occurred more frequently in irradiated patients than in nonirradiated patients with HPT. Reviewing clinical and experimental data an etiologic role of irradiation in the pathogenesis of HPT appears present.

Effect of raloxifene on activated protein C (APC) resistance in postmenopausal women and on APC resistance and homocysteine levels in elderly men: two randomized placebo-controlled studies.

Raloxifene, a selective estrogen receptor modulator, like hormonal replacement therapy increases the risk of venous thromboembolism in postmenopausal women. A possible explanation for the increased thrombotic risk could be an increase in acquired resistance to activated protein C (APC). In two randomized, placebo-controlled, double-blind studies we determined the effect of raloxifene on the normalized APC sensitivity ratios (nAPCsr). The nAPCsr were determined with the thrombin generation-based APC resistance test. In the first study 83 postmenopausal women (age, 51.1 ± 2.7 years) randomly received daily 0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate (n = 17), 60 mg raloxifene (n = 23), 150 mg raloxifene (n = 20) or placebo (n = 23) for 24 months. At baseline and after 6, 12 and 24 months the nAPCsr were measured. In the second study 30 elderly men (age, 64.4 ± 2.4 years) randomly received 120 mg raloxifene (n = 15) or placebo (n = 15) for 3 months. At baseline and after 3 months the nAPCsr and fasting homocysteine levels were measured. In postmenopausal women conjugated equine estrogen/medroxyprogesterone acetate significantly increased the nAPCsr from 1.26 ± 0.82 to 2.87 ± 0.86 at 24 months (P < 0.0005 compared with placebo). Raloxifene had no significant effect on nAPCsr compared with placebo in both women and men. The results did not change after excluding carriers of factor V Leiden. Also fasting homocysteine levels were not affected by raloxifene in the aging men. It is concluded that raloxifene, in contrast to combined hormonal replacement therapy, does not increase APC resistance.

Special Considerations for Clinical Trials in Fibrodysplasia Ossificans Progressiva (FOP): Clinical Trial Considerations for FOP

Clinical trials for orphan diseases are critical for developing effective therapies. One such condition, fibrodysplasia ossificans progressiva (FOP; MIM#135100), is characterized by progressive heterotopic ossification (HO) that leads to severe disability. Individuals with FOP are extremely sensitive to even minor traumatic events. There has been substantial recent interest in clinical trials for novel and urgently‐needed treatments for FOP. The International Clinical Council on FOP (ICC) was established in 2016 to provide consolidated and coordinated advice on the best practices for clinical care and clinical research for individuals who suffer from FOP. The Clinical Trials Committee of the ICC developed a focused list of key considerations that encompass the specific and unique needs of the FOP community – considerations that are endorsed by the entire ICC. These considerations complement established protocols for developing and executing robust clinical trials by providing a foundation for helping to ensure the safety of subjects with FOP in clinical research trials.