Effects of strength training and raloxifene on femoral neck metabolism and microarchitecture of aging female Wistar rats.

The aim of this study was to prevent female osteoporosis using strength training (ST), raloxifene (Ral) or a combination of ST plus Ral during the natural female aging process, specifically in the periestropause period. For a total of 120 days, aging female Wistar rats at 18-21 months of age performed ST on a ladder three times per week, and Ral was administered daily by gavage (1 mg/kg/day). Bone microarchitecture, areal bone mineral density, bone strength of the femoral neck, immunohistochemistry, osteoclast and osteoblast surface were assessed. We found that the treatments modulate the bone remodeling cycle in different ways. Both ST and Ral treatment resulted in improved bone microarchitecture in the femoral neck of rats in late periestropause. However, only ST improved cortical microarchitecture and bone strength in the femoral neck. Thus, we suggest that performing ST during the late period of periestropause is a valid intervention to prevent age-associated osteoporosis in females.

Evaluación de la respuesta densitométrica en pacientes con osteoporosis posmenopáusica tratadas con ranelato de estroncio o denosumab / Densitometric response in postmenopausal osteoporosis treated with strontium ranelate or denosumab

Tanto el ranelato de estroncio (RSr) como el denosumab (Dmab) son eficaces en el tratamiento de la osteoporosis (OP) posmenopáusica (PM). El efecto de cada fármaco por separado sobre la densidad mineral ósea (DMO) ha sido estudiado recientemente. Con ambas drogas se observó, al año de tratamiento, un aumento significativo de la DMO en columna lumbar (CL), cuello femoral (CF) y cadera total (CT). En este trabajo comparamos la respuesta densitométrica al año de tratamiento con una y otra droga. Utilizamos los registros de 425 pacientes PMOP tratadas con Dmab y 441 tratadas con RSr. En cada paciente analizamos el porcentaje de cambio; se clasificaron como respondedoras aquellas que mostraron un cambio ≥3%. Adicionalmente se comparó la respuesta en pacientes no previamente tratadas con bifosfonatos (BF-naïve) en comparación con pacientes que habían recibido previamente un BF. Al analizar el grupo completo para Dmab, el porcentaje de pacientes respondedoras fue de 68,4% en CL, 63,3% en CF y 49,3% en CT. Por otro lado, en el grupo de pacientes tratadas con RSr, el porcentaje de respondedoras (53,8% en CL, 40,0% en CF y 35,6% en CT) fue estadísticamente menor. Cuando comparamos la respuesta entre las pacientes BF-naïve que recibieron RSr o Dmab, el Dmab indujo mayor respuesta en CL y CF que el grupo RSr, sin diferencias en CT. Cuando se analizaron los subgrupos BF-previo, las tratadas con Dmab mostraron mayor respuesta en todas las regiones. Conclusión: en pacientes con OP-PM, el tratamiento con Dmab produjo mayores incrementos densitométricos que el RSr, siendo el porcentaje de pacientes respondedoras mayor con Dmab que con RSr. (AU)

Both strontium ranelate (SrR) and denosumab (Dmab) are effective in the treatment of postmenopausal osteoporosis (PMOP). The effect of each drug on bone mineral density (BMD) has been studied separately by us. With both treatments, there was a significant increase after one year of treatment at the lumbar spine (LS) and hip. In this paper we compared the densitometric response after one year of treatment with both drugs used separately. We used the clinical records of 425 PM patients treated with Dmab and 441 treated with SrR. For each patient we analyzed the percentage of change; those who showed a change ≥3% were classified as responders. Additionally, the response was compared in patients not previously treated with bisphosphonates (BP-naïve) compared to patients who had previously received a BP. When analyzing the complete group for Dmab, the percentage of "responders" was 65.2% at the LS, 62.9% at the femoral neck (FN) and 47.4% at the total hip (TH). On the other hand, in the group of patients treated with SrR the percentage of responders (53.8% at the LS, 40.0% at the FN and 35.6% at the TH) was statistically lower. When comparing the response between in BF-naïve patients receiving RSr or Dmab, Dmab induced a greater response at the LS and FN than the RSr group, with no statistical differences at the TH. When the subgroups with prior BP treatment were analyzed, those treated with Dmab showed greater response in all regions. Conclusion: in patients with PMOP treatment with Dmab produced greater densitometric increments than SrR, and the percentage of responders was higher with Dmab than with SrR. (AU)

Utilidad del tratamiento secuencial con teriparatide y denosumab en la osteoporosis de alto riesgo: nuestra experiencia asistencial / Benefits of sequential treatment of high risk osteoporosis with teripartide and denosumab: our experience

El tratamiento de las formas graves de osteoporosis representa un desafío en la práctica asistencial. Reportamos tres pacientes con formas graves de osteoporosis tratadas en el Instituto de Diagnóstico e Investigaciones Metabólicas con un esquema secuencial de teriparatide 20 µg/día durante 18 meses, seguidos de 12 meses de denosumab 60 mg semestral. Luego de 18 meses de tratamiento con teriparatide la densidad mineral ósea en columna aumentó 5,86±1,01% y en cuello femoral 1,92±3,10%; al finalizar los doce meses de tratamiento con denosumab se constató un aumento total en columna de 10,45±1,70% y en cuello femoral 9,28±3,86%. El tratamiento con teriparatide se acompañó de un aumento en los niveles plasmáticos de telopéptidos del colágeno óseo (CTX) y en el período de tratamiento con denosumab dichos valores disminuyeron de manera significativa, mostrando el impacto de estos fármacos sobre el remodelado óseo. Concluimos que el tratamiento secuencial con teriparatide y denosumab en dosis convencionales resultó beneficioso en las tres pacientes tratadas. Sería de utilidad ampliar esta experiencia en un trabajo prospectivo. (AU)

High risk osteoporosis treatment is a challenge in daily medical practice. We report three patients that attended our institution with severe osteoporosis who received sequentially teriparatide (20 ug daily) for eighteen months followed by denosumab (60 mg every six months) for twelve months. After teriparatide treatment bone mineral density increased 5.86±1.01% at lumbar spine and 1.92±3.10 % at femoral neck, while after denosumab it continued increasing to reach a total of 10.45±1.70% at lumbar spine and 9.28±3.86% at femoral neck. Teriparatide treatment increased bone resorption evidenced by high serum CTX while after denosumab it fell abruptly, showing the impact of these two drugs on bone turnover. We conclude that sequential treatment with teriparatide and denosumab in approved doses was beneficial for these three patients. Prospective studies are needed. (AU)

Calcium Plus Vitamin D Supplementation During the Third Trimester of Pregnancy in Adolescents Accustomed to Low Calcium Diets Does Not Affect Infant Bone Mass at Early Lactation in a Randomized Controlled Trial.

BACKGROUND: Pregnancy and lactation in adolescents with low calcium intake may impair fetal growth and infant bone mass. OBJECTIVE: We investigated the effects of calcium plus vitamin D supplementation during pregnancy in Brazilian adolescent mothers consuming low calcium diets (∼600 mg/d) on fetal biometry and infant bone mass, and the relation between infant and maternal bone mass during early lactation. METHODS: Infants of mothers who received calcium (600 mg/d) plus cholecalciferol (200 IU/d) supplementation (n = 30) or placebo (n = 26) from 26 wk of gestation until parturition were studied. Fetal biometric measurements at 23 and 36 wk of gestation were obtained from medical records. Infant anthropometric and total body bone measurements [bone mineral content (BMC), bone area (BA), and bone mineral density (BMD)] at 5 wk postpartum were assessed by dual-energy X-ray absorptiometry. Maternal BMD z scores for total body, lumbar spine, total hip, and femoral neck at 5 wk postpartum were obtained. Group comparisons were adjusted for significant covariates. RESULTS: Maternal mean serum 25-hydroxyvitamin D was 59 nmol/L at baseline in both groups. No differences in fetal measurements at 36 wk of gestation were observed between the groups, except for body weight and its increment from 23 to 36 wk, which were higher in the supplemented group (6.8%, P = 0.014 and 10.5%, P = 0.07, respectively). Infant BMC (61.1 ± 21.7 g), BA (167 ± 79 cm(2)), and BMD (0.385 ± 0.069 g/cm(2)) did not significantly differ between the groups. In the placebo group, infant BMC and BA were negatively correlated with maternal BMD z scores for total body (r = -0.40 and r = -0.47; P < 0.05) and hip (r = -0.41 and r = -0.46; P < 0.05). In contrast, no correlations were observed in the supplemented group. CONCLUSIONS: Calcium and vitamin D supplementation of the adolescents studied resulted in higher fetal body weight at 36 wk of gestation and had no effect on infant bone mass at 5 wk postpartum. Because correlations between maternal and infant bone mass were evident only in the placebo group, infant bone mass appeared to be more dependent on maternal skeletal mass when calcium intake was low. This trial was registered at clinicaltrials.gov as NCT01732328.

Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis.

CONTEXT: Abaloparatide is a novel synthetic peptide analog of parathyroid hormone-related protein (PTHrP) that is currently being developed as a potential anabolic agent in the treatment of postmenopausal osteoporosis. OBJECTIVE: This study sought to assess the effects of abaloparatide on bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck in postmenopausal women with osteoporosis. DESIGN: Multi-center, multi-national, double-blind placebo controlled trial in which postmenopausal women were randomly assigned to receive 24 weeks of treatment with daily sc injections of placebo, abaloparatide, 20, 40, or 80 µg, or teriparatide, 20 µg. A 24-week extension was also performed in a subset of subjects. PARTICIPANTS: Postmenopausal women with osteoporosis (n = 222). MAIN OUTCOME MEASURES: BMD by dual-x-ray absorptiometry and biochemical markers of bone turnover. RESULTS: At 24 weeks, lumbar spine BMD increased by 2.9, 5.2, and 6.7% in the abaloparatide, 20-, 40-, and 80-µg groups, respectively, and 5.5% in the teriparatide group. The increases in the 40- and 80-µg abaloparatide groups and the teriparatide group were significantly greater than placebo (1.6%). Femoral neck BMD increased by 2.7, 2.2, and 3.1% in abaloparatide, 20-, 40-, and 80-µg groups, respectively, and 1.1% in the teriparatide group. The increase in femoral neck BMD with abaloparatide, 80 µg was significantly greater than placebo (0.8%). Total hip BMD increased by 1.4, 2.0, and 2.6% in the abaloparatide, 20-, 40-, and 80-µg groups, respectively. The total hip increases in the 40- and 80-µg abaloparatide groups were greater than both placebo (0.4%) and teriparatide (0.5%). CONCLUSIONS: Compared with placebo, 24 weeks of daily sc abaloparatide increases BMD of the lumbar spine, femoral neck, and total hip in a dose-dependent fashion. Moreover, the abaloparatide-induced BMD increases at the total hip are greater than with the marketed dose of teriparatide. These results support the further investigation of abaloparatide as an anabolic therapy in postmenopausal osteoporosis.

Effect of calcium plus vitamin D supplementation during pregnancy in Brazilian adolescent mothers: a randomized, placebo-controlled trial.

BACKGROUND: Pregnancy and lactation in adolescents with habitually low calcium intake may adversely affect maternal bone mass. OBJECTIVE: We investigated the effect of calcium plus vitamin D supplementation during pregnancy on bone mass during lactation in Brazilian adolescent mothers with low-calcium diets (∼600 mg/d). DESIGN: Pregnant adolescents (14-19 y) randomly received daily calcium (600 mg) plus vitamin D3 (200 IU) (n = 30) or a placebo (n = 26) from 26 wk of pregnancy (baseline) until parturition. The bone mineral content (BMC), bone area (BA), and bone mineral density (BMD) at the total body, lumbar spine, and hip (total and femoral neck) were evaluated by using dual-energy X-ray absorptiometry at 5 and 20 wk postpartum. Serum hormones and 25-hydroxyvitamin D [25(OH)D] were measured. Group comparisons were adjusted for significant covariates. RESULTS: The mean serum 25(OH)D concentration was 59 nmol/L at baseline. In comparison with the placebo, 25(OH)D tended to be 14-15 nmol/L higher postpartum in the supplemented group (P = 0.08). Total body and hip BMC and BMD decreased over time (P ≤ 0.005) in both groups with a group × time interaction at the femoral neck (P < 0.04). Supplemented mothers had higher lumbar spine BA (6.7%; P = 0.002) and lumbar spine BMC (7.9%, P = 0.08) than did mothers who consumed the placebo at 5 wk postpartum. At 20 wk postpartum, differences between groups were more evident, with higher lumbar spine BMC (13.9%), lumbar spine BA (6.2%), and lumbar spine BMD (10.6%) in the supplemented group (P ≤ 0.008). CONCLUSIONS: Calcium plus vitamin D supplementation during pregnancy of adolescents with low calcium intake results in higher lumbar spine bone mass and a reduced rate of femoral neck bone loss during lactation. Additional studies are required to determine whether bone effects are temporary or long-lasting. This trial was registered at clinicaltrials.gov as NCT01732328.

Effects of D-003 (10 mg/day) on bone mineral density of the lumbar spine and femoral neck in postmenopausal women: a randomized, double-blinded study.

BACKGROUND/AIMS: Increased osteoclast activity is a pivotal finding in osteoporosis. This increase is mediated via the mevalonate-to-cholesterol pathway, which is involved in producing the intermediates required for osteoclast activity. D-003, a mixture of high molecular weight sugarcane wax acids, has been shown to inhibit cholesterol synthesis prior to mevalonate production, resulting in a reduction of bone loss and resorption in ovariectomized rats. Moreover, previous studies have demonstrated that short-term D-003 treatment reduces urinary excretion of deoxypyridinoline/creatinine in postmenopausal women. METHODS: We performed a double-blinded, placebo-controlled study to investigate the effects of D-003 (10 mg/day) treatment for 3 years on bone mineral density (BMD) in 83 postmenopausal women with low BMD. RESULTS: Over 3 years, D-003 treatment increased lumbar spine BMD (5.1%, p < 0.01) and improved osteoporosis-related quality of life scores as compared with placebo-treated controls. D-003 was also well tolerated; the frequency of adverse events in the bone, joints, or muscle with D-003 treatment (p < 0.05) was lower than in the placebo group. CONCLUSIONS: D-003 treatment (10 mg/day) for 3 years increased lumbar spine BMD and produced clinical improvements in postmenopausal women with low BMD. Further studies, however, will be required to confirm these results.

The combined contraceptive vaginal ring and bone mineral density in healthy pre-menopausal women.

BACKGROUND: Hormonal contraceptives have been associated with various effects on the bone mineral density (BMD) of pre-menopausal women. The aim of this study was to assess the effects of a vaginal contraceptive ring on BMD in pre-menopausal women and compare them with those of non-hormonal contraceptive use. METHODS: This open-label, multicentre study used dual-energy X-ray absorptiometry to measure BMD in the lumbar spine (L(2)-L(4)) and femoral neck regions. Subjects were assigned 3:1 to receive a contraceptive ring (n = 105) or a non-hormonal contraceptive control (n = 39) and were assessed after 13 and 26 cycles of contraceptive ring treatment or 12 and 24 months of control treatment. RESULTS: No change from baseline in BMD (Z-scores) was seen in contraceptive ring users (n = 73) at either time-point. In the control group (n = 30), BMD increased slightly from baseline resulting in significant differences (P < 0.0001) between the two groups at cycle 26/month 24. These differences are not clinically relevant, although some degree of acquisition of peak bone mass might have been prevented in the contraceptive ring group. The contraceptive ring was generally well tolerated; a higher incidence of treatment-related adverse events was observed in the contraceptive ring group compared with the non-hormonal contraceptive control group. CONCLUSIONS: In healthy pre-menopausal women, 2 years of contraceptive ring use produced no changes in BMD.

Osteopenia in patients with glomerular diseases requiring long-term corticosteroid therapy.

BACKGROUND: Chronic corticosteroid (CS) use is associated with bone mass loss. METHODS: Bone mineral density (BMD) was assessed in 72 patients (25 males/47 premenopausal females) with glomerular diseases, primary (n = 35) or secondary to systemic lupus erythematosus (n = 37) with normal renal function, who were taking CS, as prednisone and/or methylprednisolone, in doses > or =7.5 mg/day, for a period of at least 6 months. Cumulative dose and duration of prior CS therapy, as well as biochemical parameters and other factors contributing to bone loss were evaluated. RESULTS: We found 37 (52%) patients with LOW BMD (29 with osteopenia and 8 with osteoporosis). The low BMD group presented a lower mean weight and body mass index (BMI) versus the normal BMD group (62 +/- 15 vs. 70 +/- 10 kg and 25 +/- 4 vs. 27 +/- 5, mean +/- SD, p < 0.05). The estimated calcium intake was lower than 400 mg/day in all patients with low BMD, and they had taken furosemide as a concomitant drug for a longer mean period of time when compared to normal BMD patients (30 +/- 29 vs. 16 +/- 27 months, p < 0.05). A higher mean number of pulses per patient and mean cumulative dose of methylprednisolone were observed in the low versus normal BMD group (7.7 +/- 4.0 vs. 5.6 +/- 4.0 pulses and 6.5 +/- 3.9 vs. 3.9 +/- 2.7 g, p < 0.05). CONCLUSIONS: These findings suggest a high frequency of osteopenia among young and premenopausal patients with glomerular diseases given long-term corticosteroid therapy. The lower BMI and calcium intake, as well as the concomitant furosemide use, might have contributed to such a bone loss. The higher number of pulse therapies leading to higher cumulative intravenous doses of corticosteroid mainly in lupus nephritis patients shows that pulse therapy may be deleterious to bone.

Site-dependent bone mineral density response to oral pamidronate and calcium in postmenopausal osteoporosis: a preliminary report.

Radiologically diagnosed postmenopausal osteoporotic patients with at least one nontraumatic vertebral flattening were treated for one year with either oral pamidronate (APD), 300 mg/day plus calcium 1 g/day (n=39) or with calcium alone (n=21). Bone mineral density (BMD) was assessed in lumbar spine, femoral neck, trochanter and Ward's triangle by dual X-ray absorptiometry in order to determine the number of responders at each site. As no densitometric inclusion criteria were stipulated, wide inter- and intra-individual variations in both regional basal BMD and response to therapy were found. However, the APD-treated group showed significant mean BMD increases in spine (+3.1%; p < 0.001) and femoral neck (+3.2%; p < 0.002) versus basal level, whereas the calcium only group failed to exhibit significant differences. The entire 60-strong population was then split into two groups, according to whether individual BMD content was greater or less than the mean basal value for each skeletal site evaluated. For either treatment, subpopulations with lower basal BMD tended to achieve greater bone gain, though statistically significant differences were only disclosed at trochanter (p < 0.004) with APD and at femoral neck (p < 0.002) in the calcium only group. Globally speaking, increases in BMD were observed in 60-80% of patients receiving either treatment - who were thus defined as responders - at each particular skeletal area assessed. However, when only skeletal areas with low basal BMD were considered, the number of responders reached 60-100%. Responsive sites varied among patients: out of 56 cases, 9 (24%) on APD and 6 (32%) on calcium alone responded in all 4 areas evaluated, while a single case on the latter treatment failed to show BMD response at any site. Overall, the mean number of responsive sites was 2.7. Odds ratios were calculated considering treatment modality and high or low basal BMD as parameters, but no significant differences were found in the number of responders. It may be concluded that APD induces moderate lumbar and femoral neck bone mass gain in severe postmenopausal osteoporosis, whereas calcium alone leads to non significant variations, both findings being in agreement with reported data. Therefore, evaluated APD doses enhance mineralization in responsive sites alone, but fail to increase the total number of responders. Interestingly, responsive sites seem to be those relitively spared by the course of the disease.