Carlos Mautalen

Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture

BACKGROUND Mortality is increased after a hip fracture, and strategies that improve outcomes are needed. METHODS In this randomized, double-blind, placebo-controlled trial, 1065 patients were assigned to receive yearly intravenous zoledronic acid (at a dose of 5 mg), and 1062 patients were assigned to receive placebo. The infusions were first administered within 90 days after surgical repair of a hip fracture. All patients (mean age, 74.5 years) received supplemental vitamin D and calcium. The median follow-up was 1.9 years. The primary end point was a new clinical fracture. RESULTS The rates of any new clinical fracture were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction with zoledronic acid (P=0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8% (P=0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P=0.03). In the safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic acid group (P=0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the two groups. CONCLUSIONS An annual infusion of zoledronic acid within 90 days after repair of a low-trauma hip fracture was associated with a reduction in the rate of new clinical fractures and with improved survival. (ClinicalTrials.gov number, NCT00046254 [ClinicalTrials.gov].).

Interim report and recommendations of the World Health Organization Task-Force for Osteoporosis.

Harry K. Genant (Chairman) , Cyrus Cooper (Rapporteur) , Gyula Poor (Rapporteur) , Ian Reid (Rapporteur) , George Ehrlich (Editor), J. Kanis (Editor), B. E. Christopher Nordin (Editor), Elizabet h Barrett-Connor , Dennis Black, J.-P. Bonjour, Bess Dawson-Hughes , Pierre D. Delmas, J. Dequeker , Sergio Ragi Eis, Carlo Gennari , Olaf Johnell , C. Conrad Johnston, Jr, Edith M. C. Lau, Uri A. Liberman, Robert Lindsay, Thomas John Martin, Basel Masri, Carlos A. Mautalen, Pierre J. Meunier, Paul D. Miller , Ambrish Mithal, Hirotoshi Morii , Socrates Papapoul os, Anthony Woolf, Wei Yu and Nikolai Khaltaev (WHO Secretariat) 30

Melatonin effects on bone: experimental facts and clinical perspectives

Abstract: Bone formation proceeds through a remodeling process that runs continuously, involving the resorption of old bone by osteoclasts, and the subsequent formation of new bone by osteoblasts. This is controlled by growth factors and cytokines produced in bone marrow microenvironment and by the action of systemic hormones, like parathyroid hormone, estradiol or growth hormone (GH). One candidate for hormonal modulation of osteoblast and osteoclast formation is melatonin. Because circulating melatonin declines with age, its possible involvement in post‐menopausal and senescence osteoporosis is considered. This review article discusses early studies on melatonin–bone relationships and recent data that suggest a direct effect of melatonin on bone. Melatonin could act as an autacoid in bone cells as it is present in high quantities in bone marrow, where precursors of bone cells are located. Melatonin dose‐dependently augmented proteins that are incorporated into the bone matrix, like procollagen type I c‐peptide. Osteoprotegerin, an osteoblastic protein that inhibits the differentiation of osteoclasts is also augmented by melatonin in vitro. Another possible target cell for melatonin is the osteoclast, which degrades bone partly by generating free radicals. Melatonin through its free radical scavenger and antioxidant properties may impair osteoclast activity and bone resorption. At least in one study melatonin was both inhibitory to osteoclastic and osteoblastic cells. Therefore, the documented bone‐protecting effect of melatonin in ovariectomized rats can depend in part on the free radical scavenging properties of melatonin. Additionally, melatonin may impair development of osteopenia associated with senescence by improving non‐rapid eye movement sleep and restoring GH secretion. Whether melatonin can be used as a novel mode of therapy for augmenting bone mass in diseases deserves to be studied.

Are the etiologies of cervical and trochanteric hip fractures different

Review of results published in the past few years indicates that there are several differences between women sustaining trochanteric fractures of cervical hip fractures. In most series women with trochanteric fractures are older, shorter, and lighter than those with cervical fractures. The bone mineral density was found to be lower in trochanteric fractures, but although in the majority of the studies the diminution was statistically significant at the level of the trochanter and spine--with predominant trabecular bone--the decrease was not uniformly significant at the level of the femoral neck or total skeleton. Previous vertebral fractures were twice as common in patients with trochanteric fractures. Ultrasound exploration of the calcaneus disclosed that the values were significantly lower in women with trochanteric fractures and this finding was independent of the diminution of the bone mineral density. On the other hand, fall biomechanics have not been found to be different in the two types of hip fractures. In summary, women with trochanteric fractures have a more severe and generalized bone loss, especially of the trabecular component. Cervical fractures seem to be more related to pelvic structure-failure of the outer diameter of the femoral neck to expand with age and increased acetabular bone width-added to a focal bone loss. The two main types of fractures should be treated separately in epidemiological or clinical studies to increase the knowledge and the possibilities of preventing hip fractures.

Professional Football (Soccer) Players Have a Markedly Greater Skeletal Mineral Content, Density and Size Than Age- and BMI-Matched Controls

Abstract. The total skeletal bone mineral content (BMC), bone mineral density (BMD), bone size, and body composition were measured by dual-energy x-ray absorptiometry (DXA) in all professional male football players of a 1st division team (n = 24) and age- and BMI-matched (n = 22) controls (less than 3 hours of recreational sport activities per week). Average (±1 SD) age of the athletes was 22.6 ± 2.5 years. Intensive training is conducted during 48 weeks a year for 20–22 hours/week. The length of the registered playing career before the study was 8.2 ± 2.7 years. Total skeleton BMC was 18.0% (P < 0.001) greater in the football players. The difference resulted from the sum of 5.2% (P < 0.02) increment of bone size and 12.3% (P < 0.001) increment of BMD. The analysis of skeletal subareas revealed that the difference of the BMC and BMD was greater at the level of the pelvis and legs compared with the arms or trunk. The BMC and BMD of the head was equal for both groups. Also, the bone size of the legs and pelvis was significantly greater for the players compared with controls; there was no difference at the level of the arms or head. Within the group of football players the increment of total skeleton BMD was similar in the young players, with less than 7 years of practice (age 20.6 ± 0.9 years) compared with relative older players (age 24.6 ± 1.9) with more than 7 years of practice. Lean body mass was significantly greater in the players (63.3 ± 4.0 kg) compared with the controls (56.7 ± 3.6, P < 0.001) whereas fat mass was markedly lower (9.4 ± 2.9 kg versus 14.9 ± 6.3 kg), P < 0.002). The BMD of the controls was significantly correlated to total weight, height, and lean mass whereas the BMD of the players was only correlated to muscle mass. The calcium intake from dairy products was similar in both groups. The range of calcium intake was wide among the players (184–2519 mg/day) but it was not significantly correlated to BMD (r = 0.03). In conclusion, male professional football players develop a significant increment of BMC as a result of increased bone size and density. This is already present at the end of the second decade and maintained at least to the end of the third decade in active players. As in other high impact loading sports, the effect on area is specific involving mainly the pelvis and legs. The increment was totally unrelated to the calcium intake from dairy products. The fate of the increased BMC after intensive training is discontinued should be assessed. However, if the findings of the present cross-sectional study are supported by detailed longitudinal investigations, the presently reported observations might be important for the prevention of future osteoporotic fractures.

Body composition and bone mineral density in untreated and treated patients with celiac disease

Body composition and bone mineral density (BMD) were studied by X-ray absorptiometry in 20 untreated and 12 treated women with celiac disease, as well as in 85 age-matched control women. Untreated patients had a significantly lower body weight, fat mass, lean tissue mass and BMD at the lumbar spine and total skeleton compared to controls (p < 0.001 for all parameters). Treated patients had also a significantly lower body weight (p < 0.01) fat mass (p < 0.05) and bone mineral density at lumbar spine and total skeleton (p < 0.05) compared with controls, but lean tissue mass was not diminished. However, treated patients had a significantly higher body weight, fat mass and BMD of the total skeleton compared with untreated celiac patients (p < 0.01 for all parameters). Serum alkaline phosphatase levels were increased in untreated patients but serum 250HD was normal. In conclusion, celiac disease causes a global and almost universal reduction of fat mass and BMD. The results of this cross-sectional study suggest that osteopenia does not seem to be completely restored by adequate treatment. Alteration of vitamin D metabolism was not the cause of osteopenia in the majority of patients.

Seasonal variations of 25 hydroxyvitamin D and parathyroid hormone in Ushuaia (Argentina), the southernmost city of the world

Serum levels of calcium, phosphorus, alkaline phosphatase, 250HD, 1.25(OH)2D and PTH were studied in a group of 42 children aged 8.5 +/- 1.8 years (X +/- SD) from the city of Ushuaia (latitude 55 degrees S), at both the end of the winter and the end of summer. Calcium, phosphorus, alkaline phosphatase and 1.25(OH)2D serum levels were not different in summer and winter. The levels of serum 25OHD were significantly higher in summer (18.4 +/- 7.3 ng/ml) than in winter (9.8 +/- 3.8 ng/ml P < 0.001). The levels of 25OHD in children with fair or dark skin were similar in winter but were significantly higher in children with fair skin in summer (20.0 +/- 7.2 ng/l vs 15.3 +/- 5.1 ng/ml (P < 0.05). Serum levels of PTH were higher in winter (58.2 +/- 30.5 pg/ml) than in summer (47.9 +/- 28.3 pg/ml) (P < 0.03). The results demonstrate the existence of a population with low serum levels of 25OHD in winter. The higher levels of PTH in winter when serum 25OHD levels are lower could be the cause of the lack of seasonal variation in serum calcium and 1.25(OH)2D levels. Further studies are needed to establish whether these changes besides increasing the incidence of rickets, could also affect the mineral density of the skeleton in the population of this vitamin-D-deficient area.

Ultrasound and dual X-ray absorptiometry densitometry in women with hip fracture

To assess the usefulness of the measurement of the os calcis by ultrasound, a method that probably reflects bone quality as well as density, we have studied 54 women with hip fracture of the proximal femur and a control group. Ultrasound evaluation of the os calcis [broadband ultrasound attenuation (BUA), speed of the sound (SOS), and a combined index (“stiffness”)], and bone mineral density (BMD) determination over the proximal femur by dual X-ray absorptiometry (DXA) were performed. Weight, BMD, and ultrasound values in the hip fracture patients were significantly lower than controls (P<0.001). The Z-scores for BUA and stiffness were not different than that for femoral neck. Wards triangle or trochanteric BMD (between-1.7 and -1.5). The odds ratios determined by receiver-operating characteristics (ROC) analysis were greater at the femoral neck (25.1) and BUA (24.4). Intermediate values were found at stiffness (16.9), Wards triangle (12.8), and trochanter (11.1), and lower values were obtained at SOS (4.2). In turn, patients with trochanteric hip fractures had a significantly lower femoral neck and Wards triangle BMD, stiffness, and BUA than patients with cervical hip fractures. Comparing a subgroup of 30 women with hip fractures without vertebral fractures with an age-matched group of 87 women with osteoporotic vertebral fractures, both groups were of similar weight and BMD but all ultrasound values were significantly lower in the hip fractures compared with vertebral fracture patients (P<0.05-P<0.01). Our findings suggest that in women with hip fractures, ultrasound evaluation of the os calcis has diagnostic sensitivity comparable to DXA of the femur and could be useful to predict hip fracture risk. Ultrasound values are lower in hip fractures compared with vertebral fracture, age-matched women and in older compared with younger hip fracture patients.

Melatonin increases oestradiol-induced bone formation in ovariectomized rats

Abstract: To assess the effect of melatonin on bone metabolism in ovariectomized rats, receiving oestradiol therapy or not, melatonin was administered in the drinking water (25 μg/mL water) and oestradiol (10 μg/kg body weight) or vehicle was given subcutaneously 5 days/week for up to 60 days after surgery. Urinary deoxypyridinoline (a marker of bone resorption) and circulating levels of bone alkaline phosphatase activity (a marker of bone formation), as well as serum calcium and phosphorus levels, were measured every 15 days. Bone area (BA), bone mineral content (BMC), bone mineral density (BMD) and total body fat (expressed as 100 g body weight) were measured by dual‐energy X‐ray absorptiometry at the end of the experiment. Body weight and total body fat were augmented after ovariectomy, and decreased after melatonin or oestradiol treatment. The effect of melatonin on body weight was seen in sham‐operated rats only. Ovariectomy augmented, and melatonin or oestradiol lowered, urinary deoxypyridinoline excretion. This effect of melatonin and oestradiol was seen mainly in ovariectomized rats. The efficacy of oestradiol to counteract ovariectomy‐induced bone resorption was increased by melatonin. Melatonin or oestradiol lowered serum bone alkaline phosphatase activity. Melatonin inhibition was seen mainly on the increase of bone alkaline phosphatase activity that followed ovariectomy. Serum phosphorus levels decreased after melatonin administration and were augmented after oestradiol injection; overall, melatonin impaired the increase of serum phosphorus caused by oestradiol. Ovariectomy decreased, and oestradiol increased, serum calcium levels while melatonin augmented serum calcium in sham‐operated rats only. On day 60 after surgery, BMD and content decreased after ovariectomy and were increased after oestradiol injection. Melatonin augmented BA of spine and BMC of whole of the skeleton and tibia. The highest values observed were those of rats treated concurrently with oestradiol and melatonin. The present results indicate that: (i) melatonin treatment restrained bone remodelling after ovariectomy; (ii) the effect of melatonin required adequate concentrations of oestradiol; (iii) melatonin augmented oestradiol effects on bone in ovariectomized rats; (iv) a counter‐regulation by melatonin of the increase in body fat caused by ovariectomy was uncovered. The melatonin doses employed were pharmacological in terms of circulating melatonin levels but not necessarily for some other fluids or tissues.

Risk for developing osteoporosis in untreated premature menopause

SummaryThe bone mineral density (BMD) of the lumbar spine and proximal femur was determined by dual photon absorptiometry in 32 women with untreated premature menopause (cessation of menses before 45 years of age). The BMD of the spine and proximal femur in four obese patients was not different from the BMD of the age-matched controls. On the contrary, the BMD of the nonobese females with premature menopause was significantly lower with respect to the average values found in healthy young women, in age-matched and menopause-matched controls. The BMD deficit was greater over the lumbar spine than in the proximal femur. Forty three percent of nonobese patients were already under the vertebral fracture threshold and 25% of nonobese patients were below the hip fracture threshold. The BMD deficit in the lumbar spine was correlated to the loss observed in the femoral neck (r=0.59, P<0.001), in the trochanter (r=0.65, P<0.001) and in the Wards triangle (r=0.73, P<0.001). A negative correlation was observed between years of menopause and the BMD of the lumbar spine (r=-0.39, P<0.05). The results indicate the high individual risk for osteoporotic fractures in nonobese females with untreated premature menopause. The BMD loss was greater over the skeletal areas that are predominantly composed of trabecular bone compared with cortical bone.