Competitive physical activity early in life is associated with bone mineral density in elderly Swedish men

Summary  In this population-based study of 75-year-old men (n = 498), we investigated the association between physical activity (PA) early in life and present bone mineral density (BMD). We demonstrate that a high frequency of competitive sports early in life is associated with BMD at several bone sites, indicating that increases in BMD following PA are preserved longer than previously believed. Introduction  Physical activity (PA) increases bone mineral density (BMD) during growth. It is unclear if the positive effects remain at old age. In this study, we aimed to determine if PA early in life was associated with BMD in elderly men. Methods  In this population-based study, 498 men, 75.2 ± 3.3 (mean±SD) years old, were included. BMD was assessed using DXA. Data concerning lifetime PA, including both competitive (CS) and recreational sports (RS), and occupational physical load (OPL), were collected at interview. Results  Subjects in the highest frequency group of CS in the early period (10–35 years), had higher BMD at the total body (4.2%, p < 0.01), total hip (7.0%, p < 0.01), trochanter (8.7%, p < 0.01), and lumbar spine (7.9%, p < 0.01), than subjects not involved in CS. A stepwise linear regression model showed that frequency of CS in the early period independently positively predicted present BMD at the total body (β = 0.12, p < 0.01), total hip (β = 0.11, p < 0.01), trochanter (β = 0.12, p < 0.01), and lumbar spine (β = 0.11, p = 0.01). Conclusions  We demonstrate that PA in CS early in life is associated with BMD in 75-year-old Swedish men, indicating that increases in BMD following PA are preserved longer than previously believed. This study was supported by the Swedish Research Council, the ALF/LUA grant from the Sahlgrenska University Hospital, and the Hjalmar Svensson Foundation.     

Bisphosphonates in children with hypercalciuria and reduced bone mineral density

Previous studies have demonstrated reduced bone mineral density (BMD) and biochemical changes of excessive bone resorption in some patients with idiopathic hypercalciuria (IH). Consequently, bisphosphonates have been successfully employed in research animals and adults with IH and reduced BMD. We evaluated the effect of treatment with bisphosphonates in seven patients ages 10–16 years with persistent IH and reduced BMD. In five children, preceding traditional therapy failed. All children received oral alendronate and one also IV Zoledronic acid for 6–18 (median 9.0, mean 10.7) months. With treatment, BMD Z scores in the lumbar spine improved from −2.0 ± 0.3 to −0.8 ± 0.8 (p = 0.002) and in the femoral neck from −1.8 ± 0.4 to −0.7 ± 0.9 (p = 0.01); urine N-telopeptides/creatinine decreased from 372 ± 289 to 72 ± 39 nmol/mmol (p = 0.05) and calcium/creatinine from 0.29 ± 0.12 to 0.13 ± 0.06 mg/mg (p = 0.009). Height Z scores, normal at baseline in all, remained unaffected, and no new stones or fractures were documented throughout the treatment period. Serum creatinine, electrolytes, calcium, phosphorus and parathyroid hormone remained normal as well. In summary, in children with IH and decreased BMD, treatment with bisphosphonates normalized urine calcium excretion, eliminated urinary symptoms, and significantly improved reduced BMD. These short-term beneficial effects indicate the need for larger prospective studies on the potential of bisphosphonates to serve as a new tool in treating children with IH and reduced BMD.     

Vitamin D and Bone Mineral Density in Ambulatory Women Living in Buenos Aires, Argentina

The aim of this study was to determine possible associations between bone mineral density (BMD), 25-hydroxyvitamin D (25(OH)D) and intact parathyroid hormone (PTH). In a retrospective study we examined the case notes of free-living postmenopausal women living in our city (34° S). We also report a low prevalence of vitamin D deficiency (25(OH)D <25 nmol/l, 5.6%) and of secondary hyperparathyroidism (intact PTH >65 pg/ml, 7.5%). Age was correlated with BMD at the lumbar spine (r=−0.25, p = 0.00038) and femoral neck (r=−0.252, p = 0.0003). Body mass index (BMI) was correlated with BMD at the femoral neck (r= 0.177, p = 0.021) but not at the lumbar spine. 25(OH)D was positively correlated with BMD at the femoral neck (r = 0.149, p=0.036) but not at the lumbar spine. PTH was positively correlated with age (r= 0.279, p = 0.012) and negatively correlated with 25(OH)D (r=−0.322, p = 0.0036). PTH was also negatively correlated with BMD at the lumbar spine (r=−0.258, p=0.02) and the femoral neck (r=−0.282, p = 0.011). Forward stepwise multiple regression showed that BMI, age and 25(OH)D made significant contributions to BMD at the femoral neck. PTH also showed a significant contribution to BMD at both sites. In conclusion, weak correlations found between PTH and 25(OH)D and BMD suggest these biochemical variables, among other factors, contribute to lumbar spine and femoral neck BMD. Received: 19 February 2000 / Accepted: 20 June 2000     

Effects of a multi-component exercise program and calcium–vitamin-D3-fortified milk on bone mineral density in older men: a randomised controlled trial

Summary  We examined the independent and combined effects of a multi-component exercise program and calcium–vitamin-D₃-fortified milk on bone mineral density (BMD) in older men. Exercise resulted in a 1.8% net gain in femoral neck BMD, but additional calcium–vitamin D₃ did not enhance the response in this group of older well-nourished men. Introduction  This 12-month randomised controlled trial assessed whether calcium–vitamin-D₃-fortified milk could enhance the effects of a multi-component exercise program on BMD in older men. Methods  Men (n = 180) aged 50–79 years were randomised into: (1) exercise + fortified milk; (2) exercise; (3) fortified milk; or (4) controls. Exercise consisted of high intensity progressive resistance training with weight-bearing impact exercise. Men assigned to fortified milk consumed 400 mL/day of low fat milk providing an additional 1,000 mg/day calcium and 800 IU/day vitamin D₃. Femoral neck (FN), total hip, lumbar spine and trochanter BMD and body composition (DXA), muscle strength 25-hydroxyvitamin D and parathyroid hormone (PTH) were assessed. Results  There were no exercise-by-fortified milk interactions at any skeletal site. Exercise resulted in a 1.8% net gain in FN BMD relative to no-exercise (p < 0.001); lean mass (0.6 kg, p < 0.05) and muscle strength (20–52%, p < 0.001) also increased in response to exercise. For lumbar spine BMD, there was a net 1.4–1.5% increase in all treatment groups relative to controls (all p < 0.01). There were no main effects of fortified milk at any skeletal site. Conclusion  A multi-component community-based exercise program was effective for increasing FN BMD in older men, but additional calcium–vitamin D₃ did not enhance the osteogenic response.     

Physical activity and dietary calcium interactions in bone mass in Scottish postmenopausal women

Summary  In this population-based cohort of 1,254 older Scottish women we found significant interactions between the mechanical component of self-reported habitual physical activity (PA) and dietary calcium (Ca) in BMD, independent of other risk factors. At low and/or medium Ca intakes BMD was higher amongst the most active people. Introduction  Although there is general agreement that increased activity (PA) and dietary calcium (Ca) consumption may help maintain bone mass in later life and prevent fractures, the amount required remains uncertain. Methods  In 2001–2003, 1,847 postmenopausal women (mean ± SD age: 69.3 ± 5.5 years) underwent bone mineral density (BMD) measurement and, in 2004, 68.7% (n = 1,254) completed a bone-specific Physical Activity Questionnaire (bsPAQ) and a food frequency questionnaire. The bsPAQ measures the metabolic and mechanical components of PA. Interactions of PA and Ca in BMD were examined using ANCOVA. Results  Significant interactions were identified in the BMD of the lumbar spine (LS), right hip (RH) and left hip (LH), after adjustment for confounders, between tertiles of PA classified according to the mechanical component and tertiles of energy-adjusted Ca intake (ANCOVA p = 0.006, p = 0.004 and p = 0.013 respectively). For example, at medium Ca intakes LH BMD was higher by 7.8% in the highest tertile of PA compared with the lowest tertile of PA. Conclusions  These data suggest that health promotion campaigns to increase PA would be most effective in populations with a low/medium calcium intake.     

Increase of Bone Resorption and the Parathyroid Hormone in Postmenopausal Women in the Long-term after Roux-en-Y Gastric Bypass

Background  The effects of Roux-en-Y Gastric Bypass (RYGB) on bone in the long-term remains unclear. We assessed bone metabolism and bone mineral density (BMD) 1 to 5 years after RYGB. Methods  We designed a retrospective cohort study in 26 postmenopausal women (58.0 ± 3.9 years old) with RYGB 3.5 ± 1.1 years before (body mass index (BMI) 29.5 ± 3.8 kg/m², presurgery 43.6 ± 5.5 kg/m²) and 26 nonoperated women (57.5 ± 4.7 years old, BMI 29.2 ± 4.1 kg/m²) matched by age and BMI. The main measures were BMD, serum carboxy telopeptide (CTx), total alkaline phosphatases (ALP), parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), and ghrelin. Results  RYGB group, compared to nonoperated women, had higher CTx (0.71 ± 0.21 vs. 0.43 ± 0.15 ng/ml; P < 0.01) and PTH (68.3 ± 35 vs. 49.4 ± 16 pg/ml; P = 0.02). There were no differences between RYGB and nonoperated women in: calcium and vitamin D intake (759 ± 457 vs. 705 ± 460 mg/day; 176 ± 160 vs. 111 ± 86 UI/day), ghrelin (763 ± 336 vs. 621 ± 274 pg/ml), ALP (101 ± 22 vs. 94 ± 25 UI/l), 25OHD (18.8  ± 7.6 vs. 17.4 ± 5.9 ng/ml), lumbar spine BMD (1.059 ± 0.32 vs. 1.071 ± 0.207 g/cm²), or femoral neck BMD (0.892 ± 0.109 vs. 0.934 ± 1.1 g/cm²). Conclusions  RYGB is associated to high bone resorption and hyperparathyroidism prevalence in postmenopausal women in the long-term. This occurs independently of the intake of calcium, vitamin D status, or ghrelin and does not seem to affect BMD after RYGB.     

Changes in Bone Mineral Density, Body Composition and Adiponectin Levels in Morbidly Obese Patients after Bariatric Surgery

Background  Gastric bypass surgery (GBP) is increasingly used as a treatment option in morbid obesity. Little is known about the effects of this surgery on bone mineral density (BMD) and the underlying mechanisms. To evaluate changes on BMD after GBP and its relation with changes in body composition and serum adiponectin, a longitudinal study in morbid obese subjects was conducted. Methods  Forty-two women (BMI 45.0 ± 4.3 kg/m²; 37.7 ± 9.6 years) were studied before surgery and 6 and 12 months after GBP. Percentage of body fat (%BF), fat-free mass (FFM), and BMD were measured by dual-energy X-ray absorptiometry and serum adiponectin levels by RIA. Results  Twelve months after, GBP weight was decreased by 34.4 ± 6.5% and excess weight loss was 68.2 ± 12.8%. Significant reduction (p < 0.001) in total BMD (−3.0 ± 2.1%), spine BMD (−7.4 ± 6.8%) and hip BMD (−10.5 ± 5.6%) were observed. Adiponectin concentration increased from 11.4 ± 0.7 mg/L before surgery to 15.7 ± 0.7 and 19.8 ± 1.0 at the sixth and twelfth month after GBP, respectively (p < 0.001). Thirty-seven percent of the variation in total BMD could be explained by baseline weight, initial BMD, BF reduction, and adiponectin at the twelfth month (r ² = 0.373; p < 0.001). Adiponectin at the twelfth month had a significant and positive correlation with the reduction of BMD, unrelated to baseline and variation in body composition parameters (adjusted correlation coefficient: r = 0.36). Conclusion  GBP induces a significant BMD loss related with changes in body composition, although some metabolic mediators, such as adiponectin increase, may have an independent action on BMD which deserves further study.     

Effect of raloxifene after recombinant teriparatide [hPTH(1–34)] treatment in postmenopausal women with osteoporosis

Summary Loss of bone mineral density occurs after discontinuation of teriparatide, if no subsequent treatment is given. Sequential raloxifene prevented rapid bone loss at lumbar spine and further increased bone mineral density (BMD) at femoral neck, whether raloxifene was started immediately or after a one-year delay following teriparatide treatment. Introduction We compared the sequential effects of raloxifene treatment with a placebo on teriparatide-induced increases in bone mineral density (BMD). A year of open-label raloxifene extended the study to assess the response with and without delay after discontinuation of teriparatide. Methods Following a year of open-label teriparatide 20 μg/day treatment, postmenopausal women with osteoporosis were randomly assigned to raloxifene 60 mg/day (n = 157) or a placebo (n = 172) for year 2, followed by a year of open-label raloxifene. BMD was measured by dual energy x-ray absorptiometry. Results The raloxifene and placebo groups showed a decrease in lumbar spine (LS) BMD in year 2 for raloxifene and placebo groups (−1.0 ± 0.3%, P = 0.004; and −4.0 ± 0.3%, P < 0.001, respectively); the decrease was less with raloxifene (P < 0.001). Open-label raloxifene treatment reversed the LS BMD decrease with a placebo, resulting in similar decreases 2 years after randomization (−2.6 ± 0.4% (raloxifene-raloxifene) and −2.7 ± 0.4% (placebo-placebo). At study end, LS and femoral neck (FN) BMD were higher than pre-teriparatide levels, with no significant differences between the raloxifene-raloxifene and placebo-raloxifene groups, respectively (LS: 6.1 ± 0.5% vs. 5.1 ± 0.5%; FN: 3.4 ± 0.6% vs. 3.0 ± 0.5%). Conclusion Sequential raloxifene prevented rapid bone loss at the LS and increased FN BMD whether raloxifene was started immediately or after a one-year delay following teriparatide treatment. Preliminary data presented previously at the International Osteoporosis Foundation World Congress on Osteoporosis, Toronto Canada June 2–6, 2006, abstract published: Adami S, Munoz-Torres M, Econs MJ, Sipos A, Xie L, Dalsky GP, McClung M, Felsenberg D, Brown JP, Brandi ML, San Martin J. Effect of raloxifene after teriparatide treatment in postmenopausal women with osteoporosis. Osteoporos Int. 2006;17(Suppl 2):S137.     

Population-based reference values for bone mineral density in young men

Summary Population-based reference values for peak bone mass density in Danish men. BMD of total hip (1.078 ± 0,14 g/cm²) differed significantly from values from National Health and Nutrition Examination Survey III and of total lumbar spine ((1.073 ± 0.125 g/cm²) differed significantly from Hologic values. Introduction Geographic, ethnic, and socio-economic factors are known to affect bone mineral density (BMD) and peak bone mass significantly. Reference values for male peak bone mass are scarce, and the diagnosis of male osteoporosis often relies on values provided by producers of dual-energy X-ray absorptiometry (DXA) equipment. Methods The aim of the present study was 1) to establish population-based reference values for BMD in young men and 2) to study subgroups based on variables with suspected impact on bone metabolism. We included 783 young Caucasian men aged 20 to 30 years in the Odense Androgen Study (OAS). Results Peak BMD was attained within the third decade. Obesity (BMI > 30 kg/m²) was associated with higher BMD. Abuse of anabolic steroids as well as chronic illness was associated with lower BMD. Our population-based reference values for BMD of the total hip (1.078 ± 0.14 g/cm²) differed significantly from published values from National Health and Nutrition Examination Survey III for non-Hispanic white men, while BMD of total lumbar spine (1.073 ± 0.125 g/cm²) differed significantly from Hologic reference values. Conclusions Locally derived reference values are important to avoid false positive or false negative findings during work-up in patients evaluated for osteoporosis.     

Bone mass effects of a Smad6 gene polymorphism in Japanese postmenopausal women

Smad6 plays pivotal roles in the negative regulation of transforming growth factor β (TGFβ) family signaling as one of the feedback molecules. Here, we analyzed whether the human Smad6 gene is involved in the regulation of bone mass, using association analysis between bone mineral density (BMD) and single-nucleotide polymorphism (SNP) in the Smad6 gene. Association of an SNP at IVS3+26115A>C (intron 3, rs755451) in the Smad6 gene with BMD was examined in 721 Japanese postmenopausal Japanese women (age 65.2 ± 9.6 years; mean ± SD). The subjects bearing at least one variant C allele (CC ± AC; n = 387) had significantly lower Z-scores for total body and lumbar BMD than the subjects with no C allele (AA; n = 334) (total body, 0.23 ± 0.98 versus 0.50 ± 1.07; P = 0.0004; lumbar spine, −0.20 ± 1.38 versus 0.10 ± 1.48; P = 0.0050). These findings suggest that the Smad6 gene is a candidate for the genetic determinants of BMD in postmenopausal women, and this SNP could be useful as a genetic marker for predicting the risk of osteoporosis.     

Genetic influences on bone loss in the San Antonio Family Osteoporosis study

Summary  The genetic contribution to age-related bone loss is not well understood. We estimated that genes accounted for 25–45% of variation in 5-year change in bone mineral density in men and women. An autosome-wide linkage scan yielded no significant evidence for chromosomal regions implicated in bone loss. Introduction  The contribution of genetics to acquisition of peak bone mass is well documented, but little is known about the influence of genes on subsequent bone loss with age. We therefore measured 5-year change in bone mineral density (BMD) in 300 Mexican Americans (>45 years of age) from the San Antonio Family Osteoporosis Study to identify genetic factors influencing bone loss. Methods  Annualized change in BMD was calculated from measurements taken 5.5 years apart. Heritability (h²) of BMD change was estimated using variance components methods and autosome-wide linkage analysis was carried out using 460 microsatellite markers at a mean 7.6 cM interval density. Results  Rate of BMD change was heritable at the forearm (h² = 0.31, p = 0.021), hip (h² = 0.44, p = 0.017), spine (h² = 0.42, p = 0.005), but not whole body (h² = 0.18, p = 0.123). Covariates associated with rapid bone loss (advanced age, baseline BMD, female sex, low baseline weight, postmenopausal status, and interim weight loss) accounted for 10% to 28% of trait variation. No significant evidence of linkage was observed at any skeletal site. Conclusions  This is one of the first studies to report significant heritability of BMD change for weight-bearing and non-weight-bearing bones in an unselected population and the first linkage scan for change in BMD.     

Nucleotide variations in genes encoding carbonic anhydrase 8 and 10 associated with femoral bone mineral density in Japanese female with osteoporosis

Osteoporosis is a multi-factorial common disease, which is caused by combination of genetic as well as environmental factors. Among several factors, osteoclast acidification pathways during bone resorption might play an important role. Carbonic anhydrases, consisting of a gene family, are essential for pH regulation by the osteoclast. Clinically, use of carbonic anhydrase inhibitors has been known to be associated with a bone-sparing effect as judged by spine bone mineral density (BMD). Here, we investigated single nucleotide polymorphisms (SNPs) in carbonic anhydrase genes that are expressed in bone tissues, i.e., CA8 and CA10, for possible association with femoral and lumbar BMD among 337 Japanese women with osteoporosis participated in BioBank Japan project. Significant correlation was observed between CA8 SNP, rs6984526, and femoral BMD (P = 0.00029); homozygous carriers of the major (C) allele (n = 166) had the highest BMD (0.754 ± 0.006 g/cm², mean ± SD), while heterozygous carriers (n = 135) were intermediate (0.741 ± 0.07 g/cm²) and homozygous T-allele carriers (n = 31) had the lowest BMD (0.691 ± 0.012 g/cm²). CA8 SNP as well displayed significant association with lumbar BMD in recessive model (P = 0.00017). In addition, CA10 SNP, rs2106329, also displayed strong association with femoral BMD (P = 0.00002). The results suggest that the variations of CA8 and CA10 loci may be important determinants of osteoporosis in Japanese women.     

Effect of Roux-en Y Gastric Bypass on Bone Metabolism in Patients with Morbid Obesity: Mansoura Experiences

Background  Roux-en-Y gastric bypass (RYGBP) has been found to be the most efficient way to lose weight and maintain the weight loss in morbid obesity. However, with the formation of a new stomach and the modification of intestinal anatomy, there are significant changes on bone metabolism. The objectives of this study were to evaluate effects of weight loss on bone metabolism after Roux-en Y gastric bypass in patients with morbid obesity. Methods  Our study included 70 patients with morbid obesity; RYGB was done for all patients. Daily postoperative oral supplementation with 1,000 mg of calcium and 800 IU of vitamin D was done for each patient. Body weight (BW), body mass index (BMI), total body fat, total lean tissue mass, bone mineral content (BMC), bone mineral density (BMD), total bone area (TBA; using dual energy X-ray absorptiometry), serum calcium, parathyroid hormone (PTH), 25-OH vitamin D, 24-h urinary calcium, and bone-specific alkaline phosphatase (BSAP) were assessed preoperatively and 1 year after surgery. Results  In our study, females comprised 70% of cases. The mean age was 35 ± 8.8 years. One year after RYGB, BW decreased significantly from 132.8 ± 26.5 to 90.3 ± 17.3 kg (p = 0.001). BMI decreased significantly from 48 ± 7.3 to 32.6 ± 4.1 kg/m² (p = 0.001). BMC decreased significantly from 2,968.6 ± 71.4 to 2,700.8 ± 45.4 g (p = 0.001). BMD decreased significantly from 1.026 ± 0.03 to 1.22 ± 0.015 g/cm² (p = 0.001). TBA decreased significantly from 2,356.2 ± 35.4 to 2,216.3 ± 43.5 cm² (p = 0.001). Serum calcium, 24-h urinary calcium, and BSAP were not significantly decreased while 25-OH vitamin D and PTH were not significantly increased after surgery. Conclusions  From this study, it is shown that RYGBP operation gives very good results as regards reduction of body weight in morbidly obese patients. Postoperative supplementation with calcium and vitamin D partially corrects osteoporosis. Thus, these patients need periodic follow-up for BMD, PTH, calcium, serum vitamin D, and markers of bone resorption and formation specially postmenopausal female.     

A Comparison of Bone-Targeted Exercise With and Without Antiresorptive Bone Medication to Reduce Indices of Fracture Risk in Postmenopausal Women With Low Bone Mass: The MEDEX-OP Randomized Controlled Trial

The goal of the MEDEX-OP trial was to compare the efficacy of a known effective high-intensity resistance and impact training (HiRIT) with a low-intensity exercise control (Buff Bones® [BB]), alone or in combination with antiresorptive bone medication, on indices of fracture risk (bone mass, body composition, muscle strength, functional performance), compliance, and safety. Primary study outcomes were 8-month change in lumbar spine (LS) and total hip (TH) bone mineral density (BMD). Healthy postmenopausal women with low bone mass (T-score ≤ −1.0) on or off stable doses (≥12 months) of antiresorptive medication were recruited. A total of 115 women (aged 63.6 ± 0.7 years; body mass index [BMI] 25.5 kg/m²; femoral neck [FN] T-score −1.8 ± 0.1) were randomly allocated to 8-month, twice-weekly, 40-minute HiRIT (5 sets of 5 repetitions, >80% to 85% 1 repetition maximum) or BB (low-intensity, Pilates-based training), stratified by medication intake, resulting in four groups: HiRIT (n = 42), BB (n = 44), HiRIT-med (n = 15), BB-med (n = 14). HiRIT improved LS BMD (1.9 ± 0.3% versus 0.1 ± 0.4%, p < 0.001) and stature (0.2 ± 0.1 cm versus −0.0 ± 0.1 cm, p = 0.004) more than BB. Both programs improved functional performance, but HiRIT effects were larger for leg and back muscle strength and the five times sit-to-stand test (p < 0.05). There was a positive relationship between maximum weight lifted and changes in LS BMD and muscle strength in the HiRIT groups. Exploratory analyses suggest antiresorptive medication may enhance exercise efficacy at the proximal femur and lumbar spine. Exercise compliance was good (82.4 ± 1.3%) and both programs were well tolerated (7 adverse events: HiRIT 4; BB 3). HiRIT improved indices of fracture risk significantly more than Buff Bones®. More trials combining bone medication and bone-targeted exercise are needed. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Relation between fibroblast growth factor-23, body weight and bone mineral density in elderly men

Summary  We evaluated the relation between serum FGF23 and bone mineral density (BMD) in a community-based cohort of elderly men. There was a weak correlation between FGF23 and BMD, which was primarily dependent on body weight. Introduction  FGF23 is a hormonal factor produced in bone and regulates serum levels of phosphate (Pi) and vitamin D. FGF23 over-expression is associated with skeletal abnormalities, including rickets/osteomalacia. The relation between FGF23 and Bone Mineral Density (BMD) in the community remains unexplored. Methods  We employed a large, population-based cohort of 3014 Swedish men aged 69–80 years, without known renal disease. BMD was measured with dual X-ray absorptiometry (DXA) in the hip and lumbar spine. Serum intact FGF23 was analyzed with a two-site monoclonal ELISA. Results  There was a weak but significant correlation between FGF23 and BMD in femoral neck (r = 0.04, p < 0.05), femoral trochanter (r = 0.05, p = 0.004), total hip (r = 0.06, p = 0.0015) and lumbar spine (r = 0.07, p = 0.0004). The correlations remained significant when adjusting for biochemical covariates (Pi, calcium, PTH, 25(OH)D and renal function). However, the association became insignificant in all regions when adjusting for established confounding variables including age, height, weight and smoking. Further analysis confirmed a significant correlation between FGF23 and body weight (r = 0.13, p < 0.0001). Conclusions  The weak correlation between FGF23 and BMD in elderly male subjects is mainly due to an association between FGF23 and body weight. Therefore, FGF23 may not play a significant role in the hormonal regulation of BMD. Richard Marsell and Majd A. I. Mirza contributed equally to this work. Funding source: this study was supported by the Swedish Research Council, the Novo Nordisk Foundation, the Swedish Kidney Foundation and the Swedish Society of Medicine.     

Replication of associations between LRP5 and ESRRA variants and bone density in premenopausal women

Summary  Replication is a critical step to validate positive genetic associations. In this study, we tested two previously reported positive associations. The low density lipoprotein receptor-related protein 5 (LRP5) Val667Met and lumbar spine bone density are replicated. This result is in line with results from large consortiums such as Genomos. However, the estrogen-related receptor alpha (ESRRA) repeat in the promoter is not replicated although the polymorphism studied was functional and could have been a causative variant. Introduction  We sought to validate associations previously reported between LRP5 V667M polymorphism and lumbar spine (LS, p = 0.013) and femoral neck (FN, p = 0.0002) bone mineral density (BMD), and between ESRRA 23 base pair repeat polymorphism and LS BMD (p = 0.0036) in a sample of premenopausal Caucasian women using an independent sample. Methods  For the replication sample, we recruited 673 premenopausal women from the Toronto metropolitan area. All women were Caucasian and had BMD measured. LRP5 V667M was genotyped by allele-specific PCR and ESRRA repeats by sizing of PCR products on agarose gels. Results  We reproduced the same association as we reported previously between LRP5 V667M and LS BMD (p = 0.015) but not with FN BMD (p = 0.254). The combined data from the two populations indicate an effect size of 0.28SD for LS BMD (p = 0.00048) and an effect size of 0.26 SD for FN BMD (p = 0.00037). In contrast, the association we reported earlier between ESRRA repeats and LS BMD was not replicated in the sample from Toronto (p = 0.645). Conclusions  The association between LRP5 V667M and LS BMD is confirmed but not that between ESRRA repeats and LS BMD. This result indicates that it is imperative to validate any positive association in an independent sample.     

Vitamin D insufficiency does not affect response of bone mineral density to alendronate

Summary  We investigated whether osteoporosis therapy with alendronate in postmenopausal patients is equally effective in patients who are vitamin D insufficient as in those who are vitamin D sufficient. We found that vitamin D insufficiency is common among patients with low bone density but that vitamin D insufficiency did not impair response to alendronate. Introduction  Treatment of vitamin D deficiency leads to significant improvements in bone mineral density (BMD); however, whether insufficiency affects BMD’s response to bisphosphonate therapy is unknown. Methods  To determine whether vitamin D insufficiency at initiation of alendronate therapy for low BMD affects treatment efficacy, we used data from 1,000 postmenopausal women randomly selected from the vertebral fracture arm (n = 2,027) of the placebo-controlled Fracture Intervention Trial of alendronate. Participants were randomly assigned to placebo (50%) or alendronate therapy and most (83%) to calcium (500 mg/day) and cholecalciferol (250 IU/day). We measured serum 25-hydroxy vitamin D (25OHD) at enrollment, then categorized baseline vitamin D status according to 25OHD concentration ( ≤ 10 ng/ml = deficient; >10 but ≤ 30 ng/ml = insufficient; >30 ng/ml = sufficient) and used linear regression to compare the effects of alendronate treatment among these categories. Results and conclusion  At baseline, participants were vitamin D sufficient (14%), insufficient (83%), and deficient (2%). We found that BMD response to therapy at total hip or spine did not vary by vitamin D status at baseline (p for heterogeneity = 0.6). We determined that vitamin D insufficiency is common among participants with low BMD. However, vitamin D status at initiation of therapy does not affect BMD’s response to alendronate, when it is coadministered with cholecalciferol and calcium. Scholar’s Grant from the National Osteoporosis Foundation (to D.M.A) and National Institutes of Health grant K23 RR020343 (to D.M.A).     

Risedronate for prevention of bone mineral density loss in patients receiving high-dose glucocorticoids: a randomized double-blind placebo-controlled trial

Summary This 6-month randomized double-blind placebo-controlled trial shows that risedronate is well tolerated and effective in improving lumbar spine BMD and reducing loss of BMD at the hips in patients receiving high-dose prednisolone. Introduction Bisphosphonates have proven benefits in patients receiving chronic low-dose glucocorticoids. However, whether they are effective in preventing bone mineral density (BMD) loss during periods of high-dose glucocorticoid treatment is unclear. The objective of this paper is to study the efficacy of risedronate in preventing bone mineral density (BMD) loss in users of high-dose glucocorticoids. Methods Adult patients with medical diseases treated with high-dose prednisolone (>0.5 mg/kg/day) were randomized to receive risedronate (5 mg/day) or placebo for 6 months in a double-blind manner, along with elemental calcium (1,000 mg/day). Changes in BMD were studied. Results One hundred and twenty patients were recruited (82 women, age 42.8 ± 14.3 years, 63% corticosteroid-naive, 30% women postmenopausal) and 103 completed the study. Baseline clinical characteristics and BMD were similar in the risedronate and placebo groups. At 6 months, a significant gain in spinal BMD was observed in the risedronate group (+0.7 ± 0.3%; p = 0.03) but a drop was detected in the placebo group (−0.7 ± 0.4%; p = 0.12). After adjustment for baseline BMD, age, gender, body mass index and cumulative prednisolone dosages, the inter-group difference in spinal BMD remained significant (1.4%; p = 0.006). Both groups had a significant drop in hip BMD, but the magnitude was greater in the placebo arm (−0.8 ± 0.4% in risedronate versus −1.3 ± 0.5% the in placebo). No new fractures developed. Subgroup analysis of corticosteroid-naive patients yielded similar results. Upper gastrointestinal adverse events were numerically more frequent in the risedronate group. Conclusions Risedronate improves spinal BMD in users of high-dose glucocorticoids.     

Muscle mass deficits are associated with bone mineral density in men with idiopathic vertebral fracture

Introduction and hypothesis The causes of idiopathic vertebral fractures (IVF) in men are poorly understood. We hypothesised that in IVF, areal bone mineral density (aBMD) deficits would be associated with reduced muscle mass. Methods In this case-control study, 48 men (61.5 ± 12.1 years old) presenting with symptomatic IVF were compared with 48 healthy controls matched for age (±5 years) and stature (±5 cm). The aBMD and soft-tissue body composition were determined by dual energy X-ray absorptiometry (DXA). Muscle mass was defined as the ratio of appendicular lean mass to the square of height (ALMI). Sex hormones, IGF-I and its binding protein IGFBP-3 were measured by immunoassay. Results ALMI was significantly lower in IVF patients (8.27 ± 0.90 vs 8.65 ± 0.88 kg/m², t = 2.193, df = 47, P = 0.033 by paired sample t-test). Hierarchical regression analysis revealed that for IVF patients, ALMI explained the greatest proportion of variance in BMD at the lumbar spine, femoral neck and total hip (R ² _change = 16.4–22.7%, P = 0.012–0.002) and only IGFBP-3 explained variance in ALMI (R ² _change = 19.9%, P = 0.006). Conclusions In men with IVF, ALMI was reduced and associated with IGFBP-3. ALMI was identified as a novel factor that explained a greater proportion of variance in BMD than either fat mass or serum biochemistry. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Association between iron overload and osteoporosis in patients with hereditary hemochromatosis

Summary  In 87 patients with hereditary hemochromatosis, osteoporosis was detected in 25%, and osteopenia in 41%. Bone mineral density was independently associated with BMI, ALP levels, hypogonadism/menopause, and the amount of iron removed to reach depletion, but not with cirrhosis. Osteoporosis is influenced by iron overload in hemochromatosis. Introduction  To analyze prevalence, clinical characteristics and genetic background associated with osteoporosis in a retrospective study in Italian patients with hereditary hemochromatosis (HHC). Methods  In 87 consecutive patients with HHC, bone mineral density was systematically evaluated by dual energy x-ray absorptiometry of the lumbar spine (n = 87) and femoral neck (n = 66). Results  Osteoporosis was detected in 22 (25.3%), and osteopenia in 36 (41.4%) patients. Mean Z scores were −0.92 ± 1.42 at lumbar spine and −0.35 ± 1.41 at femoral neck. Lumbar spine T-score was independently associated with total ALP (p = 0.002), hypogonadism/menopause (p = 0.026), and iron overload (p = 0.033 for ferritin and p = 0.017 for iron removed). We observed a borderline significance for BMI (p = 0.069) and smoking status (p = 0.086). Lumbar spine osteoporosis was independently associated with lower BMI (OR 0.73, 95% CI 0.54–0.94), total ALP (OR 1.17, 95% CI 1–1.39 per 10 unit increase) and the amount of iron removed (OR 1.53, 95% CI 1–2.5 per 5 g increase). HFE genotypes did not differ between patients with and without osteoporosis. Conclusions  Osteoporosis is observed in a quarter of unselected patients with HHC, independently of the genetic background, and is associated with ALP, hypogonadism, body weight, and severity of iron overload.