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Heart Failure Is a Clinically and Densitometrically Independent Risk Factor for Osteoporotic Fractures: Population-Based Cohort Study of 45,509 Subjects

Majumdar SR, Ezekowitz JA, Lix LM, Leslie WD
J Clin Endocrinol Metab, April 2012, 97(4):1179–1186

Objective: The aim of the study was to determine whether heart failure is associated with an increased risk of major osteoporotic fractures that is independent of bone mineral density (BMD).
Methods: We conducted a population-based cohort study in Manitoba, Canada, by linking a clinical registry of all adults 50 yr of age and older who underwent initial BMD testing from 1998–2009 with administrative databases. We collected osteoporosis risk factors, comorbidities, medications, and BMD results. Validated algorithms identified recent-onset heart failure before the BMD test and new fractures after. The main outcome was time to major osteoporotic fractures (i.e. clinical vertebrae, distal forearm, humerus, and hip), and multivariable proportional hazards models were used for analyses.
Results: The cohort consisted of 45,509 adults; 1,841 (4%) had recent-onset heart failure. Subjects with heart failure were significantly (P < 0.001) older (74 vs. 66 yr) and had more previous fractures (21 vs. 13%) and lower total hip BMD [T-score, −1.3 (sd 1.3) vs. −0.9 (sd 1.2)] than those without. There were 2703 incident fractures over the 5-yr observation. Overall, 10% of heart failure subjects had incident major fractures compared with 5% of those without [unadjusted hazard ratio (HR), 2.45; 95% confidence interval (CI), 2.11–2.85]. Adjustment for osteoporosis risk factors, comorbidities, and medications attenuated but did not eliminate this association (HR, 1.33; 95% CI, 1.11–1.60), nor did further adjustment for total hip BMD (HR, 1.28; 95% CI, 1.06–1.53).
Conclusions: Heart failure is associated with a 30% increase in major fractures that is independent of traditional risk factors and BMD, and it also identifies a high-risk population that may benefit from increased screening and treatment for osteoporosis


The cross-talk between osteoclasts and osteoblasts in response to strontium treatment: Involvement of osteoprotegerin
Peng S, Liu XS, Huang S, Li Z, Pan H, Zhen W, Luk KD, Guo XE, Lu WW
Bone 2011;49:1290-8

MC3T3E1 cells were treated with Sr chloride (0-3 mM) and conditioned media were collected at 24 h after the treatment. Ovariectomized rats were oral administrated with vehicle or Sr chloride for two months supplemented with anti-IgG antibody (control) or anti-OPG antibody. The conditioned media derived from Sr-treated osteoblastic cells exerted a dose-dependent inhibitory effect on osteoclastic differentiation and resorptive activity in pre-osteoclastic cells. OPG mRNA expression and protein secretion in osteoblastic cells were increased after Sr treatment. Neutralization with anti-OPG antibody abolished the inhibitory effect of conditioned media on RANKL-induced osteoclastogenesis. The effects of Sr on trabecular bone were evidenced by greater bone volume and trabecular number, greater osteoid surface and bone formation rate, while less osteoclast surface. These effects were attenuated by the OPG neutralization by anti-OPG antibody injection.


Bone-bound bisphosphonate inhibits growth of adjacent non-bone cells
Cornish J, Bava U, Callon KE, Bai J, Naot D, Reid IR
Bone 2011;49:710-6

To determine whether cells other than osteoclasts are affected by bone-bound bisphosphonates bone slices were incubated in PBS or in solutions of bisphosphonates (100 μM), Cells from 2 cell lines were seeded onto the bone slices: Caco-2 human colorectal adenocarcinoma epithelial cells and Chinese hamster ovary (CHO) cells. Cell proliferation (cell numbers and thymidine incorporation) was assessed at 4-72 h. Cell adhesion at 4 h was normal on bone slices pre-treated with bisphosphonates, but there were progressive reductions in cell numbers from 48 h and even greater reductions in thymidine incorporation from 24 h (>90% with zoledronate at 72 h). Growth inhibition was related to the clinical potency of the bisphosphonate used. There was no evidence of increased apoptosis in cells grown on bisphosphonate-coated bone, but levels of unprenylated Rap1A increased, indicating inhibition of FPP synthase. Similar growth inhibition was observed in primary cultures of rat osteoblasts on bone. It is concluded that bisphosphonates bound to a bone surface can act on adjacent non-bone cells and inhibit their growth.


Occurrence of gastrointestinal cancer in users of bisphosphonates and other antiresorptive drugs against osteoporosis
Vestergaard P
Calcif Tissue Int 2011;89:434-41

All users of bisphosphonates and other drugs against osteoporosis between 1996-2006 (n=103,562) were used as the exposed group, with three age- and gender-matched controls from the general population (n=310,683) as the nonexposed group. Except for colon cancer, most of the GI cancers were rare. For clodronate and raloxifene, no excess risk was present. For alendronate, an excess risk of esophageal and liver cancer was observed; however, the excess risk was most pronounced at low doses and short duration of observation. No dose-response relationship was present except for colon cancer with alendronate, where a decrease was seen with increasing dose so that at high doses a seemingly protective effect was present (≥1 defined daily dose, HR=0.29, 95% CI 0.14-0.62). For etidronate, an excess risk of esophageal, liver, pancreas, and gallbladder and bile duct cancers was seen. Again, no relationship with dose or duration of observation was present. An excess risk of esophageal and liver cancers may be seen with alendronate and etidronate. However, the association may not be causal as no dose-response or time relationship was present. For colon cancer, the decline with increasing alendronate dose may be due to a "healthy user" effect.


Prolonged bisphosphonate release after treatment in women with osteoporosis: Relationship with bone turnover
Peris P, Torra M, Olivares V, Reyes R, Monegal A, Martinez-Ferrer A, Guanabens N
Bone 2011;49:706-9

43 women (aged 65±9.4 years) previously treated with alendronate (36) or risedronate (7) during a mean of 51±3 and 53±3 months, respectively with a median time of discontinuation of 13.5 and 14 months, respectively. Alendronate was detected in 41% of women previously treated with this drug whereas no patient previously treated with risedronate showed detectable urinary values. All control patients showed detectable values of both BP. In patients with detectable alendronate levels, the time of drug cessation was shorter than in patients with undetectable values (12 [6-19] vs. 31 [7-72] months, p<0.001). Alendronate was not detected in any patient 19 months after treatment cessation. Alendronate levels were inversely related to time of treatment discontinuation (r=-0.403, p=0.01) and the latter was directly related to NTx (r=0.394, p=0.02). In conclusion, contrary to risedronate, which was not detected in patients after cessation of treatment, alendronate was frequently detected in women previously treated with this agent up to 19 months after discontinuation of therapy.


Calcium and vitamin D supplements and health outcomes: A reanalysis of the Women's Health Initiative (WHI) limited-access data set
Bolland MJ, Grey A, Gamble GD, Reid IR
Am J Clin Nutr 2011;94:1144-9

The WHI CaD was a 7-y, randomized, placebo-controlled trial of CaD (1 g Ca/400 IU vitamin D daily) in 36,282 community dwelling, postmenopausal women. CaD, interactions between the use of either personal calcium or vitamin D supplements and CaD were found for total, breast, and colorectal cancers but not for fracture or mortality. In 15,646 women (43%) who were not taking personal calcium or vitamin D supplements at randomization, CaD decreased the risk of total, breast, and invasive breast cancers by 14-20% and nonsignificantly reduced the risk of colorectal cancer by 17%. In women taking personal calcium or vitamin D supplements, CaD did not alter cancer risk (HR: 1.06-1.26). For women in the WHI CaD who were not taking personal calcium or vitamin D supplements at randomization, CaD decreased the risk of total, breast, and colorectal cancers and did not change the risk of fractures or total mortality.


Maintaining femoral bone density in adults: How many steps per day are enough?
Boyer KA, Kiratli BJ, Andriacchi TP, Beaupre GS
Osteoporos Int 2011;22:2981-8

Habitual walking activity and total femur BMD were measured in 105 individuals (49-64 years). An index of cumulative loading (bone density index, BDI) was examined as a predictor of BMD. For females, BDI correlated with BMD (r maintain a T-score of -1.0) for a female with the average BW of the study cohort, walking at 1.00 m/s is 4892 steps/day. Substantially more steps (18,568 steps/day) are required for a female with a BW 20% lighter than the average for our female cohort. For these lighter females, only at a walking speed greater than 1.32 m/s was 10,000 steps/day sufficient to maintain a T-score of -1.0.


Bone mineral density is cross sectionally associated with cartilage volume in healthy, asymptomatic adult females: Geelong Osteoporosis Study
Brennan SL, Pasco JA, Cicuttini FM, Henry MJ, Kotowicz MA, Nicholson GC, Wluka AE
Bone 2011;49:839-44

160 healthy, asymptomatic females (29-50 yr) underwent magnetic resonance imaging of the knee. Medial cartilage volume was associated with BMD at the spine, total body, femoral neck, and Ward's triangle (all p<0.05), with nonsignificant associations in the same direction at the trochanter (p=0.07). The presence of medial cartilage knee defects were also associated with BMD at the spine; defects in the lateral compartment were associated with BMD at the forearm (both p=0.05). BMD was not associated with the presence of BMLs. No associations were observed with calcaneus BMD.


Testing and treatment for osteoporosis following hip fracture in an integrated U.S. healthcare delivery system
Shibli-Rahhal A, Vaughan-Sarrazin MS, Richardson K, Cram P
Osteoporos Int 2011;22:2973-80

In 3347 subjects, 96.5% were male, and 83.3% were white. Only 1.2% of hip fracture patients underwent BMD testing and 14.5% received osteoporosis therapy within 12 months of fracture. Among fracture patients with minimal comorbid illness (N=756) only 1.6% underwent BMD testing and 13.0% received pharmacotherapy. In logistic regression models, treatment rates were higher for women compared to men (odds ratio, 3.30; 95% CI, 2.16-5.04) and lower for blacks compared to whites (odds ratio, 0.67; 95% CI, 0.45-0.99).


Risk factors for in-hospital post-hip fracture mortality
Frost SA, Nguyen ND, Black DA, Eisman JA, Nguyen TV
Bone 2011;49:553-8

Outcomes among 410 men and 1094 women with a hip fracture were studied. During hospitalization, the risk of mortality was higher in men (9%) than in women (4%). After adjusting for multiple risk factors, increased risk of in-hospital mortality was associated with advancing age (rate ratio [RR] for each 10-year increase in age: 1.9; 1.47-2.49), in men (RR 2.13; 95% CI, 1.41-3.22), and the presence of comorbid conditions (RR for one or more comorbid conditions vs. none: 2.30; 95% CI 1.52-3.48); pre-existing congestive heart failure (RR 3.02; 95% CI, 1.65-5.54), and liver disease (RR 4.75; 95% CI, 1.87-12.1). These factors collectively accounted for 69% of the risk for in-hospital mortality. A nomogram was developed from these risk factors to individualize the risk of in-hospital death following a hip fracture. The area under the receiver operating characteristic curve of the final model containing age, sex and comorbid conditions was 0.76.


Patients with sclerosteosis and disease carriers: Human models of the effect of sclerostin on bone turnover
van Lierop AH, Hamdy NA, Hamersma H, van Bezooijen RL, Power J, Loveridge N, Papapoulos SE
J Bone Miner Res 2011;26:2804-11

Sclerosteosis is caused by loss-of-function mutations in the SOST gene, encoding sclerostin, a negative regulator of bone formation. In 19 patients with sclerosteosis, 26 heterozygous carriers of the C69T SOST mutation, and 77 healthy controls sclerostin was undetectable in serum but was measurable in carriers (mean 15.5 pg/mL) in whom it was lower than in controls (mean 40.0 pg/mL). P1NP was highest in patients (mean 153.7 ng/ml), but carriers also had higher P1NP (58.3 ng/m) than controls (mean 37.8 ng/mL). In patients and carriers, P1NP declined with age, reaching a plateau after the age of 20 years. Serum sclerostin and P1NP were negatively correlated in carriers and age- and gender-matched controls (r=0.40, p=0.008). Mean CTX was normal and did not differ between patients and disease carriers. These results provide evidence of increased bone formation caused by the absence or decreased synthesis of sclerostin in humans. They also suggest that inhibition of sclerostin can be titrated because the decreased sclerostin levels in disease carriers did not lead to any of the symptoms or complications of the disease but had a positive effect on bone mass.


Genetic evidence points to an osteocalcin-independent influence of osteoblasts on energy metabolism
Yoshikawa Y, Kode A, Xu L, Mosialou I, Silva BC, Ferron M, Clemens TL, Economides AN, Kousteni S
J Bone Miner Res 2011;26:2012-25

To determine whether a decrease in osteoblast numbers compromises glucose metabolism in an osteocalcin-dependent manner, osteoblasts were ablated. A partial ablation of this cell population resulted in hypoinsulinemia, hyperglycemia, glucose intolerance, and decreased insulin sensitivity. However, and unlike osteocalcin-deficient mice, osteoblast ablation decreased gonadal fat and increased energy expenditure and the expression of resistin, an adipokine proposed to mediate insulin resistance. Administration of osteocalcin reversed the glucose intolerance and reinstated normal blood glucose and insulin levels, but only partially restored insulin sensitivity and did not affect the improved gonadal fat weight and energy expenditure in osteoblast-depleted mice. These observations suggest that in addition to osteocalcin, other osteoblast-derived hormones may contribute to the emerging function of the skeleton as a regulator of energy metabolism


Increase In Hip Fractures Associated With Discontinuation Of HRT.
A significant rise in hip fractures among women is one result of the decade-long slide in the popularity of hormone replacement therapy (HRT)," according to a study published in the journal Menopause. Researchers examined data on "more than 80,000 women enrolled in Southern California Kaiser Permanente HMO plans and found that women who discontinued hormone therapy were at 55% greater risk of hip fracture compared with women who kept taking the medication." Notably, "hip fracture risk increased as early as two years after stopping hormones and the risk rose the longer women were off hormones," even for women taking bisphosphonates.


Hormone Therapy May Improve Bone Growth In Some Obese Women.
MedPage  reports, "Premenopausal women who are obese may not be spared from osteopenia, as some research has suggested, but growth hormone therapy may help spur bone formation," according to research presented at the Radiological Society of North America meeting. Researchers studied "79 obese young women" and found by "using MR spectroscopy to assess bone marrow fat, bone densitometry (DEXA) scans to assess BMD, and CT scans for abdominal fat and thigh muscles...that nearly a third of patients in the study (32%) had osteopenia and 0.4% had osteoporosis." During the study, women who took "growth hormone significantly improved a biomarker of bone formation, P1NP."


Vitamin D Levels May Predict Response To Bisphosphonates.
MedPage Today reports that according to research presented at the American Society for Bone and Mineral Research conference, "women whose mean level of serum 25 hydroxyvitamin D...was at least 33 ng/mL were almost five times more likely to benefit from bisphosphonates than those whose levels fell below that cutoff," and that "for each 1 ng/mL decrease in 25(OH)D level, there was a 5% decrease in likelihood of responding to treatment." Researchers noted, "This level [33 ng/mL] is higher than that recommended by the Institute of Medicine as adequate for the general population, and many patients have levels well below this, so vitamin D supplementation may need to be higher for this therapeutic outcome."


Vitamin D Supplementation Every Three Months May Not Improve Fall Rates.
Medscape reports, "Elderly women administered vitamin D supplementation in the form of oral cholecalciferol (D3), 150,000 IU every three months show significantly increased serum vitamin D levels, but the increases do not appear to improve the rate of falls," according to a study presented at the American Society for Bone and Mineral Research (ASBMR) 2011 Annual Meeting. After randomizing "686 women older than 70 years of age to receive D3, 150,000 IU orally every three months (n = 353), or an identical placebo (n = 333) for nine months," researchers found "rates of falls were 102 of 353 (31% at nine months) in the vitamin D group and 89 of 333 (27% at nine months) in the placebo group (odds ratio, 1.112 [95% confidence interval, 0.789 - 1.567])."


The effect of high-dose vitamin D on bone mineral density and bone turnover markers in postmenopausal women with low bone mass—a randomized controlled 1-year trial
G. Grimnes, R. Joakimsen, Y. Figenschau, P. A. Torjesen, B. Almås and R. Jorde
Vitamin D is widely used in osteoporosis treatment, although the optimal dose is not known. This 1-year clinical study among 297 women aged 50–80 years old showed that a vitamin D3 dose of 6,500 IU/day was not better than the standard dose of 800 IU/day in improving bone mineral density (BMD) in the hip and spine.
Osteoporosis International DOI: 10.1007/s00198-011-1752-5


Endocrine Regulation of Male Fertility by the Skeleton
Oury F, Sumara G, Sumara O, Ferron M, Chang H, Smith Charles E, et al
Cell. 2011;144(5):796-809.

This study, published recently in Cell, demonstrated that "in mice osteocalcin, produced by osteoblasts, binds to a specific receptor on cells of the testes." Notably, "male mice that were unable to make osteocalcin (as a result of genetic manipulation) produced less testosterone and were less fertile. When they mated, they had fewer and smaller offspring." Osteocalcin appeared to have no effect on female mouse fertility.


Effect of inhaled glucocorticoids and beta2 agonists on vertebral fracture risk in COPD patients: the EOLO study
Gonnelli S, Caffarelli C, Maggi S, Guglielmi G, Siviero P, Rossi S, Crepaldi G, Nuti R
Calcif Tissue Int 2010;87:137-43

This study aimed to evaluate whether the dose of inhaled GCs and beta(2) agonists may independently influence bone status and vertebral fracture risk in COPD patients aged 50 years or over. The risk of vertebral fractures was increased in patients taking the highest daily dose (>1500 μg) of inhaled GCs (OR=1.4, CI 1.04-1.89). The highest dose of inhaled GCs was associated with low values of stiffness index (OR=1.74, CI 1.03-2.94). Inhaled beta(2) agonists were not associated either with increased risk of vertebral fracture or with reduced values of stiffness. Moreover, the risk of fractures was increased in patients with very severe or severe COPD (OR=2.05, CI 1.28-3.28, and OR=1.40, CI 1.06-1.82, respectively). In conclusion, in COPD patients high doses of inhaled GCs, but not beta(2) agonists, are associated with an increased risk of vertebral fractures and a reduction of QUS at the calcaneus.

Evaluation of the FRAX and Garvan fracture risk calculators in older women
Bolland MJ, Siu AT, Mason BH, Horne AM, Ames RW, Grey AB, Gamble GD, Reid IR
J Bone Miner Res 2011;26:420-7

The performance of the FRAX and Garvan Institute fracture risk calculators in healthy, older, New Zealand, postmenopausal women with normal BMD for their age were assessed. Fractures were ascertained in women initially enrolled in a 5-year trial of calcium supplements and followed on average for 8.8 years. Baseline data (1422 women, mean age 74 years, mean femoral neck BMD T-score -1.3) were used to estimate fracture risk during follow-up using the FRAX and Garvan calculators. The FRAX-New Zealand tool was used both with and without baseline BMD. For each fracture subtype, the calculators had comparable moderate predictive discriminative ability (AUC range: hip fracture 0.67-0.70; osteoporotic fracture 0.62-0.64; any fracture 0.60-0.63) that was similar to that of models using only age and BMD. The Garvan calculator was well calibrated for osteoporotic fractures but overestimated hip fractures. FRAX with BMD underestimated osteoporotic and hip fractures. FRAX without BMD underestimated osteoporotic and overestimated hip fractures. None of the calculators provided better discrimination than models based on age and BMD, and their discriminative ability was only moderate, which may limit their clinical utility.


The utility of BMD Z-score diagnostic thresholds for secondary causes of osteoporosis
McKiernan FE, Berg RL, Linneman JG
Osteoporos Int 2011;22:1069-77

Adult subjects were assigned their lowest axial BMD Z-score and ICD-9 diagnosis codes for secondary causes of osteoporosis when cited at least twice in their electronic medical record. 18,674 subjects were analyzed. Secondary causes of osteoporosis were identified in 31% of men and 16% of women. The frequency of secondary causes varied with age and between genders and varied inversely with Z-score. No inflection point was observed in this relationship to suggest a useful clinical decision threshold. The difference in mean Z-score of those with and without a secondary cause of osteoporosis was ±0.3. Low Z-score diagnostic thresholds were insensitive to the presence of secondary causes of osteoporosis and provided relatively poor predictive value. Z-score thresholds discriminate poorly between the presence and absence of secondary causes of osteoporosis.

Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1alpha,25-dihydroxyvitamin D3 synthesis in leptin-deficient mice
Tsuji K, Maeda T, Kawane T, Matsunuma A, Horiuchi N
J Bone Miner Res 2010;25:1711-23

Exposure to leptin (200 ng/mL) for 24 hours stimulated FGF-23 expression by primary cultured rat osteoblasts. Administration of leptin (4 mg/kg i.p. at 12-h intervals for 2 days) to ob/ob mice increased the serum FGF-23 while reducing the serum calcium, phosphate, and 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. Administration of FGF-23 (5 μg i.p. at 12-hour intervals for 2 days) to ob/ob mice suppressed renal 1alpha-hydroxylase mRNA expression. The main site of FGF-23 mRNA expression was the bone, and leptin markedly increased the FGF-23 mRNA level in ob/ob mice. In addition, leptin reduced 1α-hydroxylase and sodium-phosphate cotransporters (NaP(i)-IIa and NaP(i)-IIc) mRNA levels but did not affect Klotho mRNA expression in the kidneys of ob/ob mice. Furthermore, the serum FGF-23 level and renal expression of 1alpha-hydroxylase mRNA were not influenced by administration of leptin to leptin receptor-deficient (db/db) mice. These results indicate that leptin directly stimulates FGF-23 synthesis by bone cells in ob/ob mice, suggesting that inhibition of renal 1,25(OH)(2)D(3) synthesis in these mice is at least partly due to elevated bone production of FGF-23.

Sclerostin and the regulation of bone formation: effects in hip osteoarthritis and femoral neck fracture
Power J, Poole KE, van Bezooijen R, Doube M, Caballero-Alias AM, Lowik C, Papapoulos S, Reeve J, Loveridge N
J Bone Miner Res 2010;25:1867-76

In 636 unremodeled osteons, ALP staining was used to classify BMUs as quiescent or actively forming bone (ALP(+)). The areal densities of scl(-) and scl(+) osteocytes (number of cells per unit area) in the BMU were inversely correlated and were determinants of ALP status in the BMU. In controls and hip fracture patients, sclerostin-negative osteocytes were closer to osteonal surfaces than positively stained cells. Osteon maturity (progress to closure) was associated with the proportion of osteonal osteocytes expressing sclerostin, and sclerostin expression was the chief determinant of ALP status. hOA patients had 18% fewer osteocytes per unit bone area than controls, fewer osteocytes expressed sclerostin on average than in controls, but wide variation was seen between subjects. Thus, in most hOA patients, there was increased osteonal ALP staining and reduced sclerostin staining of osteocytes. In FNF patients, newly forming osteons were similar in this respect to hOA osteons, but with closure, there was a sharper reduction in ALP staining that was only partly accounted for by the increased proportions of osteonal osteocytes staining positive for sclerostin. There was no evidence for a greater effect on ALP expression by osteocytes near the osteonal canal. Osteonal sclerostin appears to be a determinant of whether osteoblasts actively produce bone. In hOA, reduced sclerostin expression mediates increased osteoblastic activity. In FNF, full osteonal closure is postponed, with increased porosity, in part because the proportion of osteocytes expressing sclerostin increases with osteonal maturation.


Osteoblast specific Y1 receptor deletion enhances bone mass
Lee NJ, Nguyen AD, Enriquez RF, Doyle KL, Sainsbury A, Baldock PA, Herzog H
Bone 2011;48:461-7

Neuropeptide Y, Y1 receptors are found in neuronal as well as bone tissue and Y1 signalling has been implicated in the regulation of bone mass. Osteoblast-specific Y1 receptor deletion resulted in an increase in femoral trabecular thickness and number with increased mineral apposition rate and bone formation rate, and upregulation in the mRNA expression levels of alkaline phosphatase, osteocalcin and dentin matrix protein-1, increased mineral apposition rate on the endocortical and the periosteal surfaces.


Calcium requirements and metabolism in Chinese-American boys and girls
Wu L, Martin BR, Braun MM, Wastney ME, McCabe GP, McCabe LD, DiMeglio LA, Peacock M, Weaver CM
J Bone Miner Res 2010;25:1842-9

15 boys aged 12-15 years and 14 girls aged 11-15 years were studied twice on paired calcium intakes ranging between 629-1835 mg/day using a randomized-order crossover design. Girls and boys had low habitual mean calcium intakes of 648 and 666 mg/day, respectively, and low serum 25-hydroxyvitamin D of 19.1 and 22.2 ng/mL, respectively. True fractional calcium absorption varied inversely with calcium load. Boys had higher bone turnover rate than girls at the same calcium intake. Calcium retention increased with calcium intake; calcium intakes to achieve maximal calcium retention were 1100 mg/day in boys and 970 mg/day in girls.


Effect of a general school-based physical activity intervention on bone mineral content and density: a cluster-randomized controlled trial
Meyer U, Romann M, Zahner L, Schindler C, Puder JJ, Kraenzlin M, Rizzoli R, Kriemler S
Bone 2011;48:792-7

Twenty-eight 1st and 5th grade (6-7 and 11-12 years old) classes were cluster randomized to an intervention (INT, 16 classes, n=297) and control (CON; 12 classes, n=205) group. The intervention consisted of a multicomponent PA intervention including daily physical education with at least 10 min of jumping or strength training exercises of various intensities. 275 (72%) of 380 children who initially agreed to have DXA had also postintervention DXA and PA data. Mean age of prepubertal and pubertal children at baseline was 8.7±2.1 and 11.1±0.6years, respectively. Compared to CON, children in INT showed increases in BMC of total body, femoral neck, and lumbar spine by 5.5%, 5.4% and 4.7% (all p<0.05), respectively, and BMD of total body and lumbar spine by 8.4% and 7.3% (both p<0.01), respectively. There was no gendergroup, but a pubertal stagegroup interaction consistently favoring prepubertal children. A general school-based PA intervention can increase bone health in elementary school children of both genders, particularly before puberty.


Maternal vitamin D status affects bone growth in early childhood – a prospective cohort study
Viljakainen HT, Korhonen T, Hytinantti T, Laitinen EK, Andersson S, Makitie O, Lamberg-Allardt C
Osteoporos Int 2011;22:883-91

87 children were followed from birth to 14 months. The children were divided into two groups based on vitamin D status during pregnancy. Despite discrepant S-25-OHD at baseline (median 36.3 vs. 52.5 nmol/l, p<0.001), the values at 14 months were similar (63 vs. 66 nmol/l, p=0.58) in Low D and High D. Serum 25-OHD increased more in Low D (p<0.001) despite similar total intake of vitamin D (mean 12.3 μg/day). In Low D, tibial bone mineral content (BMC) was lower at birth but BMC gain was greater (multivariate analysis of variance [MANOVA]; p=0.032) resulting in similar BMC at 14 months in the two groups. In High D, tibial total bone cross-sectional area was higher at baseline; the difference persisted at 14 months (MANOVA; p=0.068). BMD and DeltaBMD were similar in the two groups. Postnatal vitamin D supplementation improved vitamin D status but only partly eliminated the differences in bone variables induced by maternal vitamin D status during the fetal period.


Relation of vertebral deformities to bone density, structure, and strength
Melton LJ, Riggs BL, Keaveny TM, Achenbach SJ, Kopperdahl D, Camp JJ, Rouleau PA, Amin S, Atkinson EJ, Robb RA, Therneau TM, Khosla S                      

J Bone Miner Res 2010;25:1922-30

90 postmenopausal women with no deformity (controls) with 142 women with one or more semiquantitative grade 1 (mild) deformities and 51 women with any grade 2-3 (moderate/severe) deformities were studied. Compared with controls, women with grade 1 deformities had worse values for bone density, structure, and strength parameters, although deficits all were worse for the women with grade 2-3 deformities. Nonetheless, grade 1 vertebral deformities were associated with four of the five main variable categories assessed: bone density (lumbar spine vBMD), bone geometry (vertebral apparent cortical thickness), bone strength (overall vertebral compressive strength by FEA), and load-to-strength ratio (45° forward bending/vertebral compressive strength). Thus impaired bone density, structure, and strength compared with controls indicate that many grade 1 deformities do represent early osteoporotic fractures, with corresponding implications for clinical decision making.


Trends in incidence of subtrochanteric fragility fractures and bisphosphonate use among the US elderly, 1996-2007 Wang Z, Bhattacharyya T                   

J Bone Miner Res 2011;26:553-60

From the Nationwide Inpatient Sample (NIS) and the Medical Expenditure Panel Survey (MEPS) from 1996-2007. Between 1996 and 2007, age-adjusted rates for typical hip fractures decreased by 31.6% among women (from 1020.5 to 697.4 per 100,000 population) and 20.5% among men (from 424.9 to 337.6 per 100,000 population). In contrast, overall trends in age-adjusted rates for subtrochanteric fragility fractures remained unchanged among men but increased 20.4% among women from 28.4 (95% CI 27.7-29.1) in 1999 to 34.2 (95% CI 33.4-34.9) per 100,000 population in 2007. The annual percentage increase was 2.1% (95% CI 1.3-2.8, p<0.001). In MEPS, bisphosphonate use increased in women (from 3.5% in 1996 to 16.6% in 2007) compared with men (2.3% in 2007). Incidence of subtrochanteric fragility fractures increased from 1999 among postmenopausal women; for every 100 or so reduction in typical femoral neck or intertrochanteric fractures, there was an increase of one subtrochanteric fragility fracture.


New Insights into the Biology of Glucocorticoid-Induced Osteoporosis
Nancy E. Lane and Wei Yao
, Department of Medicine, University of California at Davis Medical Center, Sacramento, California, USA



Anabolic Plus Antiresorptive: Is One Plus One More or Less Two?
Ego Seeman,
Department of Endocrinology and Medicine, Austin Health, University of Melbourne, Melbourne, Australia



Sun Exposure, Vitamin D Associated With MS Risk.

WebMD (2/7, Boyles) reported, "Higher vitamin D levels and exposure to sunlight appear to be independently protective against multiple sclerosis," according to a study published in Neurology. The study included "216 people with early symptoms of MS who had not yet been diagnosed and 395 people with no MS symptoms matched for age, sex, and area of residence." All the study participants were "asked about their level of sun exposure during different periods of their lives, and the researchers also measured blood levels of vitamin D and skin damage due to sun exposure."
        According to HealthDay (2/7, Mozes), "noting that sun exposure ranged from 500 to 6000 kilojoules per meter squared," the authors found that for "every additional 1000 kilojoules of exposure, the risk of developing the first signs of MS dropped by 30 percent." In addition, having a "higher vitamin D level was also independently linked to a lower risk for developing MS." Furthermore, those living in the "study regions furthest away from the equator faced a 32 percent greater risk for signs of MS than study participants who lived closest to the equator."
        Medscape (2/7, Anderson) reported that one of the study authors, Anne-Louise Ponsonby, PhD, "acknowledged that although the sun is believed to have direct immune effects in addition to providing vitamin D, the sun exposure effect found in the study could simply reflect longer-term vitamin D status." In any case, she said, "it's important to study both vitamin D and sun exposure to understand the effects on immune function and MS."

LINK http://www.neurology.org/content/76/6/540.abstract?sid=c3559a30-a61a-4fe3-b509-a5dc31113ac0


CTX, PINP May Be Suitable As Reference Bone Turnover Markers.
MedWire (1/11, Dean) reported that, according to a review published online in the journal Osteoporosis International, the International Osteoporosis Foundation and the International Federation of Clinical Chemistry and Laboratory Medicine "have called for serum procollagen type I N propeptide (s-PINP) and serum C-terminal telopeptide of type I collagen (s-CTX) to be used as reference bone turnover markers (BTMs) in clinical studies." Researchers came to that conclusion after finding that "18 of the 22 prospective studies they reviewed showed a significant association between one or more markers of bone formation (or resorption and fracture risk." In particular, "odds ratios and relative risks for fracture among patients with elevated procollagen type I N propeptide, osteocalcin, alkaline phosphatase (ALP), bone-derived ALP, and C-terminal and N-terminal cross-linking telopeptides, among others, ranged from 1.3-5.9."

LINK http://www.springerlink.com/content/f1383w4253567654/


Combination Of Growth Hormone Plus Low-Protein Diet Leads To Reduced BMD In Rats.
MedWire (5/26, Williams) reported that, according to a study published in the June issue of the journal Bone, "administering growth hormone (GH) to animals fed a low-protein diet leads to reduced bone mineral density (BMD) and bone strength." After feeding "female rats isocaloric diets with 2.5% or 15.0% casein for two weeks, followed by a four-week schedule of bovine GH (0.5 or 2.5 mg/kg) or a vehicle control," researchers found that "animals given a low-protein diet also exhibited a GH dose-dependent loss in BMD and bone strength that was not seen in rats fed the normal diet who showed no BMD changes."

LINK http://www.journals.elsevierhealth.com/periodicals/bon/article/S8756-3282%2810%2900437-0/abstract