Monthly Archives: June 2014

Soy Isoflavones + Vitamin D3 Improve Bone Density, Stimulate Osteoblasts, and Inhibit Osteoclasts in Ovariectomized Rats


Combined effect of soy isoflavones and vitamin D3 on bone loss in ovariectomized rats.

Several studies have shown that soy isoflavones have estrogen-like activities and might constitute an alternative to hormone replacement treatment. The present study investigated the effects of soy isoflavones alone and combined with vitamin D3 on prevention of bone loss.
Sprague-Dawley rats were sham-operated (n = 8) or ovariectomized (OVX; n = 40), and then the OVX rats were randomly assigned to five groups that were untreated or treated for 14 wk with vitamin D3, 17β-estradiol, soy isoflavone extract (SIE), or vitamin D3 plus SIE. The effects of the isoflavones and 1α,25(OH)(2)D(3) on cultured osteoblasts and osteoclasts also were investigated.
In OVX rats, the bone mineral density and trabecular bone volume loss were improved by 17β-estradiol, SIE, or SIE plus vitamin D3 treatment. SIE treatment was more effective than vitamin D3 or 17β-estradiol in inhibiting increases in serum tumor necrosis factor-α levels and osteoblast osteoprotegerin expression. SIE plus vitamin D3 was more effective in increasing osterix expression than each alone. Bone cell cultures showed that the isoflavones induced preosteoblasts to differentiate into osteoblasts and increased osteoblast mineralization. Isoflavones inhibited preosteoclasts and osteoclast proliferation and decreased osteoclast resorption. The combination of isoflavones plus 1α,25(OH)(2)D(3) showed additive effects on the increase in cell proliferation of cultured preosteoblasts.
Treatment with soy isoflavones might be an alternative to hormone replacement therapy in decreasing bone loss from postmenopausal estrogen deficiency. In addition, there are further effects on increasing transcription factor osterix expression and preosteoblast proliferation when these were combined with vitamin D3.

Chang KL, Hu YC, Hsieh BS, Cheng HL…
Nutrition Jan 2013
PMID: 22858193

Depression Associated With Bone Mass in Premenopausal Women


Do premenopausal women with major depression have low bone mineral density? A 36-month prospective study.

An inverse relationship between major depressive disorder (MDD) and bone mineral density (BMD) has been suggested, but prospective evaluation in premenopausal women is lacking.
Participants of this prospective study were 21 to 45 year-old premenopausal women with MDD (n = 92) and healthy controls (n = 44). We measured BMD at the anteroposterior lumbar spine, femoral neck, total hip, mid-distal radius, trochanter, and Ward’s triangle, as well as serum intact parathyroid hormone (iPTH), ionized calcium, plasma adrenocorticotropic hormone (ACTH), serum cortisol, and 24-hour urinary-free cortisol levels at 0, 6, 12, 24, and 36 months. 25-hydroxyvitamin D was measured at baseline.
At baseline, BMD tended to be lower in women with MDD compared to controls and BMD remained stable over time in both groups. At baseline, 6, 12, and 24 months intact PTH levels were significantly higher in women with MDD vs. controls. At baseline, ionized calcium and 25-hydroxyvitamin D levels were significantly lower in women with MDD compared to controls. At baseline and 12 months, bone-specific alkaline phosphatase, a marker of bone formation, was significantly higher in women with MDD vs. controls. Plasma ACTH was also higher in women with MDD at baseline and 6 months. Serum osteocalcin, urinary N-telopeptide, serum cortisol, and urinary free cortisol levels were not different between the two groups throughout the study.
Women with MDD tended to have lower BMD than controls over time. Larger and longer studies are necessary to extend these observations with the possibility of prophylactic therapy for osteoporosis. NCT 00006180.

Cizza G, Mistry S, Nguyen VT, Eskandari F…
PLoS ONE 2012
PMID: 22848407 | Free Full Text

Clothing Style May Lower Vitamin D and Increase Fractures in Italian Nuns


Low 25-hydroxyvitamin D levels and low bone density assessed by quantitative ultrasonometry in a cohort of postmenopausal Italian nuns.

This study was aimed at evaluating the effect of clothing style on bone mass and fractures in 70 postmenopausal nuns residing in a monastery in Naples. Sixty healthy women matched for age, body mass index, and menopausal status were enrolled as controls. Each participant underwent measurement by quantitative ultrasonometry (QUS) using a DBM Sonic Bone Profiler (IGEA S.p.A., Carpi, Modena, Italy) at proximal phalanges, responded to questionnaires regarding lifestyle, calcium intake, medical history, including clinical fragility fractures, and was submitted to routine biochemical assessment. A significant reduction in ultrasonometric parameters of bone mass was found in nuns compared with controls (p from 0.007 to <0.0001). 25-hydroxyvitamin D (25-OH vit D) levels were reduced by more than 50% in nuns (9.8 ± 4.2 vs 23.5 ± 5.7 nmol/L; p < 0.0001), whereas their estimated daily calcium intake was higher (1.004 ± 0.23 vs 0.721 ± 0.25 g of controls; p = 0.0007). Age at menopause was significantly lower in nuns’ group (p = 0.016). Incidence of fractures was higher in nuns (39% vs 10%; p = 0.0029), and the best predictors of fractures were age at menopause (odds ratio [OR]: 1.12; 95% confidence interval [CI]: 1.01-1.30), amplitude-dependent speed of sound T-score (OR: 1.15; 95% CI: 1.03-1.63), and bone transmission time T-score (OR: 1.30; 95% CI: 1.15-1.81). This study documented low 25-OH vit D levels, increased frequency of clinical fractures, and low bone mass detected by QUS in Southern Italian nuns.

Nuzzo V, Zuccoli A, de Terlizzi F, Colao A…
J Clin Densitom
PMID: 22832035

Ferutinin Inhibits Resorption in Ovariectomized Rats


Effects of different doses of ferutinin on bone formation/resorption in ovariectomized rats.

This study analyzes the effects of different doses of ferutinin on bone loss caused by estrogen deficiency in ovariectomized rats, in comparison with estradiol benzoate. Thirty female Sprague-Dawley rats were ovariectomized and treated for 30 days from the day after ovariectomy. Static/dynamic histomorphometric analyses were performed on trabecular and cortical bone of lumbar vertebrae and femurs. Very low weight increments were recorded only in all F-OVX groups, with respect to the others. Although the great differences in weight, that could imply a decrease of bone mass in F-OVX groups compared to the control ovariectomized group (C-OVX), trabecular bone in lumbar vertebrae did not show significant differences, suggesting that ferutinin, opposing estrogen deficiency, inhibits bone resorption. Newly formed cortical bone was always low in all F-OVX groups and high in C-OVX, suggesting that it is mainly devoted in answering mechanical demands. In contrast, in distal femoral metaphyses, trabecular bone was reduced and the number of osteoclasts was increased in C-OVX with respect to all other groups, suggesting that it is mainly devoted in answering metabolic demands; moreover, ferutinin dose of 2 mg/kg seemed to be more effective than the lower doses used and estrogens, particularly in those skeletal regions with higher metabolic activity. Our results suggest that the role of ferutinin in preventing osteoporosis caused by estrogen deficiency is expressed in decreasing bone erosion; moreover, in all F-OVX groups bone turnover is very low and seems correlated to the trivial body weight increase, which, in turn, depends on ferutinin treatment.

Cavani F, Ferretti M, Carnevale G, Bertoni L…
J. Bone Miner. Metab. Nov 2012
PMID: 22828874

Review: Calcium Safety and New Recommendations


Calcium builds strong bones, and more is better–correct? Well, maybe not.

Calcium supplementation has been considered the gold standard therapy for osteoporosis in the general population. It is given in both the placebo and treatment groups of trials evaluating antifracture efficacy of new therapies. Similarly, calcium-based phosphate binders have been considered the gold standard comparator for all new phosphate binders. However, large randomized trials demonstrate conflicting data on the antifracture efficacy of calcium supplementation, particularly in high doses, in patients with osteoporosis without CKD. In addition, recent data suggest an increased risk for cardiovascular events. These new studies raise safety concerns for the general approach with calcium supplementation and binders. This review describes recent data on the adverse effects of calcium supplementation for osteoporosis and how these new data should affect the strategy for phosphate binder use in CKD.

Jamal SA, Moe SM
Clin J Am Soc Nephrol Nov 2012
PMID: 22837272 | Free Full Text

It is important to note that some clinical practice guidelines have been modified on the basis of this new literature suggesting potential risk. For example, in its recently published evidence-based guidelines, Osteoporosis Canada recommended a total intake of calcium (from diet and supplement) of 1200 mg per day, a decrease from the previous recommendation of 1500 mg in supplements (32). The American Society for Bone and Mineral Research issued a statement regarding the potential risks of calcium supplements and suggested, among other points, that “the beneficial effects of calcium are found with relatively low doses. More is not necessarily better. Individuals should discuss the amount of their calcium intake with their healthcare provider” (33). The Institute of Medicine now recommends a daily dietary reference allowance of calcium of 1000–1200 mg per day in the form of diet and supplements (34,35). Finally, the draft United States Preventive Services Task Force statement, pending public comment (, currently states “the current evidence is insufficient to assess the balance of the benefits and harms of combined vitamin D and calcium supplementation for the primary prevention of fractures in premenopausal women or in men.” Thus, these authorities acknowledge that although some calcium supplements may be beneficial for bone health, too much calcium may be harmful.

Low-Dose Estrogen Increases Bone Density in Postmenopausal Women


Effects of a low-dose oral estrogen only treatment on bone mineral density and quantitative ultrasonometry in postmenopausal women.

The aim of this study was to evaluate an oral low-dose estrogen therapy on bone mineral density (BMD) and quantitative ultrasonometry (QUS) in osteopenic postmenopausal women.
This prospective, open-label cohort study investigated 120 postmenopausal hysterectomized women. Forty-seven women had been treated with 0.3 mg conjugated equine estrogen daily (ET). Primary end point was the change in BMD at the spine after 24 months. Secondary end points were among other changes in QUS at the os calcis and phalanges.
After matching 42 participants in the ET group, 42 controls were analyzed. The change in BMD differed significantly after 24 months (p = 0.019). Women on ET showed significant increase of spine and hip Z-score, whereas controls showed significant decreases in spine and total hip BMD. In QUS of the os calcis and the phalanges, a number of variables showed a significant improvements with ET.
Our results comprised a positive effect of an oral low-dose estrogen therapy on BMD. Limitations of the study are the small sample size and the open-label, non-randomized cohort study design. The findings are in accordance to the common literature and support the use of ET in the primary prevention of postmenopausal bone loss.

Ziller M, Herwig J, Ziller V, Kauka A…
Gynecol. Endocrinol. Dec 2012
PMID: 22835159

Low to Moderate Alcohol May Protect Bone


Alcohol consumption and bone mineral density in elderly women.

Findings regarding alcohol consumption and bone mineral density (BMD) in elderly women have been inconsistent. The objective of the present study was to explore the association of alcohol intake with BMD in elderly women.
This cohort study included women from the population-based Kuopio Osteoporosis Risk Factor and Prevention – Fracture Prevention Study (OSTPRE-FPS). Alcohol intake and potential confounders were assessed at baseline and after 3 years of follow-up using a lifestyle questionnaire. In addition, an FFQ was distributed in the third year to measure dietary intake, including alcohol. Women underwent BMD measurements at the femoral neck and lumbar spine at baseline and after 3 years of follow-up.
Kuopio Province, Finland.
Three hundred elderly women (mean age 67·8 years) who provided both BMD measurements and FFQ data.
Alcohol consumption estimated from the FFQ and lifestyle questionnaire was significantly associated with BMD at both measurement sites after adjustment for potential confounders, including lifestyle and dietary factors (P < 0·05). Using the FFQ, women drinking >3 alcoholic drinks/week had significantly higher BMD than abstainers, 12·0 % at the femoral neck and 9·2 % at the lumbar spine. Results based on the lifestyle questionnaire showed higher BMD values for all alcohol-consuming women at the femoral neck and for women drinking 1-3 alcoholic beverages/week at the lumbar spine, compared with non-users.
The results from OSTPRE-FPS suggest that low to moderate alcohol intake may exert protective effects on bone health in elderly women.

Sommer I, Erkkilä AT, Järvinen R, Mursu J…
Public Health Nutr Apr 2013
PMID: 22800300

Fruit Associated With Bone Density and Content in Chinese Women


Fruit and vegetable intake and bone mass in Chinese adolescents, young and postmenopausal women.

Previous studies showed an inconsistent association of fruit and vegetable consumption with bone health. We assessed the associations in Chinese adolescents, young and postmenopausal women.
A cross-sectional study conducted in China during July 2009 to May 2010.
Bone mineral density (BMD) and content (BMC) at the whole body, lumbar spine and left hip were measured with dual-energy X-ray absorptiometry. Dietary intakes were assessed using an FFQ. All these values were separately standardized into Z-scores in each population subgroup.
One hundred and ten boys and 112 girls (11-14 years), 371 young women (20-34 years, postpartum within 2 weeks) and 333 postmenopausal women (50-70 years).
After adjustment for potential covariates, analysis of covariance showed a significantly positive association between fruit intake and BMD and BMC in all participants combined (P-trend: < 0.001 to 0.002). BMD Z-score increased by 0.25 (or 2.1 % of the mean), 0.22 (3.5 %), 0.23 (3.0 %) and 0.25 (3.5 %), and BMC Z-score increased by 0.33 (5.7 %), 0.25 (5.8 %), 0.34 (5.9 %) and 0.29 (4.7 %), at the total body, lumbar spine, total hip and femoral neck in participants belonging to the top tertile compared with the bottom tertile of fruit intake (all P < 0.05), respectively. There was no significant association between vegetable intake and bone mass at all bone sites studied except for total body BMD (P = 0.030). Relatively more pronounced effects were observed in boys and postmenopausal women.
Our findings add to the existing evidence that fruits and vegetables may have a bone sparing effect.

Li JJ, Huang ZW, Wang RQ, Ma XM…
Public Health Nutr Jan 2013
PMID: 22717072

Vitamin E Does Not Prevent Bone Loss in Rats


Vitamin E does not prevent bone loss and induced anxiety in rats with ligature-induced periodontitis.

The purpose of this study was to investigate the effect of vitamin E on alveolar bone loss (ABL) and anxiety in rats with ligature-induced experimental periodontitis (EP).
Wistar rats were subjected to ligature-induced EP and treated with vitamin E (500mg/kg, orally) for 9 days. Then anxiety was tested using the elevated plus-maze (EPM) test. All of the animals were euthanised by cervical dislocation on day 11. ABL was analysed morphometrically and histopathologically. Lipid peroxidation quantification, activity of the enzyme superoxide dismutase and immunohistochemistry to tumour necrosis factor-alpha (TNF-α) and inducible isoform of nitric oxide synthases (iNOS) were also tested.
EP induced a marked inflammatory process and intense ABL. Treatment with vitamin E decreased inflammatory reaction, prevented malondialdehyde formation and reduced the immunoreactivity to iNOS, but did not decrease ABL. Vitamin E had an anxiogenic effect on rats with or without EP.
Vitamin E may have potential to reduce oxidative damage and inflammatory response in EP but does not prevent ABL. Attention should be given to indiscriminate use of vitamin E due to the risk of causing anxiety in patients.

Carvalho Rde S, de Souza CM, Neves JC, Holanda-Pinto SA…
Arch. Oral Biol. Jan 2013
PMID: 22664314

Review: New Treatments


New developments in the treatment of osteoporosis.

The last 25 years have seen the development of a plethora of new, effective agents for the treatment of osteoporosis. These agents reduce the risk of spine fractures by up to 70%, hip fractures by 40-50% and non-vertebral fractures by up to 50-80%. Amino-bisphosphonates, taken orally or intravenously, remain the dominant treatment modalities for osteoporosis. These so-called anti-resorptive or anti-catabolic agents stabilize the skeleton and reduce fracture risk in osteoporotic as well as osteopenic individuals. A monoclonal antibody against receptor activator of nuclear factor κB ligand, Denosumab, constitutes a new anti-resorptive agent recently approved worldwide. In younger postmenopausal women, low-dose estrogen or estrogen/progestin still has a place for short-term (up to 5 years) preservation of bone mass, especially in women with menopausal symptoms. Likewise, selective estrogen receptor modulators should be considered in younger postmenopausal women, especially those at increased risk of breast cancer. Anabolic (bone forming) regimens, of which parathyroid hormone is the only agent currently available, aid in the build up of new bone, increase bone mass and improve bone architecture. In cancellous bone, 30-60% increases of bone mass have been documented, but cortical bone thickness also increases. These improvements lead to profound reduction in fracture rates in both the axial and appendicular skeleton. Owing to cost and the need for parenteral administration, in most countries these agents are reserved for severe osteoporosis with multiple fractures.

Eriksen EF, Halse J, Moen MH
Acta Obstet Gynecol Scand Jun 2013
PMID: 22646526