Overview, Vol 13, Issue 9

Only doubt is certain and disbelief worth believing.
Without this courage there can be no learning.
Believe nothing.

"The quarterly journal Progress in Osteoporosis began in October 1993 as Advances in Osteoporosis. Its purpose was to provide readers without easy access to the literature with summaries of the most important literature. We now inhabit a virtual world. Information is instantaneously accessible to all at the tap of a keyboard; understanding is not. In the spirit captured by the anonymous author*, the purpose of this publication is to provide critical evaluation of the most important literature and so to provoke discussion. It is our intention to promote dialogue which examines the quality of information published and so its credibility. The opinions expressed are my own and do not necessarily reflect those of the International Osteoporosis Foundation."

We invite readers to comment on and discuss this journal entry at the bottom of the page.

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Fracture Rates
Are they declining?

Amin et al report that during three years, 3549 residents ≥50 years of age experienced 5244 fractures (1). The age- and sex-adjusted incidence of any fracture was 2704 per 100,000 person-years (95% CI 2614-2793) and that for all fractures was 4017 per 100,000 (95% CI 3908-4127). Fracture incidence increased with age in both sexes, but was 49% greater in women. Overall, comparably adjusted fracture incidence rates increased by 11% (from 3627 to 4017 per 100,000 person-years; p=0.008) between 1989-1 and 2009-2011 mainly due to increases in vertebral fractures (+47% for both sexes combined), which was partially offset by a decline in hip fractures (-25%) among the women. There was also a 26% reduction in distal forearm fractures in the women; the increase in distal forearm fractures in men age 50+ years was not significant. The increase in vertebral fractures was attributable in part to incidentally diagnosed vertebral fractures.

Of particular interest is the fall in hip fracture incidence which continues the steady decline observed in women in this community since 1950. More generally, the increases in the incidence of fractures at many skeletal sites observed decades ago have stabilized. The question is why. If there is a secular change in fracture incidence this may be the result of changes in peak bone strength in later bone generations, less bone loss or fewer falls. The challenge is how to explore these factors.

Figure 1. Age-specific incidence of all distal forearm fractures among Olmsted County, Minnesota, women (A) and men (B) ≥50 years of age, comparing 2009-11 with comparable data from 1989-91. Reproduced from J Bone Miner Res 2013; doi:10.1002/jbmr.2072 with permission of the American Society of Bone and Mineral Research.


Figure 2. Age-specific incidence of all proximal femur fractures among Olmsted County, Minnesota, women (A) and men (B) ≥50 years of age, comparing 2009-11 with comparable data from 1989-91. Reproduced from J Bone Miner Res 2013; doi:10.1002/jbmr.2072 with permission of the American Society of Bone and Mineral Research.


Testosterone for Lean Mass and Estrogen for Fat Mass in Men

Finkelstein et al treated 198 healthy men 20-50 years of age with goserelin (to suppress testosterone and estradiol) for 16 weeks and randomly assigned them to placebo gel or 1.25 g, 2.5 g, 5 g, or 10 g/d of testosterone gel for 16 weeks (2). Another 202 healthy men received goserelin, placebo gel or testosterone gel, and anastrozole (to suppress the conversion of testosterone to estradiol). Percent body fat increased in groups receiving placebo or 1.25 or 2.5 g/d testosterone without anastrozole (mean testosterone level, 44±13, 191±78, and 337±173 ng/dl, respectively). Lean mass and thigh-muscle area decreased in men receiving placebo and in those receiving 1.25 g of testosterone daily without anastrozole. Leg-press strength fell only with placebo. Sexual desire declined as the testosterone dose was reduced. The amount of testosterone required to maintain lean mass, fat mass, strength, and sexual function varied widely. Androgen deficiency accounted for decreases in lean mass, muscle size, and strength; estrogen deficiency accounted for increases in body fat; and both contributed to the decline in sexual function.

Measurement of IGF-1, remodeling markers would have been of interest to determine whether changes in lean mass associated with testosterone deficiency were accounted for by lower levels of IGF-1 and if so, whether this may be attributable to the concomitant estrogen deficiency. Similarly, changes in remodeling markers might be insightful as acute estrogen deficiency appears to modify the life span of osteoclasts and osteoblasts in opposite directions, at least transiently. A shortening of the lifespan of osteoblasts and lengthening of the lifespan of osteoclasts might contribute to acute changes in bone loss, even in a short period of 16 weeks. The data suggest a more favorable approach to treatment of hypogonadism in men being aromatizable androgens over nonaromatizable androgens given the deleterious effects of estrogen deficiency in several endpoints. While of great interest, this will require trials designed to examine safety as well as efficacy.

Figure 3. Mean serum testosterone and estradiol levels from weeks 4-16, according to testosterone dose and cohort. T bars indicate standard errors. From N Engl J Med, Finkelstein JS et al, Gonadal steroids and body composition, strength, and sexual function in men, 369, 1011-22 Copyright © (2013) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.






Figure 4. Mean percent change from baseline in percentage of body fat, lean body mass, subcutaneous- and intraabdominal-fat area, thigh-muscle area, and leg-press strength, according to testosterone dose and cohort. T bars indicate standard errors. Within each cohort, bars with the same number indicate no significant difference between dose groups. For example, the change in the percentage of body fat (Panel A) did not differ significantly among the groups that received 0 g, 1.25 g, or 2.5 g of testosterone daily in cohort 1 (all labeled '1'). The change in each of those three groups differed significantly from the change in the group that received 5 g per day (labeled ‘2’) and the change in the group that received 10 g per day (labeled ‘3’), and the change also differed significantly between these latter two groups. P values are for the cohort-testosterone dose interaction terms in analyses of variance comparing changes in each outcome measure between cohorts 1 and 2. From N Engl J Med, Finkelstein JS et al, Gonadal steroids and body composition, strength, and sexual function in men, 369, 1011-22 Copyright © (2013) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Genetic Factors Contribute to Variance in Microstructure

Variance in many traits is large; individuals vary several fold in bone size and mass, and in the rate of bone remodeling as reflected in measurements of bone remodeling markers. In many of these skeletal traits, a large proportion of the variance is accounted for by difference in genetic factors. That is, individuals differ from each other more due to differences in their genetic makeup than due to differences in life style factors. Havell et al examined right femurs from 101 baboons (74 females, 27 males; aged 7-33 years) from a single, extended pedigree to determine osteon number, osteon area (On.Ar), Haversian canal area, osteon population density, percent osteonal bone (%On.B), wall thickness (W.Th), and cortical porosity (Ct.Po) (3). Significant age and sex effects account for 9 (Ct.Po) to 21% (W.Th) of intracortical microstructural variation. After accounting for age and sex, genetic effects were evident for On.Ar (h2=0.79, p=0.002), %On.B (h2=0.82, p=0.003), and W.Th (h2=0.61, p=0.013), indicating that 61-82% of the residual variation (after accounting for age and sex effects) is due to additive genetic effects. This corresponds to 48-75% of the total phenotypic variance. Thus, normal, population level variation in cortical microstructure in these subhuman primates is influenced by genes. This likely to be the same in human subjects. As a critical mediator of crack behavior in bone cortex, intracortical microstructural variation provides another mechanism through which genetic variation may affect fracture risk.

Racial Differences in Cortical Porosity and Tissue Mineral Density

Boutroy et al explored whether greater Ct.BMD in Chinese-American women is due to greater tissue mineral density (TMD) or reduced cortical porosity (Ct.Po) (4). 78 Chinese-American women (49 pre- and 29 postmenopausal) and 114 white women (46 pre- and 68 postmenopausal) were studied. Premenopausal Chinese-American vs. white women had greater Ct.Th, Ct.BMD and Ct.TMD at the radius and tibia; and decreased Ct.Po (p<0.05). A similar pattern was observed between postmenopausal Chinese-American and white women. Postmenopausal vs. premenopausal women had lower Ct.BMD at the radius and tibia in both races (p<0.001). Ct.Po increased between pre- and postmenopausal women, while Ct.TMD decreased by 3-8% (p<0.001) in both races. Age-related differences in Ct.Po and Ct.TMD did not differ by race.

The implications are of interest. First, differences in cortical porosity and tissue density may be achieved during growth. If so the implication is that Chinese-Americans assemble a smaller skeleton but the relatively thicker and less porous more mineralized cortex is achieved by excavation of a smaller medullary canal and fewer osteons (the main determinant of porosity being the Haversian and Volkmann canal density). Studies during growth to examine whether lower remodeling rate, an earlier menarche or both may achieve these morphological features. Second, if this is correct, then at menopause, Chinese-Americans might also experience lower rates of bone loss; this is a good thing because their more robust skeleton will undergo less bone loss and might be more resistant to the limited structural decay resulting.

Figure 5. Adjusted difference in SD, between Chinese-American and White women by menopausal status, at the radius and tibia. Reproduced from J Bone Miner Res 2013; doi:10.1002/jbmr.2057 with permission of the American Society of Bone and Mineral Research.



Figure 6. Difference in SD, between pre- and postmenopausal women by race, at the radius and tibia. Reproduced from J Bone Miner Res 2013; doi:10.1002/jbmr.2057 with permission of the American Society of Bone and Mineral Research.



Marrow Fat
Confounder or independent variable?

Bone marrow fat (BMF) and BMD are negatively correlated. Schwartz et al assess relationships between vertebral BMF, BMD by QCT, and fracture in a cross-sectional study in 257 participants mean age 79 (SD 3.1) years from the Age Gene/Environment Susceptibility-Reykjavik cohort (5). Outcomes included vertebral BMF (L1-L4) measured using magnetic resonance spectroscopy, QCT and DXA scans of the hip and spine, and DXA vertebral fracture assessments. BMF was 53.5±8.1% in men and 55.0±8.4% in women. Those with prevalent vertebral fracture (21 men, 32 women) had higher BMF adjusted for BMD. The difference was significant only in men (57.3 vs. 52.8%, P=0.02). BMF was associated with lower trabecular spine vBMD (-10.5% difference for each 1 SD increase in BMF, P<0.01), total hip, and femoral neck, but not cortical vBMD, in women. In men, BMF was associated with trabecular spine vBMD (-6.1%, P=0.05). Total hip and spine aBMD were negatively correlated with BMF in women only. The authors infer that higher marrow fat correlated with lower trabecular not cortical BMD in older women, not men. Higher marrow fat was associated with prevalent vertebral fracture in men, even after adjustment for BMD.

In animals, defective brown adipogenesis leads to bone loss. Whether brown adipose tissue (BAT) mass relates to BMD in humans was explored by Lee et al who determined the relationship between BAT mass and BMD by cold-stimulated positron-emission tomography (PET) and DXA (6). In 24 healthy adults (age 28±1 years, F 10), BAT volumes were 82.4±99.5 ml in women and 49.7±54.5 ml in men. Women had higher BAT activity, by 9.4±8.1% than men. BAT volume correlated positively with total and spine BMD in women and remained a predictor after adjustment for age, fat, and lean body mass. Total and spine BMD were higher in women with detectable BAT on PET images than those without by 11±2% and 22±2%, respectively. No associations were observed between BAT parameters and BMD in men. The data suggest that brown adipogenesis may be physiologically related to modulation of bone density. Thus, adipose tissue is not just a confounder and opens a door to another world of regulators of bone remodeling.

Figure 7. (a) PET image of a 20-year-old woman demonstrating FDG uptake in cervical–supraclavicular BAT depots (red arrows). Uptake was also evident within the vertebra (blue arrows) that harbored the bone marrow with BAT characteristic. (b) A representative image of BAT uptake and the three-dimensional reconstruction of the torso-mantle (green) that was constructed to allow quantification of FDG uptake within BAT-specific region. (c) Positive correlations between BAT volume with total and spine BMD in women (left), but not in men (right). Reproduced from Osteoporos Int 2013;24:1513-8 with permission from Springer.


Collagen and Bone Strength

Wegrzyn et al studied the role of matrix composition on vertebra mechanics in 17 fresh frozen human lumbar spines (8 W, 9 M, aged 76±11years) (7). Collagen maturity correlated with whole vertebra failure load and stiffness (r=0.64 and r=0.54, respectively). The collagen maturity, mass and microarchitecture explained 71% of the variability in whole vertebra strength. There was no association between the matrix characteristics, mass or microarchitecture, mineral maturity, mineralization and crystallinity index to whole vertebra mechanics.

The Howship’s Lacuna Dimensions

Osteoclast resorption route starts perpendicularly to the bone surface, and continues parallel to the bone surface, forming a trench. Soe et al report that relative rates of collagenolysis vs. demineralization play a role in resorption patterns (8). On bone slices, round pits containing demineralized collagen suggest pits are generated when demineralization is faster than collagen degradation while elongated trenches without demineralized collagen suggesting collagen degradation is as fast as demineralization. Osteoclasts given low dose carbonic anhydrase inhibitor to slow demineralization allow collagen degradation to proceed as fast resulting in a two-fold increase in trenches. When decreasing the rate of collagenolysis using a cathepsin K inhibitor, trenches=0%, and round pits become half as deep. Osteocytes and bone lining cells surrounding the osteoclast may act on this balance to steer the osteoclast resorptive activity in order to give the excavations a specific shape.

Figure 8. Effect of inhibitors of demineralization and collagenolysis on the relative numbers of resorption trenches and pits. Resorbing OCs were treated or not with (i) 0.74 μM ethoxyzolamide (Etz) to slightly slow down demineralization, (ii) 100 nM L1873724 to specifically inhibit CatK, or (iii) 48 μM E64 to inhibit CatK and other cysteine proteases. A) Representative images of toluidine blue-stained resorption cavities generated in these respective culture conditions. Scale bar=25 μm. B-E) Effect of the culture conditions on: B) the proportion of trenches expressed in percentage of the total number of resorption events, C) the proportion of pits expressed in percentage of the total number of resorption events, D) the percentage eroded surface (ES) per total bone surface, and E) the number of all resorption events per grid. The data are shown as mean±SD, n=5. Statistical analyses were done compared to control condition unless indicated otherwise: unpaired t-test, b: p<0.01, ns: not significant. Reproduced from Bone, 56:191-8, Copyright (2013), with permission from Elsevier.

Figure 9. The levels of CatK expression correlate with the proportion of trenches and the degree of collagenolysis. The levels of CatK expression were evaluated byQ-RT-PCR in differentiated OCs from different blood donors. The analyses were normalized in two steps. In order to be able to compare the expression levels of different donors we prepared a reference standard curve from the same randomly selected donor for every gene tested. Thereafter, the CatK expression levels of the individual donor were normalized to the average expression levels of the housekeeping genes hGUS and hAbl. These adjusted CatK expression levels were plotted against the proportion of %trench surface/ES obtained from experiments with OCs of this particular donor. Statistics: Linear regression analysis, r2=0.41, p=0.033. Reproduced from Bone, 56:191-8, Copyright (2013), with permission from Elsevier.

Antiresorptives Reduce BMU Depth

Antiresorptive agents reduce the rate of bone loss by reducing the number of remodeling sites initiating or progressing with resorption and replacement of bone upon the endosteal surface. The question is whether these agents also alter the balance between the volumes of bone resorbed and deposted by each BMU. There is not a great deal of information addressing this question.

Matheny et al explored whether antiresorptives reduce resorption depth by studying adult female rats (6 months) that were ovariectomized (n=17) or had sham surgery (SHAM, n=5) (9). One month later, the ovariectomized animals were separated into untreated (OVX, n=5), raloxifene (OVX+Ral, n=6) and risedronate (OVX+Ris, n=6). At 10 months of age, lumbar vertebrae were submitted to histomorphometry of individual resorption cavities and formation events. Maximum resorption depth did not differ in the SHAM (23.66±1.87 µm, mean±SD) and OVX (22.88±3.69 µm) groups but was smaller in the OVX+Ral (14.96±2.30 µm) and OVX+Ris (14.94±2.70 µm) groups (p<0.01). Antiresorptive treatment was associated with reductions in the surface area of resorption cavities and the volume occupied by each resorption cavity (p<0.01 each). The surface area and volume of individual formation events (double-labeled events) in the OVX+Ris group were reduced as compared to other groups (p<0.02).

This is a wonderful manuscript. Well worth reading. It is of interest that raloxifene treated animals showed similar amounts of bone remodeling (ES/BS and dLS/BS) compared to sham-operated controls but smaller cavity size (depth, breadth and volume). Thus, if remodeling rate is not reduced and the negative BMU balance is lessened but not abolished, bone loss will continue. In the case of raloxifene, this may account in part for the failure to demonstrate reduced hip and nonvertebral fractures.

Figure 10. Resorption cavities were identified as eroded surfaces in gray scale images (A) after examination at 2× magnification (B). Cavities were visualized in three-dimensions (C) and traced by a trained observer using gray scales images and the three-dimensional surface (D). Reproduced from Bone, 57:277-83, Copyright (2013), with permission from Elsevier.





Figure 11. Three-dimensional images of cancellous bone fromthe rat lumbar vertebrae for the four groups are shownwith transparency to showregions of the first bone formation label (xylenol orange) and the second formation label (calcein green). Reproduced from Bone, 57:277-83, Copyright (2013), with permission from Elsevier.




Mineralization Kinetics in Murine Trabecular Bone

To measure how tissue mineral density (TMD) increases and how mineralization kinetics is influenced by mechanical stimulation Lukas et al assessed 15-week-old female mice (C57BL/6), where in one group the sixth caudal vertebra was mechanically loaded with 8N (10). Quiescent bone in the control group mineralize with a rate of 8±1 mgHA/cm3 per week, about half that for newly formed bone. Mechanical loading increased the rate of mineral incorporation by 63% in quiescent bone. The week before resorption, demineralization could be observed with a drop of TMD by 36±4 mgHA/cm3 in control and 34±3 mgHA/cm3 in the loaded group.

Figure 12. (A) Distributions of the tissue mineral density (TMD) for bone of the control group as a function of the layer number, i.e., the distance from the surface. The threshold value for the binarization of the µCT images (320 mgHA/cm3) corresponds to the lowest value in the diagram. Error bars show the standard deviation. (B) Mean values and standard error of TMD as a function of the layer number. Reproduced from Bone, 56:55-60, Copyright (2013), with permission from Elsevier.

Figure 13. Time development of the distribution of the tissue mineral density (TMD) of bone formed within the first week (A), quiescent bone, which was present during all the 4 weeks of monitoring (B), and bone before being resorbed in the last week (C). Data shown corresponds to the loaded group and layer 2, the black line shows the reference distribution (Fig. 12A). Reproduced from Bone, 56:55-60, Copyright (2013), with permission from Elsevier.














Gut Hormones and Osteoporosis

Gastrointestinal hormones such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP)-2 regulate bone turnover. Ma et al report that in OVX-induced osteoporosis in 12-month-old female Sprague Dawley rats, exendin-4, a GLP-1 receptor agonist, slowed body weight gain by decreasing fat mass, decreased urinary markers of resorption and increased serum ALP, OC and P1NP levels, prevented bone loss, and enhanced bone strength by preventing the deterioration of trabecular microarchitecture. Exendin-4 increased OPG/RANKL and promoted expression of OC, Col1, Runx2, and ALP (11).

Proton Pump Inhibition and H1 Receptor Blockade

Proton pump inhibitor (PPI) use may be associated with risk of fractures. Increased gastrin levels may cause histamine production through hypertrophy of gastric enterochromaffin like cells, which could lead to bone loss. H1 receptor antagonists (H1RA) use may reduce the effect of PPI on bone. Abrahamsen & Vestergaard studied 124,655 patients with fractures were matched 3:1 with nonfracture controls (12). PPI and H1RA use was associated wit adjusted OR 0.92, (95% CI 0.87-0.98) though not on hip fracture risk (adjusted OR 0.99, 95% CI 0.85-1.16). Fracture risk was higher in PPI users. H1RA users had lower risk of hip fractures than nonusers (adjusted OR 0.86, 95% CI 0.79-0.93). PPI effects on bone could be driven by in part by increased histamine release as the increased fracture risk can be modified by H1RA.

Figure 14. Associations between fracture outcomes and the use of PPI, H1-antagonists or both. *p<0.05. Reproduced from Bone, 57:269-71, Copyright (2013), with permission from Elsevier.





Strontium versus PTH

Bruel et al compared PTH, strontium ranelate (SrR), and PTH+SrR in preventing immobilization-induced bone loss in a rat model (13). Immobilization was induced by injecting 4 IU Botox (BTX) into the muscles of the right hind limb. Seventy-two female Wistar rats, 3-months-old, were divided into Baseline, Controls, BTX, BTX+PTH, BTX+SrR, and BTX+PTH+SrR (n=12 in each group). PTH 60 µg/kg/d, and SrR as 900 mg/kg/d in the diet for 4 weeks. BTX resulted in lower trabecular bone formation rate (-68%) and periosteal bone formation rate (-91%), and a higher fraction of osteoclast-covered surfaces (+53%) compared with controls, reduced lower trabecular bone volume fraction (-24%), trabecular thickness (-16%), and bone strength (-14% to -32% depending on site). PTH counteracted losses in trabecular and periosteal bone formation rate, trabecular thickness (+25% vs. BTX) and femoral neck strength (+24% vs. BTX). SrR did not influence BTX-induced loss of bone formation rate, trabecular bone volume fraction, trabecular thickness, or bone strength. No additive effect was found when PTH and SrR treatments were combined.

Figure 15. Dynamic histomorphometry at the femoral diaphysis: endosteal mineralizing surface (A), endosteal mineral apposition rate (B), endosteal bone formation rate (C), periosteal mineralizing surface (D), periosteal mineral apposition rate (E), and periosteal bone formation rate (F) in rats with BTX induced hind limb immobilization treated with parathyroid hormone (PTH) and/or strontium ranelate (SrR). Mean±SD. *: P<0.05 vs. control, **: P<0.01 vs. control, ***: P<0.001 vs. control, #: P<0.05 vs. BTX. Reproduced from Bone, 53:51-8, Copyright (2013), with permission from Elsevier.




Figure 16. Dynamic histomorphometry at the proximal tibial metaphysis: mineralizing surface (A), mineral apposition rate (B), bone formation rate (C), and osteoclast-covered surface (D) in rats with BTX induced hind limb immobilization treated with parathyroid hormone (PTH) and/or strontium ranelate (SrR). Mean±SD. *: P<0.05 vs. control, **: P<0.01 vs. control, ***: P<0.001 vs. control, #: P<0.05 vs. BTX, ##: P<0.01 vs. BTX, ###: P<0.001 vs. BTX. Reproduced from Bone, 53:51-8, Copyright (2013), with permission from Elsevier.

Oral PTH

Henriksen et al aimed to establish the efficacy and safety of oral tablet of rhPTH(1-31)NH2 and matching placebo tablets and open-label teriparatide positive control in postmenopausal women with osteoporosis during 24 weeks of once daily doses of 5 mg oral treatment or placebo, or open-label subcutaneous teriparatide (14). The oral tablet resulted in pharmacokinetic (PK) profiles with mean Cmax values similar to subcutaneous administration. In the rhPTH(1-31)NH2 arm, a 2.2% increase in lumbar spine BMD (p<0.001), while no change was observed in the placebo. Open-label teriparatide resulted in a 5.1% increase in LS BMD. In the oral PTH study arm, the osteocalcin increased by 32%, 21% and 23% at weeks 4, 12 and 24, respectively. There was no increase in the level of the bone resorption marker CTx-1 in contrast to teriparatide.

Figure 17. Mean PK profiles of the two PTH forms. rhPTH(1–31)NH2 is shown as a time-shifted profilewhere the data are normalized to Tmax. The difference in Tmax between the subcutaneous teriparatide injection and the oral formulation is due to the time of gastric emptying and absorption required for the enteric coated oral tablet formulation. Reproduced from Bone, 53:160-6, Copyright (2013), with permission from Elsevier.

Figure 18. Percent change in BMD from baseline to Week 12 and to the end of treatment period in three study arms (means±SEM). A) Lumbar spine (L1-L4) BMD; B) Hip BMD. The asterisks indicate significant changes between group differences in BMD when comparing active treatments to placebo. Reproduced from Bone, 53:160-6, Copyright (2013), with permission from Elsevier.

Teriparatide and Vertebral Fracture Risk Reduction

Fujita et al conducted a randomized, double-blind trial to assess the effect of 28.2 µg teriparatide vs. placebo (1.4 µg teriparatide) on the incidence of vertebral fractures (15). Individuals enrolled included patients with primary osteoporosis with one to five vertebral fractures. 316 subjects participated during 131 weeks. Incident vertebral fractures occurred in 3.3% of treated subjects and 12.6% of placebo group during 78 weeks. Kaplan-Meier estimates of risk were 7.5 and 22.2% in the teriparatide and placebo groups, respectively, with a relative risk reduction of 66.4% (P=0.008). Lumbar BMD in the 28.2 µg teriparatide group increased by 4.4±4.7% at 78 weeks, which was higher than in the placebo (P=0.001).

PTH Administration and No Evidence of Osteosarcoma

Using Danish nationwide registers, Bang et al identified patients diagnosed with osteoporosis in the period 1995-2010. Each patient treated with rPTH (‘case’) was compared with 10 gender- and age-matched patients with osteoporosis but did not receive rPTH (‘control’) (16). A total of 4104 cases (80.3% females) were identified. The mean age at the beginning of rPTH was 70.9 (SD 9.7) years. During a follow-up time of 10,118 person-years for the cases and 88,005 person-years for the controls, a total of 255 cases (6.2%) compared with 2103 controls (5.1%) experienced a cancer (chi-square, p=0.003); adjusted cancer related HR of 1.1 (95% CI 0.9-1.4). Lung cancer was the only cancer type with increased rate among patients receiving rPTH (HR 1.7; 95% CI 1.3-2.3). No cases developed osteosarcomas and 9 controls developed osteosarcoma. During follow-up, 627 (15.3%) cases died and 4175 (10.2%) controls died, which yielded an excess mortality risk of 26% (95% CI 16-37%). Osteosarcoma has not been diagnosed in any Danish patient receiving rPTH since the year 2003 when it was introduced on the market.

Eldecalcitol versus Alfacalcidol

Eldecalcitol reduces the risk of vertebral fractures in comparison to alfacalcidol. To evaluate the effects of eldecalcitol on the location and severity of vertebral fractures, and the changes in health-related quality of life (HRQOL), Hagino et al compared results with those of alfacalcidol in a post hoc analysis involving 1054 patients randomized to 0.75 µg eldecalcitol or 1.0 µg alfacalcidol daily for 3 years (17). The incidence of fracture at the lower spine was less in the eldecalcitol group than in the alfacalcidol group (p=0.029). The incidence of severe vertebral fracture (Grade 3) was 3.8% in the eldecalcitol group and 6.7% in the alfacalcidol group (p=0.036). Both improved HRQOL.

Ergocalciferol and Cholecalciferol Reduce PTH Similarly

Glendenning et al randomized 95 hip fracture patients (aged 83±8 years) with vitamin D deficiency (25OHD <50 nmol/L) to cholecalciferol 1000 IU/day (n=47) or ergocalciferol 1000 IU/day (n=48) for three months (18). Seventy participants (74%) completed the study. Total serum 1,25(OH)2D did not change. Both treatments were associated with comparable increases in D binding protein (DBP) (cholecalciferol: +18%, ergocalciferol: +16%, p=0.32 between groups), albumin (cholecalciferol: +31%, ergocalciferol: +21%, p=0.29 between groups) and calculated free 25OHD (cholecalciferol: +46%, ergocalciferol: +36%, p=0.08), with comparable decreases in free 1,25(OH)2D (cholecalciferol: -17%, ergocalciferol: -19%). In the treatment-adherent subgroup, the increase in ionized calcium was greater with cholecalciferol than ergocalciferol (cholecalciferol: +8%, ergocalciferol: +5%, p=0.03 between groups). There were no differences between the treatments on bioavailable concentrations or indices of free vitamin D metabolites. These findings may explain why cholecalciferol and ergocalciferol result in similar reductions in PTH.

A blast or whimper from the past

Trials of high-dose fluoride have reported increased bone formation and BMD but impaired mineralization. Whether lower doses may offer some benefit remains a worthwhile question. Grey et al conducted a double-blind, placebo-controlled randomized trial over one year in 180 postmenopausal women with osteopenia given daily placebo, 2.5, 5, or 10 mg fluoride (19). Compared to placebo, none of the doses altered BMD. P1NP increased in the 5 and 10 mg fluoride groups compared to placebo (P=0.04 and 0 .005, respectively). No differences were observed between placebo and any of the fluoride groups in levels of CTX. The authors infer that low-dose fluoride does not induce substantial effects on surrogates of skeletal health and is unlikely to be an effective therapy for osteoporosis.


1. Amin S, Achenbach SJ, Atkinson EJ, Khosla S, Melton LJ, 3rd. Trends in fracture incidence: A population-based study over 20 years. J Bone Miner Res 2013; doi:10.1002/jbmr.2072.

2. Finkelstein JS, Lee H, Burnett-Bowie SM, et al. Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men. N Engl J Med 2013;369:1011.

3. Havill LM, Allen MR, Harris JA, et al. Intracortical Bone Remodeling Variation Shows Strong Genetic Effects. Calcif Tissue Int 2013; doi:10.1007/s00223-013-9775-x.

4. Boutroy S, Walker MD, Liu XS, et al. Lower cortical porosity and higher tissue mineral density in Chinese-American versus white women. J Bone Miner Res 2013; doi:10.1002/jbmr.2057.

5. Schwartz AV, Sigurdsson S,  Hue TF, et al. Vertebral bone marrow fat associated with lower trabecular BMD and prevalent vertebral fracture in older adults. J Clin Endocrinol Metab 2013;98:2294.

6. Lee P, Brychta RJ, Collins MT, et al. Cold-activated brown adipose tissue is an independent predictor of higher bone mineral density in women. Osteoporos Int 2013;24:1513.

7. Wegrzyn J, Roux JP, Farlay D, Follet H, Chapurlat R. The role of bone intrinsic properties measured by infrared spectroscopy in whole lumbar vertebra mechanics: Organic rather than inorganic bone matrix? Bone 2013;56:229.

8. Soe K, Merrild DM, Delaisse JM. Steering the osteoclast through the demineralization-collagenolysis balance. Bone 2013;56:191.

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10. Lukas C, Ruffoni D, Lambers FM, et al. Mineralization kinetics in murine trabecular bone quantified by time-lapsed in vivo micro-computed tomography. Bone 2013;56:55.

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The roles of vitamin D in skeletal muscle: form, function, and metabolism
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Brown adipose tissue in adult humans: a metabolic renaissance
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these reviews and comments By Dr Seeman are great keep them coming

These data from Ma et al. are consistent with our previous findings in T2D and insulin resistant rats. In both models, GLP-1 and exendin-4 infusion for only 3 days ameliorate the altered trabecular structure in the femoral metaphysis (Nuche-Berenguer et al. Calcif. Tissue Int. 84: 453-461, 2009; Regul Pept.159:61-6, 2010). Taken together, these results are provocative regarding the putative use of gut incretins and/or derivatives for promoting bone accrual in osteoporosis.