Overview, Vol 10, Issue 4

An anabolic future

Eddleston et al report that Scl-AbI prevents inflammation-induced bone loss in a model of colitis in animals. Scl-AbI-treated animals had a higher femoral BMD and reversed the decline of both intrinsic and extrinsic mechanical properties of the femur when initiated after colitis associated bone loss had occurred so strength was no different to noncolitic controls. J Bone Miner Res 2009;24:1662-71

OPG is not an option

Ominsky et al report overexpression of OPG reduced osteoclasts and turnover, and increased peak load in vertebrae; but in femurs of OPG-Tg rats, osteopetrotic changes, reduced periosteal perimeter (-6%) and reduced bending strength were observed. J Bone Miner Res 2009;24:1234-46



Blunting or no blunting the response to PTH

Finkelstein et al compared 30 months of alendronate (ALN), teriparatide (TPTD) or both. TPTD was stopped, then administered to all subjects. BMD increased 12.5% and 16.9%, respectively, during the first 12 months of TPTD and 5.2% and 6.2%, respectively, during retreatment. Increases in osteocalcin, P1NP, and N-telopeptide were greater during the first tTPTD administration. The response to TPTD is attenuated when re-administered after a 12-month hiatus. J Clin Endocrinol Metab 2009;94:2495-501

Cosman et al report 126 women taking ALN continued ALN and received daily TPTD, cyclic TPTD (3-mo cycles), or ALN alone for 15 mo. Of the 72 patients who completed either original TPTD regimen, 49 completed a 12-mo follow-up on continued ALN alone. 32 patients recruited into the retreatment protocol and 27 completed another course of TPTD daily for 15 mo. P1NP and osteocalcin increased during both TPTD courses with median 3-mo increments of 120% and 72% above baseline during the original course and 60% and 40% above baseline during retreatment, respectively. Mean spine BMD increments were 6.2% after the first daily course and 4.7% after retreatment and 4.1% after the first course of cyclic TPTD and 4.9% after retreatment. Retreatment stimulates bone formation and increases spine BMD to a similar extent as seen during the original TPTD course. J Bone Miner Res 2009;24:1110-5




 

Watts et al report that decreases of >4% femoral neck (FN) BMD were less common in women receiving TPTD (10%) vs. placebo (16%, p<0.05), yet women on TPTD who lost FN BMD had reductions in vertebral fracture (VF) risk (RR=0.11; 95% CI: 0.03-0.45). VF risk reduction with TPTD was similar across categories of FN BMD change from baseline at 12 mo (loss >4%, loss 0-4%, gain 0-4%, or gain >4%; interaction p=0.40). Irrespective of FN BMD loss or gain, TPTD-treated women had increases in LS BMD and P1NP. J Bone Miner Res 2009;24:1125-31



 

Denosumab and fracture risk reduction

Cummings et al report 7868 women between 60 and 90 years with T-score of <-2.5 at the spine or total hip were randomly assigned to 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. Denosumab reduced new VF; 2.3% in treated vs. 7.2% in placebo (RR, 0.32; 95% CI, 0.26-0.41; P<0.001) – decrease of 68%, reduced the risk of hip fracture; 0.7% vs. 1.2% in placebo (HR, 0.60; 95% CI, 0.37-0.97; P=0.04) – a decrease of 40%; and reduced the risk of nonVF, 6.5% vs. 8.0% in placebo (HR, 0.80; 95% CI, 0.67-0.95; P=0.01) – a decrease of 20%. N Engl J Med 2009;361:756-65

Bone strength and strontium ranelate

Meunier et al report 1649 osteoporotic women randomized to strontium ranelate (SrR) or placebo for 4 years followed by a 1-year treatment-switch period for half of the patients. Over 4 years, risk of VF was reduced by 33%. Among patients with two or more prevalent VFs, risk reduction was 36%. Lumbar BMD increased over 5 years in patients who continued with SrR, and decreased in patients who switched to placebo. Osteoporos Int 2009;20:1663-73

Bain et al report OVX rats treated for 52 weeks with 125, 250, or 625 mg SrR/kg were protected from deterioration in mechanical properties with energy necessary for fracture maintained at 625 mg/kg/day. This was related to a dose-dependent effect on bone volume, higher trabeculae number, and lower trabecular separation in SrR vs. OVX. Bone formation was maintained. Osteoporos Int 2009;20:1417-28



 

Recker et al compared daily TPTD and SrR in postmenopausal women with osteoporosis. Based on a single bone biopsies from 29 patients in the TPTD group and 22 in the SrR group after 6 mo, mineral apposition rate on trabeculae did not differ between treatments but did at the endocortical surface (17.22±3.06% and 9.70±2.07%, respectively, p=0.052). Cortical porosity was higher in the TPTD than SrR group. TPTD increased markers of bone formation and resorption, significant for P1NP after 1 mo (+57%, p<0.001). SrR induced small significant reductions in P1NP at 3 mo (-14%, p=0.005) and 6 mo (-19%, p<0.001) and in βCTX at 1 mo and 3 mo (-11%, for both, p<0.05). J Bone Miner Res 2009;24:1358-68


Minodronate and fracture risk reduction

Matsumoto et al report that in 704 postmenopausal osteoporotic patients randomized to daily oral 1 mg minodronate (n=359) or placebo (n=345) for 24 mo, treatment reduced the risk of VFs by 59% (95% CI, 36.6-73.3%). Osteoporos Int 2009;20:1429-37



 

Zolendronic acid, longevity and marked suppression of remodelling

Eriksen et al report that in 2127 patients (1065 treatment, 1062 placebo; mean age, 75 yr; 76% women and 24% men) within 90 days of surgery and annually, with a median follow-up time of 1.9 yr. post hoc analyses by 2-wk intervals showed a reduction of overall clinical fractures and mortality in patients receiving the first dose 2 wk or later after surgery. J Bone Miner Res 2009;24:1308-13

Allen et al report that in beagle dogs, monthly intravenous zoledronic acid (ZOL, 0.067 mg/kg); or oral ALN for 3 months, reduced remodelling; by 6 months ZOL produced nearly complete suppression (-99%). ZOL also suppressed remodelling in the rib cortex at 3 (-83%) and 6 (-85%) months. Remodelling suppression was greater than in ALN-treated animals; ALN and vehicle were not different. Compared across skeletal sites, the absolute level of remodelling suppression with ZOL treatment was greater at those sites with higher remodelling while the percent reduction was similar among the sites. J Bone Miner Res 2009 [Epub ahead of print]

Houston, we have a problem

Lenart et al report that 41 subtrochanteric and femoral shaft fracture cases were identified and matched to one intertrochanteric and femoral neck fracture each. Bisphosphonate use was observed in 15 of the 41 subtrochanteric/shaft cases, compared to nine of the 82 intertrochanteric/femoral neck controls (OR, 4.44). In 10 of the 15 subtrochanteric/shaft cases on a bisphosphonate, cortical tenting x-ray pattern was associated with bisphosphonate use (OR, 15.33). Osteoporos Int 2009;20:1353-62

Repeating BMD is unnecessary

Bell et al report that 6459 postmenopausal women showed mean effect of 3 years ALN was to increase hip BMD by 0.030 g/cm2. There was small between-person variation compared with within-person variation. ALN increased hip bone density ≥0.019 g/cm2 in 97.5% of patients. Monitoring BMD in postmenopausal women in the first 3 years after starting treatment is unnecessary. BMJ 2009;338:b2266

Stroke and raloxifene

Barrett-Connor et al report a Framingham Stroke Risk Score (FSRS) calculated for subjects in RUTH (10,101 women) and MORE (7705 women). There was no difference in nonfatal strokes between raloxifene and placebo. In RUTH, women with FSRS <13 showed no increase in raloxifene-associated fatal stroke risk. Those with FSRS ≥13 had a 75% increased risk of raloxifene-associated fatal stroke (HR 1.75, 1.01-3.02). In MORE, 80% had a FSRS <13 and no increase in fatal stroke risk. Am J Med 2009;122:754-61

Noncompliance at lower cost but at what price

Blouin et al report women with medical possession ratio (MPR) <80% incurred higher physician care costs and hospital care costs than compliant subjects. In 15,027 women initiating ALN or risedronate predicted physician care cost (Canadian dollars) was $51 among women with MPR<80% and $34 among those with MPR≥80%. Mean predicted hospital care cost was $568 among women with MPR<80% and $379 among those with MPR≥80%. Mean predicted drug cost was $439 among women with MPR<80% and $1068 among those with MPR≥80%. Noncompliant women incurred higher physician care and hospital care costs. Due to lower drug costs, total direct health care costs were lower among noncompliant women. Osteoporos Int 2009;20:1571-81

Growth, IGF-1, structure, fractures in childhood

Yakar et al report adult liver-specific IGF-1-deficient (LID) mice have 75% reductions in serum IGF-1 and reductions in periosteal circumference, femoral cross-sectional area, cortical thickness, and total volumetric BMD. Reduced bone strength associated with low levels of IGF-1 in serum results in impaired subperiosteal expansion with impaired endosteal apposition.
J Bone Miner Res 2009;24:1481-92



 

Kirmani et al studied 6- to 21-yr-old girls (n=66) and boys (n=61). Trabecular parameters (bone volume fraction, trabecular number, and thickness) did not change in girls but increased in boys from late puberty onward. Cortical thickness and density decreased from pre- to midpuberty in girls but were unchanged in boys, before rising to higher levels at the end of puberty. Total bone strength, assessed using microfinite element models, increased across bone age with boys showing greater bone strength than girls after midpuberty. The proportion of load borne by cortical bone, and the ratio of cortical to trabecular bone volume, decreased transiently during mid- to late puberty in both sexes, with apparent cortical porosity peaking.
J Bone Miner Res 2009;24:1033-42


Cheng et al report that in 396 girls with a 7.5-year follow-up, fracture incidence peaked during puberty and 38% were in the upper limb. Girls who sustained upper limb fracture at ages 8-14 years had lower distal radial vBMD at baseline, 1-, 2- and 7-year follow-up with larger bone cross-sectional area in the fracture cohort. Low vBMD during childhood is not a transient deficit. Bone 2009;45:480-6

Rawlinson et al report fast growth in the tibiotarsi of chicks produces bones with reduced stiffness and lower resistance to fracture. Bones from fast-growing embryonic chicks display rapid radial expansion and incomplete osteonal infilling and lack mechanical responsiveness. Bone 2009;45:357-66


 

Structural failure in trabeculae before cortical bone in rat vertebrae

Kummari et al report that rat caudal vertebrae subjected to cyclic compressive loading terminated in the secondary and tertiary phases of the creep-fatigue curve resulted in trabecular microfracture with few microcracks in the cortical shell; damage occurs primarily in regions of cancellous bone before macroscopic cracks in the cortical shell. Calcif Tissue Int 2009;85:127-33

Bone microstructure – cortical bone tissue mineralization and osteons

Bergot et al report cortical bone from 193 femurs (99 female, 94 male) showed the degree of tissue mineralization (Tt.DMB-Al) decreased with age in females not in males. Tt.DMB-Al was higher in females than males until 50 years then lower in elderly females than elderly males. The first DMB-Al quartiles in osteons and interstitial tissue were not different between males and females, but the third quartile differed with greater heterogeneity in females than males. Bone 2009;45:435-42


 

Britz et al report osteons (n=12,690) in the midfemoral mid-diaphyseal specimens (n=88; 45 male, 43 female; 17-97 yrs) were mapped. Weight was negatively related to On.Ar and On.Dm. Age was related to osteon and it was also related to circularity (all p<0.001). This relation was negative for On.Ar and On.Dm and positive for On.Cr (increasing circularity with age). Females had smaller osteons. Age accounted for the largest proportion of the variance in geometry. Bone 2009;45:77-83


Shoot the messenger

Lin et al report unloading decreases Wnt/beta-catenin signaling and upregulation of Sost. Sclerostin inhibited Wnt/beta-catenin in vivo and suppressed the activity of osteoblast and viability of osteoblasts and osteocytes. Sost(-/-) mice were resistant to unloading-induced bone loss and unaccompanied by reduced bone formation or decreased Wnt/beta-catenin signaling. Sclerostin is a target for preventing disuse osteoporosis. J Bone Miner Res 2009;24:1651-61

Two is better than one, but just

Johansson et al report data from 10 prospective population based cohorts used to compute the 10-year probabilities of hip fracture. BMD selected women at higher risk of hip fracture than CRFs (6.1% vs. 5.3%) and identified more hip fracture cases (219/1000) than CRFs alone (140/1000). The combined use identified fewer women above a threshold risk than BMD alone (168/1000 vs. 219/1000, respectively), but with a higher hip fracture risk (PPV, 8.6% vs. 6.1%), and so a lower number needed to treat (33 vs. 47). The PPV and NNT were better for the combination. Osteoporos Int 2009;20:1675-82

The second hip

Ryg et al report that in 169,145 patients with a first hip fracture (HFx) followed a median of 3.8 yr, 27,834 had a second HFx; a cumulative incidence of 9% after 1 yr and 20% after 5 yr. The RR of second HFx was 2.2 (2.0-2.5) at 1 yr and normalized at 15 yr. Mortality at 1 and 5 yr after a second HFx compared with expected (men-1 yr: 27 vs. 9%; 5 yr: 64% vs. 40%; women-1 yr: 21 vs. 10%; 5 yr: 58 vs. 41%). J Bone Miner Res 2009;24:1299-307



 

Discordancy in exercise – twins convince

Ma et al studied long-term leisure time physical activity (LTPA) in twin pairs discordant for activity for at least 30 yr in 16 middle-aged (50-74 yr) same-sex twin pairs (7 MZ and 9 DZ pairs). Active members of MZ twin pairs had larger cortical bone cross-sectional area (intrapair difference: 8%, p=0.006), thicker cortex (12%, p=0.003), and greater moment of inertia (Imax, 20%, p=0.024) at the tibia shaft than their inactive co-twins. At the distal tibia, trabecular BMD (12%, p=0.050) and compressive strength index (18%, p=0.038) were higher in the active MZ pair members than their inactive co-twins. The trends were similar, but less consistently so, in DZ pairs.
J Bone Miner Res 2009;24:1427-33



 

Accelerating bone loss in elderly men

Bone loss accelerates as age advances because the same or a higher intensity of remodelling removes the same or an increasing volume of bone from an ever decreasing volume. Cawthon et al report that among 4720 community-dwelling men followed over 4.6 yr, FN BMD loss was 1.7% and accelerated with age. FN BMD in men 85 yr of age (was 2.5 times greater than for men 65 yr of age increasing the risk of hip fracture by 25%)/ Men with lower BMD at baseline lost the most BMD over follow-up. J Bone Miner Res 2009;24:1728-35

Szulc et al report that in 781 men ≥50 yr of age followed for 10 yr, those who died had lower BMD and higher BTM. In multivariate models, mortality was higher in men with low BMD (lowest quartile) at the total hip, whole body, and ultradistal radius (HR=1.49-1.70, p<0.05). After exclusion of the first 3 yr, higher levels (fourth quartile) of free and total deoxypyridinoline and urinary and serum type I collagen C-telopeptide predicted mortality (HR=1.58-2.44, p<0.05-0.001). J Bone Miner Res 2009;24:1116-24



 

Denosumab in men

Smith et al report a double-blind, multicenter study in men receiving denosumab 60 mg subcutaneously 6 months or placebo (734 patients in each group). At 24 months, denosumab reduced new VFs at 36 months (1.5% vs. 3.9% placebo) (RR, 0.38; 0.19-0.78; P=0.006). Spine BMD increased by 5.6% with denosumab and decreased 1.0% with placebo (P<0.001). Denosumab increased BMD at the total hip, femoral neck, and distal third of the radius.
N Engl J Med 2009;361:745-55


 

Note from the Editor

The purpose of Progress in Osteoporosis is to provide the reader with a summary of the most important literature published in the preceding three to four months in the field of osteoporosis. Most reviews and original research are cited. In addition, summaries and figures are provided for readers who may not have easy access to all the specialist literature. The summaries are based on the contents of abstracts, which have been abbreviated to concisely convey the main theme. The contents of the abstracts and figures should be used only as a means of directing the reader to the original literature and should not be quoted verbatim or cited as a reference. The opinions expressed in the Overview are my own and do not necessarily reflect those of the International Osteoporosis Foundation.