Overview, Vol 11, Issue 1

Bisphosphonates, a few small steps forward

It is commonly believed that bisphosphonates reduce the intensity of remodelling, but evidence for an effect on the volume of bone resorbed is lacking. For the first time, Allen et al assessed vertebral trabecular bone of beagle dogs treated with alendronate or risedronate had similarly reduced resorption area and width in the BMU with no difference in resorption depth. Calcif Tissue Int 2010;86:67-71

Periosteal apposition is vigorous during growth but virtually ceases after fusion of the epiphyses. It is held that periosteal apposition may be a compensatory response to endocortical resorption even though no evidence supports this view. If this is the case, then inhibition of endocortical resorption by bisphosphonate therapy may reduce periosteal apposition. This is not so. Feher et al report no effect of any of the bisphosphonates on periosteal bone formation. Bone 2010;46:203-07

One of the early steps in the remodelling cycle is signalling from osteocytes to flattened lining cells before creation of a remodelling compartment. Emerton et al report mice which underwent ovariectomy increased osteocyte apoptosis followed by increases in resorption at 14 and 21 days. Treatment suppressing osteocyte apoptosis also prevented resorption (Bone 2010;46:577-83). Bisphosphonates may inhibit remodelling by influencing these early steps.

Roelofs et al report that fluorescent risedronate analogs were present in osteocytic lacunae in close proximity to vascular channels, localized to the lacunae of newly embedded osteocytes and was detected in osteoclasts. The active analog FAM-RIS caused accumulation of unprenylated Rap1A in these cells. In addition, CD14 marrow monocytes showed relatively high levels of uptake of fluorescently-labelled risedronate. J Bone Miner Res 2010;25:606-16

One of the major causes of bone loss is intracortical remodelling producing cortical porosity. Borah et al report risedronate reduced pore area in the 25-100, 100-300, and 300-500 μm ranges during 5 years (p=0.0008, 0.04, NS, respectively), corresponding to an 18-25% reduction. In the placebo group, pore area was unchanged. At 5 years, pore area and pore number per mm2 in the 25-100 μm range were each 17% lower in the risedronate group than in the placebo group. J Bone Miner Res 2010;25:41-7

The reduction in remodelling produced by bisphosphonates allows more time for secondary mineralization of bone that would otherwise have been removed. This reduces the heterogeneity in tissue mineralization density. Gourion-Arsiquaud et al report one-year alendronate or risedronate given to beagles increased the mineral content and the collagen maturity mainly in cancellous bone and at the endocortical surface which may alter ductility. Bone 2010;46:666-72

By contrast, Roschger et al report that compared to 5 years alendronate plus 5 years placebo, 10 years alendronate did not cause any difference in tissue mineralization density. The weighted mean (CaMean), the calcium concentration (CaPeak), the heterogeneity of mineralization (CaWidth), the percentage of low mineralized bone areas (CaLow) and the portion of highly mineralized areas (CaHigh) were not different for the patients who continued alendronate from those who stopped alendronate after 5 years (J Bone Miner Res 2010;25:48-55). This observation is difficult to explain.

Nonvertebral fractures (NVF) were not reduced by alendronate in either FIT-1 or FIT-2. Schwartz et al report 10 years alendronate did not reduce NVF. Continuing alendronate reduced the risk of clinical vertebral fractures. A post hoc analysis using FLEX data, showed that women without vertebral fracture at FLEX baseline (N=720), continuation of alendronate reduced NVF in women with FLEX baseline (femoral neck T-score≤-2.5) (J Bone Miner Res 2010;25:976-82). Post hoc analyses are not hypothesis testing, they are hypothesis generating.

Colón-Emeric et al report zoledronic acid reduced the risk of death by 25%. Subsequent fractures were associated with death (HR 1.72), but explained only 8% of variance. Adjusting for acute events occurring during follow-up eliminated the death benefit, and zoledronic acid treated subjects were less likely to die from pneumonia and arrhythmias. J Bone Miner Res 2010;25:91-97

Vestergaard et al report 103,562 users of bisphosphonate, etidronate (HR=1.08) and alendronate (HR=1.09) were associated with an excess risk of atrial fibrillation if adjustments were made for cardiovascular disease. However, this association disappeared on adjustment for COPD. In patients using etidronate (12.5 vs. 3.8%) and alendronate (11.4 vs. 4.6%) major differences were present in prevalence of COPD compared to matched controls. Calcif Tissue Int 2010;86:335-42

Denosumab, a powerful remodelling suppressant

Kendler et al report postmenopausal women receiving alendronate transitioning to denosumab had total hip BMD increased by 1.90% at month 12 compared with a 1.05% increase in subjects continuing on alendronate. Greater BMD gains were also achieved at 12 months at the lumbar spine, femoral neck, and 1/3 radius in the denosumab group. Median serum CTX remained near baseline in the alendronate group and decreased versus alendronate. J Bone Miner Res 2010;25:72-81

Body et al report patients treated with denosumab experienced a rapid and sustained reduction in bone turnover. In patients previously treated with bisphosphonates, the rate of first on-study skeletal events was lower with denosumab (8%) than bisphosphonate (17%). J Bone Miner Res 2010;25:440-46

Teriparatide, some further insights

Chevalier et al report that the response to 12 months teriparatide following risedronate is better than following alendronate. The increase in stiffness was 24.6±3.2 vs. 14.4±2.8%, respectively). Vertebral failure load increased by 27.2±3.5% vs. 15.3±3.1%, respectively. Bone 2010;46:41-48

Kramer et al report that intermittent PTH suppresses expression of Sost. Overexpression of Sost resulted in osteopenia and Sost deletion in high bone mass. PTH increases in BMD and cortical thickness and cancellous bone gain, which is blunted in Sost overexpression and deficient mice owing to attenuated bone formation rates. Suppression of the Sost by intermittent PTH contributes to bone anabolism. J Bone Miner Res 2010;25:178-89

Strontium ranelate, consistent long term observations

Li et al report only bone packets or osteons formed during strontium ranelate treatment contain Sr and that up to 0.5 out of 10 calcium atoms in the mineral crystals are replaced by Sr. The thickness and length of the plate-shaped bone mineral crystals were not affected by the strontium ranelate (J Bone Miner Res 2010;25:968-75). Similarly, Roshger et al report 3 years strontium ranelate shifts the BMDD to higher atomic numbers as Sr is preferentially incorporated in new bone packets. The effect of strontium ranelate on BMDD seems to be mainly due to the uptake of Sr and not by changes in bone calcium content (J Bone Miner Res 2009;25:891-900).

Likewise, Boivin et al report biopsies over 5-year strontium ranelate, Sr was present in bone formed during treatment. A plateau in global bone Sr content was reached after 3 years. Cartography illustrated the extent of surfaces containing Sr, and formation activity during strontium ranelate was higher in cancellous than in cortical bone. Osteoporos Int 2010;21:667-77

Seeman et al report that in 1489 female patients over 80 years of age strontium ranelate reduced vertebral fracture risk was reduced by 31% (RR=0.69; 0.52-0.92), nonvertebral fracture risk by 27%, major nonvertebral fracture risk by 33% and hip fracture risk by 24% (NS). Treatment was cost-saving. Bone 2010;46:1038-42

Reginster et al report that 8 years treatment with strontium ranelate increased BMD. Strontium ranelate was safe and well tolerated over 8 years. Claims of antifractue efficacy cannot be sustained as there was no control group. Bone 2009;45:1059-64

Sun et al report male rats treated with methylprednisolone had better protection against architectural decay with strontium ranelate than alendronate. Alendronate decreased endosteal ES/BS. Strontium ranelate increased %Ct.Ar and bone formation indices in the periosteum as well as the endosteum, and decreased endosteal ES/BS. Strontium ranelate led to a higher cancellous and endocortical MS/BS and endocortical bone formation than alendronate. Calcif Tissue Int 2010;86:495-501

Other doors

Ominsky et al report a humanized sclerostin-neutralizing monoclonal antibody given to gonad-intact female cynomolgus monkeys increased bone formation on trabecular, periosteal, endocortical and intracortical surfaces and bone strength. J Bone Miner Res 2010;25:948-59

Yao et al report that secreted Frizzled-related protein 1 (sFRP1) is an antagonist of Wnt signalling. Overexpression in mice was associated with reduced trabecular bone mass. hPTH (1-34) increased trabecular bone volume less in mutants than controls. Percent increases in bone formation were also lower in PTH treated sFRP1-Tg mice compared to WT mice. J Bone Miner Res 2010;25:190-9

Fajardo et al report that treatment of mice with a soluble form of the activin type IIA receptor increases bone mass and strength. Ten female cynomolgus monkeys were treated with a soluble form of the ActRIIA receptor fused with the Fc portion of human IgG1 (ACE-011) had higher vertebral and distal femur BMD and trabecular volumetric bone density. Bone 2010;46:64-71

Idris et al report that the TRPV1 ion channel antagonist capsazepine inhibited osteoclast formation in marrow-osteoblast cocultures and RANKL generated osteoclast cultures. It also suppressed RANKL induced IĸB and ERK1/2 phosphorylation, apoptosis of mature osteoclasts, and also inhibited alkaline phosphatase activity and bone nodule formation in calvarial osteoblast cultures. Capsazepine (1mg/kg/day) inhibited ovariectomy induced bone loss in mice and inhibited bone resorption and formation. Bone 2010;46:1089-99

Vitamin D and confusion

Bolland et al report 1471 women followed in a 5-year trial of calcium supplementation with vitamin D <50 nmol/L were, compared to those with higher values, older, heavier and less physically active with increased incidence of stroke and cardiovascular events that did not persist after adjustment for between-group differences in age or comorbidities. They were not at increased risk of fracture, falls, low bone density, grip strength, death, myocardial infarction, cancer, heart failure, diabetes, adverse changes in blood pressure, weight, body composition, cholesterol, or glucose. Am J Clin Nutr 2010;91:82-9

Kärkkäinen et al followed 1566 women receiving daily cholecalciferol 800IU+calcium carbonate 1000mg. The supplementation was not associated with single or multiple falls reduction. In a post hoc subgroup analysis, multiple fall incidence decreased by 30%. Maturitas 2010;65:359-65

Figure out these two meta-analyses. Pittas et al reviewed 13 observational studies and 18 trials of vitamin D therapy. Three of 6 analyses reported a lower incident diabetes risk in the highest vitamin D status, 8 trials detected no association. In a meta-analysis of 3 cohorts, lower 25-hydroxyvitamin D was associated with hypertension. In meta-analyses of 10 trials, supplementation was not associated with reduced blood pressure. Lower 25-hydroxyvitamin D was associated with incident cardiovascular disease in 5 of 7 analyses (6 cohorts). Four trials found no effect of supplementation on cardiovascular outcomes. Ann Intern Med 2010;152:307-14

Wang et al examined 17 prospective studies and randomized trials; 5 prospective studies of patients receiving dialysis and one study involving a general population showed reductions in CVD mortality among adults who received vitamin D. Four prospective studies found no differences in incidence of CVD between calcium supplement recipients and nonrecipients, 8 randomized trials showed a nonsignificant reduction in CVD risk with vitamin D but not with calcium or a combination of vitamin D and calcium. Ann Intern Med 2010;152:315-23

Mahon et al report lower maternal 25-hydroxyvitamin vitamin D was associated with greater femoral metaphyseal cross-sectional area and a higher femoral splaying at 19 weeks gestation. The femoral splaying indices at 19 weeks gestation increased with greater deficiency. J Bone Miner Res 2010;25:14-9

The Achilles’ heel of the proximal femur and other tragedies

Thomas et al report trabecular buttressing may protect the femoral neck cortex against buckling not crushing. Trabecular BMD declined fastest in the supero-lateral half of the trabecular compartment in the posterior part of this region by 42% reduction in women (34% in men) over 5 decades. Trabecular bone was calculated to contribute 40% (in men) and 43% (in women) to the S-P cortex of its overall elastic stability. J Bone Miner Res 2009;24:1808-18

Poole et al report that the decline in cortical thickness with age varies according to the region of the femoral neck examined. Its Achilles’ heel appears to be the superior segment. There is relative preservation of the infero-anterior quadrant. At 25 years the predicted C.Th of the supero-posterior quadrant was 1.63 mm whereas at 85 it was 0.33 mm. The corresponding figures infero-aneriorly are 3.9 mm and 3.3 mm. J Bone Miner Res 2010;25:482-91

Chen et al report the structural decay of the femoral neck with age is characterized by cortical thinning, a doubling of cortical porosity and increase of 65-77% in the medullary canal for both women and men. Trabecular bone volume decreased by around 20%; trabecular thickness, trabecular number, and connectivity density decreased; and trabecular separation and structure model index increased. Osteoporos Int 2010;21:627-36

Abrahamsen and Vestergaard report hip fracture incidence rates declined by 20% in men and 22% in women but this was not explained by anti-osteoporotic medication. Osteoporos Int 2010;21:373-80

Nieves et al report the overall hospital discharge rates of hip fracture decreased. Subtrochanteric, femoral shaft, and lower femur rates remained stable. The overall incidence of hip fracture was <300/100,000 person-years; incidence of subtrochanteric and femoral shaft fractures combined was <25/100,000 person-years and distal femur fracture incidence was <18/100,000 person-years in females; rates were lower in males. Osteoporos Int 2010;21:399-408

Bone material composition and porosity

Bala et al report that in 18 ewes the degree of mineralization of bone and Vickers microhardness were measured during the first 6 months, degree of mineralization and microhardness increased. They then increased more slowly until at 30 months they reach their maximal values. Secondary mineralization in BSUs is completed after a period of 30 months. Bone 2010;46:1204-12

Nishiyama et al report cortical porosity is higher in postmenopausal than premenopausal women (3.2 to 12.9%) but not cortical thickness. Both osteopenic and osteoporotic women had thinner (-12.8 to -30.3%), more porous (2.1 to 8.1%) cortices than normal postmenopausal women. J Bone Miner Res 2009;25:882-90

Burghardt et al report cortical porosity, as measured by HR-pQCT, increased with age. Ct.Th, Ct.Ar, Ct.vBMD were more weakly, or not correlated to age. MicroFE analysis revealed that the biomechanical deficit associated with cortical porosity was higher for post- compared to pre-menopausal women. Age related differences in cortical porosity were more pronounced than differences in standard cortical metrics. J Bone Miner Res 2010;25:983-93

FRAX®

Tremollieres et al report that in 2651 peri- and early post-menopausal women followed 13.4 years, three risk factor predicted major osteoporotic fracture independently of BMD and age: a history of fracture, 3 or more pregnancies and current postmenopausal hormone therapy. FRAX® value was 3.8% (±2.4). The discriminative value for fracture, as measured by the area under the ROC curve was equal to 0.63 and 0.66, respectively, for FRAX® and hip BMD. Sensitivity of both tools was low (i.e., around 50% for 30% of the women classified as the highest risk). J Bone Miner Res 2010;25:1002-9

Donaldson et al report data from the placebo groups of FIT suggests that prevalent vertebral fracture plus age and FN BMD (AUC=0.76) predicted vertebral fracture as well as a combination of prevalent vertebral fracture and FRAX® with FN BMD (AUC=0.75). However, baseline vertebral fracture status plus age and FN BMD (AUC=0.76) predicted incident radiographic vertebral fracture better than FRAX® with FN BMD (AUC=0.71). J Bone Miner Res 2009;24:1793-9

Men

Szulc et al report that 43 strokes and 40 myocardial infarctions occurred in 79 of 744 men during the 7.5-year follow-up. Men in the lowest quartile of BMD had a 2-fold increased risk of cardiovascular events. Men in the highest quartile of bone resorption markers had a 2-fold increased risk of cardiovascular events three quartiles. J Bone Miner Res 2009;24:2023-31

Hannon et al report, Src inhibitor saracatinib (AZD0530) decreased bone resorption markers. At a dose of 250 mg sCTX decreased by 88% (95% CI, 84-91%) and uNTX/Cr decreased by 67% (95% CI, 53-77%) from baseline 24 hours after the final dose. There was no significant effect on bone formation markers. J Bone Miner Res 2010;25:463-71

Financial Burden

Shi et al report that mean first-year costs associated with hip, vertebral, and nonhip nonvertebral (NHNV) fractures were $26,545, $14,977, and $9183 for the 50-64 age cohort, and $15,196, $6701, and $6106 for patients ≥65 years. After taking prevalence rate into account, the proportion of the total fracture costs accounted for by NHNV, hip, and vertebral fractures were 66%, 21% and 13% for the 50-64 age cohort, and 36%, 52% and 12% for the ≥65 age cohort. NHNV fractures have a lower per-patient cost but their total first-year cost is greater for those 50-64 because of their higher prevalence. Bone 2009;45:1084-90

 

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.