Overview, Vol 11, Issue 4

Burden of fractures – Worse, not better, nonvertebral not vertebral

The notion that the burden of fractures is diminishing is flawed. The notion that fractures are vertebral or hip is flawed. Between 1986-2007, Morin et al report 21,067 incident fractures in men were associated with 10,724 (50.1%) deaths while 49,197 incident fractures in women were associated with 22,018 deaths (44.8%). 76% of the fractures were at sites other than the hip and vertebrae. The risk of death in cases was increased in both sexes for hip, vertebral, humerus, wrist (in men only), and other fracture sites. Postfracture mortality was higher in men than women. Osteoporos Int 2011;22:2439-48

Between 1994-2008, Emaus et al report the annual incidence of hip fractures (per 10,000) increased from 5.8 in women and 8.7 in men (age 50-54) to 349.2 in men and 582.2 in women. The age-adjusted incidence rates were 101.0 (women) and 37.4 (men), compared to 118.0 (women) and 44.0 (men) in Oslo. Mortality after fracture was higher in men than in women. Osteoporos Int 2011;22:2603-10

Between years 2000-2007 in Switzerland, Lippuner et al report that major osteoporotic fractures (MOF, hip, clinical spine, distal radius, and proximal humerus) in women and men aged ≥45 increased by 15.9% (women) and 20.0% (men) due to an increased nonhip fractures (+37.7% in women and +39.7% in men). Hospitalizations for hip fractures were stable (-1.8% in women, +3.3% in men). In a rapidly aging population, in which the number of individuals aged ≥45 years grew by 11.1% (women) and 14.6% (men) over the study period, the crude and age-standardized incidences of hospitalizations decreased for hip fractures and increased for nonhip MOF in women and men. The length of hospital stay decreased for all MOF in women and men, the cost impact of which was offset by an increase in the daily costs of hospitalization. Osteoporos Int 2011;22:2487-97

Leslie et al assessed costs associated with 33,887 fracture cases (22,953 women, 10,934 men) over 10 years and 101,661 controls (68,859 women and 32,802 men). At the population level, hip fractures were responsible for the largest proportion of the costs after age 80, but the other fractures were more important prior to age 80. The greatest total incremental costs were associated with hip fractures (median $16,171 in women and $13,111 for men), spine fractures ($8345 in women and $6267 in men). The lowest costs were associated with wrist fractures ($663 in women and $764 in men). The largest temporal increase in women was for hip fracture ($13/year, 95% CI $6-$21, p<0.001) and in men was for humerus fracture ($11/year, 95% CI $3-$19, p=0.007). J Bone Miner Res 2011;26:2419-29

Architecture – Porosity will get its 15 minutes of fame eventually

Bones become fragile when their structure is destroyed. Most ‘fragility’ fractures occur before the age of 50 years and before the age of 16 years. Why? The reason is that during these two vulnerable periods, either the structure needed to tolerate loads has not been fully assembled or that the assembled structure is decaying. The skeleton is 80% cortical, only 20% is trabecular. About 70% of all bone lost during ageing is cortical and of that, about 50% is lost by intracortical remodelling in the inner third of the cortex which constitutes a much smaller volume than the outer two thirds. So, if this is correct, what is the single morphological ‘footprint’ of structure decay – is it trabecular thinning or loss of connectedness of trabeculae, is it cortical thinning, porosity or is it a change in the material composition of the bone? For decades the prevailing view is that trabecular bone loss is the important measure of fragility, especially for the so-called Type 1 osteoporosis.

This notion did not arise in a vacuum. While we can be critical of history’s doors, we need to be cognisant of its whispering corridors that led to them. The trabecular door opened when vertebral fractures had their 15 minutes of fame bestowed by Albright who noted the problem in postmenopausal women. Forearm densitometry wasn’t a big hit because it did not distinguish patients with and without spine fractures, but dual photon absorptiometry topped the charts in the second half of the 20th century and has stayed there despite it ensuring no intelligent thought can come of it. Spine densitometry seemed to discriminate fracture and nonfracture cases better than single photon absorptiometry and despite about half of all fractures arising from above the nominal threshold of -2.5 SD, the invisible line in the shifting sand, its still right up there and while trabecular bone loss is more rapidly turned over than cortical bone, Parfitt made the point that the slow loss of a larger volume of bone is equally if not more important than the rapid loss of a small volume of bone.

More recently, a young investigator, Roger Zebaze explored the occurrence of porosity in cortical bone and found large pores distant from the endocortical surface. He reasoned that these pores could not arise from the endocortical surface by endocortical resorption dissolving the cortex ‘outwards’ producing cortical thinning from the marrow outwards. He recognised that the mechanism was intracortical remodelling thinning the cortex from its inside, especially the intracortical remodelling upon Haversian canals traversing in the inner part of the cortex. This is not the end of the story; it’s just a new beginning, like T.S. Eliot returning to the same place and knowing it for the first time.

The footprint of bone loss is porosity. While still to get its 15 minutes of fame, this aspect of bone is receiving more attention. Granke et al report that in 21 cortical specimens from the mid-diaphysis of 10 women (aged 66-98 years), scanning acoustic microscope (SAM) was used to evaluate the matrix elasticity and porosity. Porosity was validated against synchrotron radiation μCT measurements. Matrix impedance in the direction of the bone axis correlated to mesoscale elasticity which correlated to the cortical porosity (R2=0.72-0.84). The elastic properties of the mineralized matrix have a low variance (matrix impedance <6%) whereas change in the intracortical porosity accounts for most of the variations of mesoscopic elasticity. Bone 2011;49:1020-6

Bjornerem et al report that postmenopausal women have greater deficits in cortical than trabecular bone mass at the distal tibia and similar deficits at the distal radius, a notion challenging the concept of predominant trabecular bone loss after menopause; the slow loss of a large volume of cortical bone (80% of the skeleton) contributes more or equally to the rapid loss of a smaller initial volume of trabecular bone. A 1 SD higher tibia intracortical bone surface area was associated with 0.22-0.29 SD higher remodelling markers. A 1 SD higher porosity was associated with 0.20-0.30 SD higher remodelling markers. A 1 SD lower trabecular bone surface area was associated with 0.15-0.18 SD higher remodelling markers. Intracortical remodelling is self perpetuating by creating intracortical porosity and so more bone surface for remodelling to occur upon. Remodelling upon the trabecular surfaces is self limiting because it removes trabeculae with their surface. Bone 2011;49:1125-30

Strontium ranelate as an anabolic agent

Strontium ranelate (SR) has been convincingly shown to reduce the risk of vertebral and nonvertebral fractures in postmenopausal women and women over 80 years of age. This treatment also reduces hip fractures but the evidence is based on a post hoc analysis. The reduction in hip fracture risk was observed to be statistically significant in women over 75 years of age with osteoporosis. These data are credible. However, the question is what is the mechanism responsible for the lower fracture rate in patients compared with controls. The prevailing view is that this is a “dual acting drug”. Precisely what this means is difficult to know. Does it stimulate bone formation? In other words does it increase the volume of new bone deposited by each BMU at the cellular level? Does it have a modelling effect but depositing new bone on the periosteal, endocortical or trabecular surfaces? Is it antiresorptive – that is, does it reduce the volume of bone resorbed by the osteoclasts of each BMU remodelling bone upon its inner surfaces? Does it reduce the intensity or the numbers of BMUs remodelling bone upon these surfaces? Answers to these questions are not available. Whether the mechanism of action of this drug is mediated through the cellular machinery of bone modelling or remodelling is not known and remains an important challenge for investigators to address.

Quesada-Gomez et al report that after oral 2 g SR (n=40) or daily 100 μg PTH(1-84) (n=41) for 24 weeks, increases in P1NP and BSAP occurred with PTH(1-84) from week 4 onwards; not SR. This does not exclude an effect of this drug on bone formation of course, but it does not support one either. Osteoporos Int 2011;22:2529-37

PTH and its effects on promoting or inhibition bone formation

Horwitz et al report that continuous exposure of the human skeleton to PTH or PTHrP in vivo produces bone resorption and causes arrest in the osteoblast maturation. A 7-day continuous-infusion using hPTH(1-34) suppressed endogenous PTH(1-84) and increased resorption rapidly while suppressing bone formation by 30% to 40%. J Bone Miner Res 2011;26:2287-97

Prisby et al report PTH(1-84) given daily to rats increased trabecular bone mass but vessel number was reduced. PTH redistributed the smaller vessels closer to bone formation sites. VEGF mRNA expression in bone increased and returned to baseline by 24 h. Anti-VEGF antibody blunted the PTH-induced increase in bone mass and remodelling parameters and prevented the relocation of vessels closer to bone forming sites. J Bone Miner Res 2011;26:2583-96

Treatment depends on location, not your risk or doctor – If you want it, move

Diez-Perez et al report that among 58,009 women, antiosteoporosis medication use was lowest in Northern Europe (16%) and highest in USA and Australia (32%). Between 48% (USA, Southern Europe) and 68% (Northern Europe) of women aged ≥65 years with previous spine or hip fractures were nevertheless untreated. Among women with osteoporosis, the percentage treated was lowest in Europe (45-52% vs. 62-65% elsewhere). Women with osteopenia were treated most frequently in USA (31%) and Canada (31%), least in Southern Europe (12%), Northern Europe (13%), and Australia (16%). USA women were 3-fold more likely to be treated as Northern European women and 1.5 times more likely to be treated as Southern European women. Bone 2011;49:493-8

Vitamin D metabolites as therapy

Matsumoto et al report a 3-year randomized, double-blind, active comparator, superiority trial of in patients 46-92 years assigned to eldecalcitol 0.75 μg/d (n=528) or alfacalcidol 1.0 μg (n=526). The incidence of vertebral fractures was lower in eldecalcitol group (13.4 vs. 17.5%; HR 0.74; 90% CI 0.56-0.97). Eldecalcitol reduced turnover markers and increased BMD more than alfacalcidol. Eldecalcitol reduced the incidence of three major non-vertebral fractures, due to a reduction in wrist fractures by a post hoc analysis (1.1 vs. 3.6%; HR 0.29; 95% CI 0.11-0.77). Bone 2011;49:605-12

Cathepsin K inhibitors

Leung et al report that odanacatib (ODN), a selective, potent and reversible inhibitor of cathepsin K (CatK), inhibits bone loss. CatK inhibition had no effect on osteoclastogenesis or survival of OCs but reduces resorption activity as measured by CTx release (IC(50)=9.4 nM) or resorption area (IC(50)=6.5 nM). Untreated cells generate deep trail-like resorption lacunae, treated OCs form discrete shallow pits. ODN leads to accumulation of intracellular vesicles stained for CatK and TRAP. CatK (+) vesicles localize toward the basolateral and functional secretory membranes of the polarized OC and TRAP(+) vesicles are evenly distribute in the cytoplasm, suggesting that ODN disrupts vesicular trafficking. Intracellular levels of precursor and mature TRAP increased by 2-fold and the pre-pro and mature CatK by 6- and 2-fold in ODN-treated OCs compared to untreated controls. ODN treated OC accumulates labelled degraded bone matrix proteins in CatK containing vesicles. Bone 2011;49:623-35

Jerome et al report balicatib at 0, 3, 10, and 50 mg/kg for 18 months (groups O, L, M, H, respectively) increased spine and femur BMD. Most histomorphometric indices of bone turnover in vertebra and femoral neck were lower than controls but periosteal bone formation rates were higher. The potential for periosteal apposition is interesting as this is a biomechanically advantageous place to deposit bone. The problem is these changes need to be validated and it should not be assumed that this class of drug has an anabolic effect until further rigorous studies are reported. Osteoporos Int 2011;22:3001-11

Ochi et al report in vitro experiments indicated that ONO-5334 is a potent inhibitor of CatK. This compound inhibited cathepsin S, L and B 8 to 320 fold lower than that CatK. ONO-5334 also inhibited human osteoclasts resorption in vitro at a concentration more than 100-fold lower than that of alendronate. While alendronate disrupted actin ring and induced pyknotic nuclei in osteoclasts, ONO-5334 did not have such effects, suggesting that this compound does not affect osteoclasts viability. ONO-5334 dose-dependently reduced plasma calcium increased by parathyroid hormone related peptide in rats. In normal monkeys ONO-5334 decreases serum and urine C-telopeptide of type I collagen. ONO-5334 did not affect bone formation markers, serum osteocalcin and bone specific alkaline phosphatase. Bone 2011;49:1351-6

Growth

Bhola et al reported that hand radiographs of 29 boys and 30 girls 8-18 years of age showed differing robusticity by sex. For boys, slender metacarpals used an osteoblast-dependent growth pattern to establish function, whereas robust metacarpals used an osteoclast-dependent growth pattern. Differences in biological activity between girls with slender and robust metacarpals were largely based on the age at which the marrow surface changed from expansion to infilling. Cortical area for slender metacarpals was 19.7% and 32.2% lower than robust metacarpals for boys and girls, respectively, indicating that robustness was a major determinant of adult cortical area which was established by 8 years of age. Bone 2011;49:799-809

Treatment and mineralization of matrix

Fuchs et al report that the rate at which newly formed trabecular BMUs become fully mineralized is similar in rabbits treated for up to 414 days with clinical doses of either risedronate or alendronate. All groups exhibited a rapid increase in mineralization over the first 18 days, the period of primary mineralization, with no differences between treatments. Mineralization continued to increase, at a slower rate up, to 385 days (secondary mineralization), and was not different among treatments. If there are differences in the extent of completeness of mineralization then it is likely to be the result of factors other than the rate of mineralization. The context of this is whether the greater binding of alendronate to mineral may result in more complete and homogeneous mineralization that in turn may then result in greater material stiffness than with risedronate. This is not known. Bone 2011;49:701-5

Stopping alendronate, can you ever?

Peris et al report that in 43 women previously treated with alendronate (36) or risedronate (7) during a mean of 51 and 53 months, respectively, with a median time of discontinuation of 13.5 and 14 months, respectively, alendronate was detected in 41% of women, whereas no patient previously treated with risedronate showed detectable urinary values. 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). This is in line with the notion that this drug is more irreversibly bound to bone and so is eventually released, perhaps reabsorbed and released producing chronic suppression of bone remodelling with possible deleterious effects. Bone 2011;49:706-9

Stopping denosumab

Brown et al report that 15 subjects enrolled in a cohort study to evaluate the effects of denosumab discontinuation after ~25 months showed normal histology and bone remodelling; similar to those observed in untreated postmenopausal women with osteoporosis. With treatment cessation, 100% of biopsy specimens had evidence of tetracycline labels. Biochemical markers were comparable to and highly correlated with pretreatment levels. J Bone Miner Res 2011;26:2737-44

Eastell et al report that postmenopausal women with osteoporosis who completed the 3-year Vertebral Efficacy with Risedronate Therapy MultiNational trial, plus a 2-year extension,one year after discontinuation, NTX/Cr levels increased toward baseline, total hip and femoral trochanter BMD values decreased, whereas lumbar spine and femoral neck BMD were maintained or slightly increased. J Clin Endocrinol Metab 2011;96:3367-73

Reversibility of treatment may be seen as good or bad. It is of course possible or likely that irreversibility is not a good thing from the point of view of the material composition of bone. The prolonged suppression of the very mechanism, remodelling, that functions to remove damage and replace old bone with new bone, may contribute to both the accumulation of microdamage and the occurrence of more damage as the bone becomes more brittle due to homogeneity and complete secondary mineralization as well as increased collagen crosslinking which further reduces elasticity of bone. The alternative is also not good. If treatment is reversible, as seen in this study and others with stopping denosumab, then remodelling re-emerges, may overshoot, at least as measured using remodelling markers, and result in bone loss and probably an increase in bone fragility as structural decay recurs. The answer to this dilemma is to measure the baseline material and composition of bone, measure the changes during therapy and modulate therapy in individuals accordingly. Can it be done? Yes. Must it be done? Yes.

Treatment prevents death or life permits treatment

Sambrook et al report that 2005 institutionalized older people assessed at baseline and followed up for hip fracture and death for at least 5 years. At baseline, 78 subjects were taking oral bisphosphonates. Over 5 years of follow-up, 1596 participants (80%) died. Use of bisphosphonates was associated with a 27% lower risk of death compared to nonusers (HR 0.73; 95% CI 0.56-0.94; P=0.02) Osteoporos Int 2011;22:2551-6. The question is whether the lower mortality was caused by the treatment or whether persons with lower mortality were well enough to comply with therapy. There is no known mechanism that may account for the former, sampling bias; healthy user bias is a very reasonable explanation for these observations.

Estrogen and antiestrogen

Komm et al report that combined BZA/CE given during 12 months in ovariectomized (OVX) female Sprague Dawley rats prevented ovariectomy-induced increases in bone turnover and increased BMD and bone strength, a dose-dependent reduction in uterine wet weight and lowered total cholesterol. Bone 2011;49:376-86

Sclerostin antibody

This is one of the new kids on the block and this kid is a very potent anabolic agent and may actually be ‘dual acting’. Marenzana et al report that young dexamethosine treated mice treated with Scl-AbI antibody had increased trabecular bone at the femoral metaphysis (BV/TV +117% vs. Ctrl) and the width and volume of the cortical bone at the femoral diaphysis (+24% and +20%, respectively, vs. Ctrl). Scl-AbI also improved strength at the femoral diaphysis (maximum load +60% and ultimate strength +47% vs. Ctrl). Elevated osteocalcin levels were not detected in DEX-treated mice that received Scl-AbI, although levels of type 5b tartrate-resistant acid phosphatase were lower than those observed in mice receiving DEX and Ctrl-Ab. The suppression of bone remodelling may reflect the inhibition of RANKL reported when sclerostin inhibition. Arthritis Rheum 2011;63:2385-95

Vitamin D and everything: Is there strength in numbers really

Murad et al report that in 26 trials that enrolled 45,782 participants, mostly which elderly females. Vitamin D use was associated with a reduction in the risk of falls (0.86, 0.77-0.96). This effect was seen mainly in vitamin D deficient subjects and in studies in which calcium was co-administered. The quality of evidence was not high level because of heterogeneity and publication bias. The reduction in studies without calcium did not reach statistical significance. J Clin Endocrinol Metab 2011;96:2997-3006

The question will not be resolved with large numbers, it requires study design and we will not know the answer to the question of calcium and vitamin D until these studies are properly designed taking subjects who are deficient in calcium and vitamin D, randomising to placebo or supplement or both in a factorial design, with endpoints of efficacy and safety and executed. Meta-analysis and statistics cannot save us.

The gut as a target for prevention and treatment of osteoporosis

Inose et al report that decreasing synthesis of gut serotonin by inhibiting Tph1 prevents osteoporosis induced by ovariectomy in young mice and rats. While the role of the gut in bone metabolism remains controversial, these observations are consistent with the finding reported earlier. J Bone Miner Res 2011;26:2002-11

Osteoblasts and energy metabolism

Yoshikawa et al report that a decrease in osteoblast numbers compromises glucose metabolism in an osteocalcin-dependent manner. Partial ablation of this cell population resulted in hypoinsulinemia, hyperglycemia and decreased insulin sensitivity. 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 insulin levels, but only partially restored insulin sensitivity. Other osteoblast-derived hormones may contribute to the emerging function of the skeleton as a regulator of energy metabolism. J Bone Miner Res 2011;26:2012-25

“There is nothing more necessary to the man of science than its history, and the logic of discovery... the way error was detected, the use of hypothesis, of imagination, the mode of testing.”

Lord Acton

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.

Ego Seeman