Overview, Vol 12, Issue 1

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

"The quarterly journal Progress in Osteoporosis began in October 1993 as Advances in Osteoporosis 19 years ago.  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 still to provoke critical evaluation of the important literature for members of the International Osteoporosis Foundation family and by them. 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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Fractures and Death are Not Going Away
Nonvertebral Fractures are Here to Stay

The burden of fractures and mortality associated with them is not diminishing. The fractures are not only vertebral or hip, most are nonvertebral and nonhip. 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. Postfracture mortality was higher in men than women. Osteoporos Int 2011;22:2439

In Switzerland, Lippuner et al report that major osteoporotic fractures (hip, clinical spine, distal radius, and proximal humerus) in increased by 15.9% (women) and 20.0% (men) due to an increased nonhip fractures (+37.7% in women and +39.7% in men). The number of individuals aged ≥45 years grew by 11.1% (women) and 14.6% (men) over the study period of 7 years. Osteoporos Int 2011;22:2487

 

 

 

 

 

 


Hello Cortical, Goodbye Trabecular, Bone

The skeleton is 80% cortical, only 20% is trabecular. 70% of all age-related bone loss is cortical. 50% is lost by remodeling upon the Haversian canals of the inner third of the cortex – the cortex thins from within, not from the marrow outwards – Jepsen suggested this years ago, Zebaze proved it. Porosity is the single morphological ‘footprint’ of structure decay. Trabecular bone loss has ruled for decades, a humbling error as our children teach us.

Trabecular bone had its 15 minutes of fame bestowed by Albright, then Riggs, who noted forearm densitometry wasn’t a big hit because it did not distinguish patients with and without spine fractures. Dual photon absorptiometry topped the charts in the second half of the 20th century as spine densitometry seemed to discriminate fracture and nonfracture cases better than single photon absorptiometry. Densitometry stays in the top 40 in this dark side of the 21st century even though half of all fractures arising from above the nominal threshold of -2.5 SD; are all these ‘non-osteoporotic’ fractures? They are still called ‘osteoporotic’ fractures but what it meant is they are fragility fractures. Well, if they are fragility fractures, what is the structural basis of this half of the burden of fractures?

Parfitt made the point that the slow loss of a larger volume of cortical bone is equally if not more important than the rapid loss of a small volume of trabecular bone. Let’s not waist youth on the young. Zebaze, examining scanning electron microscopic images of bone, found large pores distant from the endocortical surface and reasoned that these could not arise by endocortical resorption dissolving the cortex ‘outwards’ producing cortical thinning from the marrow outwards. He recognized that the mechanism was intracortical remodeling thinning the cortex from its inside, especially the intracortical remodeling upon Haversian canals traversing in the inner part of the cortex.

Returning to the same place and knowing it for the first time: porous bone

Porosity is a quantifiable ‘fingerprint’ of bone loss and bone fragility. Take a look at Schaffler & Burr (J Biomech 1988;21:13). This inverse power function showed that the apparent density predicted the elastic modulus log E = 1.06 +7.4 log apparent density. A unit decrease in apparent density (produced by increasing porosity), reduced stiffness seven fold. For trabecular bone, stiffness is proportional to apparent density cubed, so increasing the void volume in cortical bone is much more deleterious than increasing the void volume of an already porous material. The current report by Granke et al is similar. Middiaphyseal cortical bone was scanned using acoustic microscope (SAM) and synchrotron radiation μCT. Stiffness correlated inversely with cortical porosity (R2=0.72-0.84). Bone 2011;49:1020

 

 

 

 

Remodeling is signaled within bone matrix, probably by osteocytes by their sacrificial death. The signals go to a point upon the internal surface of bone, the endosteal envelope. Remodeling is initiated at a point and the cells recruited orchestrate the tunneling back to the place of origination to remove that damage. So, surface area is important. Bjornerem et al report that postmenopausal women that a 1 SD higher tibia intracortical bone surface area was associated with 0.22-0.29 SD higher remodeling markers. A 1 SD lower trabecular bone surface area was associated with 0.15-0.18 SD higher remodeling markers. Intracortical remodeling is self perpetuating by creating porosity and so more surface for remodeling. Remodeling upon the trabecular surfaces is self-limiting because it removes trabeculae with their surface so no more remodeling can occur. Bone 2011;49:1125

 

 

 

 

 

 

 

 

 

 


Advances in Therapeutics

Location, location

Whether patients are treated seems to have more to do with good or bad luck than science. Diez-Perez et al report that among 58,009 women, 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 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. Bone 2011;49:493

Whaatz new pussycat?

Cathepsin K inhibitors

Cathepsin K (CatK) inhibitors are a fascinating family of drugs. Leung et al report that odanacatib (ODN), a selective, potent and reversible inhibitor of CatK, inhibits bone loss. Osteoclastogenesis and survival are unaffected but resorption is decreased as measured by CTX release or resorption area which becomes a series of shallow pits rather than a deep trail-like resorption trench. Bone 2011;49:623

What is fascinating is that remodeling intensity is either not inhibited, or less inhibited than observed with classic antiresorptive agents. That is, the number of resorption cavities upon the surfaces of bone remains either unchanged or decreases to some extent but these sites are more shallow. What is bad about this is that if resorption pits are more shallow, then osteons that come to be formed when these refill may be smaller. If they are smaller, then this may reduce the resistance to crack propagation which occurs mainly in interstitial bone (between osteons) and which now increases in absolute and relative terms. However, if remodeling intensity continues, then there may be more of the smaller osteons offsetting the potentially deleterious effect of smaller size. Another potential benefit is the material composition of bone. Classic antiresorptive agents reduce the intensity of remodeling so osteons that would have been removed are not; they continue to undergo secondary mineralization which increases material stiffness predisposing to the occurrence and lengthening of microcracks. This may be avoided if remodeling intensity is not reduced or less reduced. Is there any evidence for the above? Not yet.

Stopping antiresoptive therapy

Denosumab is a power inhibitor of bone remodeling. While this is important in reducing bone loss (as remodeling intensity drives bone loss when basic multicellular unit (BMU) balance is negative, protracted suppression of remodeling may allow secondary mineralization to go to completion in osteons that are no longer removed by high remodeling and this may increase brittleness of bone. 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 remodeling; similar to those observed in untreated postmenopausal women. 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

While denosumab does not bind to bone mineral and its suppressive effects appear to reverse quickly, the bisphosphonates are bound to bone and are released and perhaps readsorbed onto bone as remodeling is restored. Eastell et al report that postmenopausal women with osteoporosis who completed the risedronate 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

Reversibility of treatment may be good or bad. Irreversibility is not a good from the point of view of the material composition of bone. The prolonged suppression of the very mechanism, remodeling, that functions to remove damage and replace old bone with new bone, may contribute to both the accumulation of micro-damage 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, remodeling reemerges and results 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.

Atypical fractures and suppressed bone remodeling

Tjhia et al report that patients with atypical fractures and severely suppressed bone turnover (SSBT) associated with long-term bisphosphonate therapy had evidence on bone biopsy of increased brittleness assessed using nanoindentation and quantitative backscattered electron microscopy. For cortical and trabecular bone greater resistance to plastic deformation was observed. Bone 2011;49:1279

 

 

 

 

Nonvertebral fracture risk reduction

These are the most common and most challenging fractures to prevent. Few studies have demonstrated fracture risk reduction in this class. When observed, the risk reduction is usually 20-25%; half that reported for hip or spine fractures. Mackey et al combined five trials of alendronate, clodronate, denosumab, lasofoxifene, and zoledronic acid involving 30,118 women. The hazards ratio were: all fractures HR=0.76 (95% CI 0.70-0.81), high-trauma fractures HR=0.74 (95% CI 0.57-0.96), low-trauma fractures HR=0.77 (95% CI 0.71-0.83), nonvertebral six fractures HR=0.73 (95% CI 0.66-0.80), other than nonvertebral six fractures HR=0.78 (95% CI 0.70-0.87), and all fractures other than finger, face and toe HR=0.75 (95% CI 0.70-0.81). The question is whether this reduction can be improved through a better understanding of the pathogenesis and so detection of those at risk. I suspect the answer to this is yes. J Bone Miner Res 2011;26:2411

 

 

The enigma of the antifracture efficacy of strontium ranelate

Clinical trials provide consistent evidence for rapid and sustained vertebral and nonvertebral fracture risk reduction using strontium ranelate (Meunier et al, N Engl J Med 2004;350:4591; Reginster et al, J Clin Endocrinol Metab 2005;90:2816). The challenge is how? Bone becomes fragile during advancing age because remodeling becomes unbalanced at the level of the BMU; each time bone matrix is remodeled, a smaller volume of bone matrix is deposited than was removed. The rate and extent of the structural decay depends on the size of the negative BMU balance and the intensity of remodeling at the tissue level (activation frequency). The BMU imbalance at the cellular level and the remodeling intensity at the tissue level are two therapeutic targets.

Antiresorptive agents such as the bisphosphonate, alendronate, mainly target tissue level remodeling. By reducing the intensity of remodeling, fewer remodeling sites upon the trabecular, endocortical and intracortical components of the inner (endosteal) envelope remove a volume of bone matrix and replace it with less bone matrix. Structural decay continues, but more slowly, and at a rate determined by the potency of the drug in suppressing tissue level remodeling. If the antiresorptive also corrects the negative BMU balance by reducing the volume of bone matrix resorbed, by increasing the volume of bone matrix deposited, or both, then remodeling would no longer produce structural decay.

Strontium ranelate does not appear to reduce the intensity of bone remodeling. For example, in the study by Arlot et al (J Bone Miner Res 2008;23:215), activation frequency was not reduced. In a more recent study, published only in abstract form at this time, Chavassieux et al (Osteoporos Int 2011;22(Suppl1):S104) reported changes in bone remodeling in 268 postmenopausal women with osteoporosis who received strontium ranelate 2 g/day or alendronate 70 mg/week. The surface extent of remodeling as measured by the mineralizing surface/bone surface (MS/BS) increased from 2.94±3.73% at 6 months to 4.91±4.15% at 12 months with strontium ranelate. Baseline values were not reported. The surface extent of remodeling with alendronate decreased as expected.

Continued remodeling intensity at the tissue level may be an advantage if a treatment decrease in volume of bone matrix resorbed by the osteoclasts of the many BMUs continuing to remodel bone, increases the volume of bone matrix deposited by the osteoblasts of these many BMUs, or does both. If the number of resorption sites remain unchanged (as reflected in the unchanged activation frequency and MS/BS) and the volume of bone deposited is unchanged or increases sufficiently to produce a net positive BMU balance, then it is plausible that each remodeling event will deposit a net positive volume of bone upon the endocortical surface thickening the cortex focally and upon trabeculae thickening these structures. In the cortex, it is not possible to put back more bone than was removed by a BMU, but if remodeling occurs upon the surface of a large cavity, its size may be reduced focally.

The concept of ‘dual action’ applies to BMU based remodeling – a reduction in the volume of bone resorbed and an increase in the volume of bone formed. Differences in the surface extent of the endosteal envelope undergoing bone resorption at one or more locations and the surface extent of bone formation at other locations is not evidence of ‘dual action’.

There is evidence of reduced resorption of bone in in vitro cell lines and continued or increased proliferation of osteoblast cell lines tissue culture. However, evidence based on histomorphometric analysis in bone biopsy specimens is inconclusive, in part because of methodological constraints. For example, evidence for a reduction in the volume of bone resorbed was not observed in the study by Arlot et al and has not yet been reported in a recently completed study by Chavassieux et al. In the study by Arlot et al, there was evidence of higher mineral apposition rate (MAR), as well as higher osteoblast surface/bone surface (Ob.S/BS) (+38% in cancellous and endocortical bone; p=0.047) compared with controls. (The word ‘higher’ applies, not ‘increased’; few biopsies were paired.) In the study by Chavassieux et al, MAR was higher with strontium ranelate at 6 (0.630±0.127 µm/day, P=0.003) and 12 months (0.624±0.094 µm/day, P=0.009) compared with alendronate (0.553±0.108 µm/day at both time points), but baseline measurements were not available to establish if MAR actually increased relative to baseline.

While dissociation in remodeling markers, with unchanged or modestly increased markers of bone formation and unchanged or modestly decreased resorption markers (Meunier et al, N Engl J Med 2004;350:4591), are often cited as evidence for a ‘dual’ action. Remodeling markers reflect tissue level remodeling and to use these as evidence of a dissociation or uncoupling of cell based resorption and formation at the BMU level is flawed.

A recently published study directly assessed the effects of strontium ranelate on markers of bone formation by comparing changes with a known anabolic agent. Quesada-Gomez et al report increases in P1NP and BSAP with PTH, PTH(1-84), given during 6 months to 41 subjects but no changes were observed with strontium ranelate given to 40 subjects. Osteoporos Int 2011;22:2529-37 In another study, Recker et al (J Bone Miner Res 2009;24:1358) reported treatment with teriparatide (n=39, 20 mg/d) increased aminoterminal propeptide of type I collagen (PINP) after 1 month (+57%, p<0.001) while strontium ranelate (n=40, 2 g/d) induced reductions in PINP at 3 and 6 months and in serum β-C-terminal telopeptide of type I collagen (β-CTX) at 1 and 3 months (7). The increase in P1NP was thus not observed with strontium ranelate but whether the increase with reported with PTH 1-84 or 1-34 reflects increases in the number of sites undergoing remodeling or an increase in volume of bone deposited by each or is the result of modeling – the deposition of bone upon quiescent surfaces independent of the remodeling machinery is not known.

Several studies have examined the effect of strontium ranelate on bone architecture in vivo. In the study by Arlot et al, on 2-D histomorphometry, no effects on cortical thickness, porosity, or trabecular bone volume fraction were observed. In 3-D analysis of 3-year unpaired biopsies, 20 in patients who received treatment and 21 in patients who received placebo using µCT the strontium ranelate group had higher cortical thickness (+18%, p=0.008) and trabecular number (+14%, p=0.05), and lower structure model index (−22%, p=0.01) and trabecular separation (−16%, p=0.04); with no change in cortical porosity. In another study, Rizzoli et al (Rheum Int 2010;30:1341) reported that strontium ranelate increased cortical thickness, cortical area and trabecular density after one year as assessed using high resolution computed tomography. The increases in cortical thickness, area, and BV/TV and decrease in trabecular bone area were greater in the strontium ranelate than alendronate group. Trabecular number increased in both groups.

These studies are also difficult to interpret. Strontium ranelate and alendronate are likely to increase photon attenuation because strontium ranelate has twice the atomic number of calcium so the increases photon attenuation may give the impression that structural change due to bone formation has occurred. Alendronate slows remodeling so secondary mineralization of bone matrix that has not been remodeled may increase photon attenuation giving the impression that bone formation has occurred.

The notion that this is a ‘dual acting’ drug is based on studies in vitro and in animal models in which the bone undergoes modeling during advancing age, not remodeling. Methodological issues in noninvasive imaging limit interpretation of morphological studies in vivo and so information is needed such as publication of full results of the study of Chavassieux et al which may help to define whether there is evidence of new bone using this treatment. Studies are needed to address whether the antifracture efficacy is partly the result of changes in the material composition of bone.


Reviews

Forum on aging and skeletal health: Summary of the proceedings of an ASBMR workshop
Khosla S, Bellido TM, Drezner MK, Gordon CM, Harris TB, Kiel DP, Kream BE, Leboff MS, Lian JB, Peterson CA,Rosen CJ, Williams JP, Winer KK, Sherman SS
J Bone Miner Res 2011;26:2565

Investigation of differences between hip fracture types: A worthy strategy for improved risk assessment and fracture prevention
Pulkkinen P, Gluer CC, Jamsa T
Bone 2011;49:600

Hypoparathyroidism in the adult: Epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research
Bilezikian JP, Khan A, Potts JT, Jr., Brandi ML, Clarke BL, Shoback D, Juppner H, D'Amour P, Fox J, Rejnmark L, Mosekilde L, Rubin MR, Dempster D, Gafni R, Collins MT, Sliney J, Sanders J
J Bone Miner Res 2011;26:2317

Vitamin D supplementation during pregnancy
Abrams SA
J Bone Miner Res 2011;26:2338

Relationship between serum RANKL and RANKL in bone
Findlay DM, Atkins GJ
Osteoporos Int 2011;22:2597

LRP5, serotonin, and bone: Complexity, contradictions, and conundrums
Goltzman D
J Bone Miner Res 2011;26:1997

Unraveling the role of FoxOs in bone: Insights from mouse models
Almeida M
Bone 2011;49:319

Small animal bone healing models: Standards, tips, and pitfalls results of a consensus meeting
Histing T, Garcia P, Holstein JH, Klein M, Matthys R, Nuetzi R, Steck R, Laschke MW, Wehner T, Bindl R, Recknagel S, Stuermer EK, Vollmar B, Wildemann B, Lienau J, Willie B, Peters A, Ignatius A, Pohlemann T, Claes L, Menger MD
Bone 2011;49:591

Genetic mouse models for bone studies: Strengths and limitations
Elefteriou F, Yang X
Bone 2011;49:1242

Geographic trends in incidence of hip fractures: A comprehensive literature review
Cheng SY, Levy AR, Lefaivre KA, Guy P, Kuramoto L, Sobolev B
Osteoporos Int 2011;22:2575

Issues in modern bone histomorphometry
Recker RR, Kimmel DB, Dempster D, Weinstein RS, Wronski TJ, Burr DB
Bone 2011;49:955

Interpretation and use of FRAX in clinical practice
Kanis JA, Hans D, Cooper C, Baim S, Bilezikian JP, Binkley N, Cauley JA, Compston JE, Dawson-Hughes B, El-Hajj Fuleihan G, Johansson H, Leslie WD, Lewiecki EM, Luckey M, Oden A, Papapoulos SE, Poiana C, Rizzoli R, Wahl DA, McCloskey EV
Osteoporos Int 2011;22:2395

Uncertainties in the prevention and treatment of glucocorticoid-induced osteoporosis
Hansen KE, Wilson HA, Zapalowski C, Fink HA, Minisola S, Adler RA
J Bone Miner Res 2011;26:1989

Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw
Compston J
Osteoporos Int 2011;22:2951

Towards a diagnostic and therapeutic consensus in male osteoporosis
Kanis JA, Bianchi G, Bilezikian JP, Kaufman JM, Khosla S, Orwoll E, Seeman E
Osteoporos Int 2011;22:2789

Emerging therapies to prevent skeletal morbidity in men with prostate cancer
Saylor PJ, Lee RJ, Smith MR
J Clin Oncol 2011;29:3705


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