Monday, May 31, 2010

High Resolution peripheral Quantitative Tomography and bone quality.

 
  
 
 

Bisphosphonates

Bisphosphonates (BP) are synthetic analogues of inorganic pyrphosphate with a central carbon instead of an oxigen element that protect BPs from biological degradation.

P – O – P inorganic pyrophosphate

P – C – P bisphosphonates

Thos P-C-P backbone is identical across all types of BPs, and two sidechains account for their biological diversity: a hydroxyl residue at the R1 side chain enhances the affinity to bone, whereas nitrogen residues at the R2 side chain account for their potency, mechanism of action, and side effects. Developed and traditionally used to soften water in irrigation systems in the 19th century, BPs were introduced into clinical medicine in the 1970s and 1980s in the treatment of Paget’s disease of bone and hypercalcemia of malignancy. Bisphosphonates (BP) may act via many signalling pathways, some of which are specific for a given BP.

First of all two groups of BPs have been identified to date acting in a different ways:

  1. Non-amino bisphosphonates act through ATP block producing toxic analogs of ATP and causing cells death.
  2. Amino bisphosphonates act through inhibition of an enzyme called farnesyl pyrophosphate synthase, an enzyme present in in the 3 hydroxymethyl glutaryl Co A reductase pathway.

Other oossible intracellular pathways have been proposed some of wich are specific for some bisphosphonates. These includes:

- Altering key apoptotic proteins, specifically increasing BAX and decreasing Bcl-2.

- Activating mitochondrial pathway via translocation of apoptosis iducing factor.

- Inhibiting mitochondrial adenine nucleatide translocase (ANT), known to be involved in causing apoptosis

- Inducing ApppI ( an densoine triphosphate analog), which triggers direct apoptosis through blockade of mitochondrial ANT.

- Inhibiting metalloproteinases necessary for proteolytic degradation of the extracellular matrix (ECM).

- Inhibiting cancer cell adhesion ( ICMA-1, VCAM-1) and prevents cancer cells spreading at lower concentration than those required to cause apoptosis.

Main characteristics of BPs are:

- Poor oral bioavailability

- High affinity for, and accumulation in bone

- Target FPP synthase in osteoclasts

- Efficiency across a broad spectrum of osteoclast mediated diseases

Stimulated by the launch of alendronate, the first potent oral aminobisphosphonate, the mechanisms of this drug class were elucidated in the ’90. After parenteral and oral administration in which less than 1% is absorbed, BPs bind to hydroxyapatite crystals and concentrate at skeletal sites where active remodeling takes place. Following embedding into the skeleton, BPs inhibit osteoclasts activity and, under acidic conditions in resorption lacunae, are incorporated into osteoclasts.Nitrogen-containing BPs, the most widely used class of antiosteoporosis drugs, which includes alendronate, risendronate, ibandronate, and zolendronic acid interfere with the mevalonate pathway and inhibit Farnesyl Pyrophosphate synthase (FPPS). FPPS is the enzyme that generates Farnesyl Pyrophosphate and Geranyl-geranyl Pyrophosphate (GGPP), essential for post-translational isoprenylation reaction of small GTPases. These enzymes are able to modulate and coordinate subcellular protein trafficking, cell survival, and cytoskeletal integrity (called Ras, Rho, Rac, Rap).The potency of BPs depends upon the inhibitory effect on FPP synthase activity and the affinity for mineral bone.

In theory, the enzyme hydroxymethy glutaryl (HMG) Coenzyme A reductase inhibitors ( also called “statins”), used usually in therapy for reducing plasma cholesterol, which inhibit the production of mevalonate, also have an osteotropic effect. Due to their lipophilic properties, they preferentially target the liver, but not the skeletal tissue. Inhibition of FPPS by BPs results in decreased osteoclast activity, enhanced osteoclast apoptosis and a profound antiresorptive affect. A relevant finding obtained from bone biopsies of patients treated for long term with bisphosphonates is the increased number of giant, hypernucleated osteoclasts that are detached from bone lacunae and undergone slowly a protracted apoptotic process. (see Manolagas NEJM ). Apart from their specific antiosteoclastic activity, BPs protect osteoblasts and osteocytes against apoptosis, enhancing osteoblastic differentiation, and increasing osteoblastic production of Osteoprotegerin.Since the first BP, alendronate, was approved in 1995 these agents have been the first therapy for treating postmenopausal osteoporosis, male osteoporosis, glucocorticoid-induced osteoporosis, Paget’s disease of bone, Hypercalcemia of malignancy, multiple myeloma of bone, and skeletal metastases.

Bone loss associated with aromatase inhibitor therapy in women with breast cancer, which is associated with very low estrogen levels, has been treated with zolendronic acid administered twice per year.In malignant skeletal diseases, intravenous BPs ( such as zolendronic acid 4 mg, or pamidronate 90 mg) are administered every 4 weeks or also more frequently. The shorter therapy interval is required in order to control excessively enhanced bone resorption in malignant conditions. Under this regimen, the rate of side effects is considerably higher, including renal toxicity and the development of osteonecrosis of the jaw (ONJ), particularly in patients with myeloma or breast cancer following dental procedures. The reported decrease in hip fracture rates in long term clinical studies reported for osteoporosis treatment results from multiple factors. BP effectively reduce fracture risk in postmenopausal women over a period of at least 10 year, but preclinical studies demonstrated that they also negatively affect bone quality.

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Bone quality

Not all fractures have the same pathogenesis or structural abnormalities that cause bone fragility. Some fractures are associated with reduced tissue mineral density; in others, there is a reduced density of osteocytes.Women with fractures may have high, normal, or low rates of remodeling. Some women with fractures have a negative balance in the bone multicellular units owing to reduced bone formation, increased bone resorption, or both; other women with fractures have no negative balance in the bone multicellular unit balance.The heterogeneity of mechanisms suggests that all patients with fragility fractures should not be treated in the same way.In most postmenopausal women, the remodeling rate is high; in other words a large number of bone multicellular units excavate cavities while other units are at various stages involved in the completion of remodeling. When an antiresorptive agents is given, this steady state is perturbed. The birth rate of new bone multicellular units decreases quickly when treatment is started, whereas the many bone multicellular units at various stages in the remodeling cycle complete the remodeling process by depositing a volume of new bone that reduces the depth of the escavated site.The newly deposite bone undergoes primary mineralization during the deposition of osteoid (normally a rapid process) and then slower secondary mineralization with enlargement of newly yet formed crystal occurred thereafter.The increased tissue mineral density and reduced porosity slightly improve bone strength. During treatment with antiresorptive agents, the slow remodeling rate and the reduced depth of a decreased number of excavated sites produces bone loss and structural decay also if more slowly than before, and bone fragility reemerges.Fractures continue but are less frequent than in untreated controls with a rapid remodeling and a negative balance in bone multicellular units exponentially increase bone fragility.

Antiresorptive agents finally slow the progression of fragility by suppressing the rate of remodeling and reducing the depth of resorption in each of the reduced number of bone multicellular units engaged into remodeling bone.Since remodeling is slow during treatment with antiresorptive agents, more time is available for secondary mineralization of new mineral bone both in sites actively resorbing before drug exposure and in sites distant from endosteal surface. So that slower remodeling allows increased bone mineral density with more homogenous distribution of mineral between adjacent regions.

However greater secondary mineralization rate increases tissue stiffness, thereby predisposing to bone microdamage.

Whereas the greater homogeneity in tissue density offers less resistance to the propagation of cracking.

Reducing remodeling may also reduce removal of microdamage in bone.

Studies in dogs shows a nearly 30% decline in material toughness ( the normalized energy to fracture ) over 3 years of reatment at doses that stimulate those used in treating osteoporosis in postmenopausal women. This creates a material more brittle that untreated bone, facilitating microdamage, which, combined with the natural suppression of remodeling to repair it, significantly increases its burden in bone.Micro-damage accumulation is likely a consequence of the increased brittleness and reduced toughness, not its cause.

HR-pQCT

Advances in non invasive techniques are likely to provide insights into the effects of these therapeutic agents on bone structure and increasingly accurate information concerning the structural heterogeneity of bone fragility from patient to patient and so may improve the sensitivity of the prediction of fracture risk.Whereas DEXA has become the most commonly used technique worldwide to predict fracture risk and assess response to therapy, based on a two dimensional interpretation of skeletal tissue; it’s increasingly evident that it provides limited interpretation of three dimensional skeletal properties and so on its structural charateristics.Other imaging modalities such as CT and MRI offer considerable greater charaterization of bone architecture, but their software and technical evolution has not been validated until recently.

High Resolution three dimensional peripheral QuantitativeTomography (HR-pQCT) device has been developed by Xtreme CT, Scanco Medical AG, Bassersdorf, Switzerland in order to provides measures of bone microachitecture and micro Finite Element analysis software for numerical quantification of mechanical properties of bone in vivo.In the following diagram we can see the difference between osteopenic postmenopausal women and osteporotic women with fracture using DXA (BMD) and HR-pQCT parameters. Clearly the differences between two groups is more evident with the later technique.

 


This system, first described in detail by Andreas Laib on 1998, uses a two dimensional detector array in combination with a 0.08 mm point-focus X ray tube, enabling the simultaneous acquisition of a stack of 116 high-resolution parallel CT slices, using an effective energy of 40 keV, X-ray tube current of 95 mA, slice thickness of 89 μm, field of view of 90 mm, image matrix of 1536 x 1536 pixels, and pixel size of 82 μm (voxel size).Older 3-D pQCT devices used before have a voxel size of 165 μm, the need to have an higher resolution value is due to adequately solve the distance between the trabecular ridges ( about 300-500 μm) and not necessary to resolve individular trabeculae (100 μm or less ). At each site 110 CT slices were obtained, thus delivering a three dimensional representation of about 9 mm in the axial direction. The arm of leg of the patient was immobilized during the examination in an anatomically formed carbon fiber shell. An anteroposterior scout view was used to define the measurement region. Briefly, a reference line was manually placed at the endplates of the radius and the tibia. The first CT slice was 9.5 mm and 22.5 mm proximal to the reference line for the distal radius and tibia , respectively. The effective dose was less than 3 microSievert per measurement with a measurement time of 2.8 minutes.Quality control, based on Shewart rules, was monitored by daily scans of a phantom containing rods of HA ( densities of 0, 100, 200, 400, 800 mg HA/cm3 ) embedded in a soft tissue equivalent resin (QRM Moehrendorf, Germany).The entire volume of interest was automatically separated into a cortical and trabecular region using a threshold based algorithm. The threshold used to discrimite cortical from trabecular bone was set to one third of the apparent cortical bone density value (D cort). Mean cortical thicknes (CTh) was defined as the mean cortical volume diveded by the outer boe surface.Trabecular bone density (D trab) in gHA/cm3 was compouted as the average mineral density whitin the trabecular volume of interest.Trabecular bone volume (BV) fraction (BV/TV Trabecular volume %) was then expressed from trabecular density assuming fully mineralized bone to have a mineral density of 1.2 gHA/cm3

BV/TV %= 100 x 1200 mgHA/cm3

Because the thickness of every trabeculae cannot be measured accurately because of partial volume effects, a thickness independent algorithm was used to assess trabecular structure.First, a mid-axis transformation method was used to identify trabecular elements and the distance between them assessed threedimensionally using the distance transform method. Trabeculae cannot be resolved at their correct thickness because of partial volume effects, to avoid this problem the center point of every trabecula is detected in the gray-level image and called the 3-D ridges. Trabecular number is taken as the inverse of the mean spacing of the ridges.Trabecular number (TbN, mm-1) was defined as the inverse of the mean spacing of the mid-axes and is thus truly three-dimensional and it does not depend on “a priori” assumptions regarding the plate or rod-like nature of the underlying nature.

TbN = 1/Mean Tb space = nTb/mm

Trabecular thickness (TbTh, μm) and separation (TbSp, μm) were derived from BV/TV and TbN using a standard methods from histomorphometry.

TbTh = (BV/TV)/TbN

TbSp = (1-BV/TV)/TbN

Distance transformation techniques also enable the calculation of intra-individual distribution of separation (TbSp SD, μm) quantified bt the umeber of Standard Deviation (SD) of the separation mean, a parameter reflecting the heterogeneity of trabecular network.For follow-up measurements, an algorithm automatically uses the cross-sectional area (CSA, mm2 ) within the periosteal boundary of the radius and tibia to match the volumes of interest (VOI) on the baseline and fllow-up scans, and thus only the bone volume common to previous scans is used to assess density and microarchitectural measurements.Thus, of the initial 110 slices, on average 103 (range 93 to 108) were analyzed in the follow-up scans.

The outcome variables used in this analyses included volumetrical bone density (gHA/cm3) for entire (Dtot), trabecular (Dtrab), and cortical (Dcort) regions; cortical thickness (CTh, μm), trabecular bone volume fraction (BV/TV, %), trabecular thickness (TbTh, μm), trabecular number (TbN*, mm-1), trabecular separation (TbSp, μm), and intra-individual distribution of separation (TbSp SD, μm).

Interestingly trabecular and cortical densities obtained with HR-pQCT are only moderately related to each other and trabecular density is strongly correlated to trabecular achitectural measurements at both distal radius and tibia. On the contrary, cortical density is higly correlated with cortical thickness but weakly correlated with trabecular architecture in normal subject.Postmenopausal osteopenic and osteoporotic women show density and architectural parameters significantly different, with the exception of cortical density. Compared with those classified as osteopenic, osteoporotic women have lower bone density, decreased trabecular number and trabecular thickness, increased trabecular separartion and intra-individual distribution of separation, and decreased cortical thickness. Osteopenic women with and without an history of fracture did not differ with regard to BMD (measured with classic Hologic densitometr) at lumbar spine and femoral neck, nor in HR-pQCT measurements at the distal tibia. However, at the distal radius density and architectural parameters were significantly different in women with an history of fracture compared with those with no previous fractures.In men trabecular bone volume declines similarly as women over life, however the microstructural basis for the decrease in trabecular volume differ between sexes. In women there appear to be loss of trabeculae with decrease in trabecular number and incresed intertrabecular space, whereas in men the primary mechanism for the decrease in trabecular volume is trabecular thinning.

This mechanism in turn is likely to have a significant impact on age related changes in bone strength in women compared to men, because the reduction in trabecular number has a 2 or 5 times greater impact on bone strength compared with reduction in trabecular thickness that result in similar decreases in bone volume.

Micro-finite element analysis using HR-pQCT

Micro-finite element analysis (μFE) tecniques applied to HR-pQCT data sets provide an estimate of bone mechanical competence (stiffness) that distinguishes between groups of subjects with and without fractures.Each subvolume of HR-pQCT image oof the distal radius and distal tibia is converted to a micro-finite element (μFE) with an element size of 82 x 82 x 82 μm3.The HR-pQCT measurement, as writed above, include 116 slices, corresponding to a 9.02 mm sections along the axial skeleton, with a nominal voxel size of 82 μm.The mineralized phase was thresholded automatically, using Laplace-Hamming filter followed by a global threshold using a fixed value of 40% of the maximal grayscale value of the images.Using customized element-by-element pre-conditioned conjugate gradient solver, 6 μFEs were performed for each model, representing 3 uniaxial compression tests along 3 imaging axes and 3 uniaxial shear tests.The trabecular bone tissue is considered as an isotropic, linear elastic material with a Young’s modulus (E) of 15 Gpa and a Poisson’s ratio of 0.3 for all uniaxial model.The general anysotropic stifness of bone matrix is transformed into a new value through the calculation by means of appropriate algorithm, called Powell’s method, of full orthotopic stiffness tensor value by best orthotopic symmetry through the new chosed coordinate system formed by chosed 3 orthotopic axes ( X1, X2, X3 ) representing the best orthotopic symmetry calculated using an optimization procedure.The elastic constants and stiffness matrix moduli were sorted so that E11 was in the medial-to-lateral direction ( representing the lowest axial modulus), E22 along the antero-posterior direction, whereas E33 was in the direction of the highest axial direction.

Finally 6 elastic moduli were derived from the orthotopic system tensor value:

3 Young moduli: E11 < E22 < E33 for unaxial compression tests

3 Shear moduli: G23 < G31 < G12 for unaxial shear tests

Several studies have reported that HR-pQCT parameters discriminate between postmenopausal women with and without fractures, whereas BMD by DEXA did not.Melton LJ III and Delmas PJ groups reported that decreased vBMD, microstructure, and stiffness estimated by μFE of the radius are associted with forearm fracture in postmenopausal women.Patients studied with postmenopausal osteopenia, radius but not tibia HR-pQCT measurements discriminated between those with and without fractures. It is also important because tibia is a weight bearing bone and it would be predicted that mechanical loading would result in a relative sparing at this site. The study by Cohen A. confirms these data by providing the evidence of cortical and trabecular microarchitectural deterioration at both radius and tibia in premenopausal women with idiopatic osteoporosis, whether or not they have had fracture.Estimated stiffness was significantly lower in all directions at both radius and tibia. Noteworthy was the finding that trabecular bone microachitecture and stiffness were severely affected at radial site in women with low BMD (measured with standard Hologic densitometry) who had an adult low trauma fracture.

Bisphosphonates

The excessive suppression of bone remodeling by high doses of bisphosphonates is thought to compromise bone integrity by accumulation of microdamage (microcraks).However,the microdame ge accumulation has been demonstrated to peak during early period of high dose bisphosphonate treatment and the drugs does not continue to accumulate with longer treatment periods, Determinats of bone strength including ultimate load, stiffness, anergy to failure as well’s other material properties including bone maximum stress and modulus have been shown to be unaffected and preserved after three years of daily alendronate treatment also in preclinical animal models.The role of other material properties has been found to be altered by bisphosphonate treatment but they role in alteration of fracture stiffness is less evident. We talk mainly of alterations of bone mineralization quality, collagen ultrastructural quality, and mineral hydroxyapatite quality. Concerning the possible role of increased quantity of mineralized bone it is quite clear that higher bone mineralization is beneficial in increasing bone stiffness and reducing the incidence of new fractures at any site. The report of possible brittleness of new bone formed and the increasing report of new subtrochanteric and mid shaft femur fractures have not be considered osteoporotic fractures, so not related to disease treated by bisphosphonates, but related to intensity work load in a possible normal bone.

The change in bone tissue is more likely caused by larger accumulation of advanced glycation end-products, called AGEs and directly related to increased glucose levels.AGEs are the by-products of the formation of collagen cross-links by non-enzymatic processes, and naturally accumulates in bone as it ages. Undernormal bone turnover rates, AGEs are prevented from accumulating to high levels. When bone turnover is suppressed, however, they can accumulate, and laboratory studies show them to be associated with increased brittleness.The micro-damage accumulation, and possibly the build-up of AGEs in the bone extracellular matrix, can only be reversed by bone anabolic agents such as teriparatide.

Intravenous BPs and in particular zolendronic acid may be associated with hypocalcemia, renal toxicity, and an acute phase reaction with flulike symptoms during drugs infusion. The latter is thought to be due to extraskeletal effects of aminobisphosphonates, the release of cytokines from macrophages, and the activation of T lymphocytes linking to γδ T cell receptor (see NEJM letter).Accordingly, aminobisphosphonats, and in particular zolendronic acid, may also induce apoptosis in breast cancer cells, although the clinical relevance of this effect is not clear.We know that bone remodelling is a process involving T lymphocytes, bone marrow stromal cells, machrophages (antigen presenting cells) in a complex signalling pathway involving the activation of osteocytes, osteoblasts and finally osteoclasts through a signaling sequences very complexes and those more intensely studied require TNF alfa related factors and their receptors (RANK/RANKL/OPG). So that in any changes of bone turnover level a true inflammatory-like pathway is activated at bone marrow-trabecular interfaces.

According to my opinion all side-effects founded in long term studies using bisphosphonates and in particular after their parenteral administration one a months or yearly is due to an increase in local inflammatory tissutal answer, finally accounting for:

  1. Osteonecrosis of the jaw (ONJ)
  2. Atrial Fibrillation (AF)
  3. Esophageal cancer
  4. Musculoskeletal pain
  5. Atypical fractures due to increased skeletal fragility at diaphyseal or subtrochanteric femur regions.

Since late 2003 there have been reports in the literature of a possible association between bisphosphonate use and the appearance of avascular necrosis of the jaw. Marx on 2003 described a group of 36 American patients who received either pamidronate or zoledronate iv for the management of bone disease associated with metastatic cancer, multiple myeloma and osteoporosis and who subsequently developed avascular necrosis of the jaws. In the majority of patients, the latter condition developed after dental extraction, but in about 30% of cases, it apparently occurred spontaneously.

Bisphosphonates related osteomyelitis (BON) and necrosis of the jaw possibly results from the inability of hypodynamic and hypovascular bone to meet an increased demand for repair and remodeling owing to physiological stress (mastication), iatrogenic trauma ( tooth extraction or denture induced local injury ), or tooth infection in a environment that is both trauma intense and plenty of bacteria.Cofactors may include the use of other medications with antiangiogenic properties such as glucocorticoids, diabetes mellitus, irradiation of jaw bone, peripheral vascular disease, hyperviscosity syndrome such as in multiple myeloma.Bisphosphonate related osteomyelitis (BON) is a true bone infection due to direct effect of bisphosphonates on bone turnover and subsequent physiolgical reaction even more increased if we look at region with increased work load and stress such as daily work activity we spend during mastication. A great work load per cm square is exerted on oral cavity bones so that these bone regions require a very intense answer by extracellular matrix structures.

Concerning the presence of Advanced glycation end products, we know that increasing the concentration of glucose, the link of glucose to all proteins present in our body increases from hemoglobin to proteins present in the ocular structures (both cornea and retinal epithelial cells). Glycation reactions changes the biochemical properties of enzymatic proteins, or receptor proteins, or structural proteins such as collagen fibers. We can postulate that also the presence of increased Atrial Fibrillation should be attributed to altered glycations and expression at myocardial level of proteins forming ion channels, and in the presence of altered calcium homeostasis ( as we have during osteoporotic bone resorption) we have an increased probability to develop myocardial depolarizarion leading finally to Atrial Fibrillation.Cellular electrophysiolgical studies have revealed a marked reduction in the densities of L-type volatage gated Calcium channels, transient outward Potassium currents, and ultrarapid delayed rectifier Potassium currents in atrial myocites of patients affected by Atrial Fibrillation.Interestingly similar ( but not identical ) changes are present in canine models of Atrial Fibrillation, where changes in ions currents are correlated with reduced expression of the underlying channels forming subunits.In both human and canine Atrial Fibrillation, reduced Calcium voltage currents seem to be enought to explaine the reduction action potentials in duration and effective refractory period characteristics of remodelling atria.In addition the sarcoplasmic expression of Calcium dependent ATPase is reduced in myocites, suggesting that calcium cycling is affected in atrial fibrillated myocites.

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