Montag, 15. Oktober 2012

A Draft: Pathologic and Cardiovascular Calcification in Relation to Aging (2008-2010)

Some time ago, I was writing a review on this topic but had to stop due to health problems before finishing it. Here, I publish the draft from 2010 almost unmodified. I hope it is fine if I publish it for people to (possibly) learn from it. A big thank you to everyone who helped with the review, especially the SENS- and Methuselah Foundation.
Despite proof-reading, I am sure I made some mistakes, hopefully not too stupid ones. But, really, the reference to the then-controversial, now-disproven "nanobacteria" in the review makes me laugh already. (At least disproven as far as the bacteria part is concerned.) Even back then I only included it for for the sake of completeness, see if you can find it!

ABSTRACT: “In the first part of the review I am going to discuss vascular disorders involving calcification, how they relate to aging and their clinical implications. Second, I will provide a quick overview of mechanisms involved both in age-related calcification and vascular aging.
The remainder of the review is devoted to potential therapies. The third chapter shortly summarises nutritional and lifestyle influences on calcification. Thereafter, theoretical and practical concepts and problems relating to regression will be discussed, including the role of spontaneous, surgical and pharmacological regression. Lastly, in the fifth part, I will summarise the main points, identify specific targets for future research and introduce the reader to several promising “targeted” therapies in preclinical development.

The major conclusions of this review are that calcification is more dynamic than is appreciated. Calcification may regress spontaneously, albeit inefficiently, thus necessitating development of effective drugs. Therapeutic regression would likely alleviate the age-related decline of the cardiovascular system.”

WVK – model of calcification, which develops after warfarin & vitamin K administration
VDN – model of calcification, after vitamin D and nicotine administration
CVD – cardiovascular disease
VC – vascular calcification
MEC – medial elastocalcinosis, often synonymous with Mönckeberg’s sclerosis (see text)
CAC – coronary artery calcification, often measured as “Agatston score” or volumetric score, a marker of atherosclerotic disease burden, which may confer risk of its own.

1. Introduction
2. Mechanisms
3. Nutrition, lifestyle and calcification
4. Regression
General concepts, spontaneous and natural regression, Surgical regression, pharmacological regression
5. Summary and outlook

1. Introduction
The idea of postponing intrinsic aging is now considered a serious possibility among biogerontologists and is gaining acceptance.
Aging, together with lifestyle, are two major predisposing influences on the development of cardiovascular disease. Therefore vascular aging is central to any comprehensive approach to slow or reverse aging [de_grey2002] and calcification may importantly contribute to age-related vascular stiffening and loss of function.

At least three major age-related vascular disorders involve calcification. They can be distinguished according to their location and other characteristics: intimal (atherosclerotic), medial (Mönckeberg’s sclerosis) and valvular calcification [giachelli2009]. Additionally, there is a general rise in medial calcium content which could be unrelated to, or a precursor of, Mönckeberg’s sclerosis: “This elastic, tissue calcification is grossly invisible and impalpable, being revealed only by methods such as microincineration or direct chemical analysis.” [lansing1950]

The exact nature of pathologic calcification remains elusive, but complete understanding may not be necessary to develop treatments and for the purpose of this review a pragmatic definition will suffice. Herein, I consider VC and specifically MEC a kind of age-related molecular damage. As predicted by this view, deposition starts early, proceeds throughout life and eventually reaches a pathologic threshold (see for instance [shaw2006, newman2001, lansing1950, elliott1994]).
Other age-related changes in the vessel wall include glycation and lipid fixation as modifications of the extracellular matrix and alterations in cell quality as well as quantity [robert2008, dao2005]. Changes in the extracellular matrix, calcification and glycation likely play a predominant role, but the exact contribution of each to the cardiovascular decline remains unclear. And as we will see below, controversy often surrounds the impact of calcification per se (especially in atherosclerosis).

Clinical implications
It is hypothesised that cardiovascular (and -respiratory) aging ultimately limits human maximal life span to 100-120 years [robert2008] and atherosclerotic calcification has been proposed as a “measure of biologic age” even surpassing chronological age in predictive ability [shaw2006]. Indeed a meta-analysis found that presence of any vascular calcification is a powerful risk factor that predicts mortality [rennenberg2009].
Medial calcification is strongly implicated in worse outcomes in diabetes and renal disease [atkinson2008]. However, data from healthy populations is conflicting. One study found MEC not to influence mortality in the general population [everhart1988], but breast arterial calcification confers a modest risk [iribarren2004] and high ankle brachial index (an indirect measure of MEC) independently predicts mortality [resnick2004].
Similarly, valvular calcification is associated with worse outcomes independently of risk factors and atherosclerosis [fox2003].
Although, intimal calcification, as quantified by Agatston score (CAC) and variants thereof, strongly predicts mortality, it is not clear whether those effects are independent of other atherosclerotic changes. In fact atherosclerotic calcification has been suggested to aggravate and to stabilise atheroma. Perhaps, in the early phases increased interface area [abedin2004] and inflammation [spronk2006] destabilise lesions, while later calcification stabilises them. In vivo the relationship may be even more complex, and is thus an area needing further study.

[Idealised relationship, adapted from Abedin et al.]

Several other mechanisms may explain the detrimental effects of VC and especially MEC; 1) increased stiffness leading to reduced cardiorespiratory fitness [robert2008], 2) remodelling and end organ damage [dao2005], 3) isolated systolic hypertension and its sequelae [dao2005], 4) degraded vascular responsivity [atkinson2008, kitagawa1993] and 5) amplification of other pathologic processes [robert2008].

Resistance to calcification may offer valuable insights, as 10-20% of the elderly demonstrate no or only minimal CAC [shaw2006, newman2001] and after 16 years of hemodialysis some patients (~8%) still remain free from VC [goldsmith1997]. Only medial calcium deposition is universal among the elderly but absolute levels vary up to three-fold [elliott1994]. Apart from heritable factors [narayan1996], lifestyle choices may explain those differences. Some of which we will explore later in the review.

2. Mechanisms
Several mechanisms leading to vascular calcification have been proposed, but detailed discussion is beyond the scope of this paper (see [atkinson2008, giachelli2009] for a review).

Six major mechanisms have been described in the literature: lack of inhibition, stimulation, physiochemical promotion (calcium-phosphate product), apoptotic debris, circulating nucleational complexes and alterations of the elastic network. Angiogenesis and infections, though, likely of lesser significance, may also contribute to the pathology [hayden2005]. The latter includes but is not limited [Grahame-Clarke03] to the controversial “nanobacteria”. [maniscalco04]
(adapted from [giachelli2009])

Of particular interest are mechanisms lying at the crossroads between different age-related pathologies. Those include fragmentation and degradation of the protein elastin as well as glycation.
In fact virtually no de novo synthesis of functional elastin may occur in vivo [powell1992], making elastin prone to the above mentioned processes and explaining its central role in vascular aging. Mechanistically, degraded elastin fragments promote calcium deposition, may serve to nucleate hydroxyapatite, and can up-regulate elastolytic enzymes, perhaps, leading to a “vicious circle” [robert2008]. Additionally, fragmentation and degradation of the elastic network may directly contribute to stiffness [fonck2009].
Plasma advanced glycation endproducts correlate with vascular calcification in animals [bruel1996], stiffness in population studies [semba2008] and accelerate calcification in vitro.
“Catabolic insufficiency” is thought to contribute to atherosclerosis and several other age-related diseases [mathieu2009]. Impaired phagocytosis within atherosclerotic plaques leads to accumulation of apoptotic bodies [schrijvers2007] which can predispose to mineralisation by increasing the local calcium-phosphate product.
More hypothetically, similar mechanisms may underlie other forms of age-related calcification and/or senescence may contribute to decreased clearance.
Furthermore, cellular senescence is known to promote osteoblastic transdifferentiation and calcification as well as elastolysis in vitro [burton2009, robert2008].

3. Nutrition, lifestyle and calcification
In this chapter I will shortly summarise the emerging role of nutrition and “lifestyle” in the context of vascular calcification. Modifiable, sub-clinical deficiencies may contribute to VC throughout life. Most importantly in the elderly, because aging is associated with malnutrition and abnormal metabolism of many nutrients: decreased cutaneous vitamin D synthesis [holick2007], impaired absorption of B12, abnormal calcium homeostasis, alterations of magnesium metabolism and possibly increased need of vitamin K for effective γ-carboxylation [tsugawa2006].

Physiologic levels of phytate protect animals from age-related and many other types of calcification [grases2008]. Recent population studies have linked phytate to decreased incidence of kidney stones [curhan2004] and increased bone density [lopez2008], suggesting that it could beneficially modulate calcium metabolism in humans. Currently a trial exploring its influence on valvular calcification is underway (NCT01000233).
Another dietary component, taurine protects from calcification in the VDN model [yamauchi1986] and is generally antiatherogenic (e.g. [zulli2009]). Also, it has been found to reduce homocysteine levels [ahn2009] and decrease several markers of vascular stiffness [satoh2009], but its effects on pathologic calcification in man are unknown.

Administration of fish oil attenuates kidney calcification in animals [schlemmer1998], but data from population studies on fish intake has been inconsistent, albeit suggestive of modest benefits [heine-broring2010].
A combination of fish oil, statins, niacin, vitamin D and dietary intervention has shown promising results on CAC progression in a recent open-label study [davis2009]. It remains to be determined whether the results can be replicated and which of those interventions are most effective.

A question of balance? The discussion of calcium supplementation is complicated by recent studies. Neither serum nor dietary calcium intakes consistently associate with VC or mortality. However, Bolland et al. found increased event-rates in women supplemented with calcium [bolland2008] and similar trends in other trials. Suggestive but not conclusive data links use of calcium containing phosphate binders (leading to extremely high calcium intakes) to worse outcomes in renal disease as well [jamal2009].
Paradoxically, calcium supplementation reduces calcification in animal models (e.g. [hsu2006]), which may be explained by beneficial effects on lipids, bone resorption or other factors.
Vitamin K, Magnesium (vide infra)

Vitamin D has an undeservedly bad reputation due to often unjustified toxicity concerns [holick2007], including concerns over calcification.
To the contrary, the literature is largely consistent with a U-shaped dose-response curve, both in regards to mortality [melamed2008] and calcification [mathew2008], but optimal levels remain enigmatic.
Mechanistical evidence and data from observational studies is consistent with a protective effect. Evidence is often limited to cross-sectional studies, showing either null or beneficial associations of vitamin D metabolites and coronary calcification. Recently the first larger prospective study reported beneficial associations with incident CAC, but not other endpoints [de_boer2009].
Thyroid levels influence calcification in vitro and in vivo. In healthy rats hypothyroidism led to a moderate increase, while hyperthyroidism decreased calcium content below baseline levels [sato2005].
Consistently, hypothyroidism is associated with mildly elevated (cardiovascular) mortality in observational studies [ochs2008]. Although, aging increases the incidence of thyroid abnormalities, thyroid hormones, like vitamin D, have pleiotropic effects and more research is necessary to elucidate their clinical effects.

In theory vitamin B6, B12 and folic acid could exert modest effects via homocysteine metabolism [VanCampenhout2009]. While protein malnutrition has dramatic effects on experimental MEC [price2006], possibly mediated by hypoalbuminemia. Obesity is linked to increased rates of CAC [cassidy2005] and bona fide caloric restriction attenuates vascular aging in model organisms [castello2005]. Warfarin and glucocorticoid use has been linked to accelerated VC in observational studies [lerner2009, del_rincn2004].

Before we discuss regression in more detail it should be noted that despite several differences, similar principles may govern all types of biomineralisation [bonucci05, mccullough2008]. Therefore some non-vascular disorders involving calcification can (and due to lack of data sometimes must) serve as a proxy. For example, drugs used in the treatment of soft tissue calcification can work in models of VC and vice versa [palmieri1995, thompson1992]. Consequently, once developed, therapies may find broad application to various calcifying disorders with only slight modifications (e.g. in the mode of delivery).

Calcification can regress naturally or pharmacologically, but it is unknown whether all calcium deposits can regress completely and not rigorously proven that vascular calcification regresses in humans at all.
Putative mechanisms of in vivo regression involve phagocytosis [yamada2009, bas2006], acidification (presumably via carbonic anhydrase) and physiochemical dissolution [steitz2002, essalihi2005] or a combination thereof.

Some authors suggest that if a physiologic milieu and calcium homeostasis were restored, calcification might naturally regress [jahnen-dechent2008]. However, calcification starts in the 20s or 30s and thus a de facto physiologic milieu can sustain a certain level of calcification [lansing1950] and unfacilitated regression is often incomplete [bas2006, atkinson1994, essalihi2005].
Additionally, preventative interventions may provide only diminished benefits to patients with established pathology, thus justifying a research focus on the regression paradigm.

Conflicting data
Few high-quality, interventional studies have examined progression of calcification and most focused on the impact of statins on CAC. Although, monotherapy with statins can reduce the lipid core of atheroma as measured by ultrasound [klein2007], calcification usually remains. In fact slightly accelerated calcification may contribute to a plaque stabilising effect of statins [kadoglou2008].
While biologically plausible, evidence of regression is from low quality studies. In clinical practice, complete regression of calcification has been described in case-reports after treatments such as vinpocetine [ueyoshi1992], bisphosphonates and amlodipine [ramjan2009], sodium thiosulfate [subramaniam2008] and diltiazem [palmieri1995] but only bisphosphonate studies addressed VC.
Small pilot trials show impressive but extraordinarily heterogeneous responses to experimental therapies [nitta2004, maniscalco2004, davis2009]. Observational studies on the natural progression and medical therapy of calcification also demonstrated that regression is possible.
However, due to limited and contradictory interventional data there is dispute whether serial measurements of CAC are a clinically useful marker of atherosclerosis regression or
stabilisation [klein2007]. Spontaneous regression, chance or bias may explain findings in smaller studies, but it bears emphasizing that any considerable (even spontaneous) regression is incompatible with the view that calcification is a largely irreversible disease.

Several issues could contribute to lacklustre study results.
Transdifferentiated cells and damage to the elastic network may persist after regression and continue to diminish tissue function. Animal studies indicate that calcium regression partially restores function, but any effects of decalcification are difficult to isolate from structural improvements [schurgers2007, dao2002, essalihi2007, bouvet2008]. However, the situation in humans remains unclear. To this day “regression” studies mostly investigated calcification and vascular stiffness in isolation but not in relation to each other. More studies with a focus on diverse markers of tissue function are needed to provide definitive answers.
“Mature” calcification may regress poorly (e.g. as suggested by [bas2006]) or not at all. One reason is that hydroxyapatite is very insoluble compared to octacalcium phosphate and amorphous calcium phosphates [lomashvili2009, bonucci/demer], suggested to be precursors occurring during the mineralisation process.
This is supported by the observation that areas remaining calcified were not affected by treatment in the WVK model [essalihi2004]. Clinical evidence confirms that highly calcified atheromas are not easily amenable to therapy, perhaps due to lower levels of inflammation and lipids [nicholls2007] or frank inaccessibility. Indeed the least calcified plaques responded best to antihypertensive or lipid-lowering therapies [bruining2009, nicholls2007]. Conceivably, non-responders in other pilot trials could have had locally advanced calcification.
Additionally, there may be tissue-specific differences in the potential for regression. In the carotid only minimal or no regression was observed in response to darusentan and amlodipine [essalihi2005].

Spontaneous regression
The natural history of coronary calcification is not incompatible with regression.
For instance, in the MESA cohort (n=5756) regression was seen in ~13% of the sample population [kronmal2007], albeit it is unsure whether this resulted from interscan variation or not. In another study, a small cohort of paediatric kidney patients (n=52), regression was seen in four and one patient, with a baseline CAC score of 140, showed complete disappearance [civilibal2009].
Similarly, spontaneous regression has been documented in many cases of non-vascular calcification, e.g. tumoral calcinosis [okada2004], rheumatic calcification [weinberger1979], pseudoxanthoma elasticum [bryant1979] or heterotopic ossification of diverse origin [van_der_linden1984, sferopoulos1997]. Those cases may illustrate the body’s universal ability to resorb pathologic mineral deposits and the apparent overrepresentation of young patients is intriguing and consistent with calcification as a disease of old-age.
Study of such rare cases is difficult, but rigorous analysis of regression may help elucidate the mechanisms involved. Furthermore, it remains to be seen if therapies that facilitate the endogenous capacity for regression can be successfully developed.
Animal studies
Recently Bas et al. demonstrated macrophage-mediated regression of calcitriol-induced calcification suggesting that natural regression may occur once the causative factor is removed [bas2006].
In the aorta and stomach, however, regression was still incomplete after nine weeks and tissue function was not assessed. Additionally, the observed increase and absolute levels of calcium tended to be lower than those seen in human aging [elliott1994] and studies in the VDN and WVK model show modest or no regression [atkinson1994, essalihi2004]. Therefore the data is compatible with the view that calcification does not regress completely by itself.
Research in non-human primates lends further support to this hypothesis. Dietary induced intimal calcification does not regress in rhesus monkeys after a 3.5 year period of cholesterol lowering on a regular diet (and in some experiments seems to progress). Although, other plaque components may regress partly [stary2000].
Similar results were obtained in long term studies of other species. Regression of atherosclerotic calcifications in non-human primates, swine and other types of calcification in rabbits and cows is modest if it takes place at all [hnichen1990].

Surgical regression
For advanced valvular calcification insertion of bioprosthetic valves remains the only definitive treatment and surgical excision is an option for some types of extra-vascular calcification. For instance, complete resolution of tumoral calcinosis is possible after parathyroidectomy and/or excisional biopsy (n=25)[thakur1999].
A small study found that coronary calcification stabilises after kidney transplantation and may show non-significant regression from 6 to 12 months (n=31)[oschatz2006].
Select conditions may benefit from advances in tissue engineering and surgical techniques. Though, in general the invasive nature and lack of benefit for wide-spread or diffuse forms of calcification (e.g. MEC) limits the utility of surgical approaches.

Pharmacological regression
Countless modalities prevent or reduce calcification in animal models, for instance antihypertensive drugs [dao2002], pre-treatment with polyphenols, Al- or FeCl3 [atkinson2008], calcimimetics [lopez2009], chelators [herd1964], glitazones [gaillard2005], hydrogen sulfide [wu_hydrogen_2006], estrogen [manson2007], statins, pyrophosphate [schibler1968] or teriparatide [shao2003]. For most, their clinical impact on calcification and outcomes, if any, has not been firmly established.
This review summarises only some of the most promising approaches towards regression.
Pilot studies [davis2009, maniscalco2004] suggest that regression of intimal calcium deposits can be facilitated using a combined approach and can be as high as 63%.

Endothelin-A receptor antagonists
Darusentan, a selective endothelin-A receptor antagonist, has been shown to regress VC in the WVK model and bosentan to prevent VC in the VDN model [wu2003]. Regression partially restored function, reducing pulse pressure and the collagen/elastin ratio [dao2002]. The purported mechanism of action is a transient increase in carbonic anhydrase, acidification and resorption of calcium deposits.
Interestingly, bosentan has shown some promise as a treatment of digital ulcers in systemic sclerosis [dhillon2009], a disease often associated with extravascular calcification. Although preliminary results are encouraging, human studies are still lacking.

Numerous animal studies showed that bisphosphonates prevent vascular calcification approximately at therapeutic, anti-resorptive doses (see [toussaint2009] for a short review).  Pleiotropic effects beyond bone resorption including physiochemical inhibition of mineralisation and direct effects on the vasculature could contribute to their efficacy.
However, a recent study found that inhibition of calcification better correlated with suppression of bone formation than resorption. Therefore higher doses than expected may be necessary in humans [lomashvili2009].
Even though case-reports are mixed, some report considerable regression of calcinosis [ramjan2009] and several small studies in Japan found cyclical etidronate to be of benefit [toussaint2009]. However, larger studies of different bisphosphonates (ibandronate, alendronate) failed to show benefits. Among newer nitrogen-containing bisphosphonates risedronate is associated with reduced incidence of stroke [steinbuch2002] and improved arterial elasticity in a small open-label trial [luckish2008].
It is tempting to speculate that the conflicting results can be explained by differential effects of newer and older bisphosphonates and/or the mode of administration (cyclical vs. other).

Vitamin K
Vitamin K is thought to exert its beneficial effects by serving as a cofactor for γ-carboxylation of glutamate residues on a range of proteins, prominently, MGP and Gas6. High doses prevent and regress calcification in the VDN and WVK model, respectively [seyama1996, schurgers2007].
Vitamers may differ in their effects: At common dietary intakes the different menaquinones (vitamin K2), but not phylloquinone (vitamin K1), may protect from cardiovascular calcification and disease. Observational studies support this hypothesis, for instance the prospective Rotterdam study [geleijnse2004]. While cross-sectionally menaquinone intake was inversely associated with CAC [beulens2009] and breast artery calcification [maas07] (although, the latter became insignificant after adjustment).

Two preliminary interventional studies have been performed: In the first one, 1000 mcg/day of phylloquinone (and 400 IU/day of vitamin D) given over three years prevented the age-related decline in vascular elasticity [braam2004]. In the second, CAC progression was slowed by 6% in adherent subjects (500 mcg/day) [shea2009].
The amount of vitamin K1 needed to maximise vascular MGP-carboxylation is unknown, but at least 1000 mcg are necessary for maximal carboxylation of osteocalcin [binkley2002] and vitamin D is known to increase MGP expression [fraser1988]. Considering those two points, the latter study may underestimate the efficacy of a better dosing scheme. Several studies of vitamin K and VC are now underway.

Calcium channel blockers
Several drugs of this class can modulate pathologic calcification.
Diltiazem represents a promising treatment for various disorders involving ectopic calcification. The drug prevents calcification in some animal models [thompson1992], but human evidence is limited to case-series:
Diltiazem eliminated or drastically improved calcification in cases of scleroderma [palmieri1995, sharma09], dermatomyositis [oliveri1996] and other conditions. Although, one group found no clear benefit on subcutaneous calcification [vayssairat1998].
Verapamil is similarly effective in animal models [thompson1992], but may be clinically inferior [palmieri1995].
Dihydropyridines (e.g. amlodipine) can prevent and partly regress calcification in animal models [essalihi2007] and were shown to slow down progression of CAC [motro2001]. However, those modest benefits did not translate into better clinical outcomes as compared to diuretics [epstein2001].
Vinpocetine is claimed to have eliminated tumoral calcinosis in a small case-series (n=8)[ ueyoshi1992] and shows beneficial effects on calcification in a model of experimental atherosclerosis [yasui1989].

Phosphate homeostasis
Observational trials in the population at large suggest that serum phosphate, even within the reference range, may predispose to CVD and VC [kanbay2009]. The hypothesis is supported by recent data from NHANES III, which confirmed an additive risk of elevated serum alkaline phosphatase and makes a strong case for the importance of the phosphate/pyrophosphate ratio [tonelli2009].
Interestingly, a recent prospective study found phosphate binders to benefit survival of hemodialysis patients with normal phosphate levels (>3.7mg/dl) [isakova2009].
Different phosphate binders are used. Aluminium containing binders are relatively well-studied and have been historically also used to treat rheumatic calcification, often as adjuvant therapy. However, recently they have fallen into disfavour due to potential toxicity. Counterintuitively, calcium-free phosphate binders have not been proven superior to calcium salts, but a possible benefit cannot be excluded [jamal2009].
Magnesium carbonate is an emerging adjuvant phosphate binder and, at least in dialysis patients may decrease VC independently of phosphate metabolism [wei2006]. It is known that magnesium deficiency enhances CAC progression in swine [ito1990] and that the mineral may have important effects on cellular calcium homeostasis.
Probenecid, a drug known to increase phosphate excretion, has been used with some success in the treatment of calcification, further underlining the importance of phosphate metabolism.

Sodium thiosulfate (STS)
is effective in experimental uremia and other models. In humans STS has been used as an experimental treatment of tumoral calcinosis, urolithiasis, calciphylaxis [subramaniam2008] (even in a patient with normal renal function [hackett2009]) and may be able to slow CAC progression in hemodialysis patients [adirekkiat2010].
At least two trials in ESRD patients are exploring this treatment.

Doxycycline prevents calcification in animals, for instance in the WVK and VD model as well as after sub-dermal implantation (see [bouvet2008] for a recent discussion). Early human studies also documented benefits:
A treatment called “comET” consisting of tetracycline HCl, EDTA and a range of supplements was  investigated in an observational, open-label trial of questionable design. After four months “responders” (n=44) showed a 14% decrease in calcium score, but apparently there was no effect across the whole group (n=77) [maniscalco2004].
A small open label study using 50 to 100 mg minocycline as a treatment for cutaneous calcinosis reported modest decreases of calcium deposits [robertson2003].
Beneficial effects likely stem from non-selective MMP inhibition and in the case of atherosclerotic disease, perhaps strong anti-inflammatory effects. Alternative hypotheses attribute the effects to antibiotic and “nanobactericidal” activity, but as of yet they are not supported by strong evidence.

5. Summary and outlook
Systemic therapies
Countless case-reports detail the use of pharmacotherapy to treat and regress calcification, yet synergies of established treatments remain largely unexplored both in model organisms and in the clinic. Combined regimens of two or more compounds that have been shown to mitigate calcification and are unlikely to interact negatively are a possible avenue of research. Although, difficult to implement, this may be a necessary and appropriate step in the treatment of vascular calcification.
Diltiazem and a bisphosphonate [oliveri1996] or phosphate binder have been used together on at least one occasion [sharma09]. In fact phosphate binders are regularly combined with other drugs to treat chronic kidney disease and its sequelae.
To recap, phosphate has been suggested to be a neglected, important and modifiable risk factor [kanbay2009]. Although less certain, other dietary and lifestyle factors could play a similar role.
For example, wide-spread vitamin D insufficiency could predispose to a range of diseases [holick2007], including VC. Based on the available evidence vitamin D and K combination therapy seems a prudent avenue of research. However, those two vitamins should not be studied in isolation and interactions with vitamin A could merit further study [fu2008].

Bisphosphonates and pharmacologic doses of vitamin K2 are another interesting combination. Both are used in the treatment of osteoporosis, relatively safe and may modulate pathologic calcification. Furthermore, at clinically relevant doses, they show additive effects on calcification, as well as tropoelastin and MGP levels in vitro [saito2007].
In theory the above or other anti-osteoporotic drugs could synergise with therapies that reduce calcification at the cost of bone-loss (see below).
Another example, tetracyclines and low dose flurbiprofen show synergistic effects on proteinase inhibition [lee2004] and could be explored in models of calcification.

A link between bone loss and calcification has been known for a long time [warburton2007].
Several treatments that have shown promising efficacy in attenuating VC have unexpectedly neutral or beneficial effects on physiologic mineralisation, e.g. vitamin D, K, magnesium and anti-resorptive use of bisphosphonates. Those results imply that pathologic calcification might be treated without aggravating osteoporosis, another disease of old age.

Alternatively, if age-related osteoporosis could be controlled, more efficacious, anti-mineralising treatments which work at the cost of bone could be developed and used intermittently. Bone being by far the biggest reservoir of calcium would suffer considerably less from systemic calcium loss and recover faster than other calcium deposits.
For example, the induction of metabolic acidosis is an effective way to prevent calcification in vivo and is a powerful promoter of hydroxyapatite dissolution in vitro, but is associated with side-effects on bone [mendoza2008]. Interestingly, regression associated with the calcification-inhibitor osteopontin may also ocurr via acidification [steitz2002].
A negative calcium and, based on recent data, especially phosphate balance, should accelerate dissolution and resorption of mineral - partly via a decreased calcium-phosphate product. Phosphate binders are routinely used to that effect, especially in uremia, but any drugs that induce phosphaturia and hypophosphatemia are potential candidates.
Interestingly, STS may exert its effects both via acidosis and reduction of available calcium (while also being a strong antioxidant). Comprehensive studies of STS, metabolic acidosis and calcium-phosphate-balance in non-uremic calcification are lacking.

Possible targeted therapies include catheter based delivery of anti-calcifying agents, gene therapy, cell therapy, immunotherapy and selective stimulation of phagocytosis. Currently most ‘targeted’ approaches must be delivered to the vasculature directly via catheter [sharif2004].
Medial calcification is particularly inaccessible and some authors have suggested that the dense ECM is impermeable to vectors as small as 70-100nm [richter2000]. Which is a potential problem for cell, gene and immunotherapy. Another important issue is sparing vulnerable but long lived elastic tissue. It will be essential to minimise damage and if necessary to weigh harms against benefits from decalcification.

Catheters can be used to deliver various substances: First, physiochemical inhibitors e.g. acids, crystallisation inhibitors, chelators or a combination thereof. Likely, prolonged exposure would be necessary. Thus feasibility of this approach will depend on our ability to design vectors with certain characteristics. Optimally, a non-viral, biodegradable vector, with high affinity for hydroxyapatite allowing sustained-release of H+ ions could be employed.
Second, drugs, especially those with a strong affinity for calcium, should reach higher concentrations via this route (e.g. bisphosphonates, tetracyclines). Third, delivery of peptides or vectors carrying nucleic acids. If long term expression were possible, targeted peptides would become an extraordinarily promising option for delivery to the media [ogawa2009].

Gene therapy could be used to express inhibitors or suppress stimulators of calcification. Keeping with the regression paradigm, the endothelin-osteopontin-carbonic anhydrase triad is an attractive target. Alternatively, highly effective inhibitors like MGP or perhaps fetuin-A could be overexpressed locally, or, if feasible, stimulators like alkaline phosphatase inhibited.
Several animal studies have shown that downregulation of cbfa1/Runx2, an early master regulator of osteoblast differentiation, via siRNAs can prevent heterotopic ossification [xue2009].
For the treatment of advanced calcification additional or ‘downstream’ osteogenic transcription factors (and their effectors) may be preferable targets. Possible candidates include Smads [xue2009] and BMP–Msx2–Wnt signaling [shao2007] or perhaps the AP-1 or Sp family (including osterix) [jensen2010].
Fortunately, therapies targeting atherosclerotic calcification can indirectly benefit from advances in gene therapy being already developed for restenosis, atherosclerosis and other conditions. Among therapies currently in clinical development, expression of tissue inhibitors of metalloproteinases (TIMPs) holds promise for calcifying disorders.
However, depending on the combination of vector and delivery system several limitations need to be overcome: low transfection rates of the media, short-lived expression, tissue damage by the vector or delivery system and systemic dissemination. Interestingly, use of a “potent secretory transgene product“ could offset low transfection rates [sharif2004].
Nonetheless - and despite early promise - clinical development of vascular gene therapy has been arduous.

Cell therapy against VC aims to deliver or induce local osteoclast-like cells. Apart from delivery, induction and maintenance, matrix degradation via osteoclast proteases like MMP-9, is a possible stumbling block. A recent study, however, provides proof of concept that osteoclasts can limit calcification without apparent elastin degradation [simpson2007].

Immunotherapy includes tolerisation and vaccination approaches, i.e. conceivably immunisation against pro-calcifying factors, or calcium deposits [jahnen-dechent2008]. The difficulty of exploiting subtle differences between pathologic and physiologic calcification may explain why this idea has remained a theoretical proposal.
Regardless, immunotherapeutic approaches are already under investigation for atherosclerosis and their progress may benefit other fields. Immunotherapy may not be an ideal solution, though, as medial, in contrast to valvular and intimal, calcification is very inaccessible and thought to occur without extensive inflammation.

Enhancement of phagocytosis. The natural phagocytic ability of macrophages, VSMCs or other local cells could be promoted directly; by ameliorating phagocytic dysfunction (e.g. senescence); or indirectly by opsonisation of calcium deposits (via OPN, immunotherapy) or apoptotic bodies (via fetuin-A). Benefits and risks need to be investigated, because non-selective enhancement may aggravate atheroma [schrijvers2007] and inflammation as well as matrix degradation may be paradoxically enhanced [schrijvers2007, jahnen-dechent2008].
Macrophages have been associated with regression in vivo [bas2006] and although fibroblasts or chondrocytes do phagocytose mineral in vitro, it is unknown if the same applies to vascular cells, especially VSMCs. Different lines of evidence suggest this is indeed the case: VSMCs naturally phagocytose apoptotic bodies and it is the only plausible hypothesis to explain swift regression of medial calcification by vitamin K [schurgers2007].

To summarise, confirmation is needed whether atherosclerotic calcification is best treated pre-emptively, as long as it is better amenable to therapy and poses a higher risk of events. Anti-calcific therapy can potentially enhance the effects of anti-atherogenic treatments. The treatment of MEC and valvular calcification may be beneficial at all stages.
Vascular calcification most probably worsens tissue function and the totality of evidence suggests that the disease is not immutable and theoretically avoidable or reversible.
Calcification is more dynamic than generally accepted. Spontaneous regression occurs, but is rare and often incomplete, necessitating the development of effective treatments. Studies of different drugs or the natural disease progression sometimes detail considerable regression that cannot be attributed to variability. Altogether, regression seems within grasp of current or future therapies.

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