Combatting Brain Calcification in Some Autism (and Bipolar and Schizophrenia) and Osteoprotegerin (OPG) as a potential biomarker, implicating Cav1.2

In today’s post there is more supposition than normal, but plenty of anecdotal evidence.  It follows on from the previous post that suggested calcification might be an issue in some types of autism.  As we know, many unrelated biological dysfunctions can lead to autism, but there do seem to be some commonly affected pathways.

This subject is definitely worthy of much more detailed study than my post, which is based on an initial review of the science.  Some leading researchers, like Persico and Courchesne are fully aware of the issue.  I am not sure who would undertake such a study.  There is no physician specialty dedicated solely to osteoporosis, so we are lacking experts.  The bone-vascular axis is worthy of more study, as much for heart disease as autism.

A variety of medical specialists treat people with osteoporosis, including internists, gynecologists, family physicians, endocrinologists, rheumatologists, physiatrists, orthopaedists, and geriatricians.  If you do not know what a physiatrist is, I also had to look it up.  Physical Medicine and Rehabilitation (PM&R) physicians, also known as physiatrists, treat a wide variety of medical conditions affecting the brain, spinal cord, nerves, bones, joints, ligaments, muscles, and tendons.

 

Overview

There is more support for the potential use of calcium channel blockers that affect Cav1.2, via its effect on calcification by modulating Osteoprotegerin (OPG).  OPG is known to be elevated in autism and its two older brothers schizophrenia and bipolar.

It appears that in some people with severe brain calcification, that shows up on CT scans, biphosphanate drugs can be helpful, but do not actually shrink the calcification, perhaps they stop it growing.

Biphosphanate drugs used to treat osteoporosis are not without side effects in some people.

Some people have disturbed calcium homeostasis as a result of drugs they are taking, for example antiepileptic drugs.

So-called “chelation” using powerful intravenous antioxidants has been shown in the TACT clinical trial to reduce future heart problems, but only in people with diabetes. Diabetics are known to have disturbed calcium homeostasis leading to calcification, heart disease and osteoporosis.

In some counties intravenous antioxidants have long been given to people with diabetes to treat its main side effects but not to clear calcification.  In those countries this is seen as perfectly safe and routine. Preventative care for diabetics is actually rather poor in the UK and US.

Vitamin K plays a key role in calcium homeostasis and in some people just giving large amounts of this vitamin has the required therapeutic effect.  Unless given alongside blood thinning drugs, it is claimed that high dose Vitamin K does not have side effects.

Perhaps the most common osteoporosis therapy, calcium plus vitamin D is shown in some trials to be of no value whatsoever.  This therapy would most likely be ill advised in autism.

Osteoprotegerin (OPG)

Osteoprotegerin (OPG) is a cytokine involved in calcification and inflammation.

Osteoprotegerin has been used experimentally to decrease bone resorption in women with postmenopausal osteoporosis.

 It has been particularly related to the increase in cardiovascular risk in patients suffering from diabetes

Interestingly it has been shown that the L type calcium channel Cav1.2 regulates Osteoprotegerin (OPG) expression and secretion.

A NASA space shuttle flight in 2001 tested the effects of osteoprotegerin on mice in microgravity, finding that it did prevent increase in resorption and maintained bone mineralization.  Space flight is not good for your bones.

Osteoprotegerin levels are elevated in people with bipolar and schizophrenia.

Osteoprotegerin levels in patients with severe mental disorders

Severe mental disorders are associated with elevated levels of inflammatory markers. In the present study, we investigated whether osteoprotegerin (OPG), a member of the tumour necrosis factor receptor family involved in calcification and inflammation, is elevated in patients with severe mental disorders.

Methods

We measured the plasma levels of OPG in patients with severe mental disorders (n = 312; 125 with bipolar disorder and 187 with schizophrenia) and healthy volunteers (n = 239).

The mean plasma levels of OPG were significantly higher in patients than in controls (t₅₃₁ = 2.6, p = 0.01), with the same pattern in bipolar disorder and schizophrenia. The increase was significant after adjustment for possible confounding variables, including age, sex, ethnic background, alcohol consumption, liver and kidney function, diabetes, cardiovascular disease, autoimmune diseases and levels of cholesterol, glucose and C-reactive protein.

Conclusion

Our results indicate that elevated OPG levels are associated with severe mental disorders and suggest that mechanisms related to calcification and inflammation may play a role in disease development.

As shown in the study below, many inflammatory cytokines are elevated in autism, just look at those insulin-like growth factor binding proteins.  Osteoprotegerin is a modest 500% of what it might be expected to be in non autism.

Neuroglial Activation and Neuroinflammation in the Brain of Patients with Autism

Chelation

Because of the continuing non-debate in scientific terms about vaccines and autism, it is unlikely that there will ever be any study about calcium chelation and autism.  Rather than admit that in a small number of cases vaccination may trigger mitochondrial disease and result in autism, there is complete denial, at least in public. In private it is an open secret.

The planned chelation trial in autism was banned, on “safety grounds”.

It looks to me that the enemy is not mercury or other heavy metals, the problem is much less exotic. 

Oxidative Stress

Most people with autism have oxidative stress, which should be improved by any potent antioxidant.  Agents used to chelate metals have to be potent antioxidants.

Calcification

In some yet to be determined percentage of people they potentially have disturbed calcium homeostasis resulting in some calcium deposits in the brain.  Those chelating to remove, most likely non-existing, “toxins” may sometimes be reducing harmful calcification.

Fortunately there has been a very large study, called TACT, on de-calcification (calcium chelation) in Coronary Heart Disease.

One large group of people at risk from low bone density are those with diabetes.

Patients with diabetes, who made up approximately one third of the 1,708 TACT participants, had a 41 percent overall reduction in the risk of any cardiovascular event; a 40 percent reduction in the risk of death from heart disease, nonfatal stroke, or nonfatal heart attack; a 52 percent reduction in recurrent heart attacks; and a 43 percent reduction in death from any cause.

   

Chelation for Coronary Heart Disease

§  Patients with diabetes, who made up approximately one third of the 1,708 TACT participants, had a 41 percent overall reduction in the risk of any cardiovascular event; a 40 percent reduction in the risk of death from heart disease, nonfatal stroke, or nonfatal heart attack; a 52 percent reduction in recurrent heart attacks; and a 43 percent reduction in death from any cause. In contrast, there was no significant benefit of EDTA treatment in participants who didn't have diabetes.

Source:  https://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_446204.pdf

From the Mayo Clinic:-

          Results of trial to assess chelation therapy (TACT) study presented

 A further review from TACT just looking at patients with diabetes:- 

The Effect of an EDTA-based Chelation Regimen on Patients with Diabetes and Prior Myocardial Infarction in TACT

Patients with diabetes:-

Patients without diabetes (no benefit over placebo):-

Treatment

The 10 component 500 mL intravenous solution in TACT consisted of 3 g of disodium EDTA, adjusted downward based on estimated glomerular filtration rate; 7 g of ascorbic acid; 2 g of magnesium chloride; B-vitamins, and other components (eTable 4). The placebo solution consisted of 500 mL of normal saline and 1.2% dextrose (2.5 g total). The solution was infused over at least 3 hours through a peripheral intravenous line weekly for 30 weeks and then biweekly to bimonthly to complete 40 infusions.

Background

The Trial to Assess Chelation Therapy (TACT) showed clinical benefit of an ethylene diamine tetraacetic acid (EDTA-based) infusion regimen in patients 50 years or older with prior myocardial infarction (MI). Diabetes prior to enrollment was a pre-specified subgroup.

Methods and Results

Patients received 40 infusions of EDTA chelation or placebo. 633 (37%) had diabetes (322 EDTA, 311 placebo). EDTA reduced the primary endpoint (death, reinfarction, stroke, coronary revascularization, or hospitalization for angina) [25% vs 38%, hazard ratio (HR) 0.59, 95% confidence interval (CI) (0.44, 0.79), p<0.001] over 5 years. The result remained significant after Bonferroni adjustment for multiple subgroups (99.4% CI (0.39, 0.88), adjusted p=0.002). All-cause mortality was reduced by EDTA chelation [10% vs 16%, HR 0.57, 95% CI (0.36, 0.88) p=0.011], as was the secondary endpoint (cardiovascular death, reinfarction, or stroke) [11% vs 17% HR 0.60, 95% CI (0.39, 0.91), p=0.017]. After adjusting for multiple subgroups, however, those results were no longer significant. The number needed to treat to reduce one primary endpoint was 6.5 over 5 years (95% CI (4.4, 12.7). There was no reduction in events in non-diabetics (n=1075, p=0.877), resulting in a treatment by diabetes interaction (p=0.004).

Conclusions

Post-MI diabetic patients age 50 or older demonstrated a marked reduction in cardiovascular events with EDTA chelation. These findings support efforts to replicate these findings and define the mechanisms of benefit. They do not, however, constitute sufficient evidence to indicate the routine use of chelation therapy for all post-MI diabetic patients.

Effect of the Polypill on Calcification

Oral antioxidants like NAC and Alpha lipoic Acid given daily will have both a direct and indirect “chelating” effect.

Alpha-Lipoic Acid Promotes Osteoblastic Formation in H2O2 -Treated MC3T3-E1 Cells and Prevents Bone Lossin Ovariectomized Rats.

 

Alpha-lipoic acid (ALA), a naturally occurring compound and dietary supplement, has been established as a potent antioxidant that is a strong scavenger of free radicals. Recently, accumulating evidences has indicated the relationship between oxidative stress and osteoporosis (OP). Some studies have investigated the possible beneficial effects of ALA on OP both in vivo and in vitro; however, the precise mechanism(s) underlying the bone-protective action of ALA remains unclear. Considering this, we focused on the anti-oxidative capacity of ALA to exert bone-protective effects in vitro and in vivo. In the present study, the effects of ALA on osteoblastic formation in H(2)O(2) -treated MC3T3-E1 pre-osteoblasts and ovariectomy (OVX)-induced bone loss in rats were investigated. The results showed that ALA promoted osteoblast differentiation, mineralization and maturation and inhibited osteoblast apoptosis, thus increasing the OPG/receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) ratio and leading to enhanced bone formation in vitro and inhibited bone loss in vivo. Further study revealed that ALA exerted its bone-protective effects by inhibiting reactive oxygen species (ROS) generation by down-regulating Nox4 gene expression and protein synthesis and attenuating the transcriptional activation of NF-κB. In addition, ALA might exert its bone-protective effects by activating the Wnt/Lrp5/β-catenin signaling pathway. Taken together, the present study indicated that ALA promoted osteoblastic formation in H(2)O(2) -treated MC3T3-E1 cells and prevented OVX-induced bone loss in rats by regulating Nox4/ROS/NF-κB and Wnt/Lrp5/β-catenin signaling pathways, which provided possible mechanisms of bone-protective effects in regulating osteoblastic formation and preventing bone loss. Taken together, the results suggest that ALA may be a candidate for clinical OP treatment.

Statins are known to promote bone health.

Statins and osteoporosis:new role for old drugs.

Osteoporosis is the most common bone disease, affecting millions of people worldwide and leading to significant morbidity and high expenditure. Most of the current therapies available for its treatment are limited to the prevention or slowing down of bone loss rather than enhancing bone formation. Recent discovery of statins (HMG-CoA reductase inhibitors) as bone anabolic agents has spurred a great deal of interest among both basic and clinical bone researchers. In-vitro and some animal studies suggest that statins increase the bone mass by enhancing bone morphogenetic protein-2 (BMP-2)-mediated osteoblast expression. Although a limited number of case-control studies suggest that statins may have the potential to reduce the risk of fractures by increasing bone formation, other studies have failed to show a benefit in fracture reduction. Randomized, controlled clinical trials are needed to resolve this conflict. One possible reason for the discrepancy in the results of preclinical, as well as clinical, studies is the liver-specific nature of statins. Considering their high liver specificity and low oral bioavailability, distribution of statins to the bone microenvironment in optimum concentration is questionable. To unravel their exact mechanism and confirm beneficial action on bone, statins should reach the bone microenvironment in optimum concentration. Dose optimization and use of novel controlled drug delivery systems may help in increasing the bioavailability and distribution of statins to the bone microenvironment. Discovery of bone-specific statins or their bone-targeted delivery offers great potential in the treatment of osteoporosis. In this review, we have summarized various preclinical and clinical studies of statins and their action on bone. We have also discussed the possible mechanism of action of statins on bone. Finally, the role of drug delivery systems in confirming and assessing the actual potential of statins as anti-osteoporotic agents is highlighted.

Verapamil via the effect on OPG should have positive effect on bones and reduce vascular calcification.

Use of Biphosphanate Drugs to Treat Brain Calcification

Primary brain calcification in patients undergoing treatment with the biphosphanate alendronate

Brain calcification might be associated with various metabolic, infectious or vascular conditions. Clinically, brain calcification can include symptoms such as migraine, Parkinsonism, psychosis or dementia. The term Primary Brain Calcification was recently used for those patients without an obvious cause (formerly idiopathic) while Primary Familial Brain Calcifications was left for the cases with autosomal dominant inheritance. Recent studies found mutations in four genes (SLC20A2,PDGFRB, PDGFB and XPR1). However, these genes represent only 60% of all familial cases suggesting other genes remain to be elucidated. Studies evaluating treatments for such a devastating disease are scattered, usually appearing as single case reports. In the present study, we describe a case series of 7 patients treated with Alendronate, a widely prescribed biphosphanate. We observed good

tolerance and evidence of improvements and stability by some patients. No side effects were reported and no specific symptoms related to medication. Younger patients and one individual continuing a prescription (prior to study commencement) appeared to respond more positively with some referred improvements in symptoms. Biphosphanates may represent an excellent prospect for the treatment of brain calcifications due to their being well tolerated and easily available. Conversely, prospective and controlled studies should promptly address weaknesses found in the present analysis.

Patient 3. A 43-year-old man, one of seven children born to the same mother (described below as Patient 4), presented with rapid progression of parkinsonism. In the last 5 years, a progressive presentation of general bradykinesia, rigidity, and paresis in the right arm had developed. He had previously been an active individual with regular employment. Prior to recruitment, this patient had been on carbidopa/levodopa, which was continued throughout the duration of the present study. Genetic screening identified a SLC20A2 mutation (c.1483 G > A)3, and the patient was placed on alendronate therapy.

Patient 4. This 84-year-old woman presented with mild depression, late-stage parkinsonism, and large calcifications (10.85 cm3) in the basal ganglia and cerebellum. She is the mother of Patient 3 and carries the same SLC20A2 mutation. This patient had been taking alendronate for 10 years due to a diagnosis of osteoporosis. Intriguingly, she presented with fewer symptoms than her son, despite being 41 years old older.

We chose alendronate due to its availability, safety, and comfortable dosing schedule (oral administration, once a week). Etidronate probably works via a different mechanism (bulk action binding to hydroxyapatite) than

the newer amino bisphosphonate alendronate (inhibition of osteoclasts). This might explain why the effects seen in our series were less dramatic than those seen in patients treated with etidronate. Thus, while alendronate has a more convenient dosing schedule and, possibly, fewer side effects, a larger clinical trial should consider the choice of bisphosphonate carefully.

To date, there is no specific treatment for primary brain calcification; the main goal is symptom management.

Clinicians should make sure that the idiopathic/primary profile is accurately defined to rule out any underlying organic cause, e.g., in non-idiopathic basal ganglia calcification caused by abnormal calcium regulation, such as in primary endocrine disorders.

Bisphosphonates represent the only effective (although still anecdotal) treatment that could have wider applications in basal ganglia calcification. Prospective, controlled studies should be conducted to address the weaknesses of the present manuscript and establish a definitive analysis of bisphosphonate therapy for primary brain calcification. Furthermore, the excellent tolerability profile of alendronate in primary brain calcifications suggests that a trial in asymptomatic patients could help address the potential benefit of this strategy to control symptoms in younger patients.

Conclusion

Bisphosphonates may be applicable, safe and change the natural progression of primary brain calcifications, especially in younger patients and across prolonged periods. Nevertheless, future studies with adequate design should answer remaining questions.

Metabolic Bone Diseases

There are numerous things that can affect the bone-vascular axis including various  metabolic diseases.  This is rather beyond the scope of an autism blog, but if you are interested here is a link.

Imaging Findings and Evaluation of Metabolic Bone Disease

Conclusion

Unless you have evidence of osteoporosis, or a brain scan showing calcification, it might be rather extreme to take a biphosphanate drug like Fosamax.

If you already take oral NAC , ALA or L-carnitine you have a pretty potent therapy which would target any calcification, if indeed it existed.  Intravenous ALA, as used my Monty’s Grandad for years, should be even more effective as it is for diabetic neuropathy.

Those using verapamil appear to have another layer of protection against calcification. I did suggest to Agnieszka that elevated OMG might indeed be the biomarker needed for the use of verapamil in Autism. Remember to contact her to participate in her study.

Verapamil use in Autism – Request for Case Reports from Parents

Vitamin K2 is claimed to be extremely safe unless you are taking a blood thinning drug like Warfarin, that are Vitamin K antagonists.

Some studies claim great results from K2, while some others are more mixed.  It is likely that depending on what underlying dysfunction exists, high dose K2 may help or do nothing.  It is clear that low amounts of K2 are damaging.

So K2 would seem worthwhile trialing.  It is found in the not so pleasant tasting Natto.  Vitamin K (more K1 than K2) is found in broad-leafed vegetables.  The excellent Linus Pauling Institute reviewed all the vitamin K evidence and concluded people should:-

 “eat at least one cup of dark green leafy vegetables daily”

This brings me back to where I started the previous post with the Mediterranean diet, rich in dark green leafy vegetables.

Intravenous infusion of antioxidants looks like a very good idea for people with diabetes.  Where we live this has been standard practice for years, where Monty’s grandad goes twice a year for 10 days of ALA infusion, the rest of the year he is prescribed oral ALA.  This is given to control diabetic neuropathy, but clearly a side effect is that it will reduce the likelihood of a heart attack or stroke.

I have no doubt IV infusion of ALA would be beneficial for some with autism, but I think they might get sufficient benefit from oral ALA or indeed NAC.

I wish the FDA would permit the “chelation” autism trial in the US, I have no doubt it would show a positive effect, but not for the reasons put forward by DAN doctors and the chelation cults. 

The TACT chelation trial in older people showed that the therapy was very well tolerated.  IV ALA therapy is also well tolerated.

Public health officials should not fear the truth.  In the long run the truth is the best policy and when given all the facts the public are not stupid.  If vaccination is in the interest of their child, enough parents will happily cooperate. The Herd Immunity Threshold (HIT) is the percentage of people who need to be vaccinated.  HIT is 95% for measles.  Therapies used at Johns Hopkins exist to minimize the possible damaging effect on mitochondria and never give paracetamol/acetaminophen to children after a vaccination.