An abundance of recent research has drawn attention to the potential, toxic effects of elements associated with metal alloy implants and prosthesis devices. This medically-induced issue warrants serious consideration since it is well established that a variety of toxic elements can have additive or even synergistic toxic effects, and we are all subjected to at least low-level chronic exposure to xenobiotic elements from the environment. Further, too many patients have also been subjected to gadolinium-enhanced MRIs prior to implantation of metal-on-metal prostheses. This review will highlight the potential local and systemic clinical consequences of the persistent release of specific medically introduced metals, and address the current recommendations for assessing the levels of the metals in patients. Rationale for possible clinical interventions to mitigate toxic effects of the persistently released metals will also be discussed.

Dental Metal Alloy Implants

Dental implants composed primarily of titanium (Ti) have been used for decades to replace missing teeth or to support crowns and bridges. In the vast majority of cases, the implants help maintain the integrity of the underlying bone. Some patients develop immediate or delayed hypersensitivity to the Ti alloy implants. Of potential concern is corrosion, especially when dissimilar metals (mercury, nickel) are in the mouth and galvanic currents are created(1).  There is a paucity of research regarding local and systemic effects of Ti dental implants in part because of difficulties in accurately measuring Ti levels (polyatomic interferents)(2,3). Potential adverse effects of corrosion-released Ti alloys will be further discussed with respect to metal-on-metal total hip arthroplasty, but it is clear that Ti ion release by electro-corrosion is far less a concern in comparison to metal on metal wear. Titanium levels can be assessed accurately in serum, blood or plasma, by a few commercial laboratories(4). Normal serum Ti levels in the absence of implants are < 1 ng/ml(5). More recently, ceramic and zirconium dental implants have been used to avoid Ti alloy corrosion issues.

Orthopedic Metal Alloy Implants

It is well established that levels of metals in serum are increased indefinitely following all types of metal-on-metal total hip arthroplasty procedures,(6,7) and there are indeed local and remote adverse tissue responses(8). The long-term physiological responses to elevated levels of the specific metals are largely unknown(7,9). Moreover, there is no acceptable threshold above which serum concentrations of metals such as cobalt, chromium, and titanium are known to be toxic(9); individual variability to toxic effects confounds the issue. Additional concern is heightened by the fact that the procedure is being performed on younger and more active patients, which raises questions of potential reproductive effects(6). In that regard, it has been reported that metal concentrations in blood from neonates whose mothers had metal implants were higher than those of controls(10).

Total hip arthroplasty (THA) is one of the most successful treatments for patients with severe rheumatism and osteoarthritis, and most THA devices remain functionally intact for upwards of 20-plus years. THA can be a necessary blessing or a major calamity. Development of durable and safe prosthetic materials has proven to be a major challenge, and for decades millions of people have received metal-on-metal paired (M/M) THA prostheses. Until very recently the vast majority of prostheses consisted of pairings of alloys of cobalt (Co), chromium (Cr), and molybdenum (Mo) for the acetabular cup and femoral head (Co:Cr:Mo about 60:30;7)(6). The femoral head is attached to a femoral stem/shaft that is composed of Ti alloy; vanadium is a minor component of Ti alloys. The M/M prosthesis bearing surfaces invariably wear and release Co and Cr(3). Rates of wear are highly dependent on device design, surgical technique, level of physical activity and other factors that affect the health of involved bone and surrounding soft tissue. There is controversy about the continuous corrosion of the metals, including the more resistant Ti alloys, but it is apparent that physical wear is by far the biggest factor in M/M THA-induced metallosis.

The primary concern from the orthopedic perspective is excessive wear and failure of the prostheses due to periprosthetic tissue reactions to the metals. The CAM/integrative practitioner is also very concerned about remote tissue deposition and potential systemic toxic effects of the incompatible metal debris. All patients with M/M THA will have elevated levels of Co and Cr in serum as well as in periprosthetic soft tissue and bone, and in remote tissues in the body up to 20 years post-operatively(11,12). Local metallosis can cause pseudotumors (inflammatory soft tissue mass), decreased viability of osteoblastic bone marrow cells, osteoclastic bone resorption (release of lead), necrosis, and infiltration of macrophages, eosinophilic granulocytes, and lymphocytes(13). The net effect can be an aseptic loosening/misalignment of the components that, in turn, further increases wear and release of metal debris. Because it is not possible to assess wear radiographically, the levels of metals in serum (Table 1, below) are used as part of the evaluation of the functional condition of prosthetic implants and decisions regarding revision surgery(14). However, there is limited published data on appropriate reference ranges for the metals, which raises questions regarding the clinical utility of the data. It has been emphasized that elevated serum Co and Cr levels in the absence of corroborating symptoms do not independently predict prosthesis failure(15).)

Serum Metal Concentrations (ng/ml) and Implied Condition of Prosthetic Implants. Data Compiled from Mayo Medical Laboratories.

In addition to local toxic effects, CAM doctors are also very much concerned about systemic effects of the released metal debris. Transition metals such as Co, Cr, Ti, Mo, nickel, manganese, and iron induce production of highly reactive oxygen species (ROS) by Fenton or Fenton-like reactions in fluids in the body. Excessive ROS compromise redox buffering and can diminish levels of quintessential glutathione. The extremely reactive hydroxyl radical is of particular concern because it causes oxidative damage to proteins, lipids, and nuclear and mitochondrial DNA and RNA(16). Clinical studies have linked M/M THA to white blood cell DNA and chromosomal damage(17). However, underpowered epidemiological studies to date have not found increased risk or incidence of cancer(11). Nonetheless, excessive exposure to such metals can result in excessive oxidative stress, inflammation, low levels of quintessential glutathione, and compromised redox capacity. Further, excessive Co has been shown to compromise hepatic cytochrome P450 activity in laboratory rats (Phase I detoxification)(18).

It should be noted that it appears that little if any hexavalent Cr (Cr6) is released from the CoCr alloy prostheses(14). Highly genotoxic Cr6 from occupational/environmental exposure is preferentially taken up, reduced, and retained by red blood cells (RBC). Juxtaposed, implant-derived and dietary trivalent Cr is excluded from RBC. RBC Cr is not elevated in association with M/M THA(11,14,19), It is emphasized that Cr in RBCs is attributable specifically to exposure to Cr(6) and provides no indication of the nutritional status of physiological Cr(19).

The most abundantly released metal from the CoCrMo alloys is Co. Cobalt and Cr particles/ions accumulating in lymph nodes can cause necrosis and fibrosis, and associated inflammation is primarily an immunological response(20). Research regarding systemic toxic effects is rather sparse(21). However there are case reports regarding neurotoxicity and cardiomyopathy associated with the disseminated metal debris, particularly Co(22,23). Possible toxic effects include somatic mutations (animal models), aberrant immune function, impaired renal function, compromised endogenous detoxification (Phases I and II), excessive inflammation, and breakdown of arterial endothelial cell tight junctions(7). Safe levels of serum Co ions have not been established, and Co poisoning is defined by serum Co levels ≥ 5 ng/ml(7).  Is one not to be concerned about potential systemic toxic effects when serum Co levels are 4-10 ng/ml just because a prosthetic implant is thereby implied to be in “good condition”?

Signs and symptoms of arthroprosthetic cobaltism include visual and auditory impairment, tinnitus, vertigo, cardiomyopathy, cognitive dysfunction/dementia, mood disorders, hypothyroidism, peripheral neuropathy, and skin rashes(15,22). Adverse reactions to Co ion release can be clinically silent yet severe, so early detection is very important. The American Academy of Orthopaedic Surgeons generally recommended follow up testing/evaluation of M/M THA patients annually (asymptomatic), and every four-six months with mild symptoms.

Serum Ti levels will be elevated in patients with M/M THA even when only the femoral shaft is composed of Ti alloy(9). Titanium has been long regarded as an inert biocompatible metal due to its corrosion resistance. However, recent studies have shown that Ti and vanadium (minor component of Ti alloys) from non-bearing implant components can be released with potentially consequential effects both locally and systemically. Specifically, Ti may have adverse effects in blood, fibrotic tissues, and osteogenic cells after transport through the circulatory or lymphatic systems(4). That Ti corrosion occurs in bone in the absence of wear was demonstrated in a well-designed long-term study (18 months) in which a Ti wire was implanted into the femurs of rats(4). The corrosion-released Ti increased blood Ti levels, and Ti concentrated primarily in the spleen and lungs. Titanium was also sequestered to a lesser extent in the heart, kidneys, and liver. It has been stated that elevated serum Ti levels associated with prostheses are not necessarily associated with toxicity(5). However, there is a dearth of clinical data regarding potential adverse health effects. The lack of clinical studies is disconcerting since it has been reported that serum Ti levels can be 18 times greater 10 years post-surgery than at baseline; the M/M hip prostheses in the subjects consisted of Ti alloy acetabular sockets (bearing) and Ti femoral stems(9).

Vanadium (V), an element that interferes with a vast array of biochemical reactions, is another metal that is released from THA prostheses. Vanadium is a minor constituent of titanium-aluminum-vanadium alloys used in hip prostheses, both in the femoral stem and less frequently in bearing surfaces (acetabular sockets). Serum V levels are expected to be higher than normal (< 1ng/ml) with Ti-alloy prostheses in good condition (1-2 ng/ml), and even higher with significant prosthesis wear (>5 ng/ml)(15). A case report indicated V toxicity associated with a broken Ti alloy femoral stem and a serum V level of 5.8 ng/ml(24). The patient exhibited sensory-motor axonal neuropathy and bilateral sensorineural hearing loss, and did not have Ti alloy bearing surfaces.

Clinical Intervention

The most fundamental rule of toxicology is to eliminate the exposure(s). Dreadful revision surgery with non-M/M prosthetic materials goes a long way in that regard. However, patients that do not have revisions have perpetual exposure to the offending metals. It is generally recommended that chelation therapy should be reserved for patients who cannot undergo revision. A strong case could be made for consideration of chelation after revision. In one reported case the symptoms of severe arthroprosthetic cobaltism, except deafness, were gradually resolved with DMPS-enhanced decorporation of Co after revision(23). Chelation with EDTA has also been suggested as a treatment option post-revision(25). In animal models of cobaltism, EDTA has been shown to be the most effective chelator(26,27).

The big question is what can be done on an ongoing basis for asymptomatic patients who still bear functional M/M THA prosthetics? Aminothiols such as N-acetyl-cysteine (N-AC) and glutathione (GSH) have been long known to increase Co excretion and decrease tissue Co levels following acute Co intoxication in animal models(26,27). More recently, various aminothiols administered in different forms orally or intravenously were compared with respect to enhancing 60Co excretion in a rat model(28). After five daily doses, intravenous and oral liposomal GSH were most effective at enhancing 60Co excretion; 64% and 47%, respectively. Oral cysteine was slightly less effective in lowering tissue 60Co than IV cysteine. Poorly bioavailable powdered oral GSH was without effect. In patients, the beneficial effects of N-AC to enhance Co excretion have been reported as well(22,27). Of particular interest was the efficacy of very high-dose oral N-AC (300 mg/kg) for ten days to markedly lower blood Co and Cr (up to 87%), and enhance urinary Co excretion(27). In one case the effects of the N-AC to lower blood Co persisted for about six months. That data from the patients who did not undergo revision surgery are very encouraging, but it would seem to make more sense to use an aminothiol at a reasonable dose habitually.

Chelation

Chelation therapy should be given serious consideration for managing the perpetual release of Co and Cr and associated pro-oxidative effects after M/M THA. Selection of a chelating agent, timing of administration, and clinical efficiency are subjects of debate(29,30). Currently there are no established indications for chelation therapy for asymptomatic M/M THA patients. There are case reports regarding chelation with Ca-Na2-EDTA or DMPS for asymptomatic M/M THA patients, but that application has not been appropriately evaluated. EDTA has good affinities for Co, Cr,3 V, and Ti, in vitro,(31) and it has been used to treat severe acute experimental cobaltism (animal models)(32). Intravenous EDTA also enhanced free Cr(3) excretion in human subjects, and significantly decreased oxidative stress and damage to DNA(33). Without revision that uses more compatible prosthetic materials, the source of exposure is still present, and metal levels would no doubt rebound over time after chelation.

Clinical research regarding chelation after M/M THA is long overdue. Intravenous EDTA appears to be the agent of choice, but issues regarding the frequency and number of rounds of periodic chelation are open for discussion. There is no evidence that chelation will adversely affect the integrity of the prostheses or increase the rate of release of the metals from the devices. It is proposed that a protocol incorporating dietary/supplemental antioxidants, and metal conjugating agents (e.g. liposomal GSH, N-AC), and intermittent chelation may greatly ameliorate the potential, local and systemic toxic effects associated with the life-long release of metals in patients with M/M THA prosthetic devices.

What say you?

David Quig, PhD, received his BS and MS degrees in human nutrition from Virginia Tech and a PhD in nutritional biochemistry from the University of Illinois. After a five-year stint as a research associate studying lipid biochemistry and cardiovascular disease at Cornell University, he worked as a senior cardiovascular pharmacologist for seven years with a major pharmaceutical company. For the past 22 years, David has served as the Vice President of Scientific Support for Doctor’s Data, Inc. He has focused on toxic metals, methylation and amino acid metabolism, the clinical application of the biochemistry of endogenous detoxification, and the influence of the gastrointestinal metabolome on health and sustained adverse conditions. David regularly speaks at national and international medical conferences and has facilitated and co-authored an array of studies, spanning exposure and retention of environmental toxicants, nutritional status, and gastrointestinal dysbiosis.

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