Acute and ongoing exposures should be assessed and, to the degree possible, identified before starting heavy metal chelation. Sources of acute and ongoing metal exposure are many but may include exposure via food, drink, respiratory, skin, and others. Bone turnover can also cause metals to be released from bone and appear on heavy metal testing.

Any person at risk for increased bone turnover should be screened prior to heavy metal chelation for bone turnover. This allows a safe chelation procedure, appropriate consent, and reduces the risk of chelating metals from active bone turnover.

Data [5,8] shows lower levels of metals (blood or urine) associated with lower levels of osteopenia and osteoporosis. This is because people with greater bone turnover have more release of metals from bone. Heavy metals are also associated with lower bone mineral density [5,8,13].

QUESTIONS:

  1. Is this a problem (What is the propensity of heavy metals to incorporate into bone)?
  2. Who should be assessed (What are the average ages and comorbid health issues to consider prior to testing bone turnover)?

PROBLEM?

As for heavy metals becoming incorporated into bone, many references support this pathologic effect. Two papers reviewed for this update include one which not only affirms bone uptake of toxicant metals but also outlines the extensive variety of pathogenic effects toxicant metals have on bone. [11] The other paper used bone biopsies with metal assays from 65 patients including two pathological groups and a health control group. [13] This paper found not only higher heavy metals in the pathological (osteoporotic) groups but also a likely causal connection between heavy metals and osteoporosis.

WHO SHOULD BE SCREENED?

Age and comorbidity are additional considerations in who we decide to add bone turnover screening prior to chelation therapy. Clinicians are generally trained that peak bone mineral density is reached in the second decade and begins to degrade in the third and fourth decades. Indeed, in healthy individuals, decreases in bone mineral density do start in the early to middle forties in men and women. [12] Based on available data it would be wise to screen for increased bone turnover in healthy men and women starting in their forties. There are other factors in addition to age that should be considered which may lower the bone turnover screening age.

The two main categories (beyond age) are inflammatory and chronic diseases and medication induced bone loss:

  • Inflammatory and other diseases can trigger bone loss at any age. [3] This includes children with rheumatological or other inflammatory conditions, as young as 13 years of age in some studies. [7]
  • Medication induced bone loss is more widespread than often considered. An enlightening quote from a review paper helps to show the initial scope [10] “While glucocorticoids (GCs) are most commonly associated with drug-induced osteoporosis, the use of several other therapeutic agents increase the risk of significant bone loss and fracture. These medications include: 
  • proton pump inhibitors (PPIs), 
  • selective serotonin receptor inhibitors (SSRIs), 
  • thiazolidinediones (TZDs), 
  • anticonvulsants, 
  • medroxyprogesterone acetate (MPA), 
  • hormone deprivation therapy, 
  • calcineurin inhibitors, 
  • chemotherapies, and 
  • anticoagulants.” 

In addition, other papers [15] have even broader pharmacological categories triggering bone density loss.

WHY IS THIS SCREENING CRITICAL?

If the process of chelation begins while there is increased bone turnover and net loss you will have high metals on the testing as long as the patient is alive (as you are speeding metal elimination from the bone). Unless you stop or slow the bone turnover you will never chelate them appropriately as you are pulling heavy metals and nutrient minerals out while the bones are unstable.

To oppose these dangers require:

  • Bone turnover assessment
  • Supportive detox
  • Bone support to slow bone turnover and clean up metals as they move out of the bone.

Who should we test for bone turnover prior to initiating chelation?

  • All patients of any gender in their forties and older.
  • Any patient younger than their forties with a chronic disease, especially rheumatological or inflammatory diseases.
  • Pediatric patients with rheumatological diagnoses or chronic inflammatory diseases.
  • Patients of any age on medications known to cause bone loss.
  • Post chemotherapy patients.
  • Hyperthyroidism.

MONITORING:

Testing may show elevated lead (and other metals) if bone turnover is elevated regardless of how long chelation therapy lasts. Also, elevated metals on a non-challenged urine toxic metals test, normed to NHANES [16], will be seen for the same reason. This has created trouble (legal and patient management) for practitioners who “chelated for months” only to find the lead and other metals never decrease.

While DEXA testing is recommended for benchmarking and management of osteopenia and osteoporosis, the requirement in assessing and managing a chelation patient may need to be more dynamic. Crosslink testing such as NTx and CTX are dynamic and easier to perform (and less costly) to the patient. They, if used as serial measures, can track trends in bone turnover. NTx can be performed on urine or serum whereas CTX is generally a serum test. Which test is chosen does not matter as long as the same test is used for serial testing through the course of treatment and follow-up.

NTx – N-Telopeptide Cross-links (NTx), Urine (Serial Monitor) is available at most reference laboratories.

  • Subsequent specimens for comparison should be collected at approximately the same time of day as the baseline specimen.
  • Note that the “NTx” in the example below (and reported via most labs) is the N-telo/Creat. Ratio (not the raw N-Telopeptide value).
  • The reference ranges for NTx in urine, as measured in BCE/mM creatinine, are as follows [Mayo Labs]: Male: 21-83, Female (premenopausal): 17-94, Female (postmenopausal): 26-124

In anyone (male or female) with suspected bone turnover (see list above) obtain an NTx, (urine) and if greater than:

  • 90 in a male
  • 100 in a premenopausal female
  • 130 in a postmenopausal female

Initiate bone health support (see below) and re-test at least every 6 months.

Elevated non-challenged urine toxic metals (over NHANES 95th percentile) should have bone turnover in the differential diagnosis.

Carboxy-terminal collagen crosslinks (CTX) is an analogous test to the NTx. NTx can be obtained via serum or urine, where CTX is normally serum only. As the goal is to test, on serial measurements, the rate of bone turnover to protect the patient during chelation either test may be used. CTX and NTx are considered equally efficacious for this purpose. [1] In the therapeutic guidelines below if using CTX simply substitute CTX for NTx, and the clinical process is the same.

NTx levels of elevation [Mayo Labs]:

                                                                       Mild to Moderate        Marked Elevation

  • Male:                                                     90 – 134                                             135 +
  • Premenopausal female:                     100 – 149                                             150 +
  • Postmenopausal female:                    130 – 194                                             195 +

Although these ranges appear to be arbitrary, they do reflect standard NTx/bone turnover norms.

THERAPEUTIC APPROACHES TO LOWERING BONE TURNOVER:

Mild to moderate bone turnover elevation: 

  • Consent / Procedure:
    • Chelation may be held until bone turnover is slowed.
    • If chelation proceeds for any reason, the patient should consent to initiating detoxification and chelation as usual but acknowledge that there will be added bone health support in the protocol.
    • Patient needs to acknowledge the inclusion of baseline NTx, and that a repeat NTx will be run at the first re-check of the Urine Toxic Metals (UTM) (Pre and Post challenge).
    • All follow up UTM are Pre and Post challenge, with the Pre challenge normed to NHANES.

Marked bone turnover elevation: 

  • Consent / Procedure:
    • If chelation therapy proceeds, follow the above.
      • Consent the patient that they need to include aggressive bone support while chelating and that follow up NTx and UTM (Pre and Post UTM) are required for safety.
      • They should be consented that their UTM levels will likely stay high until the bone turnover is under control.
    • If chelation therapy is held temporarily:
      • Consent the patient and explain the dynamics of bone release of heavy metals and that it is recommended to perform baseline NTx (with Pre/Post UTM) and treat the bone health aggressively for 3 months while gentle detoxification is supported.
        • This can include glutathione, fiber and bowel regularity and low weekly doses of oral DMSA to “mop up” metals that are circulating. 
  • The author usually gives 250 – 500 mg DMSA orally, QHS two nights a week for this purpose.

It is critical to notify the patient of the dynamics, and that they cannot expect metal levels on the UTM to decrease until bone turnover stabilizes. Clinically, testing and monitoring are most critical.

BONE SUPPORT IDEAS:

  • Physical support [aka ‘Super Heavy/Super Slow’ workout programs] “Osteostrong” or “Perfect Workout” are examples.
  • Vitamin D Sufficient to keep 25(OH) and 1,25(OH) in upper 50 – 75% of normal range [See resources below]
  • Vitamin K2: (MK-4) 45 – 90 mg / day [4] or (MK-7) 180 – 250 mcg / day [6]
  • Vitamin C, Ca/Mg/Zn etc. (Any other nutrients as clinically indicated).
  • Boron 3-6 mg QD
  • Strontium Citrate 500-700 mg BID [9,14] **
  • Bisphosphonate Rx if indicated [2]
  • Appropriate hormone replacement therapy

** The use of high dose strontium citrate is indicated in non-responsive bone loss.

REFERENCES:

1.       Australian Journal for General Practitioners. Bone turnover markers. May, 2013. VOL 42-No 5, pages 285—287. https://www.racgp.org.au/afp/2013/may/bone-turnover-markers –NTX versus CTX?

2.       Eom S-Y, Yim D-H, Hong S-M, et al. Changes in blood and urinary cadmium levels and bone mineral density according to osteoporosis medication in individuals with an increased cadmium body burden. Human & Experimental Toxicology. 2018;37(4):350-357. doi:10.1177/0960327117705425

3.       Hanna B, Sakiniene E, Gjertsson I, Pullerits R, Jin T. Osteopenia/osteoporosis develops in the early phase of disease in patients with idiopathic inflammatory myopathies. Scand J Rheumatol. 2021 Sep;50(5):398-401. doi: 10.1080/03009742.2021.1882558. Epub 2021 Apr 15. PMID: 33856955.

4.       Iwamoto J. Vitamin K₂ therapy for postmenopausal osteoporosis. Nutrients. 2014 May 16;6(5):1971-80. doi: 10.3390/nu6051971. PMID: 24841104; PMCID: PMC4042573.

5.       Jalili C, Kazemi M, Taheri E, Mohammadi H, Boozari B, Hadi A, Moradi S. Exposure to heavy metals and the risk of osteopenia or osteoporosis: a systematic review and meta-analysis. Osteoporosis Int. 2020 Sep;31(9):1671-1682. doi: 10.1007/s00198-020-05429-6. Epub 2020 May 2. PMID: 32361950.

6.       Knapen MH, Drummen NE, Smit E, Vermeer C, Theuwissen E. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013 Sep;24(9):2499-507. doi: 10.1007/s00198-013-2325-6. Epub 2013 Mar 23. PMID: 23525894.

7.       Lien G, Flatø B, Haugen M, Vinje O, Sørskaar D, Dale K, Johnston V, Egeland T, Førre Ø. Frequency of osteopenia in adolescents with early-onset juvenile idiopathic arthritis: a long-term outcome study of one hundred five patients. Arthritis Rheum. 2003 Aug;48(8):2214-23. doi: 10.1002/art.11097. PMID: 12905475.

8.       Lim, Hee-sook & Lee, Hae-Hyeog & Kim, Tae-Hee & Lee, Bo-Ra. (2016). Relationship between Heavy Metal Exposure and Bone Mineral Density in Korean Adult. Journal of Bone Metabolism. 23. 223. 10.11005/jbm.2016.23.4.223.

9.       Marx D, Rahimnejad Yazdi A, Papini M, Towler M. A review of the latest insights into the mechanism of action of strontium in bone. Bone Rep. 2020 Apr 24;12:100273. doi: 10.1016/j.bonr.2020.100273. PMID: 32395571; PMCID: PMC7210412.

10.   Panday K, Gona A, Humphrey MB. Medication-induced osteoporosis: screening and treatment strategies. Ther Adv Musculoskelet Dis. 2014 Oct;6(5):185-202. doi: 10.1177/1759720X14546350. PMID: 25342997; PMCID: PMC4206646.               

11.   Rodríguez J, Mandalunis PM. A Review of Metal Exposure and Its Effects on Bone Health. J Toxicol. 2018 Dec 23;2018:4854152. doi: 10.1155/2018/4854152. PMID: 30675155; PMCID: PMC6323513.

12.   Rondanelli M, Gasparri C, Perdoni F, Riva A, Petrangolini G, Peroni G, Faliva MA, Naso M, Perna S. Bone Mineral Density Reference Values in 18- to 95-Year-Old Population in Lombardy Region, Italy. Am J Mens Health. 2022 Sep-Oct;16(5):15579883221119363. doi: 10.1177/15579883221119363. PMID: 36305327; PMCID: PMC9619280.

13.   Scimeca M, Feola M, Romano L, Rao C, Gasbarra E, Bonanno E, Brandi ML, Tarantino U. Heavy metals accumulation affects bone microarchitecture in osteoporotic patients. Environ Toxicol. 2017 Apr;32(4):1333-1342. doi: 10.1002/tox.22327. Epub 2016 Jul 27. PMID: 27464007.

14.   Taylor BA, Bezuhly M, Brace M, Carter M, Hong P. Effect of strontium citrate on bone consolidation during mandibular distraction osteogenesis. Laryngoscope. 2017 Jul;127(7):E212-E218. doi: 10.1002/lary.26623. Epub 2017 May 9. PMID: 28485552.

15.   Vestergaard P. Drugs Causing Bone Loss. Handb Exp Pharmacol. 2020;262:475-497. doi: 10.1007/164_2019_340. PMID: 31889220.

16. NHANES summary: https://www.consultdranderson.com/nhanes-2015-updates-from-the-fourth-report/