Osteoporosis: 1+1+1+1 = more than 4! | The American Chiropractor | MAY 2022

Osteoporosis: 1+1+1+1 = more than 4! | The American Chiropractor | MAY 2022

Osteoporosis is the most common bone disease worldwide, causing millions of fractures and consequent mortality.(1) With a growing elder population, it has an ever-increasing impact on both individual and public health. Escalating rates of osteoporosis over the last decades demands successful primary prevention and treatment targeting improved bone health. This article highlights two osteoporosis studies using natural compounds with excellent outcomes.

Currently, dual-energy X-ray absorptiometry (DXA) is the standard of care for assessing bone mineral density (BMD). Tightly correlated with fracture risk, BMD provides a means of assessing bone loss or gain over time. DXA results are expressed as a T-score.

There are important interventions to both maintain and restore BMD. Unfortunately, treatment is often delayed until the patient’s skeleton becomes osteoporotic.(2)

Pharmacologic interventions can reduce fracture risk, but lack of compliance is associated with morbidity and mortality.(3-4) Also, increasing numbers of patients decline pharmacotherapy due to potential adverse effects. These include esophageal and breast cancers,(5-6) atypical femur fractures,(7) osteonecrosis of the jaw,(8) and atrial fibrillation.(9)

Currently, the typical nonpharmacologic prevention/ treatment protocol is calcium and vitamin D; a strategy proven to be largely inadequate.(10,11)  Several micronutrients have been identified in the scientific literature as vital for bone health. Depletion, inadequate intake, and impaired digestion may contribute to skeletal compromise. However, assessment and maintenance of nutritional intake have been limited almost exclusively to calcium and vitamin D.(12)

Clinical trials have investigated the effect of single nutrients with regards to bone health. The stated bias that combination nutrient intervention is less credible than isolated elements or compounds is questionable. The living skeleton is highly vascularized, metabolically active, and constantly responding to its environment. Bone consists of organic compounds (mostly collagen type 1 protein) and inorganic calcium hydroxyapatite (Ca10 (P04)6 (OH)2), plus other minerals.(13) Two osteoporosis studies investigating the use of combinations of natural compounds for osteopenic and osteoporotic subjects offer a convincing counterargument.(14,15)

Seventy-seven patients met the inclusion criteria and complied with the one-year protocol. At the start of the study, patients were either osteoporotic (22/77), osteopenic (36/77), or normal (19/77). Of these patients, 29 reported lack of success with previous use of bisphosphonate medication, and 48 declined drug therapy.

The year-long COMB trial had some limitations; small sample size and the lack of a placebo-controlled group. One year negated the possibility of long-term follow up for sustained gains in BMD and ongoing safety. However, the results were impressive, with significant improvements in BMD in both the femoral neck and total spine, comparable to the most successful osteoporosis prescription medications.

In addition, the inclusion of 29 of the 77 patients who failed to respond to bisphosphonate therapy, represents a selection bias that may underestimate the potential benefit of the COMB protocol for the general population.

The MOTS study looked at the effect of a supplement combination on osteopenia. Twenty-two osteopenic postmenopausal women completed a one-year trial. The subjects were randomized into placebo (11/22) and treatment (11/22) groups. This selective trial excluded women with normal BMD, perimenopause, osteoporosis, osteopenia being treated with medication, and blood pressure/cholesterol-lowering/antipsychotic medications.

Skeletal changes were measured via BMD, serum bone markers, and fracture risk probability (FRAX®).

The MOTS trial showed significant increases in BMD, seen at the lumbar spine and femoral neck. As compared with baseline, the treatment group had a 6.48% lower fracture risk, while the placebo group had a 10.82% increase in fracture risk. This is a total of 17.2% less fracture risk for the treatment versus placebo groups.

A strength of the MOTS study was in the thorough preand post-measurements of BMD, serum markers of bone formation and resorption, inflammation, serum melatonin sulfate, sleep quality, vitamin D, and the numbers of bone-forming osteoblasts versus bone-resorbing osteoclasts. There was improvement in each of these measures. The compounds selected for both the COMB and MOTS trials were all evidence-based in regard to bone health.

Studies that investigated DHA (a component of fish oil) intake and osteoporosis find a positive relationship on both BMD and bone turnover markers.16'19

Many studies focused on vitamin D and bone health with positive and negative results. In reviewing negative studies, several items need to be understood.

The current recommended daily allowance for vitamin D is 600 to 800 IU/day. Many researchers state that this intake is far too low. Blood levels of vitamin D are easily measured via 25,OH-vitamin D. The current thresholds for normal versus insufficient versus deficient are as follows:

Though research suggests these reference ranges to be suboptimal, even at those levels, the rates of vitamin D deficiency range from 42 to 95% in the United States. Vitamin D insufficiency and deficiency is a worldwide problem.20'24

In many of the negative studies, vitamin D supplements were given without testing the study participants’ initial levels and used modest doses (e.g., ;800 IU/day); too low to meaningfully impact study outcomes.25 Both COMB and MOTS used 2,000 IUs per day; an amount many researchers consider to be on the low end of a therapeutic dose.

Vitamin K2 has been shown to prevent bone loss, reduce the incidence of fractures, and modestly increase bone density while improving or preserving bone quality.2627 Additionally, vitamin K, especially K2M7, has been demonstrated to have a synergistic effect with vitamin D, further promoting bone health.28'31

Strontium can be prescribed as a pharmacologic dose (2 grams of strontium) or as a supplement (400 to 800 mg of strontium citrate). Strontium ranelate, a prescription item, is associated with an increase in BMD and fragility fracture reduction.32'37 A high dose can be detrimental and cause a decrease of bone calcium content,38 dissolution of mineralized bone,39 disruption of bone architecture,40 and lower BMD.41

At lower supplemental doses, studies show increases in both bone formation rate and trabecular bone density.41 Low doses are not associated with any mineralization defect4243 and lead to increased calcium preservation.44 Importantly, low-dose strontium shows the ability to recalcify osteopenic areas characterized by accelerated bone loss and demineralization.4145

Magnesium is required for proper calcium deposition and bone development, working synergistically with vitamin D.46 Insufficient serum magnesium correlates with low BMD and increased bone resorption.47'49

Melatonin is one of the few compounds that indirectly targets osteoblasts to increase bone formation and osteoclasts to reduce bone resorption.50 51

The combinations selected in both the COMB and MOTS studies have significant overlap. Another combination using two over-the-counter products did not have a positive result.52

The author did a search, looking at over 100 products marketed as over-the-counter supplements for bone and was unable to find one that contained an adequate combination of compounds that have been shown to offer therapeutic benefit. Few of these formulas have been included in clinical trials, even fewer in a well-designed trial. Most combinations provide sub-therapeutic doses, so if ever tested in a research setting, would be expected to have a disappointing outcome.

The retail cost of the COMB and MOTS supplement protocols are $0.59/day ($17.70/month) and $0.95/day ($28.50/month), respectively.

Interventions to improve BMD include numerous classes of medications. Poor compliance, failure to improve, intolerance to side effects, and reluctance to pursue medications reduce either their use or effectiveness. The COMB and MOTS studies demonstrate that well-conceived, nonpharmacologic combinations should be included in the discussion of treatments.

Nutrients are the fundamental building blocks of the human body. Supplementation is widely accepted for preventing birth defects, rickets, scurvy, and in the treatment of anemia. The body of evidence linking both the prevention and treatment of osteoporosis with nutrients should also be considered credible.

Combination, rather than single-nutrient therapies, take advantage of the many synergies of bone physiology. The encouraging outcomes of the COMB and MOTS trials provide both a framework and starting points. I look forward to further trials assessing additional nutrients and alternate dosages, leading to further successful options.

Osteoporosis, the most common skeletal disease, is often mistakenly considered an inevitability. In a world too full of pessimism, our profession, once informed, can offer a way out.

Alan Cook, DC, has been in practice since 1989. He ran the Osteoporosis Diagnostic Center (1996-2019), participated in four clinical trials, and lectured nationally. He currently works with the Open Door Clinic system in a multidisciplinary setting and is providing video-based continuing education with EasyWebCE. To see more of his work, log onto:www.EasyWebCE.com

Burge R, Dawson-Hughes B, Solomon D, et al. Incidence and economic burden or osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res. 2007;22(3):465–475. Kanis JA, Melton III LJ, Christiansen C, Johnston CC, and Khaltaev N, “The diagnosis of osteoporosis,” JBMR 1994;9:1137–1141. Hansen D, Bazell C, Pelizzari P, Pyenson B. Medicare cost of osteoporotic fractures: The clinical and cost burden of an important consequence of osteoporosis. https://static1.squarespace.com/static/5c0860aff793924efe2230f3/t/5d76b949deb7e9086ee3d7dd/1568061771769/Medicare+Cost+of+Osteoporotic+Fractures+20190827.pdf. August 2019.  Huas D, Debiais F, Blotman F, et al., Compliance and treatment satisfaction of post-menopausal women treated for osteoporosis, BMC Women’s Health, 2010;10, article 26. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al., Effect of estrogen plus progestin on stroke in postmenopausal women—the women’s health initiative: a randomized trial, JAMA 2003;289, no. 20: 2673–2684.  Shumaker SA, Legault C, Rapp SR, et al., Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women—the women’s health initiative memory study: a randomized controlled trial. JAMA 2003;289, no. 20:2651–2662.  Sellmeyer DE. Atypical fractures as a potential complication of long-term bisphosphonate therapy. JAMA 2010;304, no. 13:1480–1484.  Migliorati CA, Schubert MM, Peterson DE, and Seneda LM, Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer, 2005;104, no. 1:83–93.  Howard PA, Barnes BJ, Vacek JL, Chen W, and Lai SM, Impact of bisphosphonates on the risk of atrial fibrillation. American Journal of Cardiovascular Drugs, 2010;10, no. 6: 359–367. Avenell A, Mak JC, O’Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev. 2014CD000227.  Papaioannou A, Morin S, Cheung AM, et al., 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary, CMAJ 2010;182, no. 17:1864–1873. Baron R. In: Primer on the metabolic bone diseases and disorders of mineral metabolism. Favus MJ, editor. ASBMR; Washington DC: 2003. pp. 1–8. Genuis SJ, Bouchard TP. Combination of Micronutrients for Bone (COMB) Study: Bone Density after Micronutrient Intervention. J Environ Pub Health 2012, Article ID 354151. https://doi.org/10.1155/2012/354151 Maria, S, Swanson MH, Enderby LT, et al. Melatonin-micronutrients Osteopenia Treatment Study (MOTS): a translational study assessing melatonin, strontium (citrate), vitamin D3 and vitamin K2 (MK7) on bone density, bone marker turnover and health related quality of life in postmenopausal osteopenic women following a one-year double-blind RCT and on osteoblast-osteoclast co-cultures. Aging, 2017;9(1): 256–285. https://doi.org/10.18632/aging... L. A. Weiss, E. Barrett-Connor, and D. Von Muhlen, Ratio of n-6 to n-3 fatty acids and bone mineral density in older adults: the Rancho Bernardo study, American Journal of Clinical Nutrition, vol. 81, no. 4, pp. 934–938, 2005.  Albertazzi P and Coupland K, Polyunsaturated fatty acids. Is there a role in postmenopausal osteoporosis prevention, Maturitas, 2002; 42, no.1: 13–22.  Salari P, Rezaie A, Larijani B, and Abdollahi M, A systematic review of the impact of n-3 fatty acids in bone health and osteoporosis, Medical Science Monitor, 2008; 14, no. 3: RA37–RA44. Farina EK, Kiel DP, Roubenoff R, et al. Protective effects of fish intake and interactive effects of long-chain polyunsaturated fatty acid intakes on hip bone mineral density in older adults: the Framingham Osteoporosis Study. Am J Clin Nutr 2011;93:1142-1151. https://doi.org/10.3945/ajcn.110.005926 Fu M, Tian Y, Zhang T, et al. Comparative study of DHA-enriched phosphatidylcholine and EPA-enriched phosphatidylcholine on ameliorating high bone turnover via regulation of the osteogenesis-related Wnt/B-catenin pathway in ovariectomized mice. Food Funct 2020;11:10094-10104. https://doi.org/10.1039/D0FO01... Holick M: High prevalence of vitamin D inadequacy and implications for health. Mayo Clinic Proc 2006, 81:353–373. O’Malley G, Mulkerrin E. Vitamin D insufficiency: a common and treatable problem in the Irish population. Ir J Med Sci. 2011;180:7-13. Harwood RH, Sahota, Gaynor K, Masud T, and Hosking DJ, A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: the Nottingham Neck of Femur (NoNOF) study, Age and Ageing 2004;33, no. 1: 45–51.    Iwamoto J, Takeda T, Sato Y. Menatetrenone (vitamin K2) and bone quality in the treatment of postmenopausal osteoporosis. Nutr Rev. 2006; 64:509–17. doi: 10.1111/j.1753‐4887.2006.tb00184.x  Ballegooijen AJ, Pilz S, Tomashitz A, Grubler MR, Verheyen N. The synergistic interplay between vitamins D and K for bone and cardiovascular health: A narrative review. Int J Endocrin 2017; Article ID 7454376, 12 pages https://doi.org/10.1155/2017/7... Kanellakis S, Moschonis G, Tenta R, Schaafsma A, van den Heuvel EG, Papaioannou N, Lyritis G, Manios Y. Changes in parameters of bone metabolism in postmenopausal women following a 12‐month intervention period using dairy products enriched with calcium, vitamin D, and phylloquinone (vitamin K(1)) or menaquinone‐7 (vitamin K (2)): the Postmenopausal Health Study II. Calcif Tissue Int. 2012; 90:251–62. doi: 10.1007/s00223‐012‐9571‐z D. Feskanich, P. Weber, W. C. Willett, H. Rockett, S. L. Booth, and G. A. Colditz, Vitamin K intake and hip fractures in women: a prospective study, American Journal of Clinical Nutrition, vol. 69, no. 1, pp. 74–79, 1999. Genuis SJ and Schwalfenberg GK, Picking a bone with contemporary osteoporosis management: nutrient strategies to enhance skeletal integrity, Clinical Nutrition 2007;. 26, no. 2: 193–207. Meunier PJ, Roux C, Seeman E, et al., The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis, NEJM 2004; 350, no. 5: 459–468.  Marie PJ, Ammann P, Boivin G, and Rey C, Mechanisms of action and therapeutic potential of strontium in bone, Calcified Tissue International 2001; 69, no. 3:121–129.  Ortolani S and Vai S, Strontium ranelate: an increased bone quality leading to vertebral antifracture efficacy at all stages, Bone 2006;38, no. 2:S19–S22.  Eisenberg E, The biological metabolism of strontium, in Biological Mineralization, I. Zipkin, Ed., pp. 435–442, John Wiley & Sons, New York, NY, USA, 1973.  Cabrera WE, Schrooten I, De Broe ME, and D’Haese PC, Strontium and bone, Journal of Bone and Mineral Research 1999;14, no. 5: 661–668.  Grynpas MD and Marie PJ, Effects of low doses of strontium on bone quality and quantity in rats, Bone 1990;11, no. 5: 313–319.  Marie PJ, Garba MT, Hott M, and Miravet L, Effect of low doses of stable strontium on bone metabolism in rats, Mineral and Electrolyte Metabolism 1985;11, no. 1:5–13.  Riyat M and Sharma DC, An experimental study of the effect of strontium pre-treatment on calcium release from carious and non-carious teeth, Biological Trace Element Research 2010;133, no. 3: 251–254.  Skoryna SC, Metabolic aspects of the pharmacologic uses of trace elements in human subjects with specific references to stable strontium, in Trace Substances in Environmental Health-XVIII, pp. 3–23. Castiglioni S, Cazzaniga A, Albisetti W, Maier JAM. Magnesium and Osteoporosis: Current State of Knowledge and Future Research Directions. Nutrients. 2013; 5(8):3022-3033. https://doi.org/10.3390/nu5083022 Rude RK and Gruber HE, Magnesium deficiency and osteoporosis: animal and human observations, Journal of Nutritional Biochemistry 2004; 15, no. 12:710–716. Stendig-Lindbergl G, Tepper R, Leichter I. Trabecular bone density in a two-year controlled trial of peroral magnesium in osteoporosis. MagnesiumResearch 1993;6. 2.155-163. Mederle OA, Balas M, Ioanoviciu SD, Gurban CV, Tudor A, Borza C. Correlations between bone turnover markers, serum magnesium and bone mass density in postmenopausal osteoporosis. Clin Interv Aging. 2018;13:1383-1389. doi:10.2147/CIA.S170111 Li T, Jiang S, Lu C, et al. Melatonin: Another avenue for treating osteoporosis? JPR 2019;66: e12548 https://doi.org/10.1111/jpi.12548 Amstrup, AK, Sikjaer, T, Mosekilde, L. et al. Melatonin and the skeleton. Osteoporos Int 2013;24:2919–2927. https://doi.org/10.1007/s00198... Cook A, Pennington G. Phytoestrogen and Multiple Vitamin/Mineral Effects on Bone Mineral Density in Early Postmenopausal Women: A Pilot Study. J Women’s Health & Gender-Based Medicine 2004;11. https://doi.org/10.1089/152460902753473462

Images Powered by Shutterstock