Strontium Research
Skoryna SC. Effects of oral supplementation with stable strontium. Can Med Assoc J. 1981 Oct 1;125(7):703-12.
“Although stable strontium is a chemical analogue of, and interacts with, calcium, its absorption in the intestines and its biologic activity do not seem to adversely affect those of calcium - a point of physiologic significance that should be emphasized.”
“Except for bone, animal tissues did not indicate any specific predilection for strontium.”
"This lack of an absorptive limit for strontium does not invalidate the findings of Comar and Wasserman, who have shown conclusively that when equal doses of radioactive calcium and radioactive strontium are administered, calcium is absorbed preferentially and strontium is excreted preferentially."
"... increases in the dietary intake of strontium do cause it to displace bone calcium, but without any deleterious effect until very high doses are taken."
"No other trace element replaces a bulk element in its function."
"These investigations demonstrated that there is a wide margin of safety in the amount of stable strontium intake in human subjects, since doses of up to 1750 mg/d of strontium ion did not produce any side effects."
"The first study demonstrated that humans can retain considerable amounts of strontium ion without any toxic effects, and the study showing high rates of strontium excretion also indicated that strontium is not firmly bound to the crystalline lattice of bone but, after its administration is stopped, is replaced by calcium."
“Toxic or side effects were not reported in subjects who took strontium for years in doses of 200 to 400 mg Sr/d.”
"In human subjects receiving approximately 200 to 300 mg/d of Sr, the strontium:calcium ratio averaged 1:18, compared with 1:2247 in those receiving a standard diet."
"The results of our preliminary electron microscopic studies in rats indicate that when mitochondrial damage was produced in the liver by bromobenzene (02. ml/100 g body weight injected intraperitoneally) the mitochondrial structure was better preserved in animals receiving stable strontium in tap water (0.9 mg/dl) than in control animals."
The body has mechanisms "that maintain a low intracellular level of calcium... yet these same mechanisms allow a relatively high level of intracellular strontium..." This creates the "stabilizing effect of strontium on mitochondrial structure", but then he acknowledges that magnesium is "the element currently regarded as the physiologic stabilizer of mitochondrial structure".
"The replacement of calcium by massive doses of strontium (1.5% to 3% of the dietary intake) is disadvantageous since this has been shown to produce bone changes in experimental animals that were originally described as 'strontium rickets' Similar changes were observed when animals were fed diets low in calcium and high in strontium. The bone lesions produced in these studies cannot be ascribed to the high level of strontium but rather to the decrease of bone calcium".
"According to Gunatilaka the bone content of strontium in animals decrease 'as they make evolutionary advances from aquatic to terrestrial habitat',..."
"There can be little doubt that the cause of osteoporosis is multifactorial and that in any therapeutic approach the formation of bone matrix as well as mineralization should be considered."
Stanley C Skoryna, MD PhD. Effects of oral supplementation with stable strontium. Biomedical Research, CMA Journal, October 1, 1981, Vol 125-703.
“Although stable strontium is a chemical analogue of, and interacts with, calcium, its absorption in the intestines and its biologic activity do not seem to adversely affect those of calcium – a point of physiologic significance that should be emphasized.”
“Changes in the ratio of strontium to calcium in the serum of animals receiving stable strontium… increased linearly with increases in the concentration of the strontium supplement, while the levels of calcium and magnesium remained within normal limits.”
“These results indicate that the level of strontium in the serum rises following an increase in the oral intake of the element, whereas the levels of calcium and magnesium remain virtually unchanged. As a result, the normal ratio of strontium to calcium (1:1550) increases markedly. It was demonstrated originally by Schachter and Rosen, and confirmed by numerous other investigators, that calcium, in addition to being diffused, is absorbed by an active process that is affected by serum levels of vitamin D and, as shown by Wasserman and colleagues, by calcium-bonding protein. Strontium, in comparison, is absorbed from the intestinal lumen by passive diffusion only, as evidenced by the increase in content of strontium in the serum that were in proportion to the amount taken orally.”
“Supplementing a diet that provided the usual amount of calcium with stable strontium…” showed “significant clinical improvement … in 84% of the patients who had taken strontium lactate orally for periods ranging from 3 months to 3 years. These investigations demonstrated that there is a wide margin of safety in the amount of stable strontium intake in human subjects, since doses of up to 1750 mg/d of strontium ion did not produce any side effects.”
Henrotin Y, Labasse A, Zheng SX, Galais P, Tsouderos Y, Crielaard JM, Reginster JY.
Strontium ranelate increases cartilage matrix formation. J Bone Miner Res. 2001 Feb;16(2):299-308.
“Strontium ranelate and SrCl2 both strongly stimulated PG production suggesting an ionic effect of strontium independent of the organic moiety.”
Burlet N, Reginster JY. Strontium ranelate: the first dual acting treatment for postmenopausal osteoporosis. Clin Orthop Relat Res. 2006 Feb;443:55-60.
“Strontium ranelate (5- [bis(carboxy methy I)amino]-2-carboxy-4-cyana-3-thiophenacetic acid distrontium salt) is composed of an organic moiety (ranelic acid) and two atoms of stable strontium. Ranelic acid was chosen as the anion for the strontium salt from 26 other candidates because the resulting salt presented the most suitable physicochemical (eg, percentage of strontium, solubility, no chelating properties, stability) and pharmacokinetic characteristics (eg, bioavailahility, exposure to strontium) for a
therapeutic agent. It also seemed to be well tolerated and safe.”
“A multinational 5-year Phase 3 program for the development of strontium ranelate in the treatment of postmenopausal women, was prefaced by a run-in study (2 weeks to
6 months) to start the normalization of the calcium and vitamin D status of the participants. The supplementation (calcium, 500 or 1000 mg; vitamin D3, 400 or 800 lU), at doses determined by the degree of deficiency was maintained throughout the study of patients randomized to receive strontium ranelate (2 g/day) or placebo in 75 centers in 12 countries.”
“In the clinical studies, strontium ranelate treatment induced a continuous increase in BMD. This increase did not wane during a 3-year period, which is an important credential for long-term therapy. Based on the preclinical evidence, it can be assumed that strontium ranelate sustains this level of' efficacy by its stimulation of bone formation coupled with its decrease in bone resorption.”
Roux C, Reginster JY, Fechtenbaum J, Kolta S, Sawicki A, Tulassay Z, Luisetto G, Padrino JM, Doyle D, Prince R, Fardellone P, Sorensen OH, Meunier PJ. Vertebral fracture risk reduction with strontium ranelate in women with postmenopausal osteoporosis is independent of baseline risk factors. J Bone Miner Res. 2006 Apr;21(4):536-42. Epub 2006 Apr 5.
“Subjects were instructed to take the study drug once daily, at bedtime, or twice daily (one sachet 30 minutes before breakfast and one at bedtime). Most patients (>90%) chose the once daily regimen. Throughout both studies, subjects received daily calcium supplements at lunchtime (up to 1000 mg of elemental calcium, depending on their dietary calcium intake), and vitamin D (400-800 IU depending on the baseline serum concentration of 25 hydroxyvitamin D).”
“Strontium ranelate increases BMD , because of both the atomic number of strontium and the effect of the drug in increasing bone mass.”
Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD, Cannata J, Balogh A, Lemmel EM, Pors-Nielsen S, Rizzoli R, Genant HK, Reginster JY. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004 Jan 29;350(5):459-68.
“We gave calcium and vitamin D supplements to both groups before and during the study.”
"Women were eligible for the study if they were at least 50 years old, had been postmenopausal for at least five years, had had at least one fracture confirmed by spinal radiography (after minimal trauma), and had a lumbar-spine bone mineral density of 0.840 g per square centimeter or less (measured with Hologic instruments)."
"Throughout the study, subjects received daily calcium supplements at lunchtime (up to 1000 mg of elemental calcium, depending on their dietary calcium intake), to maintain a daily calcium intake above 1500 mg, and vitamin D (400 to 800 IU, depending on the base-line serum concentration of 25-hydroxyvitamin D). After a run-in period of 2 to 24 weeks, depending on the severity of the deficiency of calcium and vitamin D, the subjects were randomly assigned to receive 2 g a day of strontium ranelate (two packets a day of a powder that they mixed with water) or placebo powder for 3 years. Subjects were instructed to take the study drug once daily, at bedtime, or twice daily (one packet 30 minutes before breakfast, and one at bedtime). Most subjects (87 percent) chose the once-daily regimen."
Jupsin I, Collette J, Henrotin Y, Bruyere O, Sarlet N, Reginster JY. Strontium ranelate (Fujisawa/Servier). Curr Opin Investig Drugs. 2005 Apr;6(4):435-44.
“Strontium can substitute for calcium in many physiological processes.”
“It is a trace element in the body, but administered strontium is almost exclusively deposited in bone.”
“Calcium deposition in bone was shown in 1952 to be enhanced when strontium is administered, a finding that first hinted at the potential of strontium in the treatment of osteoporosis.”
“…pre-osteoblastic cell replication was enhanced. This effect was specific to pre-osteoblastic cells as there was no change in the numbers of osteoblasts or periosteal cells. A
subsequent increase in bone formation rate was observed ≤ 48 h after the cessation of treatment. These effects appeared to be specific to strontium ranelate, as neither calcium ranelate nor sodium ranelate at the same concentration were able to induce similar effects .”
“Because strontium ranelate dissociates after ingestion, and ranelic acid, acting as a carrier, is not absorbed in the gut, the effects of the drug on bone metabolism reflects the
effects of strontium.”
“Strontium has a strong affinity for bone and is incorporated by two mechanisms: surface exchange, an initial, rapid, saturable mode, depending on osteoblastic activity, whereby strontium is taken up by ionic exchange with calcium, or ion substitution, a slower mechanism involving the incorporation of strontium into the crystal lattice of the bone mineral. Only a small quantity of calcium in the apatite is substituted by strontium at phamacological doses, which results in a rapid decrease in bone strontium levels after treatment withdrawal.”
“In monkeys sacrificed 6 weeks after drug treatment, strontium was detected in significant amounts in the bone tissue, but was less than in those monkeys sacrificed directly after drug treatment, suggesting that there is a rapid clearance of strontium from the bone.”
“However, high doses of strontium induce hypocalcemia due to increased renal excretion of calcium, and high dietary strontium has been reported to produce insoluble
phosphates, leading to phosphorus deficiency. In addition, bone changes similar to rachitic lesions have been noted in animals given high amounts of dietary strontium, especially
if calcium intake is low.”
“Diarrhea was the most frequent gastrointestinal adverse event (6.1% in the strontium ranelate group and 3.6% in the placebo groups: p = 0.02), although this abated after the first 3 months.”
“Strontium ranelate is a bone-seeking element that is closely related to calcium.”
“Experiments showed that the administration of strontium (as carbonate, 0.52 mmol Sr/kg/day) beginning 3 months after ovariectomy in rats reduced the increase in bone turnover induced by estrogen deficiency and restored the bone mineral content lost after ovariectomy.”
“After oral administration of strontium ranelate (2000 mg) to humans, the absolute bioavailability of the compound was 27%. The simultaneous intake of strontium ranelate and calcium remarkably reduces the bioavailability of strontium ranelate.”
“In the absence of bone safety data in patients with severe renal impairment treated with strontium ranelate, the product is not recommended in patients with a creatinine clearance below 30 ml/min.”
Meunier PJ, Reginster JY. Design and methodology of the phase 3 trials for the clinical development of strontium ranelate in the treatment of women with postmenopausal osteoporosis. Osteoporos Int. 2003;14 Suppl 3:S66-76. Epub 2003 Mar 12.
"A total of 9,196 patients (mean age 74.0 years) were recruited to FIRST [22, 23, 241. During FIRST, the vitamin D status and calcium status of the patients were assessed by blood assay and completion of a calcium questionnaire, respectively [25], which allowed the necessary supplementation to be adjusted. Patients received either 0, 500 mg or 1000 mg of calcium and 400 or 800 IU of vitamin D daily, both given at lunch-time as follows: no calcium supplement if daily calcium intake > 1000 mg/day; 500 mg daily supplement if daily calcium intake between 500 mg and 1000 mg; and 1000 mg daily supplementation daily calcium intake < 500 mg. This supplementation was continued during the following intervention trials SOT1 and TROPOS."
"Many patients risked being included with deviations from the protocol, mainly because of previous treatments affecting bone turnover (which sometimes needs a long washout period) and because of concomitant diseases which could shorten the life expectancy (and the therapeutic benefit). Moreover, calcium and vitamin D deficiencies are observed in more than 40-50% of the elderly, contribute to increase the risk of osteoporotic fractures, and are often underestimated.”
“Thus, in FIRST, the calcium and vitamin D status of the patients was assessed and patients started the calcium and vitamin D supplements, in order to avoid inclusions of severely deficient patients in the therapeutic studies. Moreover, the FIRST trial aimed to ensure the inclusion of enough patients sufficiently motivated to follow the 5-year therapeutic studies SOTI and TROPOS, and allowed inclusion of patients in conformity with the requirements of the protocols.”
“The maximum expected duration of FIRST was 6 months, depending on the objectives described above and the local organization of the participating study centers. The minimum duration expected for the patients without any calcium and vitamin D deficiencies was 15 days; those with a severe vitamin D deficiency were to receive at least 3 months of supplementation before being randomized either to SOTI or to TROPOS."
"Severe osteoporosis with high risk of fracture was the primary criterion for inclusion in the phase 3 program."
"To be included in SOTI, in addition to the above criteria, women had to be 50 years or older (with no upper age limit) and had to have at least one documented
osteoporotic vertebral fracture corresponding to at least a grade 1 according to Genant. Moreover, women had to have a mean lumbar BMD 10.840 g/cm2
corresponding to -2.4 standard deviations below the mean peak BMD for premenopausal women."
"To be included in TROPOS, in addition to the above criteria, women had to be 74 years or older. However, for women from 70 to 74 years old, oneadditional risk factor was required, such as a personal history of osteoporotic fracture after the menopause, or residence in a retirement home, or maternal history of osteoporotic fracture. Moreover, women had to have a femoral neck BMD S 0,600 g/cm2, corresponding to -2.5 standard deviations below the mean peak BMD for premenopausal women."
Reginster JY, Meunier PJ. Strontium ranelate phase 2 dose-ranging studies: PREVOS and STRATOS studies. Osteoporos Int. 2003;14 Suppl 3:S56-65. Epub 2003 Mar 12.
"The exact mechanism by which SR exerts these effects is not definitely understood, but may include stimulation of osteoblast proliferation and inhibition of osteoclast formation. Not only modifying bone cell activities, strontium, which is a divalent cation-like calcium-may participate in bone mineralization with the same physical properties than calcium."
"An agent that is able to uncouple bone metabolism could provide a more sustain, long-term increase in bone mass than treatments that inhibit resorption without preventing a corresponding decrease in bone formation."
Reginster JY. Strontium ranelate in osteoporosis. Curr Pharm Des. 2002;8(21):1907-16.
“Certainly, the ranelic acid part of the Strontium ranelate compound contributes nothing to the effects of Strontium on your bones. When you swallow Strontium bound to ranelic acid, the compound splits apart into two Strontium ions and a molecule of ranelic acid. The two are then taken up into the body separately, and while the body absorbs 27% of the Strontium in a pill, it absorbs less than a tenth as much (2.5%) of the ranelic acid. And of the ranelic acid that is absorbed, 93 to 99% is excreted within 7 days without being metabolized by the body.”
Dahl SG, Allain P, Marie PJ, Mauras Y, Boivin G, Ammann P, Tsouderos Y, Delmas PD, Christiansen C. Incorporation and distribution of strontium in bone. Bone. 2001 Apr;28(4):446-53.
“After withdrawal of treatment, the bone strontium content rapidly decreases in monkeys. The relatively high clearance rate of strontium from bone can be explained by the mechanisms of its incorporation. Strontium is mainly incorporated by exchange onto the crystal surface. In new bone, only a few strontium atoms may be incorporated into the crystal by ionic substitution of calcium. After treatment withdrawal, strontium exchanged onto the crystal is rapidly eliminated, which leads to a rapid decrease in total bone strontium levels.”
Ozgur S, Sumer H, Kocoglu G. Rickets and soil strontium. Arch Dis Child. 1996 Dec;75(6):524-6.
“The subjects of this study were children aged 6-60 months living in villages in the Ulas Health Region, Sivas. The villages were divided into two groups according to the amount of strontium in the soil: region 1, > 350 ppm, 650 children; region 2, < 350 ppm, 1596 children. Overall, the prevalence of one or more clinical signs of rickets was 22.9%. The prevalence in region 1 was 31.5% and that in region 2, 19.5%. These values were significantly different (p < 0.001). When other variables which may be relevant to the occurrence of rickets were taken into account, the difference in prevalence persisted. The results suggest that in villages where nutrition is mainly based on grain cereals the presence of strontium in the soil will increase the prevalence of rickets significantly. As a preventive measure, a greater proportion of the foods given to children in these villages should be derived from animal origin, and cereals and drinking water supplies should be obtained from villages with a low soil strontium content, or calcium supplements should be given.”
Kroes R, den Tonkelaar EM, Minderhoud A, Speijers GJ, Vonk-Visser DM, Berkvens JM, van Esch GJ. Short-term toxicity of strontium chloride in rats. Toxicology. 1977 Feb;7(1):11-21.
El-Hajj Fuleihan G. Strontium ranelate--a novel therapy for osteoporosis or a permutation of the same? N Engl J Med. 2004 Jan 29;350(5):504-6.
Grynpas MD, Marie PJ. Effects of low doses of strontium on bone quality and quantity in rats. Bone. 1990;11(5):313-9.
Reginster JY, Deroisy R, Dougados M, Jupsin I, Colette J, Roux C. Prevention of early postmenopausal bone loss by strontium ranelate: the randomized, two-year, double-masked, dose-ranging, placebo-controlled PREVOS trial. Osteoporos Int. 2002 Dec;13(12):925-31.
Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C, Devogelaer JP, Curiel MD, Sawicki A, Goemaere S, Sorensen OH, Felsenberg D, Meunier PJ. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab. 2005 May;90(5):2816-22. Epub 2005 Feb 22.
Reginster JY, Deroisy R, Jupsin I. Strontium ranelate: a new paradigm in the treatment of osteoporosis. Drugs Today (Barc). 2003 Feb;39(2):89-101.
Reginster JY. Strontium ranelate in osteoporosis. Curr Pharm Des. 2002;8(21):1907-16.
Meunier PJ, Slosman DO, Delmas PD, Sebert JL, Brandi ML, Albanese C, Lorenc R, Pors-Nielsen S, De Vernejoul MC, Roces A, Reginster JY. Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis--a 2-year randomized placebo controlled trial. J Clin Endocrinol Metab. 2002 May;87(5):2060-6.
Bone Health is Multifactorial
Ilich JZ, Kerstetter JE. Nutrition in bone health revisited: a story beyond calcium. J Am Coll Nutr. 2000 Nov-Dec;19(6):715-37.
“Osteoporosis is a complex, multi-factorial condition characterized by reduced bone mass and impaired micro-architectural structure, leading to an increased susceptibility to fractures. … Each nutrient is discussed separately, however the fact that many nutrients are co-dependent and simultaneously interact with genetic and environmental factors should not be neglected. The complexity of the interactions is probably the reason why there are controversial or inconsistent findings regarding the contribution of a single or a group of nutrients in bone health.”
Saltman PD, Strause LG. The role of trace minerals in osteoporosis. J Am Coll Nutr. 1993 Aug;12(4):384-9.
“Osteoporosis is a multifactorial disease with dimensions of genetics, endocrine function, exercise and nutritional considerations. Of particular considerations are calcium (Ca) status, Vitamin D, fluoride, magnesium and other trace elements. Several trace elements, particularly copper (Cu), manganese (Mn) and zinc (Zn), are essential in bone metabolism as cofactors for specific enzymes. Our investigations regarding the role of Cu, Mn and Zn in bone metabolism include data from studies with animals on Cu- and Mn-deficient diets. We have also demonstrated cellular deficiencies using bone powder implants, as well as fundamental changes in organic matrix constituents. In clinical studies we have demonstrated the efficacy of Ca, Cu, Mn and Zn supplementation on spinal bone mineral density in postmenopausal women. Each of these studies demonstrated the necessity of trace elements for optimal bone matrix development and bone density sustenance. Osteoporosis is a multifactorial disease with dimensions of genetics, endocrine function, exercise and nutritional considerations. Of particular considerations are calcium (Ca) status, Vitamin D, fluoride, magnesium and other trace elements. Several trace elements, particularly copper (Cu), manganese (Mn) and zinc (Zn), are essential in bone metabolism as cofactors for specific enzymes.”
Miggiano GA, Gagliardi L. [Diet, nutrition and bone health] [Article in Italian] Clin Ter. 2005 Jan-Apr;156(1-2):47-56.
“An adequate intake of alkali-rich foods may help promote a favorable effect of dietary protein on the skeleton. The diet is characterized by food containing high amount of calcium, potassium, magnesium and low amount of sodium.”
Tucker KL. Dietary intake and bone status with aging. Curr Pharm Des. 2003;9(32):2687-704.
“Osteoporosis and related fractures represent major public health problems that are expected to increase dramatically in importance as the population ages. Dietary risk factors are particularly important, as they are modifiable. However, most of the attention to dietary risk factors for osteoporosis has focused almost exclusively on calcium and vitamin D. Recently, there has been considerable interest in the effects of a variety of other nutrients on bone status. These include minerals--magnesium, potassium, copper, zinc, silicon, sodium; vitamins--vitamin C, vitamin K, vitamin B12, vitamin A; and macronutrients--protein, fatty acids, sugars….Together the evidence clearly suggests that prevention of bone loss through diet is complex and involves many nutrients and other food constituents. For many, results remain inconclusive and in some cases contradictory. However, it is increasingly clear that our exposure to a complex of nutrients and food constituents interacts to affect bone status. In addition to identifying the role of individual components, there is a great need to understand the interactions of these factors within diets and, increasingly, in the presence of nutrient supplements.”
Ilich JZ, Brownbill RA, Tamborini L. Bone and nutrition in elderly women: protein, energy, and calcium as main determinants of bone mineral density. Eur J Clin Nutr. 2003 Apr;57(4):554-65.
“Our goal was to examine the relationship between various nutrients and bone mass of several skeletal sites in elderly women, taking into account possible confounding variables. RESULTS:: Magnesium, zinc and vitamin C were significantly related to BMD of several skeletal sites in multiple regression models (controlled for age, fat and lean tissue, physical activity and energy intake), each contributing more than 1% of variance. … Despite the cross-sectional nature of our study we were able to show a significant relationship between BMD and several critical nutrients: energy, protein, calcium, magnesium, zinc and vitamin C. …conclusions about the effects of a single nutrient on bone mass must be given cautiously, taking into account its interaction and co-linearity with others. Understanding relationships among nutrients, not just limited to calcium and vitamin D, but others that have not been investigated to such extent, is an important step toward identifying preventive measures for bone loss and prevention of osteoporosis.”
Nieves JW. Osteoporosis: the role of micronutrients. Am J Clin Nutr. 2005 May;81(5):1232S-1239S.
“There are clear fracture benefits demonstrated in randomized clinical trials of calcium and vitamin D supplementation. The other micronutrient needs for optimizing bone health can be easily met by a healthy diet that is high in fruits and vegetables to ensure adequate intakes for magnesium, potassium, vitamin C, vitamin K, and other potentially important nutrients.”
Marchigiano G. Osteoporosis: primary prevention and intervention strategies for women at risk, Home Care Provid. 1997 Apr;2(2):76-81; quiz 82-3.
“The growth and development of the skeleton begins in early fetal life and continues for nearly two decades in a series of well-defined events. Minerals--particularly calcium but also carbonate, magnesium, sodium, and fluoride--play vital structural and metabolic roles in bone growth and development. However, bone formation also is encouraged by hormones, such as estrogen, and by weight-bearing activity. Living bone is never metabolically at rest; its matrix and mineral stores are being remodeled constantly along the lines of mechanical stress.”
Chapuy MC, Meunier PJ. Prevention and treatment of osteoporosis. Aging (Milano). 1995 Aug;7(4):164-73.
“Regarding the prevention of the late bone loss leading to senile osteoporosis, there is now evidence that the reduction of the secondary hyperparathyroidism induced by calcium and vitamin D insufficiencies through the administration of calcium and vitamin D supplements significantly decreases the hip fracture incidence.”
Magnesium Research (a small sample)
Chou HF, Schwartz R, Krook L, Wasserman RH. Intestinal calcium absorption and bone morphology in magnesium deficient chicks. Cornell Vet. 1979 Jan;69(1):88-103.
“Microscopic examination of the tibiae showed marked alterations in morphology in chicks fed the (low) Mg diet. …The mid-diaphysis was thickened and showed marked reduction in both osteoblast and osteocytie activity. Blood calcium levels were significantly reduced in the Mg deficient chicks. It was concluded that Mg depletion in chicks altered Ca homeostasis primarily by changing bone structure and function.”
Schwartz R, Reddi AH. Influence of magnesium depletion on matrix-induced endochondral bone formation. Calcif Tissue Int. 1979 Nov;29(1):15-20.
“At each stage, plaques (implants) removed from Mg-deficient rats showed retardation in cartilage and bone differentiation and matrix calcification. Magnesium content was markedly reduced when compared to the control plaques. Histological appearance of the matrix-induced plaques confirmed the retardation in bone development and mineralization suggested by the chemical indicators. Most marked was the virtual absence of bone marrow in 20-day-old plaques in Mg-depleted rats. These data show that bone cell differentiation can occur in a severely Mg-depleted environment, although the onset of mineralization and bone remodeling was delayed and bone marrow differentiation was impaired.”
Wallach S. Effects of magnesium on skeletal metabolism.Magnes Trace Elem. 1990;9(1):1-14.
“Magnesium (Mg) makes up 0.5-1% of bone ash and is therefore not a trace element in the skeleton. Mg influences both mineral and matrix metabolism in bone by a combination of effects on hormones and other factors that regulate skeletal and mineral metabolism, and by direct effects on bone itself.”
“Mg depletion adversely affects all phases of skeletal metabolism. In the rat, cessation of bone growth is noted with a decrease in both osteoblast and osteoblast activity, decreased bone formation, osteopenia, increased fragility and development of a form of 'aplastic bone disease'.”
“Bone Mg is uniformly increased in renal insufficiency and may play a role in renal osteodystrophy since improvement has been noted in the osteomalacic component by normalizing the serum Mg. Decreased bone Mg has been reported in alcoholic patients, diabetes and in osteoporosis.”
Wallach S. Relation of magnesium to osteoporosis and calcium urolithiasis. Magnes Trace Elem. 1991-1992;10(2-4):281-6.
“Magnesium influences mineral metabolism in hard and soft tissues indirectly through hormonal and other modulating factors, and by direct effects on the processes of bone formation and resorption and of crystallization (mineralization).”
“With regard to the skeleton, experimental studies have shown that Mg depletion causes a decrease in both osteoblast and osteoclast activity with the development of a form of 'aplastic bone disease'.”
Carpenter TO, Mackowiak SJ, Troiano N, Gundberg CM. Osteocalcin and its message: relationship to bone histology in magnesium-deprived rats. Am J Physiol. 1992 Jul;263(1 Pt 1):E107-14.
“These studies examine effects of brief Mg deprivation on bone histomorphometry and on secretion and synthesis of the specific osteoblast product, osteocalcin. … Mg-deprived rats had diminished bone volume and abnormal histological features consistent with disorganized and chaotic bone remodeling. These findings indicate that low-Mg intake during growth can alter the quality and quantity of bone and suggest that Mg deprivation may contribute to the development of osteoporosis.”
Rude RK, Kirchen ME, Gruber HE, Stasky AA, Meyer MH. Magnesium deficiency induces bone loss in the rat. Miner Electrolyte Metab. 1998;24(5):314-20.
“Disorders in which magnesium (Mg) depletion is common have an associated high incidence of osteoporosis.”
“No increase in bone-forming surface or osteoblast number despite an increase in OC-resorbing surface and OC number strongly suggests impaired activation of osteoblasts and an uncoupling of bone formation and bone resorption. Our data demonstrate that Mg depletion in the rat alters bone and mineral metabolism which results in bone loss.”
Rude RK, Kirchen ME, Gruber HE, Meyer MH, Luck JS, Crawford DL. Magnesium deficiency-induced osteoporosis in the rat: uncoupling of bone formation and bone resorption. Magnes Res. 1999 Dec;12(4):257-67.
“Magnesium (Mg) intake has been linked to bone mass and/or rate of bone loss in humans. Experimental Mg deficiency in animal models has resulted in impaired bone growth, osteopenia, and increased skeletal fragility.”
“Our findings demonstrate a Mg-deficiency induced uncoupling of bone formation and bone resorption resulting in a loss of bone mass. While the fall in PTH and/or 1.25(OH)2-D may explain a decrease in osteoblast activity, the mechanism for increased osteoclast activity is unclear. These data suggest that Mg deficiency may be a risk factor for osteoporosis.”
Rude RK, Gruber HE, Wei LY, Frausto A, Mills BG. Magnesium deficiency: effect on bone and mineral metabolism in the mouse. Calcif Tissue Int. 2003 Jan;72(1):32-41. Epub 2002 Oct 10.
“Insufficient dietary magnesium (Mg) intake has been associated in humans with low bone mass. Mg deficiency in the rat has suggested bone loss is due to increased bone resorption and/or inadequate bone formation during remodeling.”
“This study demonstrates a profound effect of Mg depletion on bone characterized by impaired bone growth, decreased osteoblast number, increased osteoclast number in young animals, and loss of trabecular bone with stimulation of cytokine activity in bone.”
Rude RK, Gruber HE, Norton HJ, Wei LY, Frausto A, Mills BG. Bone loss induced by dietary magnesium reduction to 10% of the nutrient requirement in rats is associated with increased release of substance P and tumor necrosis factor-alpha. J Nutr. 2004 Jan;134(1):79-85.
“Dietary Mg intake has been linked to osteoporosis. Previous studies have demonstrated that severe Mg deficiency [0.04% of nutrient requirement (NR)] results in osteoporosis in rodent models. We assessed the effects of more moderate dietary Mg restriction (10% of NR) on bone and mineral metabolism over a 6-mo experimental period in rats.”
“By 2 mo, profound Mg deficiency had developed as assessed by marked hypomagnesemia and up to a 51% reduction in bone Mg content.”
“Increased bone resorption was suggested by an increase in osteoclast number… These data demonstrated that a Mg intake of 10% of NR in rats causes bone loss that may be secondary to the increased release of substance P and TNF-alpha.”
Rude RK, Gruber HE, Norton HJ, Wei LY, Frausto A, Kilburn J. Dietary magnesium reduction to 25% of nutrient requirement disrupts bone and mineral metabolism in the rat.
Bone. 2005 Aug;37(2):211-9.
“Low dietary magnesium (Mg) may be a risk factor for osteoporosis…. a more moderate dietary Mg restriction (10% of NR) also resulted in loss of bone. We now report the effect of Mg intake of 25% NR on bone and mineral metabolism in the rat…. No difference was noted in markers of bone turnover. Histomorphometry and micro-computerized tomography demonstrated decreased bone volume and trabecular thickness. No difference was observed for osteoclast or osteoblast number. Inflammatory cytokines may contribute to bone loss. …These data demonstrate that Mg intake of 25% NR in the rat causes lower bone mass which may be related to increased release of substance P and TNFalpha.”
Rude RK, Gruber HE, Norton HJ, Wei LY, Frausto A, Kilburn J. Reduction of dietary magnesium by only 50% in the rat disrupts bone and mineral metabolism. Osteoporos Int. 2006;17(7):1022-32. Epub 2006 Apr 7.
“INTRODUCTION: The objective of this study was to determine the effect of a moderate reduction of dietary magnesium [50% of nutrient requirement (50% NR)] on bone and mineral metabolism in the rat, and to explore possible mechanisms for the resultant reduced bone mass.”
“Although no significant change in serum Mg was observed, Mg deficiency developed, as assessed by the reduction in bone Mg content at the 3- and 6-month time points…These data demonstrate that Mg intake of 50% NR in the rat causes a reduced bone mineral content and reduced volume of the distal femur.”
Schaafsma A, de Vries PJ, Saris WH. Delay of natural bone loss by higher intakes of specific minerals and vitamins. Crit Rev Food Sci Nutr. 2001 May;41(4):225-49. Review.
“Magnesium is involved in a number of activities supporting bone strength, preservation, and remodeling. Fluorine and strontium have bone-forming effects. However, high amounts of both elements may reduce bone strength.”
Rude RK, Olerich M. Magnesium deficiency: possible role in osteoporosis associated with gluten-sensitive enteropathy. Osteoporos Int. 1996;6(6):453-61.
“Osteoporosis and magnesium (Mg) deficiency often occur in malabsorption syndromes such as (GSE) .”
“This study demonstrates that GSE patients have reduction in intracellular free Mg2+, despite being clinically asymptomatic on a gluten-free diet. Bone mass also appears to be reduced. Mg therapy resulted in a rise in PTH, suggesting that the intracellular Mg deficit was impairing PTH secretion in these patients. The increase in bone density in response to Mg therapy suggests that Mg depletion may be one factor contributing to osteoporosis in GSE.”
Classen UG, Seitz G, Grimm P, Classen HG. Influence of high and low dietary magnesium levels on functional, chemical and morphological parameters of 'old' rats. Magnes Res. 1994 Dec;7(3-4):233-43.
“… magnesium- and calcium-deficient diets were offered during 32 and 64 days to 'old' rats (34 months old, spontaneous mortality of 15 per cent). The calcium-deficient diet (2.5 per cent of the requirement) was well tolerated and no profound biochemical disturbances were noted. In contrast, dietary magnesium deficiency (12.5 per cent of the requirement) induced loss of body weight, formation of erythema, severe hypomagnesaemia and increase of tissue calcium levels.”
“Fourteen days preloading with high dietary magnesium increased plasma magnesium and also skeletal concentrations, although to an only small degree. Nevertheless, time until the appearance of erythema in 50 per cent of the rats subsequently fed the magnesium-deficient diet was significantly delayed.”
Magnesium and Menopausal Osteoporosis
Stendig-Lindberg G, Koeller W, Bauer A, Rob PM. Prolonged magnesium deficiency causes osteoporosis in the rat. J Am Coll Nutr. 2004 Dec;23(6):704S-11S.
“Peroral magnesium (Mg) administration, used as the only treatment in postmenopausal osteoporosis, has been shown to cause a significant increase of BD.”
“RESULTS: The mean BD of L3-L5 vertebral bone (BDL) was significantly higher in group than in the Mg deficient group B (p = 0.035, 1 tail). The BD of the femoral region (BDF) was also significantly higher in group A (p = 0.045, 1 tail).”
“Experimentally induced prolonged Mg deficiency causes osteoporosis in rats.”
Macdonald HM, New SA, Golden MH, Campbell MK, Reid DM. Nutritional associations with bone loss during the menopausal transition: evidence of a beneficial effect of calcium, alcohol, and fruit and vegetable nutrients and of a detrimental effect of fatty acids. Am J Clin Nutr. 2004 Jan;79(1):155-65.
“The menopausal transition is characterized by rapid bone loss. Few data exist on the role of nutrition.”
“For premenopausal women, calcium and nutrients found in fruit and vegetables (vitamin C, magnesium, and potassium) were associated with FN BMD, and calcium, vitamin C, and magnesium were associated with change in FN BMD.”
Brodowski J. [Levels of ionized magnesium in women with various stages of postmenopausal osteoporosis progression evaluated on the basis of densitometric examinations] Przegl Lek. 2000;57(12):714-6. Polish.
“In the group of women with osteoporosis and severe osteoporosis significantly lower ionized magnesium level was determined in comparison with the control group and the group of women with osteopenia (p < 0.05).”
Schaafsma A, Pakan I. Short-term effects of a chicken egg shell powder enriched dairy-based products on bone mineral density in persons with osteoporosis or osteopenia. Bratisl Lek Listy. 1999 Dec;100(12):651-6.
“During a study period of 4-8 months, the intervention group consumed twice daily a dairy-based supplement which resulted in a daily intake of, among others, 3.0 g of egg shell powder, 400 IU of vitamin D3 and 400 mg of magnesium.”
“After the intervention period, BMDs of the lumbar spine, total proximal femur and trochanter were significantly (p < 0.05) increased … Within a period of 4 months, an important reduction in pain was reported and as a consequence an improvement in general well-being.”
“This study shows that egg shell powder is a source of bioavailable calcium. Furthermore, this pilot study indicates that the chicken egg shell powder enriched dairy-based supplement increases BMD of subjects with a low bone mass in the short term and as a consequence delays bone demineralisation for a longer period.”
Sojka JE, Weaver CM. Magnesium supplementation and osteoporosis. Nutr Rev. 1995 Mar;53(3):71-4. Review.
“Among other things, magnesium regulates active calcium transport. As a result, there has been a growing interest in the role of magnesium (Mg) in bone metabolism. A group of menopausal women were given magnesium hydroxide to assess the effects of magnesium on bone density. At the end of the 2-year study, magnesium therapy appears to have prevented fractures and resulted in a significant increase in bone density.”
Tranquilli AL, Lucino E, Garzetti GG, Romanini C. Calcium, phosphorus and magnesium intakes correlate with bone mineral content in postmenopausal women. Gynecol Endocrinol. 1994 Mar;8(1):55-8.
“The dietary intake of calcium, phosphorus and magnesium was significantly reduced in osteoporotic women and correlated with BMC. Calcium and magnesium intakes were lower than the recommended daily allowance even in normal women. The results suggest that nutritional factors are relevant to bone health in postmenopausal women, and dietary supplementation may be indicated for the prophylaxis of osteoporosis.”
Stendig-Lindberg G, Tepper R, Leichter I. Trabecular bone density in a two year controlled trial of peroral magnesium in osteoporosis. Magnes Res. 1993 Jun;6(2):155-63.
“Since magnesium regulates calcium transport, and magnesium replacement in magnesium-deficient postmenopausal patients resulted in unexpected improvement in documented osteoporosis, we investigated the effect of magnesium treatment on trabecular bone density in postmenopausal osteoporosis.”
“…received two to six tablets daily of 125 mg each of magnesium hydroxide (Magnesium Magma USP/; 'Mazor', Israel) for 6 months and two tablets for another 18 months in a 2 year, open, controlled therapeutic trial.”
“Twenty-two patients (71 per cent) responded by a 1-8 per cent rise of bone density. The mean bone density of all treated patients increased significantly after 1 year (P < 0.02) and remained unchanged after 2 years (P > 0.05). The mean bone density of the responders increased significantly both after one year (P < 0.001) and after 2 years (P < 0.02), while in untreated controls, the mean bone density decreased significantly (P < 0.001). The disparity between the initial mean bone density and bone density after one year in all osteoporotic patients and in the responders differed significantly from that of the controls (both P < 0.001).”
Steidl L, Ditmar R. Osteoporosis treated with magnesium lactate. Acta Univ Palacki Olomuc Fac Med. 1991;129:99-106.
“33 patients with senile, 18 patients with postmenopausal and 9 patients with medicamentous (corticosteroids) osteoporosis were treated with single therapy of Mg lactate (37 patients) and with the combined one of Mg lactate and Na fluoride (23 patients). They were evaluated in three periods of half a year, one year, two years. The better results were achieved with the single therapy than with the combined one and in the senile and postmenopausal osteoporosis than in the medicamentous one. Pain and restricted spine movement were influenced favourably. Kyphosis and x-ray findings were stabilized.”
Steidl L, Ditmar R. Blood magnesium, calcium and zinc in osteoporosis. Acta Univ Palacki Olomuc Fac Med. 1991;129:91-8.
Steidl L, Ditmar R. Blood magnesium findings in osteoporosis. Acta Univ Palacki Olomuc Fac Med. 1990;126:117-28.
Abraham GE, Grewal H. A total dietary program emphasizing magnesium instead of calcium. Effect on the mineral density of calcaneous bone in postmenopausal women on hormonal therapy. J Reprod Med. 1990 May;35(5):503-7.
“A review of the published data does not support calcium megadosing during postmenopause.”
“A total dietary program emphasizing magnesium instead of calcium for the management of PPMO takes into account the available data on the effects of magnesium, life-style and dietary habits on bone integrity and PPMO. When this dietary program was tested on 19 postmenopausal women on hormonal replacement therapy who were compared to 7 control postmenopausal women, a significant increase in mineral bone density of the calcaneous bone (BMD) was observed within one year. Fifteen of the 19 women had had BMD below the spine fracture threshold before treatment; within one year, only 7 of them still had BMD values below that threshold.”
Steidl L, Ditmar R, Kubicek R. [Biochemical findings in osteoporosis. I. The significance of magnesium] Cas Lek Cesk. 1990 Jan 12;129(2):51-5. Czech.
“The authors examined in 60 patients with osteoporosis the serum and red cell magnesium and calcium content. Thirty-three patients suffered from senile osteoporosis, 18 patients from postmenopausal osteoporosis and nine had osteoporosis caused by corticoids. In the former two groups were signs of chronic magnesium deficiency, in the third groups there was a trend of low serum calcium levels. The results indicate the important role of magnesium in these disorders of bone metabolism.”
Nielsen FH. Studies on the relationship between boron and magnesium which possibly affects the formation and maintenance of bones. Magnes Trace Elem. 1990;9(2):61-9. Review.
“Because boron and/or magnesium deprivation causes changes similar to those seen in women with postmenopausal osteoporosis, these elements are apparently needed for optimal calcium metabolism and are thus needed to prevent the excessive bone loss which often occurs in postmenopausal women and older men.”
Ditmar R, Steidl L. [The significance of magnesium in orthopedics. V. Magnesium in osteoporosis] Acta Chir Orthop Traumatol Cech. 1989 Apr;56(2):143-59. Czech.
“The authors submit an investigation of 60 patients with senile, post-menopausal and drug-induced osteoporosis. Using the method of absorption spectrophotometry, they found a reduced level of Mg in red blood cells in 63.6% of senile, 66.7% postmenopausal and only in 22.2% drug-induced osteoporoses.”
“The authors revealed moreover that the level of red cell magnesium in the former two groups declines in proportion to the severity of osteoporosis and correlates thus with the clinical and X-ray finding. For treatment of osteoporisis the authors used magnesium lactate alone (in 37 patients) and combined with sodium fluoride (in 23 patients). In the majority of patients they had very favourable results. Based on laboratory and therapeutic results, consistent with data in the experimental literature, the authors assume that magnesium as a catalyst of bone metabolism and as one of the most important factors controlling the formation of bone matrix and its mineralization plays a significant role in the aetiopathogenesis of senile and postmenopausal osteoporosis. The authors assume that Mg deficiency which is increasing in recent years in soil as well as in foodstuffs and water may be the main cause of the increasing number of patients with osteoporosis in civilized countries. Magnesium should have its firm place not only in therapy but also in prevention of the majority of osteoporosis.”
Cohen L. Recent data on magnesium and osteoporosis. Magnes Res. 1988 Jul;1(1-2):85-7. Review.
“Larger and more perfect bone mineral crystals and decreased bone magnesium concentration were found in postmenopausal osteoporosis, senile osteoporosis, alcoholic osteoporosis and osteoporosis associated with thalassaemia. The decreased bone magnesium concentration and the increased retention of magnesium in the magnesium load test suggest magnesium deficiency in post-menoposal osteoporosis, probably caused by magnesium malabsorption.”
Ragosta KG, Bergstrom WH, Briggs DG, Brandt B. Protamine and acute depletion of magnesium limit bone response to parathyroid hormone. Anesth Analg. 1996 Jan;82(1):29-32.
“The effect of protamine on calcium homeostasis was studied in nine pediatric patients undergoing cardiopulmonary bypass. Total serum calcium decreased from 8.44 mg/dL to 7.49 mg/dL (P < 0.05) after protamine. Ionized calcium decreased from 1.39 to 1.31 mmol/L (P < 0.05). A bioassay determined the etiology of this response. Bone disks were placed in sera, protamine, parathyroid hormone, parathyroid hormone antibody, or magnesium-depleted solutions, then were incubated in solutions with known calcium content. The change in the media's calcium concentration reflects the bone's response to the initial stimulus. Calcium change is expressed as Experimental delta/Control delta (E/C). Normal bone responds to parathyroid hormone, E/C = 0.59 (P < 0.001). Protamine-treated bone loses this response, E/C = 0.9 (P = not significant [NS]). A parathyroid-hormone-induced osteoblast messenger was found. Protamine-treated bone continued to respond to this messenger, E/C = 0.42 (P < 0.001). Bone showed reversible loss of response to parathyroid hormone after incubation in magnesium-free solution, E/C = 0.93 (P = NS). With reincubation in magnesium, E/C = 0.69 (P < 0.01). Since protamine blocks parathyroid receptors, and magnesium depletion limits the bone's response to parathyroid hormone, this may explain the persistent hypocalcemia seen in some patients undergoing cardiopulmonary bypass.”
Seelig MS. Increased need for magnesium with the use of combined oestrogen and calcium for osteoporosis treatment. Magnes Res. 1990 Sep;3(3):197-215. Review.
“Prophylactic treatment of postmenopausal osteoporosis with oestrogen and calcium, often in combination, disregards the likelihood that an excess of each agent may increase magnesium requirements and decrease serum Mg levels. Relative or absolute Mg deficiency, which is likely in the Occident where the Mg intake is commonly marginal, can militate against optimal therapeutic bone response, Mg being important for normal bone structure, and can increase the risk of adverse effects. Although oestrogen has cardiovascular protective effects (expressed by the lower incidence of heart disease in premenopausal women than in men, and also in postmenopausal women given low dosage oestrogen replacement treatment), high dosage oestrogen oral contraceptives have caused increased intravascular blood clotting with resultant thromboembolic cardio- and cerebrovascular accidents. This might be contributed to by the oestrogen-mediated shift of circulating Mg to soft and hard tissues, which in persons with marginal Mg intakes may lead to suboptimal serum levels. If the commonly recommended dietary Ca/Mg ratio of 2/1 is exceeded (and it can reach as much as 4/1 in countries with low to marginal Mg intakes), relative or absolute Mg deficiency may result, and this may increase the risk of intravascular coagulation, since blood clotting is enhanced by high Ca/Mg ratios. Mechanisms by which Ca activates the various steps in blood coagulation that are also stimulated by oestrogen are considered here, as are the multifaceted roles of Mg that favourably affect blood coagulation and fibrinolysis, through its activities in lipoprotein and prostanoid metabolism.”
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