Strontium and Bone

Strontium (Sr; MW 87.62) is ranked fifteenth in the order of the elemental crustal abundance in which it occurs at a concentration of 450 mg/kg.1 The element was first isolated in an impure form in 1808 and named after “Strontian,” a Scottish town where it was found at high concentrations in calcareous rocks consisting of natural apatites in which strontium may occur at concentrations as high as 73 g/kg.2 In ocean water, strontium is the most abundant trace element, reaching values of up to 8 mg/l. Natural water sources, such as rivers, springs, and wells, contain smaller amounts of the element ranging from 0.021 mg/l up to 0.375 mg/l.3, 4 Strontium is a natural constituent of food and beverages. Meat, poultry, vegetables, and fruit contain relatively low amounts of the element (range 0.3–5.1 mg/kg), whereas in cereals, grains, and seafood it may be present at concentrations of up to 25 mg/kg. Hence, the strontium content of the human diet and the daily intake of the element varies according to the geographic area and the type of food consumed.4-6 A limited number of the series of radioactive strontium isotopes have been applied to the fields of medicine, biology, and biochemistry. The therapeutic potential of intravenously administered strontium-89 was first recognized in 1940 with the discovery that it could be used for the treatment of bone pain from metastatic prostate cancer.7 The latter isotope, as well as strontium-85 and strontium-88 have been primarily used as markers of calcium metabolism. Research on the toxicity of strontium has so far been focused mainly on the biological effects of radioactive strontium-90, which is an important constituent of nuclear fallout.8 At that time dietary supplementation of stable strontium was reported to inhibit the intestinal absorption of strontium-90, thereby serving as a deterrent to ingestion of radioactive strontium. However, caution was warranted with these preventive measures since replacement of dietary calcium with strontium was found to result in diminished growth, improper bone mineralization, and an inhibition of intestinal calcium absorption.9, 10 The gastrointestinal tract represents the main route of entry of strontium into the body. The gastrointestinal absorption of strontium largely depends on age and may vary from 90% of the element's dietary intake in infants to only 10% in the elderly.11 Within a given age group, important interindividual fluctuations of the gastrointestinal absorption have also been observed, which have been ascribed to the actual functional state of the gastrointestinal tract.12 Several mechanisms for strontium transport through the intestinal wall have been postulated. Some authors suggested that in contrast to calcium, strontium is absorbed entirely via passive diffusion, i.e., paracellular transport.13, 14 However, Papworth et al. proposed two routes of entry for the element: carrier-mediated and diffusion-mediated.15 With the exception of infants, it can generally be stated that strontium is absorbed to a lower extent than calcium, the strontium/calcium absorption ratio being ∼0.50.16 The intestinal absorption of strontium increases under fasting conditions and is negatively affected by a high dietary content of calcium, phosphate, or chelating agents, such as sodium alginates,17, 18 which are of substantial interest in view of their ability to inhibit the intestinal absorption of the element in animals and man without affecting calcium absorption.19, 20 Experimental studies have further demonstrated that intestinal strontium absorption is gradually increased during pregnancy and lactation, with a maximal fractional absorption at the end of the lactation period.21 In addition to the gastrointestinal pathway, absorption of the element may also take place via the lung and skin.5 Studies on the kinetics of strontium have mainly been performed in connection with those of calcium. Indeed, in previous experiments it has been suggested that the two elements not only share some chemical and physical characteristics but also exhibit similar involvements in a number of biological processes.5 Hence, the term observed ratio (OR) introduced by Comar et al.22 (for example: ORbone-diet = [strontium/calcium of bone]/[strontium/calcium of diet]) has been used by several authors to describe a number of aspects of the strontium metabolism, e.g., express the discrimination of strontium absorption, accumulation, and tissue deposition in relation to calcium.17, 23, 24 In animals kept on a normal calcium and strontium diet, 98.6% of the calcium and 99.1% of the absorbed strontium are deposited in bone, respectively. Under normal conditions, the bone strontium/calcium ratio varies between 1:1000 and 1:2000, which is on the same order as that noted in serum.25 Little is known about the extracellular, cellular, and subcellular localization of strontium in bone, which must be ascribed to the lack of accurate and sensitive staining and analytical methods able to demonstrate the element at a given ultrastructural site in bone. In one study, Boivin et al.,26 by means of X-ray fluorescence (XRF) analysis, demonstrated strontium to be localized in mineralized bone. At this site, the element appeared to be distributed rather heterogeneously, the highest concentration being present in newly formed bone. Recently, by means of electron probe X-ray microanalysis (EPXMA) of bone of renal failure rats loaded with strontium, Schrooten et al. found the element to be present in calcified bone in close proximity to the mineralization front.27 Blood is the second most important bodily location of strontium. Data in the literature on normal serum strontium levels in subjects with intact renal function vary between 10 μg/l and 217 μg/l and greatly depend on the analytical technique used.5 In uremic patients, either treated or not by hemodialysis, data in general point toward increased serum strontium levels as compared with subjects with normal renal function.28, 29 Recent preliminary findings of our group indicate that serum strontium levels in dialysis patients may differ greatly from center to center, ranging from values comparable to those noted in subjects with normal renal function (14 ± 7 μg/l) up to 30-fold higher, i.e., mean ± SD of 29 ± 11 μg/l, in the center with the lowest strontium concentrations, as compared with 466 ± 90 μg/l in the center with the highest levels. Although evidence still has to be presented, this wide concentration range most likely is due to differences in the dialysate strontium concentration and perhaps variations in the dietary intake. The oral intake of aluminum-containing phosphate binders, particularly Maalox® tablets, which may contain up to 217 μg/g of the element, has also been suggested as an important source of strontium within the dialysis population.30 To what extent renal insufficiency by itself also leads to increased strontium levels is the subject of current investigations. No clear-cut data on the protein binding of strontium in serum are available. Reported values on the protein-bound fraction of the element vary between 20% and 40% and depend on the technique used.31, 32 Strontium is excreted in urine and to a lesser extent in feces and sweat. In healthy adults, the total clearance varies between 9.4 ml/minute and 11.7 ml/minute, while the renal clearance appears to vary between 4.0 ml/minute and 5.4 ml/minute.33 Strontium excreted in feces either originates from nonabsorbed, orally administered strontium or strontium that is actively excreted by the intestine, which was found to correlate positively with the concentration of the element in blood.34 Once absorbed, strontium is distributed throughout the body but preferentially deposited in bone and teeth.35 Evidence has been presented in the literature that strontium may exert a number of effects on bone which may be either beneficial36-41 or toxic.42-46 As mainly demonstrated in rats with normal renal function, the element may, depending on the dose administered, interact either directly or indirectly (Table 1). Data in the literature indicate that a high dietary intake of strontium (strontium content in food or drinking water >4 g/l) may disturb bone mineralization.9, 38, 41 The mechanism by which strontium exerts a deleterious effect on bone calcification is not yet known. Several potential mechanisms have been put forward. From a chemical point of view, one may reasonably accept that because of the larger size of the strontium ion as compared with that of calcium, hydroxyapatite crystals will preferentially bind calcium as compared with strontium. At high strontium concentrations, however, the element may replace calcium in bone by heteroionic exchange.44 This takes place via a pure physicochemical process independent of the osteoblast and will ultimately result in a decreased bone calcium content.45 In addition, incorporation of the greater sized strontium ions in bone will induce a mild distortion of the crystal lattice,46 impair crystal growth, and increase the dissolution of mineralized bone.47 As a consequence, lower bone mineral density (BMD) is likely to be expected in strontium overload. Changes in the bone mineral chemistry, such as the carbonate content,39 have been reported also but require further experimental evidence. In rats with intact renal function, the development of rickets, a bone disease characterized by defective bone mineralization, was induced after adding the element to the animals' drinking water at a 4 g/l concentration. Here the observed bone lesions were more pronounced in young rats as compared with the adult animals.38, 39 In the search for a role of strontium in the development of a mineralization defect, the ability of the element to enter cells via the calcium channels and its subsequent incorporation at intracellular calcium binding sites, such as the endoplasmatic reticulum, thereby affecting the intracellular calcium homeostasis and calcium-mediated processes involved in bone mineralization, should be taken into account.48, 49 Here the element's hypothetical ability to disturb the calcium-regulated bicarbonate secretion of the osteoblast buffering the proton release during hydroxyapatite formation50 is worth considering as a possible underlying mechanism for the impaired mineralization. Chemical interactions that occur at high strontium doses will result in hypomineralization reflected by lower BMD. In this context, the opposite effects strontium and fluor exhibit on bone in terms of BMD is worth mentioning. In contrast to strontium, fluor appears to influence bone mineralization by shifting the mineralization profile toward hypermineralization. Unlike strontium, fluor does not substitute for calcium in the apatite lattice, and deposition of the latter element in bone has been reported to increase crystallinity.39 Biochemically it was demonstrated that rats fed a high strontium diet had a significantly greater amount of bone glycosaminoglycans, i.e., noncollageneous proteins, as compared with control animals.45 Interestingly, several of these noncollageneous bone proteins, such as osteopontin and bone sialoprotein, may alter bone mineralization, as indicated by their ability to prevent hydroxyapatite precipitation when added to supersaturated calcium phosphate solutions.51 While strontium seems to have an effect on the noncollageneous proteins, such as the proteoglycans, it appears not to interfere with the bone collagen content.39 Defective mineralization has also been associated with a comparatively high matrix vesicle volume fraction in the lower part of the growth plate, which may reflect a reduced rate of matrix vesicle degradation,52 a process that repeatedly has been assigned a central role in the mineralization process.53 In in vitro as well as in vivo studies, Neufeld and Boskey54 found that the strontium-induced mineralization defect was accompanied by an accumulation of the complexed acid–phospholipid content. These complexes have been found in all apatite-containing mineralizing tissues studied to date and appear to play a role in initiating mineralization in vivo.55 Others suggested that strontium interferes with bone mineralization by its ability to bind to the calcifiable collageneous matrix at potential Ca2+-binding sites.56 Histologic and radiographical studies on the effect of strontium in the rat show that the longitudinal growth of tibiae and endochondral ossification are apparently inhibited by strontium administration. The zone of the hypertrophic cartilage plate became wider, delaying the endochondreal ossification.41 In experimental studies using rats with normal renal function, histologic examination of bone samples revealed the oral administration of low strontium doses (Sr content in diet <4/gl) to increase both the bone formation rate and trabecular bone density. This observation was found to be due to a strontium-induced stimulation of the osteoblastic activity evidenced by an increase in the amount of osteoid, which was noted in the absence of any mineralization defect or any change in osteoclastic surface or in the number of active bone-resorbing cells.38, 39 The fact that the increased osteoblastic activity was not accompanied by increased bone resorption was suggested to be due to covering of the endosteal bone surface with osteoid, by which bone resorption was prevented.57 Others found that the ability of strontium to act as an uncoupling agent of both processes might be responsible for this observation.40 The effects of strontium on bone metabolism might be of particular interest when put into a pathological as well as a therapeutical perspective. Indeed, the observed increase in the trabecular bone volume as noted in the rat in the presence of low strontium doses may have therapeutic applications, particularly in pathologic conditions characterized by an accelerated bone remodeling process and extensive demineralization.25 This may also explain the therapeutic response to relatively low oral strontium doses in patients with metastatic cancer. Here a distinct remineralization of the bone lesions was reflected by a definite improvement of the erosion margin of vertebral metastases, indicating that a stimulated osteogenesis was noted.25, 46 These beneficial effects of strontium are somewhat in contrast with the failure of calcium supplements to recalcify osteopenic areas in some particular metabolic bone diseases. Most likely this is due to a strict homeostatic control of the plasma calcium level, which does not permit a of the element to in contrast to strontium, for which a to areas active bone remodeling has been A beneficial effect of low strontium doses has also been noted in Here an increase in the vertebral bone calcification was is not however, this effect from either a decreased bone resorption increased bone were the first to demonstrate that doses of strontium g/l as in the drinking can induce in renal failure as evidenced by increased in with reduced bone This appears to be in contrast with the effects of low doses of strontium administered to rats with normal renal In this context, the of strontium with fluor in the development of a mineralization defect are worth mentioning. administration of fluor to rats with normal renal function exerts a effect on the bone matrix et in a renal failure rat found that added to the drinking water in an of the induced by These findings are more or in with experimental where in rats with renal failure high doses of as evidenced by an increase in and diminished bone Recently, Schrooten et al. in a renal failure rat studied the effects of both strontium and on bone. daily dietary of strontium g/l in the drinking in the development of those at a daily oral dose of of rat 10 mg/l as to the drinking bone This characterized by a decreased mineralization in the absence of an increased osteoid, an effect of on osteoblast activity rather than on These findings are in with studies performed in rats with normal renal function, where administration to a in bone and matrix which was not accompanied by an increase in should be however, that in both experimental and in vitro studies have reported opposite i.e., found to bone To what extent these are either due to differences in the or in vitro interactions with or differences in variations in or means of administration of the is not yet in the is with the observation that rats that were loaded with strontium and either bone disease or This observation and the that in rats loaded with only bone was that the in dialysis patients might not be due to but could be the result of a A potential of with or metabolic in the development of both bone was more than a by et With to their effects on bone, the between and strontium is at given at low has been to the bone As in with normal renal function, this appears to result from stimulation of a type of bone distinct from bone Data with the osteoblast that the and stimulation may take place through an mechanism with and and protein This is an further The physicochemical between strontium and calcium the potential effects of strontium with such a mechanism in both and might also explain under experimental conditions strontium and and increase trabecular bone volume and prevent bone In it might be the by which particular bone formation and bone to a increase in bone studies the of the in bone and their functional role in bone remodeling will be of particular interest to a into the mechanism underlying the effects of strontium and on bone. from its effects on bone, strontium also seems to bone metabolism As for the these with bone metabolism also to take place in a (Table 1). As rats fed a high strontium diet may A strontium-induced bone mineralization defect, however, has also been observed in rats a low calcium as well as in those where the calcium content was or et found that the bone lesions after of strontium from the Interestingly, of the bone lesions was accompanied by an increase in both the intestinal levels of the calcium binding protein as well as of strontium with has also been observed in the Here the administration of a high strontium dose inhibited both the of and intestinal calcium However, whereas with calcium absorption, administration of had These data indicate that strontium, by a yet may the of from which in may be responsible for the development of strontium-induced In this the in vivo observation that and their activity in the presence of high strontium concentrations is also of particular one can that high doses of strontium may indirectly bone metabolism by the intestinal absorption of calcium, the concentration of the and the of to in the increased osteogenesis noted in the presence of low strontium doses was that it was not accompanied by in levels of by in intact levels. in experimental studies in rats with normal renal function, the administration of low strontium doses has been associated with a in the serum calcium levels which was observed during particular of growth of the This may have from a diminished intestinal absorption of calcium due to of the element with strontium. The in the calcium that was observed at that however, may have from a strontium-induced calcium from bone at the of in contrast to these in our experimental using renal failure differences in serum calcium levels were observed between control and However, the calcium was increased in rats that had strontium. this was not due to increased it was suggested that this observation might have been the result of a incorporation of calcium in bone to the presence of strontium, a of calcium by strontium in the hydroxyapatite or a effect of strontium on the of With to the the effect of strontium with the at the of the should not be noted that bone strontium levels in dialysis patients with were increased as compared with all of renal such as mild bone, and the found bone strontium levels to correlate with bone levels within this was a of the bone strontium levels and bone calcium levels noted in the patients as compared with that noted for the of renal At it is not in the patients strontium has either a or role in the development of this disease is it known the increased bone strontium concentrations are an of the is still as to what extent strontium in dialysis patients and accumulation is due to the impaired renal function, the dialysis the diet, or a of is worth that as as et and on et suggested a potential role for strontium in the development of renal Interestingly, in the of this accumulation of strontium levels has been associated with the development of bone Recently, an in demonstrated a significantly of the of in in a with a high strontium content and where was mainly on as compared with that in in a low strontium et al. found that the particular form of by strontium from those induced by calcium or in that supplements not the on this was to the element's ability to inhibit the in vivo of the active have a in the of which serum strontium levels were found to be with renal in patients treated by hemodialysis, serum strontium levels greatly from center to center and to (range ± μg/l up to 466 ± 90 In the latter revealed that increased serum strontium levels μg/l) could for be by the of dialysis whereas the diet, and dialysis appeared to play only a In an experimental using the oral strontium in histologic bone lesions characterized by an increased amount of in the presence of a decreased mineralization indicating the presence of and toward a role of the element in the development of this particular type of renal A effect of strontium on bone mineralization may be suggested from the element's localization in bone. Indeed, strontium could be localized in calcified bone, mainly in bone close to the a site of bone mineralization. findings were by osteoblast from rat are used to the mechanism by which strontium interferes with the bone mineralization either directly or indirectly via its with bone matrix such as bone sialoprotein, and The that in the development of the lesions in dialysis patients strontium via an can not be a effect on the element's activity has also been ascribed to with gastrointestinal absorption, and in the concentration of the Here the of human renal as well as renal able to are of particular interest to demonstrate an effect of the element on is a of a from the of of our and experimental studies were performed in the of an