Revista de Osteoporosis y Metabolismo Mineral

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Volume 2 · N. 1 Supl · March 2010


Action mechanism of strontium ranelate

Characteristics of strontium

Strontium was discovered in 1790 in a mine close to the Scottish village Strontian and was isolated in 1808. Strontium is one of the alkaline earth metals and is never found in its free form in nature because it easily oxidises, forming strontium oxide. Strontium, along with calcium and magnesium belongs to group 2 of the periodic table which are divalent cations, which, in biological liquids can have different degrees of bonds with blood proteins. The binding to proteins of strontium is in the same order of magnitude as that of calcium1. In the human body there are only traces of strontium. A normal diet supplies from 2 to 4 mg of strontium per day, although the quantity can be higher if the diet is rich in cereals or vegetables.
Given the similarity in the behaviour of both elements, the radioisotopes of strontium have been used for kinetic studies of the metabolism of calcium. However, there are important biological differences between them, which are in part explained by the greater molecular weight of strontium. Common transportation pathways have been described, for example strontium competes with calcium in intestinal absorption and in renal tubular reabsorption1. Strontium is absorbed less than calcium, this difference in the intestinal tract could be due, in part, to the smaller size of the calcium atom. On the other hand, the renal clearance of strontium is nearly three times greater than that of calcium, perhaps due to a greater secondary tubular absorption because of the larger size of the strontium atom.
Relationship of strontium with bone
The quantity of strontium in the skeleton is very small, and represents only 0.035% of the content of calcium. After its administration it is deposited almost exclusively in bone. Like sodium and lead, strontium can substitute for calcium in the position which it occupies in hydroxyapatite.
In 1952, Shorr and Carter demonstrated that the addition of a moderate quantity of strontium lactate improves the deposition of calcium in the bone2. One can say that this observation was the first suggestion in the literature that strontium could be useful in the treatment of alterations in bone metabolism. In 1959, McCaslin showed in a small study that in patients with osteoporosis strontium lactate reduced bone pain, at the same time as improving the X-ray images of demineralisation3. However, these observations did not awaken great interest in the researchers of that time, probably due to the mineralisation defects which a high dose of strontium was known to produce.

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Bone quality and strontium ranelate

Introduction. The current definition of osteoporosis, which considers the disease to be a systemic alteration characterised by low bone resistance1, indicates also that this resistance basically depends on the integration of two variables: the quantity and quality of the bone. Whilst the quantity is directly related to the mineral density of the bone tissue, the quality depends on variables such as the chemical composition of the organic and inorganic materials which make up its matrix (material properties) and the resulting spatial structure of these materials (structural properties), all of which factors depend to a greater or lesser degree on bone remodelling2. Starting from this definition, the ideal therapeutic profile for an anti-osteoporotic drug would be one which on the one hand is shown to increase bone resistance (increasing the BMD and correcting osteoporotic material and structural alterations) and on the other hand, would reduce the incidence of fractures related to fragility of this kind in the axial and peripheral skeleton, be they the first or successive3,4. These days there is a series of medications which, by means of different action mechanisms and effects on bone remodelling, are capable of mitigating and/or repairing the physiopathological changes which osteoporosis induces in the determinants of bone resistance. Among these, and depending on the mechanism or type of action which they exert on remodelling, the determinants of resistance and their effector cells, are found the anticatabolics or antiresorptives and the anabolics or bone formers. Whilst the first [oestrogens, modulators of the oestrogen receptors (SERMs), calcitonin and biphosphonates] are characterized as being capable of reducing accelerated bone remodelling by reducing the number of newly activated basic multicellular units (BMU) and the level of their osteoclastic activity, the second type (PTH 1-34 and PTH 1-84) increase bone remodelling by increasing the number of newly activated BMUs and the level of their osteoblastic activity5. However, nowadays, in addition to these large groups of anti-osteoporotic drugs, a third group of medicines should be considered with a mixed anticatabolic-anabolic action mechanism, which in some way combine the effects of antiresorptive drugs with those which form bone.

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Reference studies for strontium ranelate in the treatment of osteoporosis

Introduction. Strontium ranelate is an agent used for the treatment of osteoporosis. It consists of two atoms of stable strontium and an organic part: ranelic acid. Simultaneously, it stimulates the formation of new bone and reduces bone resorption, resulting in a deviation from the balance of bone turnover towards formation1. These actions are effected by improving the replication of pre-osteoblastic cells and the differentiation of osteoblasts, as well as reducing their capacity to induce the osteoclasts through the receptor sensors of calcium (CaR) and increase the range OPG/RANKL2. Its effectiveness in animals has been widely studied, it having been shown to augment bone mass in osteopenic animals, to prevent bone loss in ovaryectomised rats and to increase bone resistance in normal animals3-5. The action mechanism of strontium ranelate, as well as its effect on bone quality, is studied in greater detail in other chapters of this monograph. Reference studies for strontium ranelate. The SOTI and TROPOS study

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Other studies with strontium ranelate: Analysis of efficacy

Osteoporosis is characterised by a decrease in bone mass and a deterioration in the microarchitecture of bone tissue, which explains the weakness of the bone and the consequent risk of fractures.
Epidemiological studies have confirmed that postmenopausal osteoporosis is a very extensive and prevalent disease. The morbidity of osteoporosis is due, above all, to fractures of the hip, vertebrae and distal radial extremities. Hip fractures produce acute pain and loss of function and almost always result in hospital admission. Recuperation rates are low and rehabilitation is often incomplete. Many patients end up staying in a centre for the chronic sick. Vertebral fractures can produce acute pain and loss of function but are also associated with serious symptoms. Vertebral fractures often recur, and the consequent incapacity increases with their number. Fractures of the distal radial extremities also produce acute pain and loss of function but recuperation is usually satisfactory.
In addition to the pain and functional changes, the fractures can reduce mobility and social relations and result in emotional problems. All these characteristics shape the quality of life.
Quality of life covers all aspects of life, including health, the environment, economic matters and human rights. Health-related quality of life (HRQL) is a subgroup of quality of life which affects physical, emotional and social well-being.

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Safety and results for strontium ranelate

Introduction. Strontium ranelate is a therapeutic agent intro-duced in recent years for the treatment of osteo-porosis with dual action on bone metabolism. The conditions which need to be satisfied by any drug for its use in the treatment of osteoporosis include safety and efficacy in the prevention of fractures. The evidence in relation to strontium ranelate come principally from the two multi-centric, clinical reference trials in phase 3, the SOTI (Spinal Osteoporosis Therapeutic Intervention)1 study and the TROPOS (Treatment of Peripheral Osteoporosis) study2. The first was designed to access the preventative effect on vertebral fractures, whilst the second had as an objective the evaluation of non-vertebral fractures. These are the anti-osteoporotic drug trials which give results over the longest term, 4 years for the first and 5 for the second3. Additional data comes from other older trials in phase 2, the STRATOS (Strontium Ranelate for Treatment of Osteoporosis) trial4 and the PREVOS (Prevention of Osteoporosis) trial5 which had the objective of assessing the effect on bone mass and biochemical markers for bone turnover in patients with established vertebral fractures in the first, and in the second, in women in the first years of menopause.

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