M.-T. Garba

Bio: M.-T. Garba is an academic researcher from French Institute of Health and Medical Research. The author has contributed to research in topics: Bone remodeling & Bone resorption. The author has an hindex of 6, co-authored 6 publications receiving 273 citations.

Effect of low doses of stable strontium on bone metabolism in rats.

Abstract: The effects of low doses of oral stable strontium (0.19-0.40% of strontium chloride) on mineral and bone metabolism were examined in normal rats using biochemical and histomorphometrical methods. The strontium levels in serum and bone rose according to the intake of the element. Oral strontium supplementation did not produce deleterious effects on body growth or on mineral homeostasis except a transitory slight decrease in serum calcium. At the dosage level of 0.40% however, strontium induced a slight defective bone mineralization. At lower levels, treated rats showed stimulated bone formation evidenced by increased amount of osteoid and increased extent of tetracycline double-labelled surface while the mineralization lag time remained normal. The osteoclastic surface and the number of acid phosphatase-stained chondroclasts and osteoclasts remained unchanged. Stimulation of bone formation without apparent change in bone resorption resulted in a 10% increase in the trabecular calcified bone volume. The strontium-induced increased osteogenesis was not associated with changes in circulating levels of 1,25(OH)2 vitamin D or in parathyroid hormone effects. The results show that small doses of oral strontium may stimulate bone formation without altering bone resorption in the rat.

Contrasting effects of 1,25-dihydroxyvitamin D3 on bone matrix and mineral appositional rates in the mouse.

Abstract: In order to determine the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on bone matrix appositional rate (Ma AR) and bone mineral appositional rate (Mi AR), three doses (0.06, 0.13 and 0.20 microgram/kg/d) of 1,25(OH)2D3 were continuously infused for seven days in young mice. Histologic parameters of bone formation and resorption were evaluated by morphometric and autoradiographic methods. All doses of 1,25(OH)2D3 increased serum calcium and produced a dose-related increase in the metaphyseal osteoclastic surface and in the number of acid phosphatase-stained osteoclasts. The Mi AR evaluated by double tetracycline labeling was enhanced at all dosage levels. By contrast the Ma AR evaluated by double 3H-proline labeling was decreased at the two highest doses of 1,25(OH)2D3 which also produced growth impairment. We concluded that the continuous administration of 1,25(OH)2D3 in the mouse produces contrasting effects on bone matrix synthesis and calcification, resulting in a dose-related reduction in the amount of osteoid.

Alkaline phosphatase inhibition by levamisole prevents 1,25-dihydroxyvitamin D3-stimulated bone mineralization in the mouse.

Abstract: To determine the relationship between alkaline phosphatase (AP), 1,25(OD)2D3 and bone formationin vivo, we have examined the effects of levamisole, a stereospecific inhibitor of AP on bone formation and on 1,25(OH)2D3-stimulated bone mineralization in the mouse. Normal mice were injected daily with levamisole at doses of 40 and 80 mg/kg/b.w. The compound was given alone or in combination with 1,25(OH)2D3 infusion (0.05 μg/kg/d) for 7 days. Treatment with levamisole alone inhibited the serum AP activity (mainly of skeletal origin in mice) by 18.4 and 61.3% for the low and high dose respectively. No deleterious effect on body growth, tibia length, and bone cells population was detected. The moderate inhibition of AP activity produced by the lower dose of levamisole alone (18.4%) or in combination with 1,25(OH)2D3 (37.9%) was associated with a reduced endosteal matrix apposition rate (MaAR) determined by double3H-proline labeling method. This effect was related to a levamisole-induced fall in serum phosphate. Despite the moderate inhibition of AP activity, the mineral apposition rate (MiAR) determined by the double tetracycline labeling method remained normal. Moreover, 1,25(OH)2D3 infusion still resulted in increased MiAR which was stimulated to the same extent as in the absence of levamisole. By contrast, the more severe inhibition of AP activity induced by 80 mg/kg of levamisole alone (61.3%) or in combination with 1,25(OH)2D3 (45.8%) inhibited both the MaAR and the MiAR and prevented the stimulatory effect of 1,25(OH)2D3 on bone mineralization. The data show that AP activity affects the bone matrix and mineral apposition ratesin vivo and that severe inhibition of AP activity inhibits the 1,25(OH)2D3-induced stimulation of bone mineralization in the mouse.

Inhibition by aminohydroxypropylidene bisphosphonate (AHPrBP) of 1,25(OH)2 vitamin D3-induced stimulated bone turnover in the mouse.

Abstract: The purpose of this study was to evaluate whether the 1,25(OH)2D3-induced increased bone mineralization in the mouse occurs in response to stimulation of bone resorption. In order to inhibit bone resorption, 35-day-old mice were given 16 μmol/kg/day of (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (AHPrBP) for 10 days, the first injection occurring 3 days prior to the continuous infusion of 0.06, 0.13, or 0.20 μg/kg/day of 1,25(OH)2D3 for 7 days. Two groups of mice were treated with AHPrBP or 1,25(OH)2D3 alone. The skeletal changes were assessed by histomorphometric study of caudal vertebrae after double3H-proline and double tetracycline labelings for evaluation of the matrix apposition rate (MaAR) and mineral apposition rate (MiAR), respectively. Treatment with AHPrBP alone or combined to 1,25(OH)2D3 decreased the number of acid phosphatase-stained osteoclasts and reduced the endosteal MaAR and MiAR and the amount of osteoid. When given alone, 1,25(OH)2D3 increased serum calcium above normal, enhanced the number of histochemically active osteoclasts, and stimulated the endosteal MiAR. Pretreatment with AHPrBP blocked both the increase in serum calcium and the stimulation of the MiAR induced by 1,25(OH)2D3 infusion though serum 1,25(OH)2D3 levels rose according to the dose given. The results show that 1) the serum calcium and the bone resorbing responses to 1,25(OH)2D3 infusion are prevented by pretreatment with AHPrBP, and 2) the stimulatory effect of 1,25(OH)2D3 on the mineralization rate is blocked when bone resorption is inhibited. The data indicate that 1,25(OH)2D3 promotes bone mineralization in the mouse mainly in response to stimulation of bone resorption.

The Effects of Strontium Ranelate on the Risk of Vertebral Fracture in Women with Postmenopausal Osteoporosis

Abstract: background Osteoporotic structural damage and bone fragility result from reduced bone formation and increased bone resorption. In a phase 2 clinical trial, strontium ranelate, an orally active drug that dissociates bone remodeling by increasing bone formation and decreasing bone resorption, has been shown to reduce the risk of vertebral fractures and to increase bone mineral density. methods To evaluate the efficacy of strontium ranelate in preventing vertebral fractures in a phase 3 trial, we randomly assigned 1649 postmenopausal women with osteoporosis (low bone mineral density) and at least one vertebral fracture to receive 2 g of oral strontium ranelate per day or placebo for three years. We gave calcium and vitamin D supplements to both groups before and during the study. Vertebral radiographs were obtained annually, and measurements of bone mineral density were performed every six months. results New vertebral fractures occurred in fewer patients in the strontium ranelate group than in the placebo group, with a risk reduction of 49 percent in the first year of treatment and 41 percent during the three-year study period (relative risk, 0.59; 95 percent confidence interval, 0.48 to 0.73). Strontium ranelate increased bone mineral density at month 36 by 14.4 percent at the lumbar spine and 8.3 percent at the femoral neck (P<0.001 for both comparisons). There were no significant differences between the groups in the incidence of serious adverse events. conclusions Treatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures.

The role of three-dimensional trabecular microstructure in the pathogenesis of vertebral compression fractures.

Abstract: We compared indices of three-dimensional microstructure of iliac trabecular bone between 26 patients with vertebral compression fractures due to postmenopausal osteoporosis and 24 control subjects without vertebral fracture, who were matched for age, sex, race, menopausal status, and several densitometric and histologic indices of both cortical and trabecular bone mass. The patients with fracture had a significantly lower mean value (1.03±0.15 vs. 1.26±0.26;P<0.005) for indirectly calculated mean trabecular plate density, an index of the number and connectivity of structural elements, and as a necessary corollary, a significantly higher mean value for the mean thickness of structural elements. Plate density was more than one standard deviation below the age-adjusted mean value for normal postmenopausal white females in 19 (73%) of the fracture caes and in only 5 (21%) of the nonfracture cases (P<0.001). We conclude that the biomechanical competence of trabecular bone is dependent not only on the absolute amount of bone present but also on the trabecular microstructure.

Mechanisms of action and therapeutic potential of strontium in bone

Abstract: The processes of bone resorption and formation are tightly governed by a variety of systemic and local regulatory agents. In addition, minerals and trace elements affect bone formation and resorption through direct or indirect effects on bone cells or bone mineral. Some trace elements closely chemically related to calcium, such as strontium (Sr), have pharmacological effects on bone when present at levels higher than those required for normal cell physiology. Indeed, strontium was found to exert several effects on bone cells. In addition to its antiresorptive activity, strontium was found to have anabolic activity in bone, and this may have significant beneficial effects on bone balance in normal and osteopenic animals. Accordingly, strontium has been thought to have potential interest in the treatment of osteoporosis. This review summarizes the mechanisms of action of strontium on bone cells, the evidence for its beneficial effects on bone mass in vivo, and its potential therapeutic effects in osteopenic disorders.

Bisphosphonates. Pharmacology and use in the treatment of tumour-induced hypercalcaemic and metastatic bone disease.

Abstract: The geminal bisphosphonates are a new class of drugs characterised by a P-C-P bond. Consequently, they are analogues of pyrophosphate, but are resistant to chemical and enzymatic hydrolysis. The bisphosphonates bind strongly to hydroxyapatite crystals and inhibit their formation and dissolution. This physicochemical effect leads in vivo to the prevention of soft tissue calcification and, in some instances, inhibition of normal calcification. The main effect is to inhibit bone resorption, but in contrast to the effect on mineralisation, the mechanism involved is cellular. These various effects vary greatly according to the structure of the individual bisphosphonate. The half-life of circulating bisphosphonates is very brief, in the order of minutes to hours. 20% to 50% of a given dose is taken up by the skeleton, the rest being excreted in the urine. The half-life in bone is far longer and depends upon the turnover rate of the skeleton itself. Bisphosphonates are very well tolerated; the relatively few adverse events that have been associated with their use are specific for each compound. Bisphosphonates have been used to treat various clinical conditions, namely ectopic calcification, ectopic bone formation, Paget's disease, osteoporosis and increased osteolysis of malignant origin. The three compounds commercially available for use in tumour-induced bone disease are in order of increasing potency, etidronate, clodronate and pamidronate. Most data have been obtained with the latter two agents. By inhibiting bone resorption, they correct hypercalcaemia and hypercalciuria, reduce pain, the occurrence of fractures, as well as the development of new osteolytic lesions, and in consequence improve the quality of life. In view of these actions, of their excellent tolerability and of the fact that they are active for relatively long periods, these compounds are, after rehydration, the drugs of choice in tumour-induced bone disease and an excellent auxiliary to the drugs used in oncology.