Strontium ranelate for the treatment of osteoporosis
http://www.100md.com
《英国医生杂志》
Is useful, but changes in bone mineral density need careful interpretation
The successful treatment of osteoporosis is a relatively recent phenomenon. Although bisphosphonates are now established as the treatment of choice,1 this only came about with the publication in 1996 of the FIT alendronate trial.2 Nowadays the main treatment options are anti-resorptive agents that prevent bone breakdown. Most studies of these agents show good protection against fractures of the spine, while the more potent nitrogen containing bisphosphonates also show a reduction in non-vertebral fractures.1-5 For patients with previous fractures, treatment with an anabolic agent that enhances bone formation is clearly preferable, and this is now possible since the introduction of 1-34 recombinant parathyroid hormone (PTH).6 However, the use of PTH is limited by its high cost and the need for subcutaneous self injection. Recently strontium ranelate has been licensed in the United Kingdom for the treatment of osteoporosis. Here we draw attention to the unusual effect of strontium treatment on bone mineral density and discuss the potential bonus that this effect can be used for assessing adherence to therapy.
The mechanism of action of strontium ranelate is not yet fully understood, compared with other treatments, but it seems to have a unique effect in that it inhibits bone resorption as well as stimulating bone formation.7 Recent studies, the SOTI and TROPOS trials, have shown its efficacy at preventing both vertebral and non-vertebral fractures,7 8 including hip fractures in older women.8 Strontium ranelate was well tolerated in these trials without any major side effects. The most common side effects reported were a small increase in the incidence of nausea and diarrhoea.
Strontium ranelate is composed of two atoms of stable strontium combined with organic ranelic acid. The ranelic acid is a carrier that makes the treatment palatable, and the strontium is the active component with regard to the skeleton. As an alkaline earth element, strontium is similar to calcium in its absorption in the gut, incorporation in bone, and elimination from the body through the kidneys.9 Strontium is naturally present in trace amounts with around 100 μg in every gram of bone,w1 so treatment with strontium ranelate is simply making more strontium available for incorporation into bone. In the short term the strontium atoms are adsorbed on to the surface of hydroxyapatite crystals, and in the longer term some strontium will exchange with calcium in the bone mineral and may remain bound in the skeleton for years.9 Strontium not incorporated into bone is excreted through the kidneys and faeces. After three years' treatment with strontium ranelate, bone tissue will contain around one strontium atom for every 100 calcium atoms. In animal studies, up to one calcium atom in 10 was substituted with strontium without any important modifications of bone mineral at the crystal level.10 No human studies have yet reported how quickly bone strontium is washed out once treatment is stopped. However, studies with radioactive strontium show that much of the stable strontium present in bone after three years of treatment will still be there a decade later.9
What are the changes in bone mineral density with strontium ranelate? In the SOTI trial, an impressive increase in bone mineral density occurred in the spine (14.4%) and hip (8.3%).7 However, some caution is necessary in interpreting these figures because much of this effect is due to the higher atomic number of strontium (Z = 38) compared with calcium (Z = 20). When bone mineral density is measured by bone densitometry, atom for atom strontium attenuates x rays more strongly than calcium. As a result a 1% molar fraction of strontium causes a 10% overestimation of bone mineral density.11 In the SOTI trial, bone biopsy was performed in a subset of patients and the data for bone mineral density corrected on the basis of the correlation between the bone strontium content measured in the biopsy samples and concentrations of strontium in the blood. After the adjustment for bone strontium, the measured effect of treatment on bone mineral density in the spine of 14.4% was corrected to 8.1%.7
The important issue for treatment for osteoporosis is prevention of fractures and not changes in bone mineral density. This lesson was learnt with fluoride therapy, which led to dramatic increases in bone mineral density of the spine but in higher dosage caused an increased incidence of hip fracture.12 Caution is therefore needed in predicting efficacy against fractures simply on the basis of a change in bone mineral density.
Although measurements of bone mineral density are of value in diagnosing osteoporosis and in assessing the risk of fracture,w2 w3 many believe that they are of limited use in monitoring treatment. An increase of 5% in spine bone mineral density is required to confirm a notable response to treatment.w4 Often the changes are smaller than this, and as a result measurements of bone mineral density to monitor treatment are carried out only after two years.w5 With strontium ranelate, large increases in bone mineral density are often seen, and if this is the case one can be confident that the patient is complying with treatment. Though changes in bone mineral density measured during treatment with strontium are somewhat artefactual, they might still prove clinically useful. The issue of patients' long term use and compliance with treatment is important for all types of treatment for osteoporosis. For strontium ranelate, the large increase in bone density expected by 12 months may prove useful in this regard and could provide reassurance for the patient and the clinician.
Ignac Fogelman, professor
Department of Nuclear Medicine, Guy's Hospital, London SE1 9RT
(ignac.fogelman@kcl.ac.uk)
Glen M Blake, senior lecturer
Guy's, King's, and St Thomas' School of Medicine, London SE1 9RT
Additional references w1-w5 are on bmj.com
Competing interests: IF has acted as a consultant to Servier, manufacturer of strontium ranelate.
References
Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C. Summary of meta-analyses of therapies for postmenopausal osteporosis. Endocrine Rev 2002;23: 570-8.
Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. Randomised trial of the effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348: 1535-41.
Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the fracture intervention trial. JAMA 1998;280: 2077-82.
Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, et al. Effects of risedronate treatment on vertebral and non-vertebral fractures in women with postmenopausal osteoporosis. JAMA 1999;282: 1344-52.
McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, et al. Effect of risedronate treatment on hip fracture risk in elderly women. N Engl J Med 2001;344: 333-40.
Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster J-Y, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344: 1434-41.
Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350: 459-68.
Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: TROPOS study. J Clin Endocrinol Metab 2005. (Published online 22 Feb; doi: 10.1210/jc.2004-1774.)
Marshall JH, Lloyd EL, Rundo J, Liniecki J, Marotti G, Mays CW, et al. Alkaline earth metabolism in adult man. A report prepared by a task group of committee 2 of the International Commission on Radiological Protection (ICRP publication 20). Health Phys 1973;24: 129-221.
Boivin G, Deloffre P, Perrat B, Panczer G, Boudeulle M, Mauras Y, et al. Strontium distribution and interactions with bone mineral in monkey iliac bone after strontium salt administration (S12911). J Bone Miner Res 1996;11: 1302-11.
Pors Nielsen S, Slosman D, Sorensen OH, Basse-Cathelinat B, De Casin P, Roux C, et al. Influence of strontium on bone mineral density and bone mineral content measurements by dual x-ray absorptiometry. J Clin Densitom 1999;2: 371-9.
Riggs BL, Hodgson SF, O'Fallan M, Chao EYS, Wahner HW, Muhs JM, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990;322: 802-9.
The successful treatment of osteoporosis is a relatively recent phenomenon. Although bisphosphonates are now established as the treatment of choice,1 this only came about with the publication in 1996 of the FIT alendronate trial.2 Nowadays the main treatment options are anti-resorptive agents that prevent bone breakdown. Most studies of these agents show good protection against fractures of the spine, while the more potent nitrogen containing bisphosphonates also show a reduction in non-vertebral fractures.1-5 For patients with previous fractures, treatment with an anabolic agent that enhances bone formation is clearly preferable, and this is now possible since the introduction of 1-34 recombinant parathyroid hormone (PTH).6 However, the use of PTH is limited by its high cost and the need for subcutaneous self injection. Recently strontium ranelate has been licensed in the United Kingdom for the treatment of osteoporosis. Here we draw attention to the unusual effect of strontium treatment on bone mineral density and discuss the potential bonus that this effect can be used for assessing adherence to therapy.
The mechanism of action of strontium ranelate is not yet fully understood, compared with other treatments, but it seems to have a unique effect in that it inhibits bone resorption as well as stimulating bone formation.7 Recent studies, the SOTI and TROPOS trials, have shown its efficacy at preventing both vertebral and non-vertebral fractures,7 8 including hip fractures in older women.8 Strontium ranelate was well tolerated in these trials without any major side effects. The most common side effects reported were a small increase in the incidence of nausea and diarrhoea.
Strontium ranelate is composed of two atoms of stable strontium combined with organic ranelic acid. The ranelic acid is a carrier that makes the treatment palatable, and the strontium is the active component with regard to the skeleton. As an alkaline earth element, strontium is similar to calcium in its absorption in the gut, incorporation in bone, and elimination from the body through the kidneys.9 Strontium is naturally present in trace amounts with around 100 μg in every gram of bone,w1 so treatment with strontium ranelate is simply making more strontium available for incorporation into bone. In the short term the strontium atoms are adsorbed on to the surface of hydroxyapatite crystals, and in the longer term some strontium will exchange with calcium in the bone mineral and may remain bound in the skeleton for years.9 Strontium not incorporated into bone is excreted through the kidneys and faeces. After three years' treatment with strontium ranelate, bone tissue will contain around one strontium atom for every 100 calcium atoms. In animal studies, up to one calcium atom in 10 was substituted with strontium without any important modifications of bone mineral at the crystal level.10 No human studies have yet reported how quickly bone strontium is washed out once treatment is stopped. However, studies with radioactive strontium show that much of the stable strontium present in bone after three years of treatment will still be there a decade later.9
What are the changes in bone mineral density with strontium ranelate? In the SOTI trial, an impressive increase in bone mineral density occurred in the spine (14.4%) and hip (8.3%).7 However, some caution is necessary in interpreting these figures because much of this effect is due to the higher atomic number of strontium (Z = 38) compared with calcium (Z = 20). When bone mineral density is measured by bone densitometry, atom for atom strontium attenuates x rays more strongly than calcium. As a result a 1% molar fraction of strontium causes a 10% overestimation of bone mineral density.11 In the SOTI trial, bone biopsy was performed in a subset of patients and the data for bone mineral density corrected on the basis of the correlation between the bone strontium content measured in the biopsy samples and concentrations of strontium in the blood. After the adjustment for bone strontium, the measured effect of treatment on bone mineral density in the spine of 14.4% was corrected to 8.1%.7
The important issue for treatment for osteoporosis is prevention of fractures and not changes in bone mineral density. This lesson was learnt with fluoride therapy, which led to dramatic increases in bone mineral density of the spine but in higher dosage caused an increased incidence of hip fracture.12 Caution is therefore needed in predicting efficacy against fractures simply on the basis of a change in bone mineral density.
Although measurements of bone mineral density are of value in diagnosing osteoporosis and in assessing the risk of fracture,w2 w3 many believe that they are of limited use in monitoring treatment. An increase of 5% in spine bone mineral density is required to confirm a notable response to treatment.w4 Often the changes are smaller than this, and as a result measurements of bone mineral density to monitor treatment are carried out only after two years.w5 With strontium ranelate, large increases in bone mineral density are often seen, and if this is the case one can be confident that the patient is complying with treatment. Though changes in bone mineral density measured during treatment with strontium are somewhat artefactual, they might still prove clinically useful. The issue of patients' long term use and compliance with treatment is important for all types of treatment for osteoporosis. For strontium ranelate, the large increase in bone density expected by 12 months may prove useful in this regard and could provide reassurance for the patient and the clinician.
Ignac Fogelman, professor
Department of Nuclear Medicine, Guy's Hospital, London SE1 9RT
(ignac.fogelman@kcl.ac.uk)
Glen M Blake, senior lecturer
Guy's, King's, and St Thomas' School of Medicine, London SE1 9RT
Additional references w1-w5 are on bmj.com
Competing interests: IF has acted as a consultant to Servier, manufacturer of strontium ranelate.
References
Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C. Summary of meta-analyses of therapies for postmenopausal osteporosis. Endocrine Rev 2002;23: 570-8.
Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. Randomised trial of the effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348: 1535-41.
Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the fracture intervention trial. JAMA 1998;280: 2077-82.
Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, et al. Effects of risedronate treatment on vertebral and non-vertebral fractures in women with postmenopausal osteoporosis. JAMA 1999;282: 1344-52.
McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, et al. Effect of risedronate treatment on hip fracture risk in elderly women. N Engl J Med 2001;344: 333-40.
Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster J-Y, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344: 1434-41.
Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350: 459-68.
Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: TROPOS study. J Clin Endocrinol Metab 2005. (Published online 22 Feb; doi: 10.1210/jc.2004-1774.)
Marshall JH, Lloyd EL, Rundo J, Liniecki J, Marotti G, Mays CW, et al. Alkaline earth metabolism in adult man. A report prepared by a task group of committee 2 of the International Commission on Radiological Protection (ICRP publication 20). Health Phys 1973;24: 129-221.
Boivin G, Deloffre P, Perrat B, Panczer G, Boudeulle M, Mauras Y, et al. Strontium distribution and interactions with bone mineral in monkey iliac bone after strontium salt administration (S12911). J Bone Miner Res 1996;11: 1302-11.
Pors Nielsen S, Slosman D, Sorensen OH, Basse-Cathelinat B, De Casin P, Roux C, et al. Influence of strontium on bone mineral density and bone mineral content measurements by dual x-ray absorptiometry. J Clin Densitom 1999;2: 371-9.
Riggs BL, Hodgson SF, O'Fallan M, Chao EYS, Wahner HW, Muhs JM, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990;322: 802-9.