Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study

BACKGROUND: Strontium ranelate, a new oral drug shown to reduce vertebral fracture risk in postmenopausal women with osteoporosis, was studied in the Treatment of Peripheral Osteoporosis (TROPOS) study to assess its efficacy and safety in preventing nonvertebral fractures also. METHODS: Strontium ranelate (2 g/d) or placebo were randomly allocated to 5091 postmenopausal women with osteoporosis in a double-blind placebo-controlled 5-yr study with a main statistical analysis over 3 yr of treatment. FINDINGS: In the entire sample, relative risk (RR) was reduced by 16% for all nonvertebral fractures (P = 0.04), and by 19% for major fragility fractures (hip, wrist, pelvis and sacrum, ribs and sternum, clavicle, humerus) (P = 0.031) in strontium ranelate-treated patients in comparison with the placebo group. Among women at high risk of hip fracture (age > or = 74 yr and femoral neck bone mineral density T score < or = -3, corresponding to -2.4 according to NHANES reference) (n = 1977), the RR reduction for hip fracture was 36% (P = 0.046). RR of vertebral fractures was reduced by 39% (P < 0.001) in the 3640 patients with spinal x-rays and by 45% in the subgroup without prevalent vertebral fracture. Strontium ranelate increased bone mineral density throughout the study, reaching at 3 yr (P < 0.001): +8.2% (femoral neck) and +9.8% (total hip). Incidence of adverse events (AEs) was similar in both groups. CONCLUSION: This study shows that strontium ranelate significantly reduces the risk of all nonvertebral and in a high-risk subgroup, hip fractures over a 3-yr period, and is well tolerated. It confirms that strontium ranelate reduces vertebral fractures. Strontium ranelate offers a safe and effective means of reducing the risk of fracture associated with osteoporosis.     

Strontium ranelate: vertebral and non-vertebral fracture risk reduction

Fractures are common at the spine and hip, but at least half the morbidity and mortality of fractures in the community come from fractures that involve other sites. Over half of all fractures arise in individuals without osteoporosis, whereas the highest risk group for fractures are individuals over 80 years of age. Reducing the burden of fractures should thus include an assessment of drug efficacy against all fractures in a wide range of individuals. For vertebral fractures, in the phase III Spinal Osteoporosis Therapeutic Intervention study of 1649 postmenopausal women with osteoporosis, 2 g strontium ranelate a day produced a risk reduction of 49% in the first year and 41% during 3 years. In the TReatment Of Peripheral OSteoporosis study, which was designed to examine the effect of strontium ranelate on non-vertebral fractures, of the 5091 patients, 3640 had spine X-rays. The vertebral fracture risk reduction was 45% at one year and 39% over 3 years. In a preplanned pooling of the above two studies, 1170 patients had vertebral osteopenia. Strontium ranelate reduced the risk of vertebral fracture in 3 years by 40% in these patients. In 409 patients with lumbar or femoral neck osteopenia, strontium ranelate reduced the risk of vertebral fractures by 62% over 3 years. In the pre-planned pooling of data from the two studies, in 1488 women aged between 80 and 100 years (mean age 84 +/- 3 years), the risk of vertebral fractures was reduced in one year by 59% and by 32% over 3 years. For non-vertebral fractures, in the TReatment Of Peripheral OSteoporosis study, treatment for 3 years reduced the fracture risk by 16%, and by 19% for major fragility fractures. In a post-hoc analysis of 1977 women at high risk of hip fracture (aged > or = 74 years and with a femoral neck bone mineral density T-score < or = -2.4) the hip fracture risk was reduced by 36%. In patients aged 80 and over in the pre-planned pooling of data from the two studies, the risk of an incident non-vertebral fracture was reduced by 41% in the first year and by 31% over 3 years. Strontium ranelate, a new anti-osteoporosis agent, has a broad range of antifracture efficacy.     

Effects of long-term strontium ranelate treatment on the risk of nonvertebral and vertebral fractures in postmenopausal osteoporosis: Results of a five-year, randomized, placebo-controlled trial

OBJECTIVE: This study was undertaken to assess the effect of strontium ranelate on nonvertebral and vertebral fractures in postmenopausal women with osteoporosis in a 5-year, double-blind, placebo-controlled trial. METHODS: A total of 5,091 postmenopausal women with osteoporosis were randomized to receive either strontium ranelate at 2 gm/day or placebo for 5 years. The main efficacy criterion was the incidence of nonvertebral fractures. In addition, incidence of hip fractures was assessed, by post hoc analysis, in the subset of 1,128 patients who were at high risk of fractures (age 74 years or older with lumbar spine and femoral neck bone mineral density T scores -2.4 or less). The incidence of new vertebral fractures was assessed, using the semiquantitative method described by Genant, in the 3,646 patients in whom spinal radiography (a nonmandatory procedure) was performed during the course of the study. Fracture data were analyzed using the Kaplan-Meier survival method. RESULTS: Of the 5,091 patients, 2,714 (53%) completed the study up to 5 years. The risk of nonvertebral fracture was reduced by 15% in the strontium ranelate group compared with the placebo group (relative risk 0.85 [95% confidence interval 0.73-0.99]). The risk of hip fracture was decreased by 43% (relative risk 0.57 [95% confidence interval 0.33-0.97]), and the risk of vertebral fracture was decreased by 24% (relative risk 0.76 [95% CI 0.65-0.88]) in the strontium ranelate group. After 5 years, the safety profile of strontium ranelate remained unchanged compared with the 3-year findings. CONCLUSION: Our findings indicate that treatment of postmenopausal osteoporosis with strontium ranelate results in a sustained reduction in the incidence of osteoporotic nonvertebral fractures, including hip fractures, and vertebral fractures over 5 years.     

Strontium ranelate: short- and long-term benefits for post-menopausal women with osteoporosis

Strontium ranelate is a bone-seeking element that has been assessed in post-menopausal osteoporosis in two large double-blind, placebo-controlled studies. This treatment is able to decrease the risk of vertebral fractures, by 41% over 3 yrs, and by 49% within the first year of treatment. This risk of non-vertebral fractures is decreased by 16% and, in patients at high risk for such a fracture, the risk of hip fracture is decreased by 36% over 3 yrs. Recent 5-yr data from these double-blind, placebo-controlled studies show that the anti-fracture efficacy is maintained over time. Treatment efficacy with strontium ranelate has been documented across a wide range of patient profiles: age, number of prevalent vertebral fractures, BMI, as well as family history of osteoporosis and addiction to smoking are not determinants of anti-fracture efficacy. During these clinical trials, safety was good. Its large spectrum of efficacy allows the use of strontium ranelate in the different subgroups of patients with post-menopausal osteoporosis.     

Efficacy,effectiveness and side effects of medications used to prevent fractures

There is an increasing number of effective therapies for fracture prevention in adults at risk of osteoporosis. However, shortcomings in the evidence underpinning our management of osteoporosis still exist. Evidence of antifracture efficacy in the groups of patients who most commonly use calcium and vitamin D supplements is lacking, the safety of calcium supplements is in doubt, and the safety and efficacy of high doses of vitamin D give cause for concern. Alendronate, risedronate, zoledronate and denosumab have been shown to prevent spine, nonspine and hip fractures; in addition, teriparatide and strontium ranelate prevent both spine and nonspine fractures, and raloxifene and ibandronate prevent spine fractures. However, most trials provide little information regarding long‐term efficacy or safety. A particular concern at present is the possibility that oral bisphosphonates might cause atypical femoral fractures. Observational data suggest that the incidence of this type of fracture increases steeply with duration of bisphosphonate use, resulting in concern that the benefit–risk balance may become negative in the long term, particularly in patients in whom the osteoporotic fracture risk is not high. Therefore, reappraisal of ongoing use of bisphosphonates after about 5 years is endorsed by expert consensus, and ‘drug holidays’ should be considered at this time. Further studies are needed to guide clinical practice in this area.     

How to manage postmenopausal osteoporosis?

Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased fracture risk. Several therapeutic agents are now available to treat postmenopausal osteoporosis and prevent fractures. Combined calcium and vitamin D supplementation reduce the relative risk of non-vertebral fractures by about 18%. Hormone replacement therapy (HRT) should not be prescribed for osteoporosis in women who do not experience menopausal symptoms. The marked benefits of raloxifene on the reduction in invasive breast cancer and vertebral fracture risk are partially counterbalanced by a lack of effect on non-vertebral fracture risk, and an increased risk of venous thromboembolism and stroke. All four bisphosphonates available in Belgium, except ibandronate, have been shown to reduce the risk of vertebral, non-vertebral and hip fractures in prospective, placebo-controlled trials. Globally, the incidence of vertebral fractures is reduced by 41%-70%, and the incidence of non-vertebral fractures by 25%-39%. The anti-fracture efficacy of weekly or monthly doses of oral bisphosphonates has not been directly shown but is assumed from bridging studies based on BMD changes. To date, the various bisphosphonates have not been studied in head-to-head comparative trials with fracture endpoints. There are potential concerns that long-term suppression of bone turnover associated with bisphosphonate treatment may eventually lead to adverse effects, especially atypical femoral fractures and osteonecrosis of the jaw, but these cases are extremely rare. Teri-paratide (recombinant human 1-34 PTH) administered by daily subcutaneous injections decreases by 65% the relative risk of new vertebral fractures in patients with severe osteoporosis. Pivotal trials with strontium ranelate have shown a 41% reduction in new vertebral fractures and a 16% reduction in non-vertebral fractures over 3 years. Denosumab is a fully human monoclonal antibody to RANK Ligand that is administered as a 60-mg subcutaneous injection every 6 months. In the pivotal phase III trial, there was a 68% reduction in the incidence of new vertebral fractures, whereas the incidence of non-vertebral fractures was reduced by 20%. Several new approaches are being explored, including antibodies to sclerostin, cathepsin K inhibitors, src kinase inhibitors, and drugs that act on calcium sensing receptors.     

Strontium ranelate: a novel treatment for postmenopausal osteoporosis: a review of safety and efficacy

Strontium ranelate is a new orally administered agent for the treatment of women with postmenopausal osteoporosis that reduces the risk of vertebral and hip fractures. Evidence for the safety and efficacy of strontium ranelate comes from two large multinational trials, the SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment Of Postmenopausal Osteoporosis) studies. The SOTI study evaluated vertebral fracture prevention in 1649 postmenopausal women with a mean age of 69 y. The subjects all had at least one previous vertebral fracture and a low spine bone mineral density (BMD) (equivalent to a Hologic spine T-score below −1.9). The strontium ranelate group had a 41% lower risk of a new vertebral fracture than the placebo group over the three-year study period (relative risk [RR]=0.59; 95% confidence interval [CI]: 0.48–0.73; p<0.001). The TROPOS study evaluated non-vertebral fracture prevention in 5091 postmenopausal women with a mean age of 77 y. The subjects were aged 74 y and over (or 70–74 y with one additional risk factor) and a low femoral neck BMD (equivalent to an NHANES III [Third National Health and Nutrition Examination Survey] T-score below −2.2). Over the three-year study period there was a 16% reduction in all non-vertebral fractures (RR=0.84; 95% CI 0.702–0.995; p=0.04) and a 19% reduction at the principal sites for non-vertebral fractures. The TROPOS study was not powered to investigate hip fracture risk. However, in a high risk group of women aged 74 y and over and with an NHANES III femoral neck T-score less than −2.4 there was a 36% reduction in hip fracture risk (RR=0.64; 95% CI: 0.412–0.997; p=0.046). The overall incidence of adverse events did not differ significantly from placebo and were generally mild and transient, the most common being nausea and diarrhea. Strontium ranelate is a useful addition to the range of anti-fracture treatments available for treating postmenopausal women with osteoporosis and is the only treatment proven to be effective at preventing both vertebral and hip fractures in women aged 80 y and over.     

Anabolic Agents for Osteoporosis

Antiresorptive agents for osteoporosis are a cornerstone of therapy, but anabolic drugs have recently widened our therapeutic options. By directly stimulating bone formation, anabolic agents reduce fracture incidence by improving other bone qualities in addition to increasing bone mass. Teriparatide (human parathyroid hormone[1-34]) has clearly emerged as a major approach for selected patients with osteoporosis. Teriparatide increases bone mineral density and bone turnover, improves bone microarchitecture, and changes bone size. The incidence of vertebral and non-vertebral fractures is reduced. Teriparatide is approved in many countries throughout the world for the treatment of both postmenopausal women and men with osteoporosis who are at high risk for fracture. Another anabolic agent, strontium ranelate, may both promote bone formation and inhibit bone resorption. Clinical trials support the use of strontium ranelate as a treatment for postmenopausal osteoporosis and have shown that strontium ranelate reduces the frequency of vertebral and non-vertebral fractures. Other potential anabolic therapies for osteoporosis, including other forms of parathyroid hormone, growth hormone, and insulin-like growth factor-I, have been examined, although less data are currently available on these approaches.     

Treatment options for postmenopausal osteoporosis in Asia

Treatment of osteoporosis has advanced dramatically during the past decade, with more therapeutic options than ever now available. Large‐scale randomized placebo‐controlled trials have documented the efficacy of a number of agents in reducing vertebral and non‐vertebral fractures. Anti‐resorptive agents (hormone replacement therapy, selective estrogen‐receptor modulators, calcitonin and bisphosphonates) and bone‐forming anabolic agents (parathyroid horomone and strontium ranelate) act via different mechanisms to reduce fractures and improve bone strength. In view of the high prevalence of calcium and vitamin D insufficiency in Asia, calcium and vitamin D supplementation remains a fundamental part of any treatment regimen, especially among the elderly. Given the high cost of these agents, a global assessment of the fracture risk of the patient is essential to determine the need for pharmacological treatment versus life‐style modification and dietary supplementation in the management of postmenopausal osteoporosis in Asia.     

Relationship between bone mineral density changes and fracture risk reduction in patients treated with strontium ranelate

OBJECTIVE: Our objective was to analyze the relationship between bone mineral density (BMD) changes and fracture incidence during 3-yr treatment with strontium ranelate. PATIENTS: Women from the strontium ranelate arm of the Spinal Osteoporosis Therapeutic Intervention study and the TReatment Of Peripheral OSteoporosis study were evaluated. OUTCOME MEASURES: The outcome measures included BMD at the lumbar spine, femoral neck, and total proximal femur assessed at baseline and after a follow-up of 1 and 3 yr; semiquantitative visual assessment of vertebral fractures; and nonvertebral fractures based on written documentation. RESULTS: After 3 yr of strontium ranelate treatment, each percentage point increase in femoral neck and total proximal femur BMD was associated with a 3% (95% adjusted confidence interval, 1-5%) and 2% (1-4%) reduction in risk of a new vertebral fracture, respectively. The 3-yr changes in femoral neck and total proximal femur BMD explained 76% and 74%, respectively, of the reduction in vertebral fractures observed during the treatment. Three-year changes in spine BMD were not statistically associated with the incidence of new vertebral fracture (P = 0.10). No significant associations were found between 3-yr changes in BMD and incidence of new nonvertebral fractures, but a trend was found for femoral neck BMD (P = 0.09) and for total proximal femur BMD (P = 0.07). An increase in femoral neck BMD after 1 yr was significantly associated with the reduction in incidence of new vertebral fractures observed after 3 yr (P = 0.04). CONCLUSION: During 3-yr strontium ranelate treatment, an increase in femoral neck BMD was associated with a proportional reduction in vertebral fracture incidence.     

Possible benefits of strontium ranelate in complicated long bone fractures

Osteoporosis drugs are prescribed to prevent fragility fractures, which is the principal aim of the management of osteoporosis. However, if fracture does occur, then it is also important to promote a fast and uneventful healing process. Despite this, little is known about the effect of osteoporosis drugs on bone healing in humans. Strontium ranelate is an osteoporosis agent that increases bone formation and reduces bone resorption and may therefore be beneficial in fracture healing. We report four cases of fracture non-union for up to 20 months. Treatment with strontium ranelate (2 g/day) for between 6 weeks and 6 months appeared to contribute to bone consolidation in the four cases. Animal studies support beneficial effects of strontium ranelate on bone healing via improvement of bone material properties and microarchitecture in the vicinity of the fracture. The clinical cases described herein provide new information on these effects, in the absence of randomized controlled studies on the clinical efficacy of pharmacological treatments in osteoporosis in fracture repair. Further studies are necessary. Fracture healing is an important topic in orthopedic research and is also a concern for patients with postmenopausal osteoporosis. Evidence from case reports and animal studies suggests that strontium ranelate improves bone microarchitecture and accelerates fracture healing. A positive effect of osteoporosis treatments on bone healing is an interesting possibility and merits further clinical research.     

Strontium ranelate and alendronate have differing effects on distal tibia bone microstructure in women with osteoporosis

The structural basis of the antifracture efficacy of strontium ranelate and alendronate is incompletely understood. We compared the effects of strontium ranelate and alendronate on distal tibia microstructure over 2 years using HR-pQCT. In this pre-planned, interim, intention-to-treat analysis at 12 months, 88 osteoporotic postmenopausal women (mean age 63.7 ± 7.4) were randomized to strontium ranelate 2 g/day or alendronate 70 mg/week in a double-placebo design. Primary endpoints were changes in microstructure. Secondary endpoints included lumbar and hip areal bone mineral density (aBMD), and bone turnover markers. This trial is registered with , number ISRCTN82719233. Baseline characteristics of the two groups were similar. Treatment with strontium ranelate was associated with increases in mean cortical thickness (CTh, 5.3%), cortical area (4.9%) and trabecular density (2.1%) (all P < 0.001, except cortical area P = 0.013). No significant changes were observed with alendronate. Between-group differences in favor of strontium ranelate were observed for CTh, cortical area, BV/TV and trabecular density (P = 0.045, 0.041, 0.048 and 0.035, respectively). aBMD increased to a similar extent with strontium ranelate and alendronate at the spine (5.7% versus 5.1%, respectively) and total hip (3.3% versus 2.2%, respectively). No significant changes were observed in remodeling markers with strontium ranelate, while suppression was observed with alendronate. Within the methodological constraints of HR-pQCT through its possible sensitivity to X-ray attenuation of different minerals, strontium ranelate had greater effects than alendronate on distal tibia cortical thickness and trabecular volumetric density.     

Osteoporosebehandlung: Bisphosphonate, SERM’s, Teriparatide und Strontium

The therapy of osteoporosis is mostly based upon the use of drugs which inhibit bone resorption. Among these, the bisphosphonate family is the best known and mostly used by clinicians. Both second and third generation bisphosphonates, like alendronate and risedronate, are now available as weekly tablets which have facilitated the patient compliance to treatment together with a decreased occurrence of gastrointestinal side effects. These compounds are used efficiently to treat postmenopausal osteoporosis and osteoporosis of men as well. Their use did provide good evidence of increased bone mineral density (BMD) and a reduction in fracture rates. The use of intravenous bisphosphonates such as Zoledronate, Ibandronate and Pamidronate remains in most of the cases limited to special indications such as intolerance to the oral formulations and treatment of patients with bone metastases. The selective estrogen modulators (SERM's) family is limited to a single product on the market as of now, Raloxifene, which does inhibit bone resorption and is well documented by postmenopausal women to increase BMD and reduce vertebral fractures. In addition, a large range of positive nonosseous effects have been documented such as the reduction of the incidence of breast cancer. Other substances do have a strong anabolic effect such as Teriparatide, a recombinant human formulation of PTH 1-34. This compound has demonstrated good efficacy in postmenopausal women, increasing vertebral and hip BMD and reducing the incidence of fractures at both sites. The exact role of Teriparatide in the clinical setting is still open but its overall impact in the therapy of osteoporosis could be major due to its major efficiency over shorter periods of time. Strontium ranelate, a new divalent Strontium salt taken orally, acts both as an anti-catabolic and anabolic agent. The first results provided with strontium ranelate are very promising due to its major effect on the increase in BMD both at the vertebral and hip sites and its ability to reduce the incidence of fractures at both locations. Additional data are awaited to confirm these initial positive results.     

Addressing and meeting the needs of osteoporotic patients with strontium ranelate: a review

Patients with osteoporosis need a safe and effective treatment that reduces the risk of vertebral and non-vertebral fractures, leading to clinical benefits such as reduced back pain and height loss. Strontium ranelate corrects bone turnover, producing a more physiological state. Double-blind, placebo-controlled studies in postmenopausal osteoporosis show it to be effective in reducing vertebral and non-vertebral fracture risks. Treatment efficacy has been documented across a wide range of patient profiles, and appears to be independent of all the major determinants of fracture risk, including the severity of the disease at baseline, the number of prevalent fractures, and the age of the patient. This antifracture efficacy translates into clinical benefits, such as a 20% reduction in the rate of height loss and a 29% increase in the number of patients free of back pain. The effect of treatment with strontium ranelate on well-being has been assessed using the Quality-of-Life Questionnaire in Osteoporosis, which is a supplement to the 36-question Short-Form Health Survey. Treatment with strontium ranelate had a significant beneficial effect on the emotional, physical, and global Quality-of-Life Questionnaire in Osteoporosis scores compared with placebo. The rates of compliance with treatment were over 80% in phase III studies, reflecting the tolerability and safety profile and the ease of administration of this agent. Together with the antifracture data, the clinical benefits and quality of life data endorse the treatment of postmenopausal osteoporosis with strontium ranelate.     

The Treatment of Severe Postmenopausal Osteoporosis

Several chemical entities have shown their ability to reduce axial and/or appendicular fractures in patients with osteoporosis. Since patients who have experienced a previous fracture are at high risk for subsequent vertebral or hip fracture, it is of prime importance to treat such patients with medications that have unequivocally demonstrated their ability to reduce fracture rates in patients with prevalent fractures. Results obtained with calcium and vitamin D, in this particular population, are not fully satisfactory and these medications are probably better used in conjunction with other therapeutic regimens. Bisphosphonates have shown their ability to reduce vertebral (alendronate, risedronate, ibandronate) and non-vertebral (alendronate, risedronate) fractures in patients with established osteoporosis. Raloxifene has also shown similar properties, notwithstanding its effect on non-vertebral fractures, which has only been derived from a post hoc analysis limited to patients with prevalent severe vertebral fractures at baseline. This compound also has interesting non-skeletal benefits, including effects on the breast and heart. Teriparatide, a bone-forming agent, promptly reduces the rate of vertebral and all non-vertebral fractures, without significant adverse effects. Strontium ranelate, the first agent shown to concomitantly decrease bone resorption and stimulate bone formation, has also shown its ability to reduce rates of vertebral and non-vertebral fractures in patients with established osteoporosis. It significantly reduces hip fractures in elderly individuals at high risk for such events. Its safety profile is also excellent.     

Clinical Pharmacology of Potent New Bisphosphonates for Postmenopausal Osteoporosis

Bisphosphonates are potent inhibitors of bone resorption, used in most bone diseases associated with high bone resorption levels. Several bisphosphonates, developed to prevent and treat postmenopausal osteoporosis, increase bone mineral density and decrease biochemical markers of bone turnover, and more importantly, reduce fracture risk. Alendronate and risedronate have proven their efficacy to reduce vertebral and hip fracture risk among postmenopausal osteoporotic women, using daily regimens. Weekly intermittent schedules, however, are now most commonly prescribed, because they have shown pharmacologic equivalence to the daily regimen. Ibandronate has been the first bisphosphonate to demonstrate vertebral fracture risk reduction using an intermittent regimen. Studies using ibandronate as intravenous injections every 3 months are under way. Zoledronic acid may also be an attractive option for the treatment of postmenopausal osteoporosis if a large ongoing trial proves that a single annual injection of this compound allows osteoporotic fracture risk reduction.     

Treating osteoporosis to prevent fractures: current concepts and future developments

Antiresorptive drugs, such as the bisphosphonates and the RANKL inhibitor denosumab, are currently the most widely used osteoporosis medications. These drugs increase bone mineral density (BMD) and reduce the risk of vertebral (by 40–70%), nonvertebral (by 25–40%) and hip fractures (by 40–53%) in postmenopausal women with osteoporosis. Due to the risk of rare side‐effects, the use of bisphosphonates has been limited to up to 10 years with oral bisphosphonates and 6 years with intravenous zoledronic acid. Despite their well‐proven efficacy and safety, few women at high risk of fracture are started on treatment. Case finding strategies, such as fracture risk‐based screening in primary care using the fracture risk assessment tool (FRAX) and Fracture Liaison Services, have proved effective in increasing treatment rates and reducing fracture rates. Recently, anabolic therapy with teriparatide was demonstrated to be superior to the bisphosphonate risedronate in preventing vertebral and clinical fractures in postmenopausal women with vertebral fracture. Treatment with the sclerostin antibody romosozumab increases BMD more profoundly and rapidly than alendronate and is also superior to alendronate in reducing the risk of vertebral and nonvertebral fracture in postmenopausal women with osteoporosis. For patients with severe osteoporosis and high fracture risk, bisphosphonates alone are unlikely to be able to provide long‐term protection against fracture and restore BMD. For those patients, sequential treatment, starting with a bone‐building drug (e.g. teriparatide), followed by an antiresorptive, will likely provide better long‐term fracture prevention and should be the golden standard of future osteoporosis treatment.     

Drug insight: Bisphosphonates for postmenopausal osteoporosis

Bisphosphonates are potent antiresorptive agents, which have largely been used for the treatment of postmenopausal osteoporosis during the past 10 years. When embedded in bone matrix, bisphosphonates are taken up by osteoclasts engaged in bone resorption, leading--mainly by inhibition of farnesyl diphosphate synthase, a key enzyme of the mevalonate pathway--to osteoclast apoptosis. Bone resorption decreases, with consequent improvement in the mechanical properties of bone and a reduced risk of fracture. Alendronate and risedronate are oral nitrogen-containing bisphosphonates. Several randomized, placebo-controlled trials have shown the ability of these bisphosphonates to halve the risk of vertebral fracture when taken daily for 3 years. Nonvertebral fracture risk, including that at the hip, was also significantly decreased. Weekly regimens have simplified the administration of bisphosphonates and, probably, improved adherence to treatment. A significant reduction in the risk of vertebral fracture has also been demonstrated with an intermittent regimen of ibandronate, which is a new, potent, nitrogen-containing bisphosphonate. Ibandronate was recently marketed for use in an oral, once-monthly dose of 150 mg, with the goal of improving compliance. Bisphosphonates are usually well tolerated in the long term. Intravenous administration of bisphosphonates in women with osteoporosis, which is currently under investigation, might be an interesting future option for women who cannot tolerate oral regimens, and for enhancing compliance.     

Strontium ranelate decreases plasma homocysteine levels in postmenopausal osteoporotic women

We analyzed the effect of strontium ranelate treatment on plasma homocysteine (Hcy) levels in postmenopausal osteoporotic women. Forty-nine postmenopausal women diagnosed with osteoporosis with a mean age of 54.07 +/- 7.5 years (range 40-70) who visited our menopause clinic were participated in this prospective study. Patients with bone mineral density (BMD) at least 2.5 SD below the average value in young adults (T score < -2.5) were considered to have osteoporosis. Patients received strontium ranelate 2 g/day (Servier) orally with additional calcium supplements. Fasting plasma Hcy levels were assessed at baseline, 3, 6 and 12 months of the therapy with strontium ranelate. The mean plasma Hcy level (10.45 micromol/l) after 3 months of therapy was significantly lower compared to the basal plasma Hcy level (12.61 micromol/l) (P = 0.002). The plasma homocysteine level (10.54 micromol/l) of the 43 patients that were present at the 6 months of the therapy was also significantly lower compared to the basal plasma Hcy level (P = 0.005). At the end of the 12 months of the study, there were 42 patients. The plasma homocysteine level (10.107 micromol/l) at 12 months of therapy was also significantly lower compared to the basal Hcy level (P < 0.001). Strontium ranelate 2 g/day treatment for 1 year significantly decreases plasma Hcy levels in postmenopausal women with osteoporosis. Since the increased Hcy levels could lead to an increase risk of osteoporosis and fracture risk, this effect of strontium ranelate on Hcy level may cause additional benefit in terms of reducing the risk of fracture.     

Osteoporosis therapies Bisphosphonates, SERMs, PTH, and new therapies

Osteoporosis therapies include antiresorptive and anabolic agents. Antiresorptive agents include the bisphosphonates (etidronate, alendronate, risedronate, ibandronate, and off-label use of the intravenous drugs pamidronate and zolendronate), selective estrogen receptor modulators (SERMs) (raloxifene), calcitonin, and estrogens. An anabolic agent, teriparatide (rhPTH 1–34) was released in 2002. New therapies may be available in the coming years, including new SERMs, strontium ranelate, and an antibody to RANK ligand.