Broad antifracture efficacy coupled with unique benefits on bone: Protelos, the logical response to osteoporosis




Philippe HALBOUT, PhD
Servier International
Paris, FRANCE

Broad antifracture efficacy
coupled with unique benefits
on bone: Protelos, the logical
response to osteoporosis

by P. Halbout ,France

Osteoporosis is a common insidious disease seen typically in middleaged and elderly women due to the postmenopausal fall in estrogen levels. The combination of progressive bone loss and decreased bone quality increases the risk of vertebral, nonvertebral, and hip fracture, causing major morbidity and mortality. In spite of this apparent simple picture, treatment confronts clinicians with three major challenges: first, drugs against osteoporosis have been around for 40 years, but few have proved effective in preventing fractures at all sites; second, the increase in fracture risk in postmenopausal women with osteoporosis is due to a variety of risk factors, whose combination results in a great number of different profiles, obliging clinicians to select a drug that is effective for their patient’s particular profile; third, solid evidence of long-term efficacy is required when treating a chronic disease such as osteoporosis. As an antiosteoporotic agent with a unique mode of action, Protelos (strontium ranelate) is the first drug to meet these challenges. It has a unique mode of action, by means of which it increases bone formation and reduces bone resorption, thus rebalancing bone turnover in favor of bone formation. Protelos builds strong new bone in osteoporotic women, providing protection against vertebral, nonvertebral, and hip fractures. Protelos has been shown to be effective across a variety of profiles: from the youngest to the oldest patients, and from those with osteopenia to those with the most severe osteoporosis. The 2008 European Guidance acknowledged Protelos as the treatment with the most robust evidence of comprehensive antifracture efficacy and, hence, as an unequivocal first-line choice in the treatment of postmenopausal osteoporosis.

Medicographia. 2010;32:59-66 (see French abstract on page 66)

Osteoporosis is a devastating disease that induces progressive bone loss and bone fragility in postmenopausal women, thereby increasing fracture risk in a silent fashion. However, in spite of this apparently simple picture, treatment confronts clinicians with three challenges: first, drugs against osteoporosis have been around for 40 years, but few have proved effective in preventing fractures at all sites; second, the increase in fracture risk in postmenopausal women with osteoporosis is due to a variety of risk factors, whose combination results in a great number of different profiles, obliging clinicians to select a drug that is effective for their patient’s particular profile; third, evidence of long-term efficacy is required when treating a chronic disease such as osteoporosis. Very few treatments have proved effective against fractures at all sites, irrespective of patient profile, and in the long term. This article reviews the extent to which Protelos satisfies these three criteria (Figure 1).

Figure 1
Figure 1. Three key criteria for the treatment of osteoporosis.

Protelos: comprehensive efficacy against vertebral, nonvertebral, and hip fracture

Treatments of osteoporosis are generally assessed by their ability to prevent two types of fracture: vertebral fractures (the most common type) and hip fractures (the most serious type in terms of morbidity and mortality, especially in the elderly). Surprisingly, few treatments among the armamentarium available to clinicians have proved effective against both vertebral and hip fractures.

Two pivotal efficacy trials, both multinational, randomized, double-blind, and placebo-controlled have confirmed the efficacy of Protelos on each fracture type in a total of 6740 postmenopausal women, all of whom received concomitant calcium/vitamin D supplementation at a dose tailored to the degree of deficiency (calcium 500/1000 mg, vitamin D3 400/800 IU).

The efficacy of Protelos against vertebral fracture was assessed in the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial in 1649 postmenopausal women aged ≥_50 years with ≥_1 vertebral fracture(s) and lumbar spine bone mineral density (BMD) ≤0.840 g/cm2 (Hologic: www.hologic.com). Protelos decreased new vertebral fracture risk by 49% after only 1 year (relative risk [RR], 0.51; 95% confidence interval [CI], 0.36-0.74; P<0.001). Clinical vertebral fractures, defined as vertebral fracture coupled with back pain and/or height loss ≥_1 cm, fell by 52% also as early as the first year of treatment (RR, 0.48; 95% CI, 0.29-0.80; P=0.003). Reductions in vertebral and clinical vertebral fractures at 3 years (41%; RR, 0.59; 95%CI, 0.48-0.73, and 38%; RR, 0.62; 95% CI, 0.47-0.83, respectively; both P<0.001) further confirmed the long-termefficacy of Protelos (Figure 2).1

The second study, TReatment Of Peripheral Osteoporosis Study (TROPOS), assessed the efficacy of Protelos against nonvertebral and hip fractures in 5091postmenopausal women with femoral neck BMD equivalent to a T-score below –2.5 SD (centralized normative data analysis: Dr D. O. Slosman, Geneva, Switzerland) and age ≥_74 years or 70 to 74 years with an additional fracture risk factor. At 3 years, Protelos decreased the risk of nonvertebral fractures by 16% (RR, 0.84; 95% CI, 0.702-0.995; P<0.05) and the risk of major nonvertebral fractures (hip, wrist, pelvis, sacrum, ribs-sternum, clavicle, and humerus) by 19% (RR, 0.81; 95% CI, 0.66-0.98; P<0.05).2 Special attention was paid to the effect of Protelos on hip fractures, because of their devastating consequences in terms of morbidity and mortality. In the subgroup of patients at highest hip fracture risk, ie, those aged ≥_74 years with femoral neck T score ≤–2.4 SD, Protelos decreased the risk of hip fractures by 36% (RR, 0.64; 95% CI, 0.412-0.667; P=0.046) over 3 years (Figure 3). At the same time, TROPOS confirmed the SOTI data by showing that Protelos decreased the risk of new vertebral fractures over 1 and 3 years by 45%(RR, 0.55; 95% CI, 0.39-0.77; P<0.001) and 39% (RR, 0.61; 95% CI, 0.51-0.73; P<0.001), respectively, versus placebo. Figure 2
Figure 2. The effects of Protelos on the risk of vertebral fracture in women with postmenopausal osteoporosis in the SOTI study.

Abbreviations: ARR, absolute risk reduction; CI, confidence interval; RR, relative risk; SOTI, Spinal Osteoporosis Therapeutic Intervention.

Figure 3
Figure 3. Significant decreases in the relative risks of nonvertebral, major nonvertebral, and hip fractures with Protelos vs placebo in the TROPOS study.

Abbreviations: ARR, absolute risk reduction; BMD, bone mineral density; CI, confidence interval; RR, relative risk; SD, standard deviation, TROPOS, TRreatment Of Peripheral Osteoporosis Study. After reference 2: Reginster JY, Seeman E, de Vernejoul MC, et al. J Clin Endocrinol Metab. 2005;90:2816-2822. Copyright © 2005, The Endocrine Society.

Protelos is thus effective against osteoporotic fractures at all major sites in postmenopausal women,3 regardless of disease severity, as recently acknowledged in the European Guidance for the Treatment and Management of Osteoporosis in Postmenopausal Women (Table I).4

Table I
Table I. Protelos is the only treatment to have demonstrated its efficacy on vertebral, nonvertebral, and hip fractures, whatever the severity of osteoporosis.

Abbreviations: HRT, hormone replacement therapy; NA, no evidence available; PTH, parathyroid hormone. Adapted from reference 4: Kanis JA, Burlet N, Cooper C, et al. Osteoporos Int. 2008;19:399-428. Copyright © 2008, Springer London.

_ Absolute risk reduction (ARR) and number needed to treat (NNT): two key parameters in interpreting clinical studies
A head-to-head clinical trial comparing the antifracture efficacy between two drugs is undoubtedly the ideal option; but, this would require a huge number of patients and long-term follow-up. However, at least two other options are available. The first is to use surrogatemarkers of fracture risk (eg, BMD, bone quality analysis, and bone markers).5 Unfortunately, these are not sufficiently accurate or fracture-predictive to be useful. The second is to analyze the clinical studies in depth and consider every parameter that reflects efficacy. Relative risk reduction (RRR) is clearly a major parameter, but absolute risk reduction (ARR) and number needed to treat (NNT, the reciprocal of ARR) are also important and should not be overlooked,6 all the more so as they both are directly applicable to clinical practice. ARR reflects the real risk of osteoporotic patients that a clinician has to treat (there is no placebo group in the waiting room), while NNT readily translates into patient terms. SOTI and TROPOS show very low NNTs for Protelos: only 9 patients need to be treated in order to prevent 1 vertebral fracture and 48 to prevent 1 hip fracture, over 3 years.1,2 Protelos outperforms other treatments in terms of both ARR and NNT.

Protelos is effective across a broad range of patient profiles

Hitherto, osteoporosis and osteopenia have been determined based solely on bone mineral density. Osteoporosis and osteopenia are defined by T-scores <–2.5 SD and between –1 SD and –2.5 SD, respectively. However, fracture risk does not depend on BMD alone, but also on other risk factors, including prevalent fractures, age, steroid treatment, smoking, alcohol intake, maternal fracture history, and low body mass index (BMI), thereby creating a range of fracture risk profiles. An ideal treatment should be risk profile–independent. The first indication that Protelos would meet this requirement by preventing osteoporotic fractures independently of risk factors came in 2006,7 well before the World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX®) began to quantify the contribution of such risk factors to fracture prediction.4

_ Risk factors
BMD remains the main fracture risk factor and the basis for diagnosis. Independently of other risk factors, Protelos de- creases vertebral fracture risk by 39% (RR, 0.61; 95% CI, 0.53-0.70; P<0.001) in osteoporotic women with hip/lumbar spine T-score ≤–2.5 SD.7 It is also the only treatment to reduce vertebral fracture risk in osteopenic women (hip/lumbar spine T-score between –1 and –2.5 SD) by a margin as high as 72% (RR, 0.28; 95% CI, 0.07-0.99; P=0.045).8 Efficacy is independent of the number of prevalent fractures: in osteoporotic women with no, one, or two prevalent fractures, Protelos reduced vertebral fracture risk by 48% (RR, 0.52; 95% CI, 0.40-0.67; P<0.001), 45% (RR, 0.55; 95% CI, 0.41-0.74; P<0.001), and 33% (RR, 0.67; 95% CI, 0.55-0.81; P<0.001), respectively.7 Similarly, in osteopenic women with and without prevalent fractures, Protelos decreased vertebral fracture risk by 38% (RR, 0.62; 95% CI, 0.44-0.88; P=0.008), and 59% (RR, 0.41; 95% CI, 0.17-0.99; P=0.039).8

Bone markers, which allow estimation of the level of bone remodeling in postmenopausal women, are sometimes used to confirm the diagnosis of osteoporosis. Even though the relationship between bone markers and fracture risk has not been established, a treatment that works whatever the level of bone markers can only bolster clinician confidence. In the pooled SOTI and TROPOS populations, Protelos decreased vertebral fracture risk by a significant 31% to 42% (nonsignificant difference) across all ranges of the bone formation marker bALP (bone alkaline phosphatase). Similar decreases, from 37% to 47%, were achieved across all ranges of the bone resorption marker sCTX (serum cross-linked C-telopeptides of type I collagen). The two markers can be combined to differentiate patients into low- and high-turnover groups. Protelos decreased vertebral fracture risk by 33% (RR, 0.67; 95% CI, 0.47-0.95; P=0.023) and 49% (RR, 0.51; 95% CI, 0.37-0.70; P<0.001) in low- and high-turnover women, respectively.9

Finally the efficacy of Protelos has been shown to be independent of family history of osteoporosis, body mass index, and smoking.7

_ Young patients with severe osteoporosis
Osteoporosis is one of the most common disorders in young postmenopausal women. Bone loss, due to a dramatic increase in bone turnover, can be rapid in the first decade after the fall in estrogens. This explains why treatment needs to be initiated early if it is to maximize its effect and prevent more devastating consequences. In postmenopausal women aged 50-65 years, Protelos reduced vertebral fracture risk by 47% (RR, 0.53; 95% CI, 0.33-0.85; P=0.006) over 3 years10 and this effect was found to be sustained over a further year, as shown by a 40% reduction in vertebral fracture risk at 4 years (RR, 0.60; 95% CI, 0.39-0.92; P=0.017).11 Efficacy was also independent of age in the pooled SOTI and TROPOS populations: 3-year vertebral fracture risk fell by 37% in women <70 years (RR, 0.63; 95% CI, 0.46-0.85; P=0.003) and by 42% in those aged 70-80 years (RR, 0.58; 95% CI, 0.48- 0.68; P<0.001).7

_ Elderly and frail patients
Women over the age of 80 are particularly prone to fractures due to the frequent combination of risk factors in that age group. These women represent about 8% of the postmenopausal population, but account for over 30% of fragility fractures and over 60% of hip fractures. These have particularly debilitating sequelae in terms of delayed fracture healing, functional impairment, loss of autonomy, as well as increased consumption of nursing homes resources, financial cost, and mortality.

In patients over 80, Protelos reduced vertebral fracture risk by 59% (RR, 0.41; 95% CI, 0.22-0.75; P=0.002), clinical fractures by 37% (RR, 0.63; 95% CI, 0.44-0.91; P=0.012), and nonvertebral fractures by 41% (RR, 0.59; 95% CI, 0.37- 0.95; P=0.027) after 1 year, and by 32% (RR, 0.68; 95% CI, 0.50-0.92; P=0.013), 22% (RR, 0.78; 95% CI, 0.61-0.99; P=0.040), and 31% (RR, 0.69; 95% CI, 0.52-0.92; P=0.011) after 3 years.12 Protelos is the only treatment to have shown long-term efficacy in the elderly, with decreases of 31% in vertebral fracture risk (RR, 0.69; 95% CI, 0.52-0.92; P=0.010) and 26% in nonvertebral fracture risk (RR, 0.74; 95% CI, 0.57-0.95; P=0.019) over 5 years.13

The concept of frailty takes into account a variety of health status factors in addition to age, including decreased strength, tiredness, involuntary weight loss, slowness, and inactivity.14 Frail osteoporotic women are more vulnerable when exposed to stressors and more likely not only to fall, but to fracture as a result. In frail patients from the SOTI and TROPOS populations, Protelos decreased vertebral fractured risk by 58% (RR, 0.41; 95% CI, 0.23-0.73; P=0.002) and overall osteoporotic fracture risk by 28% (RR, 0.72; 95% CI, 0.49-1.04; P=0.08) after 3 years.15

Thus, Protelos is similarly effective in reducing the risk of vertebral and nonvertebral fractures in young and elderly postmenopausal women and in the frail elderly, suggesting that the earlier it is introduced after menopause onset, the greater the anticipated benefit.

Protelos: the only antiosteoporotic treatment with long-term antifracture efficacy proven beyond 3 years

_ Protelos: proven antifracture efficacy beyond 3 years
Only treatments with proven long-term efficacy can hope to be effective in treating a lifelong disease such as osteoporosis. Despite this obvious requirement, there are long-term fracture data for few, if any, treatments. At best, they tend to be BMD data and/or fracture data in open studies or calculated as an annual incidence, rather than in terms of efficacy over time. Protelos is alone in having proven antifracture efficacy beyond 3 years, as shown by the findings fromTROPOS, which evidenced efficacy sustained over 5 years, and even as much as 8 years in an open-label extension study in a subgroup of SOTI and TROPOS patients.

Figure 4
Figure 4. The efficacy of Protelos is sustained over 8 years on (A) vertebral and (B) nonvertebral fractures, as demonstrated by the similar incidence of fractures over the first and last 3 years of follow-up.

Abbreviations: SOTI, Spinal Osteoporosis Therapeutic Intervention; TROPOS, TRreatment Of Peripheral Osteoporosis Study. After reference 17: Reginster JY, Bruyère O, Sawicki A, Roces-Varela A, Fardellone P, Roberts A, Devogelaer JP. Bone. 2009;45:1059-1064. Copyright © 2009, Elsevier Inc.

_ Protelos: unique in being effective over 5 years
Proof of the efficacy of Protelos was afforded by TROPOS, a randomized, double-blind, multicenter, placebo-controlled study with preplanned analysis over 5 years in the intentionto- treat population (n=2714).

During that period, Protelos reduced nonvertebral fracture risk by 15% (RR, 0.85; 95% CI, 0.73-0.99; P=0.032) and the risk of new major nonvertebral osteoporotic fracture by 18% (RR, 0.82; 95% CI, 0.69-0.98; P=0.025) versus placebo.

In a high-risk subgroup (n=1128; ≥74 years and lumbar/ femoral neck T-score ≤–2.4 SD), Protelos reduced hip fracture risk by 43% versus placebo over 5 years (RR, 0.57; 95% CI, 0.33-0.97; P=0.036)16 and vertebral fracture risk by 24% (RR, 0.76; 95% CI, 0.65-0.88; P<0.001). Overall, Protelos reduced the risk of osteoporotic fracture by 20% versus placebo independently of location (RR, 0.20; 95% CI, 0.71-0.90; P<0.001). Only 21 patients needed to be treated with Protelos to prevent 1 new osteoporotic fracture; safety was similar to that over 3 years, with mostly mild and transient side effects. Rates of venous thromboembolism were comparable to those on placebo (2.7% vs 2.1%; odds ratio 1.30). _ Confirmation of Protelos efficacy extended to 8 years
Having been treated for 5 years in SOTI or TROPOS, an 893-patient subgroup was included in a 3-year open-label extension study. For ethical reasons, it was decided to stop treating patients with placebo as the fracture risk was too high. Longer-term efficacy was assessed by comparing cumulative fracture incidence over the first and last 3-year periods in the 8-year follow-up.

The cumulative incidence of new vertebral fractures over the 3-year extension was 13.7% compared with 11.5% in the first 3 years. In TROPOS patients, the respective figures for new nonvertebral fractures were 12%and 9.6%. Thus, Protelos, in contrast to any other treatment, remains effective over the very long term (Figure 4) as well as safe and well tolerated.17

Protelos and bone architecture

_ Protelos improves bone architecture
Treatment strategy used to focus on decreasing bone resorption, but this strategy had limitations: strong downregulation of bone resorption hindered repair of normal stress-induced microcracks, while there is an inevitable decrease in bone formation induced by antiresorptive treatment due to the coupling between osteoblast and osteoclast activity. Protelos is currently alone among antiosteoporotic agents in decreasing bone resorption while increasing bone formation. The net balance is the creation of new bone. Benefits on bone were first shown in bone biopsies from SOTI and TROPOS patients. Treatment for 3 years resulted in bone microarchitecture benefits, as evidenced by increased cortical bone thickness of 18%(P=0.008) and trabecular number by 14%(P=0.05), while decreasing trabecular separation by 16% (P=0.004). These improvements were associated with a change in bone structure from “rod-like” on placebo to “plate-like” on Protelos (Figure 5, page 64).18

These benefits of Protelos in terms of bone architecture result from increased osteoblast activity, shown by increases in mineral apposition rate (+9%; P=0.019) and osteoblast sur- face (+38%; P=0.047), and a 10% trend toward a decrease in osteoclast surface. Bone biopsy analysis at 5 years revealed no abnormalities in structure or mineralization.19

Figure 5
Figure 5. Protelos improves bone microarchitecture at the cortical and trabecular sites in postmenopausal women with osteoporosis.

Modified from reference 18: Arlot ME, Jiang Y, Genant HK, et al. J Bone Miner
Res. 2008;23:215-222. Copyright © 2008, The American Society for Bone and Mineral Research.

Figure 6
Figure 6. Comparison of the changes in cortical thickness and the ratio of bone volume to total volume for Protelos and alendronate.

Abbreviations: C.Th, cortical thickness; BV/TV, bone volume/total volume. Modified from reference 20: Rizzoli R, Felsenberg D, Laroche M, et al. Ann Rheum Dis. 2009;68(suppl 3): 669. Abstract SAT0388.

_ Protelos is more effective than bisphosphonates in improving microarchitecture
A recent head-to-head randomized, double-dummy, double- blind study in osteoporotic women used high-resolutionperipheral quantitative computed tomography (HR-pQCT, Scanco Medical) to compare the effect on bone microarchitecture for 1 year of treatment with Protelos versus alendronate. Cortical thickness increased by 5.3% (P<0.001) and the trabecular bone volume/total volume ratio by 2.0% (P=0.002) on Protelos; the changes in each parameter were already significant at 3 months (P=0.012 and P=0.042, respectively; Figure 6). No improvement occurred in the alendronate group, confirming that this latter type of treatment is not able to build new bone.20

_ Protelos improves hip architecture
Impact on hip geometry after treatment for 5 years was studied in 483 TROPOS patients (Protelos, n=251; placebo, n=231) using the dual-energy x-ray absorptiometry (DXA)-derived hip structure analysis (HSA) program, devised by Thomas Beck and incorporated in Hologic densitometers. The program includes cross-sectional area (CSA), section modulus, cortical thickness, and buckling ratio. Protelos increased cortical thickness—the main determinant of hip fracture risk—at the femoral neck, intertrochanteric region, and proximal shaft (+5.2±9.8% vs –3.6±7.9%, P<0.001 vs placebo). This improvement in bone microarchitecture resulted in improved bending strength, with an increase in sectionmodulus of +8.6± 14.3% vs –2.3±11.6% on placebo (P<0.001; Figure 7).21

Thus three studies by different teams using different techniques confirm the benefits of Protelos on bone architecture. Not only does Protelos increase cortical thickness, the main determinant of hip fracture risk, as early as after 3 months’ treatment, but it also rapidly improves hip geometry, as evidenced at three different sites. Protelos also rapidly improves trabecular bone, the main component involved in vertebral fractures. Protelos therefore improves the two main components of bone strength, thus ensuring optimal prevention of osteoporotic fractures in postmenopausal women.

Protelos: unique dual mode of action

The experimental evidence accumulated for the dual mode of action of Protelos, notably on osteoblasts, osteoclasts, and bone architecture, has been reviewed elsewhere (Figure 8).22 An intensive effort is underway to elucidate the molecular basis of its innovative mode of action. Studies in various models have shown that Protelos has a direct effect on both osteoblasts and osteoclasts by increasing osteoblast replication, differentiation, and activity,23-26 while simultaneously downregulating osteoclast differentiation and activity.26-29 A recent Australian study also shows that Protelos promotes osteocyte differentiation into osteoblasts.30

Protelos modulates the level of two major factors closely involved in regulating osteoclastogenesis by osteoblasts. Osteoprotegerin (OPG) and receptor activator nuclear factor-êB ligand (RANKL) are both expressed by osteoblasts. The OPG/ RANKL ratio governs osteoclastogenesis: a low ratio promotes osteoclastogenesis, a high ratio downregulates it. Two studies in human osteoblasts have shown Protelos to increase mRNA expression of OPG, while simultaneously decreasing mRNA expression of RANKL. This is highly predictive of subsequent downregulation of osteoclastogenesis.30,31 In the same studies, Protelos increased the replication and differentiation of human osteoblasts, which are similarly highly predictive of subsequent enhancement of bone formation. This was the first evidence to show that Protelos modulates both bone formation and bone resorption by acting directly on human osteoblasts, suggesting that osteoblasts play a key role in the drug’s mechanism of action.

Figure 7
Figure 7. Protelos improves hip geometry and bone strength compared with the placebo group.

Abbreviations: CSA, cross-sectional area; CSMI, cross-sectional moment of inertia.

Figure 8
Figure 8. Protelos increases bone formation through an increase in osteoblast replication, differentiation, and activity.

In parallel, Protelos decreases bone resorption via a decrease in osteoclast differentiation and activity and the upregulation of the osteoprotegerin/receptor activated nuclear factor-κB ligand (OPG/RANKL) ratio in osteoblasts. Abbreviation: CaSR, calcium-sensing receptor.

A remarkable mouse model of severe osteoporosis and spontaneous fracture recently confirmed the link between the benefits of Protelos on bone architecture and osteoporotic fracture prevention. Protelos decreased the number of new fractures by 60% vs controls after 9 weeks. Spontaneous fracture prevention was related to a net improvement in both trabecular and cortical microarchitecture.32

Bone marker monitoring in clinical trials has consistently confirmed the dual mode of action revealed in the in vitro studies. In women receiving Protelos in both SOTI and TROPOS, bALP (a marker of bone formation) independently increased, while sCTX (a marker of bone resorption) decreased. These effects were detected as early as after 3 months of treatment (bALP, +8.1%; P<0.001; and sCTX, –12.2%; P<0.001) and were sustained over 3 years.1 These trials thus confirmed the clinical benefits of the dual mode of action of Protelos: new bone formation, improved bone quality, greater bone strength, and lower fracture risk.

Conclusion

Protelos has proved its efficacy against vertebral, nonvertebral, and hip fractures. This treatment is the only one to have also proven its efficacy across a wide spectrum of patient profiles. In addition, Protelos is the only treatment to have proven its efficacy over 5 years, which is sustained for up to 8 years. Furthermore, this long-term efficacy was associated with very good safety and tolerability. These unique benefits are explained by the ability of Protelos to build new, strong bone, thanks to its unique dual mode of action. The benefits on the microarchitecture have been proven consistently, with improvement in both cortical and trabecular bone (the main determinants of hip and vertebral fractures, respectively). Protelos has all the characteristics of a major treatment and must be considered a first-line treatment in the armamentarium of clinicians concerned with the treatment of osteoporosis. _

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