Comprehensive antifracture efficacy, improvement of bone quality: Protelos, a first-line treatment in osteoporosis




Mélanie HUEBER, PhD
Servier International – Suresnes, FRANCE

Comprehensive antifracture efficacy, improvement of bone quality: Protelos, a first-line treatment in osteoporosis


by M. Hueber, France



Osteoporosis is a chronic disease generally linked to aging. For a long time, it was considered a normal process and later considered a fatal disease. Nowadays, many treatment options are available to delay or even stop the process. Several of them have demonstrated efficacy on specific patient profiles or fracture sites. An ideal treatment, however, should be able to prevent/treat osteoporosis at any fracture site (vertebral or nonvertebral, including hip) and in different types of patients: aged or young, osteoporotic or osteopenic, with or without previous fracture, regardless of fracture risk, whatever the sex, etc. In this article, we will show that Protelos, an original antiosteoporotic treatment, prevents fracture in all these kinds of patients. Moreover, Protelos has demonstrated its safety and efficacy against fractures for the longest period ever followed for an antiosteoporotic treatment, up to 10 years. In addition, the specific mode of action of Protelos and its effect on microarchitecture will be reviewed, in order to explain why Protelos is a first-line treatment, as acknowledged in several national and international guidelines.

Medicographia. 2012;34:203-212 (see French abstract on page 212)



Osteoporosis was long considered a physiological phenomenon due to aging. Nowadays, we know that this disease is linked to a substantial increase in morbidity and mortality, but fortunately, there are several treatments that can prevent it. These treatments, however, have different modes of action and different levels of efficacy and safety. Hence, it can be difficult to choose the best treatment that is the most effective and safe over the long term and for different patient profiles. In this article, we provide a full update of the numerous data recently published on Protelos, an antiosteoporotic treatment with a unique mode of action.

Protelos is effective whatever the site: vertebral, nonvertebral, and hip sites

In order to be really effective in the treatment of osteoporosis a drug must prevent both vertebral and nonvertebral fractures. Surprisingly, only a few antiosteoporotic treatments have shown efficacy against these two kinds of fractures. Protelos has demonstrated its efficacy to prevent both vertebral and nonvertebral fracture (including hip fracture) in 2 pivotal international, multicenter, double-blind studies: SOTI (the Spinal Osteoporosis Therapeutic Intervention study) and TROPOS (TReatment Of Peripheral Osteoporosis Study). These studies included 6740 postmenopausal women. All of them received calcium/vitamin D supplementation at a dose tailored to their degree of deficiency (500/1000 mg of calcium and 400/800 international units [IU] of vitamin D3) as well as either Protelos 2 g/day or placebo.


Figure 1
Figure 1. TROPOS study: Effect of Protelos on relative risk of
nonvertebral and major nonvertebral fractures versus placebo after
3 years of treatment.

Abbreviations: ARR, absolute risk reduction; CI, confidence interval; RR, relative risk.
Modified after reference 1: Reginster et al. J Clin Endocrinol Metab. 2005;90:
2816-2822. © 2005, The Endocrine Society.



Both studies demonstrate that, in osteoporotic patients, Protelos significantly reduced the risk of new vertebral fracture as well as new clinical vertebral fracture (vertebral fracture associated with back pain and/or height loss ≥1 cm) after three years of treatment compared with placebo. In the SOTI study, Protelos reduced the vertebral risk of fractures by 41% (relative risk [RR], 0.59; 95% confidence interval [CI], 0.48-0.73; P<0.001) and clinical vertebral fractures by 38% (RR, 0.62; 95% CI, 0.47-0.83; P<0.001).2 In the TROPOS study, the risk of new vertebral fractures was decreased by 39% (RR, 0.61; 95% CI, 0.51-0.73; P<0.001).1

The TROPOS study shows that, after 3 years of treatment, Protelos also significantly decreased the risk of non-vertebral fracture by 16% (RR, 0.84; 95% CI, 0.702-0.995; P<0.05) and of major non-vertebral fractures (hip, wrist, pelvis, sacrum, ribs-sternum, clavicle, and humerus) by 19% (RR, 0.81; 95% CI, 0.66-0.98; P<0.05) (Figure 1).1 An analysis of the subgroup of patients with the highest risk of hip fracture (>74 years with femoral neck T-score ≤-3 standard deviations [SD]) shows that Protelos significantly decreased the risk of hip fractures by 36% (RR, 0.64; 95% CI, 0.412-0.667; P=0.046).

Altogether, these studies confirmed the strong efficacy of Protelos against different kinds of osteoporotic fractures, including vertebral and hip fractures.

Protelos is effective in a wide range of patient profiles

The idea that the risk of fracture depends on several different factors is relatively new. Indeed, until recently, the fracture risk was only assessed in postmenopausal women and was basedon bone mineral density (BMD) measurement. Nowadays, we know that it is more complicated and that several other factors can be involved, such as age, existence of previous fracture, family history, and individual habits. The existence of osteoporosis is now even proven in men and a growing number of men are treated for this disease. The goal of this chapter is to demonstrate the efficacy of Protelos, whatever the patient profile.








_ Protelos is effective in patients with main fracture risk factors at baseline
Even with implication of several fracture risk factors, diagnosis of osteoporosis is still based on BMD level. A subanalysis from the SOTI and TROPOS studies demonstrates that, in osteoporotic women for which hip/lumbar spine T-score is under -2.5 SD, Protelos significantly decreased vertebral fracture risk by 39% (RR, 0.61; 95% CI, 0.53-0.70; P<0.001). Moreover, Protelos efficacy was also independent of the previous number of fractures. Indeed, with 0, 1, or 2 prevalent fractures, Protelos decreased 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.3

Protelos also significantly reduced vertebral fracture in osteopenic women (hip/lumbar spine T-score between -1 and -2.5 SD) with a decrease as high as 72% (RR, 0.28; 95% CI, 0.07- 0.99; P=0.045). Furthermore, in these osteopenic women, the risk of vertebral fracture was decreased by 38% and 59% in patients with and without previous fracture, respectively (with previous fracture: RR, 0.62; 95%CI, 0.44-0.88; P=0.008; without previous fracture: RR, 0.41; 95%CI, 0.17-0.99; P=0.039).4

Protelos is also effective in both young and older postmenopausal women. Women over 80 years account for more than 60% of hip fracture, while they only represent around 8% of the postmenopausal population. Moreover, the elderly are the most affected by osteoporotic fracture consequences, including delayed fracture healing, loss of autonomy, and increased morbidity and mortality. Hence, it is very important to treat them with an adapted treatment. After only 1 year of treatment, in patients over 80, Protelos significantly decreased the risk of vertebral fracture (-59%), clinical fractures (-37%), and non-vertebral fractures (-41%) (vertebral fractures: RR, 0.41; 95% CI, 0.22-0.75; P=0.002; clinical fractures: RR, 0.63; 95% CI, 0.44-0.91; P=0.012; non-vertebral fractures: RR, 0.59; 95% CI, 0.37-0.95; P=0.027). Even after 5 years, vertebral fracture risk remained decreased by 31% and non-vertebral fracture risk by 26%(RR, 0.69; 95%CI, 0.52-0.92; P=0.010; and RR, 0.74; 95% CI, 0.57-0.95; P=0.019, respectively). Hence, Protelos has demonstrated long-term efficacy against vertebral and non-vertebral fractures in the elderly.5

Similarly, Protelos has shown its antifracture efficacy in young postmenopausal women. After 4 years of treatment, vertebral fracture risk is decreased by 40% (RR, 0.60; 95% CI, 0.39- 0.92; P=0.017).6

_ Protelos is effective whatever the FRAX® score at baseline
Very recently, the group of John Kanis demonstrated Protelos efficacy whatever the 10-year probability of fracture at baseline. Patients from SOTI and TROPOS treated for 3 years were included. The results show, for the first time, association of a reatment with a significant reduction in clinical osteoporotic fractures across the full range of baseline 10-year probability of fracture. Moreover, the interaction between treatment effect and fracture probability was not significant for both clinical vertebral fracture and morphometric vertebral fracture (P>0.3 and P=0.1, respectively; Figure 2), with or without inclusion of BMD in the FRAX® (World Health Organization Fracture Risk Algorithm) model.7 These data show that the effectiveness of Protelos was comparable over the whole range of FRAX® probability. Using the same methodology, treatments such as clodronate, bazedoxifene, and denosumab seem to be more effective in women with higher FRAX® probabilities.


Figure 1
Figure 2. Probability of morphometric vertebral fracture (computed
with bone mineral density included) and the effect of Protelos
on morphometric vertebral fractures (HR+95% confidence intervals).

The interaction between efficacy and 10-year fracture probability is not significant
(P=0.1).
Modified from reference 7: Kanis et al. Osteoporos Int. 2011;22(8):2347-2355.
© 2011, International Osteoporosis Foundation and National Osteoporosis
Foundation.



_ Protelos is effective in male osteoporosis
Osteoporosis is often considered a women’s disease, appearing after menopause. However, men are affected as well. In fact, approximately 20%of osteoporotic patients are men, and this percentage is expected to increase with longer life expectancy for men. Moreover, 1-year mortality due to hip fracture is greater for men than women (20.7% for men versus 7.5% for women over 75 years of age with hip fracture).8 But, while several therapies are available for women, only a few studies on osteoporosis treatment have been performed in men.

Two studies were performed with Protelos. The first study, CASIMO (Comparing Alendronate and Strontium ranelate In Male Osteoporosis), an open-label study (n=150), compared the effect of Protelos and alendronate on BMD after 12 months of treatment. Treatment with Protelos increased lumbar spine BMD by 5.8±3.7% and total hip BMD by 3.5±2.8% (P<0.001 compared with baseline for both parameters). Treatment with alendronate increased lumbar spine BMD by 4.5±3.4% and the total hip BMD by 2.7±3.2% (P<0.001 compared with baseline for both parameters). The mean increases in BMD were significantly higher for patients treated with Protelos: 22% greater for lumbar spine BMD (P=0.033) and 23%greater for total hip BMD (P=0.002) (Figure 3).9 Moreover, even though both treatments reduce back pain, significantly higher pain relief is observed with Protelos compared with alendronate (69% and 47% decrease, respectively; P=0.001).9

The second study, MALEO (MALE Osteoporosis), is a 2-year, double-blind, placebo-controlled, randomized trial which included 243 men with osteoporosis (ratio of Protelos/placebo, 2:1). This study demonstrates that, after 1 year of treatment, Protelos significantly increased lumbar spine and femoral neck BMD compared with placebo (5.3±0.75%; P<0.001 and 2.9±0.62%; P<0.001, respectively) (Figure 4).10


Figure 3
Figure 3. Mean percentage change (from baseline) in bone mineral
density of the lumbar spine and total hip with Protelos and
alendronate therapy.

Abbreviation: BMD, bone mineral density.
After reference 9: Ringe et al. Arzneimittelforschung. 2010;60(5):267-272. © 2010,
ECV Edit Cantor Verlag, Aulendorf, Germany.



Figure 4
Figure 4. Mean percentage change (from baseline) in bone mineral
density of the lumbar spine and femoral neck with Protelos
therapy. ***P<0.001 versus baseline

Abbreviation: BMD, bone mineral density.
Modified from reference 10: Kaufman et al. Ann Rheum Dis. 2011;70(suppl 3):
224. Abstract 11-4358.



Considering the present results in men and the previously established relationship between change in BMD and reduction in fracture risk in women treated with Protelos, a similar antifracture effect in men can reasonably be expected. In addition, safety results did not reveal any unexpected adverse events in men treated with Protelos.10

These new results from the MALEO study have been submitted to the European Medicines Agency (EMA) as a basis for the new indication of Protelos in male osteoporosis.

Position of Protelos, in terms of efficacy, among antiosteoporotic treatments

A large number of antiosteoporotic treatments have been available on themarket for several years. Thediversity in theirmodes of action and the different characteristics of the populations included in clinical trials do not make it easy to compare their efficacies. However, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) published in 2008 the European Guidance for the Treatment and Management of Osteoporosis in Postmenopausal Women, which compared the efficacy of antiosteoporotic treatments on the basis of data available from large trials. These data are summarized in Table I and show that Protelos, in comparison with other treatments, has demonstrated efficacy at vertebral and non-vertebral (including hip) levels, even in the presence of previous fractures.11


Table I
Table I. Protelos is the only antiosteoporotic
treatment to have demonstrated efficacy
against vertebral, nonvertebral, and hip fractures,
whatever the severity of the disease.

Abbreviations: HRT, hormone replacement therapy;
NA, no evidence available; PTH, parathyroid hormone.
Adapted from reference 11: Kanis et al. Osteoporos
Int. 2008;19:399-428. © 2008, International
Osteoporosis Foundation and National
Osteoporosis Foundation.



Another way to compare these different treatment efficacies would be to analyze all clinical studies in depth and to consider every parameter that reflects efficacy, such as relative risk reduction (RRR), absolute risk reduction (ARR), and number needed to treat (NNT).12 A recent study from Ringe and Doherty has compared the different treatments with regard to the number of patients needed to treat in order to avoid 1 fracture. They demonstrated that Protelos has a very low NNT, with only 9 patients needed to be treated over 3 years to avoid 1 vertebral fracture, compared with 21 for ibandronate, and 48 patients needed to be treated to avoid hip fracture, compared with 91 for alendronate, risedronate, or zoledronate (Figure 5).13 These results fully confirm the position of Protelos as a first line treatment.

Protelos is effective whatever the duration of the treatment

Another new event this year was the publication of the 10-year efficacy of Protelos. We have already seen that Protelos action is rapid (as soon as 1 year) and maintained for 3 years at both vertebral and nonvertebral sites. But osteoporosis is a chronic disease. Hence, treatments need to maintain long-term efficacy and safety. To date, there is no evidence showing that conventional antiosteoporotic treatments, even bisphosphonates, are able to decrease fractures beyond 3 to 4 years of treatment. Moreover, there are controversial data showing possible association of prolonged bisphosphonate use with atypical femoral fractures.14 On the contrary, Protelos has now shown its safety and efficacy at vertebral and nonvertebral levels over a 10-year follow-up period, the longest evaluation ever, made possible by the 4- and 5-year SOTI and TROPOS studies and their extensions.

_ Protelos efficacy after 5 years of treatment
The results of the preplanned 5-year TROPOS study show that Protelos significantly reduced the risk of vertebral fracture by 24% versus placebo (RR, 0.76; 95% CI, 0.65-0.88; P<0.001), the risk of nonvertebral fracture by 15% (RR, 0.85; 95% CI, 0.73-0.99; P=0.032), and the risk of new major nonvertebral fracture by 18% (RR, 0.82; 95% CI, 0.69-0.98; P=0.025).

In a subgroup of patients with a high risk of hip fractures (n=1128; ≥74 years; 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). This means that only 21 patients need to be treated with Protelos for 5 years in order to prevent 1 new osteoporotic fracture.15

_ Protelos efficacy after 10 years of treatment
At the end of the TROPOS study, Protelos long-term efficacy and safety was assessed by 3- and 5-year extension studies (open-labeled), leading to a full follow-up of 10 years.


Figure 5
Figure 5. Comparison of the efficacy of different treatments on (A) vertebral and (B)
hip fractures.

Abbreviations: NA, no evidence available; NNT, number needed to treat.
Adapted from reference 13: Ringe and Doherty. Rheumatol Int. 2010;30:863-869. © 2009, Springer-
Verlag.



The studies included 237 patients. The cumulative incidence of new vertebral or non-vertebral fractures over the 5-year extension period (6-10 years, TROPOS extension) was fully comparable with that in the first 5-year study period (0-5 years, TROPOS study): 20.6% versus 18.5%, respectively, for vertebral fractures and 13.7%versus 12.9%for non-vertebral fractures (Figure 6).16

Another interesting way to assess treatment efficacy would be to compare the 10-year long-term antifracture efficacy of Protelos with a placebo group. As, for ethical reasons, it isn’t allowed to treat patients with placebo for 10 years, the authors sought a matching population in the placebo group of TROPOS (0-5 years). 10-Year fracture probabilities for major osteoporotic fracture in the extension population at year 6 and in the placebo population at year 0 were calculated by FRAX®. To ensure the comparability of the two populations, patients with the same FRAX® score in the 2 groups were identified. This FRAX®-matched placebo population comprised 458 patients.

The comparison of fracture incidence between the patients treated with Protelos for 10 years in the 5-year extension study and the patients from the FRAX®-matched placebo group shows that the cumulative incidence of new fractures was significantly decreased in the treated group. Indeed, the risk decreased by 35% in the treated group for non-vertebral fracture (13.7±2.3% versus 20.2±2.2%; P=0.023) and by 38% for new vertebral fracture (20.6±3.0% versus 28.2±2.4%; P=0.016) (Figure 6). These results are particularly important as it is the first time that an antiosteoporotic treatment has been compared with a placebo group over such a long follow-up period. Altogether, these results confirm the long-term efficacy of Protelos, whatever the site.16,17


Figure 6
Figure 6. 10-Year
efficacy of Protelos
on (A) vertebral and
(B) nonvertebral
fractures.

Fracture incidence does
not increase between
years 0 to 5 and 6 to 10,
but is significantly decreased
compared with
FRAX®-matched placebo.
Abbreviations: NS, nonsignificant;
RR, relative risk.
Adapted from reference
16
: Reginster et al. Osteoporosis
Int. 2012;23(3):
1115-1122. © 2011, The
Author(s). This article is
published with open access
at Springerlink.com.


Protelos efficacy is explained by its unique mode of action, building strong and healthy new bone

_ Protelos efficacy through its mechanism of action
Although fracture risk reduction remains the logical main objective of each antiosteoporotic treatment, the long-term effect of treatment on bone is crucial. Bone is a living tissue. Due to everyday actions, such as walking and climbing stairs for example, bones are damaged by microcracks and need to be continuously repaired through bone remodeling; otherwise, bone fragility is increased, leading to fracture. Conventional treatments, including antiresorptive treatments, are not able to prevent fracture risk in the long term. This is probably due to their mechanisms of action which decrease bone resorption, but also bone formation. Hence, bone remodeling is stopped, as well as microcrack reparation, leading to an increased risk of atypical fractures. These events remain rare, but are dangerous and are a growing concern for the EMA and US Food and Drug Administration (FDA).

Protelos has a very different mechanism of action, allowing formation of new and strong bone. Indeed, studies in various models have shown that Protelos increases osteoblast replication, differentiation, and activity,18-21 and decreases osteoclast differentiation and activity.21-24 It has already been demonstrated that Protelos action is mediated by osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL),25,26 and a recent article has shown new in vivo evidence of this mechanism, showing that Protelos action is partly due to OPG increase.27

Another new nonclinical study from Rybchyn and colleagues has demonstrated that the effect of Protelos is also mediated by its action on the Wnt canonical pathway, inducing sclerostin decrease, thus allowing microcrack repair.28

_ Protelos builds strong new bone
Protelos is the first antiosteoporotic treatment to have demonstrated benefits, compared with bisphosphonate, on bone formation in the largest double-blind, international bone biopsy study ever, including 268 postmenopausal women with osteoporosis. Women were around 63 years of age and were treated with Protelos or alendronate (ratio 2:1). There were 2 biopsies taken for each woman: 1 at baseline and 1 after 6 or 12 months of treatment.

After 6 and 12 months of treatment, mineralizing surface per bone surface (MS/BS), which reflects tissue activity, was 2.9±3.7%and 4.9±4.2%, respectively, with Protelos and 0.2±0.9% and 0.3±0.6%, respectively, with alendronate. The difference between groups increased up to 4.7% (P<0.001) at 12months. The mineral apposition rate (MAR), which reflects cellular activity, was also significantly higher with Protelos at 6 months (0.630±0.127 μm/day) and 12 months (0.624±0.094 μm/day), compared with alendronate (0.553±0.108 μm/day at both time points, P=0.003 and P=0.009 between groups at 6 and 12 months, respectively).Bone formation rate (BFR=MAR×MS/ BS) was also significantly different between groups (P<0.001) (Protelos: 0.021±0.024 and 0.033±0.027 μm3/μm2/day at 6 and 12 months, respectively; alendronate: 0.003±0.003 μm3 /μm2/day at both time points). This study demonstrates that bone forming activity was much higher in patients treated with Protelos, with an amplified effect after 12 months of treatment (Figures 7 and 8).29

It also confirms the results obtained previously in a smaller study which had demonstrated increased cortical thickness (CTh), trabecular number, and decreased trabecular separation after 3 years of treatment with Protelos.30

Other evidence of the bone forming activity of Protelos is provided by a new study from Rizzoli and colleagues, which compared alendronate and Protelos activity in a head-to-head randomized, double-dummy, double-blind study in 88 postmenopausal osteoporotic women. This study used high-resolution peripheral quantitative computed tomography (HRpQCT, SCANCO Medical). This device gives three-dimensional datasets providing bone geometry, cortical, and trabecular structures. It also allows noninvasive quantification of bone strength and mechanical features of cortical and trabecular bone, determined by finite element analysis (FEA). The results show that, at the distal tibial level, 1 year of treatment with Protelos led to a significant increase in CTh (+5.3%, P<0.001) and BV/TV (+2.0%, P=0.002) compared with baseline, while alendronate had no significant effect.31 After 2 years of treatment, the CTh increased from baseline by 6.3% (P<0.0001) in the Protelos treated group, while it did not significantly change in the alendronate treated group (P<0.005 for between groups comparison). In the same way, trabecular bone volume per trabecular volume (BV/TV) increased by 2.5% from baseline with Protelos (P<0.0001), compared with 0.8% with alendronate (non-significant [NS]) (P<0.05 for between groups comparison). The increase compared with alendronate was significant from 3 months (Figure 9, page 210).32 FEA results show that, with Protelos, failure load increased by 2.1% (P<0.005 versus baseline) after 2 years of treatment, versus no change with alendronate (-0.6%, NS) (P<0.01 between groups).

Figure 7
Figure 7. Illustration of bone forming activity after 6 months of
treatment with (A) alendronate and (B) Protelos.

Bone forming activity is represented by tetracycline labeling. (Courtesy of
R. Chapurlat)



Figure 8
Figure 8.
Comparison of bone formation rate after 6 and 12
months of treatment with alendronate and Protelos.

Data from reference 29: Chavassieux et al. Osteoporosis Int. 2011;22(suppl 1):
S104. Abstract OC16.



This study also confirms the effect of Protelos on bone turnover markers. Indeed, serum c-terminal cross-linked telopeptide of type I collagen (s-CTX-I) decreased by 16% and 59% for Protelos and alendronate, respectively. The CTX-I value was significantly decreased from baseline at months 3 and 6 (P<0.05) and 18 and 24 (P<0.005) with Protelos treatment. In contrast, bone-specific alkaline phosphatase (bALP) increased with Protelos from 3 months, while it significantly decreased with alendronate for all time points (+18% and -31%, respectively, at year 2) (Figure 10, page 210).32


Figure 9
Figure 9. Comparison
between the
evolution of (A) cortical
thickness and (B)
BV/TV during 2
years of treatment
with Protelos and
alendronate.

*P<0.05; **P<0.01; ***P<0.001 versus baseline; †P<0.05 strontium ranelate versus alendronate. Abbreviations: BV/TV,
bone volume per trabecular
volume; SR, strontium
ranelate.
Modified from reference
32
: Rizzoli et al. Osteoporos
Int. 2012;23(1):
305-315. © 2011, International
Osteoporosis
Foundation and National
Osteoporosis Foundation.



Figure 10
Figure 10. Comparison
between the
evolution of bone
turnover markers
during 2 years of
treatment with Protelos
and alendronate.

*P<0.05; **P<0.005; ***P<0.0005; ****P<0.0001 versus baseline. Abbreviations: bALP,
bone-specific alkaline
phosphatase; CTX,
c-terminal cross-linked
telopeptide of type I
collagen.
Modified from reference
32
: Rizzoli et al. Osteoporos
Int. 2012;23(1):
305-315. © 2011, International
Osteoporosis
Foundation and National
Osteoporosis Foundation.



_ Protelos builds strong new bone, remains safe, and preserves bone mineralization
It is known that the degree of mineralization of bone (DMB) is influenced by the rate of bone remodeling and the mean duration of secondary mineralization. For example, when the bone remodeling rate increases, like during treatment with anabolic agents such as parathyroid hormone (PTH), the birthrate of new bone structural units (BSUs) increases, resulting in less time to complete secondary mineralization, and, ultimately, DMB decreases. On the contrary, when the bone remodeling rate is decreased, like during treatment with antiresorptive agents, the birthrate of BSUs is greatly decreased, their lifespan increases, the duration of secondary mineralization is greatly increased, and the DMB increases. Hence, it could be hypothesized that due to its specific mode of action, Protelos preserves the level of secondary mineralization.

A recent study addressed this hypothesis and also investigated the distribution of strontium in bone during treatment with Protelos. Transiliac bone biopsies from 31 patients treated for 36, 48, or 60months with Protelos were analyzed and demonstrated that, up to 60 months, DMB, reflecting the secondary mineralization of bone, remains constant in cortical (1.12±0.08), cancellous (1.13±0.07), and total bone (1.13±0.07).

Global x-ray mapping of these biopsies shows that, contrary to calcium and phosphorus, strontium was always heterogeneously distributed and almost exclusively present in new bone formed during treatment (Figure 11).sup>33 Whatever the duration of treatment, the percentage of bone area with strontium was higher in cancellous bone (36.25±28.52%) than in cortical bone (24.70±15.34%). Moreover, focal strontium content measured in total bone was constant whatever the treat- ment duration. Indeed, the BSUs containing strontium had mean strontium contents that did not significantly differ over time: 2, 12, 24, 36, 48, and 60 months (P=0.81). In recent bone, the ratio Sr/(Ca+Sr) showed between 0 and 6% (mean: 1.6%) replacement of Ca by Sr. Altogether, these results confirm that long-term treatment with strontium ranelate remains very safe for bone: strontium is absent from old bone built before initiation of the treatment, the focal strontium content is constant in bone formed during treatment, and secondary mineralization is maintained.33


Figure 11
Figure 11. Distribution and content of strontium in bone.

Abbreviations: Ca Kα, calcium; O, old bone; P Kα, phosphorus; R, recent
bone; SEI, secondary electron image; Sr Lα, strontium.
Adapted from reference 33: Doublier et al. Eur J Endocrinol. 2011;165(3):469-
476. Copyright © 2011, European Society of Endocrinology.


Protelos remains safe after long-term use

Data obtained from the developmental studies are very reassuring concerning Protelos safety. Indeed, during the 5 years of the placebo-controlled TROPOS study, the incidence of adverse events (AEs) and serious AEs were well balanced between the 2 groups (95.3% and 30.9%, respectively, in the Protelos treated group versus 94.9% and 30.0%, respectively, in the placebo treated group).1 AEs usually reported are nausea (7.8% in the Protelos group versus 4.8% in the placebo, TROPOS study), diarrhea (7.2% versus 5.45%), headache (3.6% versus 2.7%), dermatitis (2.3% versus 2.0%), and eczema (2.0% versus 1.5%). The incidence of venous thromboembolic events (VTE) was 2.7% in the Protelos group versus 2.1% in the placebo group after 5 years.1 However, according to the new summary of product characteristics, Protelos should not be used in patients with current or previous VTE as well as in patients that are permanently or temporarily immobilized. Long-term treatment with Protelos has not demonstrated an increase in AE rates. During the marketing development of Protelos, cases of severe hypersensitivity syndromes, including, in particular, drug rash with eosinophilia and systemic symptoms (DRESS)were described. DRESS incidence is 1/13 725 treated patients. Hence, patients should be informed to stop Protelos therapy immediately and permanently if a rash occurs.

The future of Protelos

Protelos has largely demonstrated its efficacy in postmenopausal women, but the story does not end there. A combination of Protelos and vitamin D is under development. Moreover, the proven efficacy of Protelos in men should lead very soon to a new indication in male osteoporosis. Furthermore, more and more clinical data are being published on Protelos efficacy in fracture healing inmany circumstances: osteoporotic fractures, atypical fractures linked to long-term use of bisphosphonates, and also traumatic fracture in younger patients (male and female) due to accidents.34,35

Finally, during the last International Osteoporosis Foundation (IOF) congress in Dubai, the rationale and design for a new phase 3 clinical study assessing Protelos efficacy in osteoarthritis were presented. Due to the lack of effective treatment for structural progression of osteoarthritis, a structuremodifying drug would be a real answer to a medical need.

Conclusion

Again this year, several very interesting results were published demonstrating the long-term efficacy and safety of Protelos. Its antifracture efficacy has been demonstrated over a 10-year period, the longest period ever studied for an antiosteoporotic drug. New data have also shown the long-term safety of Protelos in bone without bone accumulation or change in mineralization. The mechanism of action for Protelos is progressively well known as a result of new nonclinical studies and clinical results from biopsies. Moreover, a new therapeutic area should be opened to Protelos during the coming years. Altogether, these findings confirm that Protelos should be considered a first-line treatment for osteoporotic patients.


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Keywords: bone; efficacy; formation; osteoporosis; Protelos; resorption; strontium ranelate