Emerging drugs for osteoporosis.

Review

Emerging drugs for osteoporosis Elodie Feurer† & Roland Chapurlat †

Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Universitaet Zuerich on 07/08/14 For personal use only.

INSERM UMR 1033 -- Universite´ de Lyon, Hoˆpital Edouard Herriot, Hospices Civils de Lyon, Department of Rheumatology, Lyon, France

1.

Background

2.

Medical need

3.

Existing treatment

4.

Market review

5.

Current research goals

6.

Scientific rationale

7.

Competitive environment

8.

Potential development issues

9.

Conclusion

10.

Expert opinion

Introduction: Osteoporotic fracture is a cause of pain, loss of autonomy and excess mortality. Current drugs however, do not allow for a satisfactory non vertebral fracture risk reduction and the compliance is suboptimal. Areas covered: Current treatments consist of mainly bisphosphonates, denosumabs, selective estrogen receptor modulators and teriparatides. All drugs currently in development will target some aspect of bone remodeling by using the recent advances in our knowledge of bone biology: cathepsin-K inhibitors (odanacatib) are antiresorptive, antisclerostin monoclonal antibodies (romosozumab and blosozumab) are anabolic agents and PTHrp 1-34 (abaloparatide) is an anabolic agent. Expert opinion: New drugs with better tolerance and ideally with intermittent administration may improve their compliance. New drugs will have to provide higher efficiency levels with regards to reducing the risk of fractures. They may be second-line options, targeted at patients who are poor responders, or those who display contraindications to the older drugs, as a result of cost issues. In addition, some of these new drugs with potent anabolic effect may be confined to niches, for those patients at high risk of refracture after an initial severe fracture such as a hip fracture or a clinical vertebral fracture. Keywords: antisclerostin monoclonal antibodies, bisphosphonates, cathepsin-K inhibitors, osteoporosis, PTHrp Expert Opin. Emerging Drugs [Early Online]

1.

Background

Definition of osteoporosis Osteoporosis is a bone disease characterized by a low bone mineral density (BMD) and an alteration of the bone microarchitecture [1], leading to bone fragility and fracture. Osteoporosis is usually assessed with dual x-ray absorptiometry (DXA) that compares the patient’s BMD with that of young normal individuals using T-scores [2]. This assessment, however, does not take into account the bone quality. The fracture risk evaluation must also consider the other risk factors, including age, sex, race, genetics, reproductive status, low calcium intake, exercise, associated treatment (such as glucocorticoids) or associated diseases (such as hyperparathyroidism, celiac disease or rheumatoid arthritis). The risk of fracture can be quantified on an individual basis by the FRAX score, developed in large cohorts around the world, using clinical risk factors and BMD [3]. 1.1

Epidemiology of osteoporosis Osteoporosis is an important public health issue with an estimated prevalence of 200 million people worldwide [4]. Forty percent of women and 15 -- 30% of men will suffer from an osteoporotic fracture [5]. Hip, vertebral and distal forearm fractures are the most common fragility fractures; the incidence of forearm fracture increases up to 60 years, vertebral fracture is observed mainly after age 60 years and hip fracture after age 75. A meta-analysis of prospective studies has shown an 1.2

10.1517/14728214.2014.936377 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted

1

E. Feurer & R. Chapurlat

increased risk of any fracture by 86% in those individuals with prior fractures compared with those without fractures [6]. Osteoporosis can be debilitating: those fractures are responsible for pain, hospitalizations, loss of autonomy and quality of life [7], and an excess mortality has also been observed after hip, lower femur, vertebral, humeral and pelvic fracture [8].


2.

Medical need

Existing treatment

Nonpharmacological treatment Adequate intakes in calcium and vitamin D3 could result in a modest decrease in fracture risk. In postmenopausal women, the daily recommended intake has been set at 1200 mg of calcium and 800 IU of vitamin D3. These intakes are often not achieved and supplementation is recommended for patients to ensure that they reach these intake levels. The calcium supplementation is usually administered via a single dose of calcium citrate or carbonate. Side effects, specifically gastrointestinal, are commonly observed, thus affecting the compliance. The concomitant drug administration could also decrease its intestinal absorption, for example, with levothyroxine, certain antibiotics or even bisphosphonates. The value of calcium supplements alone to decrease fracture risk remains controversial. Calcium supplementation has 3.1

2

Pharmacological treatments Pharmacological treatments can be classified into two categories: antiresorptive agents (hormone replacement therapy, selective estrogen receptor modulators [SERMs], bisphosphonates, denosumab) and anabolic agents (teriparatide and intact parathyroid hormone [PTH]). 3.2

With the aging of the population, we are observing an increase in osteoporosis and associated fractures. The worldwide incidence of hip fracture is predicted to rise from 1.7 million in 1990 to 6.3 million in 2050 [9], even if age-adjusted incidence rates for hip fracture remain stable. The main objective of the treatment is to prevent fracture, especially those severe fractures associated with increased mortality. The current treatments allow for fracture risk reduction, ranging from a 30 to 70% relative risk reduction in vertebral fracture and a 20 to 30% relative risk reduction in nonvertebral fracture. Specifically, some molecules -- like zoledronic acid and denosumab -- reduce the risk of hip fracture by about 40% [10]. Raloxifene, which is a weak antiresorptive, does not reduce nonvertebral fracture risk. The poor adherence to those treatments can be partly responsible for the lack of efficacy [11,12]. For example, the modalities of administration are often not respected by the patient, who may not have accepted the daily or weekly regimens. The intravenous injection can also be poorly tolerated in the short term, with the associated flu-like syndrome. Moreover, those treatments can also have side effects, which have been shown to be among the main barriers to good compliance. Therefore, there is still a need to improve the fracture risk reduction -- essentially for nonvertebral fracture -- and to improve patient compliance. 3.

also been associated with an increase in kidney stone formation and perhaps myocardial infarction [13]. Vitamin D3 supplementation is often needed because insufficiency is so common. An adequate intake of protein is also recommended in the treatment or prevention of osteoporosis.

Hormone replacement therapy Estrogen deficiency increases the osteoclastic activity, with a coupled increased osteoblastic activity that is not commensurate to the resorption. Bone loss as a result of relative estrogen deficiency starts several years before menopause (perimenopause) and is responsible for a rate of bone loss that is similar to that observed during the early menopausal phase [14]. In a meta-analysis, hormone replacement therapy effected a reduction by 27% of nonvertebral fracture [15]. In the WHI study, the conjugated equine estrogen decreased the risk of fractures by 65% at the hip, 64% [0.44 -- 0.93] for clinical vertebral fracture and 58% [0.47 -- 0.72] for nonvertebral fracture [16]. In another analysis from the WHI study, this treatment increased, by 3.7%, the total hip bone density compared with 0.14% in the placebo group (p < 0.001) [17]. A recent analysis assessed its safety among 27,347 postmenopausal women who received either hormone replacement therapy (estrogen with or without progesterone) or placebo during 5 to 7 years [18]. The risk of coronary heart disease was higher among the hormone group with a hazard ratio (HR) of 1.18 [0.95 -- 1.45]. The risk of breast cancer was also higher with a HR of 1.24 [1.01 -- 1.53] and it was persistent after treatment removal (HR 1.28 [1.11 -- 1.48]). The hormone replacement therapy also appeared to increase the risk of stroke, pulmonary embolism or dementia, whereas the risk of hip fracture was reduced. 3.2.1

Bisphosphonates The nitrogenous bisphosphonates inhibit the enzyme farnesyl pyrophosphate synthase, which is essential for the osteoclastogenesis, cell survival and cytoskeletal dynamics, with osteoclast apoptosis and strong bone resorption inhibition as a result. Bisphosphonates strongly adhere to the bone surface, with a prolonged effect after treatment cessation, with certain molecules (alendronate, zoledronic acid). Bisphosphonates dominate the market, with several molecules such as alendronate, risedronate, ibandronate and zoledronic acid. These drugs are widely known to lower the vertebral fracture risk from 40 to 70%, depending on the molecule (alendronate [19] and zoledronic acid [20], 3.2.2

Expert Opin. Emerging Drugs (2014) 19(3)


Emerging drugs for osteoporosis

respectively). But their effectiveness on nonvertebral fracture is less important with a reduction of about 25%. Bisphosphonates can be administered through several regimens. The initial method was to administer daily, weekly or monthly oral doses, which was followed shortly after by the development of quarterly and annual intravenous injections. The latter remains the regimen currently in use. The intestinal absorption is < 1%, which requires that patients take the treatment on an empty stomach. It is sometimes poorly tolerated, with the occurrence of epigastralgia and, rarely, esophageal ulcers. The drug infusion was found to also result in a flu-like syndrome in ~ 25% of the patients. Side effects observed also include osteonecrosis of the jaw, which is rare in the osteoporosis population with an estimated risk between 1 in 10,000 and 1 in 100,000 patient-treatment years [21]. Atypical subtrochanteric femoral fractures are spontaneous or trauma-induced [22]. They could be explained by the oversuppression of the bone turnover induced by bisphosphonates, with accumulation of microdamage, and a reduction of energy absorption capacity and toughness [23]. Other rare side effects are described as transient hypocalcemia (with the intravenous administration), ocular inflammation [24], acute renal failure (intravenous injection) [25]. Denosumab Denosumab is a fully human monoclonal antibody, specifically targeting receptor activator of NFkB ligand (RANKL), with a resultant marked reduction in osteoclastogenesis. In the treatment of postmenopausal osteoporosis, denosumab is injected subcutaneously every 6 months. The Phase III trial, the FREEDOM study, enrolled 7,868 postmenopausal women aged 60 to 90, randomly assigned to denosumab (60 mg subcutaneous every 6 months) or placebo for 3 years [26]. The comparison showed a significant reduction of new vertebral fracture (relative decrease by 68%, p < 0.001), but also a reduction in hip fracture (40%, p = 0.04), and nonvertebral fracture (20%, p = 0.01). Denosumab also increased BMD at the lumbar spine and the total hip (9.2 vs 0%, and 4 vs 2% respectively). Moreover, in the FREEDOM extension study, lumbar spine and hip density continued to increase significantly over 6 years (15.2 and 7.2%, respectively), while maintaining a low incidence of fracture [27]. Brown et al. have compared denosumab to alendronate in a double-blind, placebo-controlled, multicenter Phase III study. Denosumab produced greater gains in bone density at 12 months (3.5 vs 2.6%, p < 0.0001) and reduction in bone markers [28]. Denosumab is generally well tolerated, but atypical fracture and osteonecrosis of the jaw also have been associated with denosumab use. 3.2.3

Selective estrogen receptor modulators SERMs are molecules with estrogen-like properties in some tissues and antiestrogen properties in other tissues. Raloxifene is a second-generation SERM, which is an estrogen agonist in 3.2.4

bones and the liver, that conversely does not stimulate the breast and endometrial tissues. The MORE trial involved 7,705 women followed for a duration of 8 years, who were randomly assigned to raloxifene or placebo [29]. The increase of bone density was comparable with other trials using this drug, ranging from 2 to 3% over 3 years. The reduction of vertebral fracture was 30% in women with prevalent fracture and 50% in those without fracture; there was no significant reduction of nonvertebral fracture. Cranney et al. carried out a meta-analysis of seven trials assessing the effect of raloxifene on the BMD [30]. They observed an increase of 2.5% on the lumbar spine and 2.1% on the hip (p < 0.01 on all sites). Reduction of vertebral fracture was significant with a relative risk of 0.60 (p < 0.01), but there was no evidence of reduction in nonvertebral fracture. The most common side effects are hot flashes, leg cramps, flu-like syndrome or peripheral edema. Moreover, in a specifically designed trial, Barrett-Connor et al. observed an increased incidence of fatal stroke (absolute risk increase of 0.7 per 1000 women-years) and venous thromboembolism (1.2 per 1000 women-years) [31]. Bazedoxifene is a third-generation SERM, approved in the European Union (marketed in Italy and Spain) and recently approved by the FDA in the US, but only in association with conjugated estrogens [32]. In clinical trials, 10, 20 and 40 mg of bazedoxifene effected a significant increase in spine BMD by 1.08 to 1.49%, respectively, over 24 months, compared with the placebo. Similar improvements were observed in total hip BMD [33]. In a Phase III study among 7,492 postmenopausal women, bazedoxifene reduced the risk of spine fracture by 42% (20 mg), 37% (40 mg) and 42% (60 mg) [34]. Bazedoxifene’s combination with conjugated estrogen has also been approved recently in the US.

Teriparatide Teriparatide is a recombinant human PTH with the 34 Nterminal identical sequence of the 84-amino acid human PTH. PTH is responsible for multiple avenues of bone turnover activation, with increases in a variety of factors such as IGF-1, Runx2, RANKL, M-CSF and a decrease in sclerostin. This results in enhanced differentiation and activation of osteoblasts. Teriparatide is administered with daily subcutaneous injection of 20 µg. In a Phase III trial enrolling 1637 women, teriparatide increased BMD by 9.7% at the lumbar spine (p < 0.001) and by 2.6% at the total hip (p < 0.001) [35]. The risk of new vertebral fracture was reduced by 65%, whereas the risk of nonvertebral fracture was reduced by 50% at 21 months. Nevertheless, there was no significant decrease in hip fracture incidence in those women on teriparatide. Currently, a double-blind Phase IV trial is enrolling postmenopausal women with vertebral fracture to compare 3.2.5


3



the antifracture efficacy of teriparatide with that of risedronate. The most common side effects are nausea, muscle cramping and headache. Because of the continuous stimulation of osteoblasts, teriparatide should not be used in patients with history of Paget’s disease and radiation therapy to avoid an increased risk of osteosarcoma [36]. One can speculate that combining an antiresorptive and an anabolic agent might improve the bone mass and fracture benefit. Teriparatide is prescribed mostly in patients with severe osteoporosis. Those women, however, have often received other therapies for osteoporosis, for example, raloxifene or bisphosphonates, before PTH may be started, because they continue to fracture. In postmenopausal women treated with alendronate and PTH 1-84, the increase in volumetric density was comparable to that observed in those receiving alendronate alone and significantly lower to that of women taking PTH 1-84 alone, suggesting that concurrent use of alendronate and PTH 1-84 may reduce the anabolic effects of PTH [37]. Similar findings have been made in women on the association of teriparatide and alendronate and also in men taking alendronate, PTH 1-34 or PTH 1-34 + alendronate [38]. Another way to conceive an association of anabolic and antiresorptive agents may be to start the drugs not simultaneously. Based on the premise that the most important anabolic effect of teriparatide is obtained during the first months of therapy because the increased bone resorption occurring after a few months of treatment offsets the boneforming effect, Muschitz et al. have designed a clinical trial to answer this specific question [39]. To this end, postmenopausal women who had been on teriparatide for 9 months have been randomized to receive raloxifene, alendronate 70 mg or no medication. They found that adding alendronate produced significantly greater improvements in BMD, including volumetric BMD, at the various sites. In another trial, the bisphosphonate zoledronic acid was administered concomitantly to teriparatide, but once a year [40]. The combination of teripatide and zoledronic acid was associated with greater and more rapid increases in aBMD at the hip and spine than zoledronic acid alone and teriparatide alone. The magnitude of this better increment compared with teriparatide alone, however, was small; also the antifracture benefit of such an improvement in aBMD remains uncertain. The combination of denosumab and teriparatide has also been attempted. In a randomized trial testing the variation in aBMD in response to teriparatide, denosumab and the combination of the two drugs, Tsai et al. found that the combination therapy improved aBMD at the spine and hip better than either drug alone [41]. At 2 years, this combination of drugs also increased BMD at all sites more than each individual agent and the magnitude of the increases was significantly greater than that achieved by any currently available agent [42]. There was an unprecedented 6.8% 2-year increase in femoral 4

neck BMD and a 12.9% gain at the spine. The antifracture influence and the cost-effectiveness of this kind of regimen remain to be studied. Of note, the stark difference that is observed in this trial compared with prior studies examining the value of the combination of teriparatide and oral bisphosphonates may stem from the unique mechanism of action of denosumab. 4.

Market review

The calculation of total cost may prove a challenge due to the fact that it takes into account the direct cost of fractures, osteoporosis diagnosis and follow-up and osteoporosis treatment. In 2001, the estimated direct cost for osteoporosis fracture was US$17 billion in the US. In the European Union, this cost was evaluated at over e32 million in the year 2000 and is expected to increase to e77 million in the 2050s due to the aging population [43,44]. For instance, the mean total lifetime costs of oral bisphosphonates are ~ US$65,000 to 75,000, whereas denosumab costs US$71,000 [45]. The bone disease of patients with fragility fracture, however, is generally neglected. For example, in a US cohort study, Solomon et al. observed an osteoporosis drug use at 28.5% 1 year after discharge for hip fracture. The rate decreased from 40.2% in 2002 to 20.5% in 2011 [46]. This undertreatment was also described by Panneman et al. only 15% of the patients were prescribed antiosteoporotic drugs within 1 year after a hospitalization for an osteoporotic fracture, during the period 1998 -- 2000 in the Netherlands [47]. Similar results are described in a prospective cohort study in the Province of Quebec [48]. Moreover, a decline in the osteoporosis treatment market has been observed over the last 5 years in various European and American countries, perhaps the consequence of vigorous communication by the lay media concerning the side effects of bisphosphonate. 5.

Current research goals

Despite the wide availability of several efficient and inexpensive drugs that have the potential to substantially reduce the risk of fracture, most patients with nonvertebral fracture still do not receive adequate therapy. This has been observed in various countries, regardless of the type of healthcare system in place. In addition, this phenomenon -- which was identified in the early 2000s -- has not improved over the last decade. Fracture liaison services, however, have been shown to be effective in improving the rate of DXA measurements and osteoporosis drug use after fracture [49]. If this kind of approach were applied on a large scale, it could significantly increase drug use and have a tremendous impact on the incidence of refracture. Compliance is generally poor with antiosteoporosis drugs. It could be speculated that adverse events associated with these medications are the main cause of limited compliance.



Programs that involve improved drug safety control measures and more specific targeting of certain drugs to particular patients should be encouraged.


6.

Scientific rationale

Bone tissue is in constant remodeling, to replace the old bone containing microdamage with new bone, in order to improve bone strength. This process consists of a resting phase, followed by activation, resorption, reversal and eventually the bone formation, within the basal multicellular unit (Figure 1). Bone drugs have been designed to target specific phases and cells involved in bone remodeling. Anticatabolic drugs decrease bone resorption by inhibiting some aspect of the osteoclastic differentiation or function, and anabolic agents stimulate the osteoblastic activity. All drugs currently in development will address, in some way, either bone resorption or bone formation, or both. These future drugs of osteoporosis are based on the recent discoveries made in the pathophysiology of osteoporosis, regarding bone resorption and bone formation. 7.

Competitive environment

Proposed treatments are summarized in Table 1. Cathepsin K inhibitors Cathepsin K (CatK) is a lysosomal cysteine protease with a high collagenase activity. It is secreted by osteoclasts to degrade type 1 collagen. During bone resorption, CatK is secreted under the ruffled border and accumulates in the acidified resorption lacunae where it degrades matrix proteins. It is activated at low pH, allowing the breakdown of type 1 collagen molecules generating N- and C-telopeptides, in addition to triple helical region fragments. Knockout mice for CatK develop osteopetrosis because of decreased bone resorption by osteoclasts [50,51]. Elimination of CatK does not appear to have any other nonskeletal developmental consequences in these animals. Pycnodysostosis is a rare autosomal recessive disease due to loss-of-function CatK mutations, responsible for increased bone mass, but with high risk of fracture because of brittle bone. Reversible inhibitors of the active form of human CatK have been developed. Preclinical models have highlighted the efficacy of anticathepsin K in rabbits and in adult rhesus monkeys, with prevention of lumbar BMD loss and improved mechanical properties at the femur and spine [52,53]. In parallel, they did not reduce bone formation at any bone site. In a head-to-head comparison among monkeys receiving either odanacatib (ODN) or alendronate, BMD increased more at the femoral neck with the anticathepsin K [54]. The pharmacology of ODN has been studied on postmenopausal women in two double-blind, randomized, placebocontrolled Phase I trials [55]. A prolonged half-life (t1/2: 7.1

66 -- 93 h) has been observed, allowing for a weekly administration. The efficacy of various doses of ODN was examined in a randomized placebo-controlled trial among 399 postmenopausal women [56]. After 24 months, the lumbar and hip bone density increased significantly in comparison with placebo (5.5 and 3.2%, respectively), with a weekly dose of 50 mg. Bone resorption markers decreased sharply, whereas formation markers decreased mildly, suggesting a relative preservation of bone formation. A 3- and 5-year extension showed similar results, with a good safety profile [57,58]. Brixen et al. have studied ODN in 214 postmenopausal women over 2 years, in comparison with placebo. ODN decreased bone resorption, maintained bone formation, increased areal and volumetric BMD, and increased estimated bone strength at both the hip and spine [59]. A randomized double-blind, placebo-controlled trial studied the effect of ODN in 243 postmenopausal women who had been treated with > 3 years of alendronate. The BMD gain was significantly higher in the ODN group (1.7% at the neck, 0.8% at the hip and 2.3% at the lumbar spine) than in the placebo group [60]. A Phase III trial involving > 16,000 postmenopausal women, 65 years of age with low BMD was conducted to prove the antifracture efficacy of ODN. Women were randomized to receive ODN 50 mg or placebo, which was then taken for a duration of 3 years. The primary outcomes were time to first morphometric vertebral fracture, time to first hip fracture and time to first clinical nonvertebral fracture. This trial was event-driven, thus it was stopped after an interim analysis showed a robust reduction in the incidence of vertebral and hip fracture. The exact numbers have not been released so far to preserve blinding because many participants are enrolled in a 2-year preplanned extension that is still ongoing. Efficacy and safety continue to be monitored in the preplanned extension. Another cathepsin-K inhibitor -- ONO5334 -- has been evaluated in a double-blind, placebo- and active-controlled trial in 285 postmenopausal women. At 1 year, this compound increased lumbar and hip bone density; bone formation was preserved and bone resorption was reduced to a similar level as that obtained with alendronate [61]. At 2 years, a rebound in bone turnover was observed in patients who stopped the drug, while BMD plateaued, whereas in those continuing the therapy, bone turnover remained suppressed and BMD continued to increase [62]. The development of ONO5334, however, was discontinued in 2012, taking into consideration competitiveness and marketing conditions in the osteoporosis area. Antisclerostin monoclonal antibodies Sclerostin, coded by the gene SOST, is an osteocyte-secreted glycoprotein. Sclerostin appears as a crucial regulator of bone formation because it antagonizes the Wnt signaling pathway on cell membranes of osteoblasts, decreases osteoblastic 7.2


5


Anti-sclerostin antibobies Sclerostin

Bone formation

PTHrp Teriparatide

Bone resorption Wnt signaling pathway HRT

SERMs

Intermittent PTH

Osteoclast

Estrogens


Biphosphonates

Osteoblast

Denosumab

New bone

Synthesis Inhibition

RANKL

Activation Cathepsin-K inhibitors

Drugs in osteoporosis Osteoprotegerin

Cathepsin-K

Figure 1. Osteogenesis and osteoporosis drugs. HRT: Hormone replacement therapy; PTH: Parathyroid hormone; RANKL: Receptor activator of NFkB ligand; SERMs: Selective estrogen receptor modulators.

Table 1. Competitive environment table. Compound

Company

Structure

Odanacatib

Merck

Cathepsin-K inhibitor

Romosozumab Blosozumab

Amgen Lilly

Sclerostin human monoclonal antibodies

BA058

Radius Health

PTHrp

Indication Postmenopausal osteoporosis Postmenopausal osteoporosis

Phase III

Postmenopausal osteoporosis

Phase III

proliferation and function, leading to a decrease in bone formation. Sclerostin is an attractive target because SOST expression is bone-specific, which limits unwanted extraskeletal side effects. A rare homozygous mutation of SOST, the gene encoding for sclerostin, leads to general and severe osteosclerosis. Those individuals have no detectable circulating sclerostin and die early. In contrast, individuals with heterozygous mutation have a normal phenotype, a normal lifespan, but strong bones and a low risk of fracture [63]. Mice in which the sclerostin gene was deleted had increased bone formation and high bone mass and strength [64]. Therefore, several groups have reasoned that inhibiting the inhibitor of bone formation could produce bone gains. At least two monoclonal antibodies against sclerostin have been recently developed: romosozumab and blosozumab. 6

Stage of development

Phase III

Mechanism of action Inhibits cathepsin-K, a proteas involved in bone resorption Inhibits sclerostin, enhancing Wnt signaling pathway, and bone formation Anabolic agent with intermittent secretion

In a rat model of postmenopausal osteoporosis, the antisclerostin antibody romosozumab effected an increase in bone mass and bone strength, which became even greater than that found in nonovariectomized rats [65]. Similar trends were found in cynomologus monkeys [66]. Li et al. studied the effect of a pretreatment with alendronate, or in a cotreatment with sclerostin antibody [67]. First, rats received either alendronate or vehicle during a 6-week period. Following this, the alendronate rats were then switched to either sclerostin antibody or sclerostin antibody associated to alendronate. The vehicle rats were switched to either sclerostin antibody or vehicle as a control group. After 6 weeks, the increase in bone formation, bone mass and bone strength induced by sclerostin antibody were not found to have been affected with pre- or cotreatment by alendronate.




In a randomized, double-blind, placebo-controlled, Phase I trial, multiple doses of sclerostin antibody romosozumab were assessed [68]. Thirty-two postmenopausal women and 16 healthy men with low bone mass received the treatment. Mean serum romosozumab increased dose-proportionally. Type 1 aminoterminal propeptide (P1NP) increased by 66 to 147%, whereas C-telopeptide (CTX) decreased by 15 to 50%, suggesting bone remodeling uncoupling. The lumbar spine bone density increased by 4 to 7%. Adverse events were similar in the two groups. Of particular interest were two subjects who developed neutralizing antibodies, without any evidence of effect on pharmacokinetics, pharmacodynamics or safety. In a Phase II, multicenter, international, randomized, placebo-controlled, parallel-group, romosozumab was evaluated over a 12-month period in 419 postmenopausal women with low BMD [69]. Romosozumab was associated with a significant increase in lumbar BMD of 11.3% in the 210 mg monthly dose compared with a decrease of 0.1% in the placebo group and increases of 4.1% with alendronate and 7.1% with teriparatide. Four Phase III studies are currently being carried out in order to assess the efficacy and safety of romosozumab. The first study is a multicenter, randomized, multiple-dose, placebo-controlled enrolling postmenopausal women and assessing BMD modifications (NCT02016716). The second study evaluates romosozumab versus placebo in postmenopausal women (NCT01575834), whereas the third study is alendronate-controlled (NCT01631214). The fourth and final study evaluates romosozumab versus teriparatide in postmenopausal women with osteoporosis previously treated with bisphosphonates (NCT01796301). Blosozumab is another antisclerostin antibody that has been assessed in a single- and multiple-dose Phase I trial [70]. The tolerance was good. Dose-dependent effects were observed regarding increasing P1NP and declining CTX. Lumbar spine BMD was significantly better at day 85. Prior bisphosphonate use seemingly did not alter the effect of blosozumab, regarding bone density and biomarkers. Antibodies to blosozumab were detected, as well as in the romosozumab Phase I trial, without consequences on its effect. Parathyroid hormone PTHrp is the product of the same gene as PTH, but it performs a different role in bone, with an important paracrine action promoting bone formation [71]. It is also well known to induce humoral hypercalcemia of malignancy [72]. PTHrp binds to and activates a single G-protein coupled receptor, the type-1 PTH receptor. It is important to note that recent studies have demonstrated notable differences in receptor conformation selectivity, subcellular localization of ligandreceptor complexes and duration of intracellular signaling, compared with PTH [73]. Stewart et al. assessed a 6-month daily administration of PTH, PTHrp (1-36) and human PTH (1-34) on adults ovariectomized rats [74]. All three drugs 7.3

allowed for an increase in bone mass and improvement in bone histomorphometric parameters of both bone mass and biomechanical properties. An intermittent administration -reminiscent of that of teriparatide -- allows an increase of bone mass. In a Phase I short-term trial of PTHrp 1-36, Plotkin et al. [75] observed increasing bone formation markers at day 14, as with PTH. In parallel, markers of bone resorption did not increase. In a double-blind, prospective, placebo-controlled, randomized trial, Horwitz et al. assessed the efficacy of PTHrp 1-36 in 16 postmenopausal women [76]. In the PTHrp group, at 3 months, an increase of 4.7% of the lumbar spine bone density was observed, but also an increase of bone formation markers (osteocalcin). There was no significant adverse event. Moreover, PTHrp 1-36 seems to have a wide therapeutic window (9 -- 28 µg/kg/day in the study of Horwitz et al.) with a good safety (no case of hypercalcemia) [77]. With the higher doses, PTHrp increased 1,25 dihydroxyvitamin D production, which could favor the risk of hypercalcemia [78]. A randomized, placebo- and teriparatide-controlled, dosefinding study with PTHrp 1-34 analog BA058 -- also known as abaloparatide -- in 222 postmenopausal osteoporosis affected women showed a dose-dependent increase in BMD (lumbar spine, total hip and femoral neck) at 6 months (NCT005 42425). These results were similar to those observed on teriparatide, with the same tolerability. Other dose escalation studies are also in progress (clinicaltrials.gov). PTHrp seems to be a potential drug for use in postmenopausal osteoporosis, but its use has to be assessed in longer studies. We await the results of the Phase III trial on its efficacy to reduce vertebral and nonvertebral fractures. 8.

Potential development issues

Given the large number of available drugs in the field of osteoporosis, new therapies have to be developed in Phase III trials conducted in comparison with compounds that have established antifracture efficacy because it is no longer ethical to conduct long-term placebo-controlled trials. As older drugs are both efficient and inexpensive, new drugs must be able to demonstrate some degree of superiority, that is, in terms of efficacy or safety. This will lead to head-to-head superiority comparison trials. These studies are generally challenging to design and complete because of the large sample size that is necessary. 9.

Conclusion

Several promising drugs to treat osteoporosis are currently being developed. ODN is an antiresorptive agent, but it also preserves some degree of bone formation. Several anabolic agents, which have a great potential to provide a greater antifracture benefit than existing therapies, are also being studied,


7


including PTHrp 1-34 (abaloparatide) and antisclerostin antibodies (romosozumab and blosozumab).


10.

Expert opinion

There are several unmet needs in the treatment of osteoporosis. First, the compliance of current antiosteoporosis drugs is suboptimal, sometimes due to inadequate tolerance of the established drugs. Second, most patients with fracture are not prescribed any treatment in emergency departments and orthopedic wards. This phenomenon has been observed 15 years ago and has not improved so far, despite a large body of evidence on the effectiveness of fracture liaison services. As a result, most patients with a high risk of fracture and refracture are not managed appropriately. Third, the side effects of osteoporosis drugs -- in particular bisphosphonates -- have been widely criticized in the lay press, which has probably contributed to the decline in osteoporosis drugs prescription in recent years. Finally, the value of the current drugs essentially stem from their efficacy on vertebral fracture, whereas their ability to decrease nonvertebral risk is more limited. A great deal of knowledge on the pathophysiology of bone fragility has been obtained in the past decade. This has led to the discovery on new important drugs, some of them biologics. To be successful, these new medications will have to address the several shortcomings that have hindered the bone field so far. First, new drugs should be better tolerated than the older ones. This will improve the public and doctors’ trust in the osteoporosis drugs. Also, intermittent administration may improve the care gap. Second, most current medications decrease the risk of vertebral fracture by half or two-thirds, but their effect on nonvertebral fracture risk is less significant around 20 -- 25%. New drugs will have to Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

2.

3.

4.

8

Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet 2002;359(9319):1761-7 Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet 2002;359(9321):1929-36 Kanis JA, McCloskey EV, Johansson H, et al. Case finding for the management of osteoporosis with FRAX -- assessment and intervention thresholds for the UK. Osteoporos Int 2008;19(10):1395-408

exhibit much better efficacy in this regard. It is now well established that the main burden of fracture is the nonvertebral fracture. Therefore, we need new therapies that are more efficient to curb the incidence of fracture in the population. Third, these newcomers will be more expensive than the current, generic drugs, like bisphosphonates. To gain access to most highly regulated markets, they will have to prove themselves to be satisfactorily cost-effective. It may be acquired through substantially increased drug efficacy. Also, the new drugs may be second-line options, targeted at patients with contraindications to older drugs, or patients who are failing to respond to these drugs. In addition, some of these new drugs with potent anabolic effect may be confined to niches, for those patients at high risk of refracture after a first severe fracture such as a hip fracture or a clinical vertebral fracture. This certainly deserves to update most therapeutic guidelines to target the most severely affected patients with the new expensive biologics and use the old inexpensive drugs for moderate forms of the disease. The general organization of fracture care has also to be discussed to implement more widely the fracture liaison services, which could be the first place to screen for low bone mass and start therapy.

Declaration of interest R Chapurlat has received research funding, is on the advisory board of or has attended conferences for Servier, Chugai, Amgen, Novartis, Merck, Eli Lilly, Pfizer, Bristol-Myers Squibb and Bioiberica. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

5.

Melton LJ III, Chrischilles EA, Cooper C, et al. Perspective. How many women have osteoporosis? J Bone Miner Res 1992;7(9):1005-10

10.

Honig S, Rajapakse CS, Chang G. Current treatment approaches to osteoporosis - 2013. Bull Hosp Jt Dis (2013) 2013;71(3):184-8

6.

Kanis JA, Johnell O, De Laet C, et al. A meta-analysis of previous fracture and subsequent fracture risk. Bone 2004;35(2):375-82

11.

7.

Nevitt MC, Ettinger B, Black DM, et al. The association of radiographically detected vertebral fractures with back pain and function: a prospective study. Ann Intern Med 1998;128(10):793-800

Caro JJ, Ishak KJ, Huybrechts KF, et al. The impact of compliance with osteoporosis therapy on fracture rates in actual practice. Osteoporos Int 2004;15(12):1003-8

12.

Yood RA, Emani S, Reed JI, et al. Compliance with pharmacologic therapy for osteoporosis. Osteoporos Int 2003;14(12):965-8

8.

Bliuc D, Nguyen ND, Milch VE, et al. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA 2009;301(5):513-21

13.

Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010;341:c3691

9.

Sambrook P, Cooper C. Osteoporosis. Lancet 2006;367(9527):2010-18

14.

Greendale GA, Sowers M, Han W, et al. Bone mineral density loss in relation to

Cooper C, Campion G, Melton LJ III. Hip fractures in the elderly: a world-wide projection. Osteoporos Int 1992;2(6):285-9



the final menstrual period in a multiethnic cohort: results from the Study of Women’s Health Across the Nation (SWAN). J Bone Miner Res 2012;27(1):111-18


15.

Torgerson DJ, Bell-Syer SE. Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. JAMA 2001;285(22):2891-7

16.

Jackson RD, Wactawski-Wende J, LaCroix AZ, et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the women’s health initiative randomized trial. J Bone Miner Res 2006;21(6):817-28

17.

Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA 2003;290(13):1729-38

18.

Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA 2013;310(13):1353-68

19.

20.

21.

22.

23.

Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996;348(9041):1535-41 Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356(18):1809-22

24.

Mashiba T, Turner CH, Hirano T, et al. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone 2001;28(5):524-31

(SMART) trials. J Womens Health (Larchmt) 2014;23(1):18-28 33.

Miller PD, Chines AA, Christiansen C, et al. Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of a randomized, double-blind, placebo-, and activecontrolled study. J Bone Miner Res 2008;23(4):525-35

34.

Silverman SL, Chines AA, Kendler DL, et al. Sustained efficacy and safety of bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study. Osteoporos Int 2012;23(1):351-63

25.

Ozdemir A, Dalbeler A, Bilen A, et al. Acute renal failure associated with diphosphonic acid (HEDP): a case report. Am J Ind Med 2013;56(6):720-3

26.

Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361(8):756-65

27.

Bone HG, Chapurlat R, Brandi M-L, et al. The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab 2013;98(11):4483-92

35.

Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344(19):1434-41

28.

Brown JP, Prince RL, Deal C, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res 2009;24(1):153-61

36.

Orwoll ES, Scheele WH, Paul S, et al. The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res 2003;18(1):9-17

37.

Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003;349(13):1207-15

38.

Finkelstein JS, Hayes A, Hunzelman JL, et al. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 2003;349(13):1216-26

39.

Muschitz C, Kocijan R, Fahrleitner-Pammer A, et al. Antiresorptives overlapping ongoing teriparatide treatment result in additional increases in bone mineral density. J Bone Miner Res 2013;28(1):196-205

40.

Cosman F, Eriksen EF, Recknor C, et al. Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH (1-34)] in postmenopausal osteoporosis. J Bone Miner Res 2011;26(3):503-11

41.

Tsai JN, Uihlein AV, Lee H, et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet 2013;382(9886):50-6 A randomized trial showing that the combination of denosumab and teriparatide seems to be more efficacious than either drug alone,

29.

30.

Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22(10):1479-91 Gedmintas L, Solomon DH, Kim SC. Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis. J Bone Miner Res 2013;28(8):1729-37

B€oni C, Kordic H, Chaloupka K. Bisphosphonate-associated orbital inflammatory disease and uveitis anterior -- a case report and review. Klin Monatsbl Fu¨r Augenheilkd 2013;230(4):367-9

31.

32.

Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999;282(7):637-45 Cranney A, Tugwell P, Zytaruk N, et al. Meta-analyses of therapies for postmenopausal osteoporosis. IV. Metaanalysis of raloxifene for the prevention and treatment of postmenopausal osteoporosis. Endocr Rev 2002;23(4):524-8 Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355(2):125-37 Pinkerton JV, Abraham L, Bushmakin AG, et al. Evaluation of the efficacy and safety of bazedoxifene/ conjugated estrogens for secondary outcomes including vasomotor symptoms in postmenopausal women by years since menopause in the Selective estrogens, Menopause and Response to Therapy


.

9


preserving endocortical bone formation and stimulating periosteal bone formation in the ovariectomized adult rhesus monkey. J Bone Miner Res 2012;27(3):524-37

61.

Eastell R, Nagase S, Ohyama M, et al. Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: the OCEAN study. J Bone Miner Res 2011;26(6):1303-12

54.

Williams DS, McCracken PJ, Purcell M, et al. Effect of odanacatib on bone turnover markers, bone density and geometry of the spine and hip of ovariectomized monkeys: a head-to-head comparison with alendronate. Bone 2013;56(2):489-96

62.

Eastell R, Nagase S, Small M, et al. Effect of ONO-5334 on bone mineral density and biochemical markers of bone turnover in postmenopausal osteoporosis: 2-year results from the OCEAN study. J Bone Miner Res 2014;29(2):458-66

63.

55.

Stoch SA, Zajic S, Stone J, et al. Effect of the cathepsin K inhibitor odanacatib on bone resorption biomarkers in healthy postmenopausal women: two doubleblind, randomized, placebo-controlled phase I studies. Clin Pharmacol Ther 2009;86(2):175-82

Lewiecki EM. Sclerostin: a novel target for intervention in the treatment of osteoporosis. Discov Med 2011;12(65):263-73

64.

Li X, Ominsky MS, Niu Q-T, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 2008;23(6):860-9

65.

Li X, Ominsky MS, Warmington KS, et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 2009;24(4):578-88

66.

Ominsky MS, Vlasseros F, Jolette J, et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Miner Res 2010;25(5):948-59

67.

Li X, Ominsky MS, Warmington KS, et al. Increased bone formation and bone mass induced by sclerostin antibody is not affected by pretreatment or cotreatment with alendronate in osteopenic, ovariectomized rats. Endocrinology 2011;152(9):3312-22

68.

Padhi D, Allison M, Kivitz AJ, et al. Multiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: a randomized, double-blind, placebo-controlled study. J Clin Pharmacol 2013. [Epub ahead of print] A dose-finding study of romosozumab.

based on surrogates like bone mineral density variation and biochemical markers. 42.


43.

44.

45.

46.

47.

Leder BZ, Tsai JN, Uihlein AV, et al. Two years of Denosumab and teriparatide administration in postmenopausal women with osteoporosis (The DATA Extension Study): a randomized controlled trial. J Clin Endocrinol Metab 2014;99(5):1694-700 Reginster J-Y, Burlet N. Osteoporosis: a still increasing prevalence. Bone 2006;38(2 Suppl 1):S4-9 Kanis JA, Johnell O. Requirements for DXA for the management of osteoporosis in Europe. Osteoporos Int 2005;16(3):229-38 Parthan A, Kruse M, Yurgin N, et al. Cost effectiveness of denosumab versus oral bisphosphonates for postmenopausal osteoporosis in the US. Appl Health Econ Health Policy 2013;11(5):485-97 Solomon DH, Johnston SS, Boytsov NN, et al. Osteoporosis medication use after hip fracture in U.S. patients between 2002 and 2011. J Bone Miner Res 2014. [Epub ahead of print] Panneman MJM, Lips P, Sen SS, et al. Undertreatment with anti-osteoporotic drugs after hospitalization for fracture. Osteoporos Int 2004;15(2):120-4

48.

Bessette L, Ste-Marie L-G, Jean S, et al. The care gap in diagnosis and treatment of women with a fragility fracture. Osteoporos Int 2008;19(1):79-86

49.

Ganda K, Puech M, Chen JS, et al. Models of care for the secondary prevention of osteoporotic fractures: a systematic review and meta-analysis. Osteoporos Int 2013;24(2):393-406

50.

Pennypacker B, Shea M, Liu Q, et al. Bone density, strength, and formation in adult cathepsin K (-/-) mice. Bone 2009;44(2):199-207

51.

Gowen M, Lazner F, Dodds R, et al. Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res 1999;14(10):1654-63

52.

53.

10

56.

57.

58.

.

59.

..

60.

Pennypacker BL, Duong LT, Cusick TE, et al. Cathepsin K inhibitors prevent bone loss in estrogen-deficient rabbits. J Bone Miner Res 2011;26(2):252-62 Cusick T, Chen CM, Pennypacker BL, et al. Odanacatib treatment increases hip bone mass and cortical thickness by

..

Bone HG, McClung MR, Roux C, et al. Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J Bone Miner Res 2010;25(5):937-47 Eisman JA, Bone HG, Hosking DJ, et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect. J Bone Miner Res 2011;26(2):242-51 Langdahl B, Binkley N, Bone H, et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: five years of continued therapy in a phase 2 study. J Bone Miner Res 2012;27(11):2251-8 The Phase II study of odanacatib, with 5 years of follow-up. Brixen K, Chapurlat R, Cheung AM, et al. Bone density, turnover, and estimated strength in postmenopausal women treated with odanacatib: a randomized trial. J Clin Endocrinol Metab 2013;98(2):571-80 A randomized trial showing that odanacatib increases bone strength as estimated by finite element analysis. Bonnick S, De Villiers T, Odio A, et al. Effects of odanacatib on BMD and. safety in the treatment of osteoporosis in postmenopausal women previously treated with alendronate: a randomized placebo-controlled trial. J Clin Endocrinol Metab 2013;98(12):4727-35 A randomized trial showing that odanacatib can increase bone density in women pretreated with alendronate.


.

69.

..

70.

McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 2014;370(5):412-20 The Phase II trial of romosozumab showing substantial increments in bone mass in response to treatment. McColm J, Hu L, Womack T, et al. Single- and multiple-dose randomized studies of blosozumab, a monoclonal


..

71.


72.

73.

74.

adult ovariectomized rats markedly enhances bone mass and biomechanical properties: a comparison of human parathyroid hormone 1-34, parathyroid hormone-related protein 1-36, and SDZparathyroid hormone 893. J Bone Miner Res 2000;15(8):1517-25

antibody against sclerostin, in healthy postmenopausal women. J Bone Miner Res 2014;29(4):935-43 The Phase II trial of blosozumab showing its potent effect on bone formation. Martin TJ. Osteoblast-derived PTHrP is a physiological regulator of bone formation. J Clin Invest 2005;115(9):2322-4 Casez J-P, Pfammatter R, Nguyen Q-V, et al. Diagnostic approach to hypercalcemia: relevance of parathyroid hormone and parathyroid hormonerelated protein measurements. Eur J Intern Med 2001;12(4):344-9 Ferrandon S, Feinstein TN, Castro M, et al. Sustained cyclic AMP production by parathyroid hormone receptor endocytosis. Nat Chem Biol 2009;5(10):734-42 Stewart AF, Cain RL, Burr DB, et al. Six-month daily administration of parathyroid hormone and parathyroid hormone-related protein peptides to

75.

Plotkin H, Gundberg C, Mitnick M, et al. Dissociation of bone formation from resorption during 2-week treatment with human parathyroid hormone-related peptide-(1-36) in humans: potential as an anabolic therapy for osteoporosis. J Clin Endocrinol Metab 1998;83(8):2786-91

76.

Horwitz MJ, Tedesco MB, Gundberg C, et al. Short-term, high-dose parathyroid hormone-related protein as a skeletal anabolic agent for the treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab 2003;88(2):569-75

77.

Horwitz MJ, Tedesco MB, Sereika SM, et al. Safety and tolerability of subcutaneous PTHrP(1-36) in healthy human volunteers: a dose escalation study. Osteoporos Int 2006;17(2):225-30


78.

Horwitz MJ, Tedesco MB, Garcia-Ocan˜a A, et al. Parathyroid hormone-related protein for the treatment of postmenopausal osteoporosis: defining the maximal tolerable dose. J Clin Endocrinol Metab 2010;95(3):1279-87

Affiliation

Elodie Feurer†1 & Roland Chapurlat2 MD PhD † Author for correspondence 1 Rhumatologist Fellow, INSERM UMR 1033 -- Universite´ de Lyon, Hoˆpital Edouard Herriot, Hospices Civils de Lyon, Department of Rheumatology, 5, Place d’Arsonval 69003 Lyon, France Tel: +33 4 72 11 74 58; Fax: +33 4 72 11 74 83; E-mail: [email protected] 2 Professor of Rheumatology, INSERM UMR 1033 -- Universite´ de Lyon, Hoˆpital Edouard Herriot, Hospices Civils de Lyon, Department of Rheumatology, 5, Place d’Arsonval, 69003 Lyon, France

11

Emerging Therapies for Osteoporosis.

Emerging drugs for acromegaly.

Prevalent and Emerging Therapies for Osteoporosis.

Emerging therapies for the treatment of osteoporosis.

Emerging drugs for endometrial cancer.

Emerging tools for discovering drugs.

Emerging drugs for hemophilia B.

Emerging drugs for neuropathic pain.

Emerging drugs for urothelial carcinoma.

Emerging drugs for prostate cancer.

Emerging drugs for cystic fibrosis.

Emerging drugs for celiac disease.

Emerging drugs for coeliac disease.

Emerging drugs for allergic conjunctivitis.

Emerging drugs for biliary cancer.

Emerging drugs for the treatment of pruritus.

Emerging drugs for head and neck cancer.

Emerging and investigational drugs for premature ejaculation.

Emerging drugs for T-cell lymphoma.

Emerging drugs for the treatment of anxiety.

Emerging drugs for bipolar depression: an update.

Corrigendum to "New and Emerging Therapies for Osteoporosis".

Emerging drugs for the treatment of myelofibrosis.

Emerging drugs for the treatment of acne.