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Pharmacological Therapy of Osteoporosis:

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Clinical Interventions in Aging

Giovanni Iolascon 1 Abstract: Osteoporosis and fragility fractures are relevant health issues because of their
Antimo Moretti 1 impact in terms of morbidity, mortality, and socioeconomic burden. Despite this
Giuseppe Toro 1 alarming scenario, both underdiagnosis and undertreatment are common features of
Francesca Gimigliano 2 osteoporotic patients, particularly those who have already sustained a fragility fracture.
Pharmacotherapy of osteoporosis is the main treatment option for these patients because of
Sara Liguori 1
strong evidence about the efficacy of available drugs targeting bone metabolism. However,
Marco Paoletta 1
several issues can interfere with the effectiveness of anti-osteoporotic drugs in clinical
1
Department of Medical and Surgical practice, such as lack of awareness of both healthcare providers and patients, poor adherence
Specialties and Dentistry, University of
Campania “Luigi Vanvitelli”, Naples, Italy; to therapy, and safety in long-term treatment. Therefore, new therapeutic strategies have been
2
Department of Physical and Mental proposed to overcome these problems, such as sequential therapy or emerging molecules
Health and Preventive Medicine, mainly targeting the stimulation of bone formation. In particular, abaloparatide has
University of Campania “Luigi Vanvitelli”,
Naples, Italy been demonstrated to reduce major nonvertebral fracture risk compared with both placebo
and teriparatide, although the European Medicines Agency (EMA) refused the marketing
authorization because the benefits of this drug did not outweigh its risks. On the other side,
EMA has recently approved romosozumab, a monoclonal antibody directed against scler-
ostin and the only available therapeutic option targeting Wnt signaling, as both bone-forming
and antiresorptive intervention to treat osteoporosis and fragility fractures.
Keywords: osteoporosis, sequential therapy, antiresorptive drugs, bone anabolic drugs,
abaloparatide, romosozumab

Introduction
In the last decades, the healthcare demand in developed countries has progressively
increased along with the aging of the population. Osteoporosis is one of the main
health problems, considering that fragility fractures result in significant increases in
morbidity, mortality, as well as socioeconomic burden. In particular, osteoporosis
affects about 18.5% and 10% of Italian women and men, respectively, and an
annual incidence of over 400,000 fragility fractures has been estimated.1
Moreover, the prevalence of osteoporosis in the Italian population is expected to
increase by 25% in the next decades. Fragility fractures are a serious obstacle to
healthy aging, compromising the independence and quality of life in the affected
patients. Considering hip fractures only, over 500,000 elderly patients experienced
these devastating traumas, leading to an increased hospitalization rate up to about
30% in Italy in a 6-year period.2
Correspondence: Antimo Moretti
Department of Medical and Surgical In Europe, osteoporotic fractures are the fourth leading cause of morbidity asso-
Specialties and Dentistry, University of ciated with chronic diseases, annually contributing to over 2.6 million disability-
Campania “Luigi Vanvitelli”, Naples, Italy
Email antimomor.83@hotmail.it adjusted life years (DALYs) that is more than hypertensive heart disease and

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rheumatoid arthritis.3 In Italy, the loss of DALYs due to (anabolic window), thus limiting further accrual of bone
fragility fractures is estimated as higher than that associated mass.12 Novel routes of administration of this drug, such as
with other chronic diseases, including stroke and chronic oral, transdermal, and intranasal formulations, have been
obstructive pulmonary disease (COPD).4 Moreover, the hos- proposed and investigated in both animal models and
pital costs of hip fragility fractures are comparable to or even humans, demonstrating to be effective and more tolerable
higher than those reported for major cardiovascular diseases than subcutaneous injections, and might potentially improve
(strokes and acute myocardial infarctions, AMIs).5 compliance to anabolic therapy.13 The availability of new
Despite the relevance of these epidemiological data, formulations might be an additional factor for improving
along with the massive costs borne by the National Health adherence and persistence to anti-osteoporosis therapy, also
Systems, underdiagnosis, and, above all, undertreatment considering some limitations in the reliability of diagnostic
remain two main issues in the field of osteoporosis manage- tools to monitor the treatment response, such as the bone
ment, particularly in the secondary prevention care. This turnover markers (BTMs). Indeed, although BTMs might be
last issue represents the leading target of several national useful in this context, their dosage is not justified for routine
and international initiatives aiming to increase knowledge clinical evaluation.12
about the appropriate approach to osteoporosis, particularly Furthermore, new therapeutic solutions have been pro-
regarding the effectiveness of anti-osteoporotic drugs in posed, such as the use of already available drugs in suc-
preventing new fragility fractures. cession (sequential therapy) or new molecules mainly
Pharmacological therapy is the mainstay of interven- targeting the stimulation of bone formation (rather than
tions for patients with osteoporotic fractures. Indeed, com- decreasing bone resorption), therefore improving bone
mercially available anti-osteoporotic drugs are supported mass, structure, and ultimately skeletal strength.
by substantial evidence of efficacy as well as a favorable
safety profile. In particular, the number needed to treat
(NNT) of bisphosphonates (BPs) for secondary prevention Sequential Therapies
of low-trauma fracture is significantly lower (NNT 10) The therapeutic strategy of using anti-osteoporotic drugs
than that reported for statins in preventing major cardio- with different mechanisms of action in a sequential admin-
vascular events (NNT 56).6 istration mode based on the physiology of bone turnover
Despite strong evidence supporting anti-osteoporotic has been proposed some time ago. A first attempt was made
drugs for preventing fractures, several issues can interfere using cyclic administration of etidronate (the first studied
with their effectiveness in clinical practice.3 BP) for 2 weeks followed by 76 days of calcium and
Bisphosphonates, most commonly used for osteoporo- vitamin D supplementation, in order to simulate the periods
sis treatment, can increase matrix mineralization and bone of osteoclast and osteoblast activity, respectively, within
density up to a certain point, but they cannot restore lost bone remodeling units, thus avoiding osteomalacia.14
structure or substantially improve bone micro-architecture, In a modern view of the pharmacotherapy of osteo-
other than by the closing of resorption pits, giving their porosis, three combinations of drugs with predominantly
inability to stimulate osteoblast activity.7 Moreover, com- antiresorptive properties with agents with prevailing ana-
pliance and persistence to BP therapy are generally poor.8 bolic activity can be proposed: 1) antiresorptive therapy
Denosumab is an advancement in antiresorptive therapy first followed by an anabolic drug; 2) anabolic therapy first
especially for enhancing adherence and persistence to followed by an antiresorptive drug; or 3) co-administration
treatment9 as well as for a putative stimulation of osteoblastic of both antiresorptive and anabolic agents.
activity in specific areas of cortical bone,10 as evidenced by The first option is more frequently adopted in clinical
animal studies, but not yet confirmed in humans.11 practice because of supporting indications and costs. In
Furthermore, the suppression of bone turnover caused particular, teriparatide use follows prolonged BP therapy
by antiresorptive drugs may explain osteonecrosis of the that is often discontinued because of adverse events or the
jaw and atypical femoral fractures which can be observed occurrence of a new fragility fracture. Patients receiving
in patients with high-dose or long-term treatment. this treatment regimen usually experience a relevant
Teriparatide, the most commonly used bone anabolic reduction in bone turnover that blunts or delays the ana-
drug, stimulates bone formation before it enhances bone bolic response to teriparatide and the consequent potential
resorption, generating a period when it is maximally anabolic increase of bone mineral density (BMD).

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Therefore, in the context of a positive sequential pat- thus reducing the early increase of intracortical remodeling
tern of bone turnover modulation it would be advisable to and cortical porosity observed during PTH or teriparatide
start treatment with teriparatide followed by an antiresorp- administration.26
tive drug (BPs or denosumab), although this therapeutic In the Abaloparatide Comparator Trial in Vertebral
strategy undoubtedly goes against what is established by Endpoints (ACTIVE) phase III randomized control study,
the regulatory bodies.15 the authors observed that abaloparatide was able to reduce
In a pre-planned 2-year extension of a randomized both vertebral (compared with placebo) and major nonver-
controlled trial (RCT),16 it was demonstrated that patients tebral (compared with both placebo and teriparatide) fracture
switching from teriparatide to denosumab continued to risk.28 Regarding the safety profile, common adverse events
report an increase of BMD mainly in the hip region, associated with abaloparatide use were back pain, arthral-
while those switching from denosumab to teriparatide gia, upper respiratory infections, hypercalciuria, nausea, and
reported bone loss. According to the available evidence, dizziness.28 Palpitations were also reported,28 leading the
this therapeutic strategy seems to be the most effective for European Medicines Agency (EMA) to refuse the market-
fracture prevention in osteoporotic patients. ing authorization because the benefits of this drug did not
On the other hand, simultaneous administration of a BP outweigh its risks.29
(alendronate) and teriparatide did not show a greater ben- Furthermore, although findings about fracture preven-
efit over the single administration of these drugs,17,18 tion are encouraging, the assertion that abaloparatide is
whereas the simultaneous administration of zoledronate more effective than teriparatide in reducing fracture risk
and teriparatide led to a greater increase of hip BMD seems somewhat questionable. In fact, a large number of
compared to that obtained with the administration of ter- patients reporting a fragility fracture in the placebo and
iparatide or zoledronate alone.19 Moreover, the combined teriparatide groups sustained the traumatic event during
use of denosumab and teriparatide over a 2-year period the first few weeks of treatment28,30 and the differences
significantly increases the BMD at both lumbar spine and in fracture rates between the two treatment arms were
femoral neck more than can be obtained with the single minimal at 12 and 18 months.9,30,31 Moreover, the obser-
administration of both drugs.20,21 A possible explanation vations of both enhanced anabolic effect and lower bone
for these findings could be identified in the ability of resorption with abaloparatide use compared to teriparatide
denosumab to counteract the undeniable increase in bone therapy have also been questioned.31
resorption observed with teriparatide use, thus expanding
the anabolic window and consequently enhancing the gain
in bone density. New Anabolic Drugs Targeting Wnt
Signaling
New Anabolic Drugs: Abaloparatide A recent therapeutic option for the treatment of osteoporo-
Abaloparatide is a synthetic analog of a parathyroid hor- sis is the manipulation of the canonical Wnt pathway that
mone-related peptide (PTHrP) approved by the Food and is activated by the binding of a Wnt-protein ligand to
Drug Administration (FDA) for clinical use in 2017.22 This a Frizzled family receptor which in turn mediates signal
drug binds to the same receptor of teriparatide, an agonist of transduction in osteoblasts enhancing gene transcription.32
PTH type 1 receptor (PTH1R).23 This latter is a G-protein Sclerostin, a glycoprotein secreted by osteocytes and
coupled receptor that acts with two different conformations: encoded by the SOST gene [17q12-q21],33 binds to the
R° and RG.22,23 Pre-clinical studies showed that abalopara- LRP-5/6 co-receptors, preventing the interactions between
tide, bound with the same affinity to the RG conformation, Wnt and its receptor, and thus causing phosphorylation
but 80-fold weaker to the R° conformation than and degradation of β-catenin.34 In this way the Wnt target
teriparatide.23,24 The strong binding affinity to the RG con- genes are not activated, consequently inhibiting osteoblast
formation results in a shorter increase in intracellular cAMP proliferation, differentiation, and function. Furthermore,
levels and higher anabolic activity of osteoblasts. It was sclerostin can increase RANKL-mediated osteoclast for-
hypothesized that this different mechanism of action may mation and activation.
be responsible for the enhanced anabolic effect of The identification of genetic diseases due to impaired
abaloparatide.25 Indeed, its use is associated with a lower sclerostin expression and function, such as van Buchem
magnitude of bone remodeling and eroded bone surface26–28 disease and sclerosteosis,35 characterized by a high bone

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mass phenotype, has stimulated research for monoclonal postmenopausal women with osteoporosis were randomly
antibodies directed against this protein with the aim of intro- assigned to romosozumab subcutaneous injections
ducing an innovative therapeutic strategy for osteoporosis. (210 mg) or placebo monthly for 1 year; thereafter,
The pharmaceutical industry has recently developed patients in each group received denosumab (60 mg
three monoclonal antibodies against sclerostin: blosozu- Q6M) in the 2nd year. After the first 12 months, the
mab (LY251546), setrusumab (BPS804), and romosozu- intervention group showed an incidence of vertebral frac-
mab (AMG-785). tures of 0.5% versus 1.8% in the placebo group (−73%),
In a randomized, double-blind phase 2 clinical trial while a nonsignificant between-group difference was
versus placebo including postmenopausal women with low reported for nonvertebral fractures (1.6% in the romoso-
BMD, blosozumab (180 mg every 4 weeks, Q4W, 180 mg zumab group vs 2.1% in the placebo group). At 24
every 2 weeks, Q2W, or 270 mg Q2W) demonstrated sig- months, the significantly lower incidence of vertebral frac-
nificant dose-related improvements of BMD at both lumbar tures in women previously treated with romosozumab vs
spine and total hip after 1 year of treatment.36 After 1-year placebo group was confirmed (−75%). Adverse events
of treatment discontinuation, the same population was reported in the FRAME trial include hyperostosis, cardio-
investigated for BMD changes and incidence of delayed vascular events, osteoarthritis, and cancer, without
adverse events.37 The authors reported that the BMD of a significant difference between romosozumab and pla-
the lumbar spine remained significantly greater than placebo cebo groups. On the other side, in the romosozumab
in women treated with blosozumab at a dose of both 270 mg group were reported one atypical femoral fracture and
and 180 mg Q2W, and no adverse events occurred. two cases of osteonecrosis of the jaw.
Pharmacodynamics and safety of setrusumab were inves- The ARCH (Active-Controlled Fracture Study in
tigated in a randomized phase 2a trial including adults with Postmenopausal Women with Osteoporosis at High Risk,
moderate osteogenesis imperfecta (OI) during 21 weeks of NCT01631214) trial,42 including over 4000 women with
treatment at three escalating doses administered by intrave- a fragility fracture, compared the efficacy in terms of frac-
nous infusions Q2W. In the 14 treated patients, P1NP, P1CP, ture risk reduction of 1-year treatment with subcutaneous
BSAP, and OC increased by 84% (p<0.001), 53% (p=0.003), injections of romosozumab (210 mg monthly) vs placebo,
59% (p<0.001), and 44% (p=0.012), respectively, with followed by 12 months of oral alendronate administration
a reduction of CTX-1 by 44%.38 Moreover, this neutralizing, (70 mg weekly) in both groups. Considering the primary
anti-sclerostin antibody increased BMD of the lumbar spine endpoints, the authors reported a significantly lower risk of
by 4%, with a good safety profile as well as no treatment- incident vertebral fractures and clinical fractures (nonver-
related fractures. Setrusumab received the orphan drug des- tebral and symptomatic vertebral fracture) at 2-year follow-
ignation for OI treatment from both the FDA and the EMA in up (−48% and −27%, respectively) in romosozumab groups
2016, and was also accepted into the EMA’s Adaptive versus placebo. Moreover, women receiving romosozumab
Pathways program and granted the PRIority MEdicines reported a significantly lower risk of hip fracture (−38%).
(PRIME) designation.39 On the other hand, during the first year of treatment,
Romosozumab is the first agent of its class to have a higher percentage of serious cardiovascular adverse events
completed phase III studies at a recommended dose of were reported in the intervention group vs the alendronate
210 mg subcutaneous injection monthly. Previously, group (2.5% vs 1.9%).
experimental studies on rats and ovariectomized primates In the international multicenter STRUCTURE study
treated with romosozumab had shown significant increases (STudy evaluating effect of RomosozUmab Compared
in bone mass and strength, and phase 2 trials also demon- with Teriparatide in postmenopaUsal women with osteo-
strated the efficacy and safety of different romosozumab porosis at high risk for fracture pReviously treated with
dosages compared to placebo, alendronate, or teriparatide bisphosphonatE therapy), romosozumab was compared to
in postmenopausal osteoporotic women. teriparatide to investigate its efficacy in improving BMD
The efficacy of romosozumab in enhancing bone for- in postmenopausal osteoporosis transitioning from BP
mation and preventing fragility fractures was assessed in treatment.43 STRUCTURE data support superiority of
several RCTs.40 romosozumab in terms of BMD gains of the lumbar
In the FRAME (Fracture Study in Postmenopausal spine, total hip, and femoral neck (9.8% vs 5.4%, 2.6%
Women with Osteoporosis, NCT01575834) trial,41 vs −0.6%, and 3.2% vs −0.2%, respectively).

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The BRIDGE [A Double-blind Study to Compare the anti-osteoporotic drugs. The introduction of new pharmacolo-
Safety and Efficacy of Romosozumab (AMG 785) Versus gical approaches is essential to solve some critical issues in the
Placebo in Men With Osteoporosis, NCT02186171]44 trial management of osteoporosis and related fractures, such as
aimed to assess the efficacy and safety of romosozumab compliance and persistence to prolonged treatments, long-
(210 mg subcutaneously monthly for 12 months) versus term efficacy in reducing the risk of new fractures, and safety.
placebo in male osteoporosis, reporting significantly greater
changes in the BMD of the lumbar spine (+10.9%) and total
Acknowledgment
hip (+3%) in the intervention group. Moreover, cardiovas-
The authors would like to acknowledge the Vanvitelli per
cular events were not significantly higher with romosozu-
la Ricerca (VALERE) program for the allocation of fund-
mab use than placebo (4.9% vs 2.5%).
ing that aims to publish University of Campania “Luigi
In the aforementioned trials, safety was generally com-
Vanvitelli” research products.
parable between groups. Common adverse events observed
with romosozumab treatment were arthralgia (13%), naso-
pharyngitis (12.8%), back pain (10.5%), hypocalcemia Disclosure
(<0.1%), hypersensitivity (6.8%), injection-site reaction The authors report no conflicts of interest in this work.
(5.2%), hyperostosis (0.5%), osteoarthritis (7.8%), osteone-
crosis of the jaw (<0.1%), and atypical femoral fracture References
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