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© Springer Nature Switzerland AG 2019
F. R. Pérez-López (ed.), Postmenopausal Diseases and Disorders,
https://doi.org/10.1007/978-3-030-13936-0_25
S. Minisola (*)
Department of Internal Medicine and Medical Disciplines, “Sapienza” Rome University,
Rome, Italy
e-mail: salvatore.minisola@uniroma1.it
25
Anabolic Agents fortheTreatment
ofPostmenopausal Osteoporosis
SalvatoreMinisola
25.1 Osteoporosis Definition andIts Burden
Osteoporosis is characterized by low bone mass (easily quantied by bone min-
eral density (BMD) measurement) and qualitative structural decay of bone tis-
sue (not easily evaluated by current techniques); therefore, both quantitative and
qualitative skeletal alterations lead to increased bone fragility which results in
fractures [1]. Mistakenly often considered an inevitable consequence of aging,
osteoporosis with its ominous consequences of fractures represents a substantial
and ever-growing burden on healthcare systems in many countries around the
world [2].
It has been estimated that ten million Americans over the age of 50 have osteo-
porosis, so that about 1.5 million fragility fractures occur each year [3]; another
34 million Americans are considered at risk of disease. Concerning the economic
burden, the cost has been estimated to be around $17.9 billion per year. In European
Union (EU), a report estimated that in 2010, 6.6% of men and 22.1% of women
aged 50years had osteoporosis, while the number of fragility fractures was esti-
mated to be 3.5 million. The annual direct costs attributable to fracture treatment in
the EU are approximately € 24 billion. However, if we consider indirect costs such
as long-term care and fracture prevention therapies, this gure rises to € 37 billion
per year [4, 5].
Another important factor not commonly taken into consideration is represented
by the deterioration of quality of life of those incurring in a fracture event [6, 7].
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25.2 Standard Therapies forOsteoporosis
The mainstays of treatment (and prevention) of osteoporosis are represented by fall
avoidance [8], weight-bearing exercise [9], and adequate calcium and vitamin D
intake [10–12]. These general measures can be effective [13] especially in elderly
subjects conned to nursing home and vitamin D decient; however, medical ther-
apy is needed when a previous fracture has already occurred.
Pharmacological therapy is aimed at decreasing the risk of fracture, mainly
correcting the imbalance between bone resorption and formation at the level of
bone remodeling units [14]. Indeed, there are a number of available drugs that have
been shown to reduce the risk of future fractures based on both experimental and
clinical data. Therefore, osteoporosis should be no more viewed as an inevitable
consequence of aging. These pharmacological agents can be broadly divided into
two subgroups: those decreasing bone resorption (acting on osteoclasts) and those
increasing skeletal formation (acting on osteoblasts).
Antiresorptive agents [such as estrogens, bisphosphonates, selective estrogen
receptor modulator, and the monoclonal antibody to receptor activator of nuclear
factor kappa-B ligand (denosumab)] reduce the rate of bone resorption followed
by a decrease in the rate of bone formation due to the coupling between these two
processes; after about 6months, a new equilibrium between the two phases of bone
remodeling is reached although at a lower rate. These changes are associated with
increases of bone mineral density and maintenance of some improvement of struc-
tural and material properties of bone leading to reduction of bone fragility. Long-
term increases in bone mass are largely secondary to an increase in mineralization
density that is a consequence of reduced bone turnover [15].
25.3 Anabolic Therapies
Anabolic drugs hold the ability to increase bone mass to a greater extent than tradi-
tional antiresorptive agents.
25.3.1 Teriparatide
The rst available drug licensed as an anabolic treatment for osteoporosis was
represented by parathyroid hormone (PTH) 1-34 (teriparatide). It stimulates bone
formation, particularly in those skeletal segments rich in trabecular bone such
as vertebrae, thus reducing both vertebral and non-vertebral fractures [16]. PTH
improves bone quality and strength by inducing more favorable changes in micro-
architectural features such as connectivity, density, and geometric properties com-
pared to antiresorptive agents [17, 18].
In addition, owing to its ability to primarily stimulate bone formation, PTH
1-34 should be considered a rst-line therapy in glucocorticoid-induced osteoporo-
sis, which is associated with reduced bone formation [19, 20]. Studies comparing
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antiresorptive drugs vs. PTH 1-34 have indeed demonstrated the superiority of
teriparatide both in terms of improvements in bone strength [21] and reduction in
vertebral fractures [22].
A recent trial (VERO study) evaluated for the rst time the anti-fracture efcacy
of teriparatide compared to risedronate in 1680 postmenopausal women with at least
two moderate or one severe vertebral fracture and a bone mineral density T-score
of less than or equal to −1.0. At 24months, new vertebral fractures occurred in 28
(5.4%) of 680 patients in the teriparatide group and 64 (12.0%) of 680 patients in
the risedronate group (risk ratio 0.44, 95% CI 0.29–0.68; p<0.0001). Clinical frac-
tures occurred in 30 (4.8%) of 680 patients in the teriparatide group compared with
61 (9.8%) of 680in the risedronate group (hazard ratio 0.48, 95% CI 0.32–0.74;
p=0.0009). Non-vertebral fragility fractures occurred in 25 (4.0%) patients in the
teriparatide group and 38 (6.1%) in the risedronate group (hazard ratio 0.66; 95%
CI 0.39–1.10; p= 0.10). This was the rst head-to-head study between an antire-
sorptive agent (risedronate) and an anabolic agent (teriparatide) that shows that the
risk of new vertebral and clinical fractures is signicantly lower in patient receiving
teriparatide than in those receiving an antiresorptive agent [23]. Most importantly
the anti-fracture efcacy of teriparatide was consistent in a wide range of patients
setting, including treatment-naїve and previously treated risedronate patients [24].
It is important to keep in mind that, when we use teriparatide (which primar-
ily stimulates bone formation), an increase in osteoclastic activity can be observed
after a certain period; this foretells the closure of the so-called anabolic window,
thus limiting further accrual of bone mass [25]. When treatment with teriparatide is
stopped, there is a rapid decline in bone mineral density. Therefore, it is desirable
to administer an antiresorptive agent following the completion of the treatment with
teriparatide, so that gains obtained are maintained [26].
25.3.2 Abaloparatide
This is a 34-amino acid peptide which incorporates critical N-terminal residues,
shared by PTH and PTH-related protein (PTHrP) followed by sequences unique
to PTHrP. Preclinical studies have clearly demonstrated that both peptides acti-
vate the same receptor; however, their kinetics are different determining dissimilar
responses. It has been hypothesized that the two molecules favor different receptor
conformations with abaloparatide binding with high afnity but only for a short
period of time, thus limiting the duration of signaling compared with teriparatide.
Miller and coworkers [27] reported the efcacy and safety of abaloparatide
administered in a daily dose of 80μg subcutaneously for 18months. A total of 2463
patients were initially randomized and 1901 completed the investigation. Women
were subdivided into three groups receiving subcutaneous injection of placebo,
abaloparatide 80μg, or open-label teriparatide 20μg, respectively. In the modied
intention-to-treat population analysis (dened as the intention-to-treat analysis in
participants who had both pretreatment and post-baseline X-rays), new vertebral
fractures occurred less frequently compared with placebo (0.58% vs. 4.22%; RR
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0.14, 95% CI 0.05–0.39, p<0.001). In the teriparatide group, new morphometric
vertebral fractures were detected in six women (RR 0.20, CI 0.08–0.47, p<0.001
vs. placebo). Somehow similar results were obtained considering non-vertebral
fractures; the Kaplan-Meier estimated event rate for non-vertebral fracture was
lower with abaloparatide in respect to placebo group [2.7% in patients treated with
abaloparatide vs. 4.7% in placebo-treated patients; hazard ratio, 0.57 (95 CI 0.32–
1.00) p < 0.049]. There were not signicant differences in respect to teriparatide
group (HR 0.79, CI 0.43–1.45, p=0.44), even though the Kaplan-Meier estimated
event rates in this last group were not signicantly different from placebo-treated
patients (HR 0.72, CI 0.42–1.22, p=0.22).
Considering bone mineral density, it is important to note that mean improve-
ments with abaloparatide were signicantly greater than those with teriparatide at
the total hip and femoral neck at 6, 12, and 18months (p<0.001). Regarding lumbar
spine there was a statistical signicant difference (p<0.001) at 6 and 12months.
It is also important to underline the changes in bone turnover markers in patients
treated with abaloparatide or teriparatide. Indeed, there was a similar increase of
serum procollagen type I N-terminal propeptide (P1NP) and a less increase in
serum carboxy-terminal cross-linking telopeptide of type I collagen (β-CTX) in
abaloparatide- treated patients compared to those treated with teriparatide. This
nding might be ascribed to the differential binding to PTH type 1 receptor, thus
determining a more transient stimulation and lower expression of osteoblast-derived
RANK-ligand. This very initial uncoupling of bone formation and resorption may
justify the very rapid increase of bone mass with consequent rapid protection against
future fracture. This could be particularly important in the immediate period after a
fracture occurs; indeed a number of studies have documented that the risk is higher
soon after the initial event and then declines with time [28].
Finally, concerning safety, there were more withdrawals from the study in
abaloparatide- treated group (9.9% vs. 6.8% in the teriparatide and 6.1% in the pla-
cebo groups, respectively) because of adverse events mainly represented by nausea,
dizziness, headache, and palpitations. This negative aspect, if conformed in future
studies, implies a stringent medical surveillance.
Data from this original investigation have been subsequently reanalyzed, dem-
onstrating that abaloparatide maintains its effect in postmenopausal women with
osteoporosis, regardless of age, previous fracture, or basal BMD value [
29].
The US Food and Drug Administration (FDA) approved abaloparatide for the
treatment of osteoporosis in 2017. Approval by the European Medicine Agency
(EMEA) is pending.
25.3.3 Romosozumab
An important component of the Wnt signaling pathway, a well-known metabolic
route to drive osteoblast proliferation and commitment, is represented by scleros-
tin. This is a glycoprotein mainly secreted by osteocytes (and to a lesser extent
by cementocytes and mineralized hypertrophic chondrocytes) which is a potent
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inhibitor of osteoblastogenesis. Sclerostin secreted from osteocytes reaches the
bone surface through the canaliculi where it binds to co-receptors LRP5 and LRP6.
It prevents co-receptor localization with frizzled protein and Wnt, thereby decreas-
ing osteoblastogenesis and bone formation [15, 30].
The link between sclerostin and bone formation is very well illustrated by two
rare genetic decreases. Both sclerosteosis (due to a less of function mutation)
and Van Buchem disease (caused by a deletion downstream of sclerostin gene,
which includes sclerostin protein) are characterized by high bone mass. In this
context, some scientists suggested that the effect of parathyroid hormone therapy
in humans is mediated, at least in part, by a decrease in serum sclerostin levels
[31, 32]. In addition, genetic studies have shown that polymorphism in sclerostin
gene is associated with low bone mineral density in older men and women, fur-
ther emphasizing a causal link between modied sclerostin expression and bone
mineral density.
These observations led to explore the pharmacological inhibition of sclerostin by
a monoclonal antibody in various animal models of bone disease. Data obtained in
experimental animals showed a consistent effect of sclerostin antibody (from now
on called romosozumab) to increase bone formation, bone mass, and strength at
various skeletal sites [33].
Romosozumab has been evaluated in a double-blind study at a monthly dose of
210mg versus placebo in more than 7,000 postmenopausal osteoporotic patients
[34]. At 12months of treatment, romosozumab was associated with a risk of new
vertebral fracture that was 73% lower than the risk observed in the placebo group
(16 of 3321 patients in the romosozumab group vs. 59 of 3322in the placebo group;
risk ratio 0.25, condence interval 0.16–0.47, p<0.0001). Non-vertebral fractures
had occurred in 56 patients of the romosozumab group compared with 75in the
placebo group (p=0.10).
After 12 months of romosozumab therapy, the positive percent changes of
BMD therapy were 13.3, 6.9, and 5.9 at lumbar spine, total hip, and femoral neck,
respectively.
Concerning markers of bone turnover, the serum levels of procollagen type I
N-terminal propeptide peaked at day 14, while the levels of β-CTX decreased reach-
ing the maximum decline at day 14 and then remained below the level of placebo
group during the whole treatment period.
Regarding safety prole, all adverse events were balanced between active treat-
ment and placebo.
Romosozumab has been also investigated in another trial in which 4093 post-
menopausal women with osteoporosis and a fragility fracture were randomly
assigned to receive monthly subcutaneous romosozumab or weekly oral alen-
dronate for 12 months, followed by alendronate for 12 months in both groups.
After 24months, new vertebral fractures occurred 6.2% in the romosozumab-to-
alendronate group compared with 11.9% in the alendronate to-alendronate group
(48% lower risk of new vertebral fractures in the romosozumab-to-alendronate
group). There was a 27% lower risk of clinical fractures and 38% lower risk of hip
fractures [35].
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During the rst year of treatment, serious cardiovascular adverse events were
observed more often with romosozumab than with alendronate, a nding not
observed in the previous trial utilizing this humanized monoclonal antibody [34].
This could be theoretically ascribed to the reported involvement of sclerostin in aor-
tic vascular smooth muscle remodeling or calcication. Some have also suggested
that the comparison drug (alendronate) may be cardioprotective, so that the rate of
cardiovascular events in the romosozumab group could be relatively higher than
expected. Owing to these concerns, approval for romosozumab remains pending by
both FDA and EMEA.
25.4 Practical Considerations forAnabolic Drugs
ontheMarket
Before starting the administration of an anabolic agent, we must exclude possible
causes of secondary osteoporosis, because in this case, the treatment is not cura-
tive (the same applies to antiresorptive agents). Both teriparatide and abaloparatide
should not be administered in hypercalcemic patients and those at possible increased
risk of osteosarcoma (i.e., patients with Paget’s disease, undergoing radiation ther-
apy, or with bone metastases) or in those with increased alkaline phosphatase values
of unknown origin. It is also important to exclude at the beginning of therapy raised
values of endogenous parathyroid hormone, because this represents a contradic-
tion, on theoretical grounds, to the exogenous administration of the hormone. Since
many cases of secondary hyperparathyroidism are linked to hypovitaminosis D, it
is important to test and replenish the patient in this particular situation [36, 37]. As
both teriparatide and abaloparatide might exacerbate hypercalciuria, it is impor-
tant to evaluate, in basal conditions, the 24-h urinary calcium excretion. Once the
therapy has been started, there are no ofcial guidelines on how to biochemically
monitor the patient for serum calcium and uric acid or for 24-h urinary calcium
excretion. In any case serum calcium should be obtained 24h after the last drug
injection. If hypercalcemia is found, the rst step is a reduction in the amount of
calcium and vitamin D administered. If hypercalcemia persists, drug therapy should
be adjusted to every other day [38]. If after this change hypercalcemia persists, it is
prudent to discontinue treatment.
25.5 Conclusions
New anabolic drugs will increase the portfolio of compounds available to treat
bone fragility; they also represent an opportunity to change our way of prescribing
drugs in the most common and threatening metabolic bone disease. Indeed, unlike
the majority of chronic diseases, which are generally treated by a combination of
drugs, current practice in the eld of osteoporosis is the administration of only one
drug at a xed dose. However, the chronic nature of osteoporosis will force doc-
tors to nd alternative solutions by adding and switching therapies with the goal of
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