J Popul Ther Clin Pharmacol Vol 26(4):e1–e17; 20 November 2019.

This article is distributed under the terms of the Creative Commons Attribution-Non

Journal of Population Therapeutics

& Clinical Pharmacology

Review Article

DOI: 10.15586/jptcp.v26.i4.646

Pharmacological Management of Osteoperosis in Postmenopausal Women: The

Current State of the Art

Davide Gatti and Angelo Fassio

Rheumatology Unit, University of Verona, Verona, Italy

Corresponding author: E-mail: davide.gatti@univr.it

Submitted: 3 October 2019. Accepted: 31 October 2019. Published: 20 November 2019.

ABSTRACT

Osteoporosis is a common disease that increases fracture risk. Fragility fractures bring heavy conse-

quences in terms of mortality and disability, with burdensome health and social costs. In subjects with

clinical bone fragility, the rst goal is to identify the secondary forms of osteoporosis, especially in young

subjects, in males and in patients who recently experienced a fragility fracture. In addition, before con-

sidering any sort of treatment, it is fundamental to check for adequate calcium and vitamin D intake,

since their deciency is the most common reason for drug failure.

In the last decade of the 20th century, several molecules have been developed and proved to be effective

in achieving the true goal of any antiosteoporotic drug: fracture prevention.

In this article, we considered the most commonly prescribed antiresorptive drugs (hormonal therapy,

bisphosphonates, and denosumab), the anabolic agents (teriparatide), the dual-action drugs (romo-

sozumab), and the drugs characterized by an unclear mechanism of action (strontium ranelate) to pro-

vide physicians with useful insights for their clinical practice. We discussed the main criteria for the

appropriate choice selection and management of each treatment. Finally, we addressed the current con-

troversies related to treatment discontinuation, sequential, and combination therapy.

Keywords: osteoporosis; bone metabolism; bone mineral density; bisphosphonates; teriparatide;

alendronate; zoledronate; risedronate; clodronate; hormonal therapy; TSEC; denosumab; romosozumab;

strontium ranelate; combination therapy; sequential therapy

Pharmacological management of osteoporosis in postmenopausal women

J Popul Ther Clin Pharmacol Vol 26(4):e1–e17; 20 November 2019.

This article is distributed under the terms of the Creative Commons Attribution-Non

Osteoporosis is a chronic disease character-

ized by decreased bone mineral density (BMD)

and a deterioration of the bone micro-architec-

ture that leads to an increased risk of fragility

fractures.

This condition is mainly found in post-

menopausal women, but it can also affect men,

patients with other comorbidities or who are

receiving treatment with drugs that affect bone

health (secondary osteoporosis). The denition

of osteoporosis in clinical practice is based on

BMD measurement assessed by dual-energy

X-ray absorptiometry (DXA); the diagnosis is

made when the T-score at the femoral neck or

spine is 2.5 standard deviations (SD) or more

below the young adults mean.

In 2010, 22 million women and 5.5 million

men were estimated to be affected by osteoporo-

sis in Europe,

with 3.5 million new fragility frac-

tures in the same year (610,000 hip fractures,

520,000 vertebral fractures, 560,000 forearm frac-

tures, and 1,800,000 other fractures).

Fragility fractures are associated with heavy

consequences in terms of mortality and disabil-

ity, with burdensome health and social costs.

Their recovery is usually slow and often incom-

plete.

For these reasons, a large proportion of

fractured individuals is destined to lose function

and independence and to suffer from persistent

pain and decreased quality of life.

Due to the progressive aging of the general

population, the annual incidence of fragility frac-

tures is expected to rise from 3.5 million in 2010

to 4.5 million in 2025.

In the last three decades, pharmacological treat-

ments of osteoporosis have shown to be effective

and able to reduce the fracture risk by about 50%,

with consequent benets on the patients’ health sta-

tus.

Unfortunately, only a small proportion of

them is presently receiving adequate treatment.

In this article, we summarized the most rele-

vant data regarding the requirements for treat-

ment, different drug options, and the rationale of

sequential and combination therapy. We focused

on postmenopausal osteoporosis, which currently

is the most studied and common form of bone

fragility, with the aim of providing physicians

with useful insights for their clinical practice.

This article is a narrative overview on the

pharmacological treatment of postmenopausal

osteoporosis. When appropriated, the personal

opinions of the authors will be added in the text

and explicitly pointed out as such.

We used as sources MEDLINE/PubMed,

EMBASE, and Cochrane Library, from incep-

tion to 2019.

In addition, we hand-searched references from

the retrieved articles and explored a number of

related web sites. After discussion, we chose 68

relevant papers.

REQUIREMENTS FOR THERAPY

A careful diagnosis of the nature of osteopo-

rosis is fundamental for a correct treatment. A

large and increasing number of diseases and

drugs can contribute to bone fragility

and these

conditions often require specic treatment. For

these reasons, the rst goal of the physician

should always be to identify the secondary forms

of osteoporosis, especially in young subjects, in

males and in people with recent fractures. Referral

to a qualied specialist might be needed as well.

Another key requirement for therapy is an ade-

quate vitamin D status. Recently, some large trials

and meta-analyses concluded that vitamin D sup-

plementation has no benecial effects neither on

bone health, fracture risk nor falls,

but these

statements require a critical analysis that cannot

be limited to the raw results. As a matter of fact,

most of these studies investigated the effects of

vitamin D supplementation in healthy (nonosteo-

porotic) subjects, not at signicant risk for falling

and, overall, without any vitamin D deciency. In

such a scenario, data suggesting positive results

would be indeed unexpected. In any case, these

recent papers criticized the usefulness of vitamin

D supplementation with the goal to maintain or

Pharmacological management of osteoporosis in postmenopausal women

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improve musculoskeletal health in the general

population, but its role in patients receiving treat-

ment for osteoporosis is an entirely different topic.

It is well-known that, in these patients, adequate

calcium and vitamin D intake are essential, and

their deciency represents the most common rea-

son for lack of response to any treatment,

5,8,9

This

observation has been conrmed also in a recent

large retrospective study based on Italian admin-

istrative databases.

The study showed once again

that pharmacological treatments for osteoporosis

are associated with a lower risk for both refracture

and all-cause mortality to a greater extent when

they are administered in combination with cal-

cium and vitamin D.

DRUGS FOR THE TREATMENT OF

OSTEOPOROSIS

The main goal of the treatment for osteoporo-

sis is to decrease fracture risk. This often implies

the reduction of systemic bone loss and the stabi-

lization or the increase of BMD.

From the last decade of the last century, several

molecules have been developed and proved effec-

tive in achieving these goals.

10,11

The mechanism of

action of the various drugs is dened by their rela-

tion to the bone cells on which they act (Table 1).

Hormonal erapy

The physiologic decline of estrogens in women

begins from 1 to 2 years before menopause and

reaches its plateau about 1 to 2 years after the

menses cessation.

The drop in estrogens explains

the quick rise in the rate of bone resorption and

therefore of bone loss, with an increase of the risk

of osteoporosis.

In young women in whom pre-

mature menopause is induced by surgery or cancer

treatments, the estrogen drop can be particularly

marked and its adverse effects (AEs) on bone loss

and fracture risk are therefore greater.

14,15

Estrogens are key determinants of skeletal

health due to their specic effects on bone metab-

olism. For instance, they inhibit bone resorption

by decreasing the signaling of the receptor activa-

tor of nuclear factor-κB (RANKL), they induce

gene expression and synthesis of osteoprotegerin

(OPG), and they block osteoclastogenesis and

promote osteoclasts’ apoptosis.

In addition,

estrogens inhibit bone remodeling and decrease

the development of new basic multicellular units,

probably by limiting osteocytes’ apoptosis and

their production of sclerostin,

a key inhibitor of

the Wnt pathway that is involved in the pathogen-

esis of osteoporosis.

Hormone replacement therapy (HRT) was

routinely prescribed for primary prevention of

osteoporosis (independently of the presence of

menopausal symptoms) before the publication of

the Women’s Health Initiative (WHI)

and of the

epidemiological UK-based Million Women

Study.

The results of these studies reported an

association between HRT and an increased risk

of breast and ovarian cancer. However, recent

evidence showed that estrogen-alone therapy was

not associated with any increase in mortality

TABLE 1. Drugs Available for the Treatment of Osteoporosis Classied by Mechanism of Action

Antiresorptive drugs: reducing the osteoclastic bone resorption

• Estrogens and selective estrogen receptor modulators (SERMs)

• Bisphosphonates

• Denosumab

Anabolic drugs: increasing the osteoblastic bone formation activity

• Teriparatide

Dual-action drugs: increasing the osteoblastic bone formation activity and reducing the osteoclastic bone resorption

• Romosozumab

Drugs with unclear mechanism of action

• Strontium ranelate

Pharmacological management of osteoporosis in postmenopausal women

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in the risk of breast cancer, even in the women

who carry the BRCA1 gene mutation.

We need to remember that, in females who

carry the BRCA1 mutation, the cumulative risk of

ovarian and breast cancer by age 80 is over 40 and

70%, respectively.

Prophylactic salpingo-oopho-

rectomy is currently the only strategy able to

reduce the risk of both cancers. Unfortunately, the

premature withdrawal of ovarian hormones

induced by this surgery causes long-term AEs that

can be avoided, or at least limited, with HRT with-

out a signicant increase in cancer incidence.

14,20

For this reason, there is now a large scientic con-

sensus that hormonal therapy at menopause rep-

resents an effective prevention strategy for

osteoporosis and fragility fractures, with an over-

all favorable benet to risk ratio when it is started

before 60 years of age and within 10 years from

the last menses.

The hormonal options available for the treat-

ment and prevention of postmenopausal bone

loss are HRT, tibolone, and SERMs.

The efcacy of HRT in reducing the inci-

dence of both vertebral and nonvertebral frac-

tures has been conrmed for almost 20 years.

The analysis of the intervention and postinter-

vention phases of large clinical trials showed a

different benet to risk prole when we compare

the data of estrogen plus progestin to estro-

gen-alone treated subjects.

23,24

These two hor-

monal treatments granted similar protection

from fractures and similar improvement in BMD

between them when compared to placebo, with a

better safety prole in women with prior hyster-

ectomy receiving the estrogen-alone treatment

both during the pharmacological intervention

and in the posttreatment follow-up period.

Furthermore, the breast cancer and cardiovas-

cular (CV) disease ndings tended to be worse in

the arm treated with the estrogen-progestin

combination, while no difference was found

between the placebo arm and the patients treated

with estrogen alone.

Tibolone, after oral ingestion, is metabolized

into three active molecules: two with estrogenic

action and one with androgen and progestin

activities.

Tibolone was shown to be as effective

as an estrogen–progestin combination treatment

in preventing postmenopausal bone loss and it

can also increase muscle strength and lean body

mass due to its androgen action.

Similar to

HRT, tibolone is recommended only in subjects

under 60 years of age, because the study that

involved older women (age range 60–80 years)

was prematurely stopped due to the evidence of

an increased risk of stroke in the treated arm.

Selective estrogen receptor modulators

(SERMs) are compounds with estrogen agonistic

activities on some tissues (i.e., on bone) and antag-

onistic actions on other tissues (i.e., on breast and

uterus), based on their different effects over differ-

ent estrogen receptors subtypes whose distribu-

tion is specic for each target tissue.

At present,

raloxifene (RLX), bazedoxifene (BZA) and laso-

foxifene (LSX) are the SERMs with documented

evidence of efcacy for postmenopausal osteopo-

rosis.

15,28

They prevent bone loss and reduce the

incidence of vertebral osteoporotic fractures in

postmenopausal women.

15,28

To date, RLX has not been demonstrated to

reduce the risk of hip fractures at currently

approved doses, while BZA (20 mg/die), in a post

hoc analysis on a subgroup at high fracture risk,

succeeded in reducing the risk of nonvertebral

fracture both versus placebo and versus RLX (60

mg/die).

The post hoc nature of this analysis

called for caution in the interpretation of the

results until the publication of the 2-years exten-

sion of the same study.

At its conclusion, the

trial conrmed the protective effect of BZA on

new vertebral fractures in postmenopausal

women with osteoporosis and on nonvertebral

fractures in the high-risk subgroup.

In addition,

two meta-analyses performed an indirect com-

parison of the protective effect of BZA versus

oral bisphosphonates (BPs) and estimated a

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similar efcacy on vertebral fractures and, in the

subgroup at higher fracture risk, also on nonver-

tebral events.

31,32

LSX has been approved in Europe for the

treatment of postmenopausal osteoporosis after

a 5-year placebo-controlled randomized clinical

trial (RCT) showed its efcacy in decreasing the

risk of both new vertebral and nonvertebral frac-

tures (but not hip fractures).

Similar to HRT, SERMs can increase the risk

of venous thromboembolism (primarily deep

vein thromboses), but, differently from HRT, due

to their antagonist activity on the breast, SERMs

may decrease the risk of breast cancer.

This was

shown to be true particularly for RLX, which in

the United States is also approved for the preven-

tion of breast cancer.

28,34

No effect on endome-

trial proliferation is reported with RLX and BZA,

whereas an increase of endometrial thickness,

although without a real clinical signicance, is

associated with LSX.

In our opinion, SERMs are preferable to HRT

due to their better safety prole in the long-term

and can be considered a viable second-line treat-

ment for patients AEs related to oral BPs, particu-

larly for women under 65 years of age at risk for

vertebral fractures and at some risk for breast

cancer.

SERMs represent also a possible rst-line

therapy after menopause for younger subjects

who are expected to receive treatment for many

years. Unfortunately, this opportunity is often

difcult to seize, because hot ushes are a com-

mon AE of these drugs, especially in younger

postmenopausal women within the rst year of

treatment.

For this reason, SERMs are not rec-

ommended in women with vasomotor symptoms

and HRT is preferable instead.

The observation that SERMs (particularly

BZA) inhibit the effects of conjugated estrogens in

the uterus and mammary glands has opened the

way to a new strategy for the prevention of sys-

temic bone loss and the treatment of climacteric

symptoms: the SERM-estrogen combination, now

dened “tissue selective estrogen complex”

(TSEC).

15,28

This strategy is noteworthy because

the addition of SERMs makes the progestin

unnecessary. Therefore, TSEC merges the positive

clinical effects of estrogens alone (as already seen,

they do not increase the risk of breast cancer),

with the efcacy and improved tolerability of

SERMs that antagonize their endometrial effects.

Presently, the combination of BZA (20 mg/day)

with conjugated estrogens (0.45 mg/day) is the

only one approved in the class of TSEC. The posi-

tive clinical outcomes of large RCTs support the

use of this combination therapy that can decrease

the frequency and severity of hot ushes, improve

symptoms of vulvar and vaginal atrophy and pre-

vent bone mass loss, independently of the number

of years from menopause.

15,34

Bisphosphonates

BPs are the most widely used drugs for the pre-

vention and treatment of all kinds of osteoporo-

sis. They are approved, in both males and females,

also for the treatment of glucocorticoid-induced

osteoporosis (GIOP) and of antihormonal thera-

py-associated bone disease (i.e., androgen depri-

vation therapy and treatment with aromatase

inhibitors).

33,35

These compounds have been used

for more than 25 years and several millions of

patients have been treated with BPs, and their

excellent safety prole is now well established.

2,33,36

It is therefore quite unlikely that new unexpected

side effects may be discovered in the future.

BPs are a large family of stable analogs of

pyrophosphate with a strong afnity for bone

apatite. BPs reduce the recruitment and activity

of mature osteoclasts and increase their apopto-

sis. Consequently, they act as potent inhibitors of

bone resorption and this is the rationale of their

use in postmenopausal osteoporosis.

2,33,36

Several BPs have been approved for the treat-

ment of osteoporosis, such as alendronate (ALN),

risedronate (RIS), ibandronate (IBA), and

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zoledronate (ZOL). All these drugs have shown not

only to increase BMD and bone strength but also

to be effective on a hard endpoint such as the reduc-

tion in the fracture incidence; indeed, their registra-

tion process was based on RCTs powered to detect

an effect on new vertebral fractures in patients with

moderate-to-severe osteoporosis.

2,33,36

Oral formulations are available for daily (ALN,

RIS), weekly (ALN, RIS), and monthly (IBA,

RIS) administration. Oral bioavailability of BPs is

very low, roughly 1% of the ingested dose, and it is

reduced by food (especially if rich in calcium). For

this reason, they must be ingested with plain water

on an empty stomach and after an overnight fast,

with a postdose fast of 30 to 60 minutes.

A more

recent (but still not widely available) delayed-re-

lease formulation of 35 mg risedronate (weekly

administration) can be taken before or immedi-

ately following breakfast, with a potential improve-

ment in adherence and persistence.

Two intravenous BPs have been licensed by the

European Medicines Agency for the treatment of

osteoporosis: IBA (administered every 3 months)

and ZOL (administered yearly). These options

are particularly interesting in subjects with AEs

related to oral BPs and in whom adherence to

chronic treatment might be an issue. To date,

comparative head-to-head RCTs with fracture

incidence as endpoint are not available, but if we

compare the results from each RCTs that investi-

gated each molecule, all compounds showed to

approximately halve the incidence of vertebral

fractures in patients affected by postmenopausal

osteoporosis.

On the contrary, the efcacy on nonvertebral

fractures, and particularly at the hip, differs con-

siderably across the various BPs.

However, this

observation can be largely explained from the dif-

ferent statistical power of the studies.

Regarding the better results obtained with i.v.

ZOL once yearly, they have been attributed to the

complete adherence of i.v. ZOL during the rst

year of treatment (100%) versus oral BPs

(<85%).

Despite these data, oral ALN and oral

RIS are still the most commonly prescribed BPs.

A large case-control analysis that involved more

than 90,000 patients, older than 80 years and with

previous history of fragility fractures, showed

that ALN signicantly reduces not only the hip

fracture risk (−34%) but also mortality (−12%).

Unfortunately, this treatment was also associ-

ated with a 58% increase in the risk of mild upper

gastrointestinal (GI) symptoms.

The GI side

effects are the most typical AEs associated with

oral BPs and may involve a large number of users

(about 25%).

However, of this 25%, less than 1%

require hospitalization due to GI bleeding.

Treatment with i.v. ZOL has also shown to

decrease mortality when given shortly after the

rst hip fracture

and, as expected, without GI

side effects. On the other hand, i.v. aminobis-

phosphonates (such as ZOL), in about 30% of

patients, can induce a transient acute phase reac-

tion characterized by ulike symptoms (fever,

myalgia, arthralgias, bone pain, headache, and

nausea). Usually, this undesired event occurs

within 24 hours after the rst drug administra-

tion and can be controlled by paracetamol or

nonsteroidal anti-inammatory and improves or

disappears within 3 days.

2,6

Major severe AEs with BPs are extremely rare.

Osteonecrosis of the jaw (ONJ) is a condition

characterized by long-lasting (>8 weeks) necrotic

exposed bone in the maxillofacial region associ-

ated with the use of antiresorptive drugs such as

BPs and denosumab (DMAb). ONJ has been

described in cancer patients receiving doses of

BPs (and DMAb) 10 times higher than subjects

with postmenopausal osteoporosis. Indeed, in

this latter scenario, ONJ is extremely rare (one

case every 100,000 patients/year) and its incidence

seems to be only slightly higher than the general

population.

2,6

BPs and DMAb have been associated also with

an increased risk of atypical femoral fractures.

Atypical femoral fractures are transverse or short

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cortical oblique fractures, occasionally associated

with periosteal thickening. However, this particu-

lar kind of fractures may also occur in treat-

ment-naïve subjects. The risk seems to rise with

the increase in the exposure to BPs (or DMAb)

and to decrease rapidly after its cessation.

2,6,33

In addition, atypical femoral fractures are

indistinguishable from those observed in patients

with other bone diseases characterized by bone

fragility, such as hypophosphatasia, osteopetro-

sis, or osteogenesis imperfect.

39,40

All these

remarks emphasize the key role of a correct diag-

nosis in each patient with bone fragility before

prescribing any pharmacological treatment and

they also suggest caution before considering a

longstanding antiresorptive treatment in patients

with baseline low-bone turnover states.

In any case, the incidence of atypical fractures

is extremely low (about 3–50 cases every 100,000

patients/year), and the excellent risk to benet

ratio of this drug class is out of the question.

Indeed, we need to consider the benet of the

treatment on the much more common typical hip

fractures:

for every 100 atypical fractures pre-

vented by BPs, an increase of one single atypical

fracture has been calculated.

Caution is advised also with patients at risk of

kidney impairment, given that high doses of BPs

administered over a short period of time could

induce or worsen renal failure. Because of the

very low bioavailability of oral BPs (less than

1%), the serum concentration is so low that renal

damage is an issue only for the i.v. formulation.

For this reason, i.v. BPs are contraindicated in

patients with creatinine clearance lower than 60

ml/min.

For safety concerns, however, in this

kind of patients also the oral formulations should

be prescribed very carefully.

A possible association between BPs therapy

(especially i.v. ZOL) and atrial brillation has been

reported, but subsequent studies have produced

conicting results. Presently, the possibility of this

association cannot be completely excluded.

Clodronate is a relatively weak BP, widely avail-

able for the treatment of neoplastic bone disease

and licensed for the use in osteoporosis in only a few

countries.

The data about osteoporosis are not

conclusive, and the evidence of its efcacy is weaker

than the other BPs previously discussed.

Two

RCTs showed the efcacy of 800 mg daily oral clo-

dronate in both increasing BMD and reducing the

incidence of vertebral fractures in women with

senile, postmenopausal, or secondary osteoporo-

sis.

44,45

In Italy, intramuscular clodronate is regis-

tered for postmenopausal osteoporosis and GIOP

on the basis of few low-quality studies.

46–48

Clodronate is usually prescribed in subjects at

low fracture risk or when all the other treatments

cannot be used. In conclusion, clodronate, espe-

cially when administered intramuscularly, should

not be currently considered a real option for oste-

oporosis treatment.

Denosumab

Like BPs, DMAb belongs to the antiresorptive

drugs class (Table 1). DMAb is a fully humanized

monoclonal antibody that neutralizes RANKL sig-

naling by interfering with its interaction with its

receptor located on the membrane of preosteoclasts

and mature osteoclasts (RANK). In this way, it

impairs the recruitment, maturation, and survival

of osteoclasts and leads to a stronger inhibition of

bone resorption than BPs.

Its potency and activity

at the cortical bone explain why DMAb is able to

induce greater increases in BMD than BPs both at

trabecular sites (i.e., at lumbar spine) and at cortical

ones (i.e., hip and radius).

The drug is adminis-

tered subcutaneously every 6 months at a dose of 60

mg. DMAb is not cleared by kidneys and therefore

it can be used also in patients with renal failure.

DMAb is also approved for treatment in males, in

GIOP and antihormonal therapy-associated bone

disease.

33,35

Long-term treatment determines sustained

increases in BMD (both at the spine and at

thehip), without any plateauing after 4 years of

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treatment, as commonly seen with BPs. This fea-

ture could be a consequence of a greater activity

on cortical bone and/or of its unique effects on

Wnt inhibitors and in particular on Dkk-1.

In postmenopausal osteoporosis, over 3 years of

therapy, DMAb reduced the incidence of vertebral

fractures (−68%), hip fractures (−40%), and non-

vertebral fractures (−20%), without signicant

adverse events.

2,33

The yearly incidence of new frac-

tures (both vertebral and nonvertebral) remained

low also during the long extension trial that involved

a subgroup of women treated for further 7 years.

Due to its mechanism of action, discontinua-

tion of DMAb therapy is associated with a rapid

offset of action as soon as the drug is cleared

from the plasma.

For this reason, the positive

effects of DMAb on BMD are quickly reversible

after its discontinuation, with a return to pre-

treatment values within 12 to 18 months, inde-

pendently of the treatment duration, while bone

turnover markers increase above pretreatment

levels and then return to baseline values within 1

to 2 years after its discontinuation.

Recently, RANKL serum levels have been shown

to progressively increase after suspension of long-

term DMAb treatment, and this observation may

support the hypothesis of a sudden loss-of- inhibition

of the resting osteoclast line after DMAb clearance.

This rebound effect is associated with an increase in

fracture risk of vertebral fractures, while no increase

in nonvertebral fracture has been reported to date.

Therefore, in case of DMAb discontinuation, the

initiation of a different antiresorptive treatment

(such as BPs) should be considered to prevent, or at

least limit, this rapid bone loss.

DMAb is well tolerated. Few cases of ONJ

and atypical femoral fractures have been reported

to date and the same considerations already dis-

cussed for BPs apply.

Teriparatide

Currently, teriparatide (TPD) is the sole anabolic

drug available for the treatment of osteoporosis

inEurope. TPD is the active 1–34 N-terminal frag-

ment of parathyroid hormone (PTH) and its daily

subcutaneous administration produces anabolic

effects on the bone tissue. This occurs in contrast

with the well-known bone catabolic consequences

of chronic overproduction of PTH. As known, pri-

mary hyperparathyroidism is characterized predom-

inantly by the overstimulation of osteoclast’s

activity, while daily (pulsatile) pharmacological

PTH administration determines the predominance

of bone formation over bone resorption due to a

direct action on osteoblasts.

Treatment with TPD

has been shown to reduce signicantly the risk of

vertebral and nonvertebral fractures and its use is

strongly recommended in high-risk subjects and in

patients with previous history of vertebral fractures.

The data concerning TPD and GIOP are par-

ticularly intriguing. One clinical trial versus ALN

in patients treated with glucocorticoids showed

that TPD is more effective not only in improving

BMD but also in reducing the incidence of verte-

bral fractures.

These results support the prefer-

ential use of an anabolic agent over a traditional

antiresorptive drug in patients with GIOP. The

mechanistic explanation of the clinical evidence

may rely on the inhibitory effect of glucocorti-

coids on osteoblasts, a mechanism that, together

with the increase in bone resorption, explains their

severe negative effects on the quantity and quality

of bone.

In this setting, TPD should be consid-

ered the rst-line option for patients on long-term

glucocorticoid treatment with low BMD or with

previous history of osteoporotic fractures.

The duration of treatment with TDP is limited

to a maximum of 2 years and the decline of its

positive effects on bone formation (seen after 12

to 24 months) seems to be dependent on the reg-

ulation of the Wnt pathway and the overproduc-

tion of its inhibitor Dkk-1.

The most commonly reported AEs of TPD are

nausea, pain in limbs, dizziness, and headache.

addition, cases of moderate hypercalcemia and

hypercalciuria have been reported but they are

Pharmacological management of osteoporosis in postmenopausal women

J Popul Ther Clin Pharmacol Vol 26(4):e1–e17; 20 November 2019.

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usually asymptomatic and only rarely request the

cessation of the treatment.

Besides TPD, other peptides of the PTH family

are abaloparatide (currently still in development)

and the 1 to 84 intact molecule (whose marketing

authorization has not been conrmed).

Overall, all these agents are contraindicated in

severe kidney impairment and in all diseases

characterized by increased bone turnover and/or

hypercalcemia, such as primary hyperparathy-

roidism, Paget’s disease of bone, malignancies, or

bone metastasis.

Studies on rats chronically exposed to very

high doses of TPD have reported an increased

incidence of osteosarcoma. However, the analysis

of the pivotal clinical trial and the postmarketing

surveillance did not show any increased risk of

osteosarcoma with the doses of TPD presently

used in humans (which are much smaller by rela-

tive comparison).

2,6

Unfortunately, despite these

safety data, the TPD Summary of Product still

includes a warning for physicians and patients

about this unproven complication.

Romosozumab

Romosozumab (RMZ) is a humanized mono-

clonal antibody that acts by blocking sclerostin, a

molecule almost exclusively expressed by osteo-

cytes and one of the main inhibitors of the Wnt

canonical pathway.

As known, this pathway plays a key role in

bone metabolism. On one hand, it promotes

osteoblastogenesis and directly contributes to the

differentiation, proliferation, and survival of

osteoblasts.

On the other, it enhances the expres-

sion of OPG by indirectly inhibiting osteo-

clast-mediated bone resorption.

Therefore,

sclerostin is an important negative regulator of

bone formation with a potential key role in the

pathogenesis of disuse osteoporosis.

In addition

to its antianabolic role, it enhances the catabolic

activity on the bone tissue through the up-regula-

tion of RANKL expression.

For all these reasons, RMZ represents the rst

true dual-action agent: it increases osteoblastic

bone formation by enhancing Wnt canonical sig-

naling and reduces osteoclastic bone resorption

by unbalancing the OPG/RANKL ratio (in favor

of OPG).

The dual action of RMZ was already remark-

able in the phase I study, in which it showed an

impressive (dose-dependent) increase in the

markers of bone formation (+70 to 140%),

simultaneous with a less considerable, but statis-

tically signicant, dose-dependent decrease in

the markers of bone resorption (−15 to −50%).

This interesting dual activity can explain the

extraordinary effects on BMD that overtake

what seen with any other osteoporosis treat-

ment, TPD included.

The unique metabolic effect of long-term RMZ

treatment is limited to the rst 12 months of

therapy. Markers of bone formation increase

immediately after the rst RMZ injection and

reach their peak after the rst month. Thereafter,

they decrease and return to baseline within

9months and they eventually reach values signi-

cantly lower than baseline after the 12th month.

Interestingly, during the second year of RMZ,

the serum levels of both bone formation and

bone resorption markers remained below their

baseline.

This may suggest that, within the rst

year of treatment, RMZ acts as a true dual- action

drug, but later on it probably works just as a bone

turnover inhibitor, without any further anabolic

action.

Notably, the BMD gain, which is outstanding

in the rst year of treatment, is less relevant

during the second year of RMZ. An increase in

BMD similar to the rst year of treatment has

been shown only in the subgroup of women who

were then randomized to receive DMAb for an

additional year.

For these reasons, the phase III trial (FRAME

trial) investigated the effects of subcutaneous

monthly injections of RMZ for 12 months versus

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placebo, followed by treatment with DMAb

(administered in both arms).

The effects on

fracture incidence within these 12 months were

remarkable: the incidence of vertebral fractures

was reduced by 73% and of clinical fractures by

36%. At 24 months, after the switch to DMAb,

the incidence of new vertebral fractures remained

signicantly lower in the RMZ group (−75%).

AEs incidence was balanced between the

groups. In the RMZ group, a single atypical fem-

oral fracture and two cases of ONJ were reported

among the 3,500 treated subjects.

After the publication of the results of the RCT

comparing RMZ and ALN (ARCH trial), con-

cerns were raised about a possible increased CV

risk associated with the use of RMZ.

The inci-

dence of severe CV events resulted higher in the

RMZ group versus the ALN group, despite a

similar CV risk at baseline.

It should be noted,

however, that RMZ was not associated with any

increase of the CV risk in the previous and larger

FRAME trial,

in which RMZ was compared

with placebo. Indeed, the increase in CV events in

the RMZ group might be explained by the pro-

tective CV effects of ALN (and of amino-BPs in

general), as already reported several times.

60–62

Strontium ranelate

Strontium ranelate (SrR) is an oral medication

that has been approved in Europe for the treatment

of postmenopausal osteoporotic women.

Its

mechanism of action is still not completely under-

stood, but the RCTs showed its efcacy in reducing

the risk of vertebral and nonvertebral fractures

respectively after 3 and 5 years of treatment.

A consistent increase in the risk of venous

thromboembolism has been documented in the

registration trials and, during the postmarketing

surveillance, rare but severe dermatological reac-

tions were also reported, with consequent limita-

tions to its clinical use.

During the long-term

postapproval surveillance safety analyses, the

increased risk of pulmonary embolism and

myocardial infarction was conrmed and thus, in

2014, the EMA restricted its use to patients

affected by severe osteoporosis who cannot be

treated with different medications and in whom

the risk of fracture overwhelmingly exceeds the

CV risk.

Treatment discontinuation

BPs, in particular ALN and ZOL, are the drugs

with the most persistent “tail effect” concerning

bone turnover after their discontinuation.

Their

antifracture efcacy is only partially lost after

treatment discontinuation for several months.

Unfortunately, the impact of the discontinuation

of the other drug classes is very different.

After suspension of hormonal therapy, bone

turnover and bone loss return to pretreatment

levels within few weeks. Therefore, reassessment

of fracture risk and of the opportunity of resum-

ing treatment itself is strongly warranted.

TPD is strongly recommended in severe osteo-

porosis, but the regulatory authorities limited the

treatment duration to a maximum of 2 years.

There is now a very large agreement about the

absolute need for the start of an antiresorptive

agent soon after the conclusion of the TPD treat-

ment cycle to avoid the quick rebound on BMD.

Sequential administration of ALN, ZOL, or

DMAb after TPD have been associated to further

BMD gains; however, the effects on fracture risk

reduction are to date still speculative.

In patients treated with DMAb, its discontinu-

ation is followed by an overshoot in bone turn-

over, with accelerated bone loss and increased

fracture risk.

The best exit strategy to adopt after

DMAb discontinuation is still unclear and large

randomized and active-controlled trials are war-

ranted to investigate this key topic. Presently, BPs

are recommended by most experts as the prefera-

ble choice to prevent or at least limit the rebound

effects of DMAb discontinuation.

As already discussed, RMZ has a peculiar mech-

anism of action and combines the stimulation of

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bone formation with the inhibition of bone resorp-

tion. Unfortunately, the benets in terms of BMD

are lost after its discontinuation.

Hence, sequential

treatment with antiresorptives is required, as it was

scheduled in its RCTs.

58,59

Sequential erapy

In these last decades, the number of drugs

available for the treatment of osteoporosis has

grown exponentially. The development of novel

and more potent antiresorptives (such as DMAb

and ZOL), bone anabolic agents (such as TPD),

and antisclerostin antibody (such as RMZ) deter-

mined a substantial growth in the eld. As already

discussed, the discontinuation of many of these

therapies (DMAb, TPD, and RMZ) requires the

initiation of another treatment in order to avoid

the loss of the BMD gains. Furthermore, a treat-

ment switch might need to be recommended also

in patients who experience a new fragility fracture

despite already being on osteoporosis medica-

tions, or in case of tolerability or adherence issues.

The different mechanisms of action of osteo-

porosis drugs strongly inuence the cumulative

effects of the possible sequential and/or combina-

tion approaches and should guide the physician

to the choice of the correct treatment.

Hereby we will briey discuss the different

opportunities presently available for sequential

therapy:

Antiresorptive agents aer antiresorptive agents

Sequential treatment with different antire-

sorptive agents might be required when:

• a patient discontinues DMAb and there is the

necessity to limit the rebound effect

• poor compliance with ongoing oral BP therapy

• occurrence of a new fragility fracture during

treatment with oral BPs.

As already mentioned, to prevent or at least

limit the rebound effect of DMAb discontinua-

tion, BPs are presently considered the best choice.

Injectable treatments such as DMAb and

ZOL may solve GI issues associated with oral

BPs and may also improve the adherence to the

treatment with their more deferred administra-

tion schedule.

In the case of new fractures occurring during

treatment with oral BPs, ZOL might represent a

possible choice, given its 100% adherence on the

rst year of therapy. DMAb might be considered

as well due to its stronger inhibition of bone turn-

over and the greater BMD increases at all skeletal

sites, even when compared to ZOL.

Antiresorptive agents aer agents with

anaboliceects

In patients with high fracture risk, the use of

anabolic drugs seems the most appropriate for its

quick reduction.

As already discussed, treatment with drugs

characterized by anabolic effects is limited to 12

(RMZ) or 24 months (TPD), and their benets

can be preserved only through the initiation

antiresorptive agents as soon as possible after

their discontinuation.

Therefore, prompt treat-

ment with antiresorptives after bone anabolic

agents is recommended.

Anabolic agents aer antiresorptive agents

The choice of an anabolic agent as the rst-line

therapy is not often possible due to its high cost, but

it is recommended in patients who experience a new

fragility fracture despite BPs therapy. Unfortunately,

there is some evidence suggesting that the effective-

ness of anabolic medications might be impaired

when started after prolonged exposure to antire-

sorptive drugs.

Indeed, when patients on long-

term potent antiresorptive treatments are switched

to TPD, hip BMD tends to decline for at least 12

months, especially when the antiresorptive is

DMAb.

Therefore, the switch from antiresorptive

drugs to an anabolic agent, a quite common sce-

nario in clinical practice, is not currently supported

by much evidence. How can we manage these

patients? Combination therapy might be an answer.

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Combination erapy

The dual action of RMZ demonstrates the

effectiveness of the association of strong stimula-

tion on bone formation with powerful inhibition

on bone resorption. Currently, no other drug

administered alone can act in this manner, but a

similar therapeutic framework could be obtained

by combining two different treatments and there is

evidence to support this possibility. An interesting

comparison between patents who switched from

ALN to TPD versus those who added TPD to

ongoing ALN, showed a greater benet of combi-

nation therapy on BMD and strength at the hip.

Another small study compared the changes of

bone turnover markers in patients treated with

DMAb versus TPD versus a third therapeutic

scheme: TPD added to ongoing DMAb (TPD

was started 3 months after DMAb).

The results

showed that the effects of TPD on bone turnover

markers were not blunted by prior and concur-

rent DMAb administration. In the combination

arm of the study, the increase in markers of bone

formation was observed quite earlier than the

increase in the ones of bone resorption.

This

remark supported the hypothesis of a consequent

wider anabolic window of the concurrent treat-

ment than TPD alone.

The favorable metabolic prole of the combi-

nation therapy (DMAb plus TPD) found conr-

mation in the DATA-Switch study.

This study

compared the effects on BMD of three different

therapeutic schemes: DMAb administered after

TPD, TPD after DMAb, and the combination

of the two medications given concurrently for

2years, followed by DMAb alone.

The results

conrmed that TPD to DMAb sequential ther-

apy is signicantly superior than DMAb to TPD.

At the end of the study, the TPD to DMAb arm

achieved similar BMD benets at the lumbar

spine compared to TPD plus DMAb combina-

tion therapy, but the latter reached the BMD

peak 12 months earlier than sequential treatment.

Besides, if we consider the BMD gains at total

hip, the combination arm showed the greatest

benets overall.

Obviously, these results regard only BMD

measurements and currently there is no data on

fracture incidence. However, it is noteworthy that

maximum BMD effects can be reached with an

anabolic agent (such as TPD or RMZ) followed

by an antiresorptive and that the combined

DMAb plus TPD regimen seems to provide the

greatest skeletal benets to patients with estab-

lished osteoporosis.

Like RMZ, combination

therapy of DMAb plus TPD should be consid-

ered for patients with severe osteoporosis who are

at the highest risk of imminent fragility fracture.

NEW DIRECTIONS FOR FUTURE STUDIES

Our recent improvements in the knowledge of

the RANK/RANKL/OPG and the Wnt/beta-cat-

enin pathways have led us to the development of

DMAb and RMZ.

In our opinion, RMZ represents a new era

and, as previously discussed, it is likely to open a

new scenario in the management of the imminent

fracture risk, a concept that could be considered

born and raised with RMZ itself. It cannot be

excluded that further biotechnological agents

interfering with the inhibitors of the Wnt/

beta-catenin pathway (i.e., Dkk-1) will be devel-

oped in the future. However, preclinical studies

evaluating the effects of monoclonal antibodies

to Dkk-1 as potential treatment for osteoporosis

have not shown encouraging results to date.

Other possible approaches in the future might

include stem cells transplantation, antisenescence

agents, and drugs that target specic osteoblast

pathway but, unfortunately, the relating research

is still in its very early stages.

In our opinion, the low costs and the good

effectiveness of many currently available thera-

pies (i.e., BPs) will not encourage large investment

in the eld of osteoporosis. For this reason, the

drugs that are going to be developed in the future

will be likely limited to a small proportion of

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patients affected by the most severe form of

osteoporosis.

On the contrary, we hope that the reduction in

the costs of TPD (due to the expiration of its pat-

ent) is going to encourage clinicians to prescribe

both the sequential and the combined approach.

CONCLUSION

Several pharmacological treatments are avail-

able for osteoporosis. The challenge is to identify

the optimal treatment for each patient. Indeed,

all the different drugs have specic features that

make them more or less preferable for each

patient. A possible owchart based on the opin-

ion of the authors is presented in Table 2.

Hormonal therapy is particularly indicated in

women younger than 60 years old, within 10 years

from their last menses, at risk for osteoporosis

and without known risk factors for thromboem-

bolism. In the presence of symptoms of meno-

pause (hot ushes, vulvar and vaginal atrophy,

etc.), HRT and TSEC are preferable. For protec-

tion from breast cancer risk, SERMs (RLX in

particular) are more indicated.

Bisphosphonates (BPs). Oral BPs are widely

available and should be considered the rst-line

treatment for most patients with mild to moder-

ate osteoporosis. ZOL is the rst choice in

patients with intolerance to oral formulations or

when they are contraindicated. ZOL, due to its

yearly regimen and the long-tail effect can be

also useful in patients with adherence issues.

ZOL is contraindicated in patients with impaired

kidney function.

Denosumab (DMAb) is preferable in patients

who do not tolerate oral BPs or when they are

contraindicated. As a side note, DMAb is not

contraindicated in the presence impaired kidney

function. DMAb can be also considered in

patients incurring a new fragility fracture while

already on treatment with BPs due to its stronger

inhibition of bone turnover.

TABLE 2 Proposed Flowchart for Treatment Selection in Postmenopausal Osteoporosis

1. Primary prevention of fractures in osteoporotic postmenopausal women

• Women, 50–60 years old, without risk factors for thromboembolism

 First choice: hormonal therapy

 Second choice: oral bisphosphonates

• Women over 60 years old, or with risk factors for thromboembolism, or unwilling to begin hormonal

treatment

 First choice: oral bisphosphonates

 Second choice: (i.e., in case of low compliance or tolerability of oral bisphosphonates) intravenous

bisphosphonates or denosumab

2. Secondary prevention of fractures in postmenopausal women

• Women with a single osteoporotic vertebral or nonhip fracture

 First choice: oral bisphosphonates

 Second choice: (i.e., in case of low compliance or tolerability of oral bisphosphonates) intravenous

bisphosphonates or denosumab

• Women with a more than one osteoporotic vertebral or previous hip fracture

 First choice: teriparatide

 Second choice: denosumab or bisphosphonates

3. Patients with severe osteoporosis who experienced a new vertebral fracture during treatment with

bisphosphonates

• First choice: add a treatment with teriparatide or start romosozumab

 Second choice: denosumab or intravenous bisphosphonates (in patients previously treated with oral

bisphosphonates)

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Teriparatide (TPD) is strongly recommended

in severe osteoporosis, especially in the presence

of history of vertebral fractures and for the man-

agement of GIOP. Its use is limited to 24 months

of therapy and its benets are maintained only if

followed by an antiresorptive agent. Therefore,

prompt treatment with these agents is recom-

mended after TPD discontinuation.

Romosozumab (RMZ) represents the rst true

dual-action drug. Its unique metabolic effect is

limited to the rst 12 months of therapy and after

that a sequential treatment with antiresorptive

agents is needed. The BMD effects of RMZ are

superior to any other osteoporosis treatment

already in the rst few months of therapy, with an

impressive effect on fracture risk in the rst year.

For these reasons, it is recommended in patients

with severe osteoporosis at high risk for imminent

fragility fracture.

COMPLIANCE WITH ETHICAL STANDARDS

CONFLICT OF INTEREST

Davide Gatti reports personal fees from

Abiogen, Celgene, Eli-Lilly, Janssen, Pzer, UCB,

and BMS, outside the submitted work.

Angelo Fassio reports personal fees from

Abiogen and Novartis, outside the submitted work.

ETHICAL APPROVAL

is article does not contain any studies with

human participants or animals performed by

any of the authors.

INFORMED CONSENT

For this type of study, formal consent is not

required.

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