Received: 5 May 2019 Revised: 16 January 2020 Accepted: 31 January 2020

DOI: 10.1111/bph.15024

Themed Issue: The molecular pharmacology of bone and cancer-related bone diseases

REVIEW ARTICLE

Overview of treatment approaches to osteoporosis

Bente L. Langdahl

Endocrinology and Internal Medicine, Aarhus

University Hospital, Aarhus, Denmark
Correspondence
Bente L. Langdahl, Endocrinology and Internal
Medicine, Aarhus University Hospital, Palle
Juul Jensen Boulevard 99, DK-8200 Aarhus N,
Denmark.
Email: bente.langdahl@aarhus.rm.dk
Efficient therapies are available for the treatment of osteoporosis. Anti-resorptive
therapies, including bisphosphonates and denosumab, increase bone mineral density
(BMD) and reduce the risk of fractures by 20–70%. Bone-forming or dual-action
treatments stimulate bone formation and increase BMD more than the anti-
resorptive therapies. Two studies have demonstrated that these treatments are supe-
rior to anti-resorptives in preventing fractures in patients with severe osteoporosis.
Bone-forming or dual-action treatments should be followed by anti-resorptive treat-
ment to maintain the fracture risk reduction. The BMD gains seen with bone-forming
and dual-action treatments are greater in treatment-naïve patients compared to
patients pretreated with anti-resorptive treatments. However, the antifracture effi-
cacy seems to be preserved. Treatment failure will often lead to switch of treatment
from orally to parentally administrated anti-resorptives treatment or from anti-
resorptive to bone-forming or dual-action treatment. Osteoporosis is a chronic condi-
tion and therefore needs a long-term management plan with a personalized approach
to treatment.
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1 | I N T RO DU CT I O N Bone remodelling is the process by which the skeleton is renewed

Osteoporosis is a disease characterized by reduced bone mass, deteri-
orated bone microarchitecture and fragility fractures (Johnell
et al., 2005). Osteoporosis affects more than 200 million patients
worldwide (Strom et al., 2011). Osteoporotic fractures are associated
with reduced quality of life, increased morbidity, and in the case of
spine, pelvic and hip fractures increased mortality (Kado et al., 1999;
Kannegaard, van der Mark, Eiken, & Abrahamsen, 2010; Marrinan,
Pearce, Jiang, Waters, & Shanshal, 2015).
and repaired. It is a co-ordinated process in which osteoclasts resorb
old bone and then stimulate osteoblasts to produce collagen and form
new bone. During remodelling, the activity of osteoclasts and osteo-
blasts is coupled with respect to location and time (Eriksen, 1986).
Bone modelling, however, takes place primarily during skeletal devel-
opment and growth but continues to a smaller extent into adulthood
and is responsible for the periosteal expansion of bone during aging.
During modelling lining cells on quiescent surfaces, cortical as well as
trabecular, are transformed into osteoblasts, however the activity of

Abbreviations: ACTIVE, Abaloparatide Comparator Trial In Vertebral Endpoints; AFF, atypical femoral fracture; ARCH, Active-Controlled Fracture Study in Postmenopausal Women With
Osteoporosis at High Risk; BMD, bone mineral density; DATA, Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis; FLEX, Fracture Intervention Trial
Long-term Extension; FRAME, FRActure study in postmenopausal woMen with ostEoporosis; HORIZON, Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal
Fracture Trial; ONJ, osteonecrosis of the jaw; PTH, parathyroid hormone; PTH1R, parathyroid hormone receptor 1; PTHrP, parathyroid hormone-related peptide; RANKL, receptor activator of
nuclear factor κ-B ligand; SERM, selective oestrogen receptor modulator; STRUCTURE, An Open-label Study to Evaluate the Effect of Treatment With Romosozumab or Teriparatide in
Postmenopausal Women; VERO, Effects of teriparatide and risedronate on new fractures in postmenopausal women with severe osteoporosis; Wnt, wingless/integrated.

Br J Pharmacol. 2021;178:1891–1906. wileyonlinelibrary.com/journal/bph © 2020 The British Pharmacological Society 1891


1892
osteoclasts and osteoblasts is not necessarily coupled. Thus, bone
formation can be either modelling based or remodelling based
(B. Langdahl, Ferrari, & Dempster, 2016).
Osteoporotic fractures can be prevented by pharmacological
treatment. The current available osteoporosis treatments are anti-
resorptive (inhibiting the osteoclasts), bone forming (stimulating the
osteoblasts) or dual acting (simultaneously stimulating the osteoblasts
and inhibiting the osteoclasts) (B. L. Langdahl & Harslof, 2011). The
anti-resorptive treatments are bisphosphonates, receptor activator of
nuclear factor κ-B ligand (RANKL) antibody and selective oestrogen
receptor modulators (SERMs) that either cause osteoclast apoptosis
(bisphosphonates) or inhibit osteoclast recruitment (RANKL antibody
and selective oestrogen receptor modulators). Teriparatide (parathy-
roid hormone [PTH], amino acids 1–34) and abaloparatide are bone-
forming treatments of which abaloparatide currently is only available
in the United States (B. L. Langdahl & Harslof, 2011). Romosozumab
is a dual-acting treatment that at the same time stimulates bone for-
mation and inhibits bone resorption (Figure 1).
The anti-resorptive and bone-forming treatments have one
important feature in common; bone resorption and formation as part
of bone remodelling remain coupled (B. Langdahl et al., 2016). This is
from a pharmacological and clinical point of view not optimal. The
anti-resorptive treatments can only increase bone mineral density
(BMD) to a certain extent as the decrease in osteoclast number and
release of substances from the bone matrix subsequently impair the
recruitment of osteoblasts and de novo synthesis of new bone by the
F I G U R E 1 Bone remodelling and the effect of the different treatments. Schematic presentation of the different phases of bone remodelling
and how the different treatments affect bone remodelling
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LANGDAHL
osteoblasts. The bone mineral density increase seen with anti-
resorptive treatments is therefore caused by a filling of the
remodelling space followed by increased mineralization of the bone
tissue as this is not remodelled as frequently as before initiation of
the treatment. The bone architecture will not generally be improved,
but cortical bone volume and bone strength as estimated by QCT are
improved with zoledronate and denosumab (Eastell et al., 2010;
Genant et al., 2013). Therefore, if the patient initially had very low
bone mass, anti-resorptive treatments will not be able to improve
bone mineral density enough to optimally prevent future fractures.
The bone-forming treatments stimulate osteoblasts, and this leads to
a positive remodelling balance. The osteoclasts are subsequently stim-
ulated which limits the effect of the treatment. In addition, the
response of the osteoblasts to continued stimulation levels off with
time. Therefore, some patients with very low bone mass or suboptimal
response to bone-forming treatment still have very low bone mineral
density after treatment. Only a few studies have examined if the
coupling of bone resorption and formation can be overcome by com-
bining the therapies. The dual-acting treatment, romosozumab, effec-
tively uncouples bone resorption and bone formation. The remaining
challenge is that although the inhibition of bone resorption remains
throughout the treatment period, the stimulation of bone formation
wears off despite continued treatment.
The current review will focus on the osteoporosis treatments
available and how optimized use of these treatments may help over-
come the currently unmet needs in the treatment of osteoporosis.

LANGDAHL
2 | A N T I - RE S O RP T I V E TH E R A P I E S
2.1 | Bisphosphonates
Alendronate, risedronate, ibandronate (ibandronic acid) and
zoledronate (zoledronic acid), the most commonly used
bisphosphonates, are all nitrogen-containing bisphosphonates that
primarily affect osteoclast survival and activity by inhibiting the
mevalonate pathway (Russell, 2011). The bisphosphonates have
similarities to pyrophosphate and therefore the ability to attach to
bone. Administration of bisphosphonates will therefore lead to
accumulation of bisphosphonates in bone, which is the reason why
bisphosphonates can be administrated at weekly, monthly, yearly or
perhaps even longer intervals (I. R. Reid et al., 2018) and still suppress
bone turnover, and why discontinuation of treatment can be appropri-
ate in some patients.
Treatment with bisphosphonates decreases bone resorption by
up to 70% depending on the specific bisphosphonate and bone forma-
tion is subsequently decreased (Black et al., 1996; Black et al., 2007;
Black et al., 2000; Chesnut et al., 2004; Cummings et al., 1998; Eisman
et al., 2008; Harris et al., 1999; McCLung et al., 2001; J. Reginster
et al., 2000; J. Y. Reginster et al., 2006). This leads to increases in bone
mineral density at the spine and the hip during the first 3–4 years of
treatment. Thereafter, the bone mineral density increase is maintained
but does not increase further. The reduction in bone turnover and
increase in bone mineral density lead to clinically relevant reductions
in fracture risk. A recent network meta-analysis found that treatment
of women with primary osteoporosis for 2 to 3 years with
alendronate, risedronate, ibandronate, and zoledronate resulted in
reductions in the risk of vertebral fractures by 43%, 39%, 33% and
62%, respectively. The reductions in the risks of non-vertebral and hip
fractures after 3 years of treatment with alendronate, risedronate, and
zoledronate were 16%, 22%, and 21% and 39%, 27% and 40%,
respectively (Barrionuevo et al., 2019). No significant reductions in
non-vertebral or hip fractures were seen with ibandronate. A recent
meta-analysis of phase 3 clinical trials has demonstrated that the most
important predictor of fracture risk reduction on treatment is the
increase in bone mineral density (Foundation for the National Insti-
tutes of Health Bone Quality Project; Bouxsein et al., 2019).
Smaller studies of the effects of alendronate, risedronate and
zoledronate have been conducted in men with osteoporosis. The
studies were not powered to investigate the effect on fracture risk
reduction with the exception of the study of zoledronate. The studies
showed generally similar improvements in bone mineral density in
men as were seen in postmenopausal women (Boonen et al., 2012;
E. Orwoll et al., 2000; Ringe, Farahmand, Faber, & Dorst, 2009). In
addition, zoledronate reduced the risk of vertebral fractures in men
with osteoporosis by 67% (Boonen et al., 2012).
The effects of alendronate, risedronate, ibandronate and
zoledronate have also been investigated in patients with glucocorticoid-
induced osteoporosis. The antifracture efficacy of alendronate and
risedronate was investigated compared to placebo and both treatments
were demonstrated to improve bone mineral density and prevent
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1893
vertebral fractures (Adachi et al., 2001; D. M. Reid et al., 2000).
Ibandronate was investigated in comparison with alfacalcidol and was
found to improve bone mineral density and prevent vertebral fractures
compared to alfacalcidol (Ringe, Dorst, Faber, Ibach, & Sorenson, 2003).
Finally, the efficacy of zoledronate in patients with glucocorticoid-
induced osteoporosis was investigated with risedronate as the compara-
tor. Zoledronate improved bone mineral density significantly more than
risedronate (D. M. Reid et al., 2009). The study was not powered to
investigate differences in fracture prevention.
The long-term effects of bisphosphonates have predominantly
been investigated in the extensions of the pivotal fracture prevention
studies of alendronate and zoledronate. The fracture prevention study
of alendronate, the Fracture Intervention Trial study (Black
et al., 2000), was extended into the Fracture Intervention Trial Long-
term Extension (FLEX) trial (Black et al., 2006). The fracture preven-
tion study of zoledronate, the Health Outcomes and Reduced
Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial
(HORIZON) study (Black et al., 2007), was extended into the
HORIZON Extension trial (Black et al., 2012). In both extension
studies, the participants were randomized to continue or discontinue
bisphosphonate treatment. The extension studies included relatively
few patients, and therefore, the statistical power to detect differences
in fractures, especially non-vertebral fractures, was limited. There is
no evidence of treatment effects of bisphosphonates or any other
anti-osteoporosis treatment beyond 10 years from clinical trials.
The FLEX study demonstrated that continuing alendronate for
10 years led to a continuing increase in lumbar spine bone mineral
density and a stabilization of bone mineral density at the hip com-
pared to a stabilization of bone mineral density at the lumbar spine
and decreasing hip bone mineral density in the women who discon-
tinued alendronate after 5 years. The incidence of non-vertebral frac-
tures was similar between the two groups. However, the incidence of
clinical vertebral fractures was higher in the women who stopped
alendronate compared to the women continuing (Black et al., 2006).
Similarly, the HORIZON Extension study showed that bone min-
eral density of the spine continued to increase whereas bone mineral
density of the hip remained stable in women continuing treatment
with zoledronate for 6 years. In women stopping treatment after
3 years, bone mineral density at the spine was stable, but hip bone
mineral density decreased towards baseline. The incidence of non-
vertebral fractures was similar during years 4 to 6 in women continu-
ing and discontinuing treatment with zoledronate, but the incidence
of morphometric vertebral fractures was higher among the women
who stopped treatment (Black et al., 2012).
Both studies showed that the bone mineral density remains
stable at the hip sites after a few years of treatment but seems to
continue to increase at the spine when treatment is continued. It
has been speculated that the latter is caused by other factors such
as degenerative changes, osteoarthritis and calcification of aorta
(Franck, Munz, & Scherrer, 1995). As these age-related changes do
not affect the bone mineral density measurements at the hip, the
hip is considered the most reliable site for observing long-term
changes.

1894
When bisphosphonate treatment is discontinued, bone mineral
density is generally stable at the lumbar spine but decreases at the hip
site, suggesting that the anti-resorptive effect of the bisphosphonates
is levelling off and remodelling reactivated. This has recently been
confirmed in studies of women on long-term bisphosphonate therapy
in clinical practice and in participants in the TRIO study—although the
duration of treatment was shorter in the TRIO study (Langdahl
et al., 2012; Naylor et al., 2018). The fracture outcome of the FLEX
and HORIZON Extension studies suggests that the lesser suppression
of bone resorption may be sufficient to prevent non-vertebral frac-
tures in women who have had bone remodelling substantially reduced
for 3–5 years (Black et al., 2006; Black et al., 2012).
However, the FLEX and HORIZON Extension studies also
showed that discontinuing treatment was associated with increased
risk of vertebral fractures (Black et al., 2006; Black et al., 2012). The
remodelling activity in untreated postmenopausal women is higher in
trabecular bone (Brockstedt, Kassem, Eriksen, Mosekilde, & There is currently one RANKL antibody available for treatment of
Melsen, 1993; Eriksen, Gundersen, Melsen, & Mosekilde, 1984),
which constitutes the vast majority of the vertebral bodies (Graeff
et al., 2013). Less suppression of bone resorption will lead to reac-
tivation of remodelling on trabecular surfaces more rapidly than in
cortical bone. Increased remodelling activity and the associated desta-
bilization of the trabecular structure are more important causes of
vertebral fractures than low bone mass, whereas non-vertebral frac-
tures are more dependent on bone mass in addition to falls
(Ferrari, 2014). This interpretation is corroborated by the very rapid
reduction in the risk of vertebral fractures seen with strong anti-
resorptive treatments. The reduction occurring before substantial
increases in lumbar spine bone mass is seen (Black et al., 2007; Cum-
mings et al., 2009), while the reduction in non-vertebral fractures
takes longer time and is more dependent on increases in bone mass at
the hip site (Bouxsein et al., 2019).
The evidence of the fracture outcome in patients discontinuing
treatment outside of clinical trials is still sparse and inconclusive
(Adams et al., 2018; Mignot, Taisne, Legroux, Cortet, & Paccou, 2017).
Post hoc analyses from the HORIZON Extension study aiming at iden-
tifying subgroups of women who were at increased risk of clinical
fractures during the discontinuation of treatment have demonstrated
that prevalent vertebral fractures and low hip bone mineral density
predicted vertebral fractures during the discontinuation of treatment.
Low hip bone mineral density, prevalent vertebral fractures and non-
vertebral fractures during the active treatment period predicted non-
vertebral fractures during treatment discontinuation (Cosman
et al., 2014). In the FLEX study, women with low hip bone mineral
density and higher age were found to have an increased risk of frac-
tures (Bauer et al., 2014). Bone turnover markers at the entry into the
FLEX or HORIZON Extension studies did not predict fractures. It was
also demonstrated that changes in bone mineral density or bone
turnover markers 1 year after stopping alendronate did not predict
fractures in the FLEX study (Bauer et al., 2014). These findings have
made it difficult to make recommendations regarding in which
patients treatment discontinuation may be appropriate and how to
monitor patients during treatment discontinuation.
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LANGDAHL
Bisphosphonates are generally well tolerated, however gastroin-
testinal discomfort, arthralgia, and myalgia occur in up to 10% of
patients. Uveitis is a rarer side effect. Osteonecrosis of the jaw (ONJ)
and atypical femoral fractures (AFFs) are very rare side effects
(Abrahamsen, Eiken, Prieto-Alhambra, & Eastell, 2016; Khan
et al., 2017; Shane et al., 2010). Osteonecrosis of the jaw is seen in
0.001–0.01% and atypical femoral fractures occur annually in
0.05–0.1% of patients treated for osteoporosis with bisphosphonates
or denosumab. Despite being very rare, osteonecrosis of the jaw and
atypical femoral fractures have gained much attention among physi-
cians and patients.
2.2 | Receptor activator of nuclear factor κ-B
ligand (RANKL) antibody
osteoporosis, denosumab. Denosumab is a human IgG2 antibody that
binds and neutralizes RANKL. The half-life of the antibody in plasma
is 26 days, and denosumab is administrated as a subcutaneous injec-
tion every 6 months. Neutralizing RANKL prevents the recruitment
and activation of osteoclasts. Because osteoblast activity and bone
formation are dependent on factors released from the osteoclasts and
the bone during resorption, bone formation is secondarily reduced.
The effects of treatment with denosumab in women with osteoporo-
sis were investigated in the FREEDOM trial. This study demonstrated
reductions in bone turnover and increases in bone mineral density
that were significantly different from placebo (Cummings et al., 2009).
The study continued for 10 years, however, without a placebo group
beyond 3 years. During the FREEDOM Extension study, bone mineral
density continued to increase unlike that observed in patients treated
with bisphosphonates (Bone et al., 2017; Papapoulos et al., 2012;
Papapoulos et al., 2015). Based on preclinical studies, it has been
suggested that the continued increase in bone mineral density is
explained by denosumab having better access to all bone surfaces, as
it is not attached to bone like the bisphosphonates but remains in the
circulation, and that bone formation as part of bone modelling is not
affected by denosumab since this process is not depending on signals
from bone resorption (Ominsky et al., 2015). Treatment of postmeno-
pausal women with denosumab for 3 years leads to a reduction in the
risk of vertebral, non-vertebral and hip fractures of 68%, 40%, and
20%, respectively (Cummings et al., 2009). The incidence of fractures
remained at this level, after 3 years of treatment, for up to 10 years
(Bone et al., 2017; Papapoulos et al., 2012; Papapoulos et al., 2015).
The virtual twin model has been developed to model the effect of
osteoporosis treatment beyond the placebo-controlled treatment
duration and applying this model to the FREEDOM study demon-
strated a significant reduction in vertebral and non-vertebral fractures
after treatment with denosumab for 10 years compared to the virtual
placebo-treated twin (Bone et al., 2017).
The effect of denosumab has also been investigated in men with
osteoporosis against placebo and in patients with glucocorticoid osteo-
porosis against risedronate. Neither of these studies was powered to

LANGDAHL
investigate the effect on fractures. The bone mineral density increases
in the male study were similar to the increases seen in postmenopausal
women (B. L. Langdahl et al., 2015; E. Orwoll et al., 2012). In a study of
men with prostate cancer receiving androgen deprivation therapy, treat-
ment with denosumab for 3 years prevented vertebral fractures com-
pared to placebo (Smith et al., 2009). The increases in bone mineral
density in the study of patients with glucocorticoid osteoporosis were
more prominent with denosumab compared to risedronate at both the
spine and hip (K. G. Saag et al., 2019; K. G. Saag et al., 2018).
Discontinuation of denosumab results in a rebound activation of
bone turnover to a level above pretreatment level. This leads to a rapid
bone loss and possibly an increased risk of vertebral fractures (Cummings
et al., 2018; Miller, Bolognese, et al., 2008). It is unclear if the rapid bone
loss following discontinuation of denosumab can be prevented by initia-
tion of bisphosphonate treatment (I. R. Reid, Horne, Mihov, &
Gamble, 2017; Tsourdi et al., 2017). This is currently being investigated in
a number of clinical studies (ClinicalTrials.gov identifier: NCT03087851).
Denosumab is generally well tolerated. Similarly, to treatment
with bisphosphates, osteonecrosis of the jaw and atypical femoral
fracture are very rare side effects. Applying the virtual twin model to
the FREEDOM study, the benefit–risk ratio for treatment with
denosumab for 10 years compared to placebo was found to be posi-
tive (Ferrari et al., 2018).
2.3 | Selective oestrogen receptor modulator
Selective oestrogen receptor modulators bind to the two oestrogen
receptors like oestrogen, however the affinity for the receptors is dif-
ferent for selective oestrogen receptor modulators and oestrogen.
Selective oestrogen receptor modulators therefore have some similar-
ities to oestrogen, like protection against postmenopausal bone loss
and osteoporosis. Other effects are opposite to the effects of
oestrogen. Selective oestrogen receptor modulators protect against
breast cancer and have no or only minimal effects on the uterus.
Raloxifene is approved for the prevention and treatment of post-
menopausal osteoporosis. Like oestrogen, raloxifene inhibits osteo-
clast recruitment and activation through inhibition of RANKL release
(Ott, Oleksik, Lu, Harper, & Lips, 2002). The effects of raloxifene were
investigated in the MORE trial. Raloxifene reduced bone turnover and
increased bone mass, but to a lesser degree compared to what were
seen with bisphosphonates and denosumab. Treatment with raloxi-
fene for 3 years resulted in a 30% reduction in the incidence of verte-
bral fractures but no significant reduction in non-vertebral or hip
fractures (Ettinger et al., 1999). In addition, the risk of breast cancer
was reduced by more than 60% (Martino et al., 2004). Side effects
include hot flushes, restless legs, peripheral oedema, gallstones, rarely
venous thromboembolism, and very rarely fatal outcome of stroke in
women with ischaemic heart disease (Mosca et al., 2009). Two other
selective oestrogen receptor modulators, lasofoxifene and
bazedoxifene have proved antifracture efficacy (Cummings
et al., 2010; Silverman et al., 2008), but only bazedoxifene in combina-
tion with oestrogen is approved by the authorities.
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1895
2.4 | REMODELLING-BASED BONE-FORMING
THERAPIES
Parathyroid hormone (PTH) and parathyroid hormone-related
peptide (PTHrP) act via the PTH1 receptor. The PTH1 receptor has
two different high-affinity conformations termed R0 and RG
(Hattersley, Dean, Corbin, Bahar, & Gardella, 2016) and responses of
prolonged duration are observed with ligands that bind to the R0
state, whereas short-duration responses are seen with ligands that
bind more selectively to the RG state (Hattersley et al., 2016; Hoare,
De Vries, & Usdin, 1999). The response depends on the nature of the
stimulation and it is known that sustained activation of the receptor
increases bone resorption, whereas intermittent activation primarily
increases bone formation (Tam, Heersche, Murray, & Parsons, 1982).
The currently available drugs that affect PTH1 receptor are
teriparatide and abaloparatide. Teriparatide is a recombinant human
PTH analogue comprising the first 34 amino acids of the N-terminal
end of PTH and abaloparatide is a 34-amino acid synthetic analogue
of PTHrP, which is identical to PTHrP at amino acids 1–20
(B. Z. Leder et al., 2015). Treatment with teriparatide (Neer
et al., 2001) and abaloparatide (Miller, Hattersley, et al., 2016) mark-
edly increases bone formation, but due to subsequent stimulation of
osteoclasts by the osteoblasts, a secondary increase in bone resorp-
tion occurs. This resorption is less with abaloparatide than with ter-
iparatide probably due to the higher affinity for RG (Hattersley
et al., 2016). Biochemical markers of bone formation and resorption
increase rapidly during the first few months of treatment (Miller,
Hattersley, et al., 2016; Neer et al., 2001). Hereafter, the markers
decrease slowly towards pretreatment levels and after 18 months are
near the baseline level for abaloparatide (Miller, Hattersley,
et al., 2016) but maintained at a higher level in teriparatide-treated
patients (Neer et al., 2001). A human bone biopsy study showed that
approximately 70% of the bone formation seen during teriparatide
therapy is remodelling based and represents a positive remodelling
balance in combination with an overflow of new bone formation in
existing remodelling units (Lindsay et al., 2006). The remaining 30%
was due to de novo modelling. A human biopsy study with
abaloparatide did not report on modelling/remodelling-specific effects
(Moreira, Fitzpatrick, Wang, & Recker, 2017). Both teriparatide and
abaloparatide are administered as daily subcutaneous injections.
2.5 | Teriparatide
Treatment with teriparatide leads to increases in bone mineral den-
sity. The bone mineral density increases were greater at the lumbar
spine, which is predominantly trabecular bone, than at the hip
sites. Teriparatide 20 μg daily reduced the risk of vertebral and
non-vertebral fractures by 65% and 53%, respectively, compared to
placebo after a median treatment duration of 21 months (Neer
et al., 2001).
A few studies have compared teriparatide head to head with
other osteoporotic drugs with fractures or safety as outcome

1896
measures. In the VERO trial, 1,360 postmenopausal women with at
least two moderate or one severe vertebral fractures were random-
ized to 20-μg teriparatide daily or 35-mg risedronate weekly for
24 months (Kendler et al., 2018). Teriparatide reduced the risk of ver-
tebral and clinical fractures compared to risedronate, however the
reduction in non-vertebral fractures was not significant. A pre-
planned subgroup analysis demonstrated that the differences
between the two treatment groups were similar in treatment-naïve
patients and patients previously treated with bisphosphonates and
independent of osteoporosis severity and recency of previous frac-
tures (Geusens et al., 2018).
The effect of teriparatide has also been investigated in men with
osteoporosis. The bone mineral density increases were similar as seen
in postmenopausal women and the risk of vertebral fractures was
reduced (Kaufman et al., 2005; E. S. Orwoll et al., 2003). In patients
with glucocorticoid-induced osteoporosis, the effect of teriparatide
has been investigated in comparison with alendronate. Bone mineral
density increased significantly more in the teriparatide-treated partici-
pants. The study was not powered to investigate the effect on frac-
ture risk reduction, but the risk of vertebral fractures was significantly
lower in the teriparatide-treated patients (K.G. Saag et al., 2007).
Nausea, headache, dizziness, leg cramps and mild hypercalcaemia
are relatively common side effects to teriparatide. In a preclinical
study of rats, a dose-dependent increase in the incidence of osteosar-
coma was observed in animals treated early in life, whereas this was
not seen in rats or cynomolgus monkeys treated in adulthood (Vahle
et al., 2004; Vahle et al., 2008). An epidemiological surveillance study
with up to 7 years of follow-up in patients treated with teriparatide
has not shown an increased risk of osteosarcoma (Andrews
et al., 2012). Despite of this, the lifetime use of teriparatide is limited
to 24 months.
2.6 | Abaloparatide
The effect of abaloparatide in comparison with open-label teriparatide
and placebo was investigated in postmenopausal women with osteo-
porosis in the Abaloparatide Comparator Trial In Vertebral Endpoints
(ACTIVE) trial. Abaloparatide increased bone mineral density more
than placebo at all sites and conferred a greater increase at the total
hip and femoral neck when compared to teriparatide. Treatment with
abaloparatide reduced the risk of vertebral and non-vertebral frac-
tures by 86% and 43% respectively, compared to placebo (Miller,
Hattersley, et al., 2016).
The effect of abaloparatide in men with osteoporosis is currently
under investigation (ClinicalTrials.gov identifier: NCT03512262).
The incidence of hypercalcaemia in the ACTIVE trial was lower in
women treated with abaloparatide (3.4%) than in women treated with
teriparatide (6.4%; Miller, Hattersley, et al., 2016). Nausea, dizziness,
headache and palpitations were observed more frequently in women
treated with abaloparatide (Miller, Hattersley, et al., 2016). Similarly to
teriparatide, a preclinical study showed a dose-dependent increased
incidence of osteosarcoma in abaloparatide-treated rats (Jolette
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LANGDAHL
et al., 2017) Thus, lifetime treatment with abaloparatide is limited to
18–24 months. Abaloparatide is approved by Food and Drug Adminis-
tration in the United States but was not approved by EMA and is
therefore currently not available outside the United States.
2.7 | MODELLING-BASED BONE-FORMING
THERAPY
The Frizzled family receptor and LDL co-receptors 5 and 6 located
on the surface of the osteoblasts are ligands for
wingless/integrated (Wnt; Baron & Rawadi, 2007). Activation of
these receptors leads to a series of intracellular events, which sub-
sequently results in the stimulation of the osteoblasts. The Wnt
pathway can be divided into two categories, a canonical and non-
canonical pathway, depending on signalling through β-catenin or
not. The canonical Wnt–β-catenin pathway is essential for the
development of the skeleton and bone remodelling in the adult
(Canalis, 2013). Activation of this pathway leads to translocation of
β-catenin to the nucleus of the osteoblasts followed by gene tran-
scription (Baron & Rawadi, 2007). The glycoprotein sclerostin
encoded by the sclerostin gene and predominantly expressed by
the osteocytes is an inhibitor of the canonical Wnt pathway and,
accordingly, inhibits osteoblast differentiation, proliferation and sur-
vival (Poole et al., 2005; Van Bezooijen et al., 2004). In addition,
sclerostin increases bone resorption by increasing the production
of RANKL, which in turn stimulates osteoclasts recruitment and
activation (Atkins & Findlay, 2012).
2.8 | Romosozumab
Romosozumab is a humanized antibody against sclerostin and is
administrated as monthly subcutaneous injections (Padhi, Jang,
Stouch, Fang, & Posvar, 2011). Administration of romosozumab
leads to rapid and prominent increases in markers of bone forma-
tion (McClung et al., 2014). Despite continuing administration, the
increase in bone formation levels off within 6 months and the
markers decrease to below baseline levels thereafter. Bone resorp-
tion markers decrease rapidly upon treatment initiation and remain
below baseline throughout the treatment period (McClung
et al., 2014). The changes in bone turnover markers demonstrate
the dual effect of romosozumab, stimulation of bone formation and
at the same time inhibition of bone resorption. Histomorphometric
analysis of bone from ovariectomized rats and male cynomolgus
monkeys treated with romosozumab demonstrated increased bone
formation on trabecular, periosteal, endocortical and intracortical
surfaces, in addition to a decreased resorptive activity (Ominsky,
Niu, Li, Li, & Ke, 2014). The analyses also demonstrated that treat-
ment with romosozumab predominantly stimulates modelling-based
bone formation, that is, de novo bone formation on previously qui-
escent surfaces. The transient effect of romosozumab on bone for-
mation might be explained by depletion of osteoblast progenitors

LANGDAHL
or a compensatory increase in additional inhibitors of bone forma-
tion such as Dickkopf (Ferrari, 2014).
The antifracture efficacy of romosozumab in women with oste-
oporosis was demonstrated in two phase 3 trials. In the FRActure
study in postmenopausal woMen with ostEoporosis (FRAME) study,
the effect of romosozumab was investigated in comparison with
placebo for 12 months in postmenopausal women with osteoporo-
sis followed by an open-label extension during which all women
received 60-mg denosumab every 6 months for 12 months
(Cosman et al., 2016). Romosozumab increased bone mineral den-
sity at the spine by 13.3% and at the total hip by 6.8% after
12 months. By 24 months, bone mineral density at the spine had
increased by 17.6% and 5.0% in the romosozumab ! denosumab
and placebo ! denosumab groups, respectively, and at the total
hip by 8.8% and 2.9%, respectively, demonstrating that the abso-
lute difference in bone mineral density between the two groups
was maintained during the extension (Cosman et al., 2016). During
the first 12 months, romosozumab reduced the risk of vertebral
fractures by 73%. The risk of non-vertebral fractures was non-
significantly reduced by 25%. A significant interaction between
geographical region and the effect of romosozumab on non-
vertebral fractures was seen. There was no effect among women
from Latin America but a 42% reduction in non-vertebral fractures
among women from the rest of the world (Cosman et al., 2016).
During the extension, the reduction in fracture risk was maintained,
although only significantly for vertebral fractures. In the Active-
Controlled Fracture Study in Postmenopausal Women
Osteoporosis at High Risk (ARCH) study, the effect
romosozumab was investigated in comparison with alendronate in
women with severe osteoporosis for 12 months followed by
alendronate in all women (K. G. Saag et al., 2017). After 24 months,
bone mineral density had increased by 15.2% at the lumbar spine
and 7.1% at the total hip in women treated
romosozumab ! alendronate compared to 7.1% and 3.4%, respec-
tively, in women treated with alendronate for 2 years. The risk of
vertebral fractures, non-vertebral fractures, and hip fractures was
reduced by 48%, 19% and 38% respectively, after 24 months in
women treated with romosozumab ! alendronate compared to
the women receiving alendronate for 24 months.
The effect of romosozumab in comparison with placebo in
men with osteoporosis has been investigated in the BRIDGE study.
Romosozumab increased bone mineral density at the lumbar spine
and hip (Lewiecki et al., 2018). No information about the effect of
romosozumab on fracture risk in men is available. Romosozumab
has not been investigated in patients with glucocorticoid-induced
osteoporosis.
The effect of romosozumab is reversible. This was demon-
strated in the extension of the phase 2 study (McClung
et al., 2018). After 2 years of treatment with romosozumab, serum
CTX was slightly reduced compared to baseline and increased
approximately 100% in women discontinuing romosozumab there-
after. In both the FRAME and ARCH studies, treatment with
romosozumab was followed by treatment with an anti-resorptive
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1897
drug to prevent this increase in bone resorption; in fact, both
denosumab and alendronate further suppressed bone resorption
(Cosman, Crittenden, & Grauer, 2017; K. G. Saag et al., 2017).
The adverse events in the FRAME (Cosman et al., 2016), ARCH
(K. G. Saag et al., 2017) and STRUCTURE, an open-label study of the
effect of treatment with Romosozumab or Teriparatide after bis-
phosphonate in postmenopausal women (B. L. Langdahl et al., 2017)
studies were generally balanced between the treatment groups. There
was a numeric imbalance in serious adverse events affecting the car-
diovascular system during the first 12 months in the ARCH study:
2.5% of the women treated with romosozumab compared to 1.9% of
the women treated with alendronate. The occurrences of cardiovascu-
lar serious adverse events were 6.5% and 6.1% after 24 months in
women treated with romosozumab ! alendronate and
alendronate ! alendronate, respectively. In the BRIDGE trial, adjudi-
cated cardiovascular serious adverse events were more frequent in
romosozumab-treated men (4.9%) than placebo (2.5%) (Lewiecki
et al., 2018). The incidences of death, adjudicated cardiovascular and
serious cardiovascular events in the FRAME study were well balanced
between the women treated with romosozumab and placebo
(Cosman et al., 2016). The Food and Drug Administration (2019)
reviewed the cardiovascular safety as part of the approval procedure
in the United States. Antibodies against romosozumab were found in
20% of the women treated with romosozumab in the clinical studies.
A few per cent were neutralizing in vitro but did not affect pharmaco-
dynamics, pharmacokinetics or the clinical response (Cosman
With et al., 2016; McCLung et al., 2014). The clinical relevance of these
of antibodies in relation to long-term treatment is currently not known.
Preclinical studies in rats have not demonstrated any increased risk of
osteosarcoma with romosozumab, as is the case for long-term treat-
ment with teriparatide and abaloparatide (Chouinard et al., 2016).
with
2.9 | COMBINATION THERAPY
Several treatments are available for osteoporosis, and therefore, an
even larger number of combinations of therapies are possible. Addi-
tive or synergistic effects of different combinations have been investi-
gated, but initially with disappointing results. There is no benefit of
combining strong anti-resorptive therapies. Due to the secondary
stimulation of bone resorption associated with bone-forming treat-
ment with teriparatide or abaloparatide, it has been speculated if the
effect of the bone-forming treatments could be further improved by
combining the treatment with an anti-resorptive treatment. The PATH
trial demonstrated that bone mineral density in patients treated with
a combination of PTH (1–84) and alendronate did not increase more
than with either treatment alone (Black et al., 2003). In fact,
alendronate appeared to impair the anabolic effect of teriparatide
(Black et al., 2003; Finkelstein et al., 2003). Similar results were found
in a study investigating the combination of risedronate and ter-
iparatide (Walker et al., 2013). In accordance with these findings, a
rodent study showed that chronic exposure to a bisphosphonate
blunted the response to teriparatide (Gasser, Kneissel, Thomsen, &

1898
Mosekilde, 2000). It was suggested that this was caused by the osteo-
blasts being exposed to bisphosphonates while in the circulation.
None of these studies investigated the effect on fractures, but overall,
the data do not suggest a beneficial effect of co-administration of ter-
iparatide and an oral anti-resorptive treatment as compared to ter-
iparatide monotherapy.
The potential of combining teriparatide with an intravenously,
less frequently administrated bisphosphonate was investigated in a
study comparing the effect of 5-mg zoledronate once in combination
with 20-μg teriparatide daily, 5-mg zoledronate once or 20-μg ter-
iparatide daily for 52 weeks (Cosman et al., 2011). Bone mineral den-
sity increased in all three groups. However, the increase in spine bone
mineral density was similar in the combination and teriparatide groups
and higher than in the zoledronate group, whereas the increase in hip
bone mineral density was similar in the zoledronate and combination
groups and higher than in the teriparatide group.
The DATA study compared 2 years of treatment with the combi-
nation of teriparatide and denosumab to either treatment alone
(B. Z. Leder et al., 2014). The study demonstrated that combined
treatment increased bone mineral density more than either treatment
alone. However, the bone turnover markers in the combination
groups were more similar to the markers in the denosumab-treated
women than to the markers in the teriparatide-treated women,
suggesting that the combination may blunt at least part of the bone-
forming effect of teriparatide. The bone-forming effect of teriparatide
is primarily bone remodelling based (Lindsay et al., 2006) and this
could therefore at least potentially be affected by denosumab
inhibiting bone resorption and remodelling.
None of these studies were powered to investigate the effect on
fracture risk. The effect of abaloparatide in combination with anti-
resorptive treatments has not been investigated. Based on the studies
presented, combination therapy does not seem to convey general
advantages over monotherapy with bone-forming treatments.
2.10 | SEQUENTIAL TREATMENT
2.10.1 | Bone-forming or dual-action treatment
followed by anti-resorptive treatment
The effects of bone-forming and dual-action treatments are revers-
ible. Several clinical trials have demonstrated that bone mineral den-
sity decreases when teriparatide is discontinued (Kaufman
et al., 2005; Prince et al., 2005). Follow-up of patients from the frac-
ture prevention study demonstrated that the bone mineral density
increase during teriparatide treatment could be further improved by
bisphosphonate treatment after discontinuation of teriparatide and
that the antifracture efficacy was maintained (Lindsay et al., 2004;
Prince et al., 2005). Teriparatide followed by denosumab was investi-
gated in the DATA-switch study (B. Z. Leder et al., 2015). Women
treated for 24 months with teriparatide were switched to denosumab
in the extension (teriparatide ! denosumab), and bone mineral den-
sity at the spine and hip increased further.
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LANGDAHL
The ACTIVE study was continued for an additional 24 months
where women who received abaloparatide or placebo in the original
study were transitioned to alendronate. The ACTIVE Extension study
demonstrated that bone mineral density was further increased during
the alendronate treatment period and that the fracture risk reduction
was maintained (Bone et al., 2018; Cosman et al., 2017).
The effect of bisphosphonate or denosumab after romosozumab
was investigated in the FRAME and ARCH studies. In the FRAME
study, treatment for 12 months with romosozumab or placebo was
followed by open-label denosumab. Bone mineral density increased
similarly in both groups, and by Month 24, the absolute difference in
bone mineral density between the two treatment groups seen after
the first 12 months was maintained. The fracture risk reduction was
also maintained in the romosozumab ! denosumab group compared
to placebo ! denosumab, however, only significantly for vertebral
fractures (Cosman et al., 2016). In the ARCH study, treatment with
romosozumab was followed by alendronate. The bone mineral density
increase during romosozumab was maintained by alendronate. The
fracture risk reduction of vertebral fractures was maintained whereas
the non-vertebral fracture risk was further reduced during
alendronate treatment (K. G. Saag et al., 2017).
All studies investigating anti-resorptive treatment after bone-
forming or dual-action treatment demonstrate that bone mass and
antifracture efficacy are further improved or maintained by the
sequential treatment.
2.11 | TREATMENT FAILURE AND TREATMENT
REPLACEMENT
2.11.1 | Anti-resorptive treatment replaced by
another anti-resorptive therapy
Treatment failure in osteoporosis should be considered in the case
of two or more incident fractures, significant loss of bone mineral
density, or non-suppression of bone resorption in a patient who
has been treated for more than 12 months with an anti-resorptive
treatment with good compliance and no secondary causes of bone
loss or fracture (Diez-Perez et al., 2012). Treatment failure will
often lead to change of treatment. In most cases, it will be a
replacement of one anti-resorptive with another anti-resorptive
treatment, but transition to a bone-forming or dual-action treat-
ment should be considered in the case of severe osteoporosis.
Replacement of alendronate with denosumab or zoledronate was
investigated in a clinical study comprising postmenopausal women
with osteoporosis who on average had been treated for more than
6 years with alendronate (Miller, Pannacciulli, et al., 2016). Bone
turnover markers were decreased similarly, however the suppres-
sion levelled off in women transitioned to zoledronate but remain
suppressed with denosumab treatment. Bone mineral density
increased more at the spine and hip with denosumab compared to
zoledronate. Information about fractures was collected as an
adverse event. Seven and 15 fractures were reported in the

LANGDAHL
322 women treated with denosumab and 321 women treated with
zoledronate, respectively.
2.11.2 | Anti-resorptive treatment replaced by
bone-forming or dual-action treatment
The sequence of treatment matters—at least when it comes to
bone mineral density response to treatment. The gain in bone min-
eral density in response to teriparatide is larger in treatment-naïve
patients compared to patients previously treated
bisphosphonates (Cosman, Nieves, & Dempster, 2017). However, in
clinical practice, most patients do not have the option of bone-
forming treatment as first-line treatment. Switching to bone-
forming treatments in most countries is conditioned by treatment
failure, defined in various ways during anti-resorptive treatment
and therefore, most patients initiating bone-forming treatment will
previously have been treated with anti-resorptives, most often
bisphosphonates.
Generally, bone mineral density increases with teriparatide
after anti-resorptive treatment are blunted. The effect depends on
the type of anti-resorptive treatment. Studies have shown greater
bone mineral density increases in patients pretreated with non-
bisphosphonates (raloxifene, Ettinger, San Martin, Crans,
Pavo, 2004) and bisphosphonates with a lower affinity for
hydroxyapatite (risedronate, Miller, Delmas, et al., 2008; and etidro-
nate, Boonen et al., 2008) than those with higher affinity
(alendronate, Boonen et al., 2008; Ettinger et al., 2004; Miller, Del-
mas, et al., 2008). Some studies have shown a temporary decrease
in hip bone mineral density when transitioning from alendronate to
teriparatide (B. L. Langdahl et al., 2017; Obermayer-Pietsch
et al., 2008). Despite the blunted bone mineral density response, a
pre-planned post hoc analysis from the VERO study where approx-
imately 60% of patients had been treated previously with
bisphosphonates for a median duration of 3.7 years showed that
the antifracture efficacy of teriparatide compared to risedronate
was similar in treatment-naïve patients and patients previously
treated with bisphosphonates (Geusens et al., 2018).
The DATA-switch study showed that switching
denosumab for 2 years to teriparatide leads to marked increases in
bone turnover, increase in spine bone mineral density, but a mar-
ked although temporary decrease in hip bone mineral density
(B. Z. Leder, Tsai, et al., 2015). The DATA-switch study was not
powered to investigate fracture risk. However the marked increase
in bone turnover and loss of hip bone mineral density may indicate
destabilization of the bone tissue and a temporary increase in frac-
ture risk. It has therefor been suggested to continue denosumab
concomitantly with teriparatide either for part of or the full dura-
tion of teriparatide treatment if a switch from denosumab to ter-
iparatide (or abaloparatide) is indicated. This suggestion is based on
the outcome of the teriparatide and denosumab combination group
in the DATA study that revealed bone mineral density responses
similar to teriparatide monotherapy (B. Z. Leder et al., 2014). The
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1899
caveat is that the women entering the DATA study were treatment
naïve.
The STRUCTURE study compared the effects of romosozumab
and teriparatide in postmenopausal women previously treated with
bisphosphonates for more than 6 years (B. L. Langdahl et al., 2017).
The women were randomized to treatment with romosozumab or ter-
iparatide for 1 year. In both treatment groups, bone mineral density
increases were blunted compared to bone mineral density increases
seen in treatment-naïve women. bone mineral density increased sig-
nificantly more in women treated with romosozumab than in women
with treated with teriparatide at both the spine and hip. Bone strength,
estimated by finite element analysis of hip QCT, increased by 2.5% in
women treated with romosozumab compared to decrease of 0.7% in
women treated with teriparatide (B. L. Langdahl et al., 2017). The
interpretation of these findings should consider that the full effect of
teriparatide at the hip is not seen until the end of 2 years of treatment
and therefore the findings may have differed had the study duration
been 2 instead of 1 year.
Although the studies suggest that patients will benefit more from
bone-forming therapies when administered to treatment-naïve
patients, patients with severe osteoporosis will still benefit from
bone-forming treatment despite having been previously treated with
anti-resorptive therapy. There is no evidence that a treatment gap
& between bisphosphonate treatment and bone-forming treatment will
diminish the blunting of the effect and it is therefore recommended
that patients with severe osteoporosis at high risk of fractures are
transitioned directly to teriparatide. The transition from denosumab
to teriparatide is less straight forward and perhaps best done with a
partial or full overlap with continued denosumab treatment.
2.12 | LONG-TERM MANAGEMENT OF
OSTEOPOROSIS
Figure 2 illustrates the long-term management of osteoporosis. In
patients with newly diagnosed osteoporosis, the initial treatment will
in most cases be an anti-resorptive treatment. However, in patients
with severe osteoporosis, bone-forming or dual-action treatment
from should be considered at first-line treatment (Kendler et al., 2018; K. G.
Saag et al., 2017). Compliance with oral bisphosphonates is a problem
that may be overcome with education of the patients (Nielsen, Lan-
gdahl, Sorensen, Sorensen, & Brixen, 2010) and interactions between
the patient and the health care system during the treatment. Measure-
ment of bone turnover markers will help assess compliance (Diez-
Perez et al., 2017) but has not convincingly been demonstrated to
improve compliance over discussing the disease and treatment with
the patient. Patients treated with bisphosphonates may be evaluated
for the appropriateness of treatment discontinuation when treated for
5 or 3 years with oral or intravenously administrated bisphosphonates,
respectively. Based on the outcome of the FLEX and HORIZON
Extension studies, it is recommended that treatment discontinuation
should not be considered in patients with hip bone mineral density
T score < −2.5, prevalent vertebral fractures or non-vertebral fractures
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1900 LANGDAHL

F I G U R E 2 Schematic presentation of long-term management of osteoporosis. The initial treatment (marked with *) can be anti-resorptives:
bisphosphonates and denosumab; bone forming: teriparatide and abaloparatide; or dual action: romosozumab. aReassess fracture risk in patients
treated with oral and intravenous bisphosphonates after 3–5 years, respectively. bLow risk can be assumed in patients with hip bone mineral
density (BMD) T score > −2.5, no prevalent vertebral fractures, no non-vertebral fractures during treatment based, and absence of other
indicators of high fracture risk. cHigh fracture risk in patients discontinuing treatment can be assumed if bone turnover is no longer suppressed, if
significant BMD loss occurs, or if the patient suffers a major osteoporotic fracture. dHigh risk can be assumed in patients with hip BMD T
score < −2.5, prevalent vertebral fractures, non-vertebral fractures during treatment, or other indicators of high fracture risk. eTreatment failure
(Diez-Perez et al., 2012). fSwitch therapy (Diez-Perez et al., 2012)

during treatment (Black et al., 2006; Black et al., 2012). If treatment is
discontinued, it is not clear how best to monitor the disease during
the treatment discontinuation. Some recommend discontinuation for
fixed duration of 2 years based on the non-vertebral fracture inci-
dence curves in the FLEX study starting to diverge at that time point
(Black et al., 2006), some recommend monitoring with bone turnover
markers and restart treatment when the markers are no longer
suppressed. While others recommend following bone mineral density
and when a significant bone mineral density loss occurs treatment is
restarted. Finally, most agree that a new major osteoporotic fracture
would be an indication for restarting treatment. Patients treated with
denosumab should remain on the treatment. If for one reason or
another, denosumab treatment needs to be terminated, a rebound
activation of bone turnover and the subsequent bone loss is likely to
occur. The optimal way to prevent this is not clear, but it can be
diminished by transitioning to bisphosphonates (Tsourdi et al., 2017).
Patients started in bone-forming or dual-action treatments should
be transitioned to an anti-resorptive treatment when completing the
treatment.
Treatment failure or transitioning of treatment based on other
reasons is discussed in details above.
2.13 | CAN OPTIMAL USE OF AVAILABLE
TREATMENTS FOR OSTEOPOROSIS OVERCOME
THE CURRENTLY UNMET NEEDS?
The are several unmet needs in the treatment and long-term manage-
ment of osteoporosis. The most prominent are the treatment of
severe osteoporosis, identification and treatment of patients at high
imminent fracture risk following a recent fracture, and long-term
adherence to treatment.
Patients with severe osteoporosis have very low bone mass or
deteriorated bone architecture or a combination of the two condi-
tions and often previous fractures. The goal of osteoporosis treat-
ment is to minimize the risk of future fractures and all the
approved treatments reduce the risk of vertebral fractures. Most
treatments also reduce the risk of non-vertebral and hip fractures.

LANGDAHL
However, the risk of future fractures may still be high despite
treatment with anti-resorptives in some patients with severe osteo-
porosis. Two studies published in 2017, for the first time, demon-
strated that bone-forming or dual-action treatment in patients with
severe osteoporosis is superior to treatment with anti-resorptives.
The first study was the ARCH study comparing romosozumab with
alendronate in treatment-naïve women and demonstrated that
romosozumab reduced the risk of vertebral, non-vertebral and clini-
cal fractures more than alendronate (K. G. Saag et al., 2017). The
other study is the VERO study. The VERO study compared the
effects of teriparatide and risedronate on fracture risk in patients
with severe osteoporosis, of whom approximately 60% had previ-
ously been treated with anti-resorptives, most commonly
bisphosphonates. The study demonstrated that teriparatide over a
2-year treatment period prevented vertebral and clinical fractures
more strongly than risedronate (Kendler et al., 2018). These two
studies investigating a bone-forming treatment and a dual-action
treatment against two different bisphosphonates suggest that treat-
ment of patients with severe osteoporosis with a treatment that
stimulates bone formation may help overcome the unmet need in
the treatment of severe osteoporosis.
Identification of patients at high imminent risk of fracture
relies predominantly on identification of patients with a recent
fracture as it has been demonstrated that a recent fracture is asso-
ciated with a high risk of a second fracture within the first years
after the previous fracture (Center, Bliuc, Nguyen, & Eisman, 2007;
Johansson et al., 2017; Roux & Briot, 2017). There is strong evi-
dence that the best way to identify these patients is to organize
fracture liaison services (McLellan et al., 2011; McLellan, Gallacher,
Fraser, & McQuillian, 2003). However, the implementation of these
services is only taking place very slowly around the world. Identifi-
cation of the patients is a critical starting point but is not going to
prevent the next fracture without initiation of treatment and pref-
erably a treatment that very quickly reduces the risk of a new
fracture. All the available treatments reduce the risk of new verte-
bral fractures very rapidly, but it seems to take longer to prevent
non-vertebral fractures. The ARCH and VERO studies demon-
strated that bone-forming treatments not only prevent fractures
more strongly than anti-resorptives but also do so very rapidly.
Improvement of the adherence is critical for the optimal pre-
vention of fractures. There are multiple obstacles to consider in
relation to adherence to treatment, but confidence of the patient
and the physician that the treatment is effective and will improve
the situation for the patient by reducing the risk of future frac-
tures seems to be crucial. Currently, the treatment strategy for the
individual patient is predominantly driven by strict reimbursement
criteria from their health cover, that in most cases leave very little
room for a personalized approach to the long-term management of
osteoporosis. Physicians and many patients know that one drug is
not the optimal choice for all patients. This is a major challenge to
the confidence in the treatment plan of both parties. The existing
very strong anti-resorptives with their different modes of adminis-
tration and the bone-forming treatments provide a strong platform
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1901
for considering a more personalized approach to osteoporosis man-
agement where osteoporosis severity, the age and co-morbidities
of the patient and patient preference could be taken into account
when deciding on the initial treatment as well as the long-term
management plan.
3 | CONC LU SION
There are still a number of unmet needs in the management of
osteoporosis, including treatment of severe osteoporosis, treatment
of patients at high imminent fracture risk and long-term adherence
to the treatment. The bone-forming and dual-action treatments
may help address these unmet needs. Two clinical trials have dem-
onstrated superiority of treatments that stimulate bone formation
over anti-resorptives in patients with severe osteoporosis,
suggesting that a more personalized approach to the management
of osteoporosis which includes the use of bone-forming treatments
in patients with severe osteoporosis may help address the cur-
rently unmet needs.
3.1 | Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to
corresponding entries in http://guidetopharmacology.org, the com-
mon portal for data from IUPHAR/BPS Guide to PHARMACOLOGY
Harding et al., 2018), and are permanently archived in the Concise
Guide to PHARMACOLOGY 2019/20 (Alexander, Christopoulos,
et al., 2019; Alexander, Cidlowski, et al., 2019; Alexander, Fabbro,
et al., 2019).
CONFLIC T OF INT ER E ST
I have obtained research funding to my institution from Amgen and
Novo Nordisk. I am serving on advisory boards and give lectures for
Eli Lilly, UCB, and Amgen.
OR CID
Bente L. Langdahl https://orcid.org/0000-0002-8712-7199
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1891–1906. https://doi.org/10.1111/bph.15024