Discussion
Our study included a total of 56 patients and constitutes the largest
number of cases collected in a single series. Previous studies presented
a smaller number of cases. González-Rodríguez et al (7) collected 60
spontaneous vertebral fractures in 15 women with breast cancer who were
undergoing treatment with aromatase inhibitors and in whom denosumab was
discontinued. Fernández Fernández et al (14) described 49 vertebral
fractures in 10 women and Florez et al (15) published a series of 7
women who had a median of 5 vertebral fractures. Another study collected
the first 3 cases of hip fracture produced after abrupt DMAB
discontinuation in the absence of other causes (10). Several systematic
reviews have confirmed the magnitude of the problem (6,16-18). In this
series, we publish the first two cases described in men.
The actual number of cases is probably much higher. The Spanish Agency
for Medicines and Health Products (AEMPS), which collects adverse
effects of drugs, described in 2019 a total of 64 patients with multiple
vertebral fractures that were increased in a subsequent statement in
2020, 213 patients with multiple vertebral fractures and 50 hip
fractures. There are several reasons that might explain why the
magnitude of the problem is not preceived. We would mention: a) it is a
complication not yet sufficiently known by the medical community in
general, b) they are fractures that occur in patients who have
osteoporosis, therefore, they can be attributed to the disease rather
than to the suspension of the drug, c) given that the drug is
administered every 6 months, it is possible to forget it, especially
when the questioning is directed at drugs that are taken orally, and d)
for scientific journals, the publication of new cases do not provide
anything noteworthy. So, in recent years, the number of publications on
the matter has decreased, while the number of fractures has not.
The mean age of our series was 68.1 years, somewhat older than those
described in other series, such as that of Barcelona, where the median
age was 65 years (15), and that of Madrid with a mean of 66.4 years (14
). In the González-Rodríguez series (7), the mean age was lower, 62.3
years, but they were other types of patients, women with breast cancer
and not postmenopausal osteoporosis. In a systematic review in which 24
cases were collected, the mean age was 64.1 years
(6).
Our patients had received a median of 6 doses, with DMAB having been
used a median of 30.5 months. These results coincide with those
published in other series and reports of individual cases
(6–8,10,14–16,19–23). In a “real world” study, the risk of fracture
when discontinuing DMAB treatment has been calculated to increase
markedly when the third injection is given
(16).
The time it takes for fractures to occur after the last dose of DMAB
showed a median of 11 months in our study, which represents a 5-month
delay, since the drug is administered every six months, although in one
case it occurred after the delay of a month and a half. In different
reported cases, this period ranges from 2 to 13 months
(6,8,14,15).
Probably the appearance of fractures will depend on two factors, the
severity of the disease and the withdrawal of the drug. The severity of
the disease could be determined through the FRAX or by the presence of
previous fractures. The 10-year risk of fracture calculated by the FRAX
tool showed a median of 11% for major fracture and 3.9% for hip
fracture. Although there is a debate on the optimal threshold to perform
a therapeutic intervention
(24–26),
the high risk of fracture has been established at 20% for the major
fracture and 3% for the hip fracture
(27).
In our study, the fracture risk at 10 years showed a median of 11% for
the major fracture and 3.9% for the hip fracture. FRAX has rarely been
estimated in the publications of other cases.
The other factor involved is the discontinuation of the drug. One of the
reasons DMAB was discontinued came about after reported improvement in
treatment with BMD, leading to the misconception that osteoporosis was
cured. Following this line, the idea of the “treat to target” was
developed according to which, when reaching a certain T-score value, the
drug could be suspended, without verifying the results of this
suspension
(28–30).This
led to the discontinuation of DMAB due to medical recommendation in
41.1% of cases. Closely related to this idea is the concept of
therapeutic holidays wrongly applied to DMAB
(31,32).
On the other hand, given that the association between the use of
denosumab and osteonecrosis of the jaws has been described (33–35), the
suspension of denosumab was carried out by the dentist’s indication in
21.5% of the patients. Our results coincide with those reported in
other series
(7,8,22).
The deleterious effect of DMAB suppression is determined by the sudden
increase in remodeling that can lead to a deterioration in bone strength
and facilitate the appearance of fractures. This fact had been
previously described, although an increase in fractures had not been
observed. After discontinuing
DMAB, beta-crosslaps
increase significantly, from a median of 0.071 ng/mL to 0.520 ng/mL (p
<0.001). To a lesser extent, but also significantly, the
markers of bone formation increase, the P1NP that goes from 25.3 ng/mL
to 101.2 ng/mL, p = 0.006 and osteocalcin from 10.7 ng/mL to 28.1 ng/mL.
This indicates an increase in all bone remodeling in which osteoclastic
activity clearly predominates, as has also been described in other
series
(20,36,37).
We have not observed changes in serum levels of creatinine, calcium,
phosphorus, total protein, vitamin D, measured as 25-hydroxyvitamin D,
or in PTH.
Finally, we carried out a logistic regression analysis to try to
identify which factors could be associated with the presence of a
greater number of fractures, obtaining a statistically significant
association with the time in which denosumab was previously used (p=
0.04).
Among the limitations of our study is the sample size, which is due to
the difficulty in identifying these patients. On the other hand, since
there is no control group, we have not been able to establish what the
clinical, analytical or densitometric factors could be associated with
the appearance of fractures. The strength of the study is determined by
the high number of fractures associated with a full number of
complementary tests.
To sum up, we present a series of 56 patients in which the abrupt
discontinuation of DMAB caused a total of 192 vertebral fractures, the
increase in bone removal probably being manifested through a
considerable increase in biochemical markers of bone remodeling,
especially those of resorption, which causes this effect.