Download Long-Term Use of Bisphosphonates in

Long-Term Use of Bisphosphonates in
Osteoporosis: Local experience
Dr Basmah Al Wahhabi, Dr Basil Al Suwaine
Introduction:
Alendronate (fosamax) and zolendronic acid (ZA) 5mg are nitrogen-containing bisphosphonate
that inhibit bone resorption. They have been approved by FDA for fracture prevention in
postmenopausal women, men and chronic steroid users diagnosed with osteoporosis in 1996 and
2007, respectively.
The approval for alendronate and ZA 5mg followed the FIT trial and the HORIZON-PFT trials,
respectively, both are randomized, double-blinded, placebo-controlled trial that showed
significant reduction in both vertebral and hip fractures with alendronate use for five years and
ZA 5mg use for three years, respectively. (1,2)
The benefits of bisphosphonates beyond recommended duration remained uncertain. In the
fracture Intervention trial long-term extension trial (FLEX) alendronate use was extended in a
group of FIT patients up to 10 years. (3)
FLEX trial showed that women who discontinued alendronate after five years had no increase in
fracture risk other than for clinical vertebral fractures compared with those who continued
alendronate. These results suggested that women at very high risk of clinical vertebral fractures
might benefit by continuing alendronate beyond five years.
In 2005, Odvian,(4) et al described nine patients with spontaneous non-spinal fractures while on
alendronate therapy, characterized by delayed or absent fracture healing for 3 months to 2 years
during therapy, markedly suppressed bone formation, reduced or absent osteoblastic surface, low
osteoclastic surface, and markedly diminished matrix synthesis. These worrying findings raised
the possibility that severe suppression of bone turnover may develop during long-term
Alendronate therapy, resulting in increased susceptibility to, and delayed healing of, non-spinal
fractures.
In September 2010, after a literature reviews of 310 cases, a task force from the American
Society of Bone and Mineral Research (ASBMR) found that 94% used alendronate for more than
five years. (5) The conclusion was that atypical femur fractures could be a result of long-term
bisphosphonate use.
In October 2010, the FDA issued a warning about this complication. The FDA decided to add a
warning about the fractures to the labels of all bisphosphonates.
By May 2011 there have been 56 papers describing a total of 329 similar cases (6)
Atypical femoral shaft fractures following prolonged use of ZA 5mg are not reported.
The aim of this study is to identify the clinical and radiological characteristics of patients with
history of prolonged use of bisphosphonates referred to the osteoporosis clinic in a tertiary
hospital.
Methods:
This is an observational, retrospective, cohort study. Medical files and x-rays of patients
referred to the osteoporosis clinic from January 2009 to December 2014 with history of
bisphosphonates use for more than five years were reviewed.
Clinical characteristics, cause of referral, X-rays features, management and response to treatment
of those patients are described here.
Results:
34 patients were found. 33 used alendronate (Fosamax, MSD), one used ZA 5m (Aclasta,
Novartis). Patients age range 46-89 years. Reason of referral to the osteoporosis clinic included:
1. Group 1: Review of osteoporosis therapy without new fracture or pain (11/34).
2. Group 2: patients with new fracture that occurred four or more years of BP use (21/34).
20 used alendronate and one used ZA 5mg.
3. Group 3: Two patients (2/34) had chronic severe thigh pain of unknown etiology that is
not responding to analgesia and leading to inability to walk.
Among group 2, eight patients (8/21, 38%) were chronic steroid users including the patient on
ZA 5mg.
All fractures occurred after at least four years of bisphosphonate use. Site of fracture was: 16/21
(76.1%) femoral shaft (fig 1), 4/21 (19%) tibia or fibula (fig 2) and 1/21 (4.7%) pelvic fractures
(fig 3). Fig (4) shows fracture femoral shaft after 4 years of aclasta.
All group 2 patients showed radiological signs of delayed union of fractures at time of
presentation. Delayed union is defined as absent radiological signs of healing six months after
the fracture (visible fracture line, very little callus formation or periosteal reaction).
X-ray femur of group 3 patients showed marked cortical thickening (Fig 5).
All group 2 and 3 patients (total 23/34) were treated with teriparatide 20 mcg daily for 18-24
months.
16/21 fracture Patients completed teriparatide course (18-24 months), 11/16 (68.75%) of them
showed complete healing of fracture at the end of the course (Fig 6), 5/16 (31.25%) remained
with nonunion of fracture (3 tibiae, 2 femoral shaft), 7/21 (33.3%) patients lost follow up.
Group 3 patients reported marked improvement in pain and the ability to walk but remained with
mild pain three years after completing teriparatide.
Bone density using DXA scan at time of presentation showed osteopenia in 15/32 (48%), chronic
pain group 2, fracture group 8, others 5. Osteoporosis in 19/32 (52%), fracture group 13/32,
others.
Discussion:
It is hypothesized that long-term alendronate use results in over suppression of bone turnover,
leading to an accumulation of microdamage and increased susceptibility of bone to fracture from
low-energy injury. This has been shown in animal studies. (7,8)
Chronic severe bilateral thigh pain is not reported as a separate entity that may complicate
prolonged use of alendronate. It was rather described as moderate pain during the prodromal
phase that proceeds the atypical fracture. Weather prophylactic nailing and/or teriparatide can be
used in these cases to relieve the pain, prevent development of fracture and reverse the process
needs further research. In the absence of other measures, clinicians may have low threshold to
use teriparatide in these cases. Fukuda (9) reported a patient who achieved union of bilateral AFF
after 3 months of only once-weekly administration of teriparatide 56.5 mcg/week.
Our report supports previously perceived belief that prolonged use of alendronate may increase
the risk of developing stress fractures. Doctors caring for osteoporosis patients should reassess
the fracture risk of their patient after five years of alendronate use and give them a drug holiday
unless their risk is high.
Warning signs like prodromal thigh pain should alert doctors to consider discontinuing
alendronate.
We report one patient who developed fracture femoral shaft after 4 years of ZA 5mg which is not
documented previously. This should raise a flag regarding the risk of stress fracture with
prolonged use of other bisphosphonates like ZA 5 mg or other antiresorptive therapies.
In spite of the lack of level 1 evidence, benefit of treating atypical femoral fractures with
teriparatide has been shown in many reports. (10,11) A systemic review (10) revealed that
teriparatide works positively in atypical fractures. Being the sole anabolic agent among
osteoporosis medications, teriparatide activates bone remodeling, stimulates osteoblasts required
for proper bone healing and reverse the over-suppression that is induced by bisphosphonates
which is considered the main pathophysiology underlying this type of fractures.
The limitations of this study is the fact that it is a retrospective one.
Conclusion:
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This study confirms previous reports regarding the risk of developing atypical femoral
shaft fracture in patients with history of alendronate use for more than five years.
It also suggests a new entity that these patients may develop in the form of chronic
disabling bilateral thigh pain without fracture that is described in previous reports as
“prodromal phase” to proceeds fracture.
The diagnosis of “over-suppression syndrome” in these patients should be considered as a
spectrum syndrome that ranges from severe thigh pain or radiological evidence of cortical
thickness at the femur to atypical non-spinal fracture either femoral or elsewhere.
There is a need to define the diagnostic criteria and the management methods of this
syndrome in the future.
High risk patients who continue alendronate after five years must be educated regarding
thigh pain and the small risk of atypical fracture. We suggest doing X-rays of the thigh to
measure cortical thickness in these patients.
Although we are reporting a single case of atypical femoral shaft fracture following
prolonged use of ZA 5mg (5 years or more), the true incidence of such a rare event needs
further studies. Clinicians may need to observe patients using other bisphosphonates or
other antiresorptive medications for similar complains.
Putting together all this evidence we believe that teriparatide is a viable treatment option
for enhancing fracture healing in atypical fractures that complicate prolonged
bisphosphonate use.
Teriparatide is probably the preferred drug to manage these patients even in the absence
of fracture. Teriparatide activates the bone remodeling process reversing the chronic
suppression induced by prolonged use of bisphosphonates and has the potential to
facilitate bone healing in patients with atypical femoral shaft fracture and may leads to
improvement of the chronic thigh pain in patients with pain and no fracture.
Acknowledgement:
Authors’ roles: Study design, Study conduct, data analysis, data interpretation, drafting
manuscript, manuscript content, approving the final version of manuscript. Data collection: Dr
Al Suwaine.
Dr Basmah Al Wahhabi accepts responsibility for the integrity of the data.