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longed use of an electrical bone stim- Bone turnover is a natural part of pain in the fractured limb, starting 2-
ulator, and cessation of alendronate maintaining bone health. When bone 6 months before the injury; none of
use, the fracture did not unite. After 9 turnover is inhibited by bisphospho- the patients in the non-alendronate
months, the patient had a second surgi- nates, microdamage that occurs regu- group had prodromal symptoms. In
cal procedure to replace the original larly in bone but is normally repaired 6 patients in the alendronate group,
rod with a larger one. After a delay, might accumulate after long-term cortical hypertrophy was identified
the bone finally united. The author use. There have long been concerns on the lateral side of the subtrochan-
suggested a possible causal relation- about the long-term safety of bisphos- teric region of the femur, and 3 of these
ship between long-term alendronate phonates because of their potential to also had cortical hypertrophy on the
and the femoral fracture. cause oversuppression of bone turn- contralateral femur.
Fragility fractures of the proximal over.8-13 The first report
femur are rare. However, in the past 3 suggestive of the clinical
years, multiple additional cases like relevance of these hy- Long-term alendronate
those above have been published and pothetical concerns was
the evidence continues to grow that published in 2005 by Od- therapy may suppress
14
in a small subpopulation of patients, vina et al, describing 8
long-term alendronate use may be postmenopausal women
bone turnover.
related to low-impact, nontraumatic, and a man who sustained
or “atypical” fractures of the femur, unusual nontraumatic nonspinal frac- The Singapore group recently
often with delayed healing. This paper tures while on alendronate therapy for elaborated on its findings with a ret-
reviews the older evidence for a con- 3-8 years. All 9 continued taking alen- rospective review of postmenopausal
nection between bisphosphonates and dronate after the fracture. Six of the 9 patients with subtrochanteric insuffi-
bone fragility, and summarizes recent patients had delayed or absent fracture ciency fractures admitted to their hos-
reports and recommendations. healing for 3 months to 2 years during pital over a 20-month period.16 They
continued alendronate therapy. All 9 found 17 patients, whose mean age was
Femoral fractures patients underwent iliac crest biopsy 66 years, and all had been taking alen-
and alendronate of trabecular bone. All the specimens dronate, for a mean of 4.4 years (range
Bisphosphonates are considered first- showed markedly suppressed bone for- 2.2-8), except for one patient who
line treatment for postmenopausal mation. The authors concluded that was on risedronate for 6 years after
osteoporosis. They are prescribed for long-term alendronate therapy may 4 years of alendronate. All fractures
millions of geriatric patients. Bisphos- result in severe suppression of bone were low-energy, typically sustained
phonates—alendronate (Fosamax), turnover, with increased susceptibil- after tripping. Seven of the patients re-
risedronate (Actonel), ibandronate ity to nonspinal fractures along with ported experiencing acute pain before
(Boniva), and zoledronic acid (Zo- delayed healing. they fell, suggesting that the fracture
meta, Reclast)—inhibit bone resorp- In 2007 a group from Singapore preceded the fall. Thirteen of the 17
tion by decreasing the activity of published a retrospective review of patients (76%) had experienced pro-
osteoclasts. Extensive studies have patients admitted with a low-energy dromal pain in the affected thigh rang-
shown that therapy with bisphospho- subtrochanteric fracture (defined as ing from 1 week to 2 years before the
nates improves bone density and de- one in the region of the femur that fracture. Often these patients had
creases fracture risk.2-6 When discon- extended from the lesser trochanter been treated for referred pain from a
tinued after 5 years, the physiologic to the junction of the proximal and spinal origin, without improvement.
effect of alendronate continues for at middle third of the femoral shaft.)15 Three patients had sustained prior
least 5 years, with no increase in mor- Of 13 women identified, 9 were on contralateral femoral fractures 2-4
phometric vertebral fracture risk or in long-term alendronate therapy (mean years earlier but had been continued
the risk of nonvertebral fractures com- 4.2 years, range 2.5-5). Their average on their bisphosphonate; the patient
pared with patients who continued to age was 67 years, versus 80 years in who was switched to risedronate was
take alendronate for the full 10 years.7 the non-alendronate group. Four of one of these. Five other patients had
This result is consistent with the fact the 9 patients in the alendronate group stress reactions seen on plain x-rays in
that alendronate is incorporated into reported that the fracture had occurred the contralateral femurs; a bone scan
bone matrix and has a biological half- in the absence of a fall. Five patients of one of these patients showed abnor-
life of more than 10 years. reported experiencing prodromal mal uptake in that femur. Pointing to
trauma continue to be at risk of addi- publications of multiple case reports, been proposed that discontinuation of
tional insufficiency fractures. In those a population-based analysis of IV oral bisphosphonates for a period of
in whom a stress fracture was subse- bisphosphonate therapy concluded 3 months prior to and 3 months fol-
quently diagnosed in the contralateral that the hazard ratio of being diag- lowing elective invasive dental surgery
femur, prophylactic surgical rodding is nosed with inflammatory conditions may lower the risk of bisphosphonate-
typically suggested in order to prevent or osteomyelitis of the jaw was 11.48 related ONJ.”27 There are no actual
a completed fracture. Some bone spe- for recipients of IV bisphosphonates data as yet to help determine the ap-
cialists treat such patients with teripa- as compared with non-recipients.25 propriate length of time the patient
ratide (recombinant human parathy- No randomized, controlled, double- should be off the bisphosphonate, and
roid hormone [Forteo]) in an attempt blind studies have been done regard- this depends on the particular drug.
to reverse their adynamic bone. Unlike ing bisphosphonates and ONJ, and Nonetheless, the dental profession’s
bisphosphonates, which work by de- they are unlikely to be done in the current guidelines are a model for
creasing the activity of osteoclasts that future. Nonetheless, the case reports prudent, patient-centered care in an
break down bone, recombinant PTH and population studies have led to the environment where definitive high-
strengthens bone and improves bone creation of a new syndrome in the den- grade studies are lacking but where
density by increasing the activity of os- tal world, bisphosphonate-associated there are reports of multiple, difficult-
teoblasts that build bone. Teriparatide osteonecrosis of the jaw (BON), and to-treat cases strongly suggestive of
stimulates bone formation, increases position papers on trying to prevent a bisphosphonate cause. There is al-
bone mass, and improves bone micro- this disorder have been published by ready a published case report in the
architecture.20 In patients previously several organizations concerned with dental literature of a refractory case
treated with alendronate or raloxifene, dental surgery. of ONJ that was successfully treated
subsequent treatment with teriparatide with teriparatide.28
significantly increased bone turnover,
although less so in patients formerly on Bisphosphonates, Recommendations
alendronate.21,22 This drug is recom- Citing the 2006 report by Black et al7
mended by Lenart et al of the New York osteonecrosis of about stopping or continuing alen-
City group in a recent published letter23 dronate after 5 years of treatment, the
based on findings of the effects of para-
jaw may be linked. National Osteoporosis Foundation
thyroid hormone and alendronate alone (NOF), in its Clinical Update Online
or in combination in postmenopausal Although most cases of ONJ have of July 2008, said, “Results suggest
osteoporosis.7 Results of treatment occurred in patients treated with IV that for most women, taking a 5-year
with teriparatide in women with alen- bisphosphonates (pamidronate, zole- ‘drug holiday’ after being on alendro-
dronate-related insufficiency fractures dronic acid), the finding of some nate (5-10 mg/day) for 5 years does
will be published in the near future.24 cases related to oral bisphosphonates not increase fracture risk and might
Teriparatide should not be used in pa- resulted in the recent publication by be advantageous. For women at high
tients who are at an increased risk of the American Dental Association risk for vertebral fractures, continuing
developing bone tumors (eg, patients of “Dental management of patients alendronate for a total of 10 years is a
with Paget’s disease, unexplained el- receiving oral bisphosphonate ther- reasonable clinical option.”29
evations of alkaline phosphatase, open apy.”26 This document suggests that In 2008 the NOF published a Clini-
epiphyses, or prior radiation therapy “because there is no validated diag- cian’s Guide to Prevention and Treat-
involving the skeleton). nostic technique currently available to ment of Osteoporosis. This guide in-
determine if patients are at increased troduced a new Fracture Risk Algo-
Osteonecrosis of the jaw risk for developing BON, it may be rithm (FRAX) for calculating which
The evolution of our understanding of prudent to proceed conservatively men and women over 50 require phar-
the relationship between alendronate in some cases.” For example, if full- macologic treatment for osteoporosis.
and femoral fractures parallels the mouth tooth extraction is needed, The report states that FRAX analyses
growing understanding of the relation- begin by extracting one tooth and see generally confirm that it is cost-effec-
ship between use of bisphosphonates if the jaw heals. The Association of tive to treat individuals with a prior hip
and osteonecrosis of the jaw (ONJ), Oral and Maxillofacial Surgeons pub- or vertebral fracture and those with a
which may reflect a similar mecha- lished guidelines in 2006 that state, DEXA femoral neck -T score of -2.5
nism of bone injury. After numerous “If systemic conditions permit, it has or worse.
The guide does not discuss the rec- have osteopenia, saving these drugs half life might make it more likely
ommended duration of treatment with for those who have osteoporosis. than other bisphosphonates to cause
bisphosphonates. It does discuss the There may be a group of patients problems in susceptible patients. Phy-
usefulness of biochemical markers of with low bone density who should sicians need to be aware that patients
bone metabolism, saying, “Suppres- not be treated with bisphosphonates. on bisphosphonates who experience
sion of biochemical markers of bone At present there is no way of predict- low-impact femoral fractures may re-
turnover after 3-6 month of specific ing who these patients are. There is quire additional evaluation and treat-
antiresorptive osteoporosis therapies, a need for research designed to iden- ment along with surgical fixation.
and biochemical marker increases after tify those patients who are potentially This might include bone scans to de-
1-3 months of specific anabolic thera- at risk for adverse outcomes with tect other stress fractures, stopping
pies, have been predictive of greater bisphosphonates in general, or with alendronate therapy, and referral to
BMD responses in studies evaluating alendronate in particular. These pa- specialists knowledgeable in treating
large groups of patients. Because of tients undoubtedly constitute a small these unusual cases.
the high degree of biological and ana- percentage compared to those who
lytical variability in measurement of benefit from bisphosphonates, but for References
biochemical markers, changes in in- those patients these fractures can be 1. Schneider JP. Should bisphosphonates be
dividuals must be large in order to be devastating events, to be prevented if continued indefinitely? An unusual fracture
in a healthy woman on long-term alendro-
clinically meaningful.”30 at all possible. nate. Geriatrics. 2006;61(1):31-33.
Population research is also 2. Cummings SR, Black DM, Thompson DE
et al. Effect of alendronate on risk of
needed that compares the in-
More study is needed cidence of subtrochanteric
fracture in women with low bone density
but without vertebral fractures: Results
from the Fracture Intervention Trial. JAMA.
on outcomes, durations fractures among people be-
ing treated with alendronate
1998;280(24):2077-2082.
3. Pols HA, Felsenberg D, Hanley DA, et al.
despite the absence of randomized hip fractures were also significantly 7. Black DM, Schwartz AV, Ensrud KE, et
al. Effects of continuing or stopping alen-
prospective studies.14 Patients should more common among the alendronate dronate after 5 years of treatment: The
Fracture Intervention Long-term exten-
continue weight-bearing activities, group, suggesting that that the alen- sion (FLEX): A randomized trial. JAMA.
calcium and Vitamin D, and undergo dronate-treated group had weaker 2006;296:2927-2938.
periodic DEXA scanning. Those with bones than controls in the first place. 8. Mashiba T, Turner CH, Hirano T, et al. Effects
of suppressed bone turnover by bisphos-
a high fracture risk might best be Clearly, additional population studies phonates on microdamage accumulation
served by continuing treatment with a are needed. and biomechanical properties in clinically
relevant skeletal sites in beagles. Bone.
bisphsphonate or treatment with an al- It is uncertain whether all bisphos- 2001;28(5)524-531.
ternative agent, such as teriparatide. As phonates have the potential risk of 9. Hirano T, Turner CH, Forwood MR, et
al. Does suppression of bone turnover
implied by the recent NOF guidelines, it suppressing bone repair, or only alen- impair mechanical properties by allow-
might be prudent to withhold initiating dronate. Alendronate was the first ing microdamage accumulation? Bone.
2000:227(1)13-20.
bisphosphonates in otherwise healthy bisphosphonate available and still the 10. Boivin G, Meunier PJ. Changes in bone
postmenopausal women who merely most widely used. Its long biological remodeling rate influence the degree of
w w w.g e r i . c o m 23