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Fosamax Needs a Break: Don’t use it for more than five years

Jacob Schor, ND, FABNO

February 2009

 

The drugs that have been used with apparent success to treat osteoporosis may now have a problem.  Alendronate may weaken bone and lead to increased fracture risk.

 

Alendronate is the drug we know as Fosamax.  It belongs to a class of drugs called  bisphosphonates.  These chemicals were developed in the 19th century but were not  investigated until the 1960s for bone metabolism. Their non-medical use was to soften water in irrigation systems used in orange groves. The rationale for giving them to people is that they prevent the dissolution of hydroxylapatite, the principal bone mineral, so stopping bone loss. Only in the 1990s was their actual mechanism of action explained when Merck brought Fosamax to the market place. 

 

There is little doubt that these drugs do what they are supposed to over the short term: they increase bone density and decrease fracture risk.

 

The FOSIT study published in 1999 told us this quite clearly. This study reported on 1,908  healthy, postmenopausal women with osteoporosis, 950 of whom  took either 10 mg of Fosamax for a year, while the other 958 got a placebo.  Both groups took 500 mg of calcium per day.  After a year, bone mineral density increased by almost 5% on average in those taking the Fosamax compared to the placebo group. Non-spinal fractures decreased. Of those taking the drug only 19 suffered fractures compared to 37 of those taking placebo.

 

From the first use of these drugs, there was always a theoretical worry.  Recall that there are two main processes that occur constantly in the bone: osteoclastic activity that breaks down old bone, and osteoblastic activity that builds up new bone.  This constant turnover of bone maintains healthy and strong bone.  These drugs stop the osteoclastic activity so that the old bone is left untouched.  This increases bone density measurements.  The worry was that because these drugs halt normal bone turnover people using them would end up with dense but more brittle bones.  As the early studies consistently showed a rapid reduction in fracture rates, this concern faded. 

 

These early worries unfortunately were not  just a product of naturopathic paranoia; the problems just took a few years to show up.

The May/June 2008 issue of The Journal of Orthopaedic Trauma published a report on “Low-energy femoral shaft fractures associated with alendronate use.”  The authors reviewed records of 70 patients who had sustained low energy femur fractures.  That means their femurs broke without any major stress.  Rather they did little things such as walking or stepped off a curb and thus triggered the breaks.  These weren’t young people, their average age was about 75.  Of these 70 patients, 25 of them, a little over a third  (36%), were taking Fosamax.  Nineteen (76%) of those 25 patients demonstrated a simple, transverse fracture with a unicortical beak in an area of cortical hypertrophy.  This is a rare and peculiar type of fracture.  Only 1 patient of those not taking Fossamax (2%) had this kind of bone break.  When the statistics were worked out, the numbers tell us that Fosamax use significantly increased risk of these fractures: the odds ratio was 139.33, 95% CI [19.0-939.4], P < 0.0001).   You can say those taking Fosamax were about 140 times more likely to get one of these rare fractures.  It took about 7 years for this problem to occur.  Those taking Fosamax less than 2.5 years were not at greater risk.

 

 A 2009 paper in Geriatrics continued this story.  It tells us that, “The fractures are often preceded by pain in the affected thigh…” this paper suggests that patients not take Fosamax for longer than five years.   Another 2009 article, this one in Clinical Calcium, echoed this warning and suggested that, “… alendronate treatment might be stopped for a while after 5 years to prevent [these kinds of]… fractures.”  

 

Take a break to prevent a break might become a safety slogan.

Researcher from Johns Hopkins repeated this same story in the journal Orthopedics in August 2009.    Then just last November, 2009, doctors from New York University report on seven different patients who had broken both legs. The average age of these patients was 61 years and on average they had taken Fosmax for 8.6 years.  One patient had broken both legs simultaneously. The article suggests  that we start checking the ‘good leg’ when people who have been taking Fosamax sustain a suspicious fracture.  If a problem is seen, they suggest prophylactic repair. 

 

Few doctors and fewer patients are paying attention to duration of Fosamax use.  Most patients will report they’ve taken Fosamax, “for awhile.”  We need to start spreading the message, “for awhile” should be less than five years.

In our practice we are suggesting a break from use after a shorter period of time, about three years.  Discontinuing Fosamax use and  relying solely on naturopathic treatments even for an interval of time, may, in the long run prove to be a safer course of action.

Unfortunately over the years as Fosamax was used with apparent benefit by so many people, many of us grew lax, thinking that our early worries were unfounded.  In hindsight this may have been a problem all along.  It’s only in the last few years that enough patients have taken the drug long enough that we can actually see the results of long term bone suppression.

 

References:

 

 

  Osteoporos Int. 1999;9(5):461-8.

Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Fosamax International Trial Study Group.

Pols HA, Felsenberg D, Hanley DA, Stepán J, Muñoz-Torres M, Wilkin TJ, Qin-sheng G, Galich AM, Vandormael K, Yates AJ, Stych B.

Erasmus University Medical School, Rotterdam, The Netherlands. pols@epib.fgg.eur.nl

This randomized, double-masked, placebo-controlled trial evaluated the safety, tolerability and effects on bone mineral density (BMD) of alendronate in a large, multinational population of postmenopausal women with low bone mass. At 153 centers in 34 countries, 1908 otherwise healthy, postmenopausal women with lumbar spine BMD 2 standard deviations or more below the premenopausal adult mean were randomly assigned to receive oral alendronate 10 mg (n = 950) or placebo (n = 958) once daily for 1 year. All patients received 500 mg elemental calcium daily. Baseline characteristics of patients in the two treatment groups were similar. At 12 months, mean increases in BMD were significantly (p</=0.001) greater in the alendronate than the placebo group by 4.9% (95% confidence interval 4.6% to 5.2%) at the lumbar spine, 2.4% (2.0% to 2.8%) at the femoral neck, 3.6% (3.2% to 4.1%) at the trochanter and 3.0% (2.6% to 3.4%) for the total hip. The incidence of nonvertebral fractures was significantly lower in the alendronate than the placebo group (19 vs 37 patients with fractures), representing a 47% risk reduction for nonvertebral fracture for alendronate-treated patients (95% confidence interval 10% to 70%; p = 0.021). Incidences of adverse events, including upper gastrointestinal adverse events, were similar in the two groups. Therefore, for postmenopausal women with low bone mass, alendronate is well tolerated and produces significant, progressive increases in BMD at the lumbar spine and hip in addition to significant reduction in the risk of nonvertebral fracture.

J Orthop Trauma. 2008 May-Jun;22(5):346-50.Click here to read Links

Low-energy femoral shaft fractures associated with alendronate use.

Neviaser AS, Lane JM, Lenart BA, Edobor-Osula F, Lorich DG.

Hospital for Special Surgery, New York, NY, USA.

OBJECTIVE: Increasing evidence suggests long-term alendronate use may overly suppress bone metabolism, limiting repair of microdamage and creating risk for insufficiency fractures. The purpose of this study is to demonstrate an association between alendronate use and a specific pattern of low-energy femoral shaft fracture. DESIGN, SETTING, AND PATIENTS: A retrospective review was performed of patients with femoral shaft fractures admitted to a Level 1 trauma center between January 2002 and March 2007. Seventy low-energy fractures were identified. MAIN OUTCOME MEASURE: The medical records were reviewed, and the incidence and duration of alendronate use were recorded. The incidence of a specific femoral shaft fracture in those patients taking alendronate compared with those not being treated was determined. RESULTS: There were 59 females and 11 males. The average age was 74.7 years. Twenty-five (36%) were being treated with alendronate. None of the patients had used or were using other bisphosphonates. Nineteen (76%) of these 25 patients demonstrated a simple, transverse fracture with a unicortical beak in an area of cortical hypertrophy. This fracture pattern was seen in only 1 patient (2%) not being treated with alendronate. Alendronate use was a significant risk factor for the fracture pattern (odds ratio [OR]) 139.33, 95% CI [19.0-939.4], P < 0.0001). This pattern was 98% specific to alendronate users. The average duration of alendronate use in those with the pattern was significantly longer than those who did not exhibit the pattern but were taking alendronate, 6.9 years versus 2.5 years of use, respectively (P = 0.002). Only 1 patient with the fracture pattern had been taking alendronate for less than 4 years. CONCLUSIONS: Low-energy fractures of the femoral shaft with a simple, transverse pattern and hypertrophy of the diaphyseal cortex are associated with alendronate use. This may result from propagation of a stress fracture whose repair is retarded by diminished osteoclast activity and impaired microdamage repair resulting from its prolonged use.

PMID: 18448990 [PubMed - index

Geriatrics. 2009 Jan;64(1):18-23.Links

Bisphosphonates and low-impact femoral fractures: current evidence on alendronate-fracture risk.

Schneider JP.

Tucson, AZ, USA.

Several recent medical articles have described multiple cases of unusual low-impact subtrochanteric stress fractures or completed fractures of the femur in patients who have been on the bisphosphonate alendronate for several years for osteoporosis or osteopenia. Some patients have experienced such fractures in both femurs. The fractures are often preceded by pain in the affected thigh, may have a typical x-ray appearance, and many have delayed healing. It has been hypothesized that in some patients, long-term alendronate causes oversuppression of bone turnover, resulting in bones that are brittle despite improved bone density. In patients with atypical or low-impact fractures of the femoral shaft, consider the possible connection with alendronate use. Some bone specialists now recommend stopping alendronate in most patients after 5 years.

Clin Calcium. 2009 Jan;19(1):38-43.Links

[New development in bisphosphonate treatment. When and how long should patients take bisphosphonates for osteoporosis?]

[Article in Japanese]

Yamaguchi T, Sugimoto T.

Shimane University, Faculty of Medicine, Internal Medicine 1, Japan.

Bisphosphonates such as alendronate and risedronate effectively reduce hip fracture risk, and thus are suitable for the elderly people in whom this fracture is most likely to happen. Bisphophonates should be administered when patients meet the guideline made by Japanese bone society, which picks up prevalent fractures, low bone mineral density, and established risk factors as features for starting osteoporosis treatment. Long-term alendronate administration may inhibit normal repair of microdamage arising from severe suppression of bone turnover (SSBT), which, in turn, results in accumulation of microdamage. This process would lead to brittle bone and the occurrence of unexpected stress fractures, characteristically at the subtrochanter of femur. A large-scale study suggests that for more women, discontinuation of alendronate after 5 years for up to 5 more years does not significantly increase fracture risk. Thus, alendronate treatment might be stopped for a while after 5 years to prevent SSBT and subsequent stress fractures.

Orthopedics. 2009 Aug;32(8). pii: orthosupersite.com/view.asp?rID=41933. doi: 10.3928/01477447-20090624-27.

Atraumatic bilateral femur fracture in long-term bisphosphonate use.

Goddard MS, Reid KR, Johnston JC, Khanuja HS.

Department of Orthopedic Surgery, The Johns Hopkins University, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, Baltimore, MD 21224-2780. USA.

Postmenopausal women with osteoporosis are commonly treated with the bisphosphonate class of medications, one of the most frequently prescribed medications in the United States. In the past 4 years, reports have been published implying that long-term bisphosphonate therapy could be linked to atraumatic femoral diaphyseal fractures. This article presents a case of a 67-year-old woman who presented with an atraumatic right femur fracture. She had a medical history notable for use of the bisphosphonate alendronate for 16 years before being switched to ibandronate for 1 year before presentation. She had sustained a similar fracture on the contralateral side 3 years previously. This case report, in addition to a review of the literature, shows that use of the bisphosphonate class of medications for an extended period of time may result in an increased susceptibility to atraumatic femoral diaphyseal fractures. Some studies have suggested that the reason may be the mechanism of action of bisphosphonates, resulting in decreased bone turnover and remodeling. Studies have not shown if the entire class of medications produce a similar result, but patients who have been treated with any bisphosphonate for an extended period of time should be considered at risk. In patients who have already sustained a femoral diaphyseal fracture, imaging of the contralateral side should be performed to identify cortical thickening as an early sign of fracture risk. Patients should also be questioned about thigh pain.

J Bone Joint Surg Am. 2009 Nov;91(11):2556-61.

Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term alendronate therapy.

Capeci CM, Tejwani NC.

Department of Orthopaedic Surgery, New York University Hospital for Joint Diseases, 301 East 17th Street, Suite 1401, New York, NY 10003, USA. craig.capeci@nyumc.org

BACKGROUND: While alendronate therapy has been shown to decrease the risk of vertebral and femoral neck fractures in postmenopausal osteoporotic patients, recent reports have associated long-term alendronate therapy with unilateral low-energy subtrochanteric and diaphyseal femoral fractures in a small number of patients. To our knowledge, there has been only one report of sequential bilateral femoral fractures in patients on long-term bisphosphonate therapy. METHODS: We retrospectively reviewed the case log of the senior author over the last four years to identify patients who presented with a subtrochanteric or diaphyseal femoral fracture after a low-energy mechanism of injury (a fall from standing height or less) and who had been taking alendronate for more than five years. Radiographs were reviewed, and the fracture patterns were recorded. Serum calcium levels were recorded when available. RESULTS: Seven patients who sustained low-energy bilateral subtrochanteric or diaphyseal femoral fractures while on long-term alendronate therapy were identified. One patient presented with simultaneous bilateral diaphyseal fractures, two patients had sequential subtrochanteric fractures, and four patients had impending contralateral subtrochanteric stress fractures noted at the time of the initial fracture. Of the latter four, one patient had a fracture through the stress site and the other three patients had prophylactic stabilization of the site with internal fixation. No patient had discontinued alendronate therapy prior to the second fracture. All patients were women with an average age of sixty-one years, and they had been on alendronate therapy for an average of 8.6 years. All fractures were treated with reamed intramedullary nailing and went on to union at an average of four months. CONCLUSIONS: In patients on long-term alendronate therapy who present with a subtrochanteric or diaphyseal femoral fracture, we recommend radiographs of the contralateral femur and consideration of discontinuing alendronate in consultation with an endocrinologist. If a contralateral stress fracture is found, prophylactic fixation should be considered.