Severely suppressed bone turnover due to Fosamax therapy
Severely suppressed bone turnover (SSBT): A potential complication of Alendronate therapy. See: J Clin Endocrinol Metab. 2004 Dec 14; [Epub ahead of print], Odvina CV and others. PMID: 15598694. Alendronate (Fosamax) inhibits bone resorption and thus is often used to treat osteoporosis. This study reports that 9 patients had spontaneous non-spinal fractures while on alendronate therapy for osteoporosis or osteopenia. Six of these fractures showed either delayed or no fracture healing for 3 months to 2 years during therapy. Histomorphic (microscopic examination) analysis of the cancellous (inner) bone showed markedly suppressed bone formation, with reduced or absent osteoblastic (bone forming cells) surface in most patients. The osteoclastic (bone dissolving cells) surface was low or low normal in 8 patients and eroded surface was decreased in 4. Matrix (the soft tissue precursor to bone) synthesis was markedly diminished with absence of double-tetracycline label and absent or reduced single-tetracycline label in all patients. The same trend was noted for the cortical bone (the hard outer layer of bone). The authors note that, "Our findings raise 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." Note that some of these patients were also taking either estrogen or corticosteroids, but some patients took only the alendronate. The authors conclude that, "Our observations emphasize the need for increased awareness and monitoring for potential development of excessive suppression of bone turnover during long-term alendronate therapy."
Editor's comments about this study. This study raises warning flags that are potentially important to all of us on bisphosphonate for osteoporosis therapy. Although the study's findings concerned only patients taking alendronate, there is no reason to doubt that people taking other forms of bisphosphonates couldn't develop the same problem since all bisphosphonates have the same method of action. Because of the possible very important nature of this study, I'm going to analyze the findings very deeply and from many angles to see just how concerned we should be.
Summary of my thoughts on this study: For reasons that I hope will be apparent when you read the rest of this paper, I am concerned about SSBT, but not overly worried. The small number of patients (9), and the vast number of people taking bisphosphonates world wide who apparently have not had a problem like SSBT, are cause for being positive at this time. Also, the lack of a treatment alternative, and the good results I and so many others have had while taking Fosamax, are cause for optimism. If SSBT turns out to be more common that previously reported, my guess (and hope) is that subsequent studies will uncover why only some people develop the problem and will find ways to prevent or diagnose it before damage occurs.
A more detailed look at this study. There were 8 postmenopausal women and 1 man in this study with ages ranging from 49 to 70 years old. They were on alendronate therapy from 3 to 8 years to treat either osteoporosis or osteopenia, with 2 females also taking prednisone and 3 taking estrogen for hormone replacement therapy. Fractures occurred from 1 to 8 years after starting alendronate therapy. Atraumatic fracture sites included the femoral shaft (3), proximal femur (2), sacrum (2), vertebra and rib (1), pubic rami (1), metatarsal (1). All patients were also taking calcium and vitamin D supplements while taking alendronate. Six of the patients had delayed or no healing ranging from 3 months to 2 years after discovery of the fracture. Alendronate was stopped after fracture with healing occurring in 5 patients from 3 to 9 months after stopping alendronate. The other 4 patients had no healing from 8 to 12 months after stopping. Histomorphic analysis was done from transiliac bone biopsy. A summary of the authors' findings includes reduced bone volume in all patients with striking severe depression of bone formation in the cancellous bone. Tetracycline labeling would indicate bone formation was occurring, however, 5 of 9 specimens revealed only occasional single tetracycline labels with the mean calculated bone formation rate (BFR) rate 100-fold lower than in healthy postmenopausal women. Seven of the patients showed quiescent cancellous bone surfaces with minimal or no identifiable osteoblasts. Osteoid (prebone) thickness and volume were either normal or reduced. There was a trend toward low bone resorption with a low or low normal osteoclastic surface in all but 1 patient. The cortical bone showed decreased intracortical and endocortical osteoid surface with reduced osteoblast surface in all but one patient. Laboratory studies were done with results showing calcium, phosphorus, creatinine, 25-hydroxyvitamin D and PTH within the reference range. Markers of bone formation showed BsAP ranged widely and serum Oc was either low or at the lower end of normal. Bone resorption markers showed urinary NTx was low to mid-normal in 7 and high normal in 2 patients while urinary OH-pro was low to low normal in all 5 patients in whom it was measured. Bone mineral density (BMD) results are hard to evaluate from reading the study, but appeared to have ranged from 4 patients back in the normal BMD range after alendronate therapy to the other patients still being osteoporotic or osteopenic after alendronate therapy. Alendronate therapy was stopped after the bone biopsy in all patients. Five patients subsequently had healing while four patients showed non-healing of fractures. No patients had new fractures after alendronate was stopped.
Comments and analysis pertaining to the SSBT study
Bisphosphonate's method of action and effect on bone formation. "Many of the bisphosphonates inhibit bone resorption, the newest compounds being 10,000 times more active than etidronate, the first bisphosphonate described. The antiresorbing effect is cell mediated, partly by a direct action on the osteoclasts, partly through the osteoblasts, which produce an inhibitor of osteoclastic recruitment. When given in large amounts, some bisphosphonates can also inhibit normal and ectopic mineralization through a physical-chemical inhibition of crystal growth." See PMID: 9073324. Note that the following article mentions that bisphosphonates have no effect on bone mineralization--just resorption. "The bisphosphonate alendronate has many characteristics which suggest that it is suitable for use in osteoporosis. It is a potent inhibitor of osteoclast-mediated bone resorption with no adverse effect on the mineralization of bone." PMID: 7703618. An additional study alludes to the importance of the mevalonate pathway. "The nitrogen-containing bisphosphonate alendronate inhibits osteoclast-mediated bone resorption through inhibition of the mevalonate pathway." PMID: 1190770. These same authors suggest it isn't necessarily a reduction in number of osteoclasts that is happening, rather their inactivation: "In conclusion, our findings suggest that alendronate inactivates osteoclasts by mechanisms that impair their intracellular vesicle transport, apoptosis being only a secondary phenomenon to this." An additional study summarizes the mevalonate pathway mechanism. "They act on the cholesterol biosynthesis pathway enzyme, farnesyl diphosphate synthase. By inhibiting this enzyme in the osteoclast, they interfere with geranylgeranylation (attachment of the lipid to regulatory proteins), which causes osteoclast inactivation." PMID: 12590887. For anyone wanting to really understand this mechanism, here is a study to read: PMID: 10320520. Editor's summary of this segment. Alendronate functions primarily by inhibiting bone resorption, and thus having less effect on bone formation, with a net effect of increasing bone BMD in osteoporotic patients. To understand how potent it is, note that alendronate can inhibit bone resorption up to 95% of normal.
Animal studies that include histology or microstructural analysis. Alendronate's effect is apparently on the mature osteoclasts, not precursor cells. "Alendronate (0.25 mg/kg, subcutaneously) given to mice for periods up to 4 weeks suppressed bone resorption, as expected, but did not affect the capacity of bone marrow cells to develop into mature osteoclasts and resorb the calcified matrix of bone explants." PMID: 9108353. Here is an article that found alendronate prevented the normal loss of bone in rats when there is no skeletal loading, but also showed some decrease in bone formation, even though the alendronate's main effect was on resorption. "Skeletal unloading markedly reduced the normal increase in tibial mass and calcium content during the 9 day period of observation, primarily by decreasing bone formation, although bone resorption was also modestly stimulated. Alendronate not only prevented the relative loss of skeletal mass during unloading but led to a dramatic increase in calcified tissue in the proximal tibia compared with the vehicle-treated unloaded or normally loaded controls. Bone formation, however, assessed both by tetracycline labeling and by [3H]proline and 45Ca incorporation, was suppressed by alendronate treatment and further decreased by skeletal unloading." [Note this is in disagreement with previously mentioned articles stating alendronate did not affect bone formation.] PMID: 7863829. Following is a one-year high-dose alendronate study in dogs that found significant improvements in cancellous bone structure with the authors noting: "These significant improvements of cancellous bone architecture provide a rationale for the clinical observation that fracture risk decreased by 50% in the first year of bisphosphonate therapy with only a 5% increase in bone mineral density. We conclude that bisphosphonates enhance mechanical properties and reduce fracture risk by improving architectural anisotropy of cancellous bone 3-D microarchitecture." PMID: 14563003. Here's a fracture healing study in dogs (done at Merck's facility) that showed normal healing and results in dogs. "Therefore, in this study, treatment with alendronate before or during fracture healing, or both, resulted in no adverse effects on the union, strength, or mineralization of bone in mature beagle dogs." PMID: 8618170. Another study on dogs done at Merck's facility showed no adverse effects on bone volume and indices of architecture when using alendronate (ALN). The authors concluded, "Cortical or cancellous bone volume and indices of architecture were not affected by treatment. Osteoid thickness and mineralization lag time were not changed by treatment. Tissue level bone turnover was inhibited in a dose-dependent manner in males. The results indicate that long-term ALN administration at up to 5 times the dose used for treatment of osteoporosis in clinical trials causes no abnormalities in bone remodeling or bone structure." PMID: 8558443. The following study unfortunately involves high-dose etidronate rather than alendronate, but the findings are interesting and might be applicable to the Odvina and others study's results. The authors note, "Fractures of ribs and/or thoracic spinous processes were found in 10 of 11 dogs treated with the higher dose EHDP." Additionally they state, "Histomorphometric measurements showed a significant reduction of cancellous bone turnover in both EHDP-treated groups compared with controls. In dogs treated with the higher dose EHDP, activation frequency was reduced to zero in both cortical and cancellous bone." These histomorphometric results sound almost identical to Odvina and others' results. PMID: 10865204. The following two studies looked at microdamage repair after high-dose bisphosphonate therapy in dogs. The concept is that bisphosphonates slow down or prevent the bone resorption and rebuilding that is a part of normal bone maintenance and repair. Segments of bone that aren't allowed to resorb thus have much longer life spans than normal and could be more susceptible to microdamage which could weaken the bone even in the presence of normal bone density. Microdamage repair is not the central issue of the Odvina and others study, but they do mention the concept. It doesn't appear to be particularly germane to the patients they discuss with SSBT, but it should be of importance to people taking bisphosphonates, thus my reasons for briefly discussing the issue. See PMID: 11344052 and PMID: 11768198.
Human studies that include histology or microstructural analysis. Here's a study involving transiliac biopsies on 53 postmenopausal osteoporotic women treated for 2 or 3 years with alendronate (ALN) and compared to placebo (PLA). The authors were measuring the mean degree of bone mineralization (MDBM) by quantitative microradiography. They found, "After 2 years of ALN, MDMB in compact bone was 9.3% (p = 0.0035) and in cancellous bone was 7.3% (p = 0.0009) higher, respectively, than PLA. After 3 years of ALN, MDMB in compact bone was 11.6% (p = 0.0002) and in cancellous bone was 11.4% (p = 0.0001) higher, respectively, than (placebo) PLA. After 2 and 3 years of ALN, and compared with the corresponding PLA, the distribution of the degree of mineralization in compact and cancellous bone showed a clear shift toward the highest mineralization values and a decrease in the number of bone structure units having low values of mineralization." These results appear to be opposite those found in Odvina and others, but not totally comparable since microradiography was used rather than histomorphometrics. PMID: 11062357. Here is an excellent comparative study as concerns histomorphometric measurements of transiliac biopsies of bone on osteoporotic patients. These patients had been on corticosteroid therapy before beginning alendronate therapy for osteoporosis. I suggest reading the entire abstract since there are too many details to summarize. But the authors noted, "In conclusion, alendronate treatment in patients on glucocorticoids decreased the rate of bone turnover, but did not completely suppress bone remodeling and maintained normal mineralization at all alendronate doses studied. Alendronate treatment did not influence the osteoblastic activity, which is already low in glucocorticoid-induced osteoporosis." PMID: 10780867.
What is normal histomorphometric analysis? In order to interpret the above results, it will be helpful to have a "normal" histomorphometric analysis with which to compare the findings. See: J Bone Miner Res. 1988 Apr;3(2):133-44, Static and tetracycline-based bone histomorphometric data from 34 normal postmenopausal females. Recker RR and others. PMID: 3213608 There are three important comments in this study: 1) "MAR showed a marked decline with age." MAR is mineral apposition rate. 2) "In contrast, the extent of tetracycline-labeled surfaces varied widely without a secular trend. Double-label surface (dLS/BS) ranged from 0.5 to 8.0% and single-label surface (sLS/BS), from 0.5 to 10.5%." 3) "Using only double-label surface to represent mineralizing surface, volume-based bone formation rate (BFR/BV) ranged from 0.7 to 28%/yr, and the remodeling period (Rm.P) varied from 0.28 to 4.5 years." Editor's comments: What stands out to me is the huge range in these "normal" results for BFR, MAR and tetracycline labeled surfaces. Were all the people in the Odvina and others study in the lowest percentile of all the groups mentioned here before they started alendronate therapy? Would that make a difference? Obviously we don't know, but it could be a point of major consideration for future study.
How many people have osteoporosis? According to the National Osteoporosis Foundation, www.nof.org, "Osteoporosis is a major public health threat for an estimated 44 million Americans, or 55 percent of the people 50 years of age and older. In the U.S. today, 10 million individuals are estimated to already have the disease and almost 34 million more are estimated to have low bone mass, placing them at increased risk for osteoporosis." If 10 million people have osteoporosis, I would think that conservatively there would be at least one million undergoing bisphosphonate therapy, but that is a total guess. I bring this up to try to give some consideration as to how significant the 9 individuals in the Odvina and others study are. That is, how much should we be worrying about being in the severely suppressed bone turnover group? Or should we worry that there are many more than 9 people who have had this problem and that was never reported in the literature?
If alendronate therapy is stopped due to SSBT, what option is there for therapy? For men the long-term therapy options other than bisphosphonates are pretty limited. Forteo (human parathyroid) can only be given for a year or two. If hypogonadism is the cause of the osteoporosis, then testosterone therapy as the sole treatment might be effective. But for idiopathic osteoporosis, treatment options are limited. Strontium ranelate may become an option, but it isn't yet approved for treatment of osteoporosis. See a recent Update for more information. Thus the best option is that SSBT is a rare occurrence. Or, that other ways to deal with it, prevent it, or diagnose it before fracture occurs, will be discovered with additional research and more cases being discovered.
Concerns and questions about the Odvina and others study. Since the main method of action of bisphosphonates is to block bone resorption, why was bone formation also blocked in these people? Why were all fractures nontraumatic and in bones other than the spine or hip where osteoporotic fracture is most common? Why did some people show normal BMD on dual-energy X-ray absorptiometry (DXA) and others didn't, yet all had the atraumatic fractures? Could this be because DXA measures areas that didn't fracture and for some reason BMD differed from site to site in SSBT patients? Why did the people with normal BMD on DXA still show the same histomorphometric results as those with osteoporotic DXA result? Why did healing occur when alendronate therapy was stopped? Didn't these people have osteoporosis and need therapy to improve their BMD and reduce their fracture risk? If so, why aren't they at even greater risk by stopping osteoporosis therapy? Won't some form of therapy eventually have to be started even if they are improving early on? Why did some fractures heal after stopping alendronate and some didn't? Why the apparent disconnect between DXA, histomorphic results and markers of bone formation/resorption?
Possible reason for the results: 1) It appears that high-dose bisphosphonates are capable of not only blocking bone resorption but bone formation. If some genetic or other abnormality in a very few people allowed them to absorb considerably more alendronate than the normal approximately 1% of each dose that is expected, it is possible this could lead to SSBT. It might also be possible to test the level of urinary excreted bisphosphonate after taking the medication to see if you are in this group. Or measurements of bisphosphonate levels in bone might reveal this problem if there is a fairly simple and painless way to test for that. 2). As noted above, "normal" histomorphometric results vary across a wide range. A future study designed to see how people respond to bisphosphonate therapy based upon their baseline histomorphometric values might be productive, as well as helpful to explain the results of the Odvina and others study. At a minimum those results would remove one variable from the equation.. 3) I've shown before that clinical studies report their results in terms of mean improvement, or mean BMD, etc. When you look at the entire population in the study there are often outliers that don't fit at all into the results. See a recent Update for more on this. Should investigators look at these outliers to see if it is possible to figure out why they don't appear to benefit as others in the study do? Such findings might apply to the Odvina and others study.
Summary. Fosamax has been used to treat osteoporosis for well over 10 years now with 9 reported cases of SSBT. It isn't time to panic, but to remain wary in case this is the tip of the iceberg. Certainly any type of spontaneous fracture would be cause for a thorough diagnosis and treatment, especially for anyone on long-term bisphosphonate therapy. Feel free to discuss your treatment options with your physician, but I would be very hesitant to change therapy just based upon this one study. Anyone's thoughts on this topic would be appreciated, don't hesitate to send an email.