No more newsletters. After considerable thought on the subject, I`ve decided to stop publication of the newsletter with this issue. After more than five years of issues, a lot has changed concerning men`s osteoporosis. There is more awareness, and there are several effective treatments. Thus, it is not quite as frightening a diagnosis as it once was. This has been reflected in the greatly reduced number of emails I get from men concerned by their recent diagnosis of osteoporosis. Also, I`m finding that I no longer thrive on the deadlines every three months, so I`m replacing the newsletter with a less formal and intermittent addition of information to the Men`s Osteoporosis Support Group Web site. When I find interesting new research, get worthwhile questions to Ask the Experts, or if an interesting topic needs a full discussion and presentation, then I`ll add that to a section on the Web site. So, rather than checking the Web site quarterly, you can take a look much more frequently now to see what is new there. Thanks for all your support and help with the newsletters, I hope they have been helpful. I know I`ve learned so much about osteoporosis doing them.
From our readers. Marshall Klotz was kind enough to email me a couple of times in the past months to send along some information and observations. He had asked about the superiority of Fosamax vs. Actonel, and I have included a section on that later in the newsletter with my findings. He also mentioned that for those taking one of the bisphosphonates and paying for it out of pocket, he suggests you look at the Canadian online pharmacies for a substantial price break. Here are some that he found (but has never purchased from):
www.thecanadiandrugstore.com
www.canadianmedsusa.com
www.rxcarecanada.com
www.canadameds.com
www.canusamed.com
I went to www.canadianmedsusa.com to check the price of Fosamax. Marshall indicated that if you buy the 40-mg dose it is a substantial savings, and he is definitely right. For instance, a one-month supply of 70-mg Fosamax is $45.88. If you take one 40-mg Fosamax twice weekly or two once weekly, the one-month supply would cost you $25.97. Buy and try at your own risk since I have no experience with any of these pharmacies. Check them out, be sure they are legal, and that you can have problems corrected if needed, that is, that you have some kind of guarantee. Marshall also tracks the various clinical trials sites and sent me the following list:
I assume there is some, if not almost total, information overlap on all these sites. But, some offer services that others don`t, so check them out and bookmark your favorite ones. Centerwatch will email you when a trial that you are interested in comes up, so keep that in mind.
Actonel once-weekly dosing approved. Proctor and Gamble received FDA approval for once-weekly Actonel dosing in the 35-mg tablet in May 2002 with that formulation going to market in June 2002. With the simplicity, safety, and lack of side effects of the once-weekly dosing for both Fosamax and Actonel, the other dosing regimens appear to have little to offer.
Protos, strontium ranelate, a new osteoporosis drug. Strontium ranelate is currently being studied in clinical trials. So far it has been shown to be effective both to stimulate bone formation and to block bone resorption. In the 2-gram/day dose, it has increased lumbar BMD 2.97% annually in postmenopausal women with osteoporosis and history of spinal fracture, with this result significantly different compared to placebo. Studies have found no difference in safety profile compared to placebo. For a summary of the current results for Protos, see: Curr Pharm Des 2002;8(21):19079-1916, Strontium ranelate in osteoporosis. Reginster JY. PMID: 12171530. So, the future looks bright for adding another medication to the list of those that effectively treat osteoporosis.
Literature review
Finding articles mentioned. To see abstracts of these articles, go to PubMed at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi and enter the numeric portion only of the PMID into the search block and click on Go or hit the enter key.
Caffeine`s effect on BMD. There has been a lot of conflicting information over the years about coffee, tea, and other caffeine-containing drinks and how they relate to BMD. Dr. R.P. Heaney is one of the world`s authorities on calcium and it`s relation to osteoporosis. He has a article that should put an end to the discussion and allow anyone who was worried about this topic to relax. See Food Chem Toxicol 2002 Sep;40(9):1263, Effects of caffeine on bone and the calcium economy. Heaney R. PMID: 12204390. The small negative effect of coffee/tea drinking on calcium economy appears to be mainly due to the fact that these drinkers are substituting their beverage for milk or some other calcium-containing beverage. He points out that, "The negative effect of caffeine on calcium absorption is small enough to be fully offset by as little as 1-2 tablespoons of milk." Here is a summary of his findings on this topic: "All the observations implicating caffeine-containing beverages as a risk factor for osteoporosis have been made in populations consuming substantially less than optimal calcium intakes. There is no evidence that caffeine has any harmful effect on bone status or on the calcium economy in individuals who ingest the currently recommended daily allowances of calcium." So, get your daily allowance of calcium and drink your coffee or tea without concerns.
Mortality rates after taking risedronate (Actonel). Those of us who have been taking one of the bisphosphonates, such as Fosamax or Actonel, for the last several years will probably be heartened by the results of a recent study. See: Regul Toxicol Pharmacol 2002 Jun;35(3):320, Assessment of mortality in patients enrolled in a risedronate clinical trial program: a retrospective cohort study. Steinbuch M and others. PMID: 12202047. This retrospective study looked at the mortality rates of 7,981 people who had been enrolled in risedronate clinical trials. The authors concluded: "Follow-up mortality data in this retrospective cohort study demonstrate that treatment with risedronate has no effect on overall mortality rates." Since the bisphosphonates are relatively new medications, it is always comforting to know that there are no serious side effects that were not discovered during clinical trials. The fact that mortality rates were the same between those who took placebo and those who took risedronate means those of us on risedronate, and probably all bisphosphonates, are not at risk for the most serious side effect of all-death.
Do calcium supplements deplete phosphorous? A recent study questions the use of calcium supplements that don`t also contain phosphorous, especially in older individuals with osteoporosis. See: J Am Coll Nutr 2002 Jun;21(3):239-44, Calcium effects on phosphorus absorption: implications for the prevention and co-therapy of osteoporosis. Heaney RP, Nordin BE. PMID: 12074251. Additionally, this research was discussed at the National Osteoporosis Foundation Fifth International Symposium, March 9, 2002. In this discussion, Dr. Heaney was joined by Dr. Ralph Shapiro and Dr. John J.B. Anderson. Dr. Shapiro noted, "We conclude that, in any growth situation, both calcium and phosphorus are needed to support an increase in bone mass." Further, "If the diet is low in phosphorus, calcium supplementation alone will be inadequate, and may aggravate a phosphorus deficiency. A phosphorus-containing calcium source would seem to be preferable to one providing calcium alone." Dr. Anderson added, "Individuals with low phosphorus intakes are at increased risk of low bone mass and fractures because of the development of serum phosphate concentrations below the normal range." Dr. Heaney noted, "The best way to help our patients meet their needs is to use a source that provides both calcium and phosphorus, such as dairy products and/or a calcium phosphate supplement." The problem is that if individuals just supplement calcium intake with, e.g., calcium carbonate, there is a resulting decrease in phosphate absorption. Thus, less phosphate is available to build bone which is about 50% calcium and 50% phosphorous. Natural sources of calcium such as milk products also have phosphorous, so they aren`t a problem. Those most susceptible would be older individuals with a high intake of calcium with a concomitant low intake of phosphorous. The current emphasis, especially by the companies that make the calcium supplements, is on using them solely to get adequate calcium. As I`ve indicated in this newsletter before, supplements should be secondary to getting your calcium through eating foods that are natural sources of calcium. Tofu is an alternate source of calcium if you don`t eat dairy and it appears to have about the same phosphorous content as milk. Or, if you want to be certain, take a calcium supplement containing phosphorous. In order to evaluate your phosphorous intake, here is a list of foods with high or moderate phosphorous content. High content: Liver, wheat germ, sunflower seeds, pumpkin seeds. Moderate content: Dairy products, cola beverages, meats, whole grains, muffins, chocolate, legumes, nuts and seeds, pizza, bran cereals.
Prostate Cancer and calcium consumption. In several newsletters I have discussed previous studies that have implicated high calcium intake with increased risk of prostate cancer. This apparently is due to the vitamin D-lowering effect that calcium has, with vitamin D being protective of prostate cancer. A recent study found that high-fat and high-calcium intake weren`t implicated in causing early-stage prostate cancer, but they were a risk factor for fueling the progression from localized to the advanced disease. This would be similar to the effect of testosterone-it isn`t causative of prostate cancer--but if cancer develops, testosterone fuels its growth considerably. See: Cancer Epidemiol Biomarkers Prev 2002 Aug:11(8):719-25, Associations of energy, fat, calcium, and vitamin D with prostate cancer. Kristal AR and others. PMID: 12163324. Also, see http://www.supplementquality.com/efficacy/prostate_fat_calcium.html for a thorough discussion of all aspects of this interesting study. There are several dietary factors that are noted in the study to help men decrease the risk of developing localized or advanced prostate cancer, so it is worthwhile reading. The important finding for men with osteoporosis is that it appears there is no need to worry particularly about the higher calcium intake we might have as long as regular PSA, digital rectal exams, and other prostate testing is done. With no prostate cancer present, high calcium intake is not a significant risk factor. Only once a diagnosis of prostate cancer is made is there a need to exercise caution in controlling calcium intake to help prevent spreading the cancer to regional and distant areas.
Vitamin K2 with other therapies? A recent study in Japan, with obvious implication for women on hormone replacement therapy (HRT), may also apply to others with osteoporosis. See: J Bone Miner Metab 2002;20(4):235-9, Treatment for patients with postmenopausal osteoporosis who have been placed on HRT and show a decrease in bone mineral density: effects of concomitant administration of vitamin K(2). Hidaka T and others. PMID: 12115070. These authors found that about 12% of women on HRT of Premarin or Premarin combined with Provera will show increased BMD for the first two years of therapy and then have a decrease in BMD the third year. They hypothesized that vitamin K2, which has been shown to stimulate bone formation, may combine with the HRT to increase BMD in this group of women. The women who lost BMD the third year were given 45 mg/day of vitamin K2 for one year. Bone densitometry showed a mean decrease in BMD for the ten women from 0.791 gm/cm2 at two years of HRT to 0.734 gm/cm2 after three years. There was a significant increase in BMD (P < 0.03) after one year of vitamin K2 therapy to 0.783 gm/cm2 for a 6.7% improvement in BMD. As I mentioned in a previous newsletter, a woman I know who had been on long-term HRT recently developed osteoporosis, and just last week a 56-year-old female across the street who had been on long-term HRT also developed osteoporosis. So, the findings that some women lose BMD while on HRT in this study appear to have some validity from my personal observations. Estrogen HRT inhibits bone resorption, the same method of action that bisphosphonates have. So, it is plausible that for anyone taking Fosamax, Actonel, or other bisphosphonates and not getting desired increases in BMD, the addition of vitamin K2 to their regimen might increase BMD. I would certainly discuss this option with my care provider if I was unhappy with current results from antiresorptive agents. Vitamin K can be taken as a supplement, but since it is involved in the blood clotting mechanism, should be used with caution if you are on blood thinning agents.
Fosamax vs. Actonel
Comparison of Fosamax to Actonel. I recently received a request to compare Fosamax (alendronate) and Actonel (risedronate) to try to see if there is a compelling reason to pick one over the other. Although there are probably still a lot of people taking the daily dose of these medications, I consider that dosing method passe, having been replaced by the once-weekly dosing. As concerns effectiveness, since most of those studies were done with daily dosing, and the results should be roughly equal between daily and weekly dosing, I will consider all dosing methods when comparing efficacy. NOTE: This is not a comprehensive review of all studies. I just selected several from PubMed to get a representative sample. So judge my results accordingly.
Effectiveness of BMD increase.
STUDY PMID
# OF PEOPLE
TIME & MEDICATION
SPINE/HIP
RESULT
10550467
1908
10 mg/d Fosamax 1 Year
+4.0%/2.8% 1/yr
10746426
519
70 mg/w Fosamax 1 Year
5.1% spine 1/yr
7625419
188
20 mg/d Fosamax 2 Years
7.21%/5.27% 2/yr
12020142
327
10 mg/d Fosamax 2 Years
4.4%/3.4% 2/yr
8948272
478
5 or 10 mg/d Fosamax 3 Year
9.6%/4.7% 3/yr
8833208
516
10 mg/d Fosamax 3 Years
7.4%/5.5% 3/yr
12085156
1209
35 mg/w Actonel 1 Year
3.9% 1/yr
12113633
Uncertain
30 mg/w Actonel 1 Year
4.8%/2.2% 1/yr
9425508
543
5 mg/d Actonel 2 Years
4% spine 2/yr
9467547
111
5 mg/d Actonel 2 Years
5.7%/5.4% 2/yr
10527181
489
5 mg/d Actonel 3 Years
5.4%/1.6% 3/yr
Effectiveness of fracture reduction.
STUDY PMID
# OF PEOPLE
TIME & MEDICATION
RESULTS
9875874
4272
Fosamax 5 mg/d 2 yr and 10 mg/day 2 yr
44% reduction vertebral fx and 36% reduction hip fx
7477143
994
Fosamax 10 mg/d 3/yr
48% reduction vertebral fx
10663363
1226
Actonel 5 mg/d 3/yr
49% reduction vertebral fx
10527181
2458
Actonel 5 mg/d 3/yr
41% reduction vertebral fx
G.I. side effects.
I found no case reports of G.I. side effects posted on PubMed for either medication when the weekly dose was used. In looking at all the clinical trials, none reported a difference from placebo for either alendronate or risedronate for any dosage or time period. Yet we all know that alendronate had many case reports of gastric problems with the daily dosing. Perhaps the most interesting study on this topic was done recently at the Colorado Center for Bone Research. See: Clin Ther 2000 Dec;22(12):1433-42, Rechallenge of patients who had discontinued alendronate therapy because of upper gastrointestinal symptoms. Miller PD and others. PMID: 11192135. The study involved 172 women who had stopped alendronate therapy due to upper gastrointestinal (UGI) problems. They were rechallenged with either 10 mg/day alendronate or placebo for eight weeks. 14.8% in the alendronate group and 16.7% in the placebo group discontinued therapy due to UGI problems. The authors concluded, "The results of this study suggest that many UGI adverse experiences reported during therapy with alendronate may reflect a high background incidence of UGI complaints and an increased sensitivity to detection of such complaints, rather than a causal relationship to therapy." This makes it appear that the results of the clinical trials were correct, and that, because of its reputation as being able to cause UGI problems, alendronate in the daily dose will get blamed for every gastric pain that anyone taking it ever gets. Fortunately, we now have weekly dosing as the standard so we can get beyond this issue. With the weekly dosing regimen there appears to be no difference between the two medications in UGI complications. And, as further confirmation of the tolerability of the once-weekly alendronate dosing, there is a recent endoscopic study showing no difference between alendronate and placebo over a ten-week once-weekly dosing period with individuals taking 70 mg/week of alendronate or placebo. This study confirms endoscopically what has happened clinically with the lack of problem reports with the once-weekly dosing regimen. See: Am J Gastroenterol 2002 Jan;97(1):58-64, The upper GI safety and tolerability of oral alendronate at a dose of 70 milligrams once weekly: a placebo-controlled endoscopy study. Lanza F and others. PMID: 11808969.
Summary. A close look at the change in BMD by year for the two medications appears to show them equal except for the three-year time period, with alendronate being superior at that time interval. But there is only the one study with which to compare for the three-year risedronate results. Also, keep in mind that these studies are hard to compare: They often have slightly differing dosing regimens, use a different age group for the tests, have different T-scores at the start, etc. There were several more risedronate studies available, but they dealt with corticosteroid users, so I didn`t want that variable involved. The more important end point is the reduction in fracture rate which also shows about equal results. Gastric problems appear to be a thing of the past with the once-weekly dosing regimen. Thus my analysis is that there is no apparent difference to allow someone to chose between alendronate and risedronate when used with the once-weekly dosing. If you are paying for your medications, cost could be important. I checked both U.S. and Canadian online pharmacies. By far the cheapest medication is 40 mg Fosamax and prices are about 30-40% higher in the U.S. than Canada for all dosages. Fosamax was slightly more expensive than Actonel at the one U.S. online pharmacy I checked ( $61.90 vs. $63.94 for a one-month supply of once-weekly pills).
Disclaimer. Diagnosis and treatment of osteoporosis are the responsibility of the patient and his or her physician. Nothing in this newsletter is to be interpreted as a recommendation for treatment or to change treatment that your physician has prescribed. Although we attempt to assure that information in this newsletter is factual, errors will occur. It is the responsibility of the reader to verify that information they are acting on is factual. There is no relationship between this newsletter and any national osteoporosis group, including the National Osteoporosis Foundation. All references to any such groups are for informational purposes only.
EDITOR
