The bisphosphonate drugs have gotten a bit of bad press lately, owing to a number of case reports suggesting that they can cause osteonecrosis of the jaw. The broader question is whether bisphosphonates are truly necessary for preventing osteoporosis in postmenopausal women, or more precisely, in which patients are they truly needed.
There are now 150 cases of bisphosphonate-associated maxillary osteonecrosis in the medical literature. The latest report, by researchers at the Botsford General Hospital, Farmington Hills, MI, documents the development of mandibular or maxillary osteonecrosis in 23 women treated with bisphosphonates. Though this complication is a serious concern, bear in mind that 18 of these patients had complications related to primary malignancies, and were being treated with intravenous bisphosphonates. Only 4 of the 23 had osteoporosis and were being treated with oral alendronate, a more common clinical scenario (Farrugia M, et al. Laryngoscope. 2006; 116: 115–120).
Most, though not all, of the reported cases have involved intravenous therapy, malignancies, or complicated dental interventions. The latter point is important: dental implant failures have been seen in a number of patients receiving oral bisphosphonates for osteoporosis, and it could be, especially in those patients who have suffered this necrosis after dental procedures, that there is compromised postoperative bone-healing due to the drug’s inhibition of bone turnover. A non-healing wound could then lead to osteomyelitis, and then necrosis. Another mechanism may be that the bisphosphonates are decreasing the levels of vascular endothelial growth factor.
Assuring dental health may be smart preventive medicine prior to even oral bisphosphonate therapy. More certainly, dental health assessment is essential in patients who have metastatic cancer, for whom oral or IV bisphosphonate therapy may slow the development of bone metastases.
I contend that for most perimenopausal and young postmenopausal women with osteopenia, the use of bisphosphonates constitutes over-treatment. Other osteoporosis prevention strategies including dietary advice, exercise and strength training, vitamin D, calcium, adequate trace mineral intake, and low alcohol intake are the name of the game. We should be monitoring bone density over time, to ascertain either stability or further and more problematic bone loss.
Hooray for K
A recent article in the Archives of Internal Medicine suggests that vitamin K could be a major ally in preventing osteoporosis and associated fractures.
Vitamin K has been thought for some time to be a contributing factor in preventing bone loss. It is required for the production of osteocalcin, the protein matrix on which mineralization occurs. Osteocalcin attracts calcium to bone tissue, facilitating calcium crystal formation. Vitamin K plays a key role in the formation, remodeling, and repair of bone by helping the calcium adhere to the site of this protein matrix.
Individuals with osteoporosis have been found to have lower serum vitamin K levels when compared to age-matched controls (Kanai T, et al. Int J Gynecol Obstet. 1997; 56: 25–30). The amount of vitamin K required for optimal bone health appears to be greater than that needed for normal blood clotting (Sokoll LJ, et al. Am J Clin Nutr. 1997; 65: 779–784; Binkley NC, et al. Am J Clin Nutr. 2002; 76: 1055–1060).
The most recent article is a meta-analysis of 13 published clinical trials, and it makes an even stronger case for vitamin K in osteoporosis. In 12 of the 13 clinical trials, supplementation with large doses of vitamin K prevented bone loss of the hip and vertebrae (Cockayne S, et al. Arch Intern Med. 2006; 166: 1256–1261). The one trial that showed no effect was a study of premenopausal athletic women given 10 mg per day of vitamin K1.
Even more impressive, fracture rates—which are the proof of the pudding in any bone loss prevention intervention—were available in seven of the fifteen studies, and these numbers showed that vitamin K reduced hip fractures by 77%, other non-vertebral fractures by 81%, and vertebral fractures by 60%. These individuals were using vitamin K2, specifically menaquinone-4. Two of the trials used 1 mg/day and 10 mg/day of vitamin K1. Ten trials used 45 mg/day of vitamin K2 (menaquinone-4), and 1 used 1 mg/day.
Most of the studies in this meta-analysis were of postmenopausal women, but some also included premenopausal women who had diseases associated with higher risk of osteoporosis, including primary biliary cirrhosis, or conditions requiring treatment with glucocorticoids.
Overall, the fracture reductions reported in the new metanalysis exceed those typically seen with alendronate (about 50%), and vitamin K seemed to proffer this benefit with far fewer side effects than typically seen with bisphosphonates. Approximately 17% of women taking bisphosphonates experience problematic gastroesophageal reflux and esophagitis.
Before we break out the champagne and toast the virtues of vitamin K, it is important to keep in mind that the longest study in this meta-analysis was only 3 years. Though that may count as long-term outcomes in many areas of medicine, it is a short amount of time in the world of bone density and fracture research. Still, I believe vitamin K holds tremendous promise in preventing osteoporosis-related fractures, especially in younger women.
For older women, who actually have osteoporosis, oral bisphosphonates do make some sense. Exercise, calcium and vitamin D are important in these patients, too. But realistically, they have modest benefits in women who already have frank osteoporosis. In my experience, any risk of jaw problems is far less troublesome than the risk of fractures.
Women greater than 65-years-old, who have either significant osteopenia or osteoporosis, are certainly candidates for bisphosphonates, proven to reduce fracture risk by 50%. Hopefully, future research will help determine the minimum treatment time and the lowest possible doses needed to prevent major bone loss.
Fortunately, there is no rapid bone loss after discontinuing bisphosphonate treatment, compared to the rapid loss that does occur after discontinuation of estrogen. In time, research on natural medicines can be expanded to include the role of nutrients in not only bone density, but also bone strength and bone architecture. Significantly higher doses of vitamin D than are commonly used, as well as red clover isoflavones, soy isoflavones, manganese, boron, and fish oils may have significant effects on bone strength. I believe that natural therapies will play an increasingly important role in slowing bone loss and reducing fracture rates, but we really need to see this borne out by future research.
Black Cohosh & Bone
Poor Black Cohosh (Cimicifuga racemosa) has taken a real beating from researchers in recent years. Fans of this herb can take a little bit of solace in a new report indicating that it may increase osteoblast activity in post-menopausal women. Even more important, this double-blind trial found no evidence that the herb causes liver toxicity, as was reported in a study published earlier this year.
The current trial involved 62 postmenopausal women aged 40–60 years old, who were randomized to either 40 mg of Black Cohosh extract per day, 0.625 mg of conjugated equine estrogens, or placebo for 12 weeks. The investigators measured markers of bone turnover including bone-specific alkaline phosphatase. Other tests included estradiol, FSH, LH, SHBG, triglycerides, total cholesterol HDL, and LDL. The researchers also used a vaginal maturation index and transvaginal ultrasound to measure the dimensions of the endometrial stripe in each patient.
Bone turnover markers indicated a slight but non-significant lowering of bone specific collagen in the Black Cohosh group; this was significantly decreased with the conjugated equine estrogens. Black Cohosh uniquely stimulated osteoblast activity, while estrogen inhibited osteoclast activity. Not surprising, estrogen showed a strong estrogenic effect on vaginal mucosa, while the Cohosh had only a very weak estrogen-like activity.
Estrogen-treated women showed significantly elevated estrogen levels at 4, 8 and 12 weeks (Surprise! Surprise!), and a significant suppression of FSH. Black Cohosh did not show this effect, nor did it impact LH levels. Estrogen increased sex hormone binding globulin, where Black Cohosh and placebo showed no such effect. These findings are consistent with what is typical in estrogen studies, and also with recent research on Black Cohosh (Wuttke W, et al. Menopause. 2006; 13: 185–196).
Endometrial thickness was significantly increased by estrogen and remained unchanged in the Cohosh and placebo groups. There was a significant increase in the number of vaginal superficial cells in the estrogen group, and a moderate increase in the Cohosh group, with a slight decrease in the placebo group. There were no significant effects on TC, HDL-C, or LDL-C for either of the treatments. Serum triglycerides were significantly higher in both the estrogen and Black Cohosh groups, compared to placebo. Importantly, there was no increase in liver enzymes with any of the interventions.
The results of this study suggest that Black Cohosh has a mild estrogen-like effect on vaginal mucosa, and an ability to increase a marker of bone metabolism, indicating a benefit of increased osteoblast activity. Perhaps the most important finding of this study is that there was no evidence of hepatotoxicity with Black Cohosh, and no negative hormonal effects. Though the study was small, the findings should help restore some of our clinical confidence in this useful herb.
