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Improving and Extending Management of Osteoporosis

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

7th European Congress on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ECCEO 7)

Porto, Portugal / March 28-31, 2007

According to investigators here this week, as the population gets increasingly older, more individuals will be at risk of bone density loss and fractures. Hip fracture, in particular, is associated with high morbidity and mortality—21% of women aged ³65 years die within one year of hip fracture. Vertebral fractures are also associated with loss of quality of life, back pain and higher mortality. Furthermore, as Prof. Christian Roux, Cochin Hospital, René Descartes University, Paris, France, explained, “Vertebral fractures are an important sentinel indicating the risk of sustaining second fractures in subsequent years.”

Identifying and Treating Patients at Risk

Bone densitometry measurements can identify individuals at risk, but although bone mineral density (BMD) is an indicator of greater risk of future fractures, it should be taken together with age, which is another important risk factor. For calculating risk, Prof. Roux suggested a Web-based tool ( which, although not validated for some countries, can provide a useful indication of overall risk.

“Given that we have the diagnostic tools and effective treatments, do we give these treatments?” asked Prof. Roux. “The answer is no… This is the challenge we are facing with osteoporosis.” According to a survey of 200,000 postmenopausal women attended to in 4200 primary care practices in the US, osteoporosis was not considered a problem, even though 11% had bone fracture clearly related to bone fragility. Prof. Roux emphasized, “We must improve the awareness of both clinicians and patients of the disease.”

Clinical Studies of Bisphosphonates

The first of the nitrogen (N)-containing bisphosphonates to emerge was alendronate. The pivotal randomized, placebo-controlled FIT (Fracture Intervention Trial) compared postmenopausal women receiving alendronate 5 mg, then later 10 mg/day, with placebo for 36 months (Black et al. Lancet 1996;348(9041):1535-41). The primary end point was new vertebral fractures, although nonvertebral fractures were also investigated. Among the findings demonstrated was a 90% reduction in multiple (³2) new vertebral fractures with active treatment. “Before this study came out, we had no evidence that drugs could reduce the risk of multiple fracture,” commented Dr. Sol Epstein, Mount Sinai School of Medicine, New York, New York. Meta-analyses of randomized clinical trials are perhaps the most robust way of assessing the efficacy of a compound. In one such analysis, the reduction in the risk of hip and non-spine fracture was 49 to 55% for alendronate and 26 to 27% for risedronate (Liberman et al. Int J Clin Pract 2006;60(11):1394-400).

These studies were carried out with daily dosing regimens, but as reported by Dr. Epstein, “We have moved into another era now, the era of the extended dosing interval.” According to Dr. Epstein, the extended dosing regimens are possible because the strength of the effect of bisphosphonates depends on the total cumulative dose in the bone. Thus, alendronate can now be given once a week, ibandronate once a month, risedronate once a month (on two consecutive days) and zoledronic acid as an annual infusion. Such dosing regimens should help improve treatment adherence, which is recognized as a major obstacle to improving the effectiveness of these treatments. (Note: At the time of printing, monthly and annual dosing with ibandronate, risedronate and zoledronic acid are not available in Canada.)

Noteworthy, in a well designed comparison trial of alendronate 70 mg once weekly and risedronate 35 mg once weekly in patients with postmenopausal osteoporosis, significantly more alendronate patients had achieved predefined increases in hip BMD and decreases in biochemical markers of bone turnover after three months (Sebba et al. Curr Med Res Opin 2004;20(12):2031-41). Some cohort observational studies, however, have suggested that risedronate had a lower incidence of hip fracture compared to alendronate, but Dr. Epstein cautioned, “Cohort observational studies, where the baseline risk factors are not taken into account, can bias a result.” Any interpretation of data from clinical trials should therefore take into account potential methodological weaknesses.

Support for Long-term Treatment

Some physicians advocate giving their patients a “drug holiday” but Dr. Epstein expressed concern over this strategy. In the FLEX (FIT Long-term Extension) study, patients who had received alendronate in the FIT were randomized to placebo or continued with alendronate for an additional five years (Ensrud et al. J Bone Min Res 2004;19(8):1259-69). Patients who stopped treatment had a 56% increase in the markers for bone resorption.

According to Dr. Epstein, the findings of this study suggest “cortical bone needs a constant exposure to a bisphosphonate to either increase or maintain BMD.” Regarding the implications for clinical practice, he noted, “In high-risk patients over the age of 50 with previous fracture and a T-score below 2.5, I would suggest continuing treatment.” Safety is also going to be a paramount consideration with any long-term treatment and this extension study revealed no safety concerns.

Another issue that has been voiced is the possibility that bone architecture is disturbed by long-term use of bisphosphonates. However, bone biopsies revealed no difference between in the amount of mineralized tissue, the bone architecture or excess osteoid tissue. Most importantly, dual labelling showed that active bone formation was taking place.

Vitamin D: An Important Partner in Preventing Bone Fracture

It is a widely acknowledged fact that a large part of the vitamin D (Vit D) needed by the body is synthesized when the skin is exposed to sunlight. According to Dr. Heike Bischoff-Ferrari, Institute for Physical Medicine, University Hospital, Zurich, Switzerland, “The major risk factors that impair production of Vit D include age, use of sunscreen…, dark skin tone… and living in northern latitudes where the winter is long.” Obesity can also reduce concentrations because Vit D is distributed to fatty tissue.

Data from the NHANES III, which collected data on both hip BMD and 25-hydroxyVit D3 (25[OH]D) levels, suggested that, for older patients, 25(OH)D levels should be close to 75 nmol/L to ensure optimum BMD. Studies with fractures themselves as the end point have confirmed this dosing level. However, according to a study conducted in several countries, 64% of postmenopausal women had insufficient Vit D levels (Rizzoli et al. Int J Clin Pract 2006;60(8):1013-9). In another study in the US, only 9% of Caucasians over 50 and even fewer in other ethnic groups have serum 25(OH)D levels above 90 nmol/L (Bischoff-Ferrari et al. Am J Med 2004;116(9):634-9).

To determine the optimum dose of Vit D to provide protection against falls and fractures, a study compared four different doses (200 IU, 400 IU, 600 IU or 800 IU) or placebo daily for five months in elderly nursing home residents. Those in the 800 IU dose group had the lowest number of falls. Dr. Bischoff-Ferrari concluded, “These data suggest that a dose close to 800 IU is the optimum one.”

One concern with Vit D supplementation is the possibility of toxicity, but Dr. Bischoff-Ferrari explained, “The first side effects of Vit D excess are hypercalcemia, although such conditions have only been observed with Vit D levels in excess of 220 nmol/L.” Such levels would not be reached in normal conditions.

The combination of alendronate and Vit D 2800 IU is available for weekly administration. Such a combination would improve compliance by reducing the number of medications a patient has to take. Additionally, in view of these new data on optimum Vit D dosing, Dr. Bischoff-Ferrari suggested that this dose might be increased.


Osteoporosis and its complications represent a growing problem. The introduction of N-containing bisphosphonates has changed the face of management of the disease. These compounds increase BMD and reduce the risk of both vertebral and nonvertebral fracture in postmenopausal women. In controlled clinical trials, exposure of up to 10 years to alendronate, the first of the N-containing bisphosphonates to be available, has shown this compound to be safe and well tolerated. The efficacy of these agents is determined by total cumulative dose in the bone. Therefore, a “drug holiday” should not be automatically recommended but rather should be subject to considerations for each individual patient according to risk factors.

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