Highlights of the American Society for Bone and Mineral Research Annual Meeting

Progress in science takes time, and rightly so. There were no major breakthroughs reported at this year's meeting of the American Society for Bone and Mineral Research -- the premier meeting in the world for osteoporosis -- but there were many excellent papers gently moving the field forward. Some highlights are summarized below. The work presented at the meeting has not been peer reviewed, so inferences I make must be seen in this light.

Patients with a prevalent fracture and a new incident fracture are at risk for further fractures; they should be treated promptly because another fracture is likely to occur in about 1 in 5 such individuals within 12 months. Moreover, adherence or compliance (ie, taking therapy) and persistence (ie, continuing therapy) should be monitored with prejudice -- that is, the patient should be regarded as guilty of poor compliance until proven innocent.¹

Lindsay (Helen Hayes Hospital, West Haverstraw, New York) and colleagues^[1] reported that of 7233 women developing a new vertebral fracture after their first fracture, 80% were left untreated. During 12 months of follow-up, 1039 (18%) of untreated women had a vertebral or nonvertebral fracture. Of those treated, 1056 (15%) received treatment within 90 days of their fracture, and 85 (8%) had a fracture (RR = 0.51 compared with no treatment); whereas 358 (5%) received treatment 90 days after the fracture, and 76 (21%) had a fracture.

Thus, starting treatment early after fracture is important, but so is continuing it. Weycker (Policy Analysis Inc., Brookline, Massachusetts) and colleagues^[2] reported that among 16,031 women with osteoporosis started on treatment, 5% (724) had a fracture during follow-up. The risk was reduced by 50% in those with more than 180 days of therapy compared with those receiving treatment for fewer than 30 days.

Thus, most patients do not receive treatment following fracture. Among those who do, there is a risk reduction with a trend toward fewer fractures in those receiving early rather than late treatment and in those compliant with medication.

In many cases of osteoporotic fracture -- or most cases, as the study by Lindsay and colleagues indicates -- doctors do not prescribe pharmaceutical treatment, and when it is prescribed many patients don't take it. Studies have shown that about 50% of patients stop taking prescribed osteoporosis drugs within 12 months. Weekly preparations are better adhered to than daily preparations, but not by much.

Lynch (GlaxoSmithKline, Greenford, United Kingdom) and colleagues^[3] compared oral weekly and daily bisphosphonate usage in the United Kingdom (n = 5962) and Germany (n = 288). The medical possession ratio (MPR, sum of dose supplied/followup) was 63% in the United Kingdom and 45% in Germany. Weekly users had a higher MPR than daily users. The average persistence during 12 months was 207 days (UK) and 189 days (Germany), with a longer time to discontinuation for the weekly formulation, eg, for the UK weekly 228 days vs daily 186 days. By 12 months in the United Kingdom, 43.6% of women on the weekly and 33.3% on the daily regimen had persisted with therapy.

Huybrechts (Caro Research Institute, Concord, Massachusetts) and colleagues^[4] reported that of 2905 users, 47% of weekly users and 42% of daily users persisted at 6 months. At 12 months, the figures were 28% and 19%, respectively, with an MPR of 54% weekly vs 47% daily -- not much difference, despite its being statistically significant. Fardellone (CHU Nord, Amiens, France) and colleagues^[5] reported that persistence for daily bisphosphonates (n = 1363) and weekly (n = 3969) during 2 years differed only modestly (391 vs 301 days to discontinuation). After 12 months, 50% of women with weekly and 44% of women with daily regimen persisted. At 2 years, the rates were 41% and 32%, respectively.

Whether monthly or yearly treatment will be better remains unknown. Patients who do fail to adhere sustain more fractures than those who adhere. However, poor compliers with placebo have increased morbidity and mortality also, so we must ask ourselves: Is the higher fracture rate the result of lack of treatment?

Factors associated with poor compliance have been identified, but a number of studies presented at the meeting suggest these factors account for only a small proportion of the burden of poor compliance^{[6,7,8,9,10,11]} It should be noted that these are all association studies, so an association between poor compliance and a particular factor (multiple drug treatments, for example) does not mean the given factor is the cause, nor does it mean that removing the factor (eg, eliminating some of the drug treatments) will produce better compliance. Randomized, placebo-controlled trials, the highest evidence-based method of verifying "truth," however, may not be a feasible experimental approach to studying this problem. Here are some data.

Siris (Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY) and colleagues^[12] reported that among 37,698 women who received a script for alendronate or risedronate, the fracture rate was 11.5% for women with a 70% to 75% MPR vs 8.7% for those with 95% to 100% MPR.

Silverman (David Geffen School of Med UCLA, Beverly Hills, California) and colleagues^[13] reported that among 37,698 patients, the fracture risk at 24 months was 2.3% for poor compliers and 1.5% for compliers. Nonvertebral fracture risk was 25% lower in persistent vs nonpersistent subjects and 21% lower in compliant vs poorly compliant subjects. The risk of wrist fractures was reduced by 19% among persistent and 13% among compliant subjects relative to the nonpersistent and noncompliant subjects, respectively. Gold (Duke Univ Med Center, Durham, North Carolina) and colleagues^[14] reported that among 4769 women, 3.9% of persistent patients and 4.9% of nonpersistent patients had a fracture (26% lower risk for the persistent patients).

Two factors lead to bone loss and structural decay: a negative bone balance in the basic multicellular unit (BMU) and the remodeling rate (activation frequency). The negative bone balance is produced by a reduction in the volume of bone formed and an increase in volume of bone resorption in each BMU. As each of the many remodeling events removes only a tiny amount of bone from a surface, it is the high remodeling rate that drives the eroding and thinning of trabeculae and of the cortex, making it more porous.

Remodeling suppressants (antiresorptive agents) reduce remodelling rate. Recker and colleagues (Osteoporosis Research Center, Creighton University, Omaha, Nebraska)^[15] reported that oral ibandronate reduces activation frequency, which is a measure of bone turnover. In the placebo group, the median activation frequency was 0.22 per year (range, 0.11-0.39). With continuous or intermittent ibandronate therapy, the values were halved -- 0.1 (0.04-0.2) and 0.13 (0.08-0.2), respectively -- and were comparable to values obtained for premenopausal women. Therefore, the authors concluded that ibandronate did not oversuppress bone remodeling.

This suppressant effect is rapid, and this rapidity is likely to be a factor in the early reduction in fracture risk that occurs with these agents. Gunther (Deutsches Zentrum fr Osteoporose, Fachklinik Johannesbad, Bad Essing, Germany) and colleagues^[16] reported that risedronate reduced bone resorption markers within 2 weeks using a 35-mg once-weekly formulation. The suppression of remodeling or bone turnover markers reflects the decrease in activation frequency (remodeling) at the tissue level, not within the BMU at the cellular level. Neither the ratio of remodeling markers nor their difference can be used as a measure of BMU balance or imbalance.

Although suppression of activation frequency is rapid, completion of a remodeling event after the resorptive phase is slow. When treatment with an antiresorptive agent is started, the many sites actively resorbing bone before treatment was started complete the cycle by the deposition of new bone that undergoes primary mineralization over 2 to 3 months and then secondary mineralization over 8 to 12 months. This process perhaps stabilizes stress risers (eroded sites where stress is locally concentrated, which produces microdamage) and may contribute to the lower incidence of fractures in treated subjects relative to controls in whom fragility and fractures continue. In other words, in the treated subjects, the steady state is perturbed; BMD increases because of the filling of these remodelling sites, and the slower birth rate of new BMUs does not offset this rise in BMD. The increase in BMD is a function of the number of remodeling sites active before treatment and of the potency and dose of the antiresorptive agent. The same drug given to patients with high remodeling will increase BMD (and reduce the levels of remodeling markers) more than in patients with low remodeling; however, the fracture risk reduction relative to controls with high or low remodelling, respectively, will be the same. A lesser change in BMD does not mean the fracture risk reduction will be less.

Recker and colleagues^[17] reported the first direct comparator trial between 2 antiresorptive agents comparing fracture risk reduction efficacy. This is an important trial. The average increase in BMD associated with raloxifene therapy is about 2%, whereas it is about 5% for treatment with alendronate. In this trial of 1423 women treated for 312 ± 254 days, fewer women taking raloxifene 60 mg/day had vertebral fractures than women taking alendronate 10 mg/day: 5 (1.9%) vs 8 (3.1%). The sample size was small, however, and there were few fractures, thus making interpretation difficult. There was no difference in the total number of fractures or in the numbers of vertebral, nonvertebral, or hip fractures, despite significant changes in BMD between the 2 groups.

The completion of remodeling, stabilization of stress risers, and increase in tissue mineral density partly restore bone strength. However, at the new steady state, where the slower birth rate of BMUs and closure rate of completed BMUs are the same, bone loss is likely to continue if there is a negative BMU balance within each of the now fewer foci where remodeling of bone surface is occurring. However, this bone loss will not be "seen" by the densitometer, because it only "sees" mineral, and the mineral within the diminishing bone tissue continues to increase because the slow remodeling allows more time for completion of secondary mineralization (in bone that would have been removed by high remodeling, ie, untreated bone). So BMD continues to increase in a slowly diminishing bone tissue mass. The amount of bone tissue loss is likely to be very small, however, because the remodeling rate is suppressed and the balance in the BMU is probably less negative than it would be in untreated bone. This is because the osteoclast life span is reduced by the antiresorptive agent and, therefore, less bone is resorbed. With fewer and more shallow resorption pits, the chance of perforation of a trabeculae is presumably lower.

It is possible that the relative risk after 1 to 2 years of treatment would be even more greatly reduced compared with the relative risk in the first year because the controls continue to develop more severe bone fragility, whereas in the case of the treated subjects, the fragility is initially slightly reversed and then progresses very slowly.

Watts (University of Cincinnati, Cincinnati, Ohio) and colleagues^[18] report just that. Fracture risk reduction using risedronate was no different in those who gained bone tissue and those who lost it compared with placebo. The fracture risk reduction was around 40% irrespective of the change in bone density (gain or loss) that occurred at the spine or femur.

Bone, like all structures, sustains fatigue damage, but bone can detect damage, define its location, and remove it. The osteocytes may do the detecting, and their death (where a crack occurs) might provide the topographical information and signals locating the address of the damage and contribute to recruiting the cells that resorb and form bone and so initiate remodeling focally. Treatment that is continued over time maintains the reduced remodeling rate, but remodeling is responsible for maintaining bone's material and structural strength by removing microdamage. Therefore, prolonged treatment may compromise this process and result in the accumulation of microdamage.

Normal bone tissue is a composite; cortical bone consists of regions of bone tissue that are dense and regions that are less densely packed with mineral. This makes progression of cracks difficult. When BMD increases and becomes more even or homogenous, cracks can travel and lengthen more easily. This has been reported to occur in animals treated with high doses of bisphosphonates. For example, Allen (Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis) and colleagues^[19] reported suppression of remodeling and increased microdamage in beagles after 12 months of risedronate or alendronate. The activation frequency was dose-dependently suppressed with each of the drugs. Trabecular crack density did not differ by drug, but was 3 to 4 times greater than that in controls. Higher doses increased crack density 5-fold. Both drugs increased vertebral stiffness with no other effects on mechanical properties. Perhaps other structural advantages overwhelm the deleterious effect on flexibility. The one study in humans that was presented at this year's meeting had small sample sizes and is difficult to interpret.^[20]

We do not have credible data from prolonged trials with bisphosphonates to tell us whether fracture risk remains reduced or whether it increases. What is clear is that bone loss resumes when treatment is stopped.^[21,22]

If periosteal apposition is partly a compensatory response to endosteal bone loss, then drugs that inhibit endosteal resorption should inhibit periosteal apposition. Evidence is conflicting. Bare and colleagues^[23,24] reported that menopausal hormone therapy reduced the percentage of women with double radioactive label on periosteal and endocortical envelopes, whereas alendronate reduced formation on the endocortical envelope only. Iwata (Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis)^[25] reported that 6-month female rats given risedronate or alendronate subcutaneously daily for 17 days reduced periosteal apposition in the femur and tibia.

Prior use of alendronate delays the response to PTH. This effect seems to be temporary. The response to PTH in terms of BMD and bone formation markers is similar to the response with PTH administration without prior alendronate exposure. Cosman and colleagues (Clinical Research Center, Helen Hayes Hospital, West Haverstraw, New York)^[26] reported that the response to rechallenge with PTH (1-34) 25 mcg/day 12 months after initial PTH treatment and alendronate was similar to the response obtained initially, suggesting that ongoing treatment with alendronate does not impair rechallenge with PTH to stimulate bone formation markers. Gasser and colleagues^[27] reported normal response to PTH following acute intravenous alendronate or zoledronate but delayed responses in 16-month old rats treated with alendronate for 16 weeks before PTH. The reasons for the delay in anabolic response are not known.

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Cite this: Highlights of the American Society for Bone and Mineral Research Annual Meeting - Medscape - Nov 10, 2005.