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30th Annual Meeting of the American Society for Bone and Mineral Research

Montreal, Quebec / September 12-16, 2008

Bone biology and structure are highly heterogeneous.To optimize osteoporosis therapy, researchers and clinicians must delve deeper into individual differences in bone than is now routinely done, observed Dr. Ego Seeman, Professor of Medicine and endocrinologist, Austin Health, University of Melbourne, Australia.

How Bones Age

“Bone structure during growth, whether genetically determined or in response to environment, [has a] final common pathway—bone modelling and remodelling. That process determines the structure and properties of bone; but the structure of bone determines remodelling. So we have a cycle, and because of that cycle... there are enormous differences in the structural bases of bone fragility,” Dr. Seeman explained. The baseline state and size of bones (i.e. the peak structure achieved in youth) affect both the remodelling process and its eventual impact.

Several abnormalities emerge in bone with advancing age, starting in the third decade, Dr. Seeman indicated. “Every time bone remodels, 1% is left off and 99% is put back. This eventually erodes the skeleton. During growth, periosteal apposition offsets this to some degree, but with aging, periosteal apposition decreases and the net effect is thinning of the cortices and increased bone fragility.” There is also an age-associated increase in bone resorption rate, which varies among individuals, and the heterogeneity index of bone decreases, he noted. “The pieces of bone are more similar, allowing cracks—should they occur—to travel through the bone.” Increased bone porosity decreases strength and causes more cracking.

Reversal of age-related bone abnormalities ideally involves encouraging periosteal apposition, increasing bone formation and decreasing resorption. However, osteoporosis therapy should not involve a one-size-fits-all approach, Dr. Seeman contended. “Some patients with fractures have low and some have high tissue mineral density; some have low bone remodelling, others high bone remodelling; some have reduced formation, high resorption—so a negative balance. Others have the opposite. Are we going to treat everybody the same way? Are we right in doing that? I don’t think we are.”

Although they have demonstrated positive effects on fracture incidence, current osteoporosis therapies cannot match nature’s customized skeletal development. If they lead to excess bone tissue homogeneity or overmineralization of bone, they may conceivably induce fragility, Dr. Seeman commented. Ideally, in future, investigators and clinicians will have methods of measurement and monitoring that allow a focus not simply on bone density but also on the effects of treatments on numerous variable material and structural properties of bone, he suggested.

Kyphosis a Fracture Risk Factor

One clinical and radiological indicator of bone health that might be useful in quantifying fracture risk and therapeutic success in postmenopausal women is their degree of kyphosis, researchers suggested here. Dr. Christian Roux, Professor of Rheumatology, Paris Descartes University and Director, Bone Research Unit, Cochin Hospital, France, described the finding that among 2017 women with osteoporosis, those with the highest degree of kyphosis (at least 27.16%) had a relative risk of vertebral fracture of 1.7 and 1.5 (P<0.001) over three years compared with those with lower and intermediate degrees of kyphosis. In patients with previous fracture, the risks were slightly lower but remained significant (1.58 and 1.43, respectively). Kyphosis also negatively influenced quality of life.

Targeting Bone Remodelling

Influencing the bone remodelling cycle is the fundamental aim of osteoporosis therapy, stated Dr. David Goltzman, Professor of Medicine and Director, McGill University Centre for Bone and Periodontal Research, Montreal, Quebec. “We try to harness either the bone resorption side of things with antiresorptives or to stimulate osteoblastic bone formation with anabolics. Whether you use one or the other, you get a very similar per cent reduction in the relative risk of fractures.”

By decreasing osteoclastic proteases, antiresorptive medications decrease the breakdown of bone matrix; however, they also reduce the release of growth factors from the bone matrix (Figure 1) that increase the osteoblast pool. “So you reduce the amount of osteoblast activity as well,” Dr. Goltzman explained. With treatment, a fairly rapid increase in bone mineral density (BMD) is observed; however, this effect tapers off. “This probably reflects the fact that the osteoblasts have diminished, and new bone formation is diminished – or, as has been suggested, there is little new formation and all you are seeing is hypermineralization of bone,” Dr. Goltzman indicated. “Agents such as bisphosphonates and calcitonin… reduce bone turnover, stabilize or improve microarchitecture, increase bone mineral density…and decrease fracture risk. What antiresorptives will not do is normalize the bone quantity and will not restore trabecular architecture.”

Figure 1.

Anabolic agents such as parathyroid hormone act predominantly on osteoblasts to induce formation of new bone. Their actions also lead to increase of cytokines such as RANK ligand (RANKL), which stimulates osteoclastogenesis and therefore induces bone resorption. As with antiresorptive agents, the temporal gap between the anabolic agents’ primary and secondary actions is the window of opportunity for their therapeutic effects. “Ultimately, you will get a plateau which probably occurs when resorption rate is matching the rate at which new bone is being formed,” Dr. Goltzman confirmed.

Novel Therapy

A novel drug for osteoporosis, strontium ranelate (SR), has several antiresorptive effects, including reductions in osteoclast quantity, activity and lifespan. By decreasing RANKL, it inhibits osteoclastogenesis. At the same time, however, it increases replication of osteoblasts and cellular survival and increases osteoblast differentiation, which leads to increased collagen synthesis in bone. “This results not only in increased matrix, but an increase in mineralization,” Dr. Goltzman explained. In preclinical studies, “SR preserved the degree of mineralization of bone [so it was not] poorly mineralized or mineralized inappropriately,” he added. After two years of treatment, bone strength was also improved – for example, the mechanical load sustained by vertebrae increased by 20%.

In humans, SR produces small but statistically significant effects on markers of bone resorption such as bone-specific alkaline phosphatase and C-telopeptide. In vivo studies have demonstrated that after three years of treatment, trabecular numbers and cortical thickness increase significantly, there is a significant decrease in separation between trabeculae, and tissue volume increases, although not significantly. “There does appear to be an increase in bone formation, coupled with a decrease in resorption. It reduces fractures by increasing bone strength,” Dr. Goltzman indicated.

In a separate report on 4055 women, the investigators reported that three years of treatment with SR had a small but significant preventive effect on kyphosis progression, whether or not fractures had occurred previously. They postulated that one explanation for this result might be attenuated disc deterioration.

Two pivotal phase III studies of SR, SOTI (Spinal Osteoporosis Therapeutic Intervention) (Meunier et al. N Engl J Med 2004;350(5):459-68) and TROPOS (Treatment of Peripheral Osteoporosis) (Reginster et al. J Clin Endocrinol Metab 2005;90(5):2816-22), examined BMD measurements and spinal and peripheral fracture efficacy, respectively. At three years, the agent increased BMD at the lumbar spine by 14.4%, in the hip by 9.8% and in the femoral neck by 8.3%. These BMD changes are greater than those typically observed with agents in current use in Canada; moreover, there is a more robust relationship between BMD change and fracture risk than is seen with some other agents, remarked Dr. David Kendler, Associate Professor of Medicine, University of British Columbia, Vancouver. One component of the difference, in addition to the creation of new bone, is that SR has a higher atomic number than calcium. (It is not necessary to correct for this artifact when measuring BMD in SR-treated patients, he added.)

Bone Mineral Density and Antifracture Efficacy

While bone density and other biological and morphological parameters are important markers of bone health, the most important end point for any osteoporosis therapy is antifracture efficacy, confirmed Dr. Cyrus Cooper, Professor of Rheumatology and Director, MRC Epidemiology Resource Centre, University of Southampton, and Norman Collison Chair of Musculoskeletal Sciences, University of Oxford, UK. “As you are all well aware, we want to prevent or reduce the frequency of vertebral and nonvertebral fractures, especially hip fractures.”

A report by the UK Agency for Health Care Quality Research determined that for patients at high risk, such as those with previous fractures and a T-score below -2.5, any current therapy will approximately halve the vertebral fracture risk observed with placebo. Hip fractures are reduced by about 20% to 25%.

The SOTI study determined that treatment with SR could reduce the risk of new vertebral fractures by a highly significant 41% compared with placebo. In TROPOS, the relative risk of nonvertebral fracture was reduced by up to 19% in the overall study group in comparison with the placebo group, after three years. In high-risk individuals, hip fracture risk decreased by 36% and vertebral fracture risk by 39% (all significant). The five-year prospective results from TROPOS showed that SR reduced non-spine fracture risk by 15% and vertebral fracture risk by 24% compared with placebo, Dr. Cooper stated (Reginster et al. Arthritis Rheum 2008;58(6):1687-95) (Figure 2 and 3). As yet unpublished data from an open-label extension show that increased bone density and antifracture efficacy continued out to eight years. Although the extension study had no placebo comparison group, “it appears that the individuals who have been treated with SR… have some persisting neutralization of their fracture rate similar to that in the
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Figure 2.

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Figure 3.

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Additional recent analysis by Roux et al. (Rheumatology Oxford 2008;47(Suppl 4):iv20-iv22) indicates the antifracture efficacy of SR is similar whether or not patients have baseline vertebral fractures. A report by Seeman et al (J Bone Miner Res 2008;23(3):433-8) also noted the agent has antifracture efficacy in patients with osteoporosis or osteopenia, with or without vertebral fracture at baseline.

More Studies of Elderly Needed

The evidence base for anti-osteoporosis agents in very elderly individuals is limited, despite the clear predisposition of this population to the disease and the devastating impact of such injuries as hip fracture, noted Dr. Charles Inderjeeth, geriatrician and rheumatologist, Director of Clinical Training, Research Programs, Sir Charles Gairdner Hospital, Nedlands, Western Australia. “Osteoporosis is probably a bigger problem in older than younger people and despite this, the research we have is predominantly based on women in the early postmenopausal period.” In a poster here (Sa437), Dr. Inderjeeth and colleagues noted that only SR studies reported results specifically from women aged at least 80 years, although risedronate also has shown efficacy against vertebral fractures in the very elderly. “We believe parathyroid hormone would also be a good agent but there is no evidence. More studies are needed.”

In patients aged >80 years who participated in SOTI or TROPOS (1556/6640 subjects), SR reduced vertebral fractures by 59% at one year and 32% after three years. The reductions for nonvertebral fractures were 41% and 31%, respectively (all results significant). A decrease in hip fracture in treated patients of 41% after three years was not significant. The report on five years of SR treatment included a small subset of elderly patients (age >74 and T-score <u><</u>-2.4 at two sites). In this group, there was a 43% reduction in hip fracture risk, Dr. Cooper stated.

Tolerability and Safety Evidence

SR was generally well tolerated over the five-year period, Dr. Cooper added. “There were nonsignificant slight excesses in gastrointestinal symptoms.” An excess incidence of venous thromboembolism (VTE), which had been noted in earlier trials, was also reported; however, the difference between the treatment and placebo groups (4.5% vs. 3%) was not statistically significant. Pharmacovigilance data from the UK are reassuring, he added. They indicate that the rate of VTE in patients treated with SR is approximately the same as that for patients receiving alendronate (hazard ratio 1.09 for SR, 0.92 for alendronate). Clinicians using SR must be aware of the so-called DRESS syndrome characterized by rash (usually within the first three to six weeks of administration), then widespread erythema and eosinophilia and systemic symptoms. If treatment is not withdrawn, renal and hepatic impairment may ensue.

As might be expected, bone density declines when treatment with SR is stopped. In the spine, for example, density decreases by 3% to 4% in the 12 months following discontinuation, Dr. Kendler stated. Bone turnover markers also change with withdrawal of the antiresorptive and anabolic effects of the agent.

To Monitor or Not to Monitor?

The utility of continuous monitoring of osteoporosis therapy was the subject of a lively debate here. According to Dr. Kendler, “The rationale in my mind for monitoring is twofold: to detect those patients who aren’t responding to the prescribed therapy. It’s our responsibility to understand that just as we have heterogeneous skeletons, we may have heterogeneous or different responses to different therapies. So we may choose to use intermediate end points or surrogate markers of bone density or turnover to monitor a patient’s effective response to therapy, rather than awaiting those fracture end points we want to prevent. Secondly, there is little evidence but it may... encourage patient adherence to therapy if we can tell them that their therapy is working for them and we have something to demonstrate the therapy is effective.” Over the coming years, as Dr. Seeman suggested, novel ways of looking at bone health may be validated and become more accessible to and routine for community physicians, and may also aid in proving efficacy and promoting adherence to long-term therapy.