Osteoporosis: Strength for Tomorrow

At an industry-sponsored symposium held in conjunction with the American Association of Clinical Endocrinologists’ 2003 Annual Meeting and Clinical Congress, three leaders in osteoporosis research and treatment discussed perspectives on bone strength, reviewed the available treatment options for osteoporosis and addressed issues about hip fractures.

This program was supported by an unrestricted educational grant from the Alliance for Better Bone Health, (Procter & Gamble Pharmaceuticals and Aventis Pharmaceuticals).

Mechanisms of Osteoporosis Therapies: A Bone Strength Perspective

In 2000, the National Institutes of Health Consensus Development Con-ference on Osteoporosis modified the definition of osteoporosis as a skeletal disorder characterized by compromised bone strength, which leads to an increased risk of fracture. It further characterized osteoporosis by reduced bone strength, a reflection of bone density and quality.

“There has been an increasing focus on bone quality,” said Sharmila Majumdar, PhD, Professor in the departments of Radiology, Orthopaedic Surgery and Growth & Development at the University of Southern California, San Francisco. “This is of interest because high bone density alone does not protect from fractures if the quality of the bone itself is impaired. At the end of the day, fractures are predicted and mediated by changes in bone strength.”

Bone strength depends not only on the amount of bone but also on size, geometry (shape and distribution of mass), and material composition. Other factors affecting the strength of the bone include the quality of the tissue, extent of mineralization, the collagen network and the crystalline structure.

“In order to predict fractures better and understand osteoporosis and therapy, one should be looking at a parameter which characterizes more than the density. Thus, the term ‘bone quality’ has been coined,” said Dr. Majumdar. “It includes all the characteristics which may influence the strength of the bone. These are structural measures that look at distribution and architecture and material measures of mineralization.”

There are various ways to increase bone strength. One could fill in the remodeling spaces, induce new bone formation or improve bone quality by changing the geometry and the bone mass distribution by changing the trabecular architecture, cortical bone porosity, or mineralization.

Bone geometry is an important consideration in predicting bone strength. Although different bones can have the same overall bone mineral density (BMD), their bending and compression strengths can vary greatly depending on how the BMD was distributed. In terms of the whole bone, an increase in periosteal diameter, for example, would result in increased compressive and bending strength.

“This is where the differences in geometry, primarily by therapy, can cause a difference in bone strength,” said Dr. Majumdar. “Bone geometry can be measured using peripheral quantitative computed tomography (PQCT).”

Bone micro-architecture is also an important consideration. In osteoporosis, the trabecular bone structure changes considerably. The horizontal connecting struts break away and there is thinning in the trabecula. This microarchitectural change occurs at the microscopic level and is not detectable by dual energy X-ray absorptiometry (DEXA) scans; yet these changes may have a profound impact on the strength of the bone.

Horizontal struts are important from a structural engineering standpoint. If you have a horizontal strut supporting a vertical strut, the strut is able to withstand far greater loads than something that is simply long with no horizontal underpinnings. The trabecular bone functions in the same manner as buttresses next to long beams in buildings. In osteoporosis, the loss of horizontal struts has a tremendous impact.

Matt Silva and colleagues modeled the loss of trabecular thickness and then the loss of trabecular number where the horizontal struts disappeared. He found that loss of trabecular number had a greater impact on the reduction of strength than did trabecular thickness (Silva M, et al. Bone. 1997;21:191).

A more recent study by Borah looked at risedronate treatment in a mini-pig model using micro-CT images of the bones. In the ovariectomized pigs given risedronate, trabecular thickness and connectivity was significantly greater than the untreated controls (Borah, B, et al. JBMR. 2002;17:1139).

In a study by Jiang and colleagues of human PTH via micro-CT scanning, they showed greater increases in bone trabecular connectivity than changes in bone mineral density (Jiang , et al. J Brur. 2002;17 (suppl 1):S135).

These are some of the representative studies that have shown that micro-architecture deterioration occurs as a result of osteoporosis. However, microarchitecture can be maintained or improved with therapeutic agents. According to Dr. Majumdar, “There is also the effect of bone remodeling to
consider.”

Excessive resorption can form cavities in the bone that can become an area of weakness and result in fractures. Some will heal as microcalluses, which can affect the strength of the bone. Reducing the number and size of resorption pits may enhance bone strength.

Like trabacula, cortical bone is not homogenously distributed. There is a porosity such that small holes can often be seen when the bone is sectioned. An increase in porosity has a negative effect on bone strength. Antiresorptives decrease porosity by decreasing bone turnover. A study by Roschger and colleagues showed a reduction in cortical porosity with alendronate (Roschger P, et al. Bone. 2001;29:185).

“BMD does not assess bone quality, so we would like to measure bone mass, distribution, architecture, and mineralization,” said Dr. Majumdar. “Measuring bone quality is important and as the technology advances we can form interesting compliments to BMD when assessing fracture risk, therapeutic intervention, and efficacy.”

Therapeutic Options in the Management of Osteoporosis and Treatment Strategies

In untreated patients, bone density is strongly related to fracture risk.

“When discussing the selection of therapeutic options, where change in BMD is not the sole explanation for benefit, the most important factor is fracture reduction,” said Nelson B. Watts, MD, Professor of Medicine at the University of Cincinnati, OH. “Other factors to be considered include cost, tolerability, safety, extra-skeletal benefits, and ease of administration.”

Costs are similar for the antiresorptive agents that have come into wide use over the last decade — alendronate, calcitonin, raloxifene, and risedronate all cost about $600-700 a year. The cost of the newest agent, teriparatide, which has a different mechanism of action, is about 10 times higher according to Dr. Watts.

For each agent there are different concerns about safety and tolerability. These include rare but serious gastrointestinal events with alendronate and
risedronate as well as venous thromboembolic events with raloxifene. Tolerability problems include non-serious gastrointestinal symptoms with alendronate and risedronate, nasal irritation with calcitonin, and leg cramps and hot flashes with raloxifene. Treatment of rats with high doses of teriparatide was associated with osteocarcinomas; the relevance of this to treatment in humans is not clear.

Raloxifene may have some extraskeletal effects in the breast and heart. However, these effects have not been conclusively proven in clinical trials.
Fracture reduction should be the main focus in selecting a therapeutic agent. Most of the fracture data comes from studies designed to show an effect on vertebral fractures. Vertebral fractures are important because they are the most common osteoporotic fracture and cause significant morbidity and mortality.

All of the approved agents have been shown to reduce the risk of new vertebral fractures in patients with pre-existing vertebral fractures (Black DM, et al. Lancet. 1996;348:1535; Chestnut CH, et al. Am J Med.2000;102:267; Ettinger B, et al. JAMA. 1999;282:637; Harris ST, et al. NEJM. 282;1344; Neer
RM, et al. NEJM. 2001;344:1434). Alendronate, risedronate, and raloxifene have been shown to reduce new vertebral fractures in subjects with low bone mass, but without previous fractures (Cummings SR, et al. JAMA.1998;280: 2077; Heaney RP, et al. Osteoporos Int.2002;13:501; Ettinger, 1999.).

The effect of nonvertebral fractures and hip fractures is also important. Different definitions for nonvertebral fractures have been used in different trials, making it difficult to compare across studies. Reduction in nonvertebral fracture has been shown for alendronate, risedronate, and teriparatide, but not for raloxifene or calcitonin (Black, 1994; Black DM, J Clin Endocrinol Metab. 2000;85:4118 ; Harris, 1999; Neer, 2001).

Hip fracture is the most common sequela of osteoporosis with 250,000 incidents each year. Half of the survivors are permanently incapacitated and 20% require long-term nursing home care.

The major challenge in conducting appropriate hip fracture studies is that the risk rises 10- 15 years after the rise in risk for vertebral fractures. Large numbers of subjects are required for these studies. It is more difficult to recruit older subjects and those who do volunteer are likely to be healthier than average and less likely to fracture. Reduction in hip fracture risk has been shown only for alendronate and risedronate (Black, 1996; McClung MR, et al. NEJM.2001; 344:333).

It is important to not only consider the effects seen in these long-term (3-5 years) trials,” said Dr. Watts. “It is also important to consider if there is a rapid effect, possibly as early as the first year.”

The risedronate VERT studies were designed to assess prospectively the early effect of treatment on radiographic fractures and showed a significant reduction at one year (Harris 1999; Reginster J-Y, et al. Osteoporos Int. 2000;11:83). Retrospective analysis of clinical vertebral fracture data showed significant reductions at 12 months for alendronate, risedronate, and raloxifene with significance seen as early as 6 months with risedronate (Black 2000; Maricic M, et al. Arch Intern Med. 2002;162:1140; Watts NB, et al. J Bone Miner Res. 2001 (suppl 1);S407). Time course information regarding the effect of teriparatide on clinical vertebral fractures is not yet available.

“Treatment needs to be individualized,” said Dr. Watts. “In looking over the available data, and lacking head-to-head trials with fracture endpoints, bisphosphonates have the strongest data for efficacy on a variety of fractures, as well as evidence for a rapid onset of action.”

Strategies for Preventing Hip Fractures: Targeting Clinical Risk Factors

Hip fracture is viewed as the most important consequence of osteoporosis, particularly in aging populations. Two thirds of hip fractures in the U.S. occur in women and one third occur in men. Hip fractures are associated with significant morbidity and mortality.

“There are numerous risk factors that have been identified from a whole variety of different types of trials that are important in predicting and determining fracture risk,” said Michael McClung, MD, Director of the Oregon Osteoporosis Center in Portland. “I find these lists absolutely useless to me as a clinician.”

Instead, he suggests going back to the paradigm proposed by Drs. Melton and Riggs in which the relationships between osteoporosis and risk factors for fracture fit together. Low bone density, advanced age, alterations in bone quality, as well as falls and injury are important determinants of fracture risk (Riggs BL, Melton LJ. Osteoporosis: Etiology, Diagnosis and Management. New York: Raven Press; 1988).

Data from the study of osteoporotic fractures by Cummings and colleagues showed that regardless of where bone density is measured, those with lower values are more likely to fracture than those with higher bone density. However, the strength of the relationship varies dramatically, especially with hip fractures. Hip bone density is a more powerful predictor of hip fracture risk than bone density measurements at other sites (Cummings SR, et al. NEJM. 1995;332: 767).

Dr. McClung suggests the risk factors for hip fractures can be simplified into 2 categories: skeletal and nonskeletal. The most important skeletal risk factors include low bone density and previous fractures. Among the nonskeletal risk factors are age and falls.

“We need to think about the specific risks that each of our patients have and think about what that means in terms of risk and the therapy we choose for the patient,” said Dr. McClung.

Calcium and vitamin D deficiencies are the predominant drivers of bone loss in the elderly. Supplementation with calcium and vitamin D in individuals who are deficient has been documented to reduce the risk of hip fractures. A study by Chapuy and associates in French nursing home patients showed that treatment with 800 units of vitamin D and 1,200 mgs of calcium a day reduced hip fractures by 30% over 18 months (Chapuy MR, et al. NEJM.1992;327:1637).

This is an important consideration on the one-hand, because replenishment is inexpensive. It should also be noted that the effect of bisphosphonates seen earlier by Dr. Watts is superimposed on the effect as calcium and vitamin D were administered to the control groups in the bisphosphonates studies.

Two studies have demonstrated that alendronate reduces the risk of hip fractures. Hip fracture was a secondary endpoint and a significant reduction was observed (Black DM, et al. Lancet. 1996;348:1535). In the clinical fracture arm of the Fracture Intervention Trial, reduction in hip fracture was seen only in a subgroup of patients whose hip bone density was consistent with osteoporosis. In both studies, patients with osteoporosis were protected from hip fracture (Cummings SR, et al. JAMA. 1998;280:2077).

The HIP Study is the only study to date that specifically looked at hip fracture reduction as the primary endpoint. Over 9,000 women at risk for hip fracture were enrolled in this study and randomly assigned to receive either risedronate or placebo. All patients were given calcium and vitamin D supplementation was provided if levels were low (McClung M, et al. NEJM. 2001; 344:330).

There were 2 groups enrolled in the study. Group 1 consisted of women in their 70s who all had osteoporosis defined as low femoral neck bone density. The second group, comprised of women 80 and above with clinical risk factors for hip fracture. This group was assumed to be osteoporotic because of their age, in line with the thinking in 1992 when the study began.

In the younger group with known density deficiencies, risedronate therapy resulted in a statistically and clinically significant 40% reduction in hip fracture risk. A retrospective analysis was undertaken of a subset of women at high-risk with known bone densities and previous vertebral fractures. In this subset of women, a 60% reduction in fracture risk was observed. In the women with osteoporosis but no vertebral fractures, a non-significant 40% reduction was seen. In contrast, there was a 20% reduction in hip fracture in the older group of women, selected mainly for their fall-related risks.

In a subset of control patients with bone mineral density measurements at the hip that were consistent with osteoporosis, the incidence of hip fracture was 9.7%. This was nearly twice as high as the entire older group and three times higher than the women with osteoporosis in the younger group. This is consistent with the observation that osteoporosis and fall-related risks with advancing age increases fracture risk.

“The contribution of osteoporosis to hip fracture increases with age, while at the same time the proportion of risk of having a hip fracture attributable to osteoporosis gradually diminishes with age,” said Dr. McClung. “While this seems confusing, what is happening is as people age the proportion of risk that is attributed to falls increases faster than that attributed to osteoporosis. Among the very elderly, falls and related risk factors dominate the picture despite the fact that osteoporosis is common.”

Dr. McClung noted that those in the field of geriatrics need much more information about what makes those at risk for falling not fall. If geriatricians cannot find ways to keep them on their feet, then they need to look into ways to protect them when they do fall.

“What we do know about fracture reduction is that calcium and vitamin D are effective in reducing hip fracture risk in vitamin D deficient patients,” said Dr. McClung. “Estrogen therapy has been shown to reduce risk in low risk patients in the Women’s Health Initiative. No effect on hip fracture risk has been observed with calcitonin and raloxifene while both alendronate and risedronate reduce hip fracture risk in patients with osteoporosis.”

Simply stated, Dr. McClung thinks those with osteoporosis should be treated for osteoporosis. Where falls are the major concern, actions should be taken to address these issues since medications will have little impact.

“Hip fracture is not simply an osteoporotic problem, it is a multifactorial one,” he noted. “We must consider other clinical risk factors, particularly age, falls and previous fractures, in the paradigm of assessing fracture risk and choosing the treatment and management strategies”.