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Overview Page 1

Osteoporosis and bone quality

The diagnosis of osteoporosis requires an assessment of risk factors, the documentation of fractures, an evaluation of potential secondary causes of bone loss and, most importantly, measurement of bone mineral density (BMD). Studies have demonstrated a direct relationship between bone density and bone strength1 and reductions in BMD in postmenopausal women are associated with an increased risk of fracture.2

However, there is a growing awareness that a reduction in bone mineral density is not the sole pathology underlying osteoporosis, nor do increases in BMD completely explain successful therapy. Patients with similar BMDs may have significantly different fracture risks; and agents with differing effects on BMD may produce similar reductions in fracture risk.3 The missing factor appears to be bone quality. Legrand et al examined the relationship between the quality of trabecular bone and vertebral crush fractures in 44 male patients with osteoporosis.4 There were no significant differences in BMD in patients with or without fractures. However, patients with at least one vertebral fracture had significant alterations in trabecular bone architecture compared with those who were fracture-free. The study suggests that altered trabecular bone architecture is a major determinant of osteoporotic fracture risk in men.

As the studies discussed below suggest, a universally accepted definition of bone quality does not exist. Several factors may be involved; the most important is probably the microarchitecture of bone. In high quality bone, the trabeculae are greater in number, thicker, more platelike, and better connected.3 To these characteristics, Schnitzler adds higher mineralization and less fatigue damage (which is influenced by turnover rate).5 Improved secondary mineralization, changes in cortical porosity, and the health of osteocytes may also play roles in the quality of bone.3 Bone quality, as well as quantity, declines with age. The trabecular network becomes progressively disconnected and weaker. Old osteocytes die, leading to hypermineralization and brittleness. Bone collagen becomes unstable and unremodeled bone acquires accumulated fatigue damage.5

Effects of osteoporosis therapies on bone quality

Many osteoporosis therapies have been found to affect bone quality as well as its mineral density. Turner notes that anabolic therapies, such as parathyroid hormone (PTH; also known as teriparatide), increase bone turnover and porosity, which can offset some of the positive effects on bone strength. Antiresorptive therapies reduce bone turnover, causing increased bone mineralization, which can increase brittleness.6 However, recent studies, both animal and human, suggest that the preservation or improvement of bone microarchitecture accounts for an important part of the benefits of several current osteoporosis medications. In a study by Borah et al, the effects of risedronate on bone mass and architecture were evaluated in ovariectomized minipigs. The animals were treated daily for 18 months with either vehicle or risedronate at doses of 0.5 mg/kg/day or 2.5 mg/kg/day. Bone architecture was measured by 3-D microcomputed tomography. Bone volume was higher in both treated groups (p<0.05), but bone architecture changes were more significant at the 2.5 mg/kg/day dose. At the higher dose of risedronate, trabecular thickness, trabecular number, and connectivity were higher and trabecular separation was lower compared with animals treated with vehicle (p<0.05). Both normalized maximum load (an index of strength) and normalized stiffness of vertebral cores were higher in the 2.5 mg/kg/day group compared with the vehicle group (p<0.05). Vertebral bone volume alone accounted for 76% of the variability in bone strength,while the combination of bone volume and architectural variables accounted for more than 90% of bone strength. The investigators concluded that risedronate preserved trabecular architecture and that bone strength is tightly coupled to both bone mass and architecture.

In a three-year trial, biochemical and histological studies assessed bone quality and turnover in women randomized to placebo or alendronate 5 or 10 mg/day for three years or 20 mg/day for two years, followed by 5 mg/day for one year.7 All patients also received 500 mg/day of calcium carbonate. Transiliac bone biopsies were obtained from 231 patients from Phase III alendronate studies at the end of either 24 or 36 months of continuous treatment. In patients receiving active treatment, decreased bone resorption was followed by decreases in bone formation. A steady state of bone turnover was achieved after six months of treatment. All 231 biopsy samples were evaluated for the presence or absence of qualitative abnormalities. The investigators found that alendronate did not impair bone mineralization, induce the formation of woven bone, marrow fibrosis, or focal osteomalacia, or have any other adverse effects on bone quality.

In a similar three-year trial, the effects of oral risedronate 5 mg/day on bone quality and remodeling were assessed in 55 women (27 placebo and 28 risedronate).8 Transiliac bone biopsies were obtained at baseline and after treatment. The biopsy samples showed no undesirable qualitative changes, such as osteo-malacia, peritrabecular fibrosis, or woven bone, associated with treatment.

The effects of alendronate on bone quality and turnover were also studied in secondary osteoporosis.9 This study included 52 women and 36 men aged 22-75 years who had long-term glucocorticoid exposure. Patients were randomized to receive placebo or oral alendronate 2.5, 5, or 10 mg/day for one year. Transiliac bone biopsies were then obtained for quantitative and qualitative analysis of bone. In addition to the anticipated decrease in bone turnover, the investigators found that alendronate treatment was not associated with any qualitative abnormalities. There were no differences between the placebo and alendronate groups in trabecular bone volume or parameters of microarchitecture.

Parathyroid hormone (PTH) is a bone-formation stimulating agent; it not only increases bone mass, but also seems to restore bone architecture by filling in cavities and cancellous bone. The effects of recombinant parathyroid hormone on bone quality differ with duration of treatment. A study of short-term PTH use (56 days) was conducted in 2-year-old male rats treated with daily injections of 15 nmol/kg PTH or vehicle.10 Rats treated with PTH showed a substantial increase in the strength of the vertebral body compared with those treated with vehicle. Furthermore, a biomechanical analysis showed that compressive bone strength was enhanced, even after correcting for increased bone mass. This suggests that PTH improved bone quality as well as mass. Another animal study suggested that longterm treatment with PTH may have deleterious effects on bone quality.11 Young female rats received near-lifetime treatment with recombinant PTH at doses of 5, 30, or 75 µg/kg/day or vehicle controls for up to two years as part of an oncogenicity evaluation. Substantially increased bone mass was observed for all treatment groups. However, PTH stimulated osteoblasts and skeletal growth throughout the treatment duration, resulting in abnormal bone architecture and undesirable biomechanical properties. In particular, there was an absence of distinction between trabecular and cortical bone, and the femoral midshaft showed reduced toughness and increased brittleness. The investigators concluded that PTH skeletal effects are a complex function of dose and duration and that, in rats, short-term treatment (six months or less) is more advantageous than near-lifetime treatment.

Dempster et al examined the effect of daily treatment with recombinant PTH on bone microarchitecture and turn-over in patients with osteoporosis.12 They obtained paired iliac crest bone biopsy specimens from patients with osteoporosis before and after treatment with daily injections of 400 U of recombinant PTH. The first group of eight men was treated with PTH for 18 months. The second group of eight postmenopausal women was treated with PTH for 36 months. The women were maintained on hormone replacement therapy for the duration of the trial. Results showed that cancellous bone area was maintained in both groups, while cortical width was maintained in men and significantly increased in women. There was no increase in cortical porosity. There was also an increase in trabecular connectivity density in the majority of patients. The investigators concluded that daily PTH has an anabolic effect on cortical bone in patients with osteoporosis and also improves cancellous bone microarchitecture.

Arzoxifene, a new selective estrogen-receptor modulator (SERM), has also been shown to maintain bone quality as well as BMD. The effects of arzoxifene 0.1 mg/day and 0.5 mg/day were examined in four-monthold ovariectomized rats and compared with controls.13 Both doses of arzoxifene prevented ovariectomy-induced declines in BMD. They also maintained bone formation indices and preserved trabecular number above controls. Compression testing and three-point bending testing of the femoral shaft confirmed that bone strength and toughness were higher for treated animals.

Fluoride may also have beneficial effects on bone quality.14 When prescribed for the prevention of osteoporosis, fluoride modifies the microscopic structure and biomechanical properties of bone. It stimulates bone formation, leading to trabecular hypertrophy and possibly improving interconnections within the trabecular network. However, when the concentration of fluoride in bone becomes excessive, it can lead to mineralization defects; these weaken the bone despite an increase in mass. Thus the benefits of fluoride in preventing vertebral fractures are probably the result of a balance between increases in trabecular bone mass and alterations in bone mineralization.14

The future: practical clinical techniques for measuring bone quality

Once the characteristics that determine bone quality are established, it will be desirable to develop scales for measuring and quantifying bone quality. These may ultimately prove useful for diagnosis, selecting appropriate osteoporosis therapy, and assessing the results of treatment.3,15-17

The next step will be the development of practical, noninvasive techniques for assessing bone quality. Although there are several effective techniques for measuring the quality of resected bone, such as multiple spin echos,17 noninvasive techniques for assessing bone microarchitecture have not yet been perfected.3 In a study published in 1999, Matsubara et al experimented with such a technique, using a morphological filter and pipeline analysis applied to computed radiography (CR).18 On the basis of trabecular thickness, they divided observed trabecular patterns into eight subsets. They subsequently developed criteria relating the percentage of thicker trabeculae to the strength of the bone. They were then able to correlate an abstracted percentage of thick trabeculae observed by CR to bone strength. By contrast, BMD alone correlated poorly to bone strength.

In summary, our conception of osteoporosis as a disease of low bone mass has moved toward a broader understanding that bone strength is based on both bone quantity and quality.19 A 1991 consensus conference developed a new definition of osteoporosis as a disease characterized by "low bone mass and microarchitectural deterioration." 20 Current techniques for assessing microarchitectural deterioration are limited by their invasiveness. In the future, the diagnosis of osteoporosis will probably involve more accurate assessments of bone strength using noninvasive methods to measure both bone mineral density and its architectural integrity.19


REFERENCES

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