Our group has obtained preliminary data, which suggest that long-term bisphosphonate treatment could lead to a syndrome characterized on histomorphometric analysis by severely suppressed bone turnover (to be henceforth called SSBT). Bisphosphonates are agents that are widely used in the treatment of osteoporosis. The universal presentation of patients with SSBT is spontaneous or atraumatic non-vertebral fracture(s), with most patients exhibiting delayed or non-healing fractures. These findings are not surprising given the results of previous animal studies, which showed that administration of bisphosphonates could lead to oversuppression of bone turnover, and cause impaired bone quality and decreased resistance to fractures.
With the identification of the new clinical entity described above, and additional preliminary data which suggests that long-term bisphophonate treatment could lead to impaired bone elasticity as measured by ultrasound critical angle reflectometry (Project 2), UT Southwestern's Mineral Metabolism group decided to start a large trial testing the hypothesis that an oral bone-activating agent would facilitate the "recovery" from this complication, by using two unique developments of this group: ultrasound critical angle reflectometry (UCR) to identify impaired bone quality in SSBT, and sustained-release sodium fluoride (SRNaF), a bone "activating" agent. The trial will compare SRNaF against placebo in 100 women with postmenopausal or idiopathic osteoporosis/osteopenia who have been on bisphosphonate treatment for 3 years and who have reduction in maximum elasticity of cortical bone (by UCR of 20% from premenopausal normal mean). Study subjects will be followed for 40 months after stopping bisphosphonate. This will be in line with the group's years of work in trying to establish the role of sodium fluoride and UCR in the treatment and monitoring of patients with osteoporosis. Institutional resources will support this endeavor.
This study will also examine a subset of the study population in order to elucidate the pathophysiology of SSBT. This subgroup will consist of 40 patients with SSBT (history of atraumatic fractures with evidence of delayed fracture healing). The focus of the study will be to determine how fracture healing correlate with changes in maximum elasticity of cortical bone as measured by UCR. Fracture healing will be assessed by examining evidence of callus formation and filling in of fracture gap on serial x-rays. Clinical improvement, such as decreased pain, less use of analgesics and improvement in mobility will also be monitored. Of these patients, the candidate plans to obtain paired bone biopsies in at least 30 patients for the analysis of bone structure and function.
This proposal will test the hypothesis that SSBT confirmed by bone histomorphometry
is associated with accumulation of microcracks (or microdamage) and abnormal
size, distribution and orientation of bone crystals. In experimental animals,
alendronate, a commonly prescirbed bisphosphonate for osteoporosis has been
shown to inhibit the normal repair of microdamage owing to marked suppression
of bone turnover. Accumulation of microdamage in any material or structure
is believed to lead to a reduction in the elastic modulus of the tissue, decrease
in bone strength and increase in dissipation of energy when bone is loaded.
Decreased strength and elasticity could lead to increased propensity to fracture.
In addition, chronic oversuppression of bone turnover by bisphosphonates may
allow secondary mineralization of previously formed bone to continue, resulting
in "hypermineralized" bone that has reduced fracture toughness.
We believe that the impairment of the material structure and function of the
bone are likely responsible for the clinical manifestations of SSBT i.e.,
increased propensity to non-spinal fractures and delayed fracture healing.
The applicant's background, and her earlier work on SSBT will allow her to
independently accomplish the first 2 aims listed below, and gain a better
understanding of the pathophysiologic mechanism of this new clinical entity.
Potential subjects will undergo initial screening, which include complete
history and physical examination, BMD, serum chemistries to rule out liver
and kidney disease, serum PTH, and 25-OH vitamin D (to rule out other conditions
that can affect bone metabolism such as vitamin D deficiency)
Project 2: Title of Project: DETECTION OF IMPAIRED INTRINSIC BONE STRENGTH
in vivo by ULTRASOUND CRITICAL ANGLE REFLECTOMETRY
For about 20 years, clinicians have relied on the measurement of bone density (mainly using the dual X-ray absorptiometry or DXA) to determine the individual patient's fracture risk and response to therapy for osteoporosis. However, it is now clear that although bone density is an important determinant of fracture risk, other factors such as bone quality play an important role as well. Our report on patients with severely suppressed bone turnover is a good example of the discordance between the rise in bone density and development of non-traumatic fractures with treatment. Because of these observations, we explored the possibility that an ultrasound technology (critical angle reflectometry or UCR), developed by the Advanced Radiological Sciences of the Department of Radiology, in collaboration with the Center for Mineral Metabolism will detect changes in bone quality (bone elasticity) not measured by bone densitometry (DXA). This study will be conducted at 3 sites: UT Southwestern Medical Center, Columbia University in New York and Henry Ford Hospital in Detroit.
Specific Aims
The objective of this project is to conduct a multicenter trial in order to evaluate the clinical usefulness of a novel device to estimate bone strength from normalized elastic modulus (elasticity) obtained by ultrasound critical angle reflectometry (UCR). The trial will be conducted at three study sites directed towards achieving the broad aims to be described below:
Aim 1. To obtain "normal data" for bone elasticity in normal women
of varying ages without osteoporosis.
Aim 2. To obtain "normal data" for bone elasticity in normal men
of varying ages without osteoporosis.
Aim 3. To obtain bone elasticity data for "untreated postmenopausal osteoporosis"
in postmenopausal women with spontaneous fractures or T-score for bone density
of spine or hip of less than -2.5, who have not been treated with bisphosphonate,
fluoride or parathyroid hormone peptide (teriparatide or Forteo).
Aim 4. To obtain bone elasticity data for "untreated idiopathic osteoporosis"
in premenopausal women and men with spontaneous fractures or T-score for bone
density of spine or hip of less than -2.5, who have not been treated with
bisphosphonate, fluoride or teriparatide.
Aim 5. To derive "serial" bone elasticity data obtained before and
during bisphosphonate treatment in same patients, and "parallel"
data in separate patients treated with bisphosphonate for varying periods.
Aim 6. To obtain serial bone elasticity data obtained before and during Forteo
treatment, and parallel data in separate patients treated with Forteo for
varying periods.
Aim 7. To obtain serial bone elasticity data before and during treatment with
Neosten (sustained-release sodium fluoride) in same patients.
Aim 8. To derive bone elasticity data for "renal transplantation"
in patients 2 years post-kidney transplantation.
Aim 9. To derive bone elasticity data in miscellaneous disease conditions
in which altered bone quality is suspected, including primary hyperparathyroidism,
hypoparathyroidism, and immobilization.
The hypothesis to be tested is that the elasticity of both cortical or trabecular
bone measured by UCR is:
" largely independent of age in normal women without osteoporosis,
" not very much different between normal women and men,
" slightly depressed among patients with untreated osteoporosis (postmenopausal
or idiopathic),
" substantially reduced by bisphosphonate treatment, more so in cortical
bone than in trabecular bone and among those with recurrent non-spinal fractures
than those without,
" improved by treatment with Forteo or Neosten,
" moderately-markedly reduced in renal transplantation, and
" improved in mild primary hyperparathyroidism, but reduced in hypoparathyroidism
and immobilization.
The trial will be conducted in two stages to maximize available resources and take advantage of unique strengths of the three study sites. Stage I will obtain normative bone elasticity data in women and assess the effect of treatment with bisphosphonate, Forteo and Neosten in patients with postmenopausal osteoporosis. Stage II will seek bone elasticity data in normal men, patients with idiopathic osteoporosis and other bone diseases, and assess the effect of treatment in patients with idiopathic osteoporosis.