Increases in BMD correlate with improvements in bone microarchitecture with teriparatide treatment in postmenopausal women with osteoporosis.

Increases in BMD are correlated with improvements in 2D and 3D trabecular microarchitecture indices with teriparatide treatment. Therefore, improvements in trabecular bone microarchitecture may be one of the mechanisms to explain how BMD increases improve bone strength during teriparatide treatment. INTRODUCTION: Bone strength is determined by BMD and other elements of bone quality, including bone microarchitecture. Teriparatide treatment increases BMD and improves both cortical and trabecular bone microarchitecture. Increases in lumbar spine (LS) BMD account for approximately 30-41% of the vertebral fracture risk reduction with teriparatide treatment. The relationship between increases in BMD and improvements in cortical and trabecular microarchitecture has not yet been studied. MATERIALS AND METHODS: The relationship between increases in BMD and improvements in cortical and trabecular microarchitecture after teriparatide treatment was assessed using data from a subset of patients who had areal BMD measurements and structural parameters from transiliac bone biopsies in the Fracture Prevention Trial. 2D histomorphometric and 3D microCT parameters were measured at baseline and 12 (n = 21) or 22 (n = 36) mo. LS BMD was assessed at baseline and 12 and 18 mo, and femoral neck (FN) BMD was measured at baseline and 12 mo. Pearson correlation was performed to assess the relationship between actual changes in BMD and actual changes in microarchitectural parameters. RESULTS: Changes in LS BMD at 12 mo were significantly correlated with improvements in trabecular bone structure at 22 mo: 2D bone volume (r = 0.45, p = 0.02), 2D mean wall thickness (r = 0.41, p = 0.03), 3D bone volume (r = 0.48, p = 0.006), 3D trabecular thickness (r = 0.44, p = 0.01), 3D trabecular separation (r = -0.37, p = 0.04), 3D structural model index (r = -0.54, p = 0.001), and 3D connectivity density (r = 0.41, p = 0.02). Changes in LS BMD at 18 mo had similar correlations with improvements in bone structure at 22 mo. Changes in FN BMD at 12 mo were significantly correlated with changes in 2D mean wall thickness (r = 0.56, p = 0.002), 3D bone volume (r = 0.51, p = 0.004), 3D trabecular thickness (r = 0.44, p = 0.01), 3D trabecular separation (r = -0.46, p = 0.01), and 3D structural model index (r = -0.55, p = 0.001). CONCLUSIONS: Increases in BMD are correlated with improvements in trabecular microarchitecture in iliac crest of patients with teriparatide treatment. Therefore, improvements in trabecular bone microarchitecture may be one of the mechanisms to explain how BMD increases improve bone strength during teriparatide treatment.     

Predicting human vertebral bone strength by vertebral static histomorphometry

The study investigates the relationship between static histomorphometry and bone strength of human lumbar vertebral bone. The ability of vertebral histomorphometry to predict vertebral bone strength was compared with that of vertebral densitometry, and also with histomorphometry and bone strength of iliac crest bone biopsies. The material comprised matched sets of second lumbar vertebrae, third lumbar vertebrae, and two iliac crest bone biopsies from each of 21 women (19--96 years) and 24 men (23--95 years). One of the iliac crest biopsies and 9-mm-thick mediolateral slices of half of each of the entire vertebral bodies (L-2) were used for histomorphometry. The other iliac crest biopsies and the L-3 were destructively tested by compression. High correlation was found between BV/TV or Tb.Sp and vertebral bone strength (absolute value of r = 0.86 in both cases). Addition of Tb.Th significantly improved the correlation between BV/TV and bone strength, and the addition of bone space star volume significantly improved the correlation between Tb.Sp and bone strength (from absolute value of r = 0.86 to absolute value of r = 0.89 in both cases). Bone structure (connectivity density) was not capable of improving the prediction of bone strength of the vertebral body. The correlations between BV/TV of L-2 and bone strength of L-3 were comparable with the correlation obtained by quantitative computed tomography (QCT), peripheral QCT (pQCT), and dual-energy X-ray absorptrometry (DEXA) of L-3 and bone strength of L-3. The iliac crest was found to have low predictive power of vertebral bone strength (iliac BV/TV: r = 0.62; iliac bone strength: r = 0.67). No gender-related differences were found in any of the relationships. It was shown that trabecular bone volume BV/TV and mean trabecular plate separation Tb.Sp are good predictors of vertebral bone strength. The ability of histomorphometry to predict vertebral bone strength was comparable to that of densitometry. Bone structure assessed by connectivity density did not improve the correlation between static histomorphometric measures and vertebral bone strength. No gender-related differences were found in any of the relationships. Neither static histomorphometry nor biomechanical testing of iliac crest bone biopsies is a good predictor of vertebral bone strength.     

Teriparatide Reduces Bone Microdamage Accumulation in Postmenopausal Women Previously Treated With Alendronate

Suppression of bone turnover by bisphosphonates is associated with increased bone microdamage accumulation in animal models. Our objective was to study the effects of teriparatide treatment on changes in microdamage accumulation at the iliac crest in previously treatment‐naïve patients or in those switched from alendronate to teriparatide. Sixty‐six postmenopausal women with osteoporosis (mean age, 68.0 yr; and mean BMD T‐score of ?2.8 at lumbar spine and ?1.7 at total hip; 62% with prevalent fractures) entered this prospective, nonrandomized study and started with 24‐mo 20 μg/d subcutaneous teriparatide treatment in monotherapy: 38 patients stopped previous alendronate treatment (10 mg/d or 70 mg/wk for a mean duration of 63.6 mo) and switched to teriparatide, whereas 28 were previously treatment naïve. Thirty‐one paired biopsies with two intact cortices were collected and analyzed for microstructure and microdamage accumulation at baseline and after 24 mo of teriparatide administration. After 24 mo of teriparatide treatment, crack density (Cr.Dn), crack surface density (Cr.S.Dn), and crack length (Cr.Le) were decreased in previously alendronate‐treated patients, whereas only Cr.Le was reduced in former treatment‐naïve patients. Patients with lower initial femoral neck BMD also showed a higher reduction of microdamage accumulation. Better bone microarchitecture correlated positively, whereas bone turnover markers and age did not correlate with reduced microdamage accumulation on teriparatide. In conclusion, teriparatide reduces microdamage accumulation in the iliac crest of patients previously treated with alendronate. There is insufficient evidence to suggest that age or bone turnover would be associated with this change.     

Teriparatide [PTH(1-34)] strengthens the proximal femur of ovariectomized nonhuman primates despite increasing porosity.

OVX monkeys treated for 18 months with 1 or 5 microg/kg/d teriparatide [PTH (1-34)] had significantly stronger proximal femora relative to ovariectomized controls. Teriparatide enhancement of cortical area, cortical width, and trabecular bone volume seemed to more than compensate for the dose-dependent increase in cortical porosity. Beneficial effects of teriparatide treatment on the proximal femur persisted beyond the treatment period and may extend to the marrow. INTRODUCTION: We conducted a detailed quantitative analysis of the effects of teriparatide on the proximal femur of ovariectomized monkeys. Teriparatide increased bone mass, enhanced structural architecture, and strengthened the hip, despite increasing cortical porosity. MATERIALS AND METHODS: Monkeys were treated with vehicle (sham or OVX controls), 1 microg/kg/day teriparatide [parathyroid hormone (1-34); PTH1], or 5 microg/kg/day teriparatide (PTH5) for 18 months or for 12 months followed by 6 months of treatment withdrawal (PTH1W and PTH5W, respectively). Excised proximal femora were analyzed by microCT, conventional histomorphometry, and biomechanics.RESULTS AND CONCLUSIONS: The femoral neck showed significant reduction in trabecular bone volume (BV/TV) for OVX compared with sham, whereas PTH1 BV/TV was restored to sham levels and PTH5 BV/TV was greater than sham and OVX. The withdrawal groups had BV/TVs intermediate between sham and OVX. PTH1 had trabecular number (Tb.N) greater than OVX, and PTH5 Tb.N was greater than sham and OVX. The withdrawal groups had Tb.Ns intermediate between sham and OVX. No differences between groups were observed for trabecular orientation or trabecular thickness. Teriparatide dose-dependently increased bone formation rate and activation frequency in the femoral neck. Cellular composition analyses suggested a tendency of ovariectomy to increase adiposity of marrow by 100%, whereas PTH tended to reduce adipocyte number and increase osteoblast number compared with OVX. Analyses of the cortex showed dose-dependent elevation of cortical porosity, which was consistent with enhanced bone turnover with treatment. Cortical porosity was reduced after withdrawal of teriparatide, because PTH1W cortical porosity was lower than OVX, whereas PTH5W cortical porosity was intermediate between sham and OVX. Increased cortical porosity did not weaken the proximal femora. Biomechanics showed that ovariectomy weakened proximal femora compared with sham, but PTH1, PTH5, and PTH1W were stronger than OVX and not different from sham. PTH5W strength was intermediate between sham and OVX. Therefore, teriparatide had beneficial effects on the proximal femur, despite increasing cortical porosity. Cortical porosity did not adversely affect the mechanical integrity of the proximal femora, because enhanced cortical area and trabecular bone volume more than compensated for the porosity. Much of the beneficial effects of teriparatide were retained after 6 months withdrawal from treatment. PTH effects on the femoral neck were not limited to bone but may include inhibition of OVX-stimulated adiposity of the marrow.     

Static histomorphometry of human iliac crest and vertebral trabecular bone: a comparative study.

We recently developed a new, rapid method for conducting static histomorphometry on large histologic sections. This method has now been applied on both iliac crest and lumbar vertebral bone to compare the age-related changes at these two skeletal sites and to investigate the correlation between the histomorphometric measures at the iliac crest and the vertebral body. The material comprised matched sets of unilateral transiliac crest bone biopsies and lumbar vertebral bodies (L-2) from 24 women (19-96 years) and 24 men (23-95 years) selected from a larger autopsy material. Three female subjects (80, 88, and 90 years) had a known vertebral fracture of L-2. The iliac crest biopsies and 9-mm-thick mediolateral slices of half the entire vertebral bodies were embedded in methylmetacrylate, stained with aniline blue, and scanned into a computer with a flatbed image scanner at a high resolution. With a custom-made computer program the following static histomorphometric measures were determined: trabecular bone volume; marrow and bone space star volume; node-strut analysis; trabecular bone pattern factor; trabecular thickness; trabecular number; trabecular separation; and anisotropy of bone and marrow phase. In addition, connectivity density was measured (ConnEulor method). The results showed that the age-related changes in the static histomorphometric measures are generally similar in the iliac crest and the vertebral body, and that these age-related changes are independent of gender. An exception, however, is connectivity density, where the age-related changes are similar for women and men in the vertebral body but significantly different in the iliac crest. Furthermore, the results showed that the histomorphometric measures were weakly intercorrelated between the iliac crest and the vertebral body, despite the generally similar pattern in age-related changes at these two skeletal sites. The highest correlation coefficient was found for trabecular separation (Tb.Sp; r = 0.63). Trabecular bone volume showed a correlation coefficient of r = 0.59. It is concluded that static histomorphometry performed on one skeletal site does not automatically predict static histomorphometric measures at another skeletal site. Therefore, it is recommended that static histomorphometry be performed at the skeletal site of interest-if at all possible.     

Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure.

Histomorphometry and microCT of 51 paired iliac crest biopsy specimens from women treated with teriparatide revealed significant increases in cancellous bone volume, cancellous bone connectivity density, cancellous bone plate-like structure, and cortical thickness, and a reduction in marrow star volume. INTRODUCTION: We studied the ability of teriparatide (rDNA origin) injection [rhPTH(1-34), TPTD] to improve both cancellous and cortical bone in a subset of women enrolled in the Fracture Prevention Trial of postmenopausal women with osteoporosis after a mean treatment time of 19 months. This is the first report of a biopsy study after treatment with teriparatide having a sufficient number of paired biopsy samples to provide quantitative structural data. METHODS: Fifty-one paired iliac crest bone biopsy specimens (placebo [n = 19], 20 microg teriparatide [n = 18], and 40 microg teriparatide [n = 14]) were analyzed using both two-dimensional (2D) histomorphometry and three-dimensional (3D) microcomputed tomography (microCT). Data for both teriparatide treatment groups were pooled for analysis. RESULTS AND CONCLUSIONS: By 2D histomorphometric analyses, teriparatide significantly increased cancellous bone volume (median percent change: teriparatide, 14%; placebo, -24%; p = 0.001) and reduced marrow star volume (teriparatide, -16%; placebo, 112%; p = 0.004). Teriparatide administration was not associated with osteomalacia or woven bone, and there were no significant changes in mineral appositional rate or wall thickness. By 3D cancellous and cortical bone structural analyses, teriparatide significantly decreased the cancellous structure model index (teriparatide, -12%; placebo, 7%; p = 0.025), increased cancellous connectivity density (teriparatide, 19%; placebo, - 14%; p = 0.034), and increased cortical thickness (teriparatide, 22%; placebo, 3%; p = 0.012). These data show that teriparatide treatment of postmenopausal women with osteoporosis significantly increased cancellous bone volume and connectivity, improved trabecular morphology with a shift toward a more plate-like structure, and increased cortical bone thickness. These changes in cancellous and cortical bone morphology should improve biomechanical competence and are consistent with the substantially reduced incidences of vertebral and nonvertebral fractures during administration of teriparatide.     

Effects of teriparatide and alendronate on vertebral strength as assessed by finite element modeling of QCT scans in women with osteoporosis.

FE modeling was used to estimate the biomechanical effects of teriparatide and alendronate on lumbar vertebrae. Both treatments enhanced predicted vertebral strength by increasing average density. This effect was more pronounced for teriparatide, which further increased predicted vertebral strength by altering the distribution of density within the vertebra, preferentially increasing the strength of the trabecular compartment. INTRODUCTION: Teriparatide 20 microg/day (TPTD) and alendronate 10 mg/day (ALN) increase areal, measured by DXA, and volumetric, measured by QCT, lumbar spine BMD through opposite effects on bone remodeling. Using finite element (FE) modeling of QCT scans, we sought to compare the vertebral strength characteristics in TPTD- and ALN-treated patients. MATERIALS AND METHODS: A subset of patients (N = 28 TPTD; N = 25 ALN) from the Forteo Alendronate Comparator Trial who had QCT scans of the spine at baseline and postbaseline were analyzed. The QCT scans were analyzed for compressive strength of the L(3) vertebra using FE modeling. In addition, using controlled parameter studies of the FE models, the effects of changes in density, density distribution, and geometry on strength were calculated, a strength:density ratio was determined, and a response to bending was also quantified. RESULTS: Both treatments had positive effects on predicted vertebral strength characteristics. At least 75% of the patients in each treatment group had increased strength of the vertebra at 6 months compared with baseline. Patients in both treatment groups had increased average volumetric density and increased strength in the trabecular bone, but the median percentage increases for these parameters were 5- to 12-fold greater for TPTD. Larger increases in the strength:density ratio were also observed for TPTD, and these were primarily attributed to preferential increases in trabecular strength. CONCLUSIONS: These results provide new insight into the effects of these treatments on estimated biomechanical properties of the vertebra. Both treatments positively affected predicted vertebral strength through their effects on average BMD, but the magnitudes of the effects were quite different. Teriparatide also affected vertebral strength by altering the distribution of density within the vertebra, so that overall, teriparatide had a 5-fold greater percentage increase in the strength:density ratio.     

Once-weekly teriparatide reduces serum sclerostin levels in postmenopausal women with osteoprosis

Once-weekly teriparatide treatment is widely used in the treatment of osteoporosis in Japan but the mechanisms causing the increase in bone mineral density (BMD) of the lumbar spine remain unknown. Methods: This prospective study examined the effects of once-weekly teriparatide treatment on the serum levels of sclerostin, osteocalcin, and bone formation markers as well as BMD of the lumbar spine and femoral neck in 32 postmenopausal women with osteoporosis. Results: The mean age of subjects was 76.3 ± 7.0 years old. Teriparatide significantly reduced serum sclerostin levels at 12 and 18 months in postmenopausal women with osteoporosis, and significantly increased serum osteocalcin levels at 3,12 and 18 months and PINP levels at 1 and 3 months, respectively. Teriparatide treatment significantly increased BMD of the lumbar spine at 6, 12, and 18 months, but did not affect BMD of the femoral neck. Examination of the relationships between percent changes in bone metabolic indices and BMD of the lumbar spine during the teriparatide treatment showed serum sclerostin changes at 3 months were negatively correlated with BMD changes of the lumbar spine at 6, 12, and 18 months. Serum osteocalcin changes were not correlated with BMD changes in the lumbar spine at 12 months. Conclusions: The present study showed that once-weekly teriparatide treatment reduced serum sclerostin levels in postmenopausal women with osteoporosis. The effects of teriparatide on sclerostin may be associated with the response of the BMD of the lumbar spine.     

Treatment with human parathyroid hormone (1-34) for 18 months increases cancellous bone volume and improves trabecular architecture in ovariectomized cynomolgus monkeys (Macaca fascicularis)

A key feature of postmenopausal osteoporosis is the loss of trabecular bone mass and connectivity. The current study focuses on these parameters in the assessment of long-term (12 and 18 months) parathyroid hormone (PTH) therapy and its withdrawal (6 months) in the ovariectomized cynomolgus monkey (Macaca fascicularis), a well-characterized model for bone changes associated with postmenopausal osteoporosis. We used static and dynamic histomorphometric parameters to assess the amount and architecture of cancellous bone in four clinically important sites for osteoporotic fractures, including the lumbar vertebra, femoral neck, distal radius, and iliac crest. Recombinant human PTH(1-34) was administered daily to two groups for 18 months at 1.0 microg/kg per day (n = 19) and 5.0 microg/kg per day (n = 21). To study the effects of PTH withdrawal, two groups were administered PTH(1-34) daily for 12 months at 1.0 microg/kg per day (n = 20) and 5.0 microg/kg per day (n = 20), followed by daily administration of vehicle for 6 months. Sham-ovariectomized and ovariectomized (ovx) groups each received daily injections of vehicle for 18 months. Treatment with PTH had minimal effects on bone formation rates at the timepoints studied, but markedly increased cancellous bone volume relative to ovx monkeys in iliac crest biopsies at 6 and 15 months, as well as in terminal specimens of lumbar vertebrae, femoral neck, and distal radius after 18 months. At all sites, PTH significantly improved trabecular architecture, as evidenced by increased trabecular number (Tb.N) and decreased trabecular separation (Tb.Sp), with no significant change in trabecular thickness (Tb.Th). The mechanism of these structural changes is suggested by qualitative observations of trabecular tunneling observed in the iliac crest and vertebra. Longitudinal tunneling of thickened individual trabeculae is hypothesized to convert them into multiple trabeculae, resulting in a normalization of Tb.Th, but an increase in Tb.N. A significant positive effect on cancellous bone volume was still apparent after a 3-6 month withdrawal period following 12 months of PTH treatment in the iliac crest, vertebra, and femoral neck. Corresponding increases in Tb.N and decreases in Tb.Sp also remained significant after PTH withdrawal at these three sites. The distal radius was relatively insensitive to PTH treatment or its withdrawal, compared with the other bones. In summary, PTH therapy dramatically improved cancellous bone mass and architecture in both axial and appendicular sites.     

Relationships between bone structure in the iliac crest and bone structure and strength in the lumbar spine

The purpose of this study was to examine the relationship between histomorphometric variables of cancellous bone structure and ultimate compressive strength (UCS) in the second lumbar vertebra (L2) and to determine whether structural variables in the iliac crest are predictive of the same variables and of UCS in L2. At autopsy, 7.5 mm diameter cores were removed from the iliac crest and from L2 of 29 subjects who had died suddenly without bone disease. Cancellous bone volume (BV/TV, %) was significantly lower in L2 than in iliac crest due to lower trabecular number (Tb.N, per mm) and thickness (Tb.Th, µm). There were significant correlations between iliac crest and L2 for BV/TV, Tb.N and trabecular separation (Tb.Sp, µm), but not for Tb.Th. BV/TV was negatively correlated, and Tb.Sp was positively correlated with age at both sites. Tb.Th was not significantly correlated with age in the iliac crest, but a significant negative correlation was observed in L2. The UCS of vertebral cores was negatively correlated with age. BV/TV and Tb.Th in L2 were positively correlated with UCS in L2. Cortical width and BV/TV in iliac crest were positively correlated with UCS in L2. We conclude that: (1) cancellous bone volume in the iliac crest is higher than in the lumbar spine due to thicker, more closely spaced trabecular plates, (2) the changes in structural variables with age are generally similar in the iliac crest and lumbar vertebra, but trabecular thinning with age is more evident in the spine than in the ilium, and (3) the compressive strength of cancellous bone in the lumbar spine is correlated with histomorphometric variables of bone structure, as measured both in the lumbar spine and in the iliac crest.     

Trabecular bone remodeling and bone mineral density in the adult cat during chronic dietary acidification with ammonium chloride

Ammonium chloride (NH4Cl) is used as a urinary acidifier in the treatment and prevention of feline urologic syndrome. It is reported to cause alterations in calcium and bone metabolism in humans, dogs, and rats. Adult cats with normal renal function were fed 1.5% NH4Cl for 6 months to study the effects of chronic dietary acidification on trabecular bone remodeling of the iliac crest and bone mineral density (BMD) of lumbar vertebral trabecular bone and femoral cortex. Histomorphometric analyses of iliac crest biopsies were performed before and after treatment. Static and dynamic parameters of bone resorption and formation were determined. Single-energy quantitative computed tomography (SEQCT) was used to measure lumbar trabecular and femoral cortical BMD. There were no significant treatment effects in iliac crest trabecular bone remodeling or BMD of the vertebrae and femora. Bone remodeling activity decreased with time in both acidotic and control cats. Vertebral BMD increased with time in both groups of cats, whereas no change was seen in the femora. Thus, chronic dietary acidification for 6 months with therapeutic levels of NH4Cl produced no significant changes in trabecular bone remodeling or bone mineral density in adult cats.     

Sex differences of human trabecular bone microstructure in aging are site-dependent.

In this study, we characterize bone microstructure, specifically sex differences, at multiple skeletal sites in 165 subjects >52 yr of age, using microCT technology in vitro. Significant sex differences are observed at the distal radius, femoral neck, and femoral trochanter, but not at the iliac crest, calcaneus, and lumbar vertebral body. Correlations in BV/TV between sites ranged from r = 0.13 to 0.56. INTRODUCTION: The goals of this study were (1) to assess potential sex differences of bone microstructure and their difference between skeletal sites and (2) to explore the relationship of trabecular microstructural properties between relevant skeletal sites. MATERIALS AND METHODS: Trabecular bone microstructural properties were measured in vitro in 165 subjects 52-99 yr of age using microCT. Defined volumes of interest (cylinders with 6 mm diameter and 6 mm length) were scanned at a resolution of 26 microm (isotropic) in six different anatomical sites: distal radius, femoral neck and trochanter, iliac crest, calcaneus, and second lumbar vertebral body. RESULTS: At the radius and femoral neck, trabecular bone displayed a more plate-like structure, thicker trabeculae, smaller separation/higher trabecular number, higher connectivity, and a higher degree of anisotropy in men than in women (p < 0.05). At the trochanter, men displayed more plate-like structure and thicker trabeculae (p < 0.05), but no differences in trabecular separation or other parameters compared with the women. At the calcaneus, iliac crest, and second lumbar vertebra none of the bone parameters displayed significant differences between sexes. The BV/TV at one site explained a range of only 2-32% of the variability at other sites. CONCLUSIONS: These results suggest that trabecular bone microstructural properties are remarkably heterogeneous throughout the skeleton. Significant differences between men and women are observed at some, but not at all, sites. The magnitude of sex differences in trabecular microstructure coincides with that of fracture incidence observed for some of the sites in epidemiological studies.     

Cancellous and cortical bone architecture and turnover at the iliac crest of postmenopausal osteoporotic women treated with parathyroid hormone 1-84

Treatment with parathyroid hormone [PTH(1-84)] increases lumbar spine bone mineral density and decreases vertebral fractures, but its effects on bone microarchitecture are unknown. We obtained iliac crest biopsies from postmenopausal osteoporotic women given placebo (n=8) or 100 microg PTH(1-84) for 18 (n=8) or 24 (n=7) months to assess cancellous and cortical bone formation and structure. At 18 months, cancellous bone volume (BV/TV) measured by microcomputed tomography and histomorphometry was 45-48% higher in subjects treated with PTH(1-84) versus placebo, a result of higher trabecular number (Tb.N) and thickness. The higher Tb.N appeared to result from intratrabecular tunneling. Connectivity density was higher and structure model index was lower, indicating a better connected and more plate-like trabecular architecture. Cancellous bone formation rate (BFR) was 2-fold higher in PTH(1-84)-treated subjects, primarily because of greater mineralizing surface. Osteoblast and osteoid surfaces were a nonsignificant 58% and 35%, respectively, higher with PTH(1-84) treatment. Osteoclast and eroded surface were unaffected by PTH(1-84). There were no effects of PTH(1-84) treatment on cortical thickness, or endocortical or periosteal BFR, but cortical porosity tended to be higher. Although cancellous BFR was lower at 24 than at 18 months, measures of cancellous and cortical bone structure were similar at both timepoints. The bone produced by PTH(1-84) had normal lamellar structure and mineralization with no abnormal histology. In conclusion, when compared with placebo, treatment of osteoporotic women with PTH(1-84) was associated with higher BV/TV and trabecular connectivity, with a more plate-like architecture, all consistent with the lower vertebral fracture incidence.     

Lack of Bone Neoplasms and Persistence of Bone Efficacy in Cynomolgus Macaques After Long‐Term Treatment With Teriparatide [rhPTH(1‐34)]

In rats, teriparatide [rhPTH(1‐34)] causes marked increases in bone mass and osteosarcoma. In primates, teriparatide causes lesser increases in bone mass, and osteosarcomas have not been reported. Previous studies in primates were not designed to detect bone tumors and did not include a prolonged post‐treatment observation period to determine whether tumors would arise after cessation of treatment. Ovariectomized (OVX), skeletally mature, cynomolgus monkeys (n = 30 per group) were given teriparatide for 18 mo at either 0 or 5 μg/kg/d subcutaneously. After 18 mo of treatment, subgroups of six monkeys from both groups were killed and evaluated, whereas all remaining monkeys entered a 3‐yr observation period in which they did not receive teriparatide. Surveillance for bone tumors was accomplished with plain film radiographs, visual examination of the skeleton at necropsy, and histologic evaluation of multiple skeletal sites. Quantitative assessments of bone mass, architecture, and strength were also performed. After the 18‐mo treatment period, vertebral BMD, BMC, and strength (ultimate load) were increased by 29%, 36%, and 52%, respectively, compared with OVX controls. Proximal femur BMD, BMC, and strength were also increased by 15%, 28% and 33%, respectively. After 3 yr without treatment, no differences in bone mass or strength at the vertebra were observed relative to OVX controls; however, the femoral neck showed significant persistence in stiffness (20%), BMC (14%), and trabecular BV/TV (53%), indicating a retention of teriparatide efficacy at the hip. Radiographs and histology did not identify any bone proliferative lesions or microscopic lesions of osteosarcoma at the end of the treatment or observation period. These data indicate that teriparatide did not induce bone proliferative lesions over a 4.5‐yr interval of observation, including 18 mo of treatment and 3 yr of follow‐up observation. Bone analyses confirmed that teriparatide caused increases in bone mass and strength, consistent with previous studies. During the withdrawal phase, beneficial effects of teriparatide treatment on the vertebra were lost; however, some of the beneficial effects on the proximal femur persisted for 3 yr after cessation of treatment. Although the lack of bone tumors in this study provides some additional reassurance regarding the safety of teriparatide for the primate skeleton, the small group size and other limitations of this, or any other animal study, limit the ability to draw definitive conclusions regarding the risk of bone tumor developments in patients.     

Effects of salmon calcitonin on trabecular microarchitecture as determined by magnetic resonance imaging: results from the QUEST study.

The unique noninvasive MRI technique was used to assess trabecular microarchitecture at multiple skeletal sites in 91 postmenopausal osteoporotic women receiving nasal spray salmon calcitonin (CT-NS) or placebo over 2 years. In the distal radius and lower trochanter of the hip, individuals treated with CT-NS exhibited significant preservation of trabecular bone microarchitecture compared with placebo, where significant deterioration was shown. MRI analyses of os calcis or microCT/histomorphometric analyses of bone biopsies did not reveal consistent differences in architecture between CT-NS and placebo. INTRODUCTION: It is postulated that the reduction in osteoporotic fracture risk in response to certain antiresorptive osteoporosis therapies is caused less by effects on bone quantity than on bone quality (specifically trabecular microarchitecture). To test this hypothesis, the QUEST study was conducted to assess the effects of nasal spray salmon calcitonin (CT-NS) or placebo on parameters of trabecular microarchitecture at multiple skeletal sites using noninvasive MRI technology and iliac crest bone biopsies by microCT/histomorphometry. MATERIALS AND METHODS: Ninety-one postmenopausal osteoporotic women were followed for 2 years (n = 46 for CT-NS, n = 45 for placebo); all women received 500 mg calcium daily. MRI measurements at distal radius, hip (T2 relaxation time [T2*]), and os calcis (obtained yearly), iliac crest bone biopsies with 2D histomorphometry and 3D microCT (obtained at study onset and conclusion), DXA-BMD at spine/hip/wrist/os calcis (obtained yearly), and markers of bone turnover (obtained at 2-week to 12-month intervals) were analyzed, with an analysis of covariance model used to assess treatment effect for parameters of interest. RESULTS AND CONCLUSIONS: MRI assessment of trabecular microarchitecture at individual regions of the distal radius revealed significant improvement, or preservation (no significant loss), in the CT-NS-treated group compared with significant deterioration in the placebo control group, as reflected in apparent BV/TV (p < 0.03), apparent trabecular number (p < 0.01), and apparent trabecular spacing (p < 0.01). Also, at the hip, the CT-NS group exhibited preservation of trabecular microarchitecture at the lower trochanter (p < 0.05) as determined by T2* MRI technology. Significant deterioration of trabecular bone architecture was noted in the placebo group at the femoral neck, Ward's triangle, and lower trochanteric sites. Apart from a significant increase in apparent trabecular number in the CT-NS group, significant changes within or between groups were not noted at the os calcis. Combined microCT/histomorphometric analysis of iliac crest bone biopsies did not reveal significant differences between treated and placebo groups. In the CT-NS group, regardless of the change in BMD (gain or loss) at the spine, hip, or distal radius, preservation of parameters of trabecular microarchitecture was noted, whereas in the placebo group, regardless of the change in BMD (gain or loss) at the spine, hip, or distal radius, loss or preservation was noted; however, changes in DXA/BMD (of the spine, hip, wrist, os calcis) between CT-NS and placebo groups were not significant. Serum C-telopeptide (S-CTx), a specific bone resorption marker, was reduced by 22.5% at 24 months (p = 0.056). The results of the QUEST study suggest therapeutic benefit of CT-NS compared with placebo in maintaining trabecular microarchitecture at multiple skeletal sites and support the use of MRI technology for assessment of trabecular microarchitecture in clinical research trials. However, the results also highlight site specific differences in response to antiresorptive therapies and the importance of sufficiently large sampling volumes (areas) to obtain reliable assessment of bone architecture.     

Abaloparatide Effects on Cortical Volumetric BMD and Estimated Strength Indices of Hip Subregions by 3D-DXA in Women With Postmenopausal Osteoporosis

In ACTIVE, abaloparatide increased areal BMD (aBMD) of the hip and femoral neck vs teriparatide and placebo in women with osteoporosis. Previously, 3D-processing of dual X-ray absorptiometry (DXA) scans of a subgroup of ACTIVE subjects showed similar increases in trabecular volumetric BMD (Tb.vBMD) and greater increases in cortical vBMD (Ct.vBMD) of the total hip with abaloparatide vs teriparatide. The current analyses from this subgroup describe 2D- and 3D-DXA data for hip subregions. Randomly selected subjects from ACTIVE (n = 250/treatment group) who received 18 mo of placebo, abaloparatide 80 µg, or open-label teriparatide 20 µg by daily subcutaneous injection underwent hip DXA at baseline, and mo 6 and 18 of treatment. Areal BMD of the femoral neck, trochanter, and femoral shaft was determined using standard 2D-DXA and 3D-SHAPER software to retrospectively evaluate changes from baseline in volumetric parameters of these 3 hip subregions, including trabecular and cortical segmentation. Changes in biomechanical parameters cross-sectional moment of inertia (CSMI), section modulus (Z), and buckling ratio were also evaluated. Femoral neck, trochanter, and shaft aBMD increased in the abaloparatide and teriparatide groups at mo 6 and 18 vs placebo, with greater increases for abaloparatide vs teriparatide at the femoral neck at mo 6 and the shaft at mo 6 and 18. All 3 subregions showed similar significant increases in Tb.vBMD with abaloparatide and teriparatide vs placebo, whereas Ct.vBMD of all 3 subregions showed greater increases after 18 mo of abaloparatide vs teriparatide. Biomechanical parameters improved in all subregions with abaloparatide and teriparatide vs placebo, with greater improvements in CSMI and Z of the femoral neck and lower shaft after 6 and 18 mo of abaloparatide vs teriparatide. Differential femoral neck and shaft Ct.vBMD responses may explain the greater increases in CSMI and Z of those subregions with abaloparatide vs teriparatide.     

Quantification of osteopenia in hip fracture patients

Osteopenia was assessed in 56 consecutive hip fracture patients by using dual photon absorptiometry of the lumbar spine and uninjured, contralateral femoral neck and by performing iliac crest biopsy. Of the 56 patients, 47 were female and 9 were male. The mean age was 78 years. There were 31 femoral neck and 25 intertrochanteric fractures. Two comparison populations were also studied. Population 1 consisted of 269 postmenopausal females older than 60 years of age with no history of fracture who were referred for dual photon absorptiometry of the lumbar spine as screening for osteoporosis. Population 2 included 94 patients with vertebral compression fractures who underwent transilial biopsy to evaluate osteoporosis. All transilial biopsies were assessed with the use of quantitative histomorphometry. Dual photon absorptiometry of the lumbar spine indicated that 76.9% of the hip fracture patients had severe bone loss (less than 1 gm/cm2). Nevertheless, no difference in spinal bone density was found when the hip fracture patients were compared to population 1. No difference in density of the lumbar spine or femoral neck was found in patients in the hip fracture group when intertrochanteric and femoral neck fractures were compared. No difference in histomorphometric measurements of total bone, cortical bone, and cancellous bone volume was noted between the hip fracture patients and population 2. There was no difference noted when the intertrochanteric and femoral neck fracture patients were compared. No evidence of osteomalacia was noted in any group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Iliac crest trabecular bone volume as predictor for vertebral compressive strength, ash density and trabecular bone volume in normal individuals

Whole vertebral bodies (L2) and cylindrical trabecular bone samples from the central part of the first lumbar vertebral body (L1) were obtained from 42 normal individuals aged 15-87 years (27 females and 15 males). These bone samples were analyzed by a compression test, and maximum load and stress values were calculated from the load deformation curves. After the compression the ash density of the samples was estimated. For histomorphometric measurements trabecular bone samples from L1 (n = 42) and from the iliac crest (n = 25) were embedded undecalcified, cut in 8 microns sections and stained with Masson trichrome. Trabecular bone volume (TBV) was measured by means of point counting. A significant and parallel age-related decrease in TBV was found in the iliac crest and in the vertebral trabecular bone specimens (p less than 0.001). Highly significant positive correlations were observed between iliac crest TBV and the quantitative vertebral parameters: TBV and ash density (p less than 0.001). Furthermore, the iliac crest TBV was significantly correlated to the qualitative vertebral strength parameters: Vertebral trabecular bone stress, whole vertebral body stress and whole vertebral body load (p less than 0.001). Multiple regression analyses revealed that the vertebral trabecular bone strength was unrelated to bone volume when the influence of age was considered but significantly inversely correlated to age when bone volume was taken into account. This indicates that age-related structural changes other than bone mass affect the vertebral bone strength strongly.     

Age-related changes in trabecular architecture differ in female and male C57BL/6J mice.

We used microCT and histomorphometry to assess age-related changes in bone architecture in male and female C57BL/6J mice. Deterioration in vertebral and femoral trabecular microarchitecture begins early, continues throughout life, is more pronounced at the femoral metaphysis than in the vertebrae, and is greater in females than males. INTRODUCTION: Despite widespread use of mice in the study of musculoskeletal disease, the age-related changes in murine bone structure and the relationship to whole body BMD changes are not well characterized. Thus, we assessed age-related changes in body composition, whole body BMD, and trabecular and cortical microarchitecture at axial and appendicular sites in mice. MATERIALS AND METHODS: Peripheral DXA was used to assess body composition and whole body BMD in vivo, and microCT and histomorphometry were used to measure trabecular and cortical architecture in excised femora, tibia, and vertebrae in male and female C57BL/6J mice at eight time-points between 1 and 20 mo of age (n = 6-9/group). RESULTS: Body weight and total body BMD increased with age in male and female, with a marked increase in body fat between 6 and 12 mo of age. In contrast, trabecular bone volume (BV/TV) was greatest at 6-8 wk of age and declined steadily thereafter, particularly in the metaphyseal region of long bones. Age-related declines in BV/TV were greater in female than male. Trabecular bone loss was characterized by a rapid decrease in trabecular number between 2 and 6 mo of age, and a more gradual decline thereafter, whereas trabecular thickness increased slowly over life. Cortical thickness increased markedly from 1 to 3 mo of age and was maintained or slightly decreased thereafter. CONCLUSIONS: In C57BL/6J mice, despite increasing body weight and total body BMD, age-related declines in vertebral and distal femoral trabecular bone volume occur early and continue throughout life and are more pronounced in females than males. Awareness of these age-related changed in bone morphology are critical for interpreting the skeletal response to pharmacologic interventions or genetic manipulation in mice.     

Human parathyroid hormone (1-34) increases mass and structure of the cortical shell,with resultant increase in lumbar bone strength,in ovariectomized rats

Estrogen deficiency causes reduction of bone mass and abnormal bone microarchitecture, consequently reducing bone strength. Human parathyroid hormone (hPTH) (1-34) increases bone mass and strength. To clarify the factors that determine the recovery of bone strength in the lumbar vertebrae of ovariectomized rats by intermittent hPTH administration, we analyzed the relationship between skeletal measurements and bone strength. Human PTH (1-34) administration resulted in recovery of cortical bone mineral content (BMC) and cortical bone area to sham the levels, but in resulted in a less pronounced recovery of trabecular BMC and no increase in the total cross-sectional area of the vertebral body. Of the three-dimensional (3D) trabecular bone parameters, hPTH (1-34) increased trabecular thickness (Tb.Th). The cortical shell area of L4, determined by histomorphometry, was also increased. In hPTH-treated rats, the only determinant of the compressive load of L5 was the cortical shell BMC, in the early recovery period (days 42–84). Our data suggest that increased cortical bone mass contributes more than trabecular bone mass and structure to the recovery of bone strength in response to hPTH therapy in the rat lumbar vertebral body after ovariectomy.