Early Effects of Abaloparatide on Bone Formation and Resorption Indices in Postmenopausal Women With Osteoporosis

Anabolic osteoporosis drugs improve bone mineral density by increasing bone formation. The objective of this study was to evaluate the early effects of abaloparatide on indices of bone formation and to assess the effect of abaloparatide on modeling-based formation (MBF), remodeling-based formation (RBF), and overflow MBF (oMBF) in transiliac bone biopsies. In this open-label, single-arm study, 23 postmenopausal women with osteoporosis were treated with 80 μg abaloparatide daily. Subjects received double fluorochrome labels before treatment and before biopsy collection at 3 months. Change in dynamic histomorphometry indices in four bone envelopes were assessed. Median mineralizing surface per unit of bone surface (MS/BS) increased to 24.7%, 48.7%, 21.4%, and 16.3% of total surface after 3 months of abaloparatide treatment, representing 5.5-, 5.2-, 2.8-, and 12.9-fold changes, on cancellous, endocortical, intracortical, and periosteal surfaces (p < .001 versus baseline for all). Mineral apposition rate (MAR) was significantly increased only on intracortical surfaces. Bone formation rate (BFR/BS) was significantly increased on all four bone envelopes. Significant increases versus baseline were observed in MBF on cancellous, endocortical, and periosteal surfaces, for oMBF on cancellous and endocortical surfaces, and for RBF on cancellous, endocortical, and intracortical surfaces. Overall, modeling-based formation (MBF + oMBF) accounted for 37% and 23% of the increase in bone-forming surface on the endocortical and cancellous surfaces, respectively. Changes from baseline in serum biomarkers of bone turnover at either month 1 or month 3 were generally good surrogates for changes in histomorphometric endpoints. In conclusion, treatment with abaloparatide for 3 months stimulated bone formation on cancellous, endocortical, intracortical, and periosteal envelopes in transiliac bone biopsies obtained from postmenopausal women with osteoporosis. These increases reflected stimulation of both remodeling- and modeling-based bone formation, further elucidating the mechanisms by which abaloparatide improves bone mass and lowers fracture risk. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Comparative effects of teriparatide and strontium ranelate in the periosteum of iliac crest biopsies in postmenopausal women with osteoporosis

The periosteum contains osteogenic cells that regulate the outer shape of bone and contribute to determine its cortical thickness, size and position. We assessed the effects of subcutaneous injections of teriparatide (TPTD, 20μg/day) or oral strontium ranelate (SrR, 2g/day) in postmenopausal women with osteoporosis on new bone formation activity at the periosteal and endosteal bone surfaces using dynamic histomorphometric measurements. Evaluable tetracycline-labeled transiliac crest bone biopsies were analyzed from 27 patients in the TPTD group, and 22 in the SrR group after six months of treatment. Measurements were conducted on the thicker and thinner cortices separately, and comparisons between the thicker, thinner and combined cortices were carried out. At the combined periosteal cortex, the mineralization surface as a percent of bone surface (MS/BS%) was greater for TPTD (mean±SE: 8.08±1.22%) than SrR (3.22±1.05%) (p<0.005). The difference in mineral apposition rate (MAR) between TPTD (0.35±0.06μm/day) and SrR (0.14±0.06μm/day) was also significant (p<0.05), while that of bone formation rate per bone surface (BFR/BS) between TPTD (0.014±0.004 mm(3)/mm(2)/year) and SrR (0.004±0.003 mm(3)/mm(2)/year) was not (p=0.057). Statistically significant differences between the two treatments were also observed for MS/BS%, BFR/BS, MAR and the double-labeled perimeter in the periosteum of the thicker, but not thinner, iliac crest cortices. The comparison between the thicker and thinner cortices of both periosteal and endosteal surfaces showed statistically significant differences for MAR and the double-labeled perimeter for TPTD treated women. There were no statistically significant differences in any bone formation dynamic measurements between the two cortices in the SrR group. In conclusion, most of the bone formation and mineralization variables were significantly higher for TPTD- than SrR-treated women at both the periosteal and endosteal combined cortices. The response to TPTD for dynamic bone formation measurements in the periosteal surface was greater for the thicker than thinner cortex, but this difference was not significant in SrR treated patients. This may reflect a greater ability of TPTD to enhance responsiveness of bone to the mechanical loading environment. These effects on bone formation may underlie the improvement in bone quality in patients with osteoporosis treated with TPTD.     

Effects of Daily or Cyclic Teriparatide on Bone Formation in the Iliac Crest in Women on No Prior Therapy and in Women on Alendronate

There is little information on the effects of combination therapy for osteoporosis at the tissue level. Using quadruple tetracycline‐labeled bone biopsies, we have compared the bone formation response to teriparatide (TPTD) in treatment‐naïve subjects (Rx‐Naïve) and in subjects on prior and ongoing alendronate (ALN) treatment (ALN‐Rx). Three bone envelopes were analyzed: cancellous, endocortical, and intracortical. TPTD was given as a standard, continuous daily injection or as a cyclic regimen (3 months on daily TPTD, 3 months off, 3 months on daily TPTD). Subjects were biopsied at 7 weeks and at 7 months to allow comparison of the bone formation response to the first and second cycles of TPTD. Baseline values for dynamic bone formation indices were lower in ALN‐Rx than Rx‐Naïve subjects. Both Rx‐Naïve and ALN‐RX subjects responded to TPTD with significant increases in bone formation indices at both time points. With cyclic TPTD treatment, the first and second cycles of TPTD stimulated bone formation rate in the cancellous and endocortical envelopes to a similar extent in ALN‐Rx and Rx‐Naïve subjects. However, in Rx‐Naïve patients, bone formation rate (BFR/BS) was higher in patients receiving daily treatment compared with those receiving cyclic TPTD treatment in all three envelopes in the 7‐month biopsies. This suggests that the cyclic approach does not provide a skeletal benefit in treatment‐naive patients. In the 7‐month biopsies, cortical porosity was higher in the Rx‐Naïve group receiving daily TPTD than in all other groups. These data provide supporting evidence at the tissue level for previous biochemical and densitometric data suggesting that addition of either cyclic or daily TPTD to ongoing ALN treatment may be an effective approach for patients with severe osteoporosis already treated with ALN who remain at high risk of fracture. © 2016 American Society for Bone and Mineral Research.     

Anabolic effect of prostaglandin E2 on cortical bone of aged male rats comes mainly from modeling-dependent bone gain

In this study, prostaglandin E₂ (3 mg/kg per day) was administered to 20-month-old male Wistar rats for 10 and 30 days. Histomorphometric analyses were performed on double-fluorescent-labeled undecalcified tibial shaft sections. Thirty days of prostaglandin E₂ (PGE₂) administration increased bone formation rate/total bone surface from undetectable levels to 0.6 μm/day at the periosteal surface and from 0.5 to 2.1 μm/day at the endocortical surface. Endocortical osteoid surface area increased from 2% to 67% at day 10 and decreased to 6% at day 30; woven and lamellar bone formation started at day 0, but was most obvious at day 30, resulting in a 12% increase of total bone mass. The red to yellow marrow ratio was 0.2 in pretreatment controls, and increased to 1.6 by day 10 and 2.4 by day 30 with PGE₂ administration. Intracortical cavity number and area increased after 10 days of PGE₂ treatment, but with forming osteon number and area far exceeding those of resorption cavities at day 30. Endocortical modeling surface/endocortical surface was only 1.5%, and remodeling was 11.1% in pretreatment controls. PGE₂ treatment increased modeling to 24.5% in the 10 day group and 93.7% in the 30 day group, whereas remodeling remained unchanged at 10 days, and decreased to 6.2% at 30 days. Osteoprogenitor cells and osteoblasts could not be detected in pretreatment controls, but increased by day 10, and returned almost to control levels by 30 days. Our data indicate that PGE₂ induced periosteal and endocortical bone formation mainly by modeling-dependent bone gain, accompanied by increases in intracortical remodeling and red bone marrow, and a transient increase in the osteoprogenitor cells adjacent to the endocortical surface. These findings suggest that 20-month-old male Wistar rats were very responsive to the anabolic action of PGE₂ in the tibial shaft, a site consisting mainly of cortical bone and yellow marrow.     

Anabolic effect of prostaglandin E2 on cortical bone of aged male rats comes mainly from modeling-dependent bone gain

In this study, prostaglandin E₂ (3 mg/kg per day) was administered to 20-month-old male Wistar rats for 10 and 30 days. Histomorphometric analyses were performed on double-fluorescent-labeled undecalcified tibial shaft sections. Thirty days of prostaglandin E₂ (PGE₂) administration increased bone formation rate/total bone surface from undetectable levels to 0.6 μm/day at the periosteal surface and from 0.5 to 2.1 μm/day at the endocortical surface. Endocortical osteoid surface area increased from 2% to 67% at day 10 and decreased to 6% at day 30; woven and lamellar bone formation started at day 0, but was most obvious at day 30, resulting in a 12% increase of total bone mass. The red to yellow marrow ratio was 0.2 in pretreatment controls, and increased to 1.6 by day 10 and 2.4 by day 30 with PGE₂ administration. Intracortical cavity number and area increased after 10 days of PGE₂ treatment, but with forming osteon number and area far exceeding those of resorption cavities at day 30. Endocortical modeling surface/endocortical surface was only 1.5%, and remodeling was 11.1% in pretreatment controls. PGE₂ treatment increased modeling to 24.5% in the 10 day group and 93.7% in the 30 day group, whereas remodeling remained unchanged at 10 days, and decreased to 6.2% at 30 days. Osteoprogenitor cells and osteoblasts could not be detected in pretreatment controls, but increased by day 10, and returned almost to control levels by 30 days. Our data indicate that PGE₂ induced periosteal and endocortical bone formation mainly by modeling-dependent bone gain, accompanied by increases in intracortical remodeling and red bone marrow, and a transient increase in the osteoprogenitor cells adjacent to the endocortical surface. These findings suggest that 20-month-old male Wistar rats were very responsive to the anabolic action of PGE₂ in the tibial shaft, a site consisting mainly of cortical bone and yellow marrow.     

Antiremodeling Agents Influence Osteoblast Activity Differently in Modeling and Remodeling Sites of Canine Rib

Antiremodeling agents reduce bone loss in part through direct actions on osteoclasts. Their effects on osteoblasts and bone formation activity are less clear and may differ at sites undergoing modeling vs. remodeling. Skeletally mature intact beagles, 1–2 years old at the start of the study, were treated daily with clinically relevant doses of alendronate (0.10 or 0.20 mg/kg), risedronate (0.05 or 0.10 mg/kg), raloxifene (0.50 mg/kg), or vehicle (1 mL/kg). Dynamic bone formation parameters were histologically assessed on periosteal, endocortical/trabecular, and intracortical bone envelopes of the rib. Raloxifene significantly increased periosteal surface mineral apposition rate (MAR), a measure of osteoblast activity, compared to all other treatments (+108 to +175%, P < 0.02), while having no significant effect on MAR at either the endocortical/trabecular or intracortical envelope. Alendronate (both 0.10 and 0.20 doses) and risedronate (only the 0.10 dose) significantly (P ≤ 0.05) suppressed MAR on the endocortical/trabecular envelope, while none of the bisphosphonate doses significantly altered MAR at either the periosteal or intracortical envelopes compared to vehicle. Based on these results, we conclude that (1) at clinically relevant doses the two classes of antiremodeling agents, bisphosphonates and selective estrogen receptor modulators, exert differential effects on osteoblast activity in the canine rib and (2) this effect depends on whether modeling or remodeling is the predominant mechanism of bone formation. M. R. Allen and H. Follet contributed equally to this work.     

Transient effects of subcutaneously administered prostaglandin E2 on cancellous and cortical bone in young adult dogs

The transient effects of prostaglandin E2 (PGE2) on cancellous and cortical bone in iliac crests and mid-tibial shafts of nine intact young adult dogs were evaluated following 31 days of treatment. Histomorphometric bone changes were characterized from in vivo fluorescent double-labeled undecalcified bone specimens. PGE2 caused an increase in cancellous bone remodeling evidence by increased in activation frequency; increased percent eroded and formation surfaces; increased mineral apposition and bone formation rates; and shortened resorption, formation, and total bone remodeling periods. Activated cancellous bone remodeling did not lead to decreased cancellous bone mass, indicating an imbalance between bone resorption and formation in favor of formation (activation----resorption----stimulated formation; A----R----F increases) at remodeling sites. The PGE2 treatment activated bone modeling in the formation mode (activation----formation; A----F) at the periosteal and endocortical surfaces and increased activation frequency of intracortical bone remodeling in the tibial shaft. Increased modeling activation converted quiescent bone surfaces to formation surfaces with stimulated osteoblastic activity (i.e., increased percent labeled periosteal and endocortical surfaces, mineral apposition rates, and woven and lamellar trabecular bone formation) leading to 9- to 26-fold increases in newly formed bone mass in subperiosteal, subendosteal, and marrow regions, compared to controls. However, increased intracortical bone remodelling elevated remodeling space (i.e., increased cortical porosity), producing a bone loss that partially offsets the bone gain. The combined events lead to a positive bone balance in PGE2-treated cortical bone, compared to a negative bone balance in control bones. Collectively our data suggest that in vivo PGE2 is a powerful activator of cancellous and cortical bone formation, which may be able to build a peak bone mass to prevent and/or correct the skeletal defects to cure osteoporosis.     

Prostaglandin E2 enhances cortical bone mass and activates intracortical bone remodeling in intact and ovariectomized female rats

To assess the efficacy of prostaglandin E2 (PGE2) in augmenting cortical bone mass, graded doses of PGE2 were subcutaneously administered for 30 days to seven-month old sham-ovariectomized (SHAM) and ovariectomized (OVX) rats. Both groups were operated at three months of age. Histomorphometric analyses of double fluorescent labeled tibial shafts were performed on basal control, OVX, and SHAM rats treated with 0, 0.3, 1, 3, and 6 mg PGE2/kg/d for 30 days. Baseline aging data showed increased cortical tissue and cortical bone area and reduced bone formation parameters at the periosteal and endocortical bone envelopes between three and eight months of age. The tibial shafts of OVX rats compared to SHAM controls showed elevated periosteal mineral apposition rate and endocortical bone formation parameters. PGE2 administration to OVX and SHAM rats increased cortical bone by the addition of new circumferential bone on the endocortical and periosteal surfaces, as well as woven cancellous bone in the marrow region. Stimulated osteoblastic recruitment and activity enhanced bone formation at all bone surfaces. The new bone was both lamellar and woven in nature. PGE2 treatment also activated intracortical bone remodeling (not seen in untreated eight-month old rats), creating a porous cortex. Thus, PGE2 administration activated cortical bone modeling in the formation mode (A----F), as well as intracortical bone remodeling (A----R----F). PGE2 administration to OVX rats resulted in more intracortical bone remodeling, periosteal bone formation, and new cancellous bone production than observed in PGE2 treated controls. The findings that PGE2 administration to OVX and intact female rats increases cortical bone mass, coupled with observations that mouse, rat, dog, and man respond similarly to PGE2, suggest that PGE2 administration may be useful in the prevention and treatment of postmenopausal osteoporosis.     

Bisphosphonates suppress periosteal osteoblast activity independently of resorption in rat femur and tibia

Recent studies demonstrate that bisphosphonates suppress bone resorption by leading to apoptosis of the osteoclast and inhibiting the differentiation to mature osteoclasts. The influence of bisphosphonates on bone formation is unknown, although it has been hypothesized that bisphosphonates inhibit osteoblast apoptosis and stimulate osteoblast proliferation and differentiation in vitro, leading to increased bone formation. The purpose of this study was to investigate the effect of bisphosphonates on bone formation. We administered risedronate at 0.05, 0.5 or 5.0 microg/kg/day or alendronate at 0.1, 1.0 or 10 microg/kg/day subcutaneously for 17 days to 6-month-old female Sprague-Dawley rats. Control rats were given a daily subcutaneous injection of saline. Following sacrifice, the femoral and tibial mid-diaphyses were harvested and mineralizing surface (MS/BS), mineral apposition rate (MAR) and bone formation rate (BFR/BS) were measured on periosteal and endocortical surfaces. In the femur, periosteal MAR was significantly lower in all treatment groups (22-29% for risedronate, 26-36% for alendronate) than in control. In the tibia, periosteal MAR and BFR of all treatment groups were significantly lower (41-50% for risedronate, 43-52% for alendronate) than in the control group. Because the periosteal surfaces of these bones are only undergoing bone formation in modeling mode, our results show that bisphosphonates suppress bone formation independently of bone resorption. Because this effect is seen on periosteal MAR rather than on periosteal MS/BS, we hypothesize that bisphosphonates affect the activity of individual osteoblasts at the cell level. This may help to explain the reason that the anabolic effects of teriparatide are blunted when administered concurrently with or following a course of bisphosphonates in humans.     

Teriparatide increases bone formation in modeling and remodeling osteons and enhances IGF-II immunoreactivity in postmenopausal women with osteoporosis.

Transiliac bone biopsies were obtained from 55 women treated with teriparatide or placebo for 12-24 months. We report direct evidence that modeling bone formation at quiescent surfaces was present only in teriparatide-treated patients and bone formation at remodeling sites was higher with teriparatide than placebo. INTRODUCTION: Recombinant teriparatide [human PTH(1-34)], a bone formation agent for the treatment of osteoporosis when given once daily subcutaneously, increases biochemical markers of bone turnover and activation frequency in histomorphometry studies. MATERIALS AND METHODS: We studied the mechanisms underlying this bone-forming action of teriparatide at the basic multicellular unit by the appearance of cement lines, a method used to directly classify surfaces as modeling or remodeling osteons, and by the immunolocalization of IGF-I and IGF-II. Transiliac bone biopsies were obtained from 55 postmenopausal women treated with teriparatide 20 or 40 microg or placebo for 12-24 months (median, 19.8 months) in the Fracture Prevention Trial. RESULTS: A dose-dependent relationship was observed in modeling and mixed remodeling/modeling trabecular hemiosteons. Trabecular and endosteal hemiosteon mean wall thicknesses were significantly higher in both teriparatide groups than in placebo. There was a dose-dependent relationship in IGF-II immunoreactive staining at all bone envelopes studied. The greater local IGF-II presence after treatment with teriparatide may play a key role in stimulating bone formation. CONCLUSIONS: Direct evidence is presented that 12-24 months of teriparatide treatment induced modeling bone formation at quiescent surfaces and resulted in greater bone formation at remodeling sites, relative to placebo.     

Skeletal effects of constant and terminated use of risedronate on cortical bone in ovariectomized rats

To study the skeletal effects of continual and terminated use of risedronate treatment on cortical bone in ovariectomized (Ovx) rats, we used risedronate (Ris), 5 μg · kg⁻¹, by subcutaneous injections, twice per week. The middle part of the tibial shafts (Tx) were processed undecalcified for quantitive bone histomorphometry. Cortical bone and the marrow areas of the tibial shaft did not change in either sham-Ovx or Ovx rats during the 150-day experimental period. Continued administration of Ris for 150 days decreased the marrow area and increased the percentage of cortical area compared with the matching sham and Ovx group. A decrease in bone formation indices in both periosteal and endocortical surfaces of Tx in sham-operated rats between the age of 5 and 8 months was seen. Ovariectomy increased the percentage of labeled perimeter in the periosteal area, and markedly increased the percentage of eroded perimeter in the endocortical surface compared with sham control groups in 81 and 150 days. Bone formation indices of Ris treatment were increased in periosteal surfaces, and percentages of eroded perimeter were decreased more in endocortical surfaces in 150 days than in the matching sham and Ovx groups. These data matched our static data, which showed a significantly increased percentage of cortical bone area and decreased percentage of marrow area. These bone gains were not maintained in the 90-day Ris withdrawal group. For cancellous bone, the 60-day Ris-treated high bone mass was maintained in the withdrawal group and not maintained in Ris continmuously treated group. These results indicate the effects of constant and terminated use of Ris in cortical bone were different from those in trabecular bone in the proximal tibial metaphysis. Received: Jan. 20, 1998 / Accepted: June 16, 1998     

Continuous parathyroid hormone induces cortical porosity in the rat: effects on bone turnover and mechanical properties.

We examined the time course effects of continuous PTH on cortical bone and mechanical properties. PTH increased cortical bone turnover and induced intracortical porosity with no deleterious effect on bone strength. Withdrawal of PTH increased maximum torque to failure and stiffness with no change in energy absorbed. INTRODUCTION: The skeletal response of cortical bone to parathyroid hormone (PTH) is complex and species dependent. Intermittent administration of PTH to rats increases periosteal and endocortical bone formation but has no known effects on intracortical bone turnover. The effects of continuous PTH on cortical bone are not clearly established. MATERIALS AND METHODS: Eighty-four 6-month-old female Sprague-Dawley rats were divided into three control, six PTH, and two PTH withdrawal (WD) groups. They were subcutaneously implanted with osmotic pumps loaded with vehicle or 40 microg/kg BW/day human PTH(1-34) for 1, 3, 5, 7, 14, and 28 days. After 7 days, PTH was withdrawn from two groups of animals for 7 (7d-PTH/7d-WD) and 21 days (7d-PTH/21d-WD). Histomorphometry was performed on periosteal and endocortical surfaces of the tibial diaphysis in all groups. microCT of tibias and mechanical testing by torsion of femora were performed on 28d-PTH and 7d-PTH/21d-WD animals. RESULTS AND CONCLUSIONS: Continuous PTH increased periosteal and endocortical bone formation, endocortical osteoclast perimeter, and cortical porosity in a time-dependent manner, but did not change the mechanical properties of the femur, possibly because of addition of new bone onto periosteal and endocortical surfaces. Additionally, withdrawal of PTH restored normal cortical porosity and increased maximum torque to failure and stiffness. We conclude that continuous administration of PTH increased cortical porosity in rats without having a detrimental effect on bone mechanical properties.     

Bone fragility: failure of periosteal apposition to compensate for increased endocortical resorption in postmenopausal women.

The increase in bone fragility after menopause results from reduced periosteal bone formation and increased endocortical resorption. Women with highest remodeling had greatest loss of bone mass and estimated bone strength, whereas those with low remodeling lost less bone and maintained estimated bone strength. INTRODUCTION: Bone loss from the inner (endocortical) surface contributes to bone fragility, whereas deposition of bone on the outer (periosteal) surface is believed to be an adaptive response to maintain resistance to bending. MATERIALS AND METHODS: To test this hypothesis, changes in bone mass and estimated indices of bone geometry and strength of the one-third distal radius, bone turnover markers, and fracture incidence were measured annually in 821 women 30-89 years of age for 7.1 +/- 2.5 years. The analyses were made in 151 premenopausal women, 33 perimenopausal women, 279 postmenopausal women, and 72 postmenopausal women receiving hormone replacement therapy (HRT). RESULTS: In premenopausal women, periosteal apposition increased the radius width, partly offsetting endocortical resorption; therefore, the estimated cortical thickness decreased. Outward displacement of the thinner cortex maintained bone mass and cortical area and increased estimated bending strength. Estimated endocortical resorption accelerated during perimenopause, whereas periosteal apposition decreased. Further cortical thinning occurred, but estimated bending strength was maintained by modest outward cortical displacement. Endocortical resorption accelerated further during the postmenopausal years, whereas periosteal apposition declined further; cortices thinned, but because outward displacement was minimal, estimated cortical area and bending strength now decreased. Women with highest remodeling had the greatest loss of bone mass and strength. Women with low remodeling lost less bone and maintained estimated bone strength. In HRT-treated women, loss of bone strength was partly prevented. These structural indices predicted incident fractures; a 1 SD lower section modulus doubled fracture risk. CONCLUSIONS: Periosteal apposition does not increase after menopause to compensate for bone loss; it decreases. Bone fragility of osteoporosis is a consequence of reduced periosteal bone formation and increased endocortical resorption. Understanding the mechanisms of the age-related decline in periosteal apposition will identify new therapeutic targets. On the basis of our results, it may be speculated that the stimulation of periosteal apposition will increase bone width and improve skeletal strength.     

Skeletal tissue responses to thermal injury: An experimental study

Skeletal changes occuring secondary to burn injuries were studied in an experimental animal model for thermal injury. One hindlimb of female Sprague-Dawley rats (200–250g) was subjected to a standardized thermal injury; the other hindlimb was left untreated. Control animals received no experimental treatment. Effects on skeletal architecture were studied at the proximal tibial metaphysis and tibial diaphysis using static histomorphometry. Bone formation dynamics were studied from a series of bone fluorochrome labels administered before the experiment began, early (days 8, 9) postburn treatment (PBT) and late PBT (days 17, 18). Animals were sacrificed on day 21 PBT. In proximal tibial metaphyses of burn-treated limbs, trabecular bone area (TBA) and trabecular number in all regions except the primary spongiosa, were significantly reduced. TBA was also decreased, but not significantly in nontreated limbs. Longitudinal growth rate, growth plate thickness and growth cartilage cell production rate are greater in burn-treated than in nonburned and control bones. Burn-treated diaphyses showed extensive woven bone formation at periosteal surfaces, and corresponding increases of bone areas and periosteal perimeters. Endocortical surfaces showed only typical occasional resorption areas. No intracortical changes were observed. Mineral appositional rate (MAR) and bone formation rate (BFR) at endocortical surfaces were markedly depressed after thermal injury, significant changes were noted in both limbs of treated animals. Among burned limbs, the early PBT label was absent from all specimens, indicating a virtual shutdown of osteoblast activity and recruitment. Similarly in nonburned limb bone, the label was absent from 50% of the specimens; in those bones in which the label was present, label lengths, appositional and bone formation rates were significantly reduced relative to the control specimens. Comparison of average bone formation dynamics for the total PBT interval indicates that MAR and BFR in burned treated tibiae were reduced to approximately 25% of control values. MAR and BFR from the nonburned side of treated animals were significantly reduced as well, to about 55% of control values. These data indicate that the principal metaphyseal effects of thermal injury are stimulation of growth cartilage proliferation, and depression of ossification and osteoblast activity. In diaphyses, thermal injury causes extensive local periosteal woven bone proliferation and a dramatic depression of endosteal bone formation. The latter effect, while more severe locally, is also evident systemically.     

PTH receptor signaling in osteocytes governs periosteal bone formation and intracortical remodeling

The periosteal and endocortical surfaces of cortical bone dictate the geometry and overall mechanical properties of bone. Yet the cellular and molecular mechanisms that regulate activity on these surfaces are far from being understood. Parathyroid hormone (PTH) has profound effects in cortical bone, stimulating periosteal expansion and at the same time accelerating intracortical bone remodeling. We report herein that transgenic mice expressing a constitutive active PTH receptor in osteocytes (DMP1‐caPTHR1 mice) exhibit increased cortical bone area and an elevated rate of periosteal and endocortical bone formation. In addition, DMP1‐caPTHR1 mice display a marked increase in intracortical remodeling and cortical porosity. Crossing DMP1‐caPTHR1 mice with mice lacking the Wnt coreceptor, LDL‐related receptor 5 (LRP5), or with mice overexpressing the Wnt antagonist Sost in osteocytes (DMP1‐Sost mice) reduced or abolished, respectively, the increased cortical bone area, periosteal bone formation rate, and expression of osteoblast markers and Wnt target genes exhibited by the DMP1‐caPTHR1 mice. In addition, DMP1‐caPTHR1 lacking LRP5 or double transgenic DMP1‐caPTHR1;DMP1‐Sost mice exhibit exacerbated intracortical remodeling and increased osteoclast numbers, and markedly decreased expression of the RANK decoy receptor osteoprotegerin. Thus, whereas Sost downregulation and the consequent Wnt activation is required for the stimulatory effect of PTH receptor signaling on periosteal bone formation, the Wnt‐independent increase in osteoclastogenesis induced by PTH receptor activation in osteocytes overrides the effect on Sost. These findings demonstrate that PTH receptor signaling influences cortical bone through actions on osteocytes and defines the role of Wnt signaling in PTH receptor action. © 2011 American Society for Bone and Mineral Research.     

Continuous PGE2 leads to net bone loss while intermittent PGE2 leads to net bone gain in lumbar vertebral bodies of adult female rats

The present study examined the effects of continuous and intermittent PGE₂ administration on the cancellous and cortical bone of lumbar vertebral bodies (LVB) in female rats. Six-month-old Sprague–Dawley female rats were divided into 6 groups with 2 control groups and 1 or 3 mg PGE₂/kg given either continuously or intermittently for 21 days. Histomorphometric analyses were performed on the cancellous and cortical bone of the fourth and fifth LVBs. Continuous PGE₂ exposure led to bone catabolism while intermittent administration led to bone anabolism. Both routes of administration stimulated bone remodeling, but the continuous PGE₂ stimulated more than the intermittent route to expose more basic multicellular units (BMUs) to the negative bone balance. The continuous PGE₂ caused cancellous bone loss by stimulating bone resorption greater than formation (i.e., negative bone balance) and shortening the formation period. It caused more cortical bone loss than gain, the magnitude of the negative endocortical bone balance and increased intracortical porosity bone loss was greater than for periosteal bone gain. The anabolic effects of intermittent PGE₂ resulted from cancellous bone gain by positive bone balance from stimulated bone formation and shortened resorption period; while cortical bone gain occurred from endocortical bone gain exceeding the decrease in periosteal bone and increased intracortical bone loss. Lastly, a scheme to take advantage of the marked PGE₂ stimulation of lumbar periosteal apposition in strengthening bone by converting it to an anabolic agent was proposed.     

Long-term disuse osteoporosis seems less sensitive to bisphosphonate treatment than other osteoporosis.

We sought to determine whether risedronate can preserve cortical bone mass and mechanical properties during long-term disuse in dogs, assessed by histomorphometry and biomechanics on metacarpal diaphyses. Risedronate slowed cortical thinning and partially preserved mechanical properties, but it was unable to suppress bone loss to the degree seen in other osteoporoses. INTRODUCTION: Disuse induces dramatic bone loss resulting from greatly elevated osteoclastic resorption. Targeting osteoclasts with antiresorptive agents, such as bisphosphonates, should be an effective countermeasure for preventing disuse osteoporosis. MATERIALS AND METHODS: Single forelimbs from beagles (5-7 years old, n = 28) were immobilized (IM) for 12 months. Age-matched, non-IM dogs served as controls. One-half the animals received either risedronate (RIS, 1 mg/kg) or vehicle daily. Histomorphometry was performed on second metacarpal mid-diaphyses. Cortical mechanical properties were determined by testing third metacarpal diaphyses in four-point bending. RESULTS: IM caused marked reduction in cortical area (-42%) and cortical thinning (-40%) through endocortical resorption, extensive intracortical tunneling, and periosteal resorption; both bone resorption and formation were significantly elevated over control levels on all envelopes. IM also decreased maximum load and stiffness by approximately 80% compared with controls. RIS reduced both periosteal bone loss and marrow cavity expansion; however, cortical area remained significantly lower in RIS-treated IM animals than in untreated non-IM controls (-16%). RIS also increased resorption indices in all envelopes compared with nontreated IM, indicating that RIS suppressed osteoclast activity but not osteoclast recruitment. RIS did not affect bone formation. RIS treatment conserved some whole bone mechanical properties, but they were still significantly lower than in controls. There were no significant differences in tissue level material properties among the groups. CONCLUSION: RIS treatment reduces cortical bone loss at periosteal and endocortical surfaces caused by long-term immobilization, thus partially conserving tissue mechanical properties. This modest effect contrasts with more dramatic actions of the bisphosphonate in other osteoporoses. Our results suggest that risedronate impairs osteoclastic function but cannot completely overcome the intense stimulus for osteoclast recruitment during prolonged disuse.     

Histomorphometric changes by teriparatide in alendronate-pretreated women with osteoporosis

Summary

The level of increased bone formation after 24 months of treatment with teriparatide (rhPTH (1–34), TPTD) is similar in patients who were either treatment-naïve (TN) or had lower bone turnover initially due to previous alendronate (ALN) therapy.

Introduction

Bone anabolic effects of TPTD in postmenopausal women with osteoporosis may be blunted during the initial phase after switching from ALN to TPTD. To explore the long-term implications, we examined histomorphometric and biochemical markers of bone turnover of patients on TPTD therapy after long-term ALN treatment.

Methods

Paired biopsies were obtained after tetracycline double labeling at baseline and after 24 months of TPTD treatment from 29 ALN-pretreated (64.5?±?16.4 months) and 16 TN patients. Biochemical markers were measured at baseline, during the treatment, or at study end.

Results

Compared with the baseline, after 24-month TPTD, activation frequency (Ac.F.) and osteoid surface (OS) increased in both groups: 0.11–0.34 cycles per year, 3.96–9.8% in the ALN-pretreated group and 0.19–0.33 cycles per year, 6.2–11.3% (p?<?0.05) in the TN group, respectively. Biochemical and histomorphometric markers correlated positively both at baseline and endpoint. Serum amino terminal propeptide of type I procollagen (PINP) correlated with Ac.F. (r?=?0.57, p?<?0.001 and r?=?0.48, p?<?0.01) and OS (r?=?0.51, p?<?0.01 and r?=?0.56, p?<?0.01) at baseline and endpoint, respectively. Following 3 months of treatment, increases in biochemical markers like PINP predicted the increase in Ac.F. (r?=?0.52, p?<?0.01) and OS (r?=?0.54, p?<?0.01) after 24 months.

Conclusions

The increased level of formation is similar in patients who were either TN or had lower bone turnover initially due to previous ALN therapy. Elevated bone formation in postmenopausal women with osteoporosis was sustained over a 24-month period by TPTD. Biochemical markers of bone formation are a good surrogate for the assessment of TPTD effects.     

Changes in cortical width with bone turnover in the three different endosteal envelopes of the ilium in postmenopausal osteoporosis.

Histological indicators of bone turnover were compared in the three endosteal envelopes (cancellous, endocortical, and intracortical) of iliac bone specimens obtained from 82 osteoporotic women, to assess the correlation between bone turnover and bone volume in different remodeling sites. Although there was a significant but weak correlation between the mineral apposition rate (MAR), a histological indicator of bone formation at the basic multicellular unit (BMU) level, and the three endosteal envelopes, the bone formation rate corrected for bone surface (BFR/BS) and mineralizing surface (MS/BS), indicators of the rate of bone formation reflecting activation frequency, in the cancellous and endocortical envelopes was more closely related to the rate in the intracortical envelope. The endocortical BFR/BS and MS/BS were higher than the rate in the cancellous envelope (1.6-2.1 times and 2.0-2.4 times, respectively), indicating a higher turnover rate in the endocortical envelope. According to stepwise regression analysis of the significant determinants contributing to bone mass, several histological determinants relating to bone turnover were identified: (1) trabecular thickness (Tb.Th) was a positive determinant, whereas age and cancellous bone volume referent BFR (BFR/BV) were negatively correlated determinants of the cancellous bone volume (BV/TV) (R2 = 0.50, p < 0.001); and (2) the endocortical wall thickness (W.Th) of the given side and the cortical width (Ct.Wi) of the opposite side were positive determinants, whereas the cancellous osteoid surface (OS/BS), cancellous MAR, and endocortical eroded surface (ES/BS) of the given side were the negatively correlated determinants of the Ct.Wi of the thicker cortex (R2 = 0.62, p < 0.001). In the thinner cortex, the endocortical W.Th of the given side and Ct.Wi of the opposite side were only used as the positive determinants of the Ct.Wi of the given side (R2 = 0.55, p < 0.001). In addition: (3) a significant but weak correlation was found using the intracortical BFR/BV as a positively correlated determinant of the cortical porosity (Ct.Po) in the thicker cortex (R2 = 0.17, p < 0.01). Although these histological determinants do not fully explain the mechanisms of bone loss, an increased rate of bone turnover contributes to bone loss not only in the cancellous and intracortical envelopes, but also in the endocortical envelope, indicating increased endocortical bone resorption in osteoporosis.     

Effects of teriparatide [recombinant human parathyroid hormone (1-34)] on cortical bone in postmenopausal women with osteoporosis.

Treatment with teriparatide (rDNA origin) injection [teriparatide, recombinant human parathyroid hormone (1-34) [rhPTH(1-34)]] reduces the risk of vertebral and nonvertebral fragility fractures and increases cancellous bone mineral density in postmenopausal women with osteoporosis, but its effects on cortical bone are less well established. This cross-sectional study assessed parameters of cortical bone quality by peripheral quantitative computed tomography (pQCT) in the nondominant distal radius of 101 postmenopausal women with osteoporosis who were randomly allocated to once-daily, self-administered subcutaneous injections of placebo (n = 35) or teriparatide 20 microg (n = 38) or 40 microg (n = 28). We obtained measurements of moments of inertia, bone circumferences, bone mineral content, and bone area after a median of 18 months of treatment. The results were adjusted for age, height, and weight. Compared with placebo, patients treated with teriparatide 40 microg had significantly higher total bone mineral content, total and cortical bone areas, periosteal and endocortical circumferences, and axial and polar cross-sectional moments of inertia. Total bone mineral content, total and cortical bone areas, periosteal circumference, and polar cross-sectional moment of inertia were also significantly higher in the patients treated with teriparatide 20 microg compared with placebo. There were no differences in total bone mineral density, cortical thickness, cortical bone mineral density, or cortical bone mineral content among groups. In summary, once-daily administration of teriparatide induced beneficial changes in the structural architecture of the distal radial diaphysis consistent with increased mechanical strength without adverse effects on total bone mineral density or cortical bone mineral content.