Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase

Alendronate, a nitrogen-containing bisphosphonate, is a potent inhibitor of bone resorption used for the treatment and prevention of osteoporosis. Recent findings suggest that alendronate and other N-containing bisphosphonates inhibit the isoprenoid biosynthesis pathway and interfere with protein prenylation, as a result of reduced geranylgeranyl diphosphate levels. This study identified farnesyl disphosphate synthase as the mevalonate pathway enzyme inhibited by bisphosphonates. HPLC analysis of products from a liver cytosolic extract narrowed the potential targets for alendronate inhibition (IC(50) = 1700 nM) to isopentenyl diphosphate isomerase and farnesyl diphosphate synthase. Recombinant human farnesyl diphosphate synthase was inhibited by alendronate with an IC(50) of 460 nM (following 15 min preincubation). Alendronate did not inhibit isopentenyl diphosphate isomerase or GGPP synthase, partially purified from liver cytosol. Recombinant farnesyl diphosphate synthase was also inhibited by pamidronate (IC(50) = 500 nM) and risedronate (IC(50) = 3.9 nM), negligibly by etidronate (IC50 = 80 microM), and not at all by clodronate. In osteoclasts, alendronate inhibited the incorporation of [(3)H]mevalonolactone into proteins of 18-25 kDa and into nonsaponifiable lipids, including sterols. These findings (i) identify farnesyl diphosphate synthase as the selective target of alendronate in the mevalonate pathway, (ii) show that this enzyme is inhibited by other N-containing bisphosphonates, such as risendronate, but not by clodronate, supporting a different mechanism of action for different bisphosphonates, and (iii) document in purified osteoclasts alendronate inhibition of prenylation and sterol biosynthesis.     

Switching to Denosumab or Bisphosphonates After Completion of Teriparatide Treatment in Women With Severe Postmenopausal Osteoporosis

ObjectiveTo compare bone mineral density (BMD) changes after 12 months of treatment with denosumab or bisphosphonates in postmenopausal women with severe osteoporosis after stopping teriparatide therapy.MethodsWe retrospectively analyzed 140 postmenopausal women (mean age, 74.2 years) with severe osteoporosis who had been treated with teriparatide for 18 to 24 months at our outpatient clinic in a tertiary endocrine center between 2006 and 2015. After stopping teriparatide therapy, they continued treatment with a bisphosphonate (alendronate, risedronate, ibandronate, or zoledronic acid) or denosumab while receiving daily vitamin D and calcium. BMD at the lumbar spine (LS), total hip (TH), and femoral neck (FN) was measured by dual energy x-ray absorptiometry when teriparatide therapy was discontinued (baseline) and after 12 months of further treatment. Multivariate linear regression models were used to identify the predictors of BMD gain.ResultsAfter stopping teriparatide therapy, 70 women continued treatment with bisphosphonates and 70 received denosumab. LS, but not TH or FN, BMD gain was significantly greater in the denosumab group than in the bisphosphonates group at 12 months. Multivariate analysis showed that BMD gain at the LS was negatively associated with bisphosphonate versus denosumab treatment and positively associated with baseline serum total procollagen type I N-terminal propeptide. BMD gains at the FN were predicted by higher baseline serum urate levels. BMD gains at the TH and FN were negatively associated with pretreatment BMD gains at the same site.ConclusionTwelve months after stopping teriparatide therapy, sequential denosumab treatment appeared to yield higher additional LS BMD gain on average compared with bisphosphonates treatment.     

Spontaneous incomplete transverse subtrochanteric femoral fracture with cortical thickening possibly secondary to risedronate use: a case report

ABSTRACT: INTRODUCTION: Osteoporosis is an asymptomatic disease characterized by bone weakening and predisposition to fragility (insufficiency) fractures and can have devastating effects on individual life and great financial impact on the economy. Bisphosphonates are used worldwide for the primary and secondary prevention of osteoporotic fractures. However, increasing evidence raises concern that bisphosphonates can be associated with atypical fractures. CASE PRESENTATION: A 65-year-old Caucasian woman on long-term steroid treatment for polymyalgia rheumatica was admitted with severe and constant pain in the right hip, radiating to the right knee. She had a history of steroid-induced osteoporosis, for which she was started on risedronate four years earlier. She had no history of trauma. Her blood results were unremarkable. Her X-rays confirmed that she had an incomplete right subtrochanteric femoral fracture. A bone scan confirmed the diagnosis and also ruled out any other associated fractures. Our patient successfully underwent internal nail fixation of the fracture. She was reviewed by a rheumatology team, which stopped the risedronate. She was started on treatment with denosumab injection. CONCLUSIONS: Previous case series have reported that long-term bisphosphonate use is associated with atypical fractures of the femur, and certain criteria have been established to help identify such rare fractures. Delayed union or non-union is expected in such fractures following definitive orthopedic treatment because of the long half life of bisphosphonates. In this case report, we try to raise questions related to this important subject, like the duration and safety of bisphosphonate use and the alternative medications used in osteoporosis in this rare condition. We consider this case report not only interesting but also important and unusual because it is about a patient who developed a potentially rare and serious side effect of long-term bisphosphonate use, estimated to affect 2.3 in every 10,000 patients, and who presented with a pelvic X-ray that showed the characteristic features of atypical fractures secondary to risedronate use. In addition, most of the documented cases have been associated with many years of bisphosphonate use whereas our patient had been on risedronate for only four years.     

The effects of tensile-compressive loading mode and microarchitecture on microdamage in human vertebral cancellous bone

The amount of microdamage in bone tissue impairs mechanical performance and may act as a stimulus for bone remodeling. Here we determine how loading mode (tension vs. compression) and microstructure (trabecular microarchitecture, local trabecular thickness, and presence of resorption cavities) influence the number and volume of microdamage sites generated in cancellous bone following a single overload. Twenty paired cylindrical specimens of human vertebral cancellous bone from 10 donors (47–78 years) were mechanically loaded to apparent yield in either compression or tension, and imaged in three dimensions for microarchitecture and microdamage (voxel size 0.7×0.7×5.0 μm³). We found that the overall proportion of damaged tissue was greater (p=0.01) for apparent tension loading (3.9±2.4%, mean±SD) than for apparent compression loading (1.9±1.3%). Individual microdamage sites generated in tension were larger in volume (p<0.001) but not more numerous (p=0.64) than sites in compression. For both loading modes, the proportion of damaged tissue varied more across donors than with bone volume fraction, traditional measures of microarchitecture (trabecular thickness, trabecular separation, etc.), apparent Young?s modulus, or strength. Microdamage tended to occur in regions of greater trabecular thickness but not near observable resorption cavities. Taken together, these findings indicate that, regardless of loading mode, accumulation of microdamage in cancellous bone after monotonic loading to yield is influenced by donor characteristics other than traditional measures of microarchitecture, suggesting a possible role for tissue material properties.     

Trabecular reorganization in consecutive iliac crest biopsies when switching from bisphosphonate to strontium ranelate treatment

Background

Several agents are available to treat osteoporosis while addressing patient-specific medical needs. Individuals'' residual risk to severe fracture may require changes in treatment strategy. Data at osseous cellular and microstructural levels due to a therapy switch between agents with different modes of action are rare. Our study on a series of five consecutively taken bone biopsies from an osteoporotic individual over a six-year period analyzes changes in cellular characteristics, bone microstructure and mineralization caused by a therapy switch from an antiresorptive (bisphosphonate) to a dual action bone agent (strontium ranelate).

Methodology/Principal Findings

Biopsies were progressively taken from the iliac crest of a female patient. Four biopsies were taken during bisphosphonate therapy and one biopsy was taken after one year of strontium ranelate (SR) treatment. Furthermore, serum bone markers and dual x-ray absorptiometry measurements were acquired. Undecalcified histology was used to assess osteoid parameters and bone turnover. Structural indices and degree of mineralization were determined using microcomputed tomography, quantitative backscattered electron imaging, and combined energy dispersive x-ray/µ-x-ray-fluorescence microanalysis.

Conclusions/Significance

Microstructural data revealed a notable increase in bone volume fraction after one year of SR treatment compared to the bisphosphonate treatment period. Indices of connectivity density, structure model index and trabecular bone pattern factor were predominantly enhanced indicating that the architectural transformation from trabecular rods to plates was responsible for the bone volume increase and less due to changes in trabecular thickness and number. Administration of SR following bisphosphonates led to a maintained mineralization profile with an uptake of strontium on the bone surface level. Reactivated osteoclasts designed tunneling, hook-like intratrabecular resorption sites. The appearance of tunneling resorption lacunae and the formation of both mini-modeling units and osteon-like structures within increased plate-like cancellous bone mass provides additional information on the mechanisms of strontium ranelate following bisphosphonate treatment, which may deserve special attention when monitoring a treatment switch.     

How drugs decrease fracture risk: lessons from trials

In women with osteoporosis, each 1% improvement in spine BMD (by DXA) is expected to reduce vertebral fracture risk by about 4%. However, randomized trials of antiresorptive agents show that 1 to 6% improvements in spine BMD reduce vertebral fracture risk by 35 to 50%. Less 20% of the decreased spine fracture risk produced by alendronate or raloxifene be explained by improvement in spine BMD. The discrepancy is even greater during the first year or two of treatment when 1 to 4% improvements in BMD are associated with 65-68% decreases in spine fracture risk. Bisphosphonates continue to increase BMD but the reduction in fracture risk wanes to 20 to 45%. DXA underestimates the change in bone density of spinal trabecular bone and this might explain part of the discrepancy between expected and observed reductions in spine fracture risk. Even more accurate measurement of BMD would not explain the rapid onset and later waning of effect despite gradually increasing BMD. The biomechanical effects inhibiting bone resorption could explain the early onset but not the waning effectiveness. The waning effectiveness of antiresorptives raises concerns that prolonged inhibition of remodeling may weaken bone by allowing microdamage to accumulate. The effect of drugs on nonspine fracture risk is more complex and cannot be predicted from changes in DXA BMD. For example, Beck showed that long-term users of estrogen increase section modulus vs. nonusers with a net increase in section modulus and predicted femoral neck strength despite losing about 0.4% per year in femoral neck BMD. PTH reduces spine fracture risk and this effect is more completely explained by improvement in spine BMD. This suggests that sustaining the increased BMD produced by PTH may maintain long-term reductions in fracture risk.     

PTH and interactions with bisphosphonates

We report that a therapeutic dose of the antiresorptive bisphosphonate alendronate administered to skeletally mature rats for the duration of 16 weeks significantly blunted the anabolic response to a high dose SDZ PTS 893 in the tibia and femur but not in lumbar vertebra. Effects were seen at the level of bone mass (DEXA, pQCT) as well as in biomechanical tests. In one arm of this study, rats were switched to vehicle injections after 8 weeks on alendronate for another 8 weeks before being challenged with the anabolic stimulus (washout). This recovery period was insufficient for full recovery and the response to SDZ PTS 893 was still greatly reduced after this procedure. Serial pQCT-measurements suggest that part of the interaction happened during the first two weeks of PTH treatment when bone-lining cells are activated by the anabolic drug. In addition bisphosphonate pretreated rats failed to catch up with the vehicle control at all time points suggesting a second level of drug interaction. The failure of the 'washout' period to restore the normal response to PTH is suggestive of a physico-chemical interaction on the level of the matrix embedded bisphosphonate with the overlaying bone lining cells, rather than of direct effects of the drug on osteoblasts or their precursor cells. Overall the data raises the possibility, that bisphosphonate treated patients respond to PTH and SDZ PTS 893 with a delay which could affect the shorter bone mass measurements carried out at 6 months to 1 year. Additionally, bisphosphonate pre-treated rats did not develop the full anabolic response over time. Clinical investigators studying anabolic drugs such as PTH should be aware of potential long-term interactions of bisphosphonates when assessing the outcome of their experiments. However, the beneficial effect of bisphosphonates like alendronate on PTH-induced bone remodeling, as well as its potent action in the protection of bone loss after cessation of anabolic therapy might outweigh the worries about a small delay in the bone response to parathyroid hormone.     

The prevention and treatment of osteoporosis: a review

Osteoporosis is a disorder characterized by reduced bone strength, diminished bone density, and altered macrogeometry and microscopic architecture. Adult bone mass is the integral measurement of the bone mass level achieved at the peak minus the rate and duration of subsequent bone loss. There is clearly a genetic predisposition to attained peak bone mass, which occurs by a person's mid-20s. Bone loss with age and menopause are universal, but rates vary among individuals. Both peak bone mass and subsequent bone loss can be modified by environmental factors, such as nutrition, physical activity, and concomitant diseases and medications. Osteoporosis prevention requires adequate calcium and vitamin D intake, regular physical activity, and avoiding smoking and excessive alcohol ingestion. Risk of fracture determines whether medication is also warranted. A previous vertebral or hip fracture is the most important predictor of fracture risk. Bone density is the best predictor of fracture risk for those without prior adult fractures. Age, weight, certain medications, and family history also help establish a person's risk for osteoporotic fractures. All women should have a bone density test by the age of 65 or younger (at the time of menopause) if risk factors are present. Guidelines for men are currently in development. Medications include both antiresorptive and anabolic types. Antiresorptive medications--estrogens, selective estrogen receptor modulators (raloxifene), bisphosphonates (alendronate, risedronate, and ibandronate) and calcitonins--work by reducing rates of bone remodeling. Teriparatide (parathyroid hormone) is the only anabolic agent currently approved for osteoporosis in the United States. It stimulates new bone formation, repairing architectural defects and improving bone density. All persons who have had osteoporotic vertebral or hip fractures and those with a bone mineral density diagnostic of osteoporosis should receive treatment. In those with a bone mineral density above the osteoporosis range, treatment may be indicated depending on the number and severity of other risk factors.     

A computational assessment of the independent contribution of changes in canine trabecular bone volume fraction and microarchitecture to increased bone strength with suppression of bone turnover

This study addressed the effects of changes in trabecular microarchitecture induced by suppressed bone turnover-including changes to the remodeling space-on the trabecular bone strength-volume fraction characteristics independent of changes in tissue material properties. Twenty female beagle dogs, aged 1-2 years, were treated daily with either oral saline (n=10 control) or high doses of oral risedronate (0.5mg/kg/day, n=10 suppressed) for a period of 1 year, the latter designed (and confirmed) to substantially suppress bone turnover. High-resolution micro-CT-based finite element models (18-mum voxel size) of canine trabecular bone cores (n=2 per vertebral body) extracted from the T-10 vertebrae were analyzed in both compressive and torsional loading cases. The same tissue-level material properties were used in all models, thus providing measures of tissue-normalized strength due only to changes in the microarchitecture. Suppressed bone turnover resulted in more plate-like architecture with a thicker and more dense trabecular structure, but the relationship between the microarchitectural parameters and volume fraction was unaltered (p>0.05). Though the suppressed group had a greater tissue-normalized strength as compared to the control group (p<0.001) for both compressive and torsional loading, the relationship between tissue-normalized strength and volume fraction was not significantly altered for compression (p>0.13) or torsion (p>0.09). In this high-density, non-osteoporotic animal model, the increases in tissue-normalized strength seen with suppression of bone turnover were entirely commensurate with increases in bone volume fraction and thus, no evidence of microarchitecture-related or "stress-riser" effects which may disproportionately affect strength were found.     

Low bone mass may not be the only cause of skeletal fragility in osteoporosis

Skeletal fragility in postmenopausal osteoporosis is not due solely to reduction in bone mass. This fact explains some of the overlap in bone mineral measurements observed between patients who are fracturing and age- and sex-matched normals who are not. Changes in skeletal architecture and bone remodeling occur with age which can account for some of the fragility. These changes are exaggerated in patients with postmenopausal osteoporosis who are suffering spine fractures. Three abnormalities have been described by histomorphometric methods which can account for skeletal fragility out of proportion to the degree of bone loss. They are: (i) loss of trabecular connectivity such that vertical weight-bearing bars lose their cross-attachments with each other, thus becoming susceptible to buckling; (ii) inefficient and prolonged microdamage repair due to periods of pause in the formation phase of remodeling; and (iii) accumulation of unrepaired microdamage in unremodeled bone tissue in the central part of trabeculae due to reduced osteon wall thickness coupled with maintenance of trabecular thickness. Recognition of these abnormalities should broaden our approach to the study of skeletal fragility in the syndrome of postmenopausal osteoporosis.     

Spatial distribution of trabeculae in iliac bone from 145 osteoporotic females

145 women showing clinical and radiological signs of involutional osteoporosis of the spine were biopsed at the ilium for histomorphometric analysis of bone mass including trabecular bone volume and parameters reflecting the spatial distribution of bony elements (mean trabecular plate thickness, density and separation). Results were compared with an age-matched population of 22 healthy females. Postmenopausal osteoporotics (i.e. younger than 75 years) were characterized by a significant reduction in trabecular bone volume, plate density and thickness, while senile osteoporotics (i.e. older than 75 years) did not exhibit any difference with controls. 51% of the osteoporotic patients had a trabecular bone volume higher than the spontaneous vertebral crush threshold defined by Meunier. Osteoporotic patients with trabecular bone volume under the vertebral crush threshold had a significant decrease in all trabecular parameters. On the opposite, patients with trabecular bone volume above the vertebral crush threshold had only a significant decrease in the number of trabeculae. A negative correlation was found between age and plate density in both osteoporotic patients and controls. A linear correlation was found between trabecular bone volume and plate density, but thickness and density of trabecular plates were not correlated. This study confirms that involutional osteoporosis is not only a decreased bone mass disorder. A modified spatial distribution of trabeculae or a mechanically less resistant bone matrix could be additional factors.     

Simulation of vertebral trabecular bone loss using voxel finite element analysis

Trabecular bone loss in human vertebral bone is characterised by thinning and eventual perforation of the horizontal trabeculae. Concurrently, vertical trabeculae are completely lost with no histological evidence of significant thinning. Such bone loss results in deterioration in apparent modulus and strength of the trabecular core. In this study, a voxel-based finite element program was used to model bone loss in three specimens of human vertebral trabecular bone. Three sets of analyses were completed. In Set 1, strain adaptive resorption was modelled, whereby elements which were subject to the lowest mechanical stimulus (principal strain) were removed. In Set 2, both strain adaptive and microdamage mechanisms of bone resorption were included. Perforation of vertical trabeculae occurred due to microdamage resorption of elements with strains that exceeded a damage threshold. This resulted in collapse of the trabecular network under compression loading for two of the specimens tested. In Set 3, the damage threshold strain was gradually increased as bone loss progressed, resulting in reduced levels of microdamage resorption. This mechanism resulted in trabecular architectures in which vertical trabeculae had been perforated and which exhibited similar apparent modulus properties compared to experimental values reported in the literature. Our results indicate that strain adaptive remodelling alone does not explain the deterioration in mechanical properties that have been observed experimentally. Our results also support the hypothesis that horizontal trabeculae are lost principally by strain adaptive resorption, while vertical trabeculae may be lost due to perforation from microdamage resorption followed by rapid strain adaptive resorption of the remaining unloaded trabeculae.     

Patterns of Bisphosphonates Utilization in Patients under Age 45 in a Large Cohort of Commercial Insurance Beneficiaries in the United States

Background

The effectiveness and safety of bisphosphonates treatment used in the young population have not been well studied. Despite insufficient data on effectiveness and safety of bisphosphonates in young patients, bisphosphonates are still considered in younger patients at high risk for osteoporosis or fracture. The objectives of this study were to identify bisphosphonate initiators aged 10–45 years and describe their clinical characteristics and to assess time trends of bisphosphonate use over the past decade in a large U.S. population-based cohort.

Methods

Using the medical and pharmacy claims data from a U.S. commercial insurance (2003–2012), patients aged 10–45 years without malignancy who initiated an oral or intravenous bisphosphonate after at least 1 year of insurance enrollment were selected. Baseline demographics, comorbidities, medications and health care utilization were assessed in the year prior to initiating a bisphosphonate. The trend of bisphosphonate use over time was examined.

Results

There were 9,082 bisphosphonate initiators (0.02% of the same age group in the population). The mean age was 38.1 years and 79.6% female. Osteoporosis was the most common diagnosis (41.2%). At baseline, 10.8% had a diagnosis of fracture and 29.0% had a bone mineral density measured. Of those who used glucocorticoids (39%) at baseline, the mean 1-year cumulative prednisone-equivalent dose was 2,669 milligrams. The use of bisphosphonates in the young population significantly decreased over the past decade (p<0.001).

Conclusions

Among young patients aged 10–45, the use of bisphosphonates was uncommon and significantly decreased over the past decade in the U.S. While most patients initiating bisphosphonates had a diagnosis of osteoporosis and fracture in the preceding year, some had no recorded claims with a diagnosis of fracture, osteoporosis, or long-term glucocorticoids use at baseline. Future research is needed to examine the effectiveness and safety of bisphosphonates in young patients at risk for osteoporosis.     

Peri-implant bone remodeling after total hip replacement combined with systemic alendronate treatment: a finite element analysis

In order to decrease the peri-implant bone loss during the life-time of the implant, oral use of anti-osteoporosis drugs (like bisphosphonates) has been suggested. In this study, bone remodeling parameters identified from clinical trials of alendronate were used to simulate the effect of those drugs used after total hip arthroplasty on the peri-implant bone density. Results of the simulation show that the oral administrated drugs increase bone density around the implant and decreases, at the same time, the micromovements between the implant and the surrounding bone tissue. Incorporation of drug effect in numerical studies of bone remodeling is a promising tool especially to predetermine safe bisphosphonate doses that could be used with orthopedic implants.     

Peri-implant Bone Remodeling after Total Hip Replacement Combined with Systemic Alendronate Treatment: A Finite Element Analysis

In order to decrease the peri-implant bone loss during the life-time of the implant, oral use of anti-osteoporosis drugs (like bisphosphonates) has been suggested.

In this study, bone remodeling parameters identified from clinical trials of alendronate were used to simulate the effect of those drugs used after total hip arthroplasty on the peri-implant bone density. Results of the simulation show that the oral administrated drugs increase bone density around the implant and decreases, at the same time, the micromovements between the implant and the surrounding bone tissue.

Incorporation of drug effect in numerical studies of bone remodeling is a promising tool especially to predetermine safe bisphosphonate doses that could be used with orthopedic implants.     

Effect of alendronate administration on bone mineral density and bone strength in castrated rats.

Castration of male rats leads to increased bone turnover and osteopenia. This study was conducted to examine the effects of the aminobisphosphonate alendronate on castration-induced bone changes. Bisphosphonates are drugs that inhibit bone turnover by decreasing the resorption. Since they suppress bone remodeling, they may also prevent the repair of microdamage and decrease bone strength. Although the mechanical properties of bones are directly related to the determination of fracture risk, bisphosphonate effects on the related variables have scarcely been investigated. Twenty-four male Wistar rats at two months of age were castrated or sham-operated to evaluate the effects of long-term administration (six months) of sodium alendronate at a dose of 1 mg/kg/day. The bones were tested mechanically by a three-point bending test in a Mini Bionix (MTS) testing system. High bone remodeling seen in castrated rats expressed by increased TrACP and B-ALP was suppressed by alendronate administration. Bone from castrated rats was characterized by a reduction in bone density as well as ash, calcium and phosphate content. Castration significantly altered mechanical properties of bone and femoral cortical thickness. When castrated rats were treated with high dose of alendronate, the changes in bone density resulting from castration were entirely prevented, and mechanical analysis revealed preserved mechanical strength of femur and cortical thickness. We conclude that castration induces cortical bone loss associated with high bone turnover in the male rat, and this bone loss can be prevented by alendronate through the inhibition of osteoclastic activity, while preserving the mechanical properties of bone. These results document the efficacy of alendronate, even at high doses, in preventing bone loss, loss of bone mechanical strength, and the rise in biochemical bone turnover indicators due to castration in rats, and raises the possibility that a alendronate could be equally effective in humans.     

Quantification of trabecular bone microdamage using the virtual internal bond model and the individual trabeculae segmentation technique

Trabecular bone microdamage significantly influences the skeletal integrity and bone remodelling process. In this paper a novel constitutive model, called the virtual internal bond model (VIB), was adopted for simulating the damage behaviour of bone tissue. A unique 3D image analysis technique, named individual trabeculae segmentation, was used to analyse the effects of microarchitectures on the damage behaviours of trabecular bone. We demonstrated that the process of initiation and accumulation of microdamage in trabecular bone samples can be captured by the VIB-embedded finite-element method simulation without a separate fracture criterion. Our simulation results showed that the microdamage can occur at as early as about 0.2–0.4% apparent strain, and a large volume of microdamage was accumulated around the apparent yield strain. In addition we found that the plate-like trabeculae, especially the longitudinal ones, take crucial roles in the microdamage behaviours of trabecular bone.     

Immunomodulatory effects of vitamin D3 and bisphosphonates in nutritional osteoporosis in rats

The aim of this study was to determine the effectiveness of separate and combined administration of vitamin D3 and different forms of bisphosphonate (disodium salt of methylenbisphosphonic acid dihydrate and alendronate) on the function of immune cells in rats with nutritional osteoporosis. It was shown that D-hypovitaminosis leads to reduced 25OHD3, which is a biomarker for vitamin D3 and disturbances of metabolic processes in bone tissue that correlated with osteoporosis manifestation. Immunologic disorders related to nutritional osteoporosis were accompanied by the decrease in phagocytic activity of granulocytes and impaired ability to produce bactericidal oxidants. Inhibition of B-cell immunity also occurred in patholgy. Thus, the present study revealed more pronounced immunomodulatory effects of vitamin D3 on phagocytic immunity, whereas bisphosphonates were effective in improving the humoral immune protection.     

Perforation of cancellous bone trabeculae by damage-stimulated remodelling at resorption pits: a computational analysis

Loss of trabeculae in cancellous bone is often attributed to a general decline in the bone mass leading to fracture of the thin trabeculae. It has never been investigated whether trabecular perforation may have any other biomechanical mechanism. In this paper, an alternative hypothesis is proposed and tested using a computational model. Taking it as given that osteoclastic resorption is targeted to microdamage, it is hypothesised that the creation of a resorption cavity during normal bone remodelling could cause a stress-concentration in the bone tissue. If the resorption cavities were excessively deep, as is seen during osteoporosis, then this stress concentration may be sufficient to generate more microdamage so that osteoclasts "chase" newly formed damage leading to perforation. If this were true then we should find that, for a given trabecular thickness, there is a critical depth of resorption cavity such that smaller cavities refill whereas deeper cavities cause microdamage accumulation, continued osteoclast activity, and eventual trabecular perforation. Computer simulation is used to test this hypothesis. Using a remodelling stimulus calculated from both strain and damage and a simplified finite element model of a trabeculum with cavities of different sizes, it is predicted that such a critical depth of resorption cavity does indeed exist. Therefore we suggest that an increase in resorption depth relative to the thickness of trabeculae may be responsible for trabecular perforation during osteoporosis, rather than simply trabecular fracture due to insufficient strength.     

Determinants of Microdamage in Elderly Human Vertebral Trabecular Bone

Previous studies have shown that microdamage accumulates in bone as a result of physiological loading and occurs naturally in human trabecular bone. The purpose of this study was to determine the factors associated with pre-existing microdamage in human vertebral trabecular bone, namely age, architecture, hardness, mineral and organic matrix. Trabecular bone cores were collected from human L2 vertebrae (n = 53) from donors 54–95 years of age (22 men and 30 women, 1 unknown) and previous cited parameters were evaluated. Collagen cross-link content (PYD, DPD, PEN and % of collagen) was measured on surrounding trabecular bone. We found that determinants of microdamage were mostly the age of donors, architecture, mineral characteristics and mature enzymatic cross-links. Moreover, linear microcracks were mostly associated with the bone matrix characteristics whereas diffuse damage was associated with architecture. We conclude that linear and diffuse types of microdamage seemed to have different determinants, with age being critical for both types.