Long-term Bisphosphonate Treatment Research Articles

Photobiomodulation Can Prevent Medication-Related Osteonecrosis of the Jaw Formation in Tooth Extraction Site of Rat Model.

Objective: This study aims to explore the preventive potential of photobiomodulation (PBM) in bisphosphonate-related osteonecrosis of the jaw (BRONJ) using a rat model. Methods: An experimental rat model was established, exposing rats to zoledronic acid (ZA), a primary risk factor for BRONJ. An 810 nm diode laser was applied with parameters of 0.33 W/cm2 power density and 10 J/cm2 energy density for 30 sec. PBM was initiated 1 day pre-extraction and continued for 2 weeks. The impact of PBM on wound healing in both soft and hard tissues was evaluated post tooth extraction. Results: ZA exposure hindered wound healing in both soft and hard tissues after tooth extraction. PBM intervention effectively mitigated the adverse effects of ZA, promoting healing processes in both tissue types. This suggests the potential of PBM as a preventive strategy for BRONJ in patients on long-term bisphosphonate treatment. Moreover, PBM exhibited enhanced wound healing in normal rats, indicating its broader applicability beyond BRONJ cases. Conclusions: PBM shows promise in preventing and improving wound healing in BRONJ and normal cases. These findings underscore the significance of optimizing PBM parameters and suggest its potential clinical relevance as a preventive intervention for BRONJ and a promoter of wound healing.

Bone Mineral Density Response to Long-Term Bisphosphonate Treatment and Discontinuation in a Real-World Clinical Service

ObjectiveBisphosphonate treatment does not increase bone mineral density (BMD) in all subjects particularly at the femoral neck (FN). Our aim was to evaluate the relationship between response to oral bisphosphonate (oBP) at the FN and change in BMD following discontinuation. MethodsData were collected retrospectively from postmenopausal women on oBP for ≥3 years, attending a real-world metabolic clinic at initiation of oBP, discontinuation, and 1 to 2 years post discontinuation. Improvement in BMD ≥4% in the FN and ≥5% for the lumbar spine (LS) were deemed clinically meaningful and used as least significant change (LSC) values. We divided subjects based on FN BMD response and compared outcomes between responders and non-responders after oBP discontinuation. ResultsOf the 213 subjects, 32.1% showed an increase ≥LSC at the FN compared to 57.1% at the LS on treatment (P < .0001). FN responders had lower BMD levels at pretreatment baseline than non-responders both at the FN (0.58 vs 0.62 g/cm2; P = .003) and LS (0.76 vs 0.79 g/cm2; P = .044). Off-treatment, more subjects lost BMD ≥LSC at FN in the responder group than in the non-responder group (37.5% vs 14.2%; P < .001). BMD remained above pre-treatment levels in responders after a median follow-up of 1.52 years. ConclusionBMD response at FN is suboptimal in patients on oBP and is much less common than LS response. FN responders tend to lose the accumulated bone quickly off-treatment, though BMD remains above pretreatment levels. These observations suggest that new approaches may be needed to optimize osteoporosis management in real-world patients.

Bone Morphogenetic Protein 2 Promotes Bone Formation in Bone Defects in Which Bone Remodeling Is Suppressed by Long-Term and High-Dose Zoledronic Acid.

The use of long-term and high-dose bisphosphate is associated with severely suppressed bone turnover and the delayed union of fractures. However, therapeutic methods to overcome the negative effects of bisphosphonate use are lacking. Bone morphogenetic proteins (BMPs) are powerful osteoinductive proteins. The development of the delivery system using BMP has been verified to have an excellent effect on fracture healing and the enhancement of osteointegration. We hypothesized that BMPs had similar effects as autografts in patients with decreased bone healing potential due to long-term bisphosphonate treatment. Forty rats were divided into the following four groups depending upon the materials implanted into the femoral defect after ten weeks of bisphosphonate (zoledronic acid) injections: Group I: absorbable collagen sponge (control); group II: demineralized freeze-dried bone graft; group III: autogenous bone graft; and group IV: rhBMP-2 with an absorbable collagen sponge. Radiographic union, micro-computed tomography (CT) analysis, manual palpation, and histologic analysis were evaluated. The radiographic union rate, manual union rate, and micro-CT bone volume in groups III and IV were significantly higher than those in groups I and II. Groups III and IV showed similar results to each other. Although the amount of immature bone in the BMP-treated group was large, the effect was similar to that of autografts in the bone defect model in which bone turnover was severely reduced by bisphosphonate treatment. BMP might be a good substitute for autografts in patients with decreased bone healing potential due to long-term bisphosphonate treatment.

A brief review and clinical evidences of teriparatide therapy for atypical femoral fractures associated with long-term bisphosphonate treatment.

The risk of bisphosphonate (BP)-associated atypical femur fracture (AFF) has markedly increased over recent decades due to suppression of bone turnover, accumulation of structural micro-damage and reduction of bone remodeling consequent to long-term BP treatment. These medications further delay bone union and result in challenging clinical management. Teriparatide (TPTD), a synthetic human parathyroid hormone, exhibits unique anabolic effects and can increase bone remodeling and improve bone microarchitecture, further promoting fracture healing and reducing the rate of bone non-union. In this study, we briefly define AFF as well as the effects of BPs on AFFs, detailed the role of TPTD in AFF management and the latest clinical therapeutic findings. We have confirmed that TPTD positively promotes the healing of AFFs by reducing the time to bone union and likelihood of non-union. Thus, teriparatide therapy could be considered as an alternative treatment for AFFs, however, further research is required for the establishment of effective clinical guidelines of TPTD use in the management of AFF.

Alendronate prolongs the reversal-resorption phase in human cortical bone remodeling.

Despite their ability to reduce fracture-risk and increase Bone Mineral Density (BMD) in osteoporotic women, bisphosphonates are reported to reduce formation of new bone. Reduced bone formation has been suggested to lead to accumulation of microfractures and contribute to rare side effects in cortical bone such as atypical femur fractures. However, most studies are limited to trabecular bone. In this study, the cortical bone remodeling in human iliac bone specimens of 65 non-treated and 24 alendronate-treated osteoporotic women was investigated using a new histomorphometric classification of intracortical pores. The study showed that only 12.4±11% of the cortical pore area reflected quiescent pores/osteons in alendronate-treated patients versus 8.5±5% in placebo, highlighting that new cortical remodeling events remain to be activated. The percent and size of eroded pores (events in resorption-reversal phase) remained unchanged, but their contribution to total pore area was 1.4-fold higher in alendronate versus placebo treated patients (66±22% vs 48±22%, p<0.001). On the other hand, the mixed eroded-formative pores (events with mixed resorption-reversal-formation phases) was 2-fold lower in alendronate versus placebo treated patients (19±14% vs 39±23% of total pore area, p<0.001), and formative pores (event in formation phase) was 2.2-fold lower in alendronate versus placebo treated patients (2.1± 2.4% vs 4.6±3.6%, p<0.01), and their contribution to total pore area was 2.4-fold lower (1.3±2.1% vs 3.1±4.4%, p<0.05). Importantly, these differences between alendronate and placebo treated patients were significant in patients after 3years of treatment, not after 2years of treatment. Collectively, the results support that cortical remodeling events activated during alendronate treatment has a prolonged reversal-resorption phase with a delayed transition to formation, becoming increasingly evident after 3-years of treatment. A potential contributor to atypical femur fractures associated with long-term bisphosphonate treatment.

Risks of femoral localized periosteal thickening in patients with autoimmune inflammatory rheumatic diseases.

The incidence of femoral localized periosteal thickening (LPT), which can precede atypical femoral fracture (AFF), is not low (1-10%) in Japanese patients with autoimmune inflammatory rheumatic diseases (AIRDs). We explored the associations between underlying AIRDs and the prevalence of LPT. We conducted post hoc analyses of two cohorts that included a total of 280 Japanese women, 105 of whom had AIRDs and had been taking bisphosphonate (BP) and prednisolone (PSL) and 175 of whom had rheumatoid arthritis (RA). LPT was detected in a total of 18 patients (6.4%) and 3 (1.1%) developed AFFs. RA was negatively correlated with LPT. A disease other than RA requiring glucocorticoid treatment, BP use ≥5 years, PSL use ≥7 years, and a PSL dose ≥5.5 mg/day were positively correlated with LPT. After adjusting for age, diabetes mellitus, and BP duration or daily PSL dose, RA was no longer associated with LPT. LPT in Japanese patients with AIRDs was associated with BP and glucocorticoid treatment rather than underlying AIRDs. When PSL dose ≥5.5 mg/day is required long-term [typically combined with long-term BP treatment (≥5 years)], clinicians need to pay particular attention in cases LPT and AFF as well as glucocorticoid-induced osteoporosis.

Effect of denosumab on renal function in women with osteoporosis evaluated using cystatin C

ObjectivesTo investigate renal function during denosumab therapy using the estimated glomerular filtration rate based on cystatin C (eGFRcys) which is more accurate than creatinine (eGFRcr) for renal function. MethodsBone mineral densities (BMDs) of lumbar spine and hip regions, eGFRcys, eGFRcr, creatinine clearance (Ccr), and serum total homocysteine (S-Hcy) were measured during 2-year denosumab therapy in 53 women with osteoporosis naïve to anti-osteoporosis drugs (new group) and 64 women who were switched from long-term bisphosphonate treatment to denosumab therapy (switch group). ResultsThere were no significant differences in age, eGFRcr, Ccr, eGFRcys, and S-Hcy levels at baseline between the groups. BMDs in the lumbar spine, femoral neck, and total hip increased significantly after 2-year denosumab therapy in both groups. eGFRcr decreased in the switch group, and Ccr decreased in both groups; however, eGFRcys and S-Hcy levels did not change significantly in either group. To investigate the causal factors associated with the decrease in eGFRcr and Ccr, multiple regression analysis was performed in all patients. Denosumab initiation within 3 months after fracture and eGFRcr or Ccr at baseline were independent factors for the decrease in eGFRcr or Ccr during the 2-year denosumab therapy. Decline in creatinine-based renal function could be reflected by increased muscle mass during the ongoing recovery from fracture. ConclusionsRenal function was preserved in all patients, including those in the switch group during denosumab therapy. Creatinine-based renal function should be cautiously interpreted during denosumab therapy in patients with recent fractures.

The Time-Dependent Role of Bisphosphonates on Atherosclerotic Plaque Calcification.

Atherosclerotic plaque calcification directly contributes to the leading cause of morbidity and mortality by affecting plaque vulnerability and rupture risk. Small microcalcifications can increase plaque stress and promote rupture, whereas large calcifications can stabilize plaques. Drugs that target bone mineralization may lead to unintended consequences on ectopic plaque calcification and cardiovascular outcomes. Bisphosphonates, common anti-osteoporotic agents, have elicited unexpected cardiovascular events in clinical trials. Here, we investigated the role of bisphosphonate treatment and timing on the disruption or promotion of vascular calcification and bone minerals in a mouse model of atherosclerosis. We started the bisphosphonate treatment either before plaque formation, at early plaque formation times associated with the onset of calcification, or at late stages of plaque development. Our data indicated that long-term bisphosphonate treatment (beginning prior to plaque development) leads to higher levels of plaque calcification, with a narrower mineral size distribution. When given later in plaque development, we measured a wider distribution of mineral size. These morphological alterations might be associated with a higher risk of plaque rupture by creating stress foci. Yet, bone mineral density positively correlated with the duration of the bisphosphonate treatment.

Evaluation of growth, puberty, osteoporosis, and the response to long-term bisphosphonate therapy in four patients with osteoporosis-pseudoglioma syndrome.

Osteoporosis-pseudoglioma syndrome (OPPG; MIM #259770) is a rare autosomal recessively inherited disease, characterized by early-onset osteoporosis and congenital blindness, caused by loss-of-function mutations in the LRP5 gene. Beneficial effects of bisphosphonate treatment in patients with OPPG are well known, while follow-up data on growth and pubertal parameters are limited. This article provides clinical follow-up data and long-term bisphosphonate treatment results in four OPPG patients from three unrelated families, ranging between 2.5 and 7 years of age at presentation. Clinical diagnosis was molecularly confirmed in all patients, with four different germline biallelic LRP5 mutations including a novel nonsense variant c.3517C>T (p.(Gln1173*)) in two siblings with marked phenotypic variability. Anthropometric and pubertal data and bone mineral density (BMD) measurements were evaluated retrospectively. Early puberty was observed in two patients. The bisphosphonate treatment duration of patients varied around 4-7 years and improvement in BMD z-scores with bisphosphonate treatment was demonstrated in all patients (z-score changes were +5.6, +4.0, +1.0, and +1.3). Although further research is needed to identify the possible association between early puberty and OPPG, all OPPG patients should be followed up with detailed endocrinological evaluation regarding pubertal status.

Suppression of bone remodeling associated with long-term bisphosphonate treatment is mediated by microRNA-30a-5p

ABSTRACT Oral bisphosphonates (BPs) are a first-line treatment for osteoporosis. It is becoming a hot topic to identify new indicators for the early prediction of therapeutic effects and adverse reactions during the long-term use of BPs. To determine whether microRNA (miRNA) expression is modulated by long-term BPs treatment, we performed miRNA expression profiling analysis in patients receiving long-term BP treatment for postmenopausal OP. To assess the effect of BPs on miRNA expression, we used an Affymetrix Genechip miRNA array to analyze serum samples obtained from postmenopausal OP patients on long-term BP treatment and healthy controls. MiRNAs affected by BPs and their predicted targets were examined. We also investigated the effects of miRNA on osteoblast differentiation in vitro and on ovariectomy-induced bone loss in vivo. We observed that the level of miR-30a-5p was significantly increased in patients receiving long-term BP treatment for postmenopausal OP. Furthermore, miR-30a-5p was negatively correlated with bone formation. Consistent with this, in vitro osteoblast activity and matrix mineralization were increased by an antagomir of miR-30a-5p and decreased by an agomir of miR-30a-5p. We also found that miR-30a-5p directly targeted RUNX1 to inhibit osteoblastic differentiation. Consistent with the in vitro results, miR-30a-5p antagomir administration promoted bone formation in ovariectomized mice. Our findings identified miR-30a-5p as a novel mediator of long-term BP treatment that regulates bone formation in postmenopausal OP patients.

Gene Network of Susceptibility to Atypical Femoral Fractures Related to Bisphosphonate Treatment.

Atypical femoral fractures (AFF) are rare fragility fractures in the subtrocantheric or diaphysis femoral region associated with long-term bisphosphonate (BP) treatment. The etiology of AFF is still unclear even though a genetic basis is suggested. We performed whole exome sequencing (WES) analysis of 12 patients receiving BPs for at least 5 years who sustained AFFs and 4 controls, also long-term treated with BPs but without any fracture. After filtration and prioritization of rare variants predicted to be damaging and present in genes shared among at least two patients, a total of 272 variants in 132 genes were identified. Twelve of these genes were known to be involved in bone metabolism and/or AFF, highlighting DAAM2 and LRP5, both involved in the Wnt pathway, as the most representative. Afterwards, we intersected all mutated genes with a list of 34 genes obtained from a previous study of three sisters with BP-related AFF, identifying nine genes. One of these (MEX3D) harbored damaging variants in two AFF patients from the present study and one shared among the three sisters. Gene interaction analysis using the AFFNET web suggested a complex network among bone-related genes as well as with other mutated genes. BinGO biological function analysis highlighted cytoskeleton and cilium organization. In conclusion, several genes and their interactions could provide genetic susceptibility to AFF, that along with BPs treatment and in some cases with glucocorticoids may trigger this so feared complication.

Insufficiency Fracture of Simultaneously Bilateral Femur Neck in Patient Treated with Long-Term Bisphosphonate Treatment: A Case Report

Insufficiency Fracture of Simultaneously Bilateral Femur Neck in Patient Treated with Long-Term Bisphosphonate Treatment: A Case Report

Magnesium facilitates the healing of atypical femoral fractures: A single-cell transcriptomic study

Bisphosphonates (BPs)-associated atypical femoral fractures (AFFs) present with impaired fracture healing, yet the underlying mechanism is unclear, which prevents the development of effective therapy. Peripheral sensory nerve has been shown to regulate fracture healing via releasing neuropeptides. Here we show that long-term BPs pre-treatment leads to fracture non-union in rats, characterized by reduced expression of calcitonin gene-related peptide (CGRP, a predominant type of neuropeptides) and abundant fibrous tissues in the non-bridged fracture gap, mimicking clinical AFFs. By using single-cell RNA-sequencing, long-term BPs treatment was identified to promote transition of progenitor cells into a specific cluster of fibroblasts that actively deposit dense extracellular matrix (ECM) to prevent fracture callus bridging. Administration of exogenous CGRP at early stages of fracture repair, in contrast, eliminates the ECM-secreting fibroblast cluster, attenuates fibrogenesis, and facilitates callus bridging, suggesting CGRP is a promising agent to facilitate AFF healing. Accordingly, we have developed an innovative magnesium (Mg) containing hybrid intramedullary nail fixation system (Mg-IMN) to effectively rescue BPs-impaired fracture healing via elevating CGRP synthesis and release. Such device optimizes the fracture healing in BPs-pretreated rats, comparable to direct administration of CGRP. These findings address the indispensable role of CGRP in advancing the healing of AFFs and develop translational strategies to accelerate AFF healing by taking advantage of the CGRP-stimulating effect of Mg-based biodegradable orthopedic implant. The study also indicates fibrosis could be targeted by augmenting CGRP expression to accelerate fracture healing even under challenging scenarios where fibroblasts are aberrantly activated.

Bone Quality and Fractures in Women With Osteoporosis Treated With Bisphosphonates for 1 to 14 Years.

ABSTRACTOral bisphosphonates are the primary medication for osteoporosis, but concerns exist regarding potential bone‐quality changes or low‐energy fractures. This cross‐sectional study used artificial intelligence methods to analyze relationships among bisphosphonate treatment duration, a wide variety of bone‐quality parameters, and low‐energy fractures. Fourier transform infrared spectroscopy and histomorphometry quantified bone‐quality parameters in 67 osteoporotic women treated with oral bisphosphonates for 1 to 14 years. Artificial intelligence methods established two models relating bisphosphonate treatment duration to bone‐quality changes and to low‐energy clinical fractures. The model relating bisphosphonate treatment duration to bone quality demonstrated optimal performance when treatment durations of 1 to 8 years were separated from treatment durations of 9 to 14 years. This may be due to a change in relationship of bone‐quality parameters with treatment duration. This model also showed that the effects of bisphosphonate treatment duration were most highly correlated with changes in means and standard deviations of infrared spectroscopically derived mineral and matrix parameters and histomorphometric bone turnover parameters. A second model related treatment duration to bone fracture in all 22 patients who fractured while on treatment with bisphosphonates for more than 8 years. This second model showed that bisphosphonate treatment duration, not hip bone mineral density (BMD), was the most strongly correlated parameter to these low‐energy bone fractures. Application of artificial intelligence enabled analysis of large quantities of structural, cellular, mineral, and matrix bone‐quality parameters to determine relationships with long‐term oral bisphosphonate treatment and fracture. Infrared spectroscopy provides clinically relevant bone‐quality information of which bone mineral purity is among the most relevant. Nine or more years of bisphosphonate treatment was associated with abnormal bone mineral purity, matrix abnormalities, and low‐energy fractures. These data justify limiting bisphosphonate treatment duration to 8 years. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Functional Analyses of Four CYP1A1 Missense Mutations Present in Patients with Atypical Femoral Fractures.

Osteoporosis is the most common metabolic bone disorder and nitrogen-containing bisphosphonates (BP) are a first line treatment for it. Yet, atypical femoral fractures (AFF), a rare adverse effect, may appear after prolonged BP administration. Given the low incidence of AFF, an underlying genetic cause that increases the susceptibility to these fractures is suspected. Previous studies uncovered rare CYP1A1 mutations in osteoporosis patients who suffered AFF after long-term BP treatment. CYP1A1 is involved in drug metabolism and steroid catabolism, making it an interesting candidate. However, a functional validation for the AFF-associated CYP1A1 mutations was lacking. Here we tested the enzymatic activity of four such CYP1A1 variants, by transfecting them into Saos-2 cells. We also tested the effect of commonly used BPs on the enzymatic activity of the CYP1A1 forms. We demonstrated that the p.Arg98Trp and p.Arg136His CYP1A1 variants have a significant negative effect on enzymatic activity. Moreover, all the BP treatments decreased CYP1A1 activity, although no specific interaction with CYP1A1 variants was found. Our results provide functional support to the hypothesis that an additive effect between CYP1A1 heterozygous mutations p.Arg98Trp and p.Arg136His, other rare mutations and long-term BP exposure might generate susceptibility to AFF.

Magnetic Resonance Imaging Signal Changes Mimicking Bone Metastasis in Patients Receiving Bisphosphonate Therapy

Bisphosphonates are inorganic pyrophosphate agents that reduce bone turnover. These agents reduce bone pain and delay skeletal complications, such as fractures in patients with metastatic lytic lesions, malignant-related hypercalcemia, multiple myeloma, Paget’s disease of bone, and osteoporosis. Osteonecrosis, developing in the jaw bones specifically, has been described as a complication associated with the use of bisphosphonates. In this report, we presented osteonecrosis-like magnetic resonance imaging findings that can be confused with bone metastasis in two patients who underwent long-term bisphosphonate treatment and the value of bone scan and 18flor-fluorodeoxyglucose positron emission tomography/computerized tomography in the differential diagnosis.

A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation.

ABSTRACTBisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about bone health based on oversuppression of remodeling remain. Long‐term bone remodeling suppression adversely affects bone material properties with microdamage accumulation and reduced fracture toughness in animals and increases in matrix mineralization and atypical femur fractures in patients. Although a “drug holiday” from BPs to restore remodeling and improve bone quality seems reasonable, clinical BPs have long functional half‐lives because of their high hydroxyapatite (HAP) binding affinities. This places a practical limit on the reversibility and effectiveness of a drug holiday. BPs with low HAP affinity and strong osteoclast inhibition potentially offer an alternative approach; their antiresorptive effect should reverse rapidly when dosing is discontinued. This study tested this concept using NE‐58025, a BP with low HAP affinity and moderate osteoclast inhibition potential. Young adult female C57Bl/6 mice were ovariectomized (OVX) and treated with NE‐58025, risedronate, or PBS vehicle for 3 months to test effectiveness in preventing long‐term bone loss. Bone microarchitecture, histomorphometry, and whole‐bone mechanical properties were assessed. To test reversibility, OVX mice were similarly treated for 3 months, treatment was stopped, and bone was assessed up to 3 months post‐treatment. NE‐58025 and RIS inhibited long‐term OVX‐induced bone loss, but NE‐58025 antiresorptive effects were more pronounced. Withdrawing NE‐58025 treatment led to the rapid onset of trabecular resorption with a 200% increase in osteoclast surface and bone loss within 1 month. Cessation of risedronate treatment did not lead to increases in resorption indices or bone loss. These results show that NE‐58025 prevents OVX‐induced bone loss, and its effects reverse quickly following cessation treatment in vivo. Low‐HAP affinity BPs may have use as reversible, antiresorptive agents with a rapid on/off profile, which may be useful for maintaining bone health with long‐term BP treatment. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Metabolic activities affect femur and lumbar vertebrae remodeling, and anti-resorptive risedronate disturbs femoral cortical bone remodeling

Metabolic activities are closely correlated with bone remodeling and long-term anti-resorptive bisphosphonate treatment frequently causes atypical femoral fractures through unclear mechanisms. To explore whether metabolic alterations affect bone remodeling in femurs and lumbar vertebrae and whether anti-osteoporotic bisphosphonates perturb their reconstruction, we studied three mouse strains with different fat and lean body masses (BALB/c, C57BL6, and C3H mice). These mice displayed variable physical activity, food and drink intake, energy expenditure, and respiratory quotients. Following intraperitoneal calcein injection, double calcein labeling of the femoral diaphysis, as well as serum levels of the bone-formation marker procollagen type-I N-terminal propeptide and the bone-resorption marker C-terminal telopeptide of type-I collagen, revealed increased bone turnover in mice in the following order: C3H > BALB/c ≥ C57BL6 mice. In addition, bone reconstitution in femurs was distinct from that in lumbar vertebrae in both healthy control and estrogen-deficient osteoporotic mice with metabolic perturbation, particularly in terms of femoral trabecular and cortical bone remodeling in CH3 mice. Interestingly, subcutaneous administration of bisphosphonate risedronate to C3H mice with normal femoral bone density led to enlarged femoral cortical bones with a low bone mineral density, resulting in bone fragility; however, this phenomenon was not observed in mice with ovariectomy-induced femoral cortical bone loss. Together, these results suggest that diverse metabolic activities support various forms of bone remodeling and that femur remodeling differs from lumbar vertebra remodeling. Moreover, our findings imply that the adverse effect of bisphosphonate agents on femoral cortical bone remodeling should be considered when prescribing them to osteoporotic patients.

Morphological and Morphometrical Analyses of Fracture-Healing Sites of an Atypical Femoral Fracture in Patients with and without Long-Term Bisphosphonate Treatment for Osteoporosis: A Report of Two Cases

Bisphosphonates have been the first drug of choice for osteoporosis in the recent years because of their known ability to suppress osteoclast activity. The adverse effect of long-term bisphosphonate administration in the fracture-healing process is controversial. The aim of our study was to observe not only morphology but also morphometry of the fracture site of atypical femoral fracture with and without long-term bisphosphonate administration, in a case study of two difficult-to-obtain human samples. The patients with insufficient healing of atypical femoral fracture were treated with valgus wedge osteotomy. Histomorphometrical analysis was performed in bone samples of fracture sites harvested during osteotomy. The thickness of the femoral cortex was measured in the fracture site and the adjacent, non-fracture site. A comparative analysis of the content of hypertrophic osteoclasts in fracture sites, shape and size of osteons, mass, and ratio of the woven bone to the total bone mass was performed, comparing bisphosphonate-treated and untreated samples. In bisphosphonate-treated samples, we observed femoral cortex thickening at the fracture site; the appearance of hypertrophic osteoclasts; decreased bone resorption surface, decreased osteoclast numbers on the bone resorption surface, and increased ratio of multinuclear osteoclasts; osteons were misshapen and thin; and the mass and ratio of the woven bone to the total bone mass were higher. This study demonstrated that long-term bisphosphonate administration can alter the morphological features of the fracture site compared to its physiological state.

Treatment strategy for atypical ulnar fracture due to severely suppressed bone turnover caused by long-term bisphosphonate therapy: a case report and literature review

BackgroundAtypical fractures may occur due to the combined effect of severely suppressed bone turnover (SSBT) caused by long-term bisphosphonate treatment and chronic repetitive bone microdamage. Atypical fracture of the ulna due to SSBT is a rare entity; there is no standardized treatment strategy for this condition. We successfully treated a patient with atypical fracture of the ulna. Herein, we present this patient, review the relevant literature, and discuss the treatment strategy.Case presentationAn 84-year-old woman presented with atypical fracture of the left ulnar shaft due to SSBT. She had a history of bisphosphonate therapy (ibandronate and alendronate) since more than 10 years; her bone turnover was severely suppressed. We performed open reduction and internal fixation (ORIF) using dual plate with some additional treatments. These included drilling and decortication, use of autogenous bone graft, low-intensity pulsed ultrasound (LIPUS) treatment, and administration of teriparatide. Finally, bone union was observed at 11 months after surgery.ConclusionsBased on the literature review and our experience with this case, ORIF alone may not be adequate to achieve bone union; drilling, decortication, and use of cancellus bone graft is important to achieve favorable outcomes. Administration of teriparatide and LIPUS may facilitate early bone union, although further studies are required to provide more definitive evidence. Furthermore, ORIF using dual plate may help avoid implant failure owing to the long time required for bone union.