Long-term Bisphosphonate Research Articles

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.

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

Atypical Fixation Failure after the Internal Fixation of a Peri-implant Subtrochanteric Fracture in a Patient on Long-Term Bisphosphonate Therapy and its Management

Bisphosphonate therapy should be properly monitored in the treatment of osteoporosis, since it affects the bone turnover and may cause fatigue fractures. A new clinical adverse outcome due to long-term bisphosphonate therapy specifically in a postoperative osteoporotic patient is peri-implant fractures that are rarely described in the literature. Our case report describes an untoward biomechanical failure in the fixation of a peri-implant subtrochanteric fracture in an osteoporotic patient who is on long-term alendronate therapy and had been operated previously with dynamic hip screw and its management with 1-year follow-up.

Atypical forearm fractures associated with long-term bisphosphonate use: the perspective of hand surgeons

Bisphosphonates are widely used to treat osteoporosis, but atypical femoral fractures have emerged as a serious complication. Similar fractures of the forearm have been reported since 2010, and retrospective studies have revealed a number of details. Clinicians should remember that bisphosphonates can affect all bony structures in the body. When an atypical fracture is misdiagnosed as an ordinary fracture and treated with surgical fixation, unexpected nonunion may occur. Therefore, the authors would like to share our experiences from the perspective of hand surgeons.

Long-term bisphosphonate therapy and atypical femoral fracture: Can you have too much of a good thing?

The long-term, continuous use of bisphosphonates (beyond 5 years) is not wholly without risk. Atypical femoral fracture is an uncommon but potentially very serious adverse event associated with the long-term use of bisphosphonates. Here we consider the complexities of long-term bisphosphonate prescribing, particularly in those that are low risk of osteoporotic fracture, wherein the duration of therapy should be reviewed regularly with individualised risk assessment to ensure the duration of treatment is appropriate.

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.

Atypical Fracture of Proximal Ulna Associated with Prolonged Bisphosphonate Therapy Managed with Nonoperative Treatment: A Case Report and Literature Review

Prolonged bisphosphonate (BP) treatment is associated with some complications, such as atypical femoral fractures (AFFs). Recent studies showed that atypical fractures also occurred in other bones, especially in the atypical fracture of the proximal ulna (AFPU). Although, AFPUs frequently share the same characteristics of atypical fractures as AFFs, such as fracture configuration and high risk of non-union, there is still limited evidence of the role of non-operative treatment in AFPU. The aim of the present study was to present an interesting case involving an 80-year-old female presented with non-displaced AFPU after receiving long-term BP medication and had been treated with a conservative method for 2.5 years, and to review the literature regarding the available AFPU treatment options. To the best of the authors’ knowledge, the present case report introduced new insight of the outcome of non-operative treatment for AFPU. Keywords: Non-displaced fracture; Ulna fracture; Long-term bisphosphonates; Conservative treatment; Nonunion; Osteoporosis

Serum biomarkers for bisphosphonate-related osteonecrosis of the jaw: a prospective clinical study.

Bisphosphonate-related osteonecrosis of the jaw (ONJ) is an adverse effect of long-term bisphosphonate therapy. This study aimed to identify bone biomarkers for ONJ risk assessment and diagnosis. This prospective study included patients with histories of bisphosphonate therapy without current ONJ who were in need of dentoalveolar surgery of the jaw area. Serum levels of 12 possible bone markers, selected based on their involvement in ONJ pathogenesis, were compared between ONJ and control groups before dentoalveolar surgery (T0), at 8 postoperative weeks (T1), and at 4months after diagnosis(T2). Seventy-six patients who met the inclusion criteria were included in the study; 33 were assigned to the ONJ group, and 43 patients without ONJ signs or symptoms after dentoalveolar surgery were assigned to the control group. In the ONJ group, at both T0 and T1, the mean tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) levels were significantly lower and the mean Dickkopf-related protein 1 (DKK1) levels were significantly higher than the corresponding values for the control group. Linear mixed model analysis revealed significant group effects over time for serum TRACP 5b and DKK1 after adjusting for demographic, pharmacological, and diagnostic variables. Lower serum levels of TRACP 5b under a specified cut-off value (≤ 2.899 U/L) at T0 indicated a 20.40-fold increased risk of ONJ development. Patients with abnormally low serum levels of TRACP 5b and high serum levels of DKK1 should be monitored closely before and after dentoalveolar surgery for the prevention and early diagnosis of ONJ.

Bone Nanomechanical Properties and Relationship to Bone Turnover and Architecture in Patients With Atypical Femur Fractures: A Prospective Nested Case-Control Study.

ABSTRACTAtypical femur fractures (AFFs) are well‐established serious complication of long‐term bisphosphonate and denosumab therapy in patients with osteopenia or osteoporosis. To elucidate underlying mechanism(s) for the development of AFF, we performed a nested case‐control study to investigate bone tissue nanomechanical properties and prevailing bone microstructure and tissue‐level remodeling status as assessed by bone histomorphometry. We hypothesized that there would be differences in nanomechanical properties between patients with and without AFF and that bone microstructure and remodeling would be related to nanomechanical properties. Thirty‐two full‐thickness transiliac bone biopsies were obtained from age‐ and sex‐matched patients on long‐term bisphosphonate therapy with (n = 16) and without an AFF (n = 16). Standard histomorphometric measurements were made in each sample on three different bone envelopes (cancellous, intracortical, and endosteal). Iliac bone wall thickness was significantly lower on all three bone surfaces in patients with AFF than in those without AFF. Surface‐based bone formation rate was suppressed similarly in both groups in comparison to healthy premenopausal and postmenopausal women, with no significant difference between the two groups. Nanoindentation was used to assess material properties of cortical and cancellous bone separately. Elastic modulus was higher in cortical than in cancellous bone in patients with AFF as well as compared to the elastic modulus of cortical bone from non‐AFF patients. However, the elastic modulus of the cancellous bone was not different between AFF and non‐AFF groups or between cortical and cancellous bone of non‐AFF patients. Resistance to plastic deformation was decreased in cortical bone in both AFF and non‐AFF groups compared to cancellous bone, but to a greater extent in AFF patients. We conclude that long‐term bisphosphonate therapy is associated with prolonged suppression of bone turnover resulting in altered cortical remodeling and tissue nanomechanical properties leading to AFF. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Fractures in Corticosteroid- and Bisphosphonate-treated Subjects With Longstanding Rheumatoid Arthritis

Background: Bisphosphonates are the most widely prescribed agents for the treatment of postmenopausal osteoporosis and other metabolic bone diseases. Atypical femoral fractures in bisphosphonate-treated patients have raised concerns regarding the long-term safety of this class of medications. Case Presentation: In this study, we report two patients suffering from fractures while receiving biphosphonates; a postmenopausal patient with rheumatoid arthritis and a history of long-term use of bisphosphonates and glucocorticoids presenting with multiple fractures as case one and another 52-year-old female patient diagnosed with Systemic Lupus Erythematosus (SLE) who suffered from a femoral shaft fracture without any history of prior traumatic incidents as case two. Conclusions: Considering the low risk for atypical femoral fractures, further careful screening for these types of fractures should be undertaken. In addition, in order to lower the rate of fractures in patients on long-term bisphosphonate therapy, assessment of patients’ contralateral side should be considered to prevent further fractures, especially in patients with prodromal pain.

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 Case of Teriparatide Use in Nonunion Atypical Ulnar Fracture

Background: Atypical upper limb fracture is a rare complication of bisphosphonate use. The management of nonunion fractures is challenging, especially in patients who are not surgical candidates. Teriparatide, a novel anabolic drug for osteoporosis has been increasingly used off-label for treatment of nonunion fractures and bisphosphonate related atypical fractures of the lower extremity. The proposed mechanism of healing is by enhancement of callus formation and mechanical strength. Clinical Case: A 72 year-old woman with a history of bilateral lower extremity paralysis and bilateral upper extremity paresis, who mobilized short distances with Canadian crutches, had been treated for 15 years with alendronate, for osteopenia associated with multiple risk factors for osteoporosis. 11 months before referral, and a month after alendronate was discontinued, she sustained a muscle-spasm induced fracture of the mid-shaft of the right ulna. She was treated nonoperatively due to chronic osteomyelitis with recurrent bacteremia from a prior non-healing left ulnar fracture (with internal fixation). Bone density of the right forearm had been normal. Since the right ulna break was transverse with minimal comminution, located in the diaphysis, occurred after trivial force and exhibited delayed healing, it was thought to be an atypical fracture secondary to bisphosphonates. She was initiated on cyclical teriparatide injection 20 mcg subcutaneously daily, with 2 months on and 2 weeks off. In one year, patient responded with dramatic radiographic improvement by forming a large callus with almost complete healing of the fracture. Conclusion: Mid-forearm atypical fracture from long-term bisphosphonate use is rare and is at risk for nonunion. The management of atypical upper limb nonunion fracture in nonoperative patients is not well established. Case reports exist of patients with atypical upper limb fracture who are either treated conservatively, or surgically with fixation/bone grafting +/- teriparatide. Our case showed that teriparatide, when used cyclically, exerted positive osteogenic effect and improved healing of the nonunion of an atypical fracture of forearm in a patient who continued weight bearing activity on her only functional limb.

Surgical Treatment for Bisphosphonate-related Atypical Femoral Fracture: A Systematic Review.

Atypical femoral fractures are the femoral fractures located anywhere between the lesser trochanter and the supracondylar flare of the femur. Long-term bisphosphonates, as the most common preventive and treatment medications for osteoporosis, are thought to have an important role in these fractures. Most of the fractures should be treated surgically, and the complications are considerable. We searched Medline, CENTRAL, Embase, and DART on February 26, 2020. One author reviewed and retrieved citations from these four databases for irrelevant and duplicate studies, and two other authors independently extracted data from the studies and rated their quality.Patients with surgical treatment of bisphosphonate-related atypical femoral fracture, according to the American Society for Bone and Mineral Research definition, were included. Animal studies, case reports, studies with high-energy trauma, pathological fracture, or malignancy-related fractures were excluded. In total, 316 patients (348 fractures) were included in this study. Mean age of patients was 70.47 years, and 97.5% of them were female. Duration of using bisphosphonates was 4.04 to 8.8 years, and Alendronate was the most common type. Moreover, 65.27% and 34.72% of the reported fractures were in diaphyseal and subtrochanteric, respectively. Moreover, the most common fixation type was intramedullary. Rate of complication was 17.52%, and the most frequent one was non-union, followed by implant failure. The main limitation of this research was that most of the studies did not have a high level of evidence. An increase in the rate of atypical femoral fracture with its challenging management makes it an important issue to be noted by orthopedic surgeons. Based on the results of this study, subtrochanteric fractures might have more complications post-operatively and are suggested to be operated on by more experienced surgeons. It was also found that extra-medullary fixation increases the risk of complications. Future studies on union time, outcomes of different surgical methods, and teriparatide therapy may help shed more light on the surgical management of these fractures.

Progression of atypical femur stress fracture after discontinuation of bisphosphonate therapy

Atypical femur fracture (AFF) is an uncommon complication of long-term bisphosphonate use, but the risk declines substantially after treatment cessation. We report a case of a 70-year-old woman with osteopenia treated with alendronate for 9 years who presented with right mid-thigh pain and radiographic findings of focal lateral cortical thickening in the right mid-femur and lateral cortex irregularity in the proximal-mid left femur. Alendronate was discontinued, but she remained on estrogen for menopausal symptoms. Four years later, a horizontal linear translucent defect was seen in the right mid-femur area of cortical hypertrophy, consistent with an incomplete AFF. The patient underwent prophylactic intramedullary rodding of the right femur and estrogen was discontinued. Three years later (7 years after initial presentation), the cortical irregularities in the left femur were more prominent and three small horizontal linear translucent defects were now evident, consistent with early incomplete atypical fracture development. The patient also suffered a wrist fracture. She was treated with teriparatide for 1.5 years with resolution of the translucent defects in the left but not the right femur, although abnormal thickening of the lateral cortex persisted in both femurs. Our case demonstrates incomplete atypical femur fracture progression in a patient with long-term bisphosphonate exposure, even after treatment cessation. These findings highlight the importance of follow-up for patients who develop diaphyseal femur stress fractures and the potential for early healing with anabolic therapy. This case also demonstrates the challenge in managing older patients with incomplete AFF at risk for progression to complete AFF and osteoporotic fracture.

Atypical femoral fracture after discontinuing long-term bisphosphonate use

Agents that slow bone resorption (antiresorptive) and increase bone formation (anabolic) are used as medical treatment modalities in osteoporosis. Bisphosphonates (BP) are antiresorptive drugs that suppress osteoclastic activity and slow bone resorption and are recommended to be used as first-line therapy in osteoporosis treatment guidelines. For two decades, these drugs have been prescribed in our country and worldwide to treat osteoporosis and reduce the risk of fractures. However, according to the literature, atypical femoral fractures (AFF) are encountered in patients who have been using these drugs for more than five years. In this case report, we present the diagnosis, treatment, and recovery process of a patient who developed AFF after discontinuing long-term use of BP.

Duration of Bisphosphonate Drug Holidays in Osteoporosis Patients: A Narrative Review of the Evidence and Considerations for Decision-Making.

Bisphosphonates are first-line therapy for osteoporosis, with alendronate, risedronate, and zoledronate as the main treatments used globally. After one year of therapy, bisphosphonates are retained in bone for extended periods with extended anti-fracture effects after discontinuation. Due to this continued fracture protection and the potential for rare adverse events associated with long-term use (atypical femoral fractures and osteonecrosis of the jaw), a drug holiday of two to three years is recommended for most patients after long-term bisphosphonate therapy. The recommendation for a drug holiday up to three years is derived primarily from extensions of pivotal trials with alendronate and zoledronate and select surrogate marker studies. However, certain factors may modify the duration of bisphosphonate effects on a drug holiday and warrant consideration when determining an appropriate time off-therapy. In this narrative review, we recall what is currently known about drug holidays and discuss what we believe to be the primary considerations and areas for future research regarding drug holiday duration: total bisphosphonate exposure, type of bisphosphonate used, bone mineral density and falls risk, and patient sex and body weight.

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.

Effect and timing of parathyroid hormone analog administration for preventing medication-related osteonecrosis of the jaws in a murine model

The aim of this study was to investigate the effect and timing of recombinant human parathyroid hormone analog (PTH) administration for preventing medication-related osteonecrosis of the jaws (MRONJ) using a murine model. After standardized MRONJ induction using zoledronic acid and dexamethasone injections, 48 female Sprague-Dawley rats were divided into four groups according to the timing of PTH administration before or after dental extraction. Rats were euthanized 3 weeks after dental extraction, followed by clinical and histologic analyses. No clinical improvements were observed in the preoperative and postoperative PTH groups, compared to controls (p = 0.638 and 0.496, respectively). However, on histological analysis, the number of empty lacunae reduced significantly, and the number of blood vessels increased in the preoperative PTH group (p = 0.004 and 0.002, respectively). The postoperative PTH group did not show significant differences for empty lacunae and blood vessels compared to controls (p = 0.075 and 0.194, respectively). The reduction in the empty lacunae and the increase in the blood vessels in the preoperative PTH group were significant compared to other groups, suggesting more viable bone tissue in this group.In perspective, preoperative PTH use may represent a better prophylactic regimen for preventing the occurrence of MRONJ after traumatic dental or surgical procedures, especially in patients with a history of long-term bisphosphonate administration or at high risk of developing MRONJ. However, the findings should be proven in further studies on other animals followed by clinical trials.

Early changes in bone turnover and bone mineral density after discontinuation of long-term oral bisphosphonates: a post hoc analysis.

The short-term effects of discontinuing long-term bisphosphonates are poorly characterized. This post hoc analysis investigated 1-12-month changes in bone mineral density (BMD) and bone turnover markers (BTM) after alendronate (ALN) discontinuation. Data were from a randomized, double-blind trial of MK-5442 (calcium-sensing receptor antagonist) following oral bisphosphonates, with placebo and continued ALN controls ( ClinicalTrials.gov NCT00996801). Postmenopausal women with osteoporosis had received oral bisphosphonate (≥ 3-4 preceding years; ALN for the 12 months pre-screening), continuing on ALN 70 mg/week (n = 87) or placebo (n = 88). At 12 months, least-squares mean percent changes from baseline BMD (placebo vs. ALN) were lumbar spine (LS): - 0.36 vs. 1.29, total hip: - 1.44 vs. 0.46, and femoral neck (FN): - 1.26 vs. - 0.08 (all P < 0.05). BTM levels increased by 1-3 months, to 12 months, with placebo vs. ALN (P < 0.001). FN BMD decline was greater in the placebo subgroup with higher urinary N-terminal cross-linked telopeptides of type I collagen/creatinine [uNTx/Cr] (P < 0.01), and higher serum N-terminal pro-peptide of type 1 collagen [P1NP] levels (P < 0.05), at baseline. There was a trend toward greater FN BMD loss with higher BTM levels at 3 and/or 6 months. Younger age and higher LS BMD at baseline were associated with greater LS BMD loss at 12 months (P = 0.04 and < 0.01, respectively); higher baseline FN BMD predicted greater FN BMD loss (P = 0.04). Early changes in BTM levels and BMD were observed after discontinuation of long-term ALN. Further characterization of factors associated with patients' risk of bone loss upon bisphosphonate discontinuation is warranted.