Dental implant treatment in patients with cancer on high-dose antiresorptive medication: A prospective feasibility study with 2 years follow-up.

OBJECTIVES: Dental implant treatment is considered contraindicated in patients with cancer on high-dose antiresorptive medication (HDAR). The aim of this prospective, feasibility study was to evaluate implant treatment in patients with cancer on HDAR, in terms of implant survival, implant success, and oral health-related quality of life (OHLQoL) after 2 years of loading. MATERIALS AND METHODS: Implants were inserted in three groups of HDAR patients: (1) Previous tooth extraction, no medication-related osteonecrosis of the jaw (MRONJ), (2) Previous MRONJ, now healed, (3) Existing MRONJ, planned surgical resection. Implants were placed without adjunctive bone or soft tissue argumentation. Abutment operation was performed after ≥12 weeks. Prosthetic treatment was initiated ≥14 weeks. Survival and success rate were determined, and OHLQoL was analyzed with OHIP-49 and QLQ-H&N35 questionnaires. Patients were seen for 6 months, 1- and 2 years follow-up. RESULTS: Twenty-two patients, 39 implants, completed the implant-based prosthetic treatment. Implant-supported crowns and overdentures were fabricated. Thirteen patients (59%) with 23 implants (59%) completed 2 years follow-up. Overall implant survival and success rate after 2 years of loading were 100% and 97.4%, respectively. OHLQoL for the patients increased in all groups after the treatment, a substantial increase was seen in group 3. Two patients developed MRONJ, but not related to the implant treatment. CONCLUSION: Dental implant treatment, with high survival and success rate and increased post-treatment OHLQoL, is feasible in HDAR patients after 2 years of loading. Caution with general recommendations should be exercised.

Effects of antiresorptive medications on tooth root formation and tooth eruption in paediatric patients.

Tooth eruption is a pivotal milestone for children's growth and development. This process involves with the formation of the tooth root, the periodontal ligament (PDL) and the alveolar bone, as the tooth crown penetrates the bone and gingiva to enter the oral cavity. This review aims to outline current knowledge of the adverse dental effects of antiresorptive medications. Recently, paediatric indications for antiresorptive medications, such as bisphosphonates (BPs), have emerged, and these agents are increasingly used in children and adolescents to cure pathological bone resorption associated with bone diseases and cancers. Since tooth eruption is accompanied by osteoclastic bone resorption, it is expected that the administration of antiresorptive medications during this period affects tooth development. Indeed, several articles studying human patient cohorts and animal models report the dental defects associated with the use of these antiresorptive medications. This review shows the summary of the possible factors related to tooth eruption and introduces the future research direction to understand the mechanisms underlying the dental defects caused by antiresorptive medications.

Effectiveness of denosumab for fracture prevention in real-world postmenopausal women with osteoporosis: a retrospective cohort study.

To determine denosumab's effectiveness for fracture prevention among postmenopausal women with osteoporosis in East Asia, the risk of fracture was compared between patients continuing denosumab therapy versus patients discontinuing denosumab after one dose. The real-world effectiveness was observed to be consistent with the efficacy demonstrated in the phase III trial. INTRODUCTION: After therapeutic efficacy is demonstrated for subjects in global clinical trials, real-world evidence may provide complementary knowledge of therapeutic effectiveness in a heterogeneous mix of patients seen in clinical practice. This retrospective cohort study was conducted to compare the fracture risk in real-world clinical care received in Taiwan and Hong Kong between a treatment cohort (patients receiving denosumab 60 mg subcutaneously every 6 months) versus an off-treatment cohort (patients discontinuing after 1 dose of denosumab, which has no known clinical benefit) among real-world postmenopausal women. METHODS: This study included 38,906 and 2,835 postmenopausal women receiving denosumab in Taiwan and Hong Kong, respectively. The primary endpoint was hip fracture, and secondary endpoints were clinical vertebral and nonvertebral fractures. Propensity-score-matched analysis, adjusting for known covariates, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The robustness of findings was evaluated with a series of sensitivity and quantitative bias analyses. RESULTS: In this study, 554 hip fractures were included in the primary Taiwan population analysis. The crude incidence rate was 0.9 per 100 person-years in the treatment cohort (n = 25,059) and 1.7 per 100 person-years in the off-treatment cohort (n = 13,847). After adjusting for prognostic differences between cohorts, denosumab reduced the risk of hip fractures by 38% (HR = 0.62, CI:0.52-0.75). Risk reductions of similar magnitude were observed for the secondary endpoints and for the analysis of the smaller Hong Kong population. CONCLUSION: The effectiveness of denosumab for fracture reduction among real-world postmenopausal women with osteoporosis was consistent with the efficacy demonstrated in a global clinical trial. REGISTRATION: EnCePP registration number: EUPAS26372; registration date: 12/11/2018.

Medical treatment of osteoporosis.

Osteoporosis is a common chronic condition that markedly increases the risk of fractures. Osteoporotic-related fractures increase morbidity and mortality and impair quality of life. Therefore, a correct approach for fracture prevention seems mandatory. Lifestyle changes should be recommended to all patients, including weight reduction if patients are obese/overweight, increasing physical activity and avoiding alcohol consumption and smoking. Additionally, calcium and vitamin D3 should be prescribed until the vitamin D deficit is resolved. Osteoporosis treatment options mainly include antiresorptives (i.e. estrogens, selective estrogen receptor modulators, bisphosphonates, denosumab) and anabolic agents (i.e. teriparatide, abaloparatide, romosozumab). Although presenting differences in efficacy and side effects, they have all been shown to increase bone mineral density (BMD) and to reduce osteoporotic-related fractures. Monotherapy with antiresorptive agents, particularly oral bisphosphonates, should be considered routinely as the first option for treatment of postmenopausal women. However, in the case of side effects, therapeutic failure or the need for long-term use, anabolic agents may be considered. In high-risk patients, anabolic agents may be considered as an initial therapeutic option. The combination of antiresorptive and anabolic agents may be useful to increase BMD compared with monotherapy, but more information is warranted to determine the effects on fracture risk.

Antiresorptive therapy and dental implant survival: an up to 20-year retrospective cohort study in women.

OBJECTIVES: To investigate the effects of antiresorptive treatment on the survival of plateau-root form dental implants. MATERIALS AND METHODS: Patients undergoing antiresorptive therapy via oral or intravenous administration as well as patients not undergoing antiresorptive therapy and healthy control patients were included in this retrospective cohort study. In total, 1472 implants placed in 631 postmenopausal patients (M: 66.42 ± 9.10 years old), who were followed for a period of up to 20 years (8.78 ± 5.68 years). Kaplan-Meier survival analysis was performed, and univariate and multivariate Cox regression, clustered by each patient, was used to evaluate and study factors affecting the survival of their implants. RESULTS: Implants placed in patients undergoing oral antiresorptive treatment presented significantly higher survival rates, than implants placed in the osteoporosis/osteopenia control cohort (p value < 0.001), and similar survival rates, when compared to healthy controls (p value = 0.03). Additionally, clustered univariate and multivariate Cox regression analysis also revealed higher implant survival when oral antiresorptive drugs (p value = 0.01 and 0.007, respectively) were used, and lower implant survival in the presence of untreated osteoporosis/osteopenia (p value = 0.002 and 0.005, respectively). Overall, the 20-year implant survival in osteoporotic patients undergoing antiresorptive therapy was 94%. For the failed implants, newly replaced implants in patients under antiresorptive treatment presented a 10-year survival of 89%. CONCLUSIONS: Long-term plateau-root form implant survival in osteoporotic patients taking oral antiresorptives was similar to a healthy population and significantly higher than the untreated controls. CLINICAL RELEVANCE: These results suggest that plateau-root form implants provide a robust solution for treating tooth loss in patients, who are undergoing antiresorptive therapy.

Osteoporosis and Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD): Back to Basics.

Osteoporosis is defined as a skeletal disorder of compromised bone strength predisposing those affected to an elevated risk of fracture. However, based on bone histology, osteoporosis is only part of a spectrum of skeletal complications that includes osteomalacia and the various forms of renal osteodystrophy of chronic kidney disease-mineral and bone disorder (CKD-MBD). In addition, the label "kidney-induced osteoporosis" has been proposed, even though the changes caused by CKD do not qualify as osteoporosis by the histological diagnosis. It is clear, therefore, that such terminology may not be helpful diagnostically or in making treatment decisions. A new label, "CKD-MBD/osteoporosis" could be a more appropriate term because it brings osteoporosis under the official label of CKD-MBD. Neither laboratory nor noninvasive diagnostic investigations can discriminate osteoporosis from the several forms of renal osteodystrophy. Transiliac crest bone biopsy can make the diagnosis of osteoporosis by exclusion of other kidney-associated bone diseases, but its availability is limited. Recently, a classification of metabolic bone diseases based on bone turnover, from low to high, together with mineralization and bone volume, has been proposed. Therapeutically, no antifracture treatments have been approved by the US Food and Drug Administration for patients with kidney-associated bone disease. Agents that suppress parathyroid hormone (vitamin D analogues and calcimimetics) are used to treat hyperparathyroid bone disease. Antiresorptive and osteoanabolic agents approved for osteoporosis are being used off-label to treat CKD stages 3b-5 in high-risk patients. It has now been suggested that intermittent administration of parathyroid hormone as early as CKD stage 2 could be an effective management strategy. If confirmed in clinical trials, it could mitigate the retention of phosphorus and subsequently the rise in fibroblast growth factor 23 and may be beneficial for coexisting osteoporosis.

Fracture rates in patients discontinuing alendronate treatment in real life: a population-based cohort study.

In this nationwide register-based cohort study, we found no difference in the risk of fractures in patients discontinuing versus continuing alendronate (ALN) treatment after 5 years. INTRODUCTION: Information on fracture risk in patients discontinuing ALN in a real-life setting is sparse. We aimed to examine ALN discontinuation patterns, compare fracture rates in patients discontinuing versus continuing ALN after 5 years of treatment, and define determinants of fractures in ALN discontinuers. METHODS: A nationwide population-based cohort study using Danish health registry data. Our source population was individuals who had redeemed ≥ 2 ALN prescriptions between January 1, 1995, and September 1, 2017. RESULTS: We found that 25% of all ALN initiators used ALN for less than 1 year and 43% continued treatment for at least 5 years. We classified n = 1865 as ALN discontinuers and n = 29,619 as ALN continuers. Using Cox proportional hazards regression analysis and an "as-treated" approach, we observed no increased risk of any fracture (incidence rate ratio (IRR) 1.06, 95% CI 0.92-1.23), vertebral fracture (IRR 0.59, 95% CI 0.33-1.05), hip fracture (IRR 1.04, 95% CI 0.75-1.45), or major osteoporotic fracture (IRR 1.05, 95% CI 0.88-1.25) in the ALN discontinuers compared to continuers during a follow-up time of 1.84 ± 1.56 years (mean ± SD) and 2.51 ± 1.60 years, respectively. ALN re-initiation was a major determinant of follow-up among the discontinuers. Old age (> 80 vs. 50-60 years, unadjusted IRR 2.92, 95% CI 1.18-7.24) was the strongest determinant for fractures following ALN discontinuation. CONCLUSION: In a real-world setting, less than 50% continued ALN treatment for 5 years. We found no difference in the risk of fractures in patients discontinuing versus continuing ALN after 5 years.

The predictive value of bone turnover markers during discontinuation of alendronate: the PROSA study.

In patients discontinuing ALN after a median of 7.0 years (range 5.0-20.0 years), BMD decreased, and bone turnover markers increased within the premenopausal reference range over 2 years. Increased p-CTX after 3 months was associated with greater bone loss at the hip confirming that maintenance of BMD is dependent on continued suppression of bone turnover. INTRODUCTION: It is unknown how to monitor patients discontinuing alendronate (ALN) after more than 5 years. We investigated if BTM measured before or during treatment discontinuation with ALN predict bone loss after 1 or 2 years. METHODS: PROSA was a cohort study conducted at Aarhus University Hospital including postmenopausal women and men above 50 years treated with ALN ≥ 5 years who had osteopenia at the hip and BMD T-score at the lumbar spine > - 4. ALN was discontinued and BTMs were measured at baseline, months (M) 1, 3, 6, and 12, and DXA was performed at baseline, M6, and M12. We extended the study and measured BTMs and performed DXA at M24. The primary endpoint was if changes in p-CTX at M3 or M6 predict changes in THBMD after 1 year ( Clinicaltrials.gov : NCT03051620). RESULTS: We enrolled 136 participants discontinuing ALN after a median of 7.0 years (range 5.0-20.0 years) in PROSA and 124 participants in PROSA Extension. There was a significant decrease in LSBMD - 0.74% ± 0.27, THBMD - 2.65% ± 0.39, FNBMD - 2.35% ± 0.33, and trabecular bone score - 0.97% ± 0.35 and an increase in p-CTX by 61.1% ± 4.7 (p < 0.05 for all) after 24 months. Increase in p-CTX at M3 was associated with bone loss at the hip sites at M12 and M24. CONCLUSION: In patients discontinuing ALN, BMD decreased significantly and BTMs increased within the reference range over 2 years. An increase in p-CTX after 3 months was associated with greater bone loss at the hip confirming that maintenance of BMD during treatment discontinuation is dependent on continued suppression of bone turnover.

Bone Density After Teriparatide Discontinuation With or Without Antiresorptive Therapy in Pregnancy- and Lactation-Associated Osteoporosis.

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare and severe disorder that causes low-trauma or spontaneous fractures, most commonly multiple vertebral fractures, in the late pregnancy or lactation period [1]. In severe PLO, teriparatide (TPTD) might aid in bone mineral density (BMD) recovery and subsequent fracture risk reduction. However, it is unclear whether TPTD can be discontinued without sequential antiresorptive therapy (ART) in premenopausal women with PLO. In this retrospective cohort study, we investigated the changes in BMD in premenopausal women with PLO treated with TPTD 20 mcg daily with or without sequential ART. Data for 67 patients diagnosed with PLO from 2007 through 2017 were reviewed. Among 43 women with annual follow-up dual-energy X-ray absorptiometry data for 3 years, 33 were treated with TPTD (median 12 months) with (TPTD-ART, n = 13; median, 18 months) or without (TPTD-no ART, n = 20) sequential ART. The two groups showed no differences in the mean age (31 vs. 31 years), body mass index (BMI, 20.5 vs. 21.0 kg/m2), and baseline lumbar spine (LS) BMD (0.666 vs. 0.707 g/cm2; p > 0.05 for all). LSBMD increased at 1, 2, and 3 years from baseline in both the TPTD-ART (14.1%, 21.8%, and 24.0%, respectively) and TPTD-no ART (17.3%, 24.1%, and 23.4%, respectively) groups, without significant between-group differences. Similar results were observed for the total hip BMD. LSBMD gain at 3 years did not differ by ART use (adjusted ß, 0.40; p = 0.874) in univariable and multivariable models adjusted for age, BMI, and baseline LSBMD. In summary, BMD gain by TPTD administration in premenopausal women with PLO can be well maintained without sequential ART treatment.

Effect of periosteal reaction in medication-related osteonecrosis of the jaw on treatment outcome after surgery.

INTRODUCTION: Surgical treatment in patients with medication-related osteonecrosis of the jaw (MRONJ) is superior to conservative treatment. However, treatment outcome in patients with periosteal reaction (PR) was significantly poorer than that of those without PR. The purpose of this retrospective study was to analyze the pathophysiology and clinical significance of PR in MRONJ. MATERIALS AND METHODS: Out of 181 patients with MRONJ undergoing surgery, 38 patients with PR were enrolled in the study. CT examinations, histological examinations, and bacteriological examinations using real-time polymerase chain reaction were performed, and the relationship among the opted surgical method, CT findings, and treatment outcome was investigated. RESULTS: The pattern of PR was classified into three types: type 1, new bone is formed parallel to the mandible, and no gap was evident between the mandible and new bone; type 2, new bone is formed parallel to the mandible, and a gap was evident between them; type 3, an irregular shape. Histological examinations revealed inflammatory tissue in the area visualized as a gap on CT. Bacteriological examination showed the presence of bacteria in the type 2 or type 3 PR. Complete cure was observed in 21 of 38 (55.3%) patients, which was lower than the cure rate of 73.4% in 143 patients without PR. The cure rate was significantly lower in cases with type 3 PR or with persistent osteolysis. CONCLUSIONS: It seems that complete resection of both osteolytic area and type 3 PR is necessary to obtain complete healing in patients undergoing marginal mandibulectomy.

Consensus Statement on the Use of Bone Turnover Markers for Short-Term Monitoring of Osteoporosis Treatment in the Asia-Pacific Region.

Osteoporosis is a major health issue. By 2050, a greater than 2-fold increase in patients number with hip fractures will occur in Asia representing 50% of all hip fractures worldwide. For the Asia-Pacific (AP) region, more efforts on controlling osteoporosis and the subsequent fractures are crucial. Bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) is commonly used to diagnose osteoporosis and monitor osteoporosis treatment. However, the inconvenience, cost, limited availability of DXA and the delay in detection of BMD changes after treatment initiation support an important role for bone turnover markers (BTMs), as short-term tools to monitor therapy. With regards to low adherence rates of medical treatment of osteoporosis, the experts reached consensus on the use of BTMs for both raising awareness and short-term monitoring of osteoporosis treatment in the AP region. The experts endorse the use of BTMs, especially serum C-terminal telopeptide of type 1 collagen (CTX) and serum procollagen type 1 N propeptide (P1NP), as short-term monitoring tools to help clinicians assess the responses to osteoporosis therapies and appropriately adjust treatment regimens earlier than BMD. Either the absolute values or the degree of change from baseline in BTMs can be used to monitor the potential efficacy of osteoporosis therapies. The use of BTMs can be incorporated in osteoporosis care programs, such as fracture liaison service (FLS), to improve patient adherence and treatment outcomes. Encouraging sufficient reimbursement from health care systems may facilitate widespread use of BTMs in clinical practice in the AP region.

Protocatechualdehyde inhibits receptor activator of nuclear factor kappa-B ligand-induced osteoclastogenesis and attenuates lipopolysaccharide-induced inflammatory osteolysis.

Inflammatory osteolysis as a consequence of chronic bacterial infection underlies several lytic bone conditions, such as otitis media, osteomyelitis, septic arthritis, periodontitis, periprosthetic infection, and aseptic loosening of orthopedic implants. In consideration of the lack of effective preventive or treatments options against infectious osteolysis, the exploitation of novel pharmacological compounds/agents is critically required. The present study assessed the effect of protocatechualdehyde (PCA), a natural occurring polyphenolic compound with diverse biological activities including but not limited to antibacterial and antiinflammatory properties, on nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in vitro and lipopolysaccharide (LPS)-induced bone loss in vivo. In the present study, it was found that PCA potently inhibited RANKL-induced osteoclast formation, fusion, and activation toward bone resorption in a dose-dependent manner via the suppression of the ERK/c-Fos/nuclear factor of activated T-cells, cytoplasmic 1 signaling axis. It was further demonstrated that the in vivo administration of PCA could effectively protect mice against the deleterious effects of LPS-induced calvarial bone destruction by attenuating osteoclast formation and activity in a dose-dependent manner. Collectively, these findings provided evidence for the potential therapeutic application of PCA in the prevention and treatment of infectious osteolytic conditions, and potentially other osteoclast-mediated bone diseases.

Zoledronate Causes a Systemic Shift of Macrophage Polarization towards M1 In Vivo.

BACKGROUND: Immunomodulatory properties of bisphosphonates (BP) are suggested to contribute to the development of medication-associated osteonecrosis of the jaw (MRONJ). Furthermore, bisphosphonate-derived immune modulation might contribute to the anti-metastatic effect observed in breast cancer patients. Macrophages are potential candidates for the mediation of immunomodulatory effects of bisphosphonates. The study aimed to investigate the influence of bisphosphonates alone and in combination with surgical trauma on systemic macrophage polarization (M1 vs. M2) using an in vivo rat model. METHODS: A total of 120 animals were divided into four groups. Groups 2 and 4 were treated with 8 × 40 µg/kg body weight of the BP Zoledronate i.p. (week 0-7). Groups 3 and 4 were exposed to surgical trauma (week 8, tooth extraction + tibia fracture), whereas in Group 1 neither medication nor surgical trauma was applied. After 8, 10, 12 and 16 weeks, skin, lung and spleen were immunohistochemically examined for macrophage polarization via expression analysis of CD68, CD163 and iNOS using a tissue microarray (TMA). RESULTS: A significant shift of macrophage polarization towards M1 was observed in skin, spleen and lung tissue of animals, with and without surgical trauma, treated with BP when compared to those without BP application. Surgical trauma did not cause a significant increase towards M1 polarization. CONCLUSIONS: BP application leads to a systemic pro-inflammatory situation in vivo, independent of surgical trauma, as evidenced by the shift in macrophage polarization towards M1 in various somatic tissues. This provides a possible explanation for the clinically observed anti-tumor effect of bisphosphonates and might also contribute to pathogenesis of MRONJ.

Effects of anti-resorptive drugs on implant survival and peri-implantitis in patients with existing osseointegrated dental implants: a retrospective cohort study.

The effect of anti-resorptive drug (ARD) usage among patients with successful dental implant osseointegration is controversial. This study showed an increased risk of implant failure in ARD users. Risk factors included pre-existing marginal bone loss, overdenture, diabetes, and a short interval between implant placement and ARD administration. INTRODUCTION: This retrospective study aimed to determine whether anti-resorptive drug (ARD) usage increased risk of implant failure among patients with successful implant osseointegration. Additionally, the study investigated risk factors that affected implant survival rate in ARD users. METHODS: Eighty ARD users with 344 implants who had more than 12 months of follow-up from the initiation of ARD treatment during the period between 2008 and 2017 were included, along with 80 non-ARD users from the same period. The primary outcome was dental implant survival. Kaplan-Meier survival curves and Cox proportional hazard models were used for survival analysis. RESULTS: Average follow-up was 85.3 months. Implant survival rates were 89.83% in ARD users and 96.03% in non-ARD users. In the univariate Cox proportional hazard model, risk of implant failure was significantly higher in patients with pre-existing marginal bone loss (MBL), diabetes, and concurrent bone augmentation. However, risk of implant failure was significantly lower when the interval between implant placement and ARD administration was < 36 months. Compared with overdenture, single crown and fixed splinted users had lower risk of implant failure. In multivariate analysis, variables including pre-existing MBL, diabetes, < 36-month interval between implant placement and ARD treatment, and usage of fixed splinted prosthesis were significantly associated with increased risk of implant failure. CONCLUSIONS: ARD administration after implant osseointegration was correlated with a reduced implant survival rate. Pre-existing MBL, diabetes, type of final prosthesis, and the interval between implant placement and initiation of ARD administration influenced risk of implant failure.

Change in Quantitative Ultrasound-assessed Speed of Sound as a Function of Age in Women and Men and Association With the Use of Antiresorptive Agents: The Canadian Multicentre Osteoporosis Study.

INTRODUCTION: Five-year changes in multisite quantitative ultrasound-assessed speed of sound (SOS in m/s) were studied in a cohort of women and men. The impacts of antiresorptive therapies and menopausal status on SOS were also assessed. METHODOLOGY: Two SOS assessments, clinical assessments, and comprehensive questionnaires were completed 5 years apart on 509 women and 211 men. Age at first assessment was grouped into: <40 yr, 40-49 yr, 50-59 yr, 60-69 yr, 70-79 yr and 80+ yr. Mean rate of change in SOS at the distal radius and tibia were calculated for each age grouping by sex. SOS changes were stratified by antiresorptive use (yes, no) or menopausal status (premenopausal, postmenopausal, or bilateral oophorectomy). RESULTS: Mean losses in SOS occurred over the 5 years in almost all age groupings. In women, mean losses in SOS for the <40 yr, 40-49 yr, 50-59 yr, 60-69 yr, 70-79 yr, and 80+ yr age groupings were -59, -83, -107, -92, -80 and -66 (p = 0.30; differences among age groupings) at the radius and -18, -16, -54, -1, -9 and 31 at the tibia (p < 0.05), respectively. In men, mean SOS losses were -101, -56, -69, -67, -83 and -127 at the radius (p = 0.61) and -46, -61, 0, -35, -29, and -26 at the tibia (p = 0.23). At the tibia, women prescribed antiresorptives had a mean increase in SOS (8.6 m/s) whereas untreated participants had a mean loss (-23.0; p < 0.001); there was no significant impact at the distal radius. There were no significant differences in change in SOS among menopausal groups (p > 0.26). CONCLUSIONS: Mean SOS generally declined over 5 years in all age groupings of both sexes. The consistent mean losses in SOS over the age spans investigated are coincident with increasing fracture risk. Women on antiresorptive therapy had increased mean SOS over the 5-year assessment period at the tibia, whereas untreated women had mean losses in SOS.

Reduced Bone Modeling and Unbalanced Bone Remodeling: Targets for Antiresorptive and Anabolic Therapy.

Bone loss during advancing age is the net result of reduced modeling-based bone formation upon the outer (periosteal) envelope and unbalanced remodeling by basic multicellular units (BMUs) upon the three (intracortical, endocortical, and trabecular) components of the inner (endosteal) bone envelope. Each BMU deposits less bone than resorbed, reducing total bone volume and deteriorating the microstructure of the diminished residual bone volume.Antiresorptive agents like bisphosphonates reduce, but do not abolish, the rate of bone remodeling - fewer BMUs remodel, "turn over," the volume of bone. Residual unbalanced remodeling continues to slowly reduce total bone volume and deteriorate bone microstructure. By contrast, denosumab virtually abolishes remodeling so the decrease in bone volume and the deterioration in microstructure cease. The less remodeled matrix remains, leaving more time to complete the slow process of secondary mineralization which reduces the heterogeneity of matrix mineralization and allows it to become glycosylated, changes that may make the smaller and microstructurally deteriorated bone volume more brittle. Neither class of antiresorptive restores bone volume or its microstructure, despite increases in bone mineral density misleadingly suggesting otherwise. Nevertheless, these agents reduce vertebral and hip fractures by 50-60% but only reduce nonvertebral fractures by 20-30%.Restoring bone volume, microstructure, and material composition, "curing" bone fragility, may be partly achieved using anabolic therapy. Teriparatide, and probably abaloparatide, produce mainly remodeling-based bone formation by acting on BMUs existing in their resorption, reversal, or formation phase at the time of treatment and by promoting bone formation in newly initiated BMUs. Romosozumab produces modeling-based bone formation almost exclusively and decreases the surface extent of bone resorption. All three anabolic agents reduce vertebral fracture risk relative to untreated controls; parathyroid hormone 1-34 and romosozumab reduce vertebral fracture risk more greatly than risedronate or alendronate, respectively. Evidence for nonvertebral or hip fracture risk reduction relative to untreated or antiresorptive-treated controls is lacking or inconsistent. Only one study suggests sequential romosozumab followed by alendronate reduces vertebral, nonvertebral, and hip fracture risk compared to continuous alendronate alone. Whether combined antiresorptive and anabolic therapy result in superior fracture risk reduction than monotherapy is untested.

Incidence of osteonecrosis of the jaw in Japanese osteoporosis patients taking minodronic acid.

Osteonecrosis of the jaw (ONJ) associated with bisphosphonate therapy is a rare but severe side effect in osteoporosis patients. Recently, the number of osteoporosis patients with ONJ has dramatically increased in Japan. This has contributed to an increase in the number of patients avoiding extractions. However, there has been no prospective study providing definitive incidence data for ONJ in Japanese patients. The purpose of this study was to elucidate the true as well as suspected incidence of ONJ. A total of 3229 subjects (1612 subjects in the minodronic acid group and 1617 subjects in the raloxifene group) in the Japanese Osteoporosis Intervention Trial protocol number 4 participated in this study. ONJ was diagnosed by experienced dentists. Suspected Stage 0 and 1 (bone exposure of the jaw) ONJ was assessed by a structured questionnaire at baseline and at 6, 12, 18, and 24 months. No established ONJ cases were diagnosed during the study. The incidence of suspected Stage 0 and/or Stage 1 ONJ was 6.14 per 1000 patient-years in the minodronic acid group and 3.38 per 1000 patient-years in the raloxifene group [hazard ratio (95% confidence interval) = 1.82 (0.84-3.93), P = 0.13]. Approximately 50-60% of bone exposures that appeared during the study had disappeared at the next observation. Although the subjects in this study may have developed a greater interest in the health of the oral cavity, the incidence of ONJ after minodronic acid treatment would be lower than the expected incident rate.

Zoledronate treatment duration is linked to bisphosphonate-related osteonecrosis of the jaw prevalence in rice rats with generalized periodontitis.

OBJECTIVES: To determine the extent that zoledronate (ZOL) dose and duration is associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ) prevalence in rice rats with generalized periodontitis (PD), characterize structural and tissue-level features of BRONJ-like lesions in this model, and examine the specific anti-resorptive role of ZOL in BRONJ. MATERIALS AND METHODS: Rice rats (n = 228) consumed high sucrose-casein diet to enhance generalized PD. Groups of rats received 0, 8, 20, 50 or 125 µg/kg IV ZOL/4 weeks encompassing osteoporosis and oncology ZOL doses. Rats from each dose group (n = 9-16) were necropsied after 12, 18, 24 and 30 weeks of treatment. BRONJ-like lesion prevalence and tissue-level features were assessed grossly, histopathologically and by MicroCT. ZOL bone turnover effects were assessed by femoral peripheral quantitative computed tomography, serum bone turnover marker ELISAs and osteoclast immunolabelling. RESULTS: Prevalence of BRONJ-like lesions was significantly associated with (a) ZOL treatment duration, but plateaued at the lowest oncologic dose, and (b) there was a similar dose-related plateau in the systemic anti-resorptive effect of ZOL. ZOL and BRONJ-like lesions also altered the structural and tissue-level features of the jaw. CONCLUSION: The relationship between BRONJ-like lesion prevalence and ZOL dose and duration varies depending on the co- or pre-existing oral risk factor. At clinically relevant doses of ZOL, BRONJ-like lesions are associated with anti-resorptive activity.

Effects of bone remodeling agents following teriparatide treatment.

Teriparatide is an anabolic therapy used to treat patients with osteoporosis and is only approved for 2 years of treatment. This is the first study to look at two common osteoporosis drugs in maintaining its beneficial effects: denosumab and zoledronic acid. Denosumab treatment was associated with the greatest increase in bone mineral density (BMD) at the femoral neck and lumbar spine, an amount that was statistically greater than no treatment and zoledronic acid treatment. INTRODUCTION: Teriparatide, a hallmark treatment for osteoporosis, has been shown to increase BMD and bone turnover. This can be measured using BMD scans, N-terminal propeptide of type-1 collagen (P1NP) for bone formation and C-terminal telopeptide (CTX) for bone resorption. This study examines the effects of the two most common antiresorptive drugs prescribed following 2 years of teriparatide treatment: zoledronic acid and denosumab. The purpose of this study is to quantify the beneficial effects of teriparatide and compare the ability of each antiresorptive drug to maintain the effects. METHODS: Ninety-four patients with prior fragility fractures were identified from a bone health clinic associated with a level I trauma center. All of the study participants completed 2 years of treatment with teriparatide between 2008 and 2013 followed by 2 years of treatment with zoledronic acid, denosumab, or no treatment. After excluding patients with insufficient laboratory data, 64 patients remained for analysis in this retrospective cohort study. Bone mineral density was measured in the lumbar spine and femoral neck. RESULTS: Following completion of teriparatide, patients who were started on denosumab showed the largest increase in bone mineral density after 2 years of treatment: lumbar spine 4.94% ± 8.2%, femoral neck 5.68% ± 6.7%. CONCLUSIONS: Patients who elected to discontinue osteoporosis treatment experienced a significant decline in the change in BMD compared to the change on teriparatide putting them at higher risk for recurrence of fragility fractures. Patients on denosumab following teriparatide had the largest increase in BMD.

Bone Loss After Romosozumab/Denosumab: Effects of Bisphosphonates.

Romosozumab and denosumab are monoclonal antibodies for the treatment of osteoporosis. Both have a rapid offset of effect resulting in loss of bone density (BMD) gained on-treatment and, in some cases, multiple vertebral fractures following treatment cessation. We recently reported disappointing results from transitioning patients from denosumab to intravenous zoledronate at the time the next denosumab injection is due. The present report re-assesses the role of bisphosphonates following the use of denosumab. In the FRAME trial, osteoporotic women were randomized to romosozumab or placebo for 1 year, then both groups were provided with open-label denosumab for the subsequent 2 years. In women completing this study at our center, we offered treatment with either oral or intravenous bisphosphonates. In the eleven women opting for intravenous treatment, zoledronate was given after a median delay of 65 days from trial-end, in the hope that this might increase skeletal uptake of the drug and, thereby, its efficacy to maintain bone density. In these women, spine BMD was 17.3% above baseline at trial-end, and still 12.3% above baseline a year later, a 73% (CI: 61%, 85%) retention of the treatment benefit. The comparable BMD figures for the total hip were 10.7 and 9.2% above baseline, a 87% (CI: 77%, 98%) retention of treatment effect. In contrast, those not receiving treatment after the conclusion of the FRAME trial lost 80-90% of the BMD gained on-trial in the following 12 months. Women treated with risedronate showed an intermediate response. In the zoledronate group, mean PINP 6 months post-FRAME was 23 ± 4 µg/L and at 12 months it was 47 ± 8 µg/L, suggesting that repeat zoledronate dosing is needed at 1 year to maintain the BMD gains. In conclusion, delaying administration of intravenous bisphosphonate when transitioning from short-term denosumab appears to increase the extent to which the gains in BMD are maintained.