Background Hypoparathyroidism (HypoPT) is characterized by low serum calcium due to insufficient parathyroid hormone (PTH). This manuscript builds upon the 2022 international HypoPT guidelines and three systematic reviews, which have been further informed by updated narrative reviews and expert consensus. This paper presents current best practice consensus recommendations for the diagnosis and management of HypoPT. Methods An International Panel of Experts updated the previous systematic reviews (SR's), conducted narrative reviews, developed, and subsequently approved these best practice recommendations at the Parathyroid Summit, held as a pre-Endocrine Society meeting in May 2024 (Boston, USA). Results Diagnostic criteria for chronic HypoPT require hypocalcemia with inappropriately normal or low PTH levels. Conventional therapy is recommended as first line therapy and includes calcium supplementation, active vitamin D, correction of vitamin D inadequacy and correction of abnormalities in serum magnesium. Monitoring is required to achieve optimal serum calcium while avoiding hyperphosphatemia, hypercalciuria and declines in renal function. Assessment of HypoPT complications is required including skeletal health assessment in postmenopausal women and men over the age of 50 years. Specific strategies are provided for managing HypoPT during pregnancy and lactation as well as in children. PTH replacement with palopegteriparatide has been approved and is an important therapeutic option, especially when conventional therapy is inadequate or not tolerated. Conclusion These best practice recommendations provide a framework for HypoPT diagnosis and management, emphasizing individualized care, role of DNA analysis in the diagnosis of nonsurgical HypoPT, and role of PTH or PTH analogue therapy as appropriate. They complement the 2022 international guidelines and incorporate updated therapeutic recommendations from the past 3 years including the positioning of the newly approved molecule palopegteriparatide based on recent clinical trial data and expert consensus.

INTRODUCTION:Urolithiasis is a common complication of primary hyperparathyroidism (PHPT). Parathyroidectomy has been shown to decrease the rate of stone formation. The purpose of this study was to evaluate healthcare resource utilization before and after parathyroidectomy and identify predictors of increased healthcare utilization. METHODS:A retrospective analysis of patients who had a parathyroidectomy for PHPT in Nova Scotia from 2013-2018 was performed. Data from five years before parathyroidectomy to three years after were included. Outcomes included emergency department (ED) visits and the number of urologic interventions. Random-effects Poisson regression models were used to calculate the primary outcomes, ED visits, and the number of urologic interventions while adjusting for prespecified characteristics. RESULTS:Fifty patients (62% female) with a mean age of 60±11 years were identified. ED visits were 0.42 per year before parathyroidectomy and 0.20 per year after in a multivariate analysis (incidence rate ratio [IRR] 0.48, confidence interval [CI] 0.25-0.91, p=0.024). There was no statistical difference between male and female ED visits (p=0.6719). There was no difference in the rate of ED visits for non-urologic reasons after parathyroidectomy (p=0.0749). The incidence of urologic intervention for stones was 1.24 per year before parathyroidectomy and 0.53 per year after (IRR 0.42, CI 0.26-0.68, p=0.0005). CONCLUSIONS:Healthcare resource utilization, in terms of ED visits and urologic intervention, significantly decreased after parathyroidectomy. Sex showed no statistical difference in predicting healthcare utilization, while non-urologic ED visits remained the same after surgery. Expedited parathyroidectomy for PHPT patients may decrease urologic interventions and ED visits, resulting in less healthcare utilization.

Introduction: Urolithiasis is a common complication of primary hyperparathyroidism (PHPT). Parathyroidectomy has been shown to decrease the rate of stone formation. The purpose of this study was to evaluate healthcare resource utilization before and after parathyroidectomy and identify predictors of increased healthcare utilization. Methods: A retrospective analysis of patients who had a parathyroidectomy for PHPT in Nova Scotia from 2013–2018 was performed. Data from five years before parathyroidectomy to three years after were included. Outcomes included emergency department (ED) visits and the number of urologic interventions. Random-effects Poisson regression models were used to calculate the primary outcomes, ED visits, and the number of urologic interventions while adjusting for prespecified characteristics. Results: Fifty patients (62% female) with a mean age of 60±11 years were identified. ED visits were 0.42 per year before parathyroidectomy and 0.20 per year after in a multivariate analysis (incidence rate ratio [IRR] 0.48, confidence interval [CI] 0.25–0.91, p=0.024). There was no statistical difference between male and female ED visits (p=0.6719). There was no difference in the rate of ED visits for non-urologic reasons after parathyroidectomy (p=0.0749). The incidence of urologic intervention for stones was 1.24 per year before parathyroidectomy and 0.53 per year after (IRR 0.42, CI 0.26–0.68, p=0.0005). Conclusions: Healthcare resource utilization, in terms of ED visits and urologic intervention significantly decreased after parathyroidectomy. Sex showed no statistical difference in predicting healthcare utilization, while non-urologic ED visits remained the same after surgery. Expedited parathyroidectomy for PHPT patients may decrease urologic interventions and ED visits, resulting in less healthcare utilization.

Sedentary behavior (SB) or sitting is associated with multiple unfavorable health outcomes. Bone tissue responds to imposed gravitational and muscular strain with there being some evidence suggesting a causal link between SB and poor bone health. However, there are no population-based data on the longitudinal relationship between SB, bone change, and incidence of fragility fractures. This study aimed to examine the associations of sitting/SB (defined as daily sitting time), areal BMD (by DXA), and incident low trauma (fragility) osteoporotic fractures (excluding hands, feet, face, and head). We measured baseline (1995-7) and 10-yr self-reported SB, femoral neck (FN), total hip (TH), and lumbar spine (L1-L4) BMD in 5708 women and 2564 men aged 25 to 80+ yr from the population-based, nationwide, 9-center Canadian Multicentre Osteoporosis Study. Incident 10-yr fragility fracture data were obtained from 4624 participants; >80% of fractures were objectively confirmed by medical records or radiology reports. Vertebral fractures were confirmed by qualitative morphological methods. All analyses were stratified by sex. Multivariable regression models assessed SB-BMD relationships; Cox proportional models were fit for fracture risk. Models were adjusted for age, height, BMI, physical activity, and sex-specific covariates. Women in third/fourth quartiles had lower adjusted FN BMD versus women with the least SB (first quartile); women in the SB third quartile had lower adjusted TH BMD. Men in the SB third quartile had lower adjusted FN BMD than those in SB first quartile. Neither baseline nor stable 10-yr SB was related to BMD change nor to incident fragility fractures. Increased sitting (SB) in this large, population-based cohort was associated with lower baseline FN BMD. Stable SB was not associated with 10-yr BMD loss nor increased fragility fracture. In conclusion, habitual adult SB was not associated with subsequent loss of BMD nor increased risk of fracture.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract Disclosure: J.M. Ferris: None. J. Merrimen: None. S.M. Kaiser: Advisory Board Member; Self; Amgen Inc. Speaker; Self; Amgen Inc. Background: Graves’ disease is the most common cause of hyperthyroidism. Classic extrathyroidal manifestations include Graves orbitopathy and pretibial myxedema (also known as thyroid dermopathy). Both involve cytokine-induced hyaluronic acid secretion by fibroblasts, likely related to TSH-receptor antibodies. Pretibial myxedema is now rare, but nearly always coexists with orbitopathy. It classically involves the shins, but has been described in other locations. Here we present a case of myxedema changes affecting the periureteric soft tissue of a patient with Graves’ disease. Case: A 46-year-old male was seen by endocrinology for symptomatic hyperthyroidism. His clinical presentation was consistent with Graves’ disease and the diagnosis was confirmed with a strongly positive TSH receptor antibody of 25 IU/L (normal <1 IU/L). He had findings of moderate thyroid eye disease and had bilateral skin changes suspicious for pretibial myxedema. The skin findings preceded his hyperthyroidism by a few years. Dermatology was consulted and a skin biopsy confirmed pretibial myxedema, which was treated with triamcinolone injections with good effect. His thyroid function normalized with methimazole. Coincidentally, while being treated for Graves’ disease he altruistically donated a kidney to a transplant recipient. During the nephrectomy, it was noted that part of the periureteric tissue appeared thickened and firm, and further dissection revealed a soft tissue, lipoma-like mass surrounding the ureter. A frozen section sent from the operating room was found to contain myxomatous adipose tissue with very little cellularity. The final pathology reported adipose tissue with myxoid degeneration and reactive lymphoid aggregates. The histomorphology was consistent with a reactive process and there was no evidence of malignancy. In the context of the patient’s history the findings were concluded to be related to his Graves’ disease. Discussion: While pretibial myxedema most commonly affects the shins, it has also been described at other dermatologic sites, often associated with areas of trauma. Our patient, who had biopsy proven thyroid dermopathy, was also found to have myxedema affecting the ureter. To our knowledge this is only the third reported case of ureteral myxedema, and the first in a kidney donor. The patient’s renal function before surgery was normal, and post-nephrectomy his eGFR is mildly decreased, but stable. His thyroid function remains normal on methimazole. Presentation: Friday, June 16, 2023

Dana Bliuc, Thach Tran, Jonathan D. Adachi, Gerald J. Atkins, Claudie Berger, Joop van den Bergh, Roberto Cappai, John A Eisman, Tineke van Geel, Piet Geusens, David Goltzman, David A Hanley, Robert Josse, Stephanie Kaiser, Christopher S. Kovacs, Lisa Langsetmo, Jerilynn C Prior, Tuan V Nguyen, Lucian B. Solomon, Catherine Stapledon, and Jacqueline R Center, For the CaMos Research Group Osteoporosis and Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia Clinical School, St Vincent’s Hospital, Faculty of Medicine, UNSW Sydney, Kensington, NSW, Australia Department of Medicine, McMaster University, Hamilton, ON, Canada Centre for Orthopaedic and Trauma Research, University of Adelaide, Adelaide, SA, Australia CaMos National Coordinating Centre, McGill University, Montreal, QC, Canada Maastricht University Medical Center, Research School Nutrim, Department of Internal Medicine, Subdivision of Rheumatology, Maastricht, The Netherlands Department of Internal Medicine, VieCuri Medical Centre of Noord-Limburg, Venlo, The Netherlands School of Biomedical Sciences, University of Melbourne, Melbourne, VIC, Australia School of Medicine Sydney, University of Notre Dame Australia, Sydney, NSW, Australia M axima Medical Center, Department of Data and analytics, Veldhoven, The Netherlands Biomedical Research Institute, University Hasselt, Hasselt, Belgium Department of Medicine, McGill University, Montreal, QC, Canada Department of Medicine, University of Calgary, Calgary, AB, Canada Department of Medicine, University of Toronto, Toronto, ON, Canada Department of Medicine, Dalhousie University, Halifax, NS, Canada Faculty of Medicine, Memorial University, St. John’s, NL, Canada School of Public Health, University of Minnesota, Twin Cities, Minneapolis, MN, USA Department of Medicine and Endocrinology, University of British Columbia, Vancouver, BC, Canada Centre for Health Technologies, University of Technology Sydney, Australia School of Population Health, UNSW Medicine, UNSW Sydney, Australia Orthopaedic and Trauma Service, Royal Adelaide Hospital, Adelaide, SA, Australia

Prevention of early menopausal bone loss may reduce the future burden of osteoporosis. In this modelling exercise, an osteoporosis prevention strategy involving 5-year infusions of zoledronic acid, beginning early in menopause, reduced long-term fracture risk and the proportion of aging women with femoral neck densitometric osteoporosis. This strategy warrants further evaluation. Preventing early menopausal bone loss may substantially reduce the future burden of osteoporosis. We modelled the effects of infrequent zoledronic acid infusions on long-term fracture risk. Data from the Canadian Multicentre Osteoporosis Study (CaMos) were used to determine the expected natural history of femoral neck areal bone mineral density (BMD) and fracture risk (using FRAX®) from ages 50–80 for women with no antiresorptive drug exposures. We modelled the effects of three infusions of zoledronic acid (at ages 50, 55, 60) on long-term fracture risk, assuming this intervention would preserve BMD until age 65 years, followed by losses mirroring early menopausal BMD loss. At age 65, untreated women and zoledronic acid recipients had expected mean (SD) femoral neck T-scores of − 1.5(1.0) and − 0.8(1.0), 10-year major osteoporotic fracture (MOF) risks of 9.8%(5.0) and 8.0%(3.7) and hip fracture risks of 1.7%(2.4) and 0.8%(1.2), respectively. At age 80, untreated women and zoledronic acid recipients had expected femoral neck T-scores of − 1.9(0.9) and − 1.4(0.9), MOF risks of 17.9%(8.2) and 14.9%(6.4) and hip fracture risks of 6.3%(6.2) and 4.4%(4.5), respectively. The expected proportion of women with femoral neck T-score ≤ − 2.5 was 14.9% for untreated women and 3.8% for zoledronic acid recipients at age 65, increasing to 28.1% and 12.0%, respectively, at age 80. Numbers-needed-to-treat to prevent one case of densitometric osteoporosis were 9 at age 65 and 5 at age 80. Infrequent infusions of zoledronic acid, initiated early in menopause, are expected to reduce long-term fracture risk and result in a substantial reduction in the proportion of women with densitometric osteoporosis after age 65.

Cognitive decline and osteoporosis often coexist and some evidence suggests a causal link. However, there are no data on the longitudinal relationship between cognitive decline, bone loss and fracture risk, independent of aging. This study aimed to determine the association between: (i) cognitive decline and bone loss; and (ii) clinically significant cognitive decline (>= 3 points) on Mini Mental State Examination (MMSE) over the first 5 years and subsequent fracture risk over the following 10 years. A total of 1741 women and 620 men aged >= 65 years from the population-based Canadian Multicentre Osteoporosis Study were followed from 1997 to 2013. Association between cognitive decline and (i) bone loss was estimated using mixed-effects models; and (ii) fracture risk was estimated using adjusted Cox models. Over 95% of participants had normal cognition at baseline (MMSE >= 24). The annual % change in MMSE was similar for both genders (women -0.33, interquartile range [IQR] -0.70 to +0.00; and men -0.34, IQR: -0.99 to 0.01). After multivariable adjustment, cognitive decline was associated with bone loss in women (6.5%; 95% confidence interval [CI], 3.2% to 9.9% for each percent decline in MMSE from baseline) but not men. Approximately 13% of participants experienced significant cognitive decline by year 5. In women, fracture risk was increased significantly (multivariable hazard ratio [HR], 1.61; 95% CI, 1.11 to 2.34). There were too few men to analyze. There was a significant association between cognitive decline and both bone loss and fracture risk, independent of aging, in women. Further studies are needed to determine mechanisms that link these common conditions. (c) 2021 American Society for Bone and Mineral Research (ASBMR).

Study Purpose: Morphometric methods categorize potential osteoporotic vertebral fractures (OVF) on the basis of loss of vertebral height. A particular example is the widely used semiquantitative morphometric tool proposed by Genant (GSQ). A newer morphologic algorithm-based qualitative (mABQ) tool focuses on vertebral end-plate damage in recognizing OVF. We used data from both sexes in the Canadian Multicentre Osteoporosis Study (CaMos) to compare the 2 methods in identifying OVF at baseline and during 10 years of follow-up. Materials and Methods: We obtained lateral thoracic and lumbar spinal radiographs (T4-L4) 3 times, at 5-year intervals, in 828 participants of the population-based CaMos. Logistic regressions were used to study the association of 10-year changes in bone mineral density (BMD) with incident fractures. Results: At baseline, 161 participants had grade 1 and 32 had grade 2 GSQ OVF; over the next 10 years, only 9 of these participants had sustained incident GSQ OVF. Contrastingly, 21 participants at baseline had grade 1 and 48 grade 2 mABQ events; over the next 10 years, 79 subjects experienced incident grade 1 or grade 2 mABQ events. Thus, incident grades 1 and 2 morphologic fractures were 8 times more common than morphometric deformities alone. Each 10-year decrease of 0.01 g/cm2 in total hip BMD was associated with a 4.1% (95% CI: 0.7-7.3) higher odds of having an incident vertebral fracture. Conclusions: This analysis further suggests that morphometric deformities and morphologic fractures constitute distinct entities; morphologic fractures conform more closely to the expected epidemiology of OVF.

We examined the underlying relationship between fracture risk factors and their imminent risk. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher imminent fracture risk. Past year falls indirectly predicted imminent risk through physical functioning and general health. This study aimed to examine direct and indirect effects of several factors on imminent (1 year) fracture risk. Data from women age 65 and older from population-based Canadian Multicentre Osteoporosis Study were used. Predictors were identified from study years 5 and 10, and imminent fracture data (1-year fracture) came from years 6 and 11 (year 5 predicts year 6, year 10 predicts year 11). A structural equation model (SEM) was used to test the theoretical construct. General health and physical functioning were measured as latent variables using items from the 36-Item Short Form Health Survey (SF-36) and bone mineral density (BMD) T-score was a latent variable based on observed site-specific BMD data (spine L1-L4, femoral neck, total hip). Observed variables were fractures and falls. Model fit was evaluated using root mean square error of approximation (RMSEA), Tucker Lewis index (TLI), and comparative fit index (CFI). The analysis included 3298 women. Model fit tests showed that the SEM fit the data well; χ2(172) = 1122.10 < .001, RMSEA = .03, TLI = .99, CFI = .99. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher risk of fracture in the subsequent year (p < .001). Past year falls had a statistically significant but indirect effect on imminent fracture risk through physical functioning and general health (p < .001). We found several direct and indirect pathways that predicted imminent fracture risk in elderly women. Future studies should extend this work by developing risk scoring methods and defining imminent risk thresholds.

ABSTRACT Existing fracture risk assessment tools are not designed to predict fracture-associated consequences, possibly contributing to the current undermanagement of fragility fractures worldwide. We aimed to develop a risk assessment tool for predicting the conceptual risk of fragility fractures and its consequences. The study involved 8965 people aged ≥60 years from the Dubbo Osteoporosis Epidemiology Study and the Canadian Multicentre Osteoporosis Study. Incident fracture was identified from X-ray reports and questionnaires, and death was ascertained though contact with a family member or obituary review. We used a multistate model to quantify the effects of the predictors on the transition risks to an initial and subsequent incident fracture and mortality, accounting for their complex interrelationships, confounding effects, and death as a competing risk. There were 2364 initial fractures, 755 subsequent fractures, and 3300 deaths during a median follow-up of 13 years (interquartile range [IQR] 7–15). The prediction model included sex, age, bone mineral density, history of falls within 12 previous months, prior fracture after the age of 50 years, cardiovascular diseases, diabetes mellitus, chronic pulmonary diseases, hypertension, and cancer. The model accurately predicted fragility fractures up to 11 years of follow-up and post-fracture mortality up to 9 years, ranging from 7 years after hip fractures to 15 years after non-hip fractures. For example, a 70-year-old woman with a T-score of −1.5 and without other risk factors would have 10% chance of sustaining a fracture and an 8% risk of dying in 5 years. However, after an initial fracture, her risk of sustaining another fracture or dying doubles to 33%, ranging from 26% after a distal to 42% post hip fracture. A robust statistical technique was used to develop a prediction model for individualization of progression to fracture and its consequences, facilitating informed decision making about risk and thus treatment for individuals with different risk profiles. © 2020 American Society for Bone and Mineral Research.

OBJECTIVE We aimed to assess whether individuals with type 2 diabetes (T2D) have increased risk of vertebral fractures (VFs) and to estimate nonvertebral fracture and mortality risk among individuals with both prevalent T2D and VFs. RESEARCH DESIGN AND METHODS A systematic PubMed search was performed to identify studies that investigated the relationship between T2D and VFs. Cohorts providing individual participant data (IPD) were also included. Estimates from published summary data and IPD cohorts were pooled in a random-effects meta-analysis. Multivariate Cox regression models were used to estimate nonvertebral fracture and mortality risk among individuals with T2D and VFs. RESULTS Across 15 studies comprising 852,705 men and women, individuals with T2D had lower risk of prevalent (odds ratio [OR] 0.84 [95% CI 0.74-0.95]; I-2 = 0.0%; P-het = 0.54) but increased risk of incident VFs (OR 1.35 [95% CI 1.27-1.44]; I-2 = 0.6%; P-het = 0.43). In the IPD cohorts (N = 19,820), risk of nonvertebral fractures was higher in those with both T2D and VFs compared with those without T2D or VFs (hazard ratio [HR] 2.42 [95% CI 1.86-3.15]) or with VFs (HR 1.73 [95% CI 1.32-2.27]) or T2D (HR 1.94 [95% CI 1.46-2.59]) alone. Individuals with both T2D and VFs had increased mortality compared with individuals without T2D and VFs (HR 2.11 [95% CI 1.72-2.59]) or with VFs alone (HR 1.84 [95% CI 1.49-2.28]) and borderline increased compared with individuals with T2D alone (HR 1.23 [95% CI 0.99-1.52]). CONCLUSIONS Based on our findings, individuals with T2D should be systematically assessed for presence of VFs, and, as in individuals without T2D, their presence constitutes an indication to start osteoporosis treatment for the prevention of future fractures.

Parity and lactation showed no associations with incident clinical fragility fractures or radiographic vertebral compression fractures in the 16-year CaMos prospective study. Parity was associated with slightly greater decline in femoral neck but not hip or spine areal bone mineral density (aBMD), while lactation showed no associations with aBMD change. Pregnancy and especially lactation cause loss of bone mass and microarchitectural changes, which temporarily increase fracture risk. After weaning, aBMD increases but skeletal microarchitecture may be incompletely restored. Most retrospective clinical studies found neutral or even protective associations of parity and lactation with fragility fractures, but prospective data are sparse. CaMos is a randomly selected observational cohort that includes ~ 6500 women followed prospectively for over 16 years. We determined whether parity or lactation were related to incident clinical fragility fractures over 16 years, radiographic (morphometric and morphologic) vertebral fractures over 10 years, and aBMD change (spine, total hip, and femoral neck) over 10 years. Parity and lactation duration were analyzed as continuous variables in predicting these outcomes using univariate and multivariate regression analyses. Three thousand four hundred thirty-seven women completed 16 years of follow-up for incident clinical fractures, 3839 completed 10 years of morphometric vertebral fracture assessment, 3788 completed 10 years of morphologic vertebral fracture assessment, and 4464 completed 10 years of follow-up for change in aBMD. In the multivariate analyses, parity and lactation duration showed no associations with clinical fragility fractures, radiographic vertebral fractures, or change in aBMD, except that parity associated with a probable chance finding of a slightly greater decline in femoral neck aBMD. Parity and lactation have no adverse associations with clinical fragility or radiographic vertebral fractures, or the rate of BMD decline over 10 years, in this prospective, multicenter study of a randomly selected, population-based cohort of women.

OBJECTIVE We aimed to explore whether frailty was associated with fracture risk and whether frailty could modify the propensity of type 2 diabetes toward increased risk of fractures. RESEARCH DESIGN AND METHODS Data were from a prospective cohort study. Our primary outcome was time to the first incident clinical fragility fracture; secondary outcomes included time to hip fracture and to clinical spine fracture. Frailty status was measured by a Frailty Index (FI) of deficit accumulation. The Cox model incorporating an interaction term (frailty × diabetes) was used for analyses. RESULTS The analysis included 3,149 (70% women) participants; 138 (60% women) had diabetes. Higher bone mineral density and FI were observed in participants with diabetes compared with control subjects. A significant relationship between the FI and the risk of incident fragility fractures was found, with a hazard ratio (HR) of 1.02 (95% CI 1.01–1.03) and 1.19 (95% CI 1.10–1.33) for per-0.01 and per-0.10 FI increase, respectively. The interaction was also statistically significant (P = 0.018). The HR for per-0.1 increase in the FI was 1.33 for participants with diabetes and 1.19 for those without diabetes if combining the estimate for the FI itself with the estimate from the interaction term. No evidence of interaction between frailty and diabetes was found for risk of hip and clinical spine fractures. CONCLUSIONS Participants with type 2 diabetes were significantly frailer than individuals without diabetes. Frailty increases the risk of fragility fracture and enhances the effect of diabetes on fragility fractures. Particular attention should be paid to diabetes as a risk factor for fragility fractures in those who are frail.

ABSTRACT Bisphosphonates, potent antiresorptive agents, have been found to be associated with mortality reduction. Accelerated bone loss is, in itself, an independent predictor of mortality risk, but the relationship between bisphosphonates, bone loss, and mortality is unknown. This study aimed to determine whether the association between bisphosphonates and mortality is mediated by a reduction in the rate of bone loss. Participants from the population-based Canadian Multicentre Osteoporosis Study were followed prospectively between1996 and 2011. Comorbidities and lifestyle factors were collected at baseline and bone mineral density (BMD) at baseline and at years 3 (for those aged 40 to 60 years), 5, and 10. Rate of bone loss was calculated using linear regression. Information on medication use was obtained yearly. Bisphosphonate users grouped into nitrogen bisphosphonates (nBP; alendronate or risedronate) and etidronate and non-users (NoRx) were matched by propensity score, including all baseline factors as well as time of treatment. Cox's proportional hazards models, unadjusted and adjusted for annual rate of bone loss, were used to determine the association between nBP and etidronate versus NoRx. For the treatment groups with significant mortality risk reduction, the percent of mortality reduction mediated by a reduction in the rate of bone loss was estimated using a causal mediation analysis. There were 271 pairs of nBP and matched NoRx and 327 pairs of etidronate and matched NoRx. nBP but not etidronate use was associated with significant mortality risk reduction (hazard ratios [HR] = 0.61 [95% confidence interval 0.39–0.96] and 1.35 [95% CI 0.86–2.11] for nBP and etidronate, respectively). Rapid bone loss was associated with more than 2-fold increased mortality risk compared with no loss. Mediation analysis indicated that 39% (95% CI 7%–84%) of the nBP association with mortality was related to a reduction in the rate of bone loss. This finding provides an insight into the mechanism of the relationship between nBP and survival benefit in osteoporotic patients. © 2019 American Society for Bone and Mineral Research.