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Osteoporosis is a chronic condition characterized by decreased bone mass, loss of skeletal integrity, and increased susceptibility to fracture. Drugs used to treat osteoporosis can be classified as those that block bone resorption (antiresorptive), stimulate bone formation (anabolic), or do both. While all currently approved medications reduce the risk of fragility fractures in high-risk populations, they are generally unable to fully restore bone strength in most patients with established disease. Thus, the majority of patients require disease management over many years. Unfortunately, the continuous use of a single drug has limitations, both in terms of efficacy and safety, and so sequential therapy is commonly required. Given the expanding list of pharmacological agents currently available, careful consideration needs to be given as to which drugs to use and in what sequence. This review will evaluate the differential effects of antiresorptive, bone-forming, and dual-acting drugs when used in specific sequences and will explore the current evidence favoring the initial use of bone-forming/dual-acting drugs followed by antiresorptive medications. This review will also examine the notion that long-term treatment with an antiresorptive drug may diminish the efficacy of subsequent treatment with a bone-forming/dual-acting drug. Finally, this review will explore the current evidence pertaining to the specific issue of how to best prevent the clinical ramifications of denosumab cessation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Fragility fractures increase risks for future fractures, morbidity, and mortality. Available pharmacotherapy for underlying osteoporosis is safe and effective but underused., Objective: To improve pharmacotherapy rate representing secondary prevention of osteoporotic fractures., Methods: This single-center, observational, follow-up study included patients with fragility fractures admitted to the Massachusetts General Hospital between February 2016 and December 2019. For patients admitted to the orthopedics service with fragility fracture, the Massachusetts General Hospital Fracture Liaison Service (FLS) was systematically consulted. Initial outpatient follow-up with FLS was established in conjunction with the orthopedic postoperative follow-up visit. Patients at risk for failing timely outpatient follow-up were administered zoledronic acid (ZA) during the index fracture hospitalization. The main outcome measures were percentage of patients with fragility fracture(s) started on pharmacotherapy for osteoporosis and average length of stay and 30-day readmission rate of patients treated with ZA., Results: Compared with baseline (8-11%) and reference (5-20%) rates, integration of FLS to the orthopedics service, along with appropriate inpatient administration of ZA, increased the pharmacotherapy rate to 70% (412/589) among eligible patients with verified treatment status. Inpatient ZA administration neither affected the average length of stay nor 30-day readmission rate. Treatment status of 37.9% (471/1240) of the study patients remained unknown due to lack of or unknown follow-up., Conclusion: Integration of a FLS and orthopedics services along with inpatient ZA administration improved the osteoporosis pharmacotherapy rate among patients with fragility fracture(s) who often had obstacles for outpatient follow-up., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Anabolic osteoporosis drugs improve bone mineral density by increasing bone formation. The objective of this study was to evaluate the early effects of abaloparatide on indices of bone formation and to assess the effect of abaloparatide on modeling-based formation (MBF), remodeling-based formation (RBF), and overflow MBF (oMBF) in transiliac bone biopsies. In this open-label, single-arm study, 23 postmenopausal women with osteoporosis were treated with 80 μg abaloparatide daily. Subjects received double fluorochrome labels before treatment and before biopsy collection at 3 months. Change in dynamic histomorphometry indices in four bone envelopes were assessed. Median mineralizing surface per unit of bone surface (MS/BS) increased to 24.7%, 48.7%, 21.4%, and 16.3% of total surface after 3 months of abaloparatide treatment, representing 5.5-, 5.2-, 2.8-, and 12.9-fold changes, on cancellous, endocortical, intracortical, and periosteal surfaces (p < .001 versus baseline for all). Mineral apposition rate (MAR) was significantly increased only on intracortical surfaces. Bone formation rate (BFR/BS) was significantly increased on all four bone envelopes. Significant increases versus baseline were observed in MBF on cancellous, endocortical, and periosteal surfaces, for oMBF on cancellous and endocortical surfaces, and for RBF on cancellous, endocortical, and intracortical surfaces. Overall, modeling-based formation (MBF + oMBF) accounted for 37% and 23% of the increase in bone-forming surface on the endocortical and cancellous surfaces, respectively. Changes from baseline in serum biomarkers of bone turnover at either month 1 or month 3 were generally good surrogates for changes in histomorphometric endpoints. In conclusion, treatment with abaloparatide for 3 months stimulated bone formation on cancellous, endocortical, intracortical, and periosteal envelopes in transiliac bone biopsies obtained from postmenopausal women with osteoporosis. These increases reflected stimulation of both remodeling- and modeling-based bone formation, further elucidating the mechanisms by which abaloparatide improves bone mass and lowers fracture risk. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Background: Denosumab is effective for osteoporosis, but discontinuation leads to rapid reversal of its therapeutic effect., Objective: To estimate the risk for fracture among users of denosumab who delayed subsequent doses compared with users who received doses on time., Design: Population-based cohort study., Setting: The Health Improvement Network U.K. primary care database, 2010 to 2019., Patients: Persons aged 45 years or older who initiated denosumab therapy for osteoporosis., Measurements: Observational data were used to emulate an analysis of a hypothetical trial with 3 dosing intervals: subsequent denosumab injection given within 4 weeks after the recommended date ("on time"), delay by 4 to 16 weeks ("short delay"), and delay by more than 16 weeks ("long delay"). The primary outcome was a composite of all fracture types at 6 months after the recommended date. Secondary outcomes were major osteoporotic fracture, vertebral fracture, hip fracture, and nonvertebral fracture., Results: Investigators identified 2594 patients initiating denosumab therapy. The risk for composite fracture over 6 months was 27.3 in 1000 for on-time dosing, 32.2 in 1000 for short delay, and 42.4 in 1000 for long delay. Compared with on-time injections, short delay had a hazard ratio (HR) for composite fracture of 1.03 (95% CI, 0.63 to 1.69) and long delay an HR of 1.44 (CI, 0.96 to 2.17) ( P for trend = 0.093). For vertebral fractures, short delay had an HR of 1.48 (CI, 0.58 to 3.79) and long delay an HR of 3.91 (CI, 1.62 to 9.45)., Limitation: Dosing schedules were not randomly assigned., Conclusion: Although delayed administration of subsequent denosumab doses by more than 16 weeks is associated with increased risk for vertebral fracture compared with on-time dosing, evidence is insufficient to conclude that fracture risk is increased at other anatomical sites with long delay., Primary Funding Source: National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation.

Context: Discontinuation of denosumab leads to a rapid reversal of its therapeutic effect. However, there are no data regarding how unintended delays or missed injections of denosumab impact bone mineral density (BMD) response., Objective: We examined the association of delays in injections of denosumab with BMD change., Design: We used electronic medical records from two academic hospitals from 2010 to 2017., Participants: Patients older than 45 years of age and used at least 2 doses of 60 mg denosumab. Denosumab adherence was evaluated by the medication coverage ratio (MCR). Good adherence corresponds to a dosing interval ≤7 months (defined by MCR ≥93%), moderate adherence corresponds to an interval of 7 to 10 months (MCR 75%-93%), and poor adherence corresponds to an interval ≥10 months (MCR ≤75%)., Outcome Measures: Annualized percent BMD change from baseline at the lumbar spine, total hip, and femoral neck., Results: We identified 938 denosumab injections among 151 patients; the mean (SD) age was 69 (10) years, and 95% were female. Patients with good adherence had an annualized BMD increase of 3.9% at the lumbar spine, compared with patients with moderate (3.0%) or poor adherence (1.4%, P for trend .002). Patients with good adherence had an annualized BMD increase of 2.1% at the total hip, compared with patients with moderate (1.3%) or poor adherence (0.6%, P for trend .002)., Conclusions: A longer interval between denosumab injections is associated with suboptimal BMD response at both spine and total hip. Strategies to improve the timely administration of denosumab in real-world settings are needed., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Teriparatide and denosumab are effective treatments for osteoporosis and typically reserved as second-line options after patients have used bisphosphonates. However, limited head-to-head comparative effectiveness data exist between teriparatide and denosumab., Objective: We compared changes in bone mineral density (BMD) between groups treated with teriparatide or denosumab after using bisphosphonates, focusing on the change in BMD while on either drug over 2 years., Design: Observational cohort study using electronic medical records from two academic medical centers in the United States., Participants: The study population included osteoporotic patients >45 years who received bisphosphonates >1 year before switching to teriparatide or denosumab., Outcome Measures: Annualized BMD change from baseline at the lumbar spine, total hip, and femoral neck., Results: Patients treated with teriparatide (n = 110) were compared with those treated with denosumab (n = 105); the mean (SD) age was 70 (10) years and median duration (interquartile range) of bisphosphonate use was 7.0 (5.6 to 9.7) years. Compared with denosumab users, teriparatide users had higher annualized BMD change at the spine by 1.3% (95% CI 0.02, 2.7%) but lower at the total hip by -2.2% (95% CI -2.9 to -1.5%) and the femoral neck by -1.1% (95% CI -2.1 to -0.1%). Those who switched to teriparatide had a transient loss of hip BMD for the first year, with no overall increase in the total hip BMD over 2 years., Conclusions: Among patients who use long-term bisphosphonates, the decision of switching to teriparatide should be made with caution, especially for patients at high risk of hip fracture., (Copyright © 2019 Endocrine Society.)

Context: It is uncertain which osteoporosis therapy is more effective: bisphosphonates or denosumab., Objective: To determine whether denosumab therapy increases bone mineral density (BMD) and reduces fracture risk more so than bisphosphonates in patients with low BMD or osteoporosis., Methods: The PubMed, Embase, and the Cochrane Library databases were searched through November 2018 for head-to-head, randomized, controlled trials comparing denosumab and bisphosphonates among adult patients with low BMD or osteoporosis. Random-effects models were used., Results: We identified 10 eligible trials including 5361 participants. Denosumab increased BMD more than bisphosphonate at 12 months (mean difference, 1.42%; 95% CI, 0.95% to 1.89%; P < 0.001) at lumbar spine, 1.11% (95% CI, 0.91% to 1.30%; P < 0.001) at total hip, and 1.00% (95% CI, 0.78% to 1.22%; P < 0.001) at femoral neck. At 24 months, the respective increase differences were 1.74% (95% CI, 1.05% to 2.43%; P < 0.001), 1.22% (95% CI, 0.66% to 1.77%; P < 0.001), and 1.19% (95% CI, 0.65% to 1.72%; P < 0.001). There was no difference in fracture end point at 12 months, but denosumab had a lower osteoporotic fracture incidence than alendronate at 24 months (risk ratio, 0.51; 95% CI, 0.27 to 0.97)., Conclusion: Denosumab improved BMD significantly more than bisphosphonate treatment at the lumbar spine, total hip, and femoral neck at 12 and 24 months. Only one study demonstrated greater osteoporotic fracture reduction with denosumab treatment. Longitudinal studies with longer follow-up and large sample size are needed to confirm the efficacy difference., (Copyright © 2019 Endocrine Society.)

Intervals between dual-energy X-ray absorptiometry (DXA) scans were evaluated in a large cohort of typical clinical practice. Intensive DXA scanning (intervals < 23 months) decreased substantially, from 16.7% in 2006 to 6.7% in 2015., Introduction: Serial dual-energy X-ray absorptiometry (DXA) measurements are suggested for patients at high risk of fractures. However, little is known about how often DXA testing occurs in clinical practice., Methods: We examined time intervals between DXA testing for monitoring purpose at two academic medical centers in the US between 2004 and 2017. The primary outcome was the presence of testing intervals < 23 months (termed "intensive DXA testing"). A generalized linear mixed model was used to evaluate the association between selected patient-level clinical factors and intensive DXA testing., Results: Forty-nine thousand four hundred ninety-four DXA tests from 20,200 patients were analyzed. The mean time interval between scans was 36 ± 21 months. Only 11.1% of the repeated DXA testing met the criterion for intensive testing. The percentage of intensive DXA testing dropped from 16.7% in 2006 to 6.7% in 2015 (p for trend < 0.001). After adjusting for age, gender, number of outpatient visits, and calendar year, correlates of intensive DXA testing included a baseline T-score < -2.5 at any anatomic site (OR, 4.8; 95%CI, 4.0-5.7), active use of drugs for osteoporosis (OR, 1.6; 95%CI, 1.3-1.9), and active use of glucocorticoids (OR, 1.3; 95%CI, 1.2-1.4)., Conclusions: The predictors of intensive DXA testing suggest that this practice is used preferentially in patients with multiple risk factors and to monitor the response to pharmacotherapy. However, intensive DXA testing has become less common in real-world clinical practice over the last decade. Further studies are required to better define the optimal use of bone mineral density testing in this vulnerable population.

Purpose of Review: The purpose is to review the efficacy and optimal use of parathyroid hormone and parathyroid hormone-related protein analogs in osteoporosis treatment., Recent Findings: The parathyroid hormone analog teriparatide, a potent stimulator of bone remodeling, increases hip and spine bone mineral density and reduces the risk of vertebral and non-vertebral fractures in postmenopausal osteoporotic women. The parathyroid hormone-related protein analog, abaloparatide, also reduces fracture incidence but has pharmacological effects that differ from teriparatide, particularly in cortical bone. These analogs provide maximal benefit when their use is followed by a potent antiresorptive medication. Moreover, studies have shown that the combination of teriparatide and the RANK-ligand inhibitor, denosumab, increase bone density and estimated strength more than monotherapy and more than any currently available regimen. Parathyroid hormone and parathyroid hormone-related protein analogs, whether as monotherapy, in combination with antiresorptive agents or in sequence with antiresorptive agents, will likely play an expanding role in osteoporosis management.

Background: Severe gonadal steroid deficiency induces bone loss in adult men; however, the specific roles of androgen and estrogen deficiency in hypogonadal bone loss are unclear. Additionally, the threshold levels of testosterone and estradiol that initiate bone loss are uncertain., Methods: One hundred ninety-eight healthy men, ages 20-50, received goserelin acetate, which suppresses endogenous gonadal steroid production, and were randomized to treatment with 0, 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. An additional cohort of 202 men was randomized to receive these treatments plus anastrozole, which suppresses conversion of androgens to estrogens. Thirty-seven men served as controls and received placebos for goserelin and testosterone. Changes in bone turnover markers, bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA), and BMD by quantitative computed tomography (QCT) were assessed in all men. Bone microarchitecture was assessed in 100 men., Results: As testosterone dosage decreased, the percent change in C-telopeptide increased. These increases were considerably greater when aromatization of testosterone to estradiol was also suppressed, suggesting effects of both testosterone and estradiol deficiency. Decreases in DXA BMD were observed when aromatization was suppressed but were modest in most groups. QCT spine BMD fell substantially in all testosterone-dose groups in which aromatization was also suppressed, and this decline was independent of testosterone dose. Estradiol deficiency disrupted cortical microarchitecture at peripheral sites. Estradiol levels above 10 pg/ml and testosterone levels above 200 ng/dl were generally sufficient to prevent increases in bone resorption and decreases in BMD in men., Conclusions: Estrogens primarily regulate bone homeostasis in adult men, and testosterone and estradiol levels must decline substantially to impact the skeleton., Trial Registration: ClinicalTrials.gov, NCT00114114., Funding: AbbVie Inc., AstraZeneca Pharmaceuticals LP, NIH.

As the first FDA-approved anabolic agent for osteoporosis, teriparatide has proven effective for people at highest risk of fracture, despite limitations of expense, route of delivery, and length of treatment. Available data show that combination therapy with teriparatide and antiresorptive agents does not offer a therapeutic advantage. However, treatment with an antiresorptive agent after teriparatide discontinuation is essential to prevent the ensuing bone loss. Although pretreatment with bisphosphonates may somewhat attenuate the anabolic effect of teriparatide, significant gains in bone mineral density are still achieved and prior bisphosphonate use should not dissuade clinicians from using teriparatide in select patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Androgen-deprivation therapy is well-established for treating prostate cancer but is associated with bone loss and an increased risk of fracture. We investigated the effects of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, on bone mineral density and fractures in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer., Methods: In this double-blind, multicenter study, we randomly assigned patients to receive denosumab at a dose of 60 mg subcutaneously every 6 months or placebo (734 patients in each group). The primary end point was percent change in bone mineral density at the lumbar spine at 24 months. Key secondary end points included percent change in bone mineral densities at the femoral neck and total hip at 24 months and at all three sites at 36 months, as well as incidence of new vertebral fractures., Results: At 24 months, bone mineral density of the lumbar spine had increased by 5.6% in the denosumab group as compared with a loss of 1.0% in the placebo group (P<0.001); significant differences between the two groups were seen at as early as 1 month and sustained through 36 months. Denosumab therapy was also associated with significant increases in bone mineral density at the total hip, femoral neck, and distal third of the radius at all time points. Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5%, vs. 3.9% with placebo) (relative risk, 0.38; 95% confidence interval, 0.19 to 0.78; P=0.006). Rates of adverse events were similar between the two groups., Conclusions: Denosumab was associated with increased bone mineral density at all sites and a reduction in the incidence of new vertebral fractures among men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. (ClinicalTrials.gov number, NCT00089674.), (2009 Massachusetts Medical Society)

Context: In postmenopausal women, bone mineral density (BMD) declines after teriparatide therapy is stopped. The pattern of BMD loss after teriparatide therapy is stopped in men is less clear., Objective: The aim of the study was to determine whether the pattern of teriparatide-induced bone accrual and post-teriparatide bone loss differs between postmenopausal women and eugonadal men., Design: We conducted a prospective cohort substudy., Patients: The study included 14 postmenopausal women and 17 eugonadal men, ages 46-85 yr, with lumbar spine or femoral neck BMD T-scores below -2., Intervention: Teriparatide (37 microg sc daily) was administered for 24 months, followed by 12 months off therapy., Main Outcome Measures: We measured BMD at various anatomic sites by dual-energy x-ray absorptiometry, trabecular spine BMD by quantitative computed tomography, and bone turnover markers during the treatment and observation periods. The response to teriparatide administration and discontinuation was compared between females and males., Results: BMD of the spine, femoral neck, total hip, and trabecular spine increased similarly during the treatment period in men and women, whereas BMD at the radius was stable in men but decreased by 8.1 +/- 3.3% in women (P < 0.0001). After teriparatide was stopped, BMD at the posterior-anterior spine decreased by 7.1 +/- 3.8% in women and by 4.1 +/- 3.5% in men (P = 0.036). BMD at the total hip and femoral neck decreased by 3.8 +/- 3.9 and 3.1 +/- 4.3%, respectively, in women but remained stable in men (P < 0.05 for both sites). BMD at the distal radius remained stable in men but increased in women by 1.6 +/- 3.1% (P = 0.069)., Conclusions: Teriparatide appears to increase BMD similarly in postmenopausal women and eugonadal men with osteoporosis. After teriparatide is stopped, the decline in BMD is greater in women than in men. If confirmed in larger cohorts, these findings would suggest that the indication for immediate antiresorptive therapy after teriparatide may not be as urgent in men as in women.

Context: The stimulatory effect of teriparatide on bone mineral density (BMD) and bone turnover is initially exuberant, but then diminishes., Objective: Our objective was to determine whether retreating with teriparatide after a drug-free period can restore the initial exuberant response to teriparatide., Design and Setting: This was a planned extension of a randomized controlled trial conducted in a single university hospital., Patients and Intervention: Subjects previously participated in a 30-month randomized trial comparing the effects of alendronate (group 1), teriparatide (group 2), or both (group 3) on BMD and bone turnover in men and women with low BMD (phase 1). Subjects who completed phase 1 on their assigned therapy entered phase 2 (months 30-42), during which teriparatide was stopped in groups 2 and 3. Teriparatide was administered to all subjects during months 42 to 54 (phase 3)., Main Outcome Measures: We compared changes in BMD and markers of bone turnover (serum osteocalcin, N-terminal propeptide of type 1 collagen, and N-telopeptide) between phase 1 and 3 in subjects receiving teriparatide alone., Results: Posterior-anterior and lateral spine BMD increased 12.5 +/- 1.5 and 16.9 +/- 1.7%, respectively, during the first 12 months of teriparatide administration and 5.2 +/- 0.8 and 6.2 +/- 1.8%, respectively, during teriparatide retreatment (P < 0.001 and P = 0.001). Increases in osteocalcin (P < 0.001), N-terminal propeptide of type 1 collagen (P < 0.001), and N-telopeptide (P < 0.001) were greater during the first period of teriparatide administration., Conclusion: The response to teriparatide is attenuated when readministered after a 12-month hiatus.

Context: We have previously demonstrated that alendronate reduces the ability of teriparatide to increase bone mineral density (BMD) in osteoporotic men. The underlying basis for this observation is poorly understood., Objective: The primary aim of this study was to determine whether teriparatide increases osteoblast activity when the ability of teriparatide to increase osteoclast activity is suppressed by alendronate., Design: This was a nonblinded, randomized, controlled trial., Setting: The study was conducted at the General Clinical Research Center of a teaching hospital., Patients: We studied 63 men, age 46-85, with low spine and/or hip BMD., Interventions: Subjects received alendronate 10 mg daily (group 1), teriparatide 37 microg sc daily (group 2), or both (group 3) for 30 months. Teriparatide was begun at month 6., Main Outcome Measures: The primary endpoint was the change in serum N-telopeptide, osteocalcin, and amino-terminal propeptide of type 1 procollagen., Results: In men receiving teriparatide monotherapy (group 2), levels of all bone turnover markers increased markedly during the first 6 months of teriparatide administration and then declined toward baseline during the next 18 months. In men who received combination therapy (group 3), bone turnover marker levels declined in the first 6 months (while receiving alendronate alone) and then returned to baseline levels (N-telopeptide) or above (osteocalcin and amino-terminal propeptide of type 1 procollagen) after teriparatide was added. Changes in each marker were significantly different between groups 1 and 2 (all P values < 0.001), groups 1 and 3 (all P values < 0.001), and groups 2 and 3 (all P values < 0.03)., Conclusions: As with BMD, alendronate impairs the action of teriparatide to increase bone turnover in men.

Background While changes in biochemical markers of bone turnover (BTM) have been reported to predict changes in bone mineral density (BMD), the relationship between changes in BMD and BTMs with combined antiresorptive/anabolic therapy is unknown. Methods In the DATA study, 94 postmenopausal osteoporotic women (ages 51–91) received either teriparatide 20-mcg SC daily, denosumab 60-mg SC every 6 months, or both for 2 years. Pearson's correlation coefficients (R) were calculated to determine the relationship between baseline and early changes in BTMs (as well as serum sclerostin) and 2-year changes in BMD. Results In women receiving teriparatide, baseline BTMs did not correlate with 2-year BMD changes though 12-month increases in osteocalcin and P1NP were associated with 2-year increases in spine BMD. In women receiving denosumab, spine and hip BMD gains correlated with both baseline and changes in P1NP and C-telopeptide. In women receiving combined teriparatide/denosumab, while both baseline and decreases in P1NP were associated with spine BMD gains, distal radius increases were associated with less CTX suppression. Neither baseline nor changes in serum sclerostin correlated with BMD in any treatment group. Summary and conclusions In women treated with teriparatide or denosumab, early BTM changes (increases and decreases, respectively) predict 2-year BMD gains, especially at the spine. In women treated with combined teriparatide/denosumab therapy, BMD increases at the distal radius were associated with less suppression of bone turnover. These results suggest that efficacy of combination therapy at cortical sites such as the radius may depend on residual bone remodeling despite RANKL inhibition. [ABSTRACT FROM AUTHOR]