Potent Antiresorptive Agents Research Articles

Medication-Related Osteonecrosis of the Jaw – 2024 Update

As the global number of patients with osteoporosis and malignant diseases such as breast cancer, multiple myeloma, and prostate cancer increases every year, there is an associated rise in the use of antiangiogenic medications and antiresorptive medications. With increasing frequencies in the use of antiangiogenic and antiresorptive medications, there is an associated increase in the number of medication-related osteonecrosis of the jaw (MRONJ) cases reported from patients. MRONJ has emerged as a significant comorbidity in cancer patients treated with antiangiogenics or high doses of potent antiresorptive agents, such as bisphosphonates (BPs) or denosumab. MRONJ first emerged from BP-treated cancer patients who presented with a spectrum of dental problems, including delayed wound healing following a dental extraction or oral surgery, exposed bone, soft tissue infection and inflammation, anesthesia, paresthesia, odontalgia, sinus pain, and aching bone pain in the mandible, which continues to be a significant source of problems for dentists, physicians, and patients today. A significant number of MRONJ cases secondary to osteoporosis have also been reported in osteoporotic patients receiving antiresorptive medications. The American Association of Oral and Maxillofacial Surgeons (AAOMS) has established diagnostic standards for MRONJ based on pharmacological history, clinical signs, and radiographic findings. However, as the expertise and knowledge base for MRONJ continues to evolve, revisions and refinements for MRONJ pathogenesis and treatment strategies are necessary to reflect the current research status of the disease correctly. This review highlights current scientific information associated with MRONJ to identify and summarize preventative measures, and treatment interventions for reading the impact of this debiliating disorders.

Identifying therapeutic biomarkers of zoledronic acid by metabolomics.

Zoledronic acid (ZOL) is a potent antiresorptive agent that increases bone mineral density (BMD) and reduces fracture risk in postmenopausal osteoporosis (PMOP). The anti-osteoporotic effect of ZOL is determined by annual BMD measurement. In most cases, bone turnover markers function as early indicators of therapeutic response, but they fail to reflect long-term effects. We used untargeted metabolomics to characterize time-dependent metabolic shifts in response to ZOL and to screen potential therapeutic markers. In addition, bone marrow RNA-seq was performed to support plasma metabolic profiling. Sixty rats were assigned to sham-operated group (SHAM, n = 21) and ovariectomy group (OVX, n = 39) and received sham operation or bilateral ovariectomy, respectively. After modeling and verification, rats in the OVX group were further divided into normal saline group (NS, n = 15) and ZOL group (ZA, n = 18). Three doses of 100μg/kg ZOL were administrated to the ZA group every 2weeks to simulate 3-year ZOL therapy in PMOP. An equal volume of saline was administered to the SHAM and NS groups. Plasma samples were collected at five time points for metabolic profiling. At the end of the study, selected rats were euthanatized for bone marrow RNA-seq. A total number of 163 compound were identified as differential metabolites between the ZA and NS groups, including mevalonate, a critical molecule in target pathway of ZOL. In addition, prolyl hydroxyproline (PHP), leucyl hydroxyproline (LHP), 4-vinylphenol sulfate (4-VPS) were identified as differential metabolites throughout the study. Moreover, 4-VPS negatively correlated with increased vertebral BMD after ZOL administration as time-series analysis revealed. Bone marrow RNA-seq showed that the PI3K-AKT signaling pathway was significantly associated with ZOL-mediated changes in expression (adjusted-p = 0.018). In conclusion, mevalonate, PHP, LHP, and 4-VPS are candidate therapeutic markers of ZOL. The pharmacological effect of ZOL likely occurs through inhibition of the PI3K-AKT signaling pathway.

Osteonecrosis of the Jaws due to Drugs: Series of Clinical Cases

Osteonecrosis of the jaw is a rare but severe condition manifested as necrotic bone lesion, it has been linked to the use of potent antiresorptive agents and antiangiogenic medication, in the absence of prior radiation treatment. Staging the pathology once installed, helps us to continue with the protocol guide and is essential to be able to apply the indicated therapy in each case. Clinical Relevance: The contribution of this work is for general dentist, in the observation and clinical management of patients at risk or with development of osteonecrosis of the jaw due to medication, through their staging

EXTENSIVE EXPERTISE IN ENDOCRINOLOGY: Osteoporosis management.

Fractures occur in about half of older White women, and almost a third of older White men. However, 80% of the older individuals who have fractures do not meet the bone density definition of osteoporosis, suggesting that this definition is not an appropriate threshold for offering treatment. Fracture risk can be estimated based on clinical risk factors with or without bone density. A combination of calculated risk, fracture history, and bone density is used in treatment decisions. Medications available for reducing fracture risk act either to inhibit bone resorption or to promote bone formation. Romosozumab is unique in that it has both activities. Bisphosphonates are the most widely used interventions because of their efficacy, safety, and low cost. Continuous use of oral bisphosphonates for >5 years increases the risk of atypical femoral fractures, so is usually punctuated with drug holidays of 6-24 months. Denosumab is a further potent anti-resorptive agent given as 6-monthly s.c. injections. It is comparable to the bisphosphonates in efficacy and safety but has a rapid offset of effect after discontinuation so must be followed by an alternative drug, usually a bisphosphonate. Teriparatide stimulates both bone formation and resorption, substantially increases spine density, and reduces vertebral and non-vertebral fracture rates, though data for hip fractures are scant. Treatment is usually limited to 18-24 months, followed by the transition to an anti-resorptive. Romosozumab is given as monthly s.c. injections for 1 year, followed by an anti-resorptive. This sequence prevents more fractures than anti-resorptive therapy alone. Because of cost, anabolic drugs are usually reserved for those at very high fracture risk. 25-hydroxyvitamin D levels should be maintained above 30 nmol/L, using supplements if sunlight exposure is limited. Calcium intake has little effect on bone density and fracture risk but should be maintained above 500 mg/day using dietary sources.

Clodronate detection and effects on markers of bone resorption are prolonged following a single administration to horses.

Clodronate is a potent antiresorptive agent labelled for use in horses over 4 years of age, for the treatment of navicular syndrome. Concerns regarding the extra-label use of clodronate in equine athletes, such as racehorses, have been raised as inhibition of osteoclast activity by clodronate has been postulated to interfere with normal bone healing, which is imperative to the repair of microfractures. The paucity of data describing the long-term pharmacokinetics of clodronate and effects on biomarkers of bone resorption necessitates further study. (1) To determine clodronate concentrations in blood and urine over a 6-month period in horses undergoing treadmill exercise and (2) to assess the effects of clodronate on protein biomarkers of bone remodelling in this same group of horses. Randomised controlled experimental study. Seven exercised Thoroughbred horses received a single im administration of 1.8mg/kg clodronate and four horses received an equivalent volume of saline. Blood and urine samples were collected prior to, during and for 182 days post drug administration for drug concentration determination using liquid chromatography-tandem mass spectrometry, and determination of protein biomarker (CTX-1 and TRAcP5B) concentrations. Clodronate was detectable in blood for 14-175 days and for up to 175 days in urine. For some horses, concentrations were nondetectable at one time point but detectable at a subsequent time point. The terminal serum half-life ranged from 1.80 to 283.9 days. CTX-1 concentrations were significantly higher, relative to baseline, in both treated and control groups while concentrations of TRAcP5B were significantly lower in the treated group. Relatively small number of horses studied. Based on assessment of protein biomarkers, clodronate appears to influence osteoclasts at label doses. Furthermore, results of this study support racing regulations that preclude horses administered bisphosphonates for medical reasons, from racing for a prolonged period of time.

Osteogenesis imperfecta and bisphosphonate

Osteogenesis Imperfecta (OI) is defined as genetic disorders presented by various clinical presentations, such as bone deformities, abnormalities in dental structure, deafness, blue sclera, growth retardation, and ligament laxity. Most OI patients have a mutation in collagen type I alpha chains genes, COL1A1 and COL1A2. All those genes are expressed in osteoblasts and mostly responsible for the direct metabolism of collagen type I. Bisphosphonates (BPs), as potent antiresorptive agents, inhibit bone resorption through direct actions in the osteoclasts. They cut the excessive turnover rate and prevent bone tissue loss. The selection of BP regimens for OI patients is still a significant obstacle due to the lack of standardization of therapy and the lack of published evidence to determine the most appropriate type for different OI patients. The current use of BP and its benefit in OI are discussed in this review.

Hypocalcemia After the Administration of Denosumab in a Patient With Osteoporotic Fracture and Vitamin D Deficiency

Denosumab is a potent antiresorptive agent used for the treatment of osteoporosis and the prevention of skeletal-related events in patients with multiple myeloma or bone metastasis from solid tumors. Although denosumab generally seems to be safe and well tolerated, denosumab-associated hypocalcemia may occur, and the majority of cases are asymptomatic or mild. Underlying malignancy, renal failure, calcium or vitamin D deficiency, and high bone turnover have been reported as risk factors for hypocalcemia. Here, the author reports a case of hypocalcemia and hypophosphatemia following the administration of denosumab for the treatment of osteoporotic fracture in a patient with underlying but unrecognized severe vitamin D deficiency. Following the supplementation of calcium, vitamin D, and phosphorus, serum calcium and phosphorus levels returned to normal levels after about 2 weeks. To avoid denosumab-associated hypocalcemia, calcium and vitamin D status, as well as renal function should be assessed and corrected if appropriate. J Endocrinol Metab. 2022;12(3):111-115 doi: https://doi.org/10.14740/jem810

Pharmacological treatment of osteoporosis: 2022 update

Background: Osteoporosis is a skeletal disorder characterized by compromised bone strength resulting in a predisposition to fracture. Osteoporosis-related fractures can lead to pain, disability, and increased healthcare costs. We aimed to explore the guidelines and criteria for selecting medications for osteoporosis.Current Concepts: Osteoporosis medications can be classified mainly as antiresorptive drugs and osteogenesis promoters. The former includes selective estrogen receptor modulators, bisphosphonates, and receptor activators of nuclear factor kappa-B ligand inhibitors, e.g., denosumab. The latter includes human parathyroid hormone, e.g., teriparatide, and the dual-action agent, romosozumab. Selective estrogen receptor modulators (raloxifene or bazedoxifene) can be considered suitable for younger postmenopausal women with low spine bone mineral density. It also can be used for patients with low glomerular filtration rates due to low excretion in urine and patients who need dental care. Bisphosphonate has a residual effect on bone; therefore, osteonecrosis of the jaw and atypical fractures should be considered as side effects for its long-term use. Presently, denosumab is the most potent antiresorptive agent, but its favorable skeletal effects can be reversed quickly after its cessation. Therefore, subsequent antiresorptive treatment is mandatory. Romosozumab is a dual-action agent that simultaneously stimulates bone formation and inhibits bone resorption. It also needs a subsequent antiresorptive treatment.Discussion and Conclusion: Tailored treatment is needed in a patient with osteoporosis. Even in the case of the same bone density, the risk of fracture and the fracture sites differ depending on age. After setting an achievable goal of bone density within a suitable period, the appropriate medication should be selected.

Romosozumab for the treatment of osteoporosis in women: Efficacy, safety, and cardiovascular risk.

Increased understanding of the Wnt signaling pathway has led to the development of romosozumab, one of the most potent osteoanabolic agents to date for osteoporosis treatment. Romosozumab is a monoclonal antibody that inhibits sclerostin, a natural inhibitor of the Wnt signaling pathway. Romosozumab, by inhibiting sclerostin activates the Wnt signaling pathway, leading to increased bone formation and decreased bone resorption. The pivotal ARCH and FRAME studies established romosozumab’s fracture reduction efficacy. Romosozumab was superior to alendronate in fracture reduction and bone mineral density gain in the ARCH study. Romosozumab treatment should be followed sequentially with a potent antiresorptive agent. The antifracture efficacy gained from romosozumab is maintained or improved after transitioning to an antiresorptive agent. As one of the most potent osteoanabolic agents, the introduction of romosozumab has significantly increased our ability to treat osteoporosis. Studies have provided important information on using romosozumab with other osteoporosis medications to optimize osteoporosis treatment. Romosozumab used before antiresorptive medications is associated with more significant bone mineral density increases than when an antiresorptive agent is used before romosozumab. Romosozumab is recommended for osteoporosis treatment in patients at very high risk for fracture with low cardiovascular risk. Romosozumab is generally well tolerated, with 4%–5% of patients having injection site reactions. The ARCH trial showed a higher risk of cardiovascular events in patients receiving romosozumab. Romosozumab carries a black box warning that romosozumab should not be initiated in patients with myocardial infarction or stroke in the preceding year. However, the information on romosozumab and increased cardiovascular risk is conflicting. The risk of cardiovascular disease with romosozumab is unclear. While romosozumab has demonstrated significant osteoanabolic effect and antifracture efficacy and will benefit high fracture risk patients, further studies are needed to investigate the cardiovascular safety of romosozumab.

Comparison of Denosumab and Zoledronic Acid in Postmenopausal Women With Osteoporosis: Bone Mineral Density (BMD) and Trabecular Bone Score (TBS).

BackgroundDenosumab (DEN) and zoledronic acid (ZOL) currently represent the most potent antiresorptive agents for the treatment of osteoporosis. Despite similar effects on bone resorption, these agents have distinct mechanisms of action. The objective of this study was to compare the effect of DEN and ZOL after two-year administration on bone mineral density (BMD), trabecular bone score (TBS), bone turnover markers, and persistence.MethodsA total of 585 postmenopausal women with osteoporosis who did not use osteoporosis medications were retrospectively reviewed. 290 patients were administered 60 mg DEN subcutaneously every 6 months from 2017 to 2018, and 295 patients were treated with 5 mg ZOL intravenously yearly from 2015 to 2017. BMD, TBS, and C-terminal cross-linking telopeptide of type 1 collagen (CTX) measurements were obtained at baseline and two-year after DEN injection or ZOL infusion.ResultsAfter two-year follow-up, 188 patients in the DEN group and 183 patients in the ZOL group were compared. BMD change from baseline at two years was significantly greater in the DEN group compared with the ZOL group (P < 0.001). The changes of TBS in the DEN group were statistically significant compared with baseline (P < 0.001) and the ZOL group (P < 0.001). The DEN group led to significantly greater reduction of CTX compared with ZOL group (P = 0.041).ConclusionIn postmenopausal women with osteoporosis, DEN was associated with greater BMD increase at all measured skeletal sites, greater increase of TBS, and greater inhibition of bone remodeling compared with ZOL.

Osteonecrosis of the Jaw and Antiresorptive Agents in Benign and Malignant Diseases: A Critical Review Organized by the ECTS.

ContextAntiresorptive therapy significantly reduces fracture risk in patients with benign bone disease and skeletal-related events (SREs) in patients with bone metastases (BM). Osteonecrosis of the jaw (ONJ) is a rare but severe condition manifested as necrotic bone lesion or lesions of the jaws. ONJ has been linked to the use of potent antiresorptive agents, termed medication-related ONJ (MRONJ).ObjectiveWe aimed to identify the differences various aspects of MRONJ among distinct patient categories and provide recommendations on how to mitigate the risk and optimally manage MRONJ in each of them.MethodsA working group of the European Calcified Tissue Society (ECTS) and 2 experts performed an updated detailed review of existing literature on MRONJ incidence, characteristics, and treatment applied in bone diseases with variable severity of skeletal insult, ranging from osteoporosis to prevention of cancer treatment–induced bone loss and SREs in cancer patients with BM.ResultsThe risk for MRONJ is much higher in patients with advanced malignancies compared to those with benign bone diseases because of the higher doses and more frequent administration of antiresorptive agents in individuals with compromised general health, along with coadministration of other medications that predispose to MRONJ. The overall risk for MRONJ is considerably lower than the benefits in all categories of patients.ConclusionThe risk for MRONJ largely depends on the underlying bone disease and the relevant antiresorptive regimen applied. Physicians and dentists should keep in mind that the benefits of antiresorptive therapy far outweigh the risk for MRONJ development.

Detection and residence time of bisphosphonates in bone of horses.

Bisphosphonates are potent anti-resorptive agents that have the potential to adversely affect bone healing in equine athletes, and normal bone adaption in young racehorses. A concern exists that bisphosphonate inhibition of normal bone metabolism could lead to increased bone fractures during high-intensity exercise. We found only a single report describing concentrations of tiludronate in the bone of horses, and no studies describing clodronate. Knowledge of the residence time in bone could allow for a better understanding of the long-term effects of these compounds. Our objectives were to develop a method for detection of bisphosphonates in bone and add to the limited information available regarding the disposition of these drugs in the bone of horses. Two horses received clodronate and 2 tiludronate disodium. Postmortem collection of bones and teeth occurred either 4 or 30 d post drug administration. Additionally, postmortem blood, synovial fluid, aqueous humor, and bone samples from racehorses with various histories of bisphosphonate administration were collected, and concentrations determined using the developed LC-MS/MS method. Bisphosphonates were detected in bones and teeth tested at 4 and 30 d. In a postmortem sample, clodronate was detected in bone from a horse with reported administration 18 mo prior; clodronate was not detected in other sample types collected from this horse. Bisphosphonates reside in bone for extended periods of time, which could lead to potential long-term effects, increasing the potential for bone fractures in young and/or athletic horses.

Bisphosphonate-enoxacin inhibit osteoclast formation and function by abrogating RANKL-induced JNK signalling pathways during osteoporosis treatment.

Osteoporosis is an age‐related disease characterized by low mineral density, compromised bone strength and increased risk of fragility fracture. Most agents for treating osteoporosis focus primarily on anti‐resorption by inhibiting osteoclast activity. Bisphosphonate (BP) is a potent anti‐resorptive agent that has been used clinically for decades and is proven to be effective. However, BP has a variety of side effects and is far from being an ideal anti‐osteoporosis agent. BP selectively binds to calcium crystals, which are subsequently taken up or released by osteoclasts. Based on the action of BP, we previously demonstrated the inhibitory effect of a novel bone‐targeting BP derivative, bisphosphonate‐enoxacin (BE). In the current study, we used bone marrow‐derived osteoclast cultures to further assess the inhibitory effect of BE on osteoclastogenesis and employed reverse transcription PCR and real‐time PCR to examine expression of osteoclast‐specific genes. Additionally, we used bone resorption and F‐actin immunofluorescence assays to evaluate the effect of BE on osteoclast function and investigated the potential mechanisms affecting osteoclast differentiation and function in vitro. Furthermore, an ovariectomized (OVX) rat model was established to evaluate the therapeutic effects of BE on preventing bone loss. Results showed that BE exerted potent inhibitory effects on osteoclast formation and bone resorption by specifically abrogating RANKL‐induced JNK signalling, and that it preserved OVX rat bone mass in vivo without any notable side effects. Collectively, these results indicated that the BP derivative BE may have significant potential as a treatment for osteoporosis and other osteolytic diseases.

Update on Glucocorticoid Induced Osteoporosis.

Glucocorticoids are used to treat many autoimmune and inflammatory diseases. However, an adverse systemic effect is a deleterious effect on bone, which may lead to glucocorticoid-induced osteoporosis, characterized by a rapid and transient increase in bone resorption and fracture risk, which may increase rapidly within 3 months of commencing oral glucocorticoids. Therefore, early risk assessment and intervention are crucial for preventing fractures in patients receiving glucocorticoids. Recent practice guidelines recommend an assessment for fracture risk in patients beginning or receiving glucocorticoids for more than 3 months, and they have suggested fracture risk assessment tool values for identifying patients who need preventive treatment. Bisphosphonates are currently the recommended first-line therapy for the prevention and treatment of glucocorticoid-induced osteoporosis. These have been shown to increase the bone mineral density in the spine and hip and to decrease the incidence of vertebral fractures. Recently, a more potent antiresorptive agent, denosumab, has been shown to increase the bone density in patients receiving glucocorticoids. Teriparatide has been shown to have a preventive effect on vertebral fractures, but not on nonvertebral fractures. In this article we aimed to provide an update on glucocorticoid-induced osteoporosis by focusing on the assessment of its risk and treatment options.

Denosumab Discontinuation and the Rebound Phenomenon: A Narrative Review.

Denosumab is a potent antiresorptive agent that substantially increases bone mineral density and reduces fracture rates at all skeletal sites for as long as it is administered. However, its favorable skeletal effects reverse quickly upon its discontinuation, because of a vast increase of osteoclast number and activity, which leads to a subsequent profound increase of bone turnover above pre-treatment values, a phenomenon commonly described as “rebound phenomenon”. More importantly, most patients experience rapid, profound bone loss due to this burst of bone resorption that may lead in a minority of these patients to occurrence of fractures, especially multiple vertebral fractures. Therefore, subsequent antiresorptive treatment is mandatory, although the optimal regimen is yet to be clarified. In the present review, we outline what is currently known regarding the negative effects of denosumab discontinuation on different aspects of bone status, the factors that may affect them, and strategies to prevent them.

Denosumab (RANKL Inhibitor): A Potent Anti-Resorptive Agent

Denosumab (RANKL Inhibitor): A Potent Anti-Resorptive Agent

New insight into unexpected bone formation by denosumab

Denosumab (Dmab) was the first monoclonal antibody (mAb) approved for the treatment of osteoporosis. It blocks the receptor activator for nuclear factor κB ligand (RANKL) and acts as a potent antiresorptive agent. In contrast to classic antiresorptive agents, Dmab treatment leads to a progressive increase in bone mass, but the mechanisms remain controversial. Recently, RANKL signaling in osteoblastogenesis and bone formation and RANKL reverse signaling in coupling bone resorption and formation were demonstrated. Thus, here we discuss the roles of RANKL signaling and RANKL reverse signaling in the bone-forming effects of Dmab.

Zoledronate.

Zoledronate is the most potent and most long-acting bisphosphonate in clinical use, and is administered as an intravenous infusion. Its major uses are in osteoporosis, Paget's disease, and in myeloma and cancers to reduce adverse skeletal related events (SREs). In benign disease, it is a first- or second-line treatment for osteoporosis, achieving anti-fracture efficacy comparable to that of the RANKL blocker, denosumab, over 3years, and it reduces fracture risk in osteopenic older women. It is the preferred treatment for Paget's disease, achieving higher rates of remissions which are much more prolonged than with any other agent. Some trials have suggested that it reduces mortality, cardiovascular disease and cancer, but these findings are not consistent across all studies. It is nephrotoxic, so should not be given to those with significant renal impairment, and, like other potent anti-resorptive agents, can cause hypocalcemia in patients with severe vitamin D deficiency, which should be corrected before administration. Its most common adverse effect is the acute phase response, seen in 30-40% of patients after their first dose, and much less commonly subsequently. Clinical trials in osteoporosis have not demonstrated increases in osteonecrosis of the jaw or in atypical femoral fractures. Observational databases are currently inadequate to determine whether these problems are increased in zoledronate users. Now available as a generic, zoledronate is a cost-effective agent for fracture prevention and for management of Paget's disease, but wider provision of infusion facilities is important to increase patient access. There is a need to further explore its potential for reducing cancer, cardiovascular disease and mortality, since these effects could be substantially more important than its skeletal actions.

Hypophosphatasia: Current Literature for Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment.

Hypophosphatasia (HPP) is a rare inherited bone disorder identified by impaired bone mineralization. There are seven subtypes of HPP mainly characterized by their age of onset. These subtypes consist of perinatal (prenatal) benign, perinatal lethal, infantile, childhood, adult, odontohypophosphatasia, and pseudohypophosphatasia. Due to limited awareness of the condition, either misdiagnosis or delayed diagnosis is common. Furthermore, the condition is frequently treated with contraindicated drugs. This literature illustrates the most recent findings on the etiology, pathophysiology, clinical manifestations, diagnosing, and treatment for HPP and its subtypes. The etiology of the disease consists of loss-of-function mutations of the ALPL gene on chromosome one, which encodes for tissue nonspecific isoenzyme of alkaline phosphatase (TNAP).A decrease of TNAP reduces inorganic phosphate (Pi) for bone mineralization and allows for an increase in inorganic pyrophosphate (PPi) and phosphorylated osteopontin (p-OPN), which further reduces bone mineralization. The combination of these processes softens bone and mediates a clinical presentation similar to rickets/osteomalacia. HPP has an additional wide range of clinical features depending on its subtype.Although a concrete diagnostic guideline has not yet been established, many studies have supported a similar method of identifying HPP. Clinical features, radiological findings, and/or biomarker levels of the disorder should raise suspicion and encourage the inclusion of HPP as a differential diagnosis. Biomarkers, especially alkaline phosphatase (ALP), are major contributors to diagnosis. However, genetic testing is done for definitive diagnosis.The primary treatment for HPP is the reintroduction of TNAP as a recombinant enzyme called asfotase alfa. There are additional pharmaceutical treatments and in some cases, surgical intervention may be indicated. Pharmaceutical therapies such as bisphosphonates, denosumab, potent antiresorptive agents, and vitamin D are contraindicated in adults with HPP.We hope to raise awareness for HPP in order to prevent delayed diagnosis or misdiagnosis. We plan to encourage appropriate care and avoid treatments that may be contraindicating. We also encourage the development of a diagnostic guideline that will promote a consistently favorable patient prognosis.

Standard Versus Cyclic Teriparatide and Denosumab Treatment for Osteoporosis: A Randomized Trial.

In the absence of an intervening antiresorptive agent, cyclic administration of teriparatide does not increase bone mineral density (BMD) more than standard daily therapy. Because denosumab is a potent antiresorptive agent with a rapid off-effect, we hypothesized that it might be the optimal agent to help maximize bone gains with cyclic teriparatide. In this 3-year protocol, 70 postmenopausal women with osteoporosis were randomized to 18 months of teriparatide followed by 18 months of denosumab (standard) or three separate 12-month cycles of 6 months of teriparatide followed by 6 months of denosumab (cyclic). BMD (dual-energy X-ray absorptiometry [DXA]) measurements of lumbar spine (LS), total hip (TH), femoral neck (FN), and 1/3 radius (RAD) were performed every 6 months and total body bone mineral (TBBM) at 18 and 36 months. Baseline descriptive characteristics did not differ between groups except for a minimal difference in LS BMD but not T-score (mean age 65 years, mean LS T-score - 2.7). In the standard group, BMD increments at 36 months were: LS 16%, TH 4%, FN 3%, and TBBM 4.8% (all p < 0.001 versus baseline). In the cyclic group, 36-month BMD increments were similar: LS 12%, TH 4%, FN 4%, and TBBM 4.1% (all p < 0.001 versus baseline). At 36 months, the LS BMD increase with standard was slightly larger than with cyclic (p = 0.04), but at 18 months, in the cyclic group, there was no decline in RAD or TBBM (p = 0.007 and < 0.001, respectively, versus standard). Although the cyclic regimen did not improve BMD compared with standard at 36 months, there appeared to be a benefit at 18 months, especially in the highly cortical skeletal sites. This could be clinically relevant in patients at high imminent risk of fracture, particularly at nonvertebral sites. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.