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The influence of pyrophosphate, condensed phosphates, phosphonates and other phosphate compounds on the dissolution of hydroxyapatite in vitro and on bone resorption induced by parathyroid hormone in tissue culture and in thyroparathyroidectomised rats
Abstract
Earlier studies have shown that inorganic pyrophosphate (PPi) inhibits the dissolution of hydroxyapatite crystalsin vitro and it has been suggested that PPi might be a physiological regulator of bone resorption. In this study PP1 and other phosphate compounds have been tested for their ability to inhibit bone resorption induced by parathyroid hormone in mouse calvaria and to inhibit the rise in plasma calcium induced by parathyroid hormone in thyroparathyroidectomised rats on a low calcium diet. Orthophosphate, pyrophosphate, polyphosphate and two polymeric phosphate inhibitors of phosphatases did not inhibit the resorption of calvaria or the rise in plasma calcium. In contrast, several phosphonates containing P-C-P bonds retarded the dissolution of hydroxyapatite crystalsin vitro, and, at concentrations down to 1.6×10−6M, inhibited bone resorption in tissue culture. Some diphosphonates also inhibited the rise in plasma calcium in thyroparathyroidectomised rats. One reason for the difference between the effects of compounds containing P-O-P and P-C-P bonds may be related to the greater resistance of the latter to chemical and enzymic hydrolysis. Phosphonates may provide a model for the effect of endogenous PP1 in bone, and might be of use in elucidating provide a model for the effect of endogenous PP1 in bone, and might be of use in elucidating mechanisms of bone formation and resorption and in the therapy of diseases that involve increased resorption of bone.
... However, the possibility that calcium ion complexation by PP i could be made a basis for treating bone diseases was disregarded due to the instability of PP i to hydrolysis under physiological conditions Fleisch et al., 1969). Instead, as hydrolytically stable PP i analogues with a much greater potential for extensive derivatization, bisphosphonates appeared to be a more promising platform for bone drug development (Russell et al., 1970). Fig. 2), the first BP used for the treatment of a human disease (myositis ossificans progressiva in a 16-month-old infant (Bassett et al., 1969)), was patented in 1966 (Quimby and Prentice, 1966) and approved for medical use in 1977 under the brand name of Didronel ® for osteoporosis, hypercalcemia of malignancy, and Paget's disease of bone (Smith et al., 1971(Smith et al., , 1973. ...
... Fig. 2), the first BP used for the treatment of a human disease (myositis ossificans progressiva in a 16-month-old infant (Bassett et al., 1969)), was patented in 1966 (Quimby and Prentice, 1966) and approved for medical use in 1977 under the brand name of Didronel ® for osteoporosis, hypercalcemia of malignancy, and Paget's disease of bone (Smith et al., 1971(Smith et al., , 1973. Clodronate (CLO, Fig. 2), patented in 1989 (Demmer and Stemmle, 1989) and initially commercialized by Instituto Gentili (now Abiogen) in Italy, was discovered to possess higher antiresorptive activity than etidronate, but exhibited less affinity to bone, attributed to its lack of an a-hydroxy group (Russell et al., 1970). CLO has been used for medication under the trade names of Bonefos®, Clasteon®, and Ostac® for treatment of osteolytic lesions, hypercalcemia and bone pain associated with skeletal morbidity in metastatic breast cancer patients (Paterson et al., 1993). ...
... Pioneering studies on bone resorption, induced by the parathyroid hormone by Russell et al. examined the differential effects on thyroparathyroidectomized (TPTX) rats of phosphate, PP i , and BPs (including MED, ETI, and CLO) (Russell et al., 1970). Further in vivo investigations on the antiresorptive effects of ETI and CLO were done by Schenk et al., who observed changes in trabecular bone in rats during BP treatment (Schenk et al., 1973). ...
“Bisphosphonate” (BP) is a commonly used generic term for a pyrophosphate (PPi) analogue containing a pCR¹R²p group. This replacement of the bridging O atom in PPi by a carbon atom greatly enhances stability to hydrolysis and make possible substitution (R¹, R²) derivatives that exhibit diverse chemical, biological and pharmacological properties, while sharing the ability to chelate metal dications. The synthesis and characteristics of representative BPs are briefly described. Certain BPs are useful in the treatment of resorptive bone diseases, including osteoporosis and bone cancers, and new applications for BPs are emerging in biology and medicine.
... For this reason, the use of pyrophosphate as a drug was constrained by its pharmacokinetics because it was hydrolyzed and inactivated when was administered orally [42,43]. Consequently, bisphosphonates were found to be chemically stable analogues of pyrophosphate that could inhibit pathological calcification and bone resorption when they were administered orally [44,45]. Similar to their natural analogue pyrophosphate, bisphosphonates have a very high affinity for bone mineral because they bind to hydroxyapatite crystals. ...
... Therefore, the retention of bisphosphonates on bone surface depends on the availability of hydroxyapatite binding sites. To date, many studies using in vitro systems, animal models, and clinical trials have shown that a variety of bisphosphonates can inhibit bone resorption [44,45]. ...
The main objective of this work was to explore the association of dietary phytate intake with bone mineral density (BMD) in a Mediterranean population of postmenopausal women. For this purpose, a cross-sectional analysis of 561 women aged 55–75 years with overweight/obesity and metabolic syndrome from a Mediterranean area and with data on dual-energy X-ray absorptiometry (DXA) scans in femur and lumbar spine was performed. Estimated phytate intake was calculated using a validated food frequency questionnaire. Our results indicated that phytate intake was associated with BMD [β(95%CI) per each 25 mg/100 kcal] in femoral neck [0.023(0.060–0.040) g/cm2], femoral Ward’s triangle [0.033(0.013–0.054) g/cm2], total femur [0.018(0.001–0.035) g/cm2], and all the analyzed lumbar spine sites [L1–L4: 0.033(0.007–0.059) g/cm2] after adjusting for potential confounders. The sensitivity analysis showed that phytate intake was directly associated with lumbar spine BMD in women younger than 66 years, with a body mass index higher than 32.6 kg/cm2 and without type 2 diabetes (all p-for interactions < 0.05). The overall results indicated that phytate, a substance present in food as cereals, legumes and nuts, was positively associated with BMD in Mediterranean postmenopausal women. Phytate may have a protective effect on bone resorption by adsorbing on the surfaces of HAP. Nevertheless, large, long-term, and randomized prospective clinical studies must be performed to assess the possible benefits of phytate consumption on BMD in postmenopausal women.
... Bisphosphonates are generally divided into two categories, depending on the presence of nitrogen in the two covalently-bonded groups attached to the geminal carbon. Simple bisphosphonates consist of two phosphate groups bonded to a carbon atom to which two side chains (R 1 and R 2 ) are bonded [80][81][82]. In etidronate, R 1 is a hydroxyl, while R 2 is a methyl. ...
... Even more effective in inhibiting bone resorption than etidronate are clodronate and tiludronate, where the R 1 and R 2 consist of chlorine atoms and R 1 is a hydrogen atom and R 2 is a chlorophenyl group. Non-nitrogenous bisphosphonates inhibit the activity of osteoclasts by inducing their apoptosis in vitro and in vivo, meaning osteoclast retraction, condensation, and cellular fragmentation [80,81,[83][84][85][86][87][88]. ...
The use of therapeutic agents that inhibit bone resorption is crucial to prolong implant life, delay revision surgery, and reduce the burden on the healthcare system. These therapeutic agents include bisphosphonates, various nucleic acids, statins, proteins, and protein complexes. Their use in systemic treatment has several drawbacks, such as side effects and insufficient efficacy in terms of concentration, which can be eliminated by local treatment. This review focuses on the incorporation of osteoclast inhibitors (antiresorptive agents) into bioactive coatings for bone implants. The ability of bioactive coatings as systems for local delivery of antiresorptive agents to achieve optimal loading of the bioactive coating and its release is described in detail. Various parameters such as the suitable concentrations, release times, and the effects of the antiresorptive agents on nearby cells or bone tissue are discussed. However, further research is needed to support the optimization of the implant, as this will enable subsequent personalized design of the coating in terms of the design and selection of the coating material, the choice of an antiresorptive agent and its amount in the coating. In addition, therapeutic agents that have not yet been incorporated into bioactive coatings but appear promising are also mentioned. From this work, it can be concluded that therapeutic agents contribute to the biocompatibility of the bioactive coating by enhancing its beneficial properties.
... The adsorption of such compounds to crystal faces can also inhibit crystal dissolution. Consequently, bisphosphonates could inhibit hydroxyapatite crystal dissolution [4,5] and bone resorption [4][5][6] when they are orally administered. Like their natural analogue pyrophosphate, bisphosphonates have a very high affinity for bone mineral because they bind to hydroxyapatite crystals. ...
... The adsorption of such compounds to crystal faces can also inhibit crystal dissolution. Consequently, bisphosphonates could inhibit hydroxyapatite crystal dissolution [4,5] and bone resorption [4][5][6] when they are orally administered. Like their natural analogue pyrophosphate, bisphosphonates have a very high affinity for bone mineral because they bind to hydroxyapatite crystals. ...
Myo-inositol hexaphosphate (phytate; IP6) is a natural compound that is abundant in cereals , legumes, and nuts, and it can bind to crystal surfaces and disturb crystal development, acting as crystallization inhibitor. The adsorption of such inhibitors to crystal faces can also inhibit crystal dissolution. The binding of phytate to metal cofactors suggests that it could be used for treatment of osteoporosis. Our in-vitro study showed that phytate inhibits dissolution of hydroxyapatite (HAP). The effect of phytate was similar to that of alendronate and greater than that of etidronate. This led us to perform a cross-sectional study to investigate the impact of consumption of IP6 on bone mineral density (BMD) in post-menopausal women. Our data indicate that BMD and t-score of lumbar spine increased with increasing phytate consumption, and a phytate consumption higher than 307 mg/day was associated with a normal BMD (t-score > −1). These data suggest that phytate may have a protective effect in bone decalcification by adsorbing on the surfaces of HAP, and a daily consumption of phytate-rich foods (at least one serving/day of legumes or nuts) may help to prevent or minimize bone-loss disorders, such as osteoporosis. However, further studies are needed to gain a better understanding about the mechanism of inhibition of phytate in bone-related diseases (see graphical abstract).
... This decreased bone resorption and turnover prevents bone loss and improves bone strength. 2,3 Long-term bisphosphonate treatment of osteoporosis is a generally safe and effective therapy. However, long-term therapy can potentially oversuppress bone turnover. ...
... Inclusion criteria consisted of patients who (1) had a history of bisphosphonate use for more than 2 years, (2) presented with a complete atypical subtrochanteric femur fracture as defined by ASBMR radiologic criteria (transverse or short oblique fracture line, medial spike, focal lateral cortical thickening, and lack of comminution), (3) were treated with a cephalomedullary nail, and (4) had at least 1 year of follow-up postoperatively. Patients who were younger than 50 year and those who sustained high-energy injuries including open fractures were excluded. ...
Objectives:
The purpose of this study was to determine the healing rate and time-to-union of atypical subtrochanteric fractures treated with cephalomedullary nailing DESIGN: Retrospective review, descriptive and analytic study SETTING: Six level 1 trauma centers PATIENTS/PARTICIPANTS: The study included 42 patients with 48 displaced, atypical, bisphosphonate-associated subtrochanteric femur fractures who underwent surgical intervention.
Intervention:
Cephalomedullary femur nailing MAIN OUTCOME MEASUREMENT: The main outcome measures were radiologic healing and time to union.
Results:
The primary healing rate after cephalomedullary nailing of bisphosphonate-associated subtrochanteric femur fractures was 68.7% (33/48 patients). Mean time-to-union was 10.7 months. Malalignment was determined using the differences in neck-shaft angle (the difference between the normal side and the surgically repaired side), and sagittal angulation. These all proved to be significantly correlated with failure and delayed healing time. The cutoff points for neck-shaft angle, difference in neck-shaft angle, and sagittal angulation were 125.6°, 4.4°, and 5.5°, respectively (receiver operating characteristic, ROC curve analysis).
Conclusions:
The healing rate of atypical subtrochanteric femur fractures treated with cephalomedullary nailing is lower than that previously reported for atypical femur fractures. The quality of fracture reduction proved to be the most important factor in bony union and time-to-union.
Level of evidence:
Therapeutic Level IV.See Instructions for Authors for a complete description of levels of evidence.
... БФ, не поглощенные костной тканью в скелете быстро выводятся, быстро выводится из кровообращения путем почечной экскреции. Помимо способности ингибировать кальцификацию, БФ ингибируют распад гидроксиапатита, тем самым эффективно подавляя резорбцию костной ткани [3]. Это фундаментальное свойство БФ привело к их клиническому использованию. ...
Osteoporosis (OP) is one of the common chronic diseases in the elderly, which requires long–term therapy. Bisphosphonates (BP) belong to the first-line choice medications for the treatment of OP, however, prolonged period of bisphosphonates use has been associated with increased risk of atypical femoral fractures (AFFs), medication-related osteonecrosis of the jaw (MRONJ) and the impact on fracture healing, which attracts increased attention to the current widespread use of them.
The article presents the existing classes of BP according to their chemical structure and mechanism of action, differences in their antiresorptive potencies. The data of studies on animal models on the effect of BP on the mechanical properties of bone, fracture repair, as well as the development of MRONJ are presented.
... BPs are characterized by their phosphorus-carbon-phosphorus structural backbone and are connected to inorganic pyrophosphates on a molecular level [6]. BPs are synthetic, hydrolysis-resistant compounds with a high affinity for calcium that target regions of high resorption on bone hydroxyapatite surfaces in contrast to inorganic pyrophosphates [7,8]. Generations are another way to categorize BPs, with the first generation consisting of non-nitrogenous medications including clodronate, etidronate, and tiludronate. ...
An aberrant growth of plasma cells in the bone marrow characterizes the hematological neoplasm known as multiple myeloma, which is typically accompanied by increased bone pain and skeletal-related events such as pathological fractures and/or spinal cord compression. Changes in the bone marrow microenvironment brought on by increased osteoclastic activity and/or decreased osteoblastic activity as a result of myeloma bone disease have a detrimental effect on quality of life. Bone-modifying medications such as bisphosphonates or denosumab are used to treat myeloma bone disease. These substances can lessen bone pain and the chance of pathological fracture, but they do not stimulate the growth of new bone or heal already damaged bone. In order to conduct this study, we searched the PubMed, Google Scholar, and Cochrane databases for complete free papers published in English and studied people over the previous five years, starting in 2018. The search covered randomized clinical trials (RCT), observational studies, meta-analyses, systemic reviews, and conventional reviews. Twenty-five publications are picked after using quality evaluation techniques to determine the type of study. These papers' full-text articles are investigated, examined, and tallied. We spoke about the various treatments for bone damage in multiple myeloma. It was discovered that bisphosphonates lessen the frequency and severity of bone problems. However, we are unsure of their contribution to survival.
Although these medicines enhance life quality, it is unknown if they also increase overall survival. The focus of this study is on several kinds of bone-modifying drugs, their processes of action, the point at which therapy is started, how long it lasts, and any possible mortality advantages.
... [3][4][5][6][7][8][9][10] BPs are potent osteoclast inhibitors that reduce osteoclast-induced bone resorption and remodeling. 1,11 The most widely used BPs are nitrogen-containing, including alendronate, risedronate and zoledronate. These diphospate synthase. ...
Case summary
A 10-year-old spayed female domestic medium hair cat presented after sustaining atraumatic insufficiency fractures of the right calcaneus and the left tibia approximately 6 weeks apart. Chronic alendronate therapy had been ongoing for 9 years for the management of previously diagnosed idiopathic hypercalcemia. The right calcaneal fracture was managed non-operatively due to minimal functional impairment. The left tibial fracture was managed via open reduction and internal fixation with orthogonal plating. Alendronate therapy was discontinued at the time of the fracture repair with prednisolone being used to manage the hypercalcemia. Despite rapid clinical improvement, the tibial fracture had a protracted healing course, with clinical union only being achieved 22 weeks postoperatively. At 17 months postoperatively, the idiopathic hypercalcemia remained well controlled. Gait assessment, orthopedic examination and orthogonal radiographs performed at this time revealed resolution of left pelvic limb lameness, a normal orthopedic examination of the left pelvic limb and no evidence of implant-associated complications. Monitoring is ongoing but at the time of publication, no further fractures have occurred.
Relevance and novel information
As reported in humans, this case report gathers evidence of associations between bisphosphonate treatment and the occurrence of insufficiency fractures in cats, and provides evidence that stress reactions may precede their development. If bisphosphonate therapy is utilized in the long term, serial radiographic monitoring for signs of impending fracture may be warranted. Fracture repair can be successful in cats that have received long-term bisphosphonate therapy, but delayed healing should be anticipated and implant choices made accordingly.
... BFs have the capacity to prevent bone resorption and to increase bone density, to prevent experimentally induced calcification, to inhibit ectopic bone mineralization, to inhibit the dissolution of hydroxyapatite crystals. By increasing the bone resistance, the fracture incidence is decreased [8][9][10][11][12]. But in animals, high doses result in the worsening of microfractures and even in the occurrence of fractures [13,14]. ...
This article aims to establish, on the basis of medical literature and of the authors’ experience, whether bisphosphonates still have a role in treating skeletal diseases, with increased bone resorption. The effects of bisphosphonates on the bone tissue, as well as the diseases in which they are recommended and the benefits obtained are reviewed. Possible side effects are emphasized, both the immediate ones, which are better known and the late ones, occurring after a long-term administration. It is shown that the benefit/risk ratio remains favorable. The conclusions highlight the fact that nowadays bisphosphonates still have an important place in the treatment of skeletal diseases.
... Pamidronate, a nitrogenous bisphosphonate, comes forth as the solution. Similar to all bisphosphonates, it is an inorganic derivative of pyrophosphate, and it directly binds to the hydroxyapatite crystals on the bone and inhibits bone resorption (6,13,14). Calcium level was normalized on the fourth day following the second dose of pamidronate and the child had no hypocalcemia after this treatment. No other adverse effect was observed related to pamidronate. ...
... In 1962, Fleisch and Bisaz proved this hypothesis correct when they isolated urinary pyrophosphate and demonstrated it as an effective inhibitor of calcium crystallization [3]. Another major advance in understanding bone physiology came in 1970 when it was demonstrated that both pyrophosphates and diphosphonates inhibited the dissolution of hydroxyapatite crystals and bone resorption in response to parathyroid hormone [4,5]. These findings advanced the line of scientific inquiry related to how bisphosphonates might regulate whole-body calcium metabolism and the flux of calcium into and out of bone. ...
The precise control of whole-body calcium is essential for the maintenance of normal physiological function. Disruptions in calcium homeostasis can lead to pathology including osteoporosis, kidney stone formation, and cardiac arrythmias. During the 1960s and early 1970s, a full understanding of calcium metabolism was still emerging. This commentary spotlights a seminal Clinical Science paper published in 1972 that significantly advanced the field and contributed to the eventual approval of bisphosphonate drugs commonly used to treat postmenopausal osteoporosis, cancer metastases, and other calcium disorders.
... S keletal disorders such as osteoporosis and cancer-related bone metastasis are often treated with bisphosphonates (BPs) because of their antiresorptive function. (1) By inhibiting osteoclastic activity and by binding to hydroxyapatite crystals, BPs inhibit hydroxyapatite breakdown (2) and alter the balance in bone remodeling by suppressing bone resorption (3) in favor of a net gain in bone mineral density (BMD). (4) However, treatment with BPs for a long period of time or in a high dosage has been associated with a greater risk of developing osteonecrosis of the jaw (ONJ), (5)(6)(7)(8)(9) often referred to as medication-related ONJ (MRONJ). ...
Medication‐related osteonecrosis of the jaw (MRONJ) is a known side effect of bisphosphonates (BPs). While bacterial infection is usually present, the etiology of MRONJ remains unknown. Herein, we apply a multimodal and multiscale (micro‐to‐nano) characterization approach to investigate the interface between necrotic bone and bacteria in MRONJ. A non‐necrotic bone sample was used as a control. Both necrotic and non‐necrotic bone samples were collected from the jaw of a female individual affected by MRONJ after using BPs for 23 years. For the first time, resin cast etching was used to expose bacteria at the necrotic site. The bone‐bacteria interface was also resolved at the nanoscale by scanning transmission electron microscopy (STEM). Nano‐sized particulates, likely corresponding to degraded bone mineral, were often noted in close proximity to or enclosed by the bacteria. STEM also revealed that the bone‐bacteria interface is composed of a hypermineralized front fading into a highly disordered region, with decreasing content of calcium and phosphorus, as assessed by electron energy loss spectroscopy (EELS). This, combined with the variation in calcium, phosphorus and carbon across the necrotic bone‐bacteria interface evaluated by scanning electron microscopy (SEM)‐energy dispersive X‐ray spectroscopy (EDX) and the lower mineral‐to‐matrix ratio measured by micro‐Raman spectroscopy in necrotic bone, indicates the absence of a mineralization front in MRONJ. It appears that the bone‐bacteria interface originates not only from uncontrolled mineralization, but also from the direct action of bacteria degrading the bone matrix.
... A 2011 study demonstrated the efficacy of bisphosphonate therapy in reducing hypercalciuria in patients with renal lithiasis and bone resorption [6]. Bisphosphonates are analogs of pyrophosphate with a high affinity for the hydroxyapatite of bone, especially in areas of rapid turnover and bone resorption [7,8]. These drugs inhibit osteoclast activity, which causes a net increase in bone density, calcium deposition, and mineralization [9,10]. ...
The objective is to evaluate the effect of phytate supplements on calciuria in patients with urinary stones and elevated bone resorption. The secondary objective is to analyze the therapeutic effect of phytate based on measurements of serum markers of bone resorption. This is a controlled randomized study included patients according to predefined inclusion and exclusion criteria, and randomized them into two groups. Patients in the phytate group received a 380 mg capsule of calcium-magnesium InsP6 (Salvat Laboratories ® ) every 24 h for 3 months and patients in the control group received no treatment. All included patients were male or female, 18–65 years old, had hypercalciuria (> 250 mg/24 h), had a ß-Crosslaps level greater than 0.4 ng/mL, and had bone densitometry results indicative of osteopenia or osteoporosis in the femur and/or spine. At study onset, calciuria was 321 ± 52 mg/24 h in the phytate group and 305 ± 57 mg/24 h in the control group ( p > 0.05). At 3 months, calciuria was significantly lower in the phytate group than the control group (226 ± 45 mg/24 h vs. 304 ± 58 mg/24 h, p < 0.05). At study onset, the mean ß-CrossLaps level was 1.25 ± 0.72 ng/mL in the phytate group and 0.57 ± 0.13 ng/mL in the control group ( p < 0.05). However, at 3 months, the ß-CrossLaps level was significantly lower in the phytate group than in the control group (0.57 ± 0.13 ng/mL vs. 0.77 ± 0.42 ng/mL, p < 0.05). Phytate reduced calciuria in patients with hypercalciuria secondary to bone resorption. The ß-CrossLaps assay was effective for evaluating the efficacy of phytate on hypercalciuria during follow-up.
... Several studies have proven the ability of bisphosphonates to inhibit osteoclastmediated bone resorption in vitro and in vivo. [51][52][53][54][55][56] Furthermore, bisphosphonates suppress bone resorption, induced by multiple other agents (eg, vitamin D), and are effective in preventing bone destruction. 57 Due to their high bone adsorption and their chelating properties, early research focused on labeling bisphosphonates directly with radionuclides for therapeutic purposes. ...
Radiometal-based theranostics or theragnostics, first used in the early 2000s, is the combined application of diagnostic and therapeutic agents that target the same molecule, and represents a considerable advancement in nuclear medicine. One of the promising fields related to theranostics is radioligand therapy. For instance, the concepts of targeting the prostate-specific membrane antigen (PSMA) for imaging and therapy in prostate cancer, or somatostatin receptor targeted imaging and therapy in neuroendocrine tumors (NETs) are part of the field of theranostics. Combining targeted imaging and therapy can improve prognostication, therapeutic decision-making, and monitoring of the therapy.
... Bisphosphonates (BPs) are stable pyrophosphate analogues that tightly bind to bone apatites [12]. BPs exert their effect by inhibiting osteoclast differentiation and activity, preventing bone resorption and reducing its turnover; these processes significantly reduce the risk of osteoporosis [13]. ...
Background
To evaluate the effect of postoperative BP treatment on improving the fusion rate after lumbar spinal fusion surgery by performing a meta-analysis of randomized controlled trials (RCTs) and other comparative cohort studies.
Methods
A comprehensive search of PubMed, EMBASE, the Web of Science, and the Cochrane Central Register of Controlled Trials was performed for RCTs and other comparative cohort studies on the effect of BP treatment on improving the fusion rate after lumbar spinal fusion surgery. The primary outcome measures were the number of patients with bone formation grades A, B, and C at 12 months of follow-up; fusion rates at 12 and 24 months of follow-up; vertebral compression fracture (VCF) at 12 and 24 months of follow-up; pedicle screw loosening at 24 months of follow-up; and cage subsidence, the Oswestry disability index (ODI), and the visual analogue score (VAS) at 12 months of follow-up. The final search was performed in July 2020.
Results
Seven studies with 401 patients were included. Compared with the placebo, BP treatment did not significantly alter the number of patients with bone formation grades A, B, and C, or the VAS at the 12-month follow-up or the fusion rates at the 12- and 24-month follow-ups. In addition, compared with the placebo, BPs significantly reduced the risks of VCF at the 12- and 24-month follow-ups, pedicle screw loosening at the 24-month follow-up, and cage subsidence and the ODI at the 12-month follow-up.
Conclusions
Postoperative BPs do not clearly improve bone formation and the fusion rate, but they reduce VCF, cage subsidence, and loosening of pedicle screws after lumbar fusion surgery compared with the control treatment.
... This P-C-P structure was found to be metabolically stable versus the P-O-P feature of the natural bone metabolism regulator pyrophosphate; therefore, the BP chemical class provided useful drug candidates for systemic administration. (34,44) Both of these general chemical features uniquely coordinate to calcium and to the major calcium phosphate mineral component of bone-HAP. Variants can be compared and ranked for their bone affinity, using various in vitro models comprised of calcium phosphate HAP crystals and mineral surfaces. ...
Bisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about bone health due to over‐suppression of remodeling remain. Long‐term bone remodeling suppression adversely affects bone material properties with microdamage accumulation and reduced fracture toughness in animals and increases in matrix mineralization and atypical femur fractures in patients. While a “drug holiday” from BPs to restore remodeling and improve bone quality seems reasonable, clinical BPs have long functional half‐lives due to their high hydroxyapatite (HAP) binding affinities. This places a practical limit on the reversibility and effectiveness of a drug holiday. Bisphosphonates with low HAP affinity and strong osteoclast inhibition potentially offer an alternative approach, as their antiresorptive effect should reverse rapidly when dosing is discontinued. We tested this concept using NE‐580254, a BP with low HAP affinity and moderate osteoclast inhibition potential. Experimental Design: Young adult female C57Bl/6 mice were ovariectomized (OVX) and treated with NE‐58025, Risedronate (RIS) or PBS vehicle for 3 months to test effectiveness in preventing long‐term bone loss. Bone microarchitecture, histomorphometry and whole bone mechanical properties were assessed. To test reversibility, OVX mice were similarly treated for 3 months, treatment was stopped and bone was assessed up to 3 months post‐treatment. Results: NE‐58025 and RIS inhibited long‐term OVX‐induced bone loss, but NE‐58025 antiresorptive effects were more pronounced. Withdrawing NE‐58025 treatment led to the rapid onset of trabecular resorption, with a 200% increase in osteoclast surface and bone loss within one month. Cessation of RIS treatment did not lead to increases in resorption indices or bone loss. These results show that NE‐58025 prevents OVX‐induced bone loss and its effects reverse quickly following cessation treatment in vivo. Low‐HAP affinity BPs may have utility as reversible, anti‐resorptive agents with a rapid on/off profile, which may be useful for maintaining bone health with long‐term BP treatment.
... Bisphosphonates (BPs) are stable pyrophosphate analogues that tightly bind to bone apatites [12]. BPs exert their effect by inhibiting osteoclast differentiation and activity, preventing bone resorption and reducing its turnover; these processes signi cantly reduce the risk of osteoporosis [13]. ...
BACKGROUND: To evaluate the effect of postoperative BP treatment on improving the fusion rate after lumbar spinal fusion surgery by performing a meta-analysis of randomized controlled trials (RCTs) and other comparative cohort studies.
METHODS: A comprehensive search of PubMed, EMBASE, the Web of Science and the Cochrane Central Register of Controlled Trials was performed for RCTs and other comparative cohort studies on the effect of BP treatment on improving the fusion rate after lumbar spinal fusion surgery. The primary outcome measures were the number of patients with bone formation grades A, B, and C at 12 months of follow-up, fusion rates at 12 and 24 months of follow-up, vertebral compression fracture (VCF) at 12 and 24 months of follow-up, pedicle screw loosening at 24 months follow-up, cage subsidence, the Oswestry Disability Index (ODI) and the visual analogue score (VAS) at 12 months of follow-up. The final search was performed in July 2020.
RESULTS: Seven studies with 401 patients were included. Compared with the placebo, BP treatment did not significantly alter the number of patients with bone formation grades A, B and C, or the VAS at the 12-month follow-up or the fusion rates at the 12- and 24-month follow-ups. In addition, compared with the placebo, BPs significantly reduced the risks of VCF at the 12- and 24-month follow-ups, pedicle screw loosening at the 24-month follow-up, and cage subsidence and the ODI at the 12-month follow-up.
CONCLUSIONS: Postoperative BPs do not clearly improve bone formation and the fusion rate, but they reduce VCF, cage subsidence and loosening of pedicle screws after lumbar fusion surgery compared with the control treatment.
... Modification of one or both groups would reduce the affinity for bone minerals, so both phosphonate groups are required to maintain their medicinal effectiveness. 19,27 Due to partial oxidation, multiple phosphate groups exist on the surface edge of BP. We speculate that oBPNSs might be an effective analog of Bip. ...
... BPs have a high affinity for calcium hydroxyapatite on bone cells and in this way BPs bind to osteoclasts. Ultimately, BPs inhibit development of osteoclast progenitors and osteoclast recruitment, and stimulate apoptosis of mature osteoclasts [49,50]. BPs are contra-indicated in patients with severe renal insufficiency (creatinine clearance below 30-35 ml/min) and precaution should be taken for longterm use of BPs because of the risk of osteonecrosis of the jaw (ONJ) or atypical femur fracture (AFF). ...
Introduction
Rheumatoid arthritis (RA) is a chronic disabling disease characterized by a symmetrical articular involvement due to ongoing joint inflammation, if left insufficiently treated. Local and generalized bone loss is one of the main extra-articular complications of RA and leads to an increased risk for fragility fractures, which further impair functional ability, quality of life, and life expectancy. Therefore, there is an urgent need for good fracture risk management in the vulnerable RA patient.
Areas covered
The authors review: the epidemiology and pathophysiology (i.e. risk factors) of osteoporosis (OP), fracture, and vertebral fracture risk assessment, the effects of anti-rheumatic drugs on bone loss, pharmacological treatment of OP in RA including both bisphosphonates (BP) and newer drugs including anti-resorptives and osteoanabolic treatment options.
Expert opinion
Patients with active RA have elevated bone resorption and local bone loss. Moreover, these patients are at increased risk for generalized bone loss, vertebral and non-vertebral fractures. Since general risk factors (such as low BMI, fall risk) and RA-related factors play a role, optimal fracture prevention in RA patients is based on optimal diagnostics based on both of these factors, and on the use of adequate non-medical and medical treatment options.
... The P-C-P unit is responsible for giving bisphosphonates their high affinity for bone and the ability to inhibit bone resorption in vitro and in vivo. The presence of a hydroxyl group (X) attached to the geminal carbon atom of the P-C-P motif increases the affinity for bone mineral (the so called "bone-hook" effect, as suggested by Russell et al. [100]). Bisphosphonates with variable Y substituents (see Table 1) but a common -OH in the X position bound with equal affinity to bone mineral. ...
Functionalized gem-bisphosphonic acid derivatives being pyrophosphate isosteres are of great synthetic and biological interest since they are currently the most important class of drugs developed for the treatment of diseases associated with the disorder of calcium metabolism, including osteoporosis, Paget’s disease, and hypercalcemia. In this article, we will try to give an in-depth overview of the methods for obtaining α- heteroatom-substituted methylenebisphosphonates and acquaint the reader with the synthetic strategies that are used to develop biologically important compounds of this type.
... In this way BPs bind to osteoclasts, ultimately resulting in inhibition of osteoclast recruitment, osteoclast progenitor development, and stimulation of apoptosis of mature osteoclasts. Hence, the direct action of BPs on osteoclasts is responsible for suppression of bone remodeling [63][64][65]. Moreover, it has been shown that BPs can suppress apoptosis in osteocytes and osteoblasts [66]. ...
Glucocorticoids (GCs) are often used for improvement of quality of life, particularly in the elderly, but long-term GC use may cause harm; bone loss and fractures are among the most devastating side effects. Fracture risk is particularly high in patients with a severe underlying disease with an urgent need for treatment with high-dose GCs. Moreover, it is important to realize that these patients suffer from an augmented background fracture risk as these patients have a high presence of traditional risk factors for osteoporosis, such as high age, low body mass index (BMI), smoking and relatives with osteoporosis or hip fractures. It is thus crucial for prevention of osteoporotic fractures to use the lowest dose of GC for a short period of time to prevent fractures. Another important task is optimal treatment of the underlying disease; for instance, fracture risk is higher in patients with active rheumatoid arthritis than in patients in whom rheumatoid arthritis is in remission. Thus, fracture risk is generally highest in the early phase, when GC dosage and the disease activity of the underlying disease are high. Finally, some of the traditional risk factors can be modulated, e.g., smoking and low BMI. Life-style measures, such as adequate amounts of calcium and vitamin D and exercise therapy are also crucial. In some patients, anti-osteoporotic drugs are also indicated. In general, oral bisphosphonates (BPs) are the first choice, because of their efficacy and safety combined with the low cost of the drug. However, for those patients who do not tolerate oral BPs, alternatives (“second-line therapies”) are available: BP intravenously (zoledronic acid), denosumab (Dmab), and teriparatide. Both zoledronic acid and Dmab have been proven to be superior to oral bisphosphonates like risedronate in improvement of bone mineral density. For teriparatide, vertebral fracture reduction has been shown in comparison with alendronate. Thus, to reduce the global burden of GC use and fracture risk, fracture risk management in GC users should involve at least involve life-style measures and the use of the lowest possible dose of GC. In high-risk patients, anti-osteoporotic drugs should be initiated. First choice drugs are oral BPs; however, in those with contraindications and those who do not tolerate oral BPs, second-line therapies should be started. Although this is a reasonable treatment algorithm, an unmet need is that the most pivotal (second-line) drugs are not used in daily clinical practice at the initial phase, usually characterized by high-dose GC and active underlying disease, when they are most needed. In some patients second-line drugs are started later in the disease course, with lower GC dosages and higher disease activity. As this is a paradox, we think it is a challenge for physicians and expert committees to develop an algorithm with clear indications in which specific patient groups second-line anti-osteoporotic drugs should or could be initiated as first-choice treatment.
... Pyrophosphate has a P-O-P structure, two phosphate groups are linked by an oxygen atom while bisphosphonates have a P-C-P structure, a central carbon atom replacing the oxygen. Like pyrophosphate, bisphosphonates have high affinity for bone mineral and they prevent calcification both in vitro and in vivo experiments [7,8]. ...
Zoledronate (Z) - one type of bisphosphonate has associated with bioglass (BG) to elaborate composite material for medical applications. The mixture of glass particles in zoledronate solution was stirred, frozen and lyophilized to obtain composite material containing 0.1 wt% of zoledronate (noted composite BG-0.1Z). The NMR analysis highlighted the effects of zoledronate introduced on the structure of bioglass. The ICP-OES method was used to evaluate the dissolution of synthetic composite in a simulated body fluid (SBF). Obtained results show that the introduction of 0.1 wt% of zoledronate affecting to the dissolution and bioactivity of bioglass.
... 9 The importance of these molecules was thus recognized by the scientific community. 10,11 ...
... 9 The importance of these molecules was thus recognized by the scientific community. 10,11 ...
During the last decades, several research groups have used bisphosphonates for local application to counteract secondary bone resorption after bone grafting, to improve implant fixation or to control bone resorption caused by bone morphogenetic proteins (BMPs). We focused on zoledronate (a bisphosphonate) due to its greater antiresorptive potential over other bisphosphonates. Recently, it has become obvious that the carrier is of importance to modulate the concentration and elution profile of the zoledronic acid locally. Incorporating one fifth of the recommended systemic dose of zoledronate with different apatite matrices and types of bone defects has been shown to enhance bone regeneration significantly in vivo. We expect the local delivery of zoledronate to overcome the limitations and side effects associated with systemic usage; however, we need to know more about the bioavailability and the biological effects. The local use of BMP-2 and zoledronate as a combination has a proven additional effect on bone regeneration. This review focuses primarily on the local use of zoledronate alone, or in combination with bone anabolic factors, in various preclinical models mimicking different orthopaedic conditions.
Cite this article: I. Qayoom, D. B. Raina, A. Širka, Š. Tarasevičius, M. Tägil, A. Kumar, L. Lidgren. Anabolic and antiresorptive actions of locally delivered bisphosphonates for bone repair: A review. Bone Joint Res 2018;7:548–560. DOI: 10.1302/2046-3758.710.BJR-2018-0015.R2.
... Bisphosphonates are widely used for the treatment of osteoporosis and bone malignancies [1,2]. They are synthetic analogs of pyrophosphates with high affinity for hydroxyapatite, a major component of skeletal tissues [3][4][5]. Zoledronic acid (ZA), a commonly prescribed nitrogen containing bisphosphonate, strongly binds bone tissue, inhibits osteoclast function [6] and effectively prevents bone resorption; increasing bone mass and decreasing, the rate of skeletal fractures [7]. In cancer patients with bone metastasis, bisphosphonate treatment successfully reduces the skeletal symptoms, including severe pain [7]. ...
A method for the extraction and quantification of zoledronic acid (ZA) from human bone was set up and validated. This method allowed the quantification of ZA from jawbone sequestrations of patients affected by bisphosphonate-related osteonecrosis of the jaw (BRONJ) associated with ZA treatment. The analyte was extracted from the bone tissues with phosphoric acid and derivatized using trimethylsilyl diazomethane (TMS-DAM). ZA tetramethyl phosphonate was then quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), showing high accuracy, repeatability and selectivity. Lower limits of quantification and detection (LLOQ and LLQD) were 3.4 ng/mL and 1 ng/mg, respectively. This study fully described the analytical process for the determination of ZA in human bone sequestrations, representing a pivotal step for further biomedical research on ZA and BRONJ.
... One of the earliest experiments, done to elucidate the mechanism of action of Bps was done by Russell, Muhlbauer, Bisaz, Williams, & Fleisch, 1970. They established that Bps can decrease the dissolution of HA in vitro, and therefore, the binding of Bps to HA crystals of the bone can directly decrease the bone resorption by reducing the crystals solubility [33]. ...
... This led to the development of different PPi analogues to inhibit abnormal calcification, eventually producing BP analogues (P-C-P motif). Although initially used to prevent calcification of soft tissues, BPs were soon discovered to inhibit bone resorption, thus marking the beginning of the era of their use as antiresorptives [50,51]. ...
Patients with multiple myeloma develop a devastating bone disease driven by the uncoupling of bone remodelling, excess osteoclastic bone resorption and diminished osteoblastic bone formation. The bone phenotype is typified by focal osteolytic lesions leading to pathological fractures, hypercalcaemia and other catastrophic bone events such as spinal cord compression. This causes bone pain, impaired functional status, decreased quality of life and increased mortality. Early in the disease, malignant plasma cells occupy a niche environment that encompasses their interaction with other key cellular components of the bone marrow microenvironment. Through these interactions, osteoclast-activating factors and osteoblast inhibitory factors are produced, which together uncouple the dynamic process of bone remodelling, leading to net bone loss and focal osteolytic lesions. Current management includes antiresorptive therapies, i.e. bisphosphonates, palliative support and orthopaedic interventions. Bisphosphonates are the mainstay of treatment for myeloma bone disease (MBD), but are only partially effective and do have some significant disadvantages; for example, they do not lead to the repair of existing bone destruction. Thus, newer agents to prevent bone destruction and also promote bone formation and repair existing lesions are warranted. This review summarises novel ways that MBD is being therapeutically targeted.
... 3.5. MC3T3-E1 cells differentiate into mature osteoblasts when grown on TAMP scaffolds: bone cell marker protein expression ALP enzyme expression and activity are canonical indicators of osteoblast differentiation and are known to be up-regulated during osteoblast differentiation [30,31]. Increased expression of the ALP gene in MC3T3-E1 cells growing on TAMP scaffolds was observed as described above ( figure 4(a)). ...
Tissue regeneration is a significantly improved alternative to tissue replacement by implants. It requires porous bioscaffolds for the restoration of natural tissue rather than relying on bio-inactive, often metallic implants. Recently, we developed technology for fabricating novel, nano-macroporous bioactive 'Tailored Amorphous Multi-Porous (TAMP)' hard tissue scaffolds using a 70 mol% SiO2-30 mol% CaO model composition. The TAMP silicate scaffolds, fabricated by a modified sol-gel process, have shown excellent biocompatibility via the rapid formation of hydroxyapatite in biological fluids as well as in early tests with bone forming cells. Here we report an in depth investigation of the response of MC3T3-E1 pre-osteoblast cells and bone marrow derived (BMD) osteoclasts to these TAMP scaffolds. Light and electron microscopic imaging, gene and protein expression, and enzyme activity analyses demonstrate that MC3T3-E1 pre-osteoblasts adhere, proliferate, colonize, and differentiate on and inside the bioactive TAMP scaffolds. Additionally, BMD precursor cells mature into active osteoclasts and remodel the scaffold, highlighting the exceptional qualities of this novel scaffold material for bone tissue regeneration.
Bisphosphonates are therapeutic agents that have been used for almost five decades in the treatment of various bone diseases, such as osteoporosis, Paget disease and prevention of osseous complications in cancer patients. In nuclear medicine, simple bisphosphonates such as 99mTc-radiolabelled oxidronate and medronate remain first-line bone scintigraphic imaging agents for both oncology and non-oncology indications. In line with the growing interest in theranostic molecules, bifunctional bisphosphonates bearing a chelating moiety capable of complexing a variety of radiometals were designed. Among them, DOTA-conjugated zoledronate (DOTAZOL) emerged as an ideal derivative for both PET imaging (when radiolabeled with 68Ga) and management of bone metastases from various types of cancer (when radiolabeled with 177Lu). In this context, this report provides an overview of the main medicinal chemistry aspects concerning bisphosphonates, discussing their roles in molecular oncology imaging and targeted radionuclide therapy with a particular focus on bifunctional bisphosphonates. Particular attention is also paid to the development of DOTAZOL, with emphasis on the radiochemistry and quality control aspects of its preparation, before outlining the preclinical and clinical data obtained so far with this radiopharmaceutical candidate.
Background:
Despite recognized improvements in obesity-related comorbidities, mounting evidence implicates surgical weight loss in the onset of skeletal fragility. Sleeve gastrectomy (SG) is the most commonly performed bariatric procedure and is associated with 3-7% axial bone loss in the year following surgery. Bisphosphonates are FDA-approved medications for the prevention and treatment of age-related bone loss and may represent a strategy to reduce bone loss following SG surgery.
Methods:
The Strategies to Reduce the Onset of Sleeve Gastrectomy Associated Bone Loss (STRONG BONES) trial (NCT04922333) is designed to definitively test whether monthly administration of the bisphosphonate, risedronate, for six months can effectively counter SG-associated bone loss. Approximately 120 middle-aged and older (≥40 years) SG patients will be randomized to six months of risedronate or placebo treatment, with skeletal outcomes assessed at baseline, six, and 12-months post-surgery. The primary outcome of the trial is 12-month change in total hip areal bone mineral density (aBMD), measured by dual energy x-ray absorptiometry (DXA). This will be complemented by DXA-acquired aBMD assessment at other skeletal sites and quantitative computed tomography (QCT) derived changes in bone quality. Change in muscle mass and function will also be assessed, as well as biomarkers of bone health, turnover, and crosstalk, providing mechanistic insight into intervention-related changes to the bone-muscle unit.
Discussion:
Results from the STRONG BONES trial have the potential to influence current clinical practice by determining the ability of bisphosphonate use to mitigate bone loss and concomitant fracture risk in middle-aged and older SG patients.
Purpose
The purpose of this study was to create a treatment protocol for cases of heterotopic ossification (HO) of the temporomandibular joint (TMJ), particularly those refractory to current TMJ HO protocols. Additionally, we demonstrate the success of this protocol on a unique case of recurrent HO that failed multiple TMJ HO protocols in the setting of an improvised explosive device (IED) blast in a wounded warrior.
Methods
An electronic literature review was conducted via PubMed and Web of Science. 25 studies were identified to provide supporting evidence for a proposed, up-to-date protocol for the treatment of refractory TMJ HO. The authors present a case report of a wounded warrior with HO ankylosis of bilateral TMJs in the setting of IED blast and demonstrate successful use of our surgical and pharmacotherapeutic protocol.
Results
Based upon the literature review, our proposed protocol consists of pharmacotherapy with Celecoxib and Etidronate, with weekly forced dilation (Brisement) and home physical therapy with TheraBite® Jaw Motion Rehab System. Surgically, the TMJ should be treated with two-stage reconstruction using initial polymethyl methacrylate (PMMA) spacers and subsequent total joint reconstruction (TJR) with custom prostheses, fat grafting and 3D-navigated total resection of HO. This protocol was successfully utilized in our patient’s refractory HO ankylosed TMJ secondary to IED blast and the patient’s maximal incisal opening (MIO) was regained and has remained stable two years post-surgery without recurrent HO.
Conclusion
Our method for treatment in this case deviated from the standard TMJ concepts HO protocol in that it included multimodal pharmacotherapy with Celecoxib and Etidronate. Based upon our literature review and experience, we advise that clinicians utilize our protocol for the management of all craniofacial HO, particularly in cases of recurrent HO that fail conventional therapies and/or involving high-order blast trauma.
Phosphorus is the main constitutive element of minerals and fat in the body. The process of mineral formation is defined as mineralization. The minerals in the body are mainly apatite, which is the inorganic phase that composes bones and teeth. It is worth noting that people with high fat content tend to cause excessive bone mineralization, which leads us to believe that different phosphorus-containing compounds in the body are mutually transformed and can regulate mineralization in different ways. The conversion and regulation of different phosphorus-containing compounds on the mineralization are essential for formation of a complex hierarchical structure and adaptation of the bone to various mechanical environments. Therefore, this review introduces the natural phosphorus-containing compounds in the body, introduces the hierarchical structure of the bone, and summarizes recent studies on different phosphorus-containing compounds (inorganic, organic, and phosphorus-containing proteases) involved in the biomineralization. We also discuss potential research directions of the biomineralization, offering the basis for future investigation of advanced bone substitute materials.
Novel pyrophosphate glass ceramic scaffolds (3D-Ca-P2) were fabricated and coated with several layers of CaO-P2O5-SiO2-MgO [3D-[Ca/P/Si]-XMg (X = 1,3 and 10mol%)] as potential bioactive scaffolds for bone regeneration. The core scaffolds present a homogeneous distribution of polygonal grains consisting of 97% Ca2P2O7 with CaO-P2O5 glass as the matrix phase. Incorporating MgO into coatings led to extremely porous layers, assembled by nanosized equiaxed particles, which favoured the formation of different phases of tricalcium phosphate instead of pyrophosphate. Possible applications were determined based on Standard ISO/FDIS 23317:2014 for ceramics and powder samples. The 3D-Ca-P2 scaffolds’ non-bioactivity was modulated by coatings of different bioactivity behaviours depending on MgO contents. 3D-[Ca/P/Si]-10Mg was the best scaffold as precipitated hydroxyapatite (HA), was more amorphous than in the other scaffolds because Mg was incorporated into the HA network, which could favour subsequent cell adhesion. The multilayer scaffold provides advantages over others developed until now because in a unique structure all the characteristics required for an implant are combined. On a physical level, mechanical resistance, and porosity, and on a chemical level, a combination of calcium phosphate phases, similar to the mineral phase of bone, doped with Mg ions, which are capable of being transformed into HA in different periods of time.
The present study was undertaken to test whether long term administration of HEBP could prevent the progress of bone loss induced by ovariectomy in rats. Administration of HEBP was started from day 111 after ovariectomy. The animals received subcutaneous injections of HEBP, at a dose of 0, 2, 4, or 8 mg/kg, every other day for 92 days. Tibiae, femora and incisor teeth were investigated by chemical analyses and by contact microradiography. Effects on calcium, phosphorus, and alkaline phosphatase activity in the plasma were also examined. Progress in the loss of bone density and ash content caused by ovariectomy was prevented by the administration of 2 mg/kg HEBP for 92 days and was partially prevented by the administration of 4 mg/kg. At a dose of 8 mg/kg, however, HEBP did not prevent the bone loss but, rather, potentiated it. These chemical findings were qualitatively confirmed by contact microradiography. A dose-dependent inhibition was observed in the mineralization of incisor dentin. These results suggest that HEBP, at least at low dose levels in which the inhibition of mineralization is not predominant, has a potency to prevent the progress of bone loss induced by ovariectomy. At higher doses, however, this compound seems not to be effective, because of the severe inhibition of mineralization.
Bisphosphonates that have been widely used in the treatment of osteoporosis are popular and effective agents with robust evidence for fracture risk reduction. Bisphosphonates bind avidly to bone and reduce osteoclastic bone resorption. These agents are generally safe and well-tolerated, although concerns about long-term use have emerged. For most patients with osteoporosis, the benefits of treatment outweigh the risks. Because these agents accumulate in bone with some persistent antifracture efficacy after therapy is stopped, it is reasonable to consider a bisphosphonate “holiday.” The duration of treatment and the length of the holiday should be based on individual assessments of risk and benefit.
Osteoporosis can often present challenges when instrumenting the spine for a host of spinal conditions, particularly spinal deformity. This chapter will review the different methods utilized in the evaluation and identification of patients with osteoporosis, common medical management, techniques to optimize spinal instrumentation fixation, and ways to reduce the risk of complications including screw loosening and proximal junction kyphosis (PJK) in the osteoporotic spine.
Nitrogen‐containing bisphosphonates including alendronate (ALN) are the current first line antiresorptive drug in treating osteoporosis. In our study, we found that ALN administration impaired the secretion of platelet derived growth factor‐BB (PDGF‐BB), the most important angiogenic cytokines produced by preosteoclast (POC), in both sham and ovariectomized (OVX) mice. To further understand this phenomenon, we induced bone marrow macrophages (BMMs) to POCs in vitro and detected the effects of ALN particularly in POCs. The proapoptotic effect of ALN in POCs was confirmed by flow cytometry. On the molecular level, we found that farnesyl diphosphate synthase (FDPS) inhibition of ALN led to peroxisomal dysfunction and up regulation of cytoprotective protein glucose‐regulated protein (GRP) 78. Peroxisomal dysfunction further induced endoplasmic reticulum (ER) stress in POCs and finally resulted in cell apoptosis marked by reduced expression of B‐cell lymphoma 2 (Bcl‐2) and increased expressions of CCAAT/enhancer binding protein homologous protein (CHOP), Bcl2 associated X (Bax), and cleaved caspase‐3. We concluded that ALN has no selectivity in inhibiting POC and mature osteoclast. For POCs, ALN inhibition of FDPS leads to peroxisomal dysfunction, which further mediates ER stress and finally causes cell apoptosis. Considering that decreased angiogenesis is also an important issue in treating osteoporosis, how to preserve pro‐angiogenic POCs while depleting mature osteoclasts is a problem worthy to be solved. Alendronate inhibit both mature osteoclast and preosteoclast without selectivity. Avoiding POC depletion in nitrogen‐containing bisphosphonates based antiresorptive therapy is a potential strategy in improving the curative effects.
The process of osseointegration around dental implants is similar to the biological events occurring during bone repair and fracture healing. Therefore, bone metabolic activity plays a crucial role on the success of osseointegration, and dysregulation of bone metabolism can have a negative impact on bone healing and implant osseointegration. Accordingly, it could be hypothesized that drugs interfering with healing and bone metabolism could affect osseointegration and implant survival. Looking into the relationship between pharmacology, osseointegration, and dental implant drugs can open the door for new pharmacological innovations to improve implant success and avoid unnecessary complications, and it is also of special interest because most implant patients are elder adults that are often polymedicated. In this commentary we discuss the discoveries made by us as well as by other researchers regarding the effect of several drugs on bone, osseointegration, and implant survival. Of particular interest is the growing evidence showing that commonly used drugs such as nonsteroidal anti-inflammatories, serotonin reuptake inhibitors, and proton pump inhibitors could lead to implant failure.
This chapter discusses the effects that drugs and hormones have on vitamin D metabolism. The level of active vitamin D metabolite and the activity of the renal hydroxylase enzymes that are responsible for regulating its production are governed by a variety of hormones and cations. Parathyroid hormone, phosphate, and calcium are the principal controlling factors of the renal hydroxylases yet several other hormones may also play a role in the metabolism of vitamin D. Among those discussed here are parathyroid hormone-related protein, fibroblast growth factor 23, leptin, calcitonin, prolactin, growth hormone and insulin-like growth factor, sex steroids (estrogen, testosterone, and progesterone), insulin, thyroid hormone, prostaglandins, interferon-γ, and tumor necrosis factor-α. Along with the endogenous regulators of the levels of the vitamin D metabolites, some exogenous drugs and hormones are also capable of exerting an effect on the vitamin D endocrine system. Drugs are being increasingly recognized in this regard. Drugs discussed include the anticonvulsants, ethanol, antiretroviral therapy, corticosteroids, hypolipidemics, and several others that have been implicated in affecting vitamin D metabolism. This review should offer a framework for clinicians to evaluate the effects that hormones and medications can have on vitamin D metabolism.
Bisphosphonates (BPs) are well established, widely used first-choice drugs for bone-related diseases and are one of the few classes of molecules for selective bone-targeting. Their binding to calcium cations within hydroxyapatite (HA) is a key physico-chemical event taking place on the bone surface. It is the starting point for a cascade of biochemical reactions and cellular effects that lead to the pharmacological activity of BPs. The phenomenon is known for years, yet still its physicochemical nature is not fully understood. In particular the adsorption/release processes and structure-function relationships of BPs remain to be clarified. These are elementary, yet crucial factors, which should influence design and development of new delivery tools or drugs with improved characteristics. This minireview will summarize the current understanding of the chemical interactions between clinically used BPs and bone mineral, starting from basic Ca2+ coordination chemistry through to interactions with hydroxyapatite, nanocrystalline apatites and natural bone mineral.
Zoledronic acid is a nitrogen-containing bisphosphonate agent that suppresses farnesyl diphosphate synthase, i.e., inhibits bone resorption and bone remodeling activity. Our current study evaluates the thermal behavior of zoledronic acid and performs a kinetic analysis of the main degradation process and compatibility studies between the active agent and various excipients. The thermal behavior of zoledronic acid is characterized by two thermally induced events; a dehydration process with a rate maximum at 133 °C, respectively, a complex multistep process of a deep oxidative degradation that covers a range of temperature starting at 225 °C. Kinetic parameters were determined according to ICTAC 2000 Protocol recommendations and using four kinetic methods to determine the kinetic triplet: Friedman, Flynn–Wall–Ozawa, Kissinger–Akahira–Sunose and modified nonparametric kinetic method. The thermal behavior of zoledronic acid monohydrate and of its binary mixture in 1:1 mass ratio with talc, silica, mannitol, sorbitol, hydroxyethyl cellulose and magnesium stearate, respectively, were studied by thermal analysis under nonisothermal conditions. Talc and silica were used as standard inert excipients in the binary mixture. The polyhydroxylic compounds mannitol and sorbitol and the polysaccharide hydroxyethyl cellulose have similar thermal behavior, decomposing from 300 °C. Thus, they can be used in solid formulations of zoledronic acid. Magnesium stearate is recommended to be avoided in solid formulations, due to its low thermal stability.
The synthesis of a small collection of novel bile acid-bisphosphonate (BA-BP) conjugates as potential drug candidates is reported. The disclosed methodology relied on the installation of azide and thiol functionalities at the head and tail positions, respectively, of the BA scaffold and its subsequent decoration by orthogonal click reactions (copper-catalyzed azide-alkyne cycloaddition, thiol-ene or thiol-yne coupling) to introduce BP units and a fluorophore. Because of the troublesome isolation of the target conjugates by standard procedures, the methodology culminated with the functionalization of the BA scaffold with a light fluorous tag to rapidly and efficiently purify intermediates and final products by fluorous solid-phase extraction.
The hydroxyapatite (HAP) adsorption of salivary statherin, cystatins, proline-rich proteins and histatins has been compared to the influence of these molecules on HAP crystallization in supersaturated solution. This may yield, in many cases, information about protein conformation in the adsorbed state. The results of studies involving both parent molecules and their fragments, indicated that statherin binds to HAP primarily with a 2–5 residues segment in the N-terminal part while the cystatins and proline-rich proteins bind through a segment 2–3 times larger.
We have recently suggested that inorganic pyrophosphate may be a physiological inhibitor of calcification in soft tissues and a physiological regulator of calcium homeostasis through its effect on the formation and destruction of mineralized tissues.1-6 This communication is concerned with the possible role of pyrophosphate in the metastatic calcification and bone disease associated with renal failure.Mineralization in General
Very little is known of the mechanisms responsible for the deposition of calcium salts at normal or abnormal sites within the body. In recent years some clarification has come from studies on the mechanism of precipitation in vitro. It is now established that the concentrations of calcium and phosphate in plasma, extracellular fluid, and even in fluid withdrawn from calcifying cartilage 7 are much lower than those required to form crystals in vitro.1,8 The formation of apatite crystals in vivo therefore requires some local promoting mechanism at the site
The formation of crystalline calcium hydroxyapatite from solutions of calcium and phosphate ions and the inhibition of calcium hydroxyapatite crystal growth by polyphosphonates and polyphosphates have been studied. The polyphosphonates, disodium ethane-1-hydroxy-1,1-diphosphonate and disodium dichloromethane diphosphonate, are effective inhibitors of calcium hydroxyapatite crystal growth. The polyphosphates are also effective inhibitors of calcium hydroxyapatite crystal growth as long as the required level of intact polyphosphate is present in the system. However, because of their hydrolytic instability, which is enhanced by high temperature, low pH, and certain enzymes, the concentration of the polyphosphate decreases with timein vitro, and its activity as an inhibitor is lost. In contrast to the polyphosphates, the polyphosphonates are hydrolytically stable. The polyphosphonates are chemisorbed on the surface of the microcrystallites of calcium hydroxyapatite and, in the manner of other known crystal growth poisons, thus prevent further crystal growth. The stability of the polyphosphonates and their chemisorption on apatite suggest their use in medical and dental applications involving pathological calcium and phosphate metabolism.
Ectopic calcification of the aortas of rats was induced by large doses of vit D3. The calcification was accompanied by sudanophilia of the elastic fibers, where the calcification started, and by the presence of mucopolysaccharides between the fibers, as indicated by P.A.S. and alcian blue stains. Concurrent subcutaneous administration of condensed phosphates prevented the calcification as assessed by chemical determination of calcium and by silver nitrate staining. The development of the various matrix stains was inhibited as well. The most likely mechanism of this inhibition is thought to be the prevention of the formation of calcium phosphate crystals by the condensed phosphates. Possible mechanisms of the inhibition of the matrix changes are discussed.
Twenty-four patients with various fractures were given phosphate supplements (1 g. of phosphorus daily) to their diets; twenty-seven patients with fractures at the same site as the others, did not receive these supplements. In the phosphate-treated patients with fractures of the femur and ankle, radiographically demonstrable demineralisation and the time required for clinical union were significantly reduced. Phosphate supplementation gave rise to no complications.
Soft tissue calcinosis is produced at the site of subcutaneous injection of polymyxin in rats treated intravenously with lead acetate. This phenomenon is inhibited by ATP and pyro- and meta-phosphate, but is aggravated by mono- and di-basic orthosphosphate.
Hydroxyapatite in equilibrium with physiological concentrations of pyrophos-phate showed a markedly reduced solubility during dissolution experiments in vitro. Since bone contains pyrophosphate, it is suggested that this phenomenon might be important in calcium homeostasis. It is possible that it is also involved in causation and prevention of caries.
Inorganic pyrophosphate has been detected in enamel and dentine from human and bovine teeth. The techniques used were ion exchange chromatography and paper chromatography with 32P-pyrophosphate as marker, and precipitation as the manganese salt with subsequent infrared spectroscopy. During extraction of enamel, a part of the pyrophosphate was found to bind to an unidentified substance that altered its chromatographic behaviour. Using an isotope dilution technique, pyrophosphate was measured quantitatively in human teeth. Dentine contained 6.9 and enamel 1.3 mg pyrophosphate-P/g total-P. The possible origin and significance of pyrophosphate in teeth is discussed.
Two diphosphonates containing the P-C-P bond, CH3C(OH)(PO3HNa)2 and H2C(PO3HNa)2, inhibit the crystallization of calcium phosphate in vitro and prevent aortic calcification of rats given large amounts of
vitamin D3. The diphosphonates therefore have effects similar to those described for compounds containing the P-O-P bond but are active
when administered orally.
Abstract 1. Various phosphonates, which are compounds containing C-P bonds, have been studied to see whether they are able to inhibit, in a manner similar to that of pyrophosphate and the condensed phosphates, the crystallization of calcium phosphate in vitro and the pathological calcification of the aorta and the kidneys of rats given large amounts of vitamin D3.
2. Six of the ten compounds studied markedly increased the minimum product, [Ca] × [P], required to induce the precipitation of calcium phosphate in vitro under physiological conditions of pH, ionic strength and temperature. Inhibition was observed at concentrations as low as 10-7—106M.
3. Most of the diphosphonates, particularly those possessing P-C-P bonds, showed some ability to inhibit the calcification of the aortas and kidneys of rats treated with large amounts of vitamin D3. The most effective inhibitors were methylene diphosphonate (MDP), ethane-1-hydroxy-1: I-diphosphonate (EHDP) and diehloromethylene diphosphonate (Cl2MDP).
4. The phosphonates that possess P-C-P bonds thus appear to have effects on the deposition of calcium phosphate in vitro and in vivo similar to those of inorganic pyrophosphate and the condensed phosphates, which possess P-O-P bonds. These phosphonates differ from the condensed phosphates in that they inhibit kidney calcification as well as aortic calcification and are active by mouth as well as parenterally. The wider spectrum of activity of the phosphonates in vivo may be due to the fact that they are more resistant to chemical and enzymic breakdown.
5. Phosphonates might be used therapeutically in man against diseases in which calcium salts deposit in soft tissues.
THE work reported here grew out of our studies of the possible role of inorganic pyrophosphate in calcium homeostasis1,2, as a result of which we proposed that the inorganic pyrophosphate known to be present in bone3-5 may be a factor that regulates the rates of formation arid resorption of bone mineral. This hypothesis was based on the observation that pyrophosphate retarded both the growth1,6 and dissolution1,7 of apatite crystals in vitro. According totthe hypothesis, the amount of pyrophosphate present at sies of formation and of resorption in bone would be controlled separately by different pyrophosphatases, the activity of which would in turn be controlled by hormones and other agents. Disturbances in this control might be responsible for various diseases of bone.
The effects of changing the concentration of phosphate, calcium and magnesium on the resorption of fetal rat bone, and the responses to parathyroid hormone and calcitonin were tested in organ cultures using a chemically defined medium. Resorption was measured by the release of previously incorporated 46Ca into the medium and by changes in total bone calcium content. To differentiate effects on active resorption and passive dissolution, calcium losses from living and heat-killed bones were compared. Increasing the phosphate concentration of the medium over the range of 0.25 to 4M produced a decreased release of calcium from bone, particularly in response to parathyroid hormone. The effect was greater in living than in dead bone, demonstrating that active resorption was inhibited. Inhibition by phosphate could be observed even when the Ca×PO4 product was kept constant. The effects of calcitonin and phosphate appeared to be additive. Increasing concentrations of calcium also decreased mineral loss. This was ...
Two diphosphonates containing the P-C-P bond, Cl2C(PO3HNa)2, and H2C(PO3HNa)2 retard the rate of dissolution of apatite crystals in vitro. They inhibit bone resorption induced by parathyroid extract
in mouse calvaria in tissue culture and in thyroparathyroidectomized rats in vivo.
This article has no abstract; the first 100 words appear below.
HYPERCALCEMIA occurs in a wide variety of diseases (for example, hyperparathyroidism, hypervitaminosis D, sarcoid, cancer, hyperthyroidism and poliomyelitis)¹ and is often responsible for many of the symptoms associated with them. Most often, these symptoms are more distressing than disabling and include such nonspecific complaints as constipation, dyspepsia, lassitude, easy fatigability and polyuria. Underlying these mild symptoms, however, is a process that may lead to nephrolithiasis and nephrocalcinosis. Of even more serious import² is the usually fatal syndrome that has been called hypercalcemic crisis — intractable nausea and vomiting, dehydration, stupor, coma and azotemia. Since this constitutes a true medical emergency . . .
*From the Thorndike Memorial Laboratory, Second and Fourth (Harvard) Medical Services, Boston City Hospital, and the Department of Medicine, Harvard Medical School.
Supported in part by a grant (CA01756–03) from the National Cancer Institute and a grant (843–317) from the Clinical Research Center, National Institutes of Health, Bethesda, Maryland.
§Some patients were treated under the supervision of Drs. Lewis E. Braverman, Norman G. Levinsky, Albert Schilling, Richard Shadduck and Sidney Salmon, whose co-operation and assistance are gratefully acknowledged.
We are indebted to Miss Margaret J. Finnegan and Miss Ann Baranauskas for valuable technical assistance and to Miss Loretta Eldridge for preparing the intravenous solutions.
Source Information
BOSTON
† Associate in medicine, Harvard Medical School; assisting physician, Second and Fourth (Harvard) Medical Services, Boston City Hospital.
‡ Associate professor of medicine, Harvard Medical School; physician-in-charge, Endocrine Out-Patient Department, Boston City Hospital.
Zusammenfassung Grahamsalz, ein langkettiges Polyphosphat, ist bei subcutaner Verabreichung imstande, eine pathologische Verkalkung der Haut (Calciphylaxe) bei der Ratte zu hemmen. Der Wirkungsmechanismus dieser Hemmung wird kurz diskutiert.
A small proportion of the total phosphate in normal bone salt occurs in the form of pyrophosphate. The deposit formed in vitro on incubation of rachitic cartilage with a calcifying medium does not contain pyrophosphate unless ATP is added to the medium, in which case the proportion of pyrophosphate is of the same order as that found in normal bone.
The nucleating properties of various collagens have been tested by determining quantitatively the minimum ion product, Ca times P, required to form calcium phosphate crystals. While most collagens require a product of 35 (mg%) ² or greater for calcium phosphate to precipitate, some collagens extracted from tendon induce mineralization at a product of 16 (mg%) ² . Plasma ultrafiltrate contains one or more substances which increase this minimum ion product, and therefore inhibit calcium phosphate nucleation. These substances are inactivated by alkaline phosphatase. Finally, polyphosphates, both organic and inorganic, are highly inhibitory to calcium phosphate nucleation and precipitation. It is therefore suggested that at least two mechanisms may be necessary for a tissue to mineralize: 1) the formation of a nucleating collagen and 2) the presence of phosphatase for the local destruction of the inhibitor(s) present in plasma.
The growth of embryonic chick and turkey tibiotarsi and embryonic rat and mouse tibiae on a new relatively simple chemically defined medium has been described. It has been that (1) the chick bones increase in length, wet weight, dry weight and DNA content; (2) the turkey bones increase in length, wet weight and DNA content; (8) the rat and mouse bones increase in length, wet weight and dry weight.Deficiency experiments have shown the importance of amino acids and l-glutamine in the medium.
The fate of intravenously injected P32-pyrophosphate
- A Jung
- R G G Russell
- S Bisaz
- H Fleisch
- A. Jung