Newer Advances in The Management of Osteoporosis

 

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*Jayant Kumar Saini

*Post Graduate resident, Lady Hardinge Medical College, New Delhi

 

INTRODUCTION

Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue.[1] Bone is under constant turnover throughout life in order to maintain a healthy bone mass. Bone homeostasis depends on the balance between bone resorption by osteoclast and bone formation by osteoblast. Osteoporosis (OP) results from the impairment of this balance leading to a reduction in bone mass associated with a high risk of fragility fractures. It is most often caused by an increase in osteoclastic activity that is not sufficiently compensated by an increase in bone formation.[2]

 

Two categories of osteoporosis have been identified: primary and secondary. Primary osteoporosis is the most common form of the disease and includes postmenopausal osteoporosis (Type I), and senile osteoporosis (Type II). Secondary osteoporosis is characterized as having a clearly definable etiologic mechanism.

Type I is associated with a loss of oestrogen and androgen resulting in increased bone turnover, with bone resorption exceeding bone formation and a predominant loss of trabecular bone compared with cortical bone.

Type II, which represents the gradual age-related bone loss found in both sexes caused by systemic senescence, is induced by the loss of stem-cell precursors, with a predominant loss of cortical bone.[3]

 

According to the WHO Expert Committee, the classification of BMD values is as follows:[4]

Normal: BMD > −1 SD t-score

Osteopenia: BMD between −1 SD and −2.5 SD t-score

Osteoporosis: BMD < −2.5 SD t-score

Established osteoporosis: BMD < −2.5 SD t-score + fragility fracture

 

PATHOPHYSIOLOGY

BONE REMODELING

Osteoporosis results from bone loss due to age-related changes in bone remodelling as well as extrinsic and intrinsic factors that exaggerate this process. In adults, bone remodelling, not modelling, is the principal metabolic skeletal process.

Bone remodelling has two primary functions:

(1) To repair microdamage within the skeleton to maintain skeletal strength and ensure the relative youth of the skeleton.

(2) To supply calcium when needed from the skeleton to maintain serum calcium.

Remodelling may be activated by microdamage to bone as a result of excessive or accumulated stress. Acute demands for calcium involve osteoclastmediated resorption as well as calcium transport by osteocytes. Chronic demands for calcium can result in secondary hyperparathyroidism, increased bone remodelling, and overall loss of bone tissue.[5]

 

The cytokine responsible for communication between the osteoblasts, other marrow cells, and osteoclasts is receptor activator of nuclear factor-κB (RANK) ligand (RANKL). RANKL, a member of the TNF family, is secreted by osteocytes, osteoblasts, and certain cells of the immune system. The osteoclast receptor for this protein is referred to as RANK.  Activation of RANK by RANKL is a final common path in osteoclast development and activation. A humoral decoy for RANKL, also secreted by osteoblasts, is referred to as osteoprotegerin. RANKL production is in part regulated by the canonical Wnt signalling pathway. Wnt activation through mechanical loading or by hormonal or cytokine factors stimulates bone formation by increasing formation and activity of osteoblasts and decreases RANKL secretion, which inhibits production and activity of osteoclasts. Sclerostin, also an osteocyte protein,  is  a  major  inhibitor  of  Wnt  activation and bone formation.[5]

 

In trabecular bone, if the osteoclasts penetrate trabeculae, they leave no template for new bone formation to occur, and consequently, rapid bone loss ensues and cancellous connectivity becomes  impaired.  A higher number of remodelling sites increases the likelihood of this event.[5]

CALCIUM NUTRITION

During the adult phase of life, insufficient calcium  intake  contributes to secondary hyperparathyroidism and an increase in the rate of bone remodelling to assist in maintaining normal serum calcium levels.PTH stimulates the hydroxylation of vitamin D in the kidney, leading to increased levels of 1,25-dihydroxyvitamin D [1,25(OH)2 D] and enhanced gastrointestinal calcium absorption.  PTH also reduces renal calcium loss. Although these are appropriate compensatory homeostatic responses for adjusting calcium economy, the long-term effects are detrimentalto the skeleton because the increased remodelling rates and the ongoing imbalance between resorption and formation at remodelling sites combine to accelerate loss of bone tissue. Total daily calcium intakes <400 mg is detrimental to the skeleton.[5]

VITAMIN D

Vitamin D insufficiency leads to compensatory secondary hyperparathyroidism. Recent data suggesting that those with low vitamin D levels have a more severe clinical course than those with normal vitamin D levels.[5]

ESTROGEN STATUS

Estrogen deficiency  causes  bone  loss  by  two  distinct  but  interrelated mechanisms:

(1) Activation of new bone remodelling sites

(2) Initiation or exaggeration of an imbalance between bone formation and resorption, in favour of the latter.

The remodelling imbalance, however results in a permanent decrement in mass. The most common estrogen-deficient state is the cessation of ovarian  function  at  the  time  of  menopause,  which  occurs  on  average  at  age.Marrow cells (macrophages, monocytes, osteoclast precursors, mast cells) as well as bone cells (osteoblasts, osteocytes, osteoclasts) express both  ERs  (α  and  β).  Loss of estrogen  increases  production of  RANKL and reduces production of osteoprotegerin, increasing osteoclast formation and recruitment. Estrogen also may play a role in determining the life span of bone cells by controlling the rate of apoptosis. Thus, in situations of estrogen deprivation, the life span of osteoblasts may be decreased, whereas the longevity and activity of osteoclasts are increased.[5]

PHYSICAL ACTIVITY

Inactivity, such as prolonged bed rest or paralysis, results in significant bone loss.[5]

CHRONIC DISEASES

Various genetic and acquired diseases are associated with an increase in the risk of osteoporosis. Mechanisms that contribute to bone loss are unique for each disease and typically result from multiple factors, including nutrition, reduced physical activity levels, and factors that affect rates of bone remodelling.[5]

MEDICATIONS

Glucocorticoids are the most common cause of medication-induced osteoporosis. Excessive doses of thyroid hormone can accelerate bone remodelling and result in bone loss.Anticonvulsants are thought to increase the risk of osteoporosis.Patients undergoing transplantation are at high risk for rapid bone loss and fracture not only from glucocorticoids but also from treatment with  other  immunosuppressants  such  as cyclosporine and  tacrolimus.Abnormalities such as hepatic or renal failure predispose to bone loss.Long-term use of proton pump inhibitors has been shown  in  observational  studies  to  be  associated  with  a  higher  risk of fracture. Aromatase inhibitors, which potently block the aromatase enzyme that converts androgens and other adrenal precursors to oestrogen, reduce circulating postmenopausal oestrogen supply dramatically. These agents have a detrimental effect on bone density and risk of fracture. Androgen deprivation therapies, used to treat men with prostate cancer, also result in rapid loss of bone and increased fracture risk. Various diabetes medications, including but not limited to thiazolidinediones, and antidepressants, including the selective serotonin  reuptake  inhibitors,  increase  risk  of  osteoporosis  and  fracture.[5]

SMOKING

Smoking produces detrimental effects on bone mass mediated directly by toxic effects on osteoblasts or indirectly by modifying oestrogen metabolism. Cigarette smoking also produces secondary effects that can modulate skeletal status, including intercurrent respiratory and other illnesses, frailty, decreased exercise, poor nutrition, and the need for additional medications (e.g., glucocorticoids for lung disease).[5]

OTHER POTENTIAL FACTORS

These include excessive alcohol intake and other drugs of abuse, pollution, use of triclosan, chronic obstructive pulmonary disease, excess vitamin B, and hormonal therapies utilized among the transgender population.[5]

 

 

TREATMENT OF OSTEOPOROSIS AND NOVEL APPROACHES

The AACE/ACE recommends that pharmacological treatment should be initiated for:

1) Patients with osteopenia or low bone mass and a history of fragility fracture at the hip or spine.

2) Patients with a T-score of –2.5 or less in the lumbar spine, femoral neck, total hip or 33% radius despite the absence of a fracture.

3) Patients with a T-score between –1.0 and –2.5 if the FRAX 10-year probability for a major osteoporotic fracture is greater than 20% or for a hip fracture is greater than 3%.[6]

 

NON-PHARMACOLOGICAL MANAGEMENT

Adequate calcium and vitamin D intake, weight-bearing exercise, smoking cessation and limitation of alcohol/caffeine consumption are of prime importance. The Institute of Medicine (IOM) recommends that dietary calcium intake should be limited to 1,000 mg daily for men 50 to 70 years of age and to 1,200 mg daily for women 51 years of age and older and for men 71 years of age and older.Vitamin D is a key component in calcium absorption and bone health. The IOM recommends 600 IU per day for men and women 51 to 70 years of age and 800 IU per day for men and women older than 70 years.[7]

 

 

PHARMACOLOGICAL TREATMENT

Medications to treat osteoporosis are categorized as either antiresorptive (i.e., bisphosphonates, oestrogen agonist/ antagonists [EAAs], oestrogens, calcitonin, and denosumab) or anabolic (i.e., teriparatide). Anti-resorptive medications primarily decrease the rate of bone resorption while anabolic medications increase bone formation more than bone resorption.[7]

 

  1. Antiresorptive Agents

 

  • Bisphosphonates:

AACE/ACE, ACR, NAMS and the Endocrine Society recommend bisphosphonates, excluding ibandronate, as a first-line option for the prevention and/or treatment of osteoporosis in postmenopausal women, men, and/or GIO patients. Bisphosphonates bind with high affinity to the mineral matrix of the bone and inhibit osteoclast resorption of the bone, leading to a decrease in bone turnover and a net gain in bone mass.Alendronate, risedronate, and zoledronic acid (intravenous [IV]) have demonstrated an increase in BMD and a decrease in risk of fractures due to osteoporosis in men, postmenopausal women, and GIO patients.Ibandronate is not a first-line recommendation even though high-quality evidence indicates that it reduces vertebral fractures in both men and women; there is insufficient evidence to determine its effect on hip fractures.[7]

  • Denosumab:

The AACE/ACE recommends denosumab as first-line therapy for patients at high risk of fracture and for patients who are unable to use oral therapy. Denosumab was the first biologic agent available for treatment of osteoporosis. It is a fully human monoclonal antibody that inhibits RANKL to decrease bone resorption. RANKL is a transmembrane protein required for the formation, function, and survival of osteoclasts.

Denosumab is FDA approved for the treatment of PMO with high risk for fracture, as well as for women with breast cancer receiving adjuvant aromatase inhibitor therapy. It has also been approved for the treatment of bone loss in men with osteoporosis and with prostate cancer receiving ADT. The treatment dose for osteoporosis is 60 mg subcutaneously (SC) every six months administered by a health care professional.[7]

 

  1. Hormonal Therapies Estrogen Agonist/Antagonists: This class of drugs is also known as selective estrogen receptor modulators (SERMs).

 

  • Raloxifene:

Characterized as an EAA, exhibits dual agonistic and antagonistic properties in estrogenic pathways. Raloxifene acts as an estrogenic agonist on the bone by decreasing bone resorption and bone turnover, thus increasing BMD. It also has estrogen antagonistic activity on breast and uterine tissue. The AACE/ACE recommends raloxifene as an appropriate first-line therapy for patients requiring reduced risk of spine fracture only. Due to its selective antagonistic effects on breast tissue, raloxifene may be considered in women with an increased risk of vertebral fractures who may be at risk for developing breast cancer. Raloxifene is dosed at 60 mg per day without regard to food.[7]

 

  • Conjugated Estrogens/Bazedoxifene:

A combination of conjugated estrogens with bazedoxifene (Duavee, Pfizer) received FDA approval in 2013 for use in postmenopausal women with an intact uterus for the prevention of osteoporosis and for the treatment of moderate-to-severe vasomotor symptoms. Duavee is sometimes referred to as a tissue-selective estrogen complex. Bazedoxifene acts as an EAA to reduce the risk of endometrial hyperplasia associated with the estrogen component.[7]

 

  • Estrogen-Progestin Therapy

In terms of osteoporotic management, estrogen therapy is FDA approved solely for the prevention of osteoporosis in high-risk postmenopausal women and should be used only after all nonestrogenic osteoporotic treatments have been considered inappropriate.[7]

 

  • Testosterone Therapy

Despite limited studies involving the use of such combinations, the Endocrine Society recommends combination use of antifracture treatment with testosterone therapy for men at high risk of fracture. Testosterone monotherapy is recommended either for those in whom anti-osteoporotic therapy is contraindicated and whose testosterone levels are less than 200 ng/dL, or for those at borderline high risk for fracture who have serum testosterone levels less than 200 ng/dL and have signs or symptoms of androgen deficiency or hypogonadism.[7]

 

  1. Calcitonin

A synthetic polypeptide hormone with properties similar to natural calcitonin found in mammals, birds, and fish. The effects of calcitonin on normal human bone physiology are unclear; however, calcitonin receptors have been discovered on osteoclasts and osteoblasts. Calcitonin is FDA approved for the treatment of osteoporosis in women who have been postmenopausal for more than five years when alternative treatments are not feasible.[7]

 

  1. Parathyroid Hormone Analogues

 

  • Teriparatide:

A recombinant human PTH (1–34) analogue, is the first anabolic treatment approved for osteoporosis. It mimics the physiological actions of PTH in stimulating new bone formation on the surface of bone by stimulating osteoblastic activity when given intermittently at small doses. The AACE/ACE suggests the use of teriparatide for initial PMO treatment in those with prior fragility fractures or with high fracture risk and for those who are unable to take oral therapy. It is also listed as an option for higher-risk patients on bisphosphonate holiday. The FDA-recommended dose of teriparatide is 20 mcg SC once daily in the thigh or abdomen. The duration of therapy is limited to two years due to the development of osteosarcoma in rats at high doses. The AACE/ACE recommends treatment with an antiresorptive agent immediately following teriparatide therapy to avoid bone density decline.[7]

  • Abaloparatide:

Abaloparatide (Tymlos, Radius Health), the second recombinant human PTH (1–34) analogue to reach the market, received FDA approval in April 2017.98 It is indicated for the treatment of PMO in women at high risk for fracture, defined as a history of osteoporotic fracture or multiple risk factors for fracture, and in patients who have failed or are intolerant to other available osteoporosis therapy.

 Abaloparatide is available as an injection. The recommended dose is 80 mcg SC once daily into the periumbilical region of the abdomen. The duration of therapy is limited to two years due to the development of osteosarcoma in rats.[7]

 

  1. Emerging Therapies and Investigational Drugs

 

  • Romosozumab: A humanized monoclonal antibody that inhibits sclerostin. In the skeletal tissue, sclerostin is a protein secreted by osteoclasts to reduce bone formation by interfering with the proliferation and function of osteoblasts. Other antisclerostin monoclonal antibodies being developed and tested include blosozumab and BPS804. [7]

 

  • Odanacatib: A selective inhibitor of Cathepsin K, a protease that is released by osteoclasts to promote the degradation of collagen in bones. Inhibiting Cathepsin K is theorized to decrease bone resorption without decreasing bone formation.[7]

 

  • Lasofoxifene: (Sermonix) is a third-generation SERM.[7]

 

  • Cell Therapy as a Novel Approach:

Cell therapies have attracted great interest in recent years for the treatment of certain chronic diseases including osteoporosis. This type of therapy focuses on the ability of cells to repair damaged tissue. MSCs from bone marrow or adipose tissue are the cells considered optimal for this type of treatment, as they are immunoprivileged and immunomodulatory cells and their use is approved by the FDA.

After transplantation, MSCs may contribute to bone formation through two possible mechanisms of action. On the one hand, MSCs target the damaged site and differentiate into osteogenic cells and on the other hand, MSCs secrete characteristic growth factors, such as the vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β), hepatocyte growth factor (HGF) or insulin-like growth factor-1 (IGF-1), which act by promoting bone remodelling processes and preventing bone loss For cell delivery, MSCs can be administered systemically (intravenous or intra-arterial injection) or locally (intracoronary or direct injection into damaged tissue). The cell migration procedure is not yet fully understood, so it is difficult to determine which mode of application is the most beneficial.

The transplantation of allogeneic BMMSCs reduced the loss of bone tissue mass and hardness and promoted osteoblastogenesis while maintaining bone formation. To regulate osteoblast differentiation, two very important transcription factors, Runx2 and osterix, must be taken into account. The activation or inhibition of these transcription factors controls osteogenic differentiation in MSCs. In addition, miRNA regulators are also important, as they have a suppressive effect on bone cell formation while promoting adipocyte formation. Physical and chemical factors also affect proper bone remodelling and formation and may be of help when it comes to treatment. Even so, it is necessary to continue adapting this type of therapy, as there is the problem of controlling cell migration once the MSCs have been implanted.[7]

  • Hydrogels for Osteoporosis Treatment:

The use of biomaterials in the hydrogel state stands out due to their hydrophilic properties, their good biocompatibility, their porous structure and their adjustable biodegradability mechanical properties. These properties directly influence the cell migration, proliferation and differentiation of MSCs, which favours bone regeneration. Hydrogels have been used as an emerging and promising tool in tissue engineering. They act as a substitute for the conventional materials used in restorative surgery by combining biology and engineering, improving and restoring tissue function. One of the current challenges in tissue engineering for the treatment of osteoporosis is the development of a system for the controlled release of therapeutic substances that can improve their targeting. Injectable hydrogels are presented as a versatile option for different applications in tissue engineering thanks to their adaptability. Despite this, their clinical application is still scarce, and more studies are required to improve the aspects related to the use of polymeric biomaterials, their mechanical properties or their biodegradability.

Recombinant human BMP-2 was, until a few years ago, the only osteo-inductive growth factor approved by the FDA and the European Medicines Agency (EMA) for the treatment of long fractures. However, the direct use of BMPs has been reported to lead to adverse effects, so the use of drug carriers is suggested as an option to reduce the doses applied and improve their cost-effectiveness.

In the treatment of diseases mainly caused by osteoporosis, such as hypercalcemia, the use of hydrogels may present an advantage for the regulation of calcium formation.[6]

Salmon calcitonin (sCT) is a product currently used in clinical regenerative medicine to regulate calcium metabolism in order to improve the treatment of disorders such as osteoporosis and hypercalcemia.

In osteoporosis, excessive oxidative stress causes osteoblast and osteocyte apoptosis, leading to abnormal bone formation around the damaged area [158]. Melatonin is a hormone that has previously demonstrated its capacity for cell differentiation and bone remodelling and its usefulness in curbing excessive oxidative stress.

The encapsulation of alendronate, a bone resorption inhibitor, in different chitosan-based hydrogels crosslinked using genipin (CS/bGP) for the prolonged local delivery of alendronate by injection is an aspect that could be of interest in the treatment of OP. Increasing the concentration of alendronate resulted in hydrogels with a lower porosity and higher density. The CS/bGP hydrogel ensured the controlled release of alendronate for an average of 50 days depending on the initial inhibitor load added, proved to be biocompatible and showed a low immunogenic response. In addition, alendronate-loaded hydrogel was shown to have a lower inflammatory response, higher cell proliferation and faster tissue maturation.

combination of ESW and T-Gel significantly enhanced the viability, proliferation, migration and osteogenic differentiation of MSCs, thus improving the osteogenic activity of the microenvironment in osteoporotic defects.[6]
A REVIEW OF LITERATURE

  1. The international, 24-month FRAME trial compared romosozumab with placebo in 7,180 postmenopausal women with a T-score of –2.5 to –3.5 at the total hip or femoral neck. Patients received SC romosozumab 210 mg or placebo once monthly for 12 months during the double-blind phase of the trial. Then, all patients received open-label denosumab, administered SC at 60 mg per dose every six months for an additional 12 months. The results showed that patients who received romosozumab had a 73% lower risk of new vertebral fracture at 12 months compared with placebo (incidence, 0.5% versus 1.8%; relative risk, 0.27; 95% CI, 0.16–0.47; P < 0.001); however, there was no significant difference in the risk of nonvertebral or clinical fracture at 24 months. Romosozumab increased BMD at the lumbar spine, total hip, and femoral neck by 13.3%, 6.9%, and 5.9% respectively (P < 0.001 for all comparisons).[7]

 

  1. As of July 2017, the FDA had rejected approval of romosozumab for osteoporosis treatment due to a higher rate of serious adverse cardiovascular events compared with alendronate. Amgen and UCB are pooling late-phase data and refiling their application in an effort to show the drug has a positive risk–benefit profile.[8]

 

  1. In 2016, Merck discontinued development of Odanacatib due to an increased risk of stroke.[9]

 

  1. The PEARL trial studied the effects of Lasofoxifene in an international, randomized, placebo-controlled trial of 8,556 women between 59 and 80 years of age who had a BMD T-score of 2.5 or less at the femoral neck or spine. Participants received either 0.25 mg or 0.5 mg Lasofoxifene daily versus placebo for five years. The group that received the clinically approved dose of Lasofoxifene 0.5 mg per day demonstrated a relative risk reduction of 42% and 24% in vertebral fractures and nonvertebral fractures, respectively. Researchers also found that therapy was associated with reductions in breast cancer, coronary heart disease, and stroke.[10]

 

  1. Lasofoxifene is approved for osteoporosis treatment in Europe, but approval is pending in the U.S. [11]

 

  1. The results showed that, by using a high number of progenitor stem cells with good proliferation and differentiation capacities, it is possible to control bone resorption, decrease fracture damage and improve tissue mineral density in the treatment of osteoporosis.[12]
  1. In a recent study by Lu et al., it was observed that extracellular vesicles (EVs) from MSCs possessed therapeutic potential for the treatment of osteoporosis, similar to that of progenitor cells.[13]
  1. Genetically modified BM-MSCs have also been studied in the treatment of osteoporosis. Sui et al. demonstrated that this cell line showed good homing and osteogenic capacity in glucocorticoid-induced murine osteoporosis (GIOP).[14]

 

  1. Zheng et al. analyzed different strategies based on hydrogels for the treatment of osteoporosis, concluding that the use of biomaterials based on combined natural and synthetic composites is the best therapeutic strategy. These hydrogels have low cytotoxicity and good biocompatibility and biodegradability, which, together with a physicochemical crosslinking process, improve the mechanical properties of the construct. This makes it possible to control the degradation rate of the hydrogel, generating an excellent vehicle for the controlled release of drugs.[15]

 

  1. Echave et al. developed an osteoconductive hydrogel based on gelatin and calcium sulfate-hydroxyapatite bioceramics that slowed the delivery of the required doses of growth factors such as BMP-2 to promote bone regeneration in an osteoporotic defect model. The resulting hydrogels were biocompatible and had an increased pore size, which favoured mechanical compression properties. In this study, it was demonstrated that the hydrogels promoted the adhesion and proliferation of human bone marrow-derived MSCs and also promoted the osteogenic differentiation of the cells.[16]
  1. García-García et al. developed two different scaffolds based on PLGA-Alginate in a hydrogel state (HY) and another in a solid-state as a sponge (SS), which were for the sustained delivery of β-estradiol and BMP-2 for bone regeneration in osteoporosis. In this case, both systems were flexible, adapted well to the shape of the defect and had the same controlled release rate of β-estradiol and BMP-2. According to their trials, both strategies promoted bone regeneration, but in the case of SS, the bone repair was 30% higher than that with HY. This was possible simply due to the shorter degradation time of SS compared to that of HY. This study reflects the importance of modifying the physical properties of hydrogels to optimize regenerative therapies.[1
  1. In another similar study by the same group, a heat-resistant injectable hydrogel was used to encapsulate 17β-estradiol, bone morphogenetic protein-2 (BMP-2) and plasma rich in growth factors (PRGF) microspheres. Here, the loaded hydrogel was applied locally to regenerate a critical calvarial bone defect in rats. PRGF did not increase bone repair, while the addition of BMP-2 increased the response to 17β-estradiol. However, the mineralization of newly formed bone in the osteoporosis groups was markedly lower than that in the non-osteoporosis groups.[18]

 

  1. Li et al. developed an injectable tetra-PEG-based hydrogel loaded with the drug alendronate (ALN), which allowed for the long-term controlled release of anti-osteoporotic molecules. These hydrogels effectively promoted bone regeneration at the implantation site in a minimally invasive manner.[19]
  1. As sCT in serum is rapidly cleared in vivo, Yu et al. designed a hydrogel based on the conjugation of sCT with oxidized calcium alginate (sCTOCA) and hydroxypropyl chitin (HPCH). These gels were stable for up to 28 days and showed higher biocompatibility when used on pre-osteoblastic cells than sCT alone. In sCT-OCA, the activity of some osteogenic markers such as ALP increased by up to 63%, and calcium deposition increased by 42%, enhancing osteogenic cell differentiation.[20]
  1. In a study by Xiao et al., a hydrogel with a dressing function based on methacrylate gelatin (GelMA) doped with melatonin for controlled and targeted release was developed. In a trial with MC3T3-E1 cells, it was shown that melatonin in controlled doses reduced the apoptosis caused by hydrogen peroxide-induced oxidative stress and restored the osteogenic potential of the cells. In addition, it increased the bone mass around the implant in ovariectomized rats treated with this adhesive.[21]
  1. Zhao et al. generated a bio-inspired mineralized hydrogel from the supramolecular assembly of nano-hydroxyapatite, sodium carbonate and polyacrylic acid (CHAp-PAA). These hydrogels proved to be able to maintain their morphology and mechanical properties. They were biocompatible, bioactive and osteoconductive in studies carried out using bone marrow mesenchymal stem cells. The results presented in this work demonstrated that these hydrogels enhanced bone growth by accelerating bone formation without the need for additional therapeutic agents.[22]
  1. Another study developed a Nano emulsion drug delivery system based on a Fluvastatin hydrogel, using carbopol940 as a gelling agent. The drugs were intended to be administered trans dermally and were subsequently evaluated for their anti-osteoporotic potential. The in vivo anti-osteoporotic results carried out in this research showed the formation of new bone in the trabecular region of osteoporotic rat femurs and an increase in load-bearing with respect to the damaged tissue.[23]
  1. Papathanassiou et al. fabricated and characterized silica-based hydrogels for the purpose of releasing bis-phosphonates, which are a synthetic variant of pyrophosphates with advantageous bone remodelling properties. These hydrogels are injectable and thermosensitive and can be reused and refilled. In addition, by altering several factors, such as temperature, the cations present, pH and the structural characteristics of the bis-phosphonates, the release rate can be controlled.[24]
  1. Chen et al. studied the effect of the application of extracorporeal shock waves (ESW) together with the application of a hydrogel loaded with teriparatide (T-Gel), a drug used in the treatment of osteoporosis, on the activity and cell differentiation of osteoporosis-derived MSCs and their regenerative capacity. Their results showed that the combination of ESW and T-Gel significantly enhanced the viability, proliferation, migration and osteogenic differentiation of MSCs, thus improving the osteogenic activity of the microenvironment in osteoporotic defects.[25]

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