Osteoporosis is a chronic metabolic disease characterized by an imbalance of bone resorption and formation, leading to bone fragility and increased susceptibility to fracture. Parathyroid hormone is approved therapy for the treatment of osteoporosis.
Parathyroid Hormone and Teriparatide for the Treatment of Osteoporosis: A Review of the Evidence and Suggested Guidelines for Its Use
All therapies currently recommended for the management of osteoporosis act mainly to inhibit bone resorption and reduce bone remodeling. PTH and its analog
Parathyroid hormone temporal effects on bone formation and resorption
Parathyroid hormone (PTH) paradoxically causes net bone loss (resorption) when administered in a continuous fashion, and net bone formation (deposition) when administered intermittently. Currently no pharmacological formulations are available to promote bone formation, as needed for the treatment of osteoporosis. The paradoxical behavior of PTH confuses endocrinologists, thus, a model bone resorption or deposition dependent on the timing of PTH administration would de-mystify this behavior and provide the basis for logical drug formulation. We developed a mathematical model that accounts for net bone loss with continuous PTH administration and net bone formation with intermittent PTH administration, based on the differential effects of PTH on the osteoblastic and osteoclastic populations of cells.
Regulation of Bone Remodeling by Parathyroid Hormone
Parathyroid hormone (PTH) exerts profound effects on skeletal homeostasis through multiple cellular and molecular mechanisms. Continuous hyperparathyroidism causes net loss of bone mass, despite accelerating bone formation by osteoblasts. Intermittent treatment with PTH analogs represents the only Food and Drug Administration (FDA)-approved bone anabolic osteoporosis treatment strategy. Functional PTH receptors are present on cells of the osteoblast lineage, ranging from early skeletal stem cells to matrix-embedded osteocytes. In addition, bone remodeling by osteoclasts liberates latent growth factors present within bone matrix. Here, we will provide an overview of the multiple cellular and molecular mechanisms through which PTH influences bone homeostasis. Notably, net skeletal effects of continuous versus intermittent can differ significantly. Where possible, we will highlight mechanisms through which continuous hyperparathyroidism leads to bone loss, and through which intermittent hyperparathyroidism boosts bone mass. Given the therapeutic usage of intermittent PTH (iPTH) treatment for osteoporosis, particular attention will be paid toward mechanisms underlying the bone anabolic effects of once daily PTH administration.
Mathematical Model of Paracrine Interactions between Osteoclasts and Osteoblasts Predicts Anabolic Action of Parathyroid Hormone on Bone
Abstract. To restore falling plasma calcium levels, PTH promotes calcium liberation from bone. PTH targets bone-forming cells, osteoblasts, to increase exp
Mathematical Model of Bone Remodeling Captures the Antiresorptive and Anabolic Actions of Various Therapies
A better understanding of the molecular pathways regulating the bone remodeling process should help in the development of new antiresorptive regulators and anabolic regulators, that is, regulators of bone resorption and of bone formation. Understanding the mechanisms by which parathyroid hormone (PTH) influences bone formation and how it switches from anabolic to catabolic action is important for treating osteoporosis (Poole and Reeve in Curr Opin Pharmacol 5:612–617, 2005). In this paper we describe a mathematical model of bone remodeling that incorporates, extends, and integrates several models of particular aspects of this biochemical system (Cabal et al. in J Bone Miner Res 28(8):1830–1836, 2013; Lemaire et al. in J Theor Biol 229:293–309, 2004; Peterson and Riggs in Bone 46:49–63, 2010; Raposo et al. in J Clin Endocrinol Metab 87(9):4330–4340, 2002; Ross et al. in J Disc Cont Dyn Sys Series B 17(6):2185–2200, 2012). We plan to use this model as a bone homeostasis platform to develop anabolic and antiresorptive compounds. The model will allow us to test hypotheses about the dynamics of compounds and to test the potential benefits of combination therapies. At the core of the model is the idealized account of osteoclast and osteoblast signaling given by Lemaire et al. (J Theor Biol 229:293–309, 2004). We have relaxed some of their assumptions about the roles of osteoprotegerin, transforming growth factor $$\upbeta $$, and receptor activator of nuclear factor $$\upkappa $$B ligand; we have devised more detailed models of the interactions of these species. We have incorporated a model of the effect of calcium sensing receptor antagonists on remodeling (Cabal et al. in J Bone Miner Res 28(8):1830–1836, 2013). We have also incorporated a basic model of the effects of vitamin D on calcium homeostasis. We have included a simple model of the mechanism proposed by Bellido et al. (2003), Ross et al. (J Disc Cont Dyn Sys Series B 17(6):2185–2200, 2012), of the influence of PTH on osteoblast apoptosis, a mechanism that accounts for the anabolic response to pulsatile PTH administration. Finally, we have devised a simple model of the administration and effects of bisphosphonates. The biomarkers in the model are procollagen type 1 amino-terminal propeptide and C-terminal telopeptide. Bone mineral density is the model’s principal endpoint.
The bone remodelling cycle
The bone remodelling cycle replaces old and damaged bone and is a highly regulated, lifelong process essential for preserving bone integrity and maintaining mineral homeostasis. During the bone remodelling cycle, osteoclastic resorption is tightly coupled to osteoblastic bone formation. The remodelling cycle occurs within the basic multicellular unit and comprises five co-ordinated steps; activation, resorption, reversal, formation and termination. These steps occur simultaneously but asynchronously at multiple different locations within the skeleton. Study of rare human bone disease and animal models have helped to elucidate the cellular and molecular mechanisms that regulate the bone remodelling cycle. The key signalling pathways controlling osteoclastic bone resorption and osteoblastic bone formation are receptor activator of nuclear factor-κB (RANK)/RANK ligand/osteoprotegerin and canonical Wnt signalling. Cytokines, growth factors and prostaglandins act as paracrine regulators of the cycle, whereas endocrine regulators include parathyroid hormone, vitamin D, calcitonin, growth hormone, glucocorticoids, sex hormones, and thyroid hormone. Disruption of the bone remodelling cycle and any resulting imbalance between bone resorption and formation leads to metabolic bone disease, most commonly osteoporosis. The advances in understanding the cellular and molecular mechanisms underlying bone remodelling have also provided targets for pharmacological interventions which include antiresorptive and anabolic therapies. This review will describe the remodelling process and its regulation, discuss osteoporosis and summarize the commonest pharmacological interventions used in its management.
Estrogen therapy for osteoporosis in the modern era
Menopause predisposes women to osteoporosis due to declining estrogen levels. This results in a decrease in bone mineral density (BMD) and an increase in fractures. Osteoporotic fractures lead to substantial morbidity and mortality, and are considered one of the largest public health priorities by the World Health Organization (WHO). It is therefore essential for menopausal women to receive appropriate guidance for the prevention and management of osteoporosis. The Women’s Health Initiative (WHI) randomized controlled trial first proved hormonal therapy (HT) reduces the incidence of all osteoporosis-related fractures in postmenopausal women. However, the study concluded that the adverse effects outweighed the potential benefits on bone, leading to a significant decrease in HT use for menopausal symptoms. Additionally, HT was not used as first-line therapy for osteoporosis and fractures. Subsequent studies have challenged these initial conclusions and have shown significant efficacy of HT in various doses, durations, regimens, and routes of administration. These studies support that HT improves BMD and reduces fracture risk in women with and without osteoporosis. Furthermore, the studies suggest that low-dose and transdermal HT are less likely associated with the adverse effects of breast cancer, endometrial hyperplasia, coronary artery disease (CAD), and venous thromboembolism (VTE) previously observed in standard-dose oral HT regimens. Given the need for estrogen in menopausal women and evidence supporting the cost effectiveness, safety, and efficacy of HT, we propose that HT should be considered for the primary prevention and treatment of osteoporosis in appropriate candidates. HT should be individualized and the once “lowest dose for shortest period of time” concept should no longer be used. This review will focus on the prior and current studies for various HT formulations used for the prevention and treatment of osteoporosis, exploring the safety profile of low-dose and transdermal HT that have been shown to be safer than oral standard-dose HT.
A computational framework and sensitivity analysis for the hormonal treatment of bone
It is concluded that intermittent administration of calcitonin is an effective therapy for the treatment of osteoporosis.
TRANCE Is Necessary and Sufficient for Osteoblast-mediated Activation of Bone Resorption in Osteoclasts
TRANCE (tumor necrosis factor–related activation-induced cytokine) is a recently described member of the tumor necrosis factor superfamily that stimulates dendritic cell survival and has also been found to induce osteoclastic differentiation from hemopoietic precursors. However, its effects on mature osteoclasts have not been defined. It has long been recognized that stimulation of osteoclasts by agents such as parathyroid hormone (PTH) occurs through a hormonal interaction with osteoblastic cells, which are thereby induced to activate osteoclasts. To determine whether TRANCE accounts for this activity, we tested its effects on mature osteoclasts. TRANCE rapidly induced a dramatic change in osteoclast motility and spreading and inhibited apoptosis. In populations of osteoclasts that were unresponsive to PTH, TRANCE caused activation of bone resorption equivalent to that induced by PTH in the presence of osteoblastic cells. Moreover, osteoblast-mediated stimulation of bone resorption was abrogated by soluble TRANCE receptor and by the soluble decoy receptor osteoprotegerin (OPG), and stimulation of isolated osteoclasts by TRANCE was neutralized by OPG. Thus, TRANCE expression by osteoblasts appears to be both necessary and sufficient for hormone-mediated activation of mature osteoclasts, and TRANCE-R is likely to be a receptor for signal transduction for activation of the osteoclast and its survival.
Dynamics of bone cell signaling and PTH treatments of osteoporosis
In this paper we analyze and generalize the dynamical system introduced by Lemaire and co-workers [14] as a model of cell signaling in bone remodeling. We show that for large classes of parameter values, including the physically-realistic baseline values, the system has a unique physically relevant equilibrium which is a global attractor. We generalize that model, minimally, to incorporate a mechanism by which parathyroid hormone (PTH) retards osteoblast apoptosis. We show that with this mechanism, which is a simplified version of that proposed by Bellido and co-workers [4], the model exhibits a well-known phenomenon that has puzzled researchers: the system responds catabolically to the continuous administration of PTH andally to appropriately pulsed administration of PTH.
Study of the combined effects of PTH treatment and mechanical loading in postmenopausal osteoporosis using a new mechanistic PK-PD model
One of only a few approved and available anabolic treatments for severe osteoporosis is daily injections of PTH (1-34). This drug has a specific dual action which can act either anabolically or catabolically depending on the type of administration, i.e. intermittent or continuous, respectively. In this paper, we present a mechanistic pharmacokinetic–pharmacodynamic model of the action of PTH in postmenopausal osteoporosis. This model accounts for anabolic and catabolic activities in bone remodelling under intermittent and continuous administration of PTH. The model predicts evolution of common bone biomarkers and bone volume fraction (BV/TV) over time. We compared the relative changes in BV/TV resulting from a daily injection of 20 $$\upmu$$g of PTH with experimental data from the literature. Simulation results indicate a site-specific bone gain of 8.66$$\%$$(9.4 ± 1.13$$\%$$) at the lumbar spine and 3.14$$\%$$(2.82 ± 0.72$$\%$$) at the femoral neck. Bone gain depends nonlinearly on the administered dose, being, respectively, 0.68$$\%$$, 3.4$$\%$$and 6.16$$\%$$for a 10, 20 and 40 $$\upmu$$g PTH dose at the FN over 2 years. Simulations were performed also taking into account a bone mechanical disuse to reproduce elderly frail subjects. The results show that mechanical disuse ablates the effects of PTH and leads to a 1.08% reduction of bone gain at the FN over a 2-year treatment period for the 20 $$\upmu$$g of PTH. The developed model can simulate a range of pathological conditions and treatments in bones including different PTH doses, different mechanical loading environments and combinations. Consequently, the model can be used for testing and generating hypotheses related to synergistic action between PTH treatment and physical activity.
Postmenopausal osteoporosis
Osteoporosis is a metabolic bone disorder that is characterized by low bone mass and micro-architectural deterioration of bone tissue. Fractures of the proximal femur, the vertebrae and the distal radius are the most frequent osteoporotic fractures, although most fractures in the elderly are probably at least partly related to bone fragility. The incidence of fractures varies greatly by country, but on average up to 50% of women >50 years of age are at risk of fractures. Fractures severely affect the quality of life of an individual and are becoming a major public health problem owing to the ageing population. Postmenopausal osteoporosis, resulting from oestrogen deficiency, is the most common type of osteoporosis. Oestrogen deficiency results in an increase in bone turnover owing to effects on all types of bone cells. The imbalance in bone formation and resorption has effects on trabecular bone (loss of connectivity) and cortical bone (cortical thinning and porosity). Osteoporosis is diagnosed using bone density measurements of the lumbar spine and proximal femur. Preventive strategies to improve bone health include diet, exercise and abstaining from smoking. Fractures may be prevented by reducing falls in high-risk populations. Several drugs are licensed to reduce fracture risk by slowing down bone resorption (such as bisphosphonates and denosumab) or by stimulating bone formation (such as teriparatide). Improved understanding of the cellular basis for osteoporosis has resulted in new drugs targeted to key pathways, which are under development.
Current Status of the Diagnosis and Management of Osteoporosis
Osteoporosis has been defined as the silent disease of the 21st century, becoming a public health risk due to its severity, chronicity and progression and affecting mainly postmenopausal women and older adults. Osteoporosis is characterized by an imbalance between bone resorption and bone production. It is diagnosed through different methods such as bone densitometry and dual X-rays. The treatment of this pathology focuses on different aspects. On the one hand, pharmacological treatments are characterized by the use of anti-resorptive drugs, as well as emerging regenerative medicine treatments such as cell therapies and the use of bioactive hydrogels. On the other hand, non-pharmacological treatments are associated with lifestyle habits that should be incorporated, such as physical activity, diet and the cessation of harmful habits such as a high consumption of alcohol or smoking. This review seeks to provide an overview of the theoretical basis in relation to bone biology, the existing methods for diagnosis and the treatments of osteoporosis, including the development of new strategies.
Application of a mechanism-based disease systems model for osteoporosis to clinical data
A recently proposed mechanism-based disease systems model for osteoporosis (Schmidt et al., J Pharmacokinet Pharmacodyn 38:873–900, 2011) was applied to clinical data from post-menopausal women (n = 767) receiving various doses of the selective estrogen receptor modulator tibolone. Plasma bone-specific alkaline phosphatase activity and urinary N-telopeptide were used as biomarkers reflecting the activity of osteoblasts (bone forming cells) and osteoclasts (bone removing cells), respectively. These data were analyzed in conjunction with data on osteocalcin and on bone mineral density (BMD) (both lumbar spine and total hip), which reflect the activity of both cell types. While the dynamics of bone turnover markers changes rapidly, closely following changes in the activity of bone cells, changes in BMD are slower and have their own dynamics. Application of the mechanism-based disease systems model to the clinical data allowed for an adequate description of the data and yielded parameter estimates that are consistent with physiological values reported in the literature (Lemaire et al., J Theor Biol 229:293–309, 2004). The fitted model enabled characterization of (i) the critical time scales involved in disease progression, (ii) the dynamics of the system during onset and offset of the therapeutic intervention, and (iii) the distinction between responders and low-responders to tibolone treatment.
Bone Dynamics in Metabolic Bone Disease:
Bone Remodeling in Post-menopausal Osteoporosis
Bone mass in the skeleton is dependent on the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts in discrete bone multi-cellular units. Remodeling of bone in these units is important not only for maintaining bone mass, but also to repair microdamage, to prevent accumulation of too much old bone, and for mineral homeostasis. The activities of osteoblasts and osteoclasts are controlled by a variety of hormones and cytokines, as well as by mechanical loading. Most importantly, sex hormones are very crucial for keeping bone mass in balance, and the lack of either estrogen or testosterone leads to decreased bone mass and increased risk for osteoporosis. The prevalence of osteoporotic fractures is increasing dramatically in the Western part of the world and is a major health problem in many countries. In the present review, the cellular and molecular mechanisms controlling bone remodeling and the influence of sex hormones on these processes are summarized. In a separate paper in this issue, the pathogenesis of post-menopausal osteoporosis will be compared with that of inflammation-induced bone remodeling, including the evidence for and against the hypothesis that concomitant post-menopausal osteoporotic disease influences the progression of periodontal disease.