Symptoms
Osteoporosis is a bone disorder that increases a person’s risk of fracture due to low bone mineral density (BMD), impaired bone microarchitecture/mineralization, and/or decreased bone strength.
Causes
Fine-tuning Osteoporosis Risk. The "gold standard" test for diagnosing osteoporosis is the DEXA scan (dual energy X-ray absorptiometry), which measures bone density in the spine, hip, or wrist. These are the most common locations for bone fractures. But this test, as advanced as it is, has limitations.
Prevention
Nonpharmacological management of osteoporosis includes adequate calcium and vitamin D intake, weight-bearing exercise, smoking cessation, limitation of alcohol/caffeine consumption, and fall-prevention techniques. 2 – 6, 9, 18, 34
Complications
Khosla and other osteoporosis researchers are studying new imaging and computer techniques that will allow them to look inside the bone, and see specific structural characteristics. This will help them to build models of bone strength that can help predict which patients are most likely to have fractures.
What is osteoporosis and how is it treated?
What is the best test for osteoporosis?
What are the nonpharmacological treatment options for osteoporosis?
What's new in osteoporosis research?
How to treat osteoporosis?
The treatment for osteoporosis in the first step consists of basic interventions such as prescribing exercise, weight-bearing physical activity and exercises that improve balance and posture, a diet rich in vitamin D and calcium, quitting smoking, and limiting alcohol use, measures summarized under point “Nonpharmacological treatment” In the second step, specific medication prescriptions are necessary (Figure 1(Fig. 1)). Medication groups are divided in anti-resorptive (anti-catabolic) drugs, anabolic drugs, and combinations of remedies (Ukon et al., 2019[125]). Osteoclasts remain the main targets of medical intervention, even though osteoblasts emerge as new cells of interest in that topic. The Wnt signaling pathway has become a fascinating spot for new medical interventions; Dickkopf-1 and sclerostin, both inhibitors of this pathway, are promising therapeutic targets (Chen et al., 2019[25]).
What is osteoporosis cellular?
Abstract. Osteoporosis is a metabolic bone disease that , on a cellular level, results from osteoclastic bone resorption not compensated by osteoblastic bone formation. This causes bones to become weak and fragile, thus increasing the risk of fractures. Traditional pathophysiological concepts of osteoporosis focused on endocrine mechanisms such as ...
What is polypharmacy in medicine?
Polypharmacy - the use of more than 5 drugs or the use of potentially inappropriate medication - is associated with an increased risk of hip fracture. This is the result of a case-control study on 1003 female patients (on average 71 years of age) with osteoporosis and a hip fracture after adjustment for confounders.
Why are oral preparations associated with a high number of non-adherence and reduced treatment effects?
Oral preparations are associated with a high number of non-adherence and reduced treatment effects due to side effects, low absorption of the oral preparation, and the manner of administration. Furthermore, comorbidities, polypharmacy, and functional decline in elderly patients account for this drawback (Gamboa et al., 2018[50]).
What is the role of remodeling in osteoporosis?
The crucial role of remodeling in overall bone homeostasis is highlighted by the fact that impaired remodeling favoring bone resorption over bone formation is a fundamental pathophysiological mechanism leading to bone pathologies such as osteoporosis.
What is the role of bone in the body?
Research over the years has evidenced the central role of bone as an organ that is in constant exchange with and regulates several other tissues. Accordingly, it is now well accepted that bone, in addition to its classical roles in locomotion, protection of internal organs, and regulation of mineral homeostasis, contributes to the regulation of glucose metabolism and energy expenditure and influences male fertility and cognitive functions through the secretion of osteocalcin by osteoblasts (Ponzetti and Rucci, 2019[100]; Wei and Karsenty, 2015[128]). In order to perform its diverse functions, bone undergoes continuous cycles of modeling and remodeling. During modelingeither bone formation or bone resorption occur independently at distinct sites. Thereby, changes in dimensions and shape of bone during growth and adaption of bone to altering mechanical demands are facilitated. Remodeling, in contrast, is a highly coordinated process of concomitant resorption and formation at a distinct site and is responsible for the maintenance of skeletal integrity by renewing old and damaged bone. Additionally, remodeling processes maintain calcium and phosphate homeostasis by targeted release and incorporation from and into the bone matrix. The crucial role of remodeling in overall bone homeostasis is highlighted by the fact that impaired remodeling favoring bone resorption over bone formation is a fundamental pathophysiological mechanism leading to bone pathologies such as osteoporosis.
Is osteoporosis a metabolic disease?
Osteoporosis, the most frequent form of metabolic bone diseases, is defined as a ”skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture”. Furthermore, bone strength is defined to “primarily reflect the integration of bone density and bone quality” (NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, 2001[85]). Although osteoporosis can occur at any age and in both genders, it typically is an age related disease that more frequently affects women than men. In contrast to other musculoskeletal diseases such as osteoarthritis or sarcopenia, for osteoporosis effective treatment options that interfere with the underlying disease processes are available; nevertheless, in clinical reality only a relatively small fraction of patients is treated adequately. With the aging of our societies, it is very likely that the number of patients suffering from osteoporosis will increase dramatically; thus, intensive further research to identify novel therapeutic targets urgently is needed. This article is intended to contribute to this goal in reviewing disease mechanisms, the current and potential future treatment options for osteoporosis. Based upon our personal expertise, a special focus will be given to osteoimmunology.
What phase of clinical trials are osteoporosis drugs in?
New osteoporosis drugs and their effects in clinical phase 3 trials
What are the treatments for osteoporosis?
In the late 1980s, a doctor could offer a postmenopausal woman little else but oestrogen replacement and perhaps calcitonin, along with calcium and vitamin D supplementation, as a treatment for osteoporosis. In 2017, the options include not only oestrogen and calcitonin, but also a selective oestrogen-receptor modulator (SERM; raloxifene),1four bisphosphonates (alendronate, risedronate, ibandronate, and zoledronic acid),2a human monoclonal antibody to the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL; denosumab),3and the parathyroid hormone analogue teriparatide.4On the horizon are two new drugs: a parathyroid hormone-related peptide analogue (abaloparatide)5and a humanised monoclonal antibody to sclerostin (romosozumab).6A third candidate drug, the cathepsin K inhibitor odanacatib, had significant anti-fracture efficacy, but the pivotal phase 3 clinical trial was terminated because of an unforeseen increased risk of stroke.7Despite this remarkable progress in drug development for the prevention and treatment of fractures, major challenges to implementing appropriate treatment remain, even for patients who unequivocally need therapy. For example, among 22 598 patients in an American commercial health plan who had a hip fracture, use of bisphosphonates decreased from only 15% in 2004 to 3% in 2013.8
What is the effect of parathyroid hormone on bone?
Intermittent activation of the parathyroid receptor type 1 by short pulses of full-length parathyroid hormone (an 84 aminoacid peptide) or fragments thereof (eg, the N-terminal 1–34 fragment, teriparatide) exerts anabolic effects on bone, although the underlying cellular mechanisms are not fully understood.47Despite the clear advantage of parathyroid hormone as a bone-forming agent, its clinical administration has limitations, including concurrent stimulation of bone resorption, which limits the build-up of new bone; less potency at cortical bone; and hypercalcaemia. 5Two conformations of parathyroid receptor type 1 exist (figure 1): the R0conformation, which results in prolonged cyclic adenosine monophosphate (cAMP) signalling responses in cells and prolonged hypercalcaemia in animals, and the RGconformation, with a more transient cAMP response. In subsequent comparative studies of teriparatide and abaloparatide (the 1–34 N-terminal fragment of parathyroid hormone-related peptide, known as a mediator of humoral hypercalcaemia of malignancy), was found to favour the RGconformation more than teriparatide did.48This result provided the rationale to develop abaloparatide with the prospects of stimulating bone formation with less concomitant bone resorption and less hypercalcaemia.48
What was the first drug discovery for osteoporosis?
The year 2000 can be viewed as a watershed year around which the fundamental process of drug discovery for osteoporosis changed, with the first example being denosumab. Before this time, drug development for osteoporosis grew out of clinical observations related to oestrogen and parathyroid hormone (teriparatide, abaloparatide), medicinal chemistry modifications to oestrogen (SERMs raloxifene and bazedoxifene), therapeutic extensions of physiological studies (calcitonin), or purely opportunistic discovery (bisphosphonates). The development of denosumab as a novel therapeutic, however, was driven by advances in fundamental bone biology. Subsequent drug discoveries (romosozumab, odanacatib) followed a similar research and development framework, which also relied on insights gained from studying bone biology in patients with rare bone diseases. As such, the fundamental process of drug discovery for osteoporosis has changed in the post-2000 era.
What is the role of oestrogen in bone health?
Seminal observations by Fuller Albright9in the 1940s established the key role for oestrogen in regulating bone metabolism in women, and oestrogen was subsequently found to also have an important role in the male skeleton.10Oestrogen treatment is effective in both the prevention11and treatment12of osteoporosis. The definitive study of the efficacy and side-effects of oestrogen was the Women's Health Initiative (WHI), in which 16 608 postmenopausal women aged 50–79 years were randomly assigned to receive conjugated equine oestrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day, to prevent uterine hyperplasia) or placebo for an average of 5.6 years. In addition to increasing bone mineral density (BMD) at multiple sites, oestrogen treatment reduced the risk of fracture by 24% (hazard ratio [HR] 0.76, 95% CI 0.69–0.83).13However, because of the well documented side-effects of oestrogen that were revealed in the WHI study, including an increase in cardiovascular events and breast cancer risk,14oestrogen is now used primarily for short-term prevention of menopausal hotflashes. Transdermal oestrogen (0.05–0.10 mg/day) combined with a progestin (in women with an intact uterus) is an alternative regimen for osteoporosis prevention and treatment,12but whether transdermal oestrogen causes similar adverse events as oral conjugated oestrogen remains unclear. Ultra-low dose oestrogen (0.014 mg/day) has also been shown to prevent reductions in BMD in postmenopausal women without causing uterine hyperplasia15and has been approved for osteoporosis prevention by the US Food and Drug Administration (FDA). However, whether this ultra-low dose prevents fractures or is associated with the other adverse events noted in the WHI study is not known. Thus, oestrogen-based therapies might not be viable long-term treatments for osteoporosis.
What are bisphosphonates used for?
Bisphosphonates are the most widely used drugs for the prevention and treatment of osteoporosis, with four options available at present (table 1). The history of their development is of interest, since their discovery as effective drugs for osteoporosis was largely opportunistic.22Bisphosphonates are chemically stable analogues of pyrophosphate compounds, which are widely found in nature. Naturally occurring pyrophosphate circulates in the human body as an endogenous water softener. The early use of bisphosphonates was mainly as corrosion inhibitors and as complexing agents in the textile, fertiliser, and oil industries; they were subsequently found to inhibit calcification and inhibit bone resorption. The mechanism underlying their anti-osteoclast effects was delineated decades after their clinical use had been initiated; it involves inhibition of the enzyme farnesyl pyrophosphate synthase, which generates isoprenoid lipids that are used for the post-translational modifications of small guanosine triphosphate (GTP)-binding proteins required for osteoclast viability and function.23Bisphosphonate treatment is associated with 40–70% reductions in vertebral fractures and 40–50% reductions in hip fractures. Thus, these are extremely effective drugs for the treatment of osteoporosis, but the main concerns limiting their use are the rare side-effects, such as atypical femur fractures24and osteonecrosis of the jaw,25and unproven efficacy after 5 years of treatment.26
Where did denosumab originate?
The origin of denosumab can be traced to a fetal rat intestine cDNA-sequencing project at Amgen that was unrelated to bone physiology. A novel cDNA with homology to the TNF-receptor superfamily had been isolated,32and transgenic mice overexpressing this cDNA clone had marked increases in bone mass, hence the name osteoprotegerin (“to protect bone” in Latin). Subsequently, mice with targeted ablation of osteoprotegerin were found to have severe osteoporosis and arterial calcifcations.33Further intensive studies in bone biology, including expression cloning using osteoprotegerin as a probe, led to the identification of its ligand, the receptor activator of NF-κB ligand (RANKL), and the understanding that with macrophage colony-stimulating factor (M-CSF), RANKL was both necessary and sufficient for osteoclast development.34These findings ultimately led to the development of denosumab, a human monoclonal antibody to RANKL, as a novel anti-resorptive drug for osteoporosis. Results of the FREEDOM trial35showed that treatment with denosumab was associated with a 68% reduction in vertebral fractures (RR 0.32, 95% CI 0.26–0.41) and a 40% reduction in hip fractures (HR 0.60, 95% CI 0.37–0.97).
What is the gold standard for osteoporosis?
The "gold standard" test for diagnosing osteoporosis is the DEXA scan (dual energy X-ray absorptiometry), which measures bone density in the spine, hip, or wrist. These are the most common locations for bone fractures. But this test, as advanced as it is, has limitations.
How many people will be affected by osteoporosis in 2020?
But today, advances in research are shedding new light on osteoporosis, which is predicted to affect as many as half of all Americans over age 50 by the year 2020. From diagnosis to prevention to osteoporosis treatment, new research is turning our old understanding of osteoporosis upside down.
What are biomarkers used for?
They're developing tools known as biomarkers, which are chemical measures of the rate of bone remodeling that can be found in secretions from blood or urine.
What is the purpose of Khosla's study?
Khosla and other osteoporosis researchers are studying new imaging and computer techniques that will allow them to look inside the bone, and see specific structural characteristics. This will help them to build models of bone strength that can help predict which patients are most likely to have fractures.
What is the best imaging technique for bone fracture?
One such imaging technique is computed tomography (CT) scanning of the spine and hip. Researchers take the three-dimensional image of the bone that the CT scan creates, and use a computer modeling technique that breaks the image down into tiny pieces. "The density of each piece allows you to estimate the strength of each piece, and get the overall strength of the structure," says Khosla. "Depending on where a bone is weakest, it may be more or less prone to fracture."
Why do bones lose density?
For years, we've thought we understood osteoporosis: it's a disease in which the bones become more and more fragile as they lose density, usually due to aging, menopause, and other factors like lack of calcium and vitamin D in the diet.
Do drugs slow down bone growth?
Scientists realized that the drugs were also slowing down the rate of bone remodeling -- the process in which existing areas of bone is pared away, later to be replaced with new bone. In menopausal women, that rate of bone remodeling doubles -- and then it triples by a woman's early 60s.