|SYMPOSIUM — FRAGILITY FRACTURES
|Year : 2014 | Volume
| Issue : 2 | Page : 101-107
Osteoporosis: Current review
Alok Chandra Agrawal, Roop Bhushan Kalia
Department of Orthopaedics, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
|Date of Web Publication||14-Sep-2015|
Dr. Alok Chandra Agrawal
Department of Orthopaedics, All India Institute of Medical Sciences, GE Road, Raipur - 492 099, Chhattisgarh
Source of Support: None, Conflict of Interest: None
Although hormone therapy using estrogens plus progestogens (EPT) is effective for the management of menopausal symptoms (e.g., vasomotor symptoms and vulvar/vaginal atrophy) and prevention/treatment of postmenopausal osteoporosis, EPT is associated with safety and tolerability concerns. A new alternative to EPT is the tissue selective estrogen complex (TSEC), which partners a selective estrogen receptor modulator (SERM) with one or more estrogens and is designed to treat menopausal symptoms and prevent postmenopausal osteoporosis without the tolerability concerns associated with EPT. The first TSEC to reach advanced clinical development is a combination of the SERM bazedoxifene (BZA) with conjugated estrogens (CE). BZA has been shown to inhibit the stimulatory activity of CE on uterine tissue and breast in vitro and in vivo. In clinical studies, BZA/CE treatment has been associated with significant improvements in menopausal symptoms including hot flushes and vulvar/vaginal atrophy and significant increases in bone mineral density, coupled with reductions in bone turnover marker levels and improvements in sleep and health-related quality of life. Additionally, BZA/CE has been shown to have a neutral effect on endometrial and breast tissue because BZA inhibits the stimulatory effects of estrogens in selective tissue fashion in these two organs. Taken together, results of these preclinical and clinical studies indicate that the benefits of estrogens for treating menopausal symptoms are maintained with BZA/CE without endometrial or breast stimulation, resulting in a safe and effective treatment for symptomatic postmenopausal women.
Keywords: Antiresorptives, fractures, osteoporosis
|How to cite this article:|
Agrawal AC, Kalia RB. Osteoporosis: Current review. J Orthop Traumatol Rehabil 2014;7:101-7
| Introduction|| |
Osteoporosis is a frequent age related disorder characterized by a generalized loss of bone mass and impairment of the microstructure of bone which can result in fragility fractures even with minor falls or injuries. Determinants of bone strength can be measured by different parameters such as bone mineral density (BMD), microstructure, bone mineralization, properties of the bony matrix, and bone geometry. Typically osteoporosis has been linked to postmenopausal endocrinal estrogen deficiency however, several systemic inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, chronic obstructive pulmonary disease, and certain viral infections are associated with osteoporosis. This happens because of the release of cytokines by activated T-cells and B-cells which stimulate osteoclasts and produce increased bone resorption. 
| Pathophysiology|| |
Osteoporosis results from a combination of genetic and environmental factors that affect both peak bone mass and the rate of bone loss. These factors include medications, diet, race, sex, lifestyle, and physical activity. Bone remodelling is the primary metabolic process in the skeleton. It continuously repairs microdamage in the skeleton when old bone is replaced by new bone and provides calcium for blood homeostasis. Bone remodelling process is regulated by several circulating hormones, including estrogens, androgens, Vitamin D, and parathyroid hormone (PTH), as well as locally produced growth factors such as insulin-like growth factor-I and immunoreactive growth hormone II, transforming growth factor β, PTH-related peptide (PTHrP), interleukins, prostaglandins, and tumor necrosis factor. As the skeleton ages bone remodelling is reduced due to decreased number of osteoblasts. This decrease in the number of osteoblasts is due to a lesser number of stem cells, the defective proliferation of stem cells and diversion of progenitors toward adipocyte lineage and increased apoptosis. Also due to ageing, there is an increase in osteoclastic activity with the expansion of the osteoclast precursor pool of cells. 
Osteoblasts ultimately become osteocytes which are interconnected long living cells. The declining number of osteocytes is parallel with the declining strength of bone. It is estimated that by the eight decade of life the osteocyte density is 40% in comparison with a 20 years old.  Ageing, decreased levels of estrogens, reduced physical activity, and oxidative stresses are responsible for early osteocyte death. In young adults, the two processes of bone formation and resorption are balanced, and the mass of the skeleton remains constant after peak bone mass is achieved in adulthood. After age 30-45, however, the resorption and formation processes become imbalanced, and resorption exceeds formation. This imbalance becomes exaggerated in women after menopause due to rapid fall in estrogen levels. Excessive bone loss can be due to an increase in osteoclastic activity and/or a decrease in osteoblastic activity. An increase in the number of remodelling sites, can magnify the small imbalance seen at each remodelling unit and produces a reversible reduction in bone tissue but also can result in permanent loss of tissue and disrupted skeletal architecture.
In trabecular bone when the osteoclasts penetrate bony trabeculae, they leave no template for the new bone formation to occur and rapid bone loss occurs. In cortical bone, increased activation of remodelling creates more porous bone with the loss of the dense bony microstructure. The effect of this increased porosity on cortical bone strength may be modest if the overall diameter of the bone is not changed. However, decreased apposition of new bone on the periosteal surface coupled with increased endosteal resorption of bone decreases the biomechanical strength of long bones by decreasing the cortical thickness. Even a slight exaggeration in normal bone loss dramatically increases the risk of osteoporosis-related fractures because of the adverse architectural micro changes that occur.
Osteoporosis may be either primary or secondary. Primary osteoporosis is subdivided into Types 1 and 2. Secondary osteoporosis is also called Type 3.
- Type 1, or postmenopausal, osteoporosis is thought to result from gonadal (i.e., estrogen, testosterone) deficiency. Estrogen or testosterone deficiency, regardless of the age of occurrence, results in accelerated bone loss. The exact mechanisms of this bone loss potentially are numerous, but, ultimately, an increased recruitment and responsiveness of osteoclast precursors and an increase in bone resorption, which outpaces bone formation, occurs. After menopause, women experience an accelerated bone loss of 1-5%/year for the first 5-7 years. The end result is a decrease in trabecular bone and an increased risk of Colles and vertebral fractures. Evidence indicates that estrogen deficiency causes bone to become more sensitive to the effects of PTH, leading to an increase in calcium release from bone, a decrease in renal calcium excretion, and increased production of 1,25-dihydroxyvitamin D (1,25[OH] 2 D3). Increased production of 1,25(OH) 2 D3, in turn, causes increased calcium absorption from the gut, increased calcium resorption from bone, and increased renal tubular calcium resorption. PTH secretion then decreases via a negative feedback effect, causing the opposite effects. Osteoclasts are also influenced by cytokines, such as tumor necrosis factor-alpha and interleukins 1 and 6, whose production by mononuclear cells may be increased in the presence of gonadal deficiency
- Type 2, or senile, osteoporosis occurs in women and men because of decreased formation of bone and decreased the renal production of 1,25(OH) 2 D3 occurring late in life. The consequence is a loss of cortical and trabecular bone and increased risk for fractures of the hip, long bones, and vertebrae
- Type 3 osteoporosis occurs secondary to medications, especially glucocorticoids, or other conditions that cause increased bone loss by various mechanisms.
Total daily calcium intakes of <400 mg are likely to be detrimental to the skeleton, but there is more doubt about intakes in the 600- to 800-mg range, which is the average intake among adults. The recommended daily required intake of 1000 to 1200 mg for adults accommodates population heterogeneity in controlling calcium balance.
Modest Vitamin D deficiency leads to compensatory secondary hyperparathyroidism and is an important risk factor for osteoporosis and fractures. Studies have shown that >50% of inpatients on a general medical service exhibit biochemical features of Vitamin D deficiency, including increased levels of PTH and alkaline phosphatase and lower levels of ionized calcium.
Treatment with Vitamin D and calcium supplementation prevents this seasonal effect on bone metabolism. Reduced fracture rates have also been documented among individuals in northern latitudes who have greater Vitamin D intake and have higher 25-hydroxyvitamin D [25(OH)D] levels.
| Estrogen Status|| |
Estrogen deficiency probably causes bone loss by two distinct but interrelated mechanisms: (1) Activation of new bone remodeling sites, and (2) exaggeration of the imbalance between bone formation and resorption. The change in activation frequency causes a transient bone loss until a new steady state between resorption and formation is achieved.
The remodeling imbalance, however, results in a permanent decrement in mass that can only be corrected by a remodeling event during which bone formation exceeds resorption. The most frequent estrogen-deficient state is the cessation of ovarian function at the time of menopause, which occurs on average at the age of 51.
Marrow cells (macrophages, monocytes, osteoclast precursors, mast cells), as well as bone cells (osteoblasts, osteocytes, and osteoclasts), express ERs a and b. The net effect of estrogen deficiency is increased osteoclast recruitment and perhaps activity. Estrogen may also play an important 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 of osteoclasts is increased.
Since remodeling is initiated at the surface of the bone, it follows that trabecular bone which has a considerably larger surface area (80% of the total) than cortical bone will be preferentially affected by estrogen deficiency.
Fractures occur earliest at sites where trabecular bone contributes most to bone strength; consequently, vertebral fractures are the most common early consequence of estrogen deficiency.
| Physical Activity|| |
Inactivity, such as prolonged bed rest or paralysis, results in a significant bone loss. Concordantly, athletes have higher bone mass than the general population. These changes in skeletal mass are most marked when the stimulus begins during growth and before the age of puberty.
| Medications|| |
Glucocorticoids are a common cause of medication-induced osteoporosis. Excessive doses of thyroid hormone can accelerate bone remodeling and result in bone loss.
| Cigarette Consumption|| |
The use of cigarettes over a long period has detrimental effects on bone mass. These effects may be mediated directly, by toxic effects on osteoblasts, or indirectly by modifying estrogen metabolism.
| Osteoporosis-Management|| |
Osteoporosis is largely asymptomatic until a fracture occurs, although patients may note a loss of height and gradually increasing kyphosis; therefore, prevention is a key aspect of management. Patients may present with a fracture in a typical location, such as a vertebra, proximal femur, or distal radius, after minimal trauma.
History should focus on a thorough review of risk factors, which include the following:
- Age, sex, and race.
- Family history of osteoporotic fractures.
- Reproductive factors, especially with regard to early menopause and estrogen replacement therapy.
- Lifestyle factors associated with decreased bone density:
- Strenuous exercise (such as occurs in marathon runners) that results in amenorrhea.
- Alcohol consumption.
- Low levels of physical activity.
- Dietary factors, especially calcium and Vitamin D intake (important because deficiencies of both increase osteoporosis risk), and eating disorders such as anorexia nervosa.
- Other medical conditions and medications, especially the use of corticosteroids.
- Risk factors for falls in older patients:
- Poor balance.
- Orthostatic hypotension.
- Weakness of the lower extremity muscles.
- Diminished reaction time.
- Medication use (e.g., sedatives).
- Poor vision.
- Cognitive impairments.
| Routine Laboratory Evaluation|| |
A general evaluation that includes complete blood count, serum calcium, and perhaps urine calcium is helpful for identifying selected secondary causes of low bone mass, particularly for women with fractures or very low Z-scores. Levels of serum calcium, phosphate, and alkaline phosphatase are usually normal in persons with primary osteoporosis, although alkaline phosphatase levels may be elevated for several months after a fracture.
An elevated serum calcium level suggests hyperparathyroidism or malignancy, whereas a reduced serum calcium level may reflect malnutrition and osteomalacia. In the presence of hypercalcemia, a serum PTH level differentiates between hyperparathyroidism (PTH−) and malignancy (PTH−), and a high PTHrP level can help document the presence of humoral hypercalcemia of malignancy. A low urine calcium (<50 mg/24 h) suggests osteomalacia, malnutrition, or malabsorption; a high urine calcium (>300 mg/24 h) is indicative of hypercalciuria and must be investigated further. Checking thyroid function is prudent because abnormal values may indicate a cause of secondary osteoporosis. In men, low testosterone levels can contribute to bone loss; therefore, checking testosterone levels is important.
| Hypercalciuria|| |
Hypercalciuria occurs primarily in three situations:
- A renal calcium leak, which is more frequent in males with osteoporosis;
- Absorptive hypercalciuria, which can be idiopathic or associated with increased 1,25(OH) 2 D in granulomatous disease; or
- Hematologic malignancies or conditions associated with excessive bone turnover such as Paget's disease, hyperparathyroidism, and hyperthyroidism.
Myeloma can masquerade as generalized osteoporosis, although it more commonly presents with bone pain and characteristic "punched-out" lesions on radiography. Serum and urine electrophoresis and evaluation for light chains in urine are required to exclude this diagnosis.
| Markers of Bone Turnover|| |
Markers of bone turnover (both formation and resorption) may be elevated in high bone turnover states (e.g., early Type 1 osteoporosis) and may be useful in some patients for monitoring early response to therapy. However, further study is needed to determine their clinical utility in osteoporosis management. Some of these biochemical measures include the following:
- Bone-specific alkaline phosphatase (bone formation).
- Osteocalcin (bone formation).
- Type 1 procollagen peptides (bone formation).
- Urinary deoxypyridinoline and cross-linked N- and C-telopeptide of Type 1 collagen (bone resorption).
Obtain radiographs of the affected area in patients who are symptomatic. Lateral spine radiographs are obtained in patients who are asymptomatic and at risk for detection of vertebral fracture. Radiographs may show fractures or other conditions, such as osteoarthritis, disk disease, or spondylolisthesis. Osteopenia (low bone density) may be apparent as radiographic lucency but is not always noticeable until 30% of bone mineral is lost. Radiograph findings also depend somewhat on technique and exposure.  Plain radiography is not as accurate as BMD testing [Figure 1].
|Figure 1: Multiple osteoporotic compression fractures dorsal spine with resultant dorsal kyphosis|
Click here to view
| Bone Biopsy|| |
Although the use of bone biopsy is rarely required today, it remains an important tool in clinical research. Tetracycline labeling of the skeleton allows determination of the rate of remodeling, as well as evaluation for other metabolic bone diseases.
| Measurement of Bone Mass|| |
Several noninvasive techniques are now available for estimating skeletal mass or density. These include dual energy X-ray absorptiometry (DXA), single energy X-ray absorptiometry (SXA), quantitative computed tomography (CT), and ultrasound.  DXA is a highly accurate X-ray technique that has become the standard for measuring bone density in most centers. Though it can be used for measurements of any skeletal site, clinical determinations are usually made of the lumbar spine and hip. In the DXA technique, two X-ray energies are used to estimate the area of mineralized tissue, and the mineral content is divided by the area, which partially corrects for body size. Consequently, it has become standard practice to relate the results to "normal" values using T-scores, which compare individual results to those in a young population that is, matched for race and gender [Table 1].
| Computed Tomography Scan|| |
Since this technique specifically analyzes trabecular bone and can provide a true density (mass of bone per unit volume) measurement. 
However, CT remains expensive, involves greater radiation exposure, and is less reproducible. Ultrasound is used to measure the bone mass by calculating the attenuation of the signal as it passes through the bone or the speed with which it traverses the bone. It is unclear whether ultrasound assesses bone quality, but this may be an advantage of the technique. Because of its relatively low cost and mobility, ultrasound is amenable for use as a screening procedure.
Based on bone mass results, the guidelines suggest that patients be considered for treatment when BMD >2.5 standard deviation below the mean value for young adults (T-score <−2.5). Treatment should also be considered in women with risk factors in addition to menopause, if the measurement of BMD of the hip gives a T-score <−2.0.
| Approach to the Patient|| |
The perimenopausal transition is a good opportunity to initiate discussion about risk factors for osteoporosis and to consider indications for a BMD test. A careful history and physical examination should be performed to identify risk factors for osteoporosis.
Height loss >2.5 to 3.8 cm (1-1.5 inch) is an indication for radiography to rule out asymptomatic vertebral fractures, as is the presence of significant kyphosis or back pain, particularly if it began after menopause. For patients who present with fractures, it is important to ensure that the fractures are truly due to trauma or osteoporosis and not to secondary underlying malignancy.
Usually, this is clear on routine radiography, but on occasion, CT, magnetic resonance imaging, or radionuclide scans may be helpful.
| Recent Trends in the Treatment of Osteoporosis|| |
Biphosphonates and denosumab
Most therapies currently used target osteoclast induced bone resorption using bisphosphonates such as alendronate, risedronate, ibandronate, and zoledronic acid. Antiresorptives are effective however, there are concerns about long-term adverse reactions and adherence to long-term therapies. The only anabolic agent which promotes bone formation and restores the balance of the abnormal coupling of the formation and resorption currently available is teriparatide. The disadvantages include the need of daily subcutaneous injections and the cost of therapy.
Denosumab is a fully human monoclonal antibody to receptor activation of nuclear kappa ligand (RANKL), the final common effector of osteoclast formation, activity, and survival. Denosumab binds to RANKL, inhibiting its ability to initiate formation of mature osteoclasts from osteoclast precursors which requires activation of the receptor on the cell wall of the osteoclast precursors and to bring mature osteoclasts to the bone surface and initiate bone resorption. Denosumab also plays a role in reducing the survival of the osteoclast. Through these actions on the osteoclast, denosumab induces potent antiresorptive action. The advantages include injections at 6 months interval which improves compliance. However, till date it is not available in India.
The DECIDE trial compared denosumab and alendronate on BMD and bone turnover markers (BTMs) and results revealed that BMD gains at all measured skeletal sites and BTMs reduction were significantly greater with the denosumab group (3.5 vs. 2.6, P < 0.0001) after 12 months of treatment. 
Another randomized controlled trial (FREEDOM trial) in postmenopausal women with osteoporosis denosumab has been shown to increase BMD in the spine, hip, and forearm and reduce vertebral, hip, and nonvertebral fractures over a 3-year period by 70, 40, and 20%, respectively. 
It is also possible to switch patients from alendronate to denosumab with a small gain in BMD over patients in whom alendronate was continued.  The effect of denosumab is reversible over a period of 2 years with levels of BTMs returning to baseline. Since it is required to be given at 6 months interval adherence is better than weekly alendronate. 
Safety concerns with denosumab include infections, hypocalcemia, osteonecrosis of the jaw, and atypical subtrochanteric fractures of the femur. Adverse infections like cellulitis and erysipelas may occur due to the presence of RANKL throughout many tissues including T and B - cells of the immune system although there is no clear pattern arguing against a causal relationship.  Hypocalcemia can be prevented by ensuring adequate calcium and Vitamin D supplements. There have been concerns of atypical subtrochanteric fractures in patients being treated with antiresorptives and two cases have been reported in patients being treated with denosumab.
As it blocks rapidly but reversibly blocks osteoclast formation, exerts its effect in the extracellular fluid and does not bind to bony tissues - there are clearly advantages to its use over bisphosphonates. It also induces a more rapid reduction in bone remodelling and a greater increase in BMD with positive effects in cortical and cancellous bone. 
| Tissue Specific Estrogens, Bazedoxifene, and Conjugated Estrogen|| |
Hormone replacement therapy by estrogens in most postmenopausal women is combined with progestins to counteract the endometrial hyperplasia, as well as high rates of endometrial carcinoma. Even adding progestins is fraught with difficulties as there is an increased risk of invasive breast carcinoma. 
A recent strategy is to combine a selective estrogen receptor modulator (SERM) like bazedoxifene (BZA) with estrogens known as tissue selective estrogen complex (TSEC).  BZA (20 mg) has been shown to inhibit the stimulatory activity of conjugated estrogens (CE) (0.45 mg) on uterine tissue and breast in vitro and in vivo. In clinical studies, treatment has been associated with significant improvements in menopausal symptoms including hot flushes and vulvar/vaginal atrophy and significant increases in BMD, coupled with reductions in BTM levels and improvements in sleep and health-related quality of life.  Additionally, they been shown to have a neutral effect on endometrial and breast tissue because BZA inhibits the stimulatory effects of estrogens in selective tissue fashion in these two organs. BZA has less agonist activity for endometrium than raloxifene and the use of CE as a combination is promising. The drug is yet to be launched in India but is being used in various countries.
Contraindications of BZA/CE use are abnormal uterine bleeding, breast cancer, estrogen dependent neoplasms, deep vein thrombosis, pulmonary embolism, and arterial thromboembolic diseases like stroke and myocardial infarction.
| Cathepsin K Inhibitor, Odanacatib|| |
Cathepsins are lysosomal proteases of which eleven have been described. Cathepsin K is important for bone remodelling and is abundant in osteoclasts. It on release degrades collagen I and II and is responsible for bone resorption. Odanacatib is a nonbasic molecule with a high potency for Cathepsin K.  A Phase 3 trial on 16,713 women 65 years of age or older recently has shown a significant reduction in the risk of osteoporotic fractures treated with odanacatib. Odanacatib has shown greater suppression of bone resorption than formation.
| Conclusion|| |
Newer therapies are about to be launched that will help us in our quest to treat osteoporosis more effectively and preempt many fragility fractures. The long-term efficacy, advantages, and disadvantages of newer regimens will be clearer by studies with long-term follow-up periods. Still many questions remain about osteoporosis which are enigmatic to decipher. Newer concepts such as immunological causes and endocrinal causes of osteoporosis are intertwined with each other and need further research before clear answers are obtained.
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Conflicts of interest
There are no conflicts of interest.
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