osteoporosis defination OSTEOPOROSIS IS DEFINED AS ASKETAL DISORDER

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osteoporosis

osteoporosis

defination ▶ OSTEOPOROSIS IS DEFINED AS ASKETAL DISORDER CHARACCTERISED BY COMPROMISED BONE STRENGHTH PREDISPOSING

defination ▶ OSTEOPOROSIS IS DEFINED AS ASKETAL DISORDER CHARACCTERISED BY COMPROMISED BONE STRENGHTH PREDISPOSING TO INCRAESE RISK OF FRACTURE

epidemiology ▶ white women will develop an osteoporosis-related fracture in their lifetime, ▶ The

epidemiology ▶ white women will develop an osteoporosis-related fracture in their lifetime, ▶ The most common site of osteoporotic fracture is the spine, Fractures of the proximal femur, Additional sites of fracture include the distal forearm, proximal humerus, and pelvis, with the latter two more commonly occurring in elderly people. ▶ The risk of Colles fractures ▶ The reason for the gender-based difference related to anatomic differences, bone size is larger in men than in women and confers an independent mechanical protection against fracture.

pathobiology ▶ Normal Bone Biology : BMD in adults is determined by the magnitude

pathobiology ▶ Normal Bone Biology : BMD in adults is determined by the magnitude of bone acquisition during adolescence and young adulthood, and the rate of bone loss ▶ Skeletal remodeling is a finely orchestrated process of bone resorption and subsequent formation. ▶ Osteocytes are derived from osteoblasts that are embedded within the bone matrix. During this maturation phase, this “osteoidosteocyte” cell actively secretes and calcifies bone matrix material.

▶ mature osteocytes may form new bone within their lacunae. ▶ Osteocytes also regulate

▶ mature osteocytes may form new bone within their lacunae. ▶ Osteocytes also regulate bone resorption, pre-osteoblast or mesenchymal stromal cell (MSC) development. ▶ .

Factors Affecting Peak Bone Mass and Remodeling ▶ ▶ Hereditary influence is the most

Factors Affecting Peak Bone Mass and Remodeling ▶ ▶ Hereditary influence is the most important determinant Growth hormone and sex hormones play critical roles in growth of the appendicular (long bones) and axial (vertebrae) skeleton, with the former maturing earlier than the latter (end of puberty vs. young adulthood) ▶ Males have larger bones as a result of greater periosteal (outer surface of bone) expansion of bone than occurs in females. ▶ Poor nutrition and concomitant disease may also affect bone accrual,

▶ Three known obligatory pathways of bone metabolism were identified by genome-wide association studies,

▶ Three known obligatory pathways of bone metabolism were identified by genome-wide association studies, namely Wnt, RANK-RANKL-OPG, and endochondral ossification. ▶ Endochondral ossification, a process that involves the cartilage growth plate and subsequent ossification of the cartilaginous skeleton, is dependent on transcription factors (SOX 6, RUNX 2). ▶ In adults, bone remodeling is a physiologic process through which skeletal repair and adaption to changes in biomechanical stress occur. The basic multicellular unit (BMU), which is composed of bone-resorbing osteoclasts, bone-forming osteoblasts, bone lining cells, and embedded osteocytes, is the cellular apparatus that facilitates remodeling

Mechanisms of Bone Loss “Natural” and Aging-Related Bone Loss : ▶ most important for

Mechanisms of Bone Loss “Natural” and Aging-Related Bone Loss : ▶ most important for women, rates of bone loss increase sub- stantially in the perimenopausal and early postmenopausal years, amounting to losses of 1 to 5% per year. ▶ Bone loss is slower in obese women, likely because of higher estrogen levels afforded by production through aromatization in adipose tissue. ▶ A decline in circulating estrogen is primarily responsible for bone loss ▶ In addition, OPG production is diminished, further amplifying bone resorption, although estrogen replacement can restore OPG production while reducing RANKL expression and thereby help mitigate bone loss during this period.

▶ Bone loss in later decades also is caused by lower 25 -hydroxy vitamin

▶ Bone loss in later decades also is caused by lower 25 -hydroxy vitamin D (25[OH] D) levels, related to restricted sun exposure and a reduced capacity to generate pre−vitamin D in the skin with aging, as well as limited intake of vitamin D and calcium. ▶ Low vitamin D results in secondary hyperparathyroidism, which accelerates cortical bone loss, as well as likely increasing the risk for falls. Increase in bone marrow adiposity is also inversely and significantly correlated with aging- related bone loss. ▶ Additionally, fat-derived adipokines (adiponectin and leptin) may negatively affect bone remodeling through a “bone-fat” connection by reducing bone formation, further exacerbating bone loss. 6 ▶ loss of weight and muscle mass (sarcopenia) is associated with bone loss, with evidence of a recently identified common factor (myostatin) that may provide insights on this muscle-bone interaction. 7

CLINICAL MANIFESTATIONS ▶ Classic representations of women with the so-called dowager’s hump or kyphotic

CLINICAL MANIFESTATIONS ▶ Classic representations of women with the so-called dowager’s hump or kyphotic deformity were common depictions of the disease ▶ history of fragility fracture is strongly suggestive of osteoporosis, although there is evidence that a history of high trauma fractures also identifies persons with low BMD and those at higher risk for lowtrauma fractures. ▶ The National Osteoporosis Foundation considers fractures of the spine, proximal femur, distal forearm, and proximal humerus “major” osteoporotic fractures, although other skeletal sites are also prone to fragility fractures. These include the pelvis, ribs, and proximal tibia, although there is controversy about whether ankle fractures should be considered as such. ▶ Fractures of the spine are generally from the mid-thoracic region through the lower lumbar region, with the greatest frequency at T 11 through L 2.

▶ Patient often present after a fall or a spinal flexion-loading event in which

▶ Patient often present after a fall or a spinal flexion-loading event in which they may hear a “pop” and complain of sharp midline back pain that may radiate to the flanks. ▶ complaints of back “tiredness, ” which is improved with sitting or lying down. This symptom is likely related to para- spinal weakness or spasm from abnormal spinal curvature that occurs with chronic vertebral compression. ▶ Back pain may commonly be related to other pathology, such as degenerative disc and spine disease that is concomitantly present. . ▶ Vertebral fractures may occur without acute symptoms as well, as noted later. In contrast, nonvertebral fracture events are always clinically evident. Hip fractures generally occur with falls, although they may rarely occur with limited force such as twisting.

▶ Physical examination may indicate the presence of osteoporosis and associated fractures, ▶ Measured

▶ Physical examination may indicate the presence of osteoporosis and associated fractures, ▶ Measured height loss, of greater than 4 cm since young adult maximum height is suggestive of prior vertebral fractures. ▶ Height loss also occurs with scoliosis and aging (approximately 13 inch of height is lost per decade after age 50 years). ▶ A kyphotic deformity of the upper thoracic spine may be present, . ▶ Spinal tenderness to palpation and percussion can occur with an acute vertebral compression fracture. ▶ Palpable tenderness of the long bones may suggest underlying osteomalacia instead, due to periosteal expansion and nerve irritation. Reduced rib-pelvis and increased wall-occiput distances are correlated with vertebral fractures as well.

▶ radiologic findings may identify the presence of osteoporosis, ▶ Plain films can detect

▶ radiologic findings may identify the presence of osteoporosis, ▶ Plain films can detect bone loss by means of accentuation of vertical striations on spine radiographs that represent loss of horizontal trabeculae, although this generally indicates BMD loss of at least 25% or more. ▶ Kyphosis and compression fractures may be present, ▶ When fractures are suspected, CT and MRI may be used, given that plain radiographs have a lower sensitivity acutely and with stress fractures.

▶ Finally, whole body bone scintigraphy is the most sensitive test for fracture

▶ Finally, whole body bone scintigraphy is the most sensitive test for fracture

DIAGNOSIS ▶ Most patients with osteoporosis are diagnosed on the basis of BMD measurement,

DIAGNOSIS ▶ Most patients with osteoporosis are diagnosed on the basis of BMD measurement, generally by dual-energy x-ray absorptiometry (DXA). ▶ Osteoporosis can be diagnosed if the BMD of a postmenopausal woman or man older than 50 years is more than 2. 5 SD below young average normal (T score ≤ − 2. 5). ▶ A T score between − 1. 0 and − 2. 5 is considered low bone density or osteopenia, and a Z score (age-matched BMD) in premenopausal women and men younger than 50 years that is more than 2 SD below that of an a average individual is considered low bone density for age. ▶ BMD is an independent predictor of fracture risk, such that the relative risk for fracture increases by 1. 5 - to 2 -fold for each 1 SD decrease in T score. In addition, fracture risk increases exponentially below a T score of − 2. 5

▶ BMD of the femoral neck may be used in fracture prediction models such

▶ BMD of the femoral neck may be used in fracture prediction models such as FRAX to better define an individual’s risk for subsequent fracture ▶ In addition to DXA, other modalities are also used to diagnose osteoporosis, including quantitative CT of the spine (QCT) and wrist and tibia (p. QCT), finger DXA, and ultrasound of the calcaneus or wrist. ▶ QCT and p. QCT provide additional information on cortical and trabecular bone compartments but are accompanied by higher radiation exposure and poorer reproducibility compared with DXA. ▶ ▶ Ultrasound is radiation free and easy to operate but is less sensi- tive Although DXA is an effective diagnostic tool,

Frax ▶ The best known and most widely used of these prediction models is

Frax ▶ The best known and most widely used of these prediction models is FRAX. . ▶ . the number needed to treat (NNT) can be determined to best nform patients of their expected risk and benefit of treatment (e. g. , bisphonate use roughly reduces hip fracture risk by half, or from 10 to 5%, with NNT of 1/0. 05, or 20 patients treated to prevent one hip fracture).

finally ▶ The 25(OH)D level should be measured in all patients for multiple reasons,

finally ▶ The 25(OH)D level should be measured in all patients for multiple reasons, as previously discussed. ▶ Additional investigations may also be considered, as directed by the clinical history and physical examination. ▶ In addition, a greater degree of BMD deficit (i. e. , lower Z score) indicates a need for more extensive testing, given the greater likelihood of secondary causes being present. ▶ Bone turnover markers (BTMs) are serum and urinary products of bone formation or resorption that can also be used to assist in management. ▶ Available tests include bone-specific alkaline phosphatase, osteocalcin, type I procollagen amino-terminal propeptide, and type I pro- collagen carboxyterminal propeptide as formation markers, and serum and urine C- and Nterminal peptides of type I collagen as resorption markers, among others. Their use is predicated on studies showing that high bone turnover increases fracture risk independent of BMD.

PREVENTION AND TREATMENT ▶ Calcium ▶ Adequate intake of calcium is critical to the

PREVENTION AND TREATMENT ▶ Calcium ▶ Adequate intake of calcium is critical to the optimal accumulation and maintenance of bone mineral density. ▶ Calcium supplementation has meaningful impact on BMD and fracture risk reduction, although the latter is much less certain. ▶ ▶ BMD is modestly improved by 1 to 2%, potential increase in nonfatal cardiac events with higher dose calcium supplementation, it would seem prudent to recommend that adults with osteoporosis obtain 1200 to 1500 mg of calcium from a combination of supplements and dietary sources.

▶ Vitamin D ▶ Appropriate circulating levels of 25(OH)D are necessary for optimal intestinal

▶ Vitamin D ▶ Appropriate circulating levels of 25(OH)D are necessary for optimal intestinal absorption of calcium and skeletal accrual and maintenance. ▶ a significant proportion of children and adults have vitamin D levels that would be deemed insufficient (i. e. , 25[OH]D < 20 ng/m. L). Doses of 400 to 800 IU of vitamin D combined with 1000 mg of calcium reduce the risk for hip fracture in postmenopausal women and men aged 65 years and older, ▶ In addition, it appears that a 25(OH)D level of at least 30 ng/m. L is needed to reduce the risk for hip fracture, ▶ In addition, a daily vitamin D intake of at least 800 IU also reduces the risk for falls, likely by improving muscle strength and reducing body sway

Exercise and Lifestyle ▶ ▶ Physical activity is also a critical element of osteoporosis

Exercise and Lifestyle ▶ ▶ Physical activity is also a critical element of osteoporosis management, Physical activity likely also confers additional benefits through enhanced muscle strength, improved cardiovascular status, and reduction in fall risk ▶ multiple targeted exercise interventions do reduce either the risk for falling (Tai Chi) or both the rate and risk for falling ▶ Finally, modification of aberrant lifestyles is also indicated in patients with osteoporosis, especially tobacco cessation and moderation of caffeine, carbonated beverage, and alcohol intake.

Anticatabolic Agents ▶ Anticatabolic medications, or antiresorptive as they were more commonly known, inhibit

Anticatabolic Agents ▶ Anticatabolic medications, or antiresorptive as they were more commonly known, inhibit osteoclast recruitment, function, and/or survival, resulting in reductions in skeletal turnover and bone loss. ▶ These agents, improve BMD while strengthening the skeletal microstructure and reducing fracture risk.

▶ Bisphosphonates (BPs) are the most widely prescribed and used medications for the treatment

▶ Bisphosphonates (BPs) are the most widely prescribed and used medications for the treatment of osteoporosis, (from once weekly to once yearly, depending on the drug). ▶ As a result, BPs have an extremely high affinity for hydroxyapatite crystals within bone. , BPs are taken up by osteoclasts and thereafter inhibit cellular attachment, function, and survival. ▶ The first-generation BP etidronate, is the least potent agent of the class. ▶ Nonetheless, it is has been shown to reduce the risk for vertebral but nonvertebral nor hip fractures.

▶ The oral BPS may be administered once weekly (alendro- nate and risedronate) or

▶ The oral BPS may be administered once weekly (alendro- nate and risedronate) or once monthly (risedronate and ibandronate), fasting in the morning with water only, and the patient must remain fasting in a sitting or standing position for 30 to 60 minutes after the dose. ▶ a delayed- release formulation of risedronate (Atelvia) was approved that may be taken immediately after breakfast. ▶ The most common side effect is precipitation or aggravation of gastroesophageal reflux, ▶ In light of this side effect and a potential risk for esophageal irritation and ulceration, these drugs are contraindicated in patients with functional or anatomic disorders of esophageal transit (i. e. , esophageal stricture, achalasia). ▶ All three drugs significantly reduce the risk for vertebral fractures,

Parenteral BPs are also approved and available for osteoporosis treatment, ▶ They may be

Parenteral BPs are also approved and available for osteoporosis treatment, ▶ They may be consid- ered for use in patients with contraindications to oral BPs (e. g. , esophageal disease, inability to sit upright and/or fast after dose), documented or expected poor adherence to oral BPs, or failure to respond to oral BPs or other FDA- approved therapies (recurrent fractures, declining BMD). ▶ Zoledronic acid, 5 mg once yearly, and ibandronate, 3 mg quarterly, may be given. zoledronic acid has also been shown to reduce mortality in women and men following a lowtrauma hip fracture ▶

▶ ▶ patients on intravenous BPs should maintain optimal oral hygiene Atypical femoral fractures

▶ ▶ patients on intravenous BPs should maintain optimal oral hygiene Atypical femoral fractures have also been recently described in patients on long-term bisphonate therapy, generally after 5 years or more of treatment.

Selective Estrogen Receptor Modulators ▶ Selective estrogen receptor modulators (SERMs) are compounds that bind

Selective Estrogen Receptor Modulators ▶ Selective estrogen receptor modulators (SERMs) are compounds that bind to the estrogen receptor and thereby influence bone and reproductive biology. As with estrogen (see later), SERMs are anticatabolic agents in bone, acting through a reduction in cytokines (RANKL, tumor necrosis factor-α) that engen- der osteoclast activation and function. ▶ Raloxifene is the only FDA-approved drug for prevention and treatment of osteoporosis in menopausal women, although the breast cancer drug tamoxifen likely has skeletal benefits as well. ▶ Raloxifene does reduce the risk for vertebral fractures by approximately 30 to 50% but does not reduce the risk for hip and nonvertebral fractures. ▶ This antifracture profile positions it as an alternative to bisphonates in postmenopausal women with osteopenia and a relatively low risk for hip and other nonspine fractures. SERMs also increase the risk for deep vein thrombosis, Raloxifene has also been associated with an increased risk for fatal stroke in women at higher baseline risk for stroke,

Estrogen ▶ ERT, either alone or in combination with a progestin in women with

Estrogen ▶ ERT, either alone or in combination with a progestin in women with an intact uterus, had historically been a frontline agent in the management of osteoporosis in postmenopausal women. ▶ ERT prevents bone loss if administered to women at menopause and significantly increases BMD by approximately 3 to 5% in woman who are well into their menopausal years. ▶ Long-term estrogen therapy reduces the risk for all clinical fractures by about 27%, ▶ ERT is associated with an increased risk for stroke (34% increase), A 9 and the use of continuous combined hormone replacement therapy (HRT) confers an unacceptable greater global risk than benefit in woman initiating HRT, based on the results of the Woman’s Health Initiative.

▶ Denosumab increased osteoclast activation through the RANKL pathway is a key mechanism through

▶ Denosumab increased osteoclast activation through the RANKL pathway is a key mechanism through which bone loss occurs in menopause and other osteoporotic conditions. ▶ Denosumab is a fully human monoclonal antibody to RANKL for the treatment of osteoporosis in postmenopausal women and in men, as well as for individuals with breast and prostate cancer to reduce bone loss associated with hormonal deprivation therapy. ▶ It is administered twice yearly as a subcutaneous injection in the clinic and clearly reduces the risk for spine, hip, and nonvertebral fractures. In contrast to BPs, it is reversible, such that robust bone loss ensues once the medication is stopped. the drug is not suitable for patients on immunosuppressant therapy who are at higher baseline risk for infection.

▶ Anabolic Agents ▶ Although anticatabolic drugs are effective at retarding bone loss and

▶ Anabolic Agents ▶ Although anticatabolic drugs are effective at retarding bone loss and reducing fracture risk, anabolic or “bone-building” drugs would be preferred. Teriparatide (TPTD) is a recombinant human parathyroid hormone analogue a self-administered once-daily subcutaneous injection, TPTD is truly anabolic based on robust increases in bone density ▶ More important, TPTD significantly reduces the risk for vertebral and nonvertebral fractures by approximately two thirds and one half, respectively. ▶ Because bone resorption increases along with bone formation, bone loss generally ensues on cessation of therapy, necessitating the initiation of an anticatabolic bone drug to preserve the increase in BMD facilitated by TPTD.

▶ TPTD has a black box warning, based on the fact that toxicology studies

▶ TPTD has a black box warning, based on the fact that toxicology studies in rats revealed an increase in risk for osteosarcoma ▶ the drug is contra-indicated for patients who are at a higher baseline risk for osteosarcoma, including patients with Paget disease and previous therapeutic radiotherapy, as well as younger individuals with open epiphyses.

Other Therapies and Treatment Considerations Nasal calcitonin ▶ ▶ Strontium ranelate -anticatabolic effect on

Other Therapies and Treatment Considerations Nasal calcitonin ▶ ▶ Strontium ranelate -anticatabolic effect on bone. It has been shown to reduce the risk for vertebral and nonvertebral fractures, as well as clinical osteoporotic fractures ▶ ▶ new anticatabolic agents (e. g. , cathep- sin K inhibitors) and new anabolic therapies (e. g. , sclerostin antibody). Odana- catib is an oral, small molecule ▶ Odanacatib also does not significantly suppress bone formation, perhaps “uncoupling” bone turnover in a favorable fashion to potentiate improvements in BMD. ▶ Sclerostin is a naturally occurring inhibitor of the Wnt pathway and bone formation,

Glucocorticoid-induced and Male Osteoporosis ▶ glucocorticoids are a major cause of and the most

Glucocorticoid-induced and Male Osteoporosis ▶ glucocorticoids are a major cause of and the most common etiology of medication-related secondary osteoporosis. ▶ They are potent suppressors of bone forma- tion and at higher doses likely increase bone resorption, ▶ In addition to bone loss, there is good evidence to support that individuals on glucocorticoids may fracture at a higher level on BMD compared with non-glucocorticoid-treated patients.

▶ The treatment approach to glucocorticoid-induced osteoporosis is similar to osteoporosis in general, with

▶ The treatment approach to glucocorticoid-induced osteoporosis is similar to osteoporosis in general, with the exception that attempts should be made to reduce the steroid dose to as low as the underlying treated disease will permit. 12 Calcium and vitamin D are important adjuncts but are insufficient to prevent bone loss or fractures. ▶ The BPs alendronate, risedronate, and zoledronic acid are approved for glucocorticoid-induced osteoporosis in women and men, ▶ A more logical and indeed superior treatment of glucocorticoid- induced osteoporosis is TPTD, which as an anabolic drug more directly addresses the primary mechanism of bone loss in glucocorticoid-induced osteoporosis: osteoblast inhibition. ▶ TPTD is approved for treatment of glucocorticoid-induced osteoporosis in women and is superior to alendronate in improving BMD and vertebral fracture risk reduction.

▶ Vertebroplasty and Kyphoplasty and Low-intensity Vibration ▶ Although often clinically silent, vertebral fractures

▶ Vertebroplasty and Kyphoplasty and Low-intensity Vibration ▶ Although often clinically silent, vertebral fractures may cause acute and severe back pain. In addition, up to one third of vertebral fractures remain chronically painful, perhaps related to incomplete healing or instability of the fracture. ▶ vertebroplasty and kyphoplasty have been developed and advanced to reduce the morbidity associated with acute spine fractures.

▶ Low-intensity vibration is also under active investigation as an anticatabolic and possibly anabolic

▶ Low-intensity vibration is also under active investigation as an anticatabolic and possibly anabolic intervention for osteoporosis. Clinical studies suggest a modest but significant BMD benefit in postmenopausal women and other groups (children with cerebral palsy, adults on prolonged bed rest), although further studies are needed to confirm a true clinical and ideally antifracture benefit of this intervention.

prognosis ▶ Although there is no true “cure” for osteoporosis, current pharmacotherapies reduce the

prognosis ▶ Although there is no true “cure” for osteoporosis, current pharmacotherapies reduce the risk for fracture roughly by half. ▶ This reduction is critical because there is robust evidence to suggest an independent increase in mortality after an osteoporotic fracture, including fractures of the spine, humerus, tibia, and pelvis, as well as the proximal femur.