Osteoporosis

Osteoporosis

The World Health Organization (WHO) operationally defines osteoporosis as a bone density that falls 2.5 standard deviations (SD) below the mean for young healthy adults of the same gender—also referred to as a T-score of –2.5. Postmenopausal women who fall at the lower end of the young normal range (a T-score of >1 SD below the mean) are defined as having low bone density and are also at increased risk of osteoporosis

The epidemiology of fractures follows the trend for bone density loss. Fractures of the distal radius increase in frequency before age 50 and plateau by age 60, with only a modest age-related increase thereafter. In contrast, incidence rates for hip fractures double every 5 years after age 70. Hip fractures are associated with a high incidence of deep vein thrombosis and pulmonary embolism (20–50%) and a mortality rate between 5 and 20% during the year after surgery. Thoracic fractures can be associated with restrictive lung disease, whereas lumbar fractures are associated with abdominal symptoms including distention, early satiety, and constipation.

Chronic diseases with inflammatory components that increase skeletal remodeling, such as rheumatoid arthritis, increase the risk of osteoporosis, as do diseases associated with malabsorption. osteoporosis-related fractures are more common among women than men, presumably due to a lower peak bone mass as well as postmenopausal bone loss in women. a fracture in a person over 50 should trigger evaluation for osteoporosis.

Pathophysiology: although true bone density remains similar between sexes. Heritability estimates of 50–80% for bone density and size have been derived based on twin studies. In osteoporosis, Bone remodeling has two primary functions: (1) to repair microdamage within the skeleton to maintain skeletal strength, and (2) to supply calcium from the skeleton to maintain serum calcium. 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. 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

expert consensus panel has suggested that the accepted levels for serum 25-hydroxyvitamin D [25(OH)D] have been set too low, and that optimal targets for serum 25(OH)D are >75 nmol/L (30 ng/mL). To achieve this level for most adults requires intakes of 800–1000 units/day

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 original National Osteoporosis Foundation guidelines recommend bone mass measurements in postmenopausal women, assuming they have one or more risk factors for osteoporosis in addition to age, gender, and estrogen deficiency. The guidelines further recommend that bone mass measurement be considered in all women by age 65, a position ratified by the U.S. Estrogen-deficient women at clinical risk of osteoporosis

Vertebral abnormalities on x-ray suggestive of osteoporosis (osteopenia, vertebral fracture)

Glucocorticoid treatment equivalent to 7.5 mg of prednisone, or duration of therapy >3 months

Primary hyperparathyroidism

Monitoring response to an FDA-approved medication for osteoporosis

Repeat BMD evaluations at >23-month intervals, or more frequently, if medically justified

Treatment should also be considered in postmenopausal women with risk factors, even if BMD is not in the osteoporosis range. It is important to consider the risk of fracture for individuals, including those whose BMD is within the premenopausal range. Risk factors (age, prior fracture, family history of hip fracture, low body weight, cigarette consumption, excessive alcohol, steroid use, and rheumatoid arthritis) can be combined with BMD to assess the likelihood of a fracture over a 5- or 10-year period. Treatment thresholds depend on cost-effectiveness analyses but will likely be ~1% per year of risk in the United States.

A careful history and physical examination should be performed to identify risk factors for osteoporosis. A low Z-score increases the suspicion of a secondary disease. Height loss > 2.5–3.8 cm (>1–1.5 in.) is an indication for radiography or vertebral fracture assessment by DXA 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 not caused by an underlying malignancy.

Bone formation

Serum bone-specific alkaline phosphatase

Serum osteocalcin

Serum propeptide of type I procollagen

Bone resorption

Urine and serum cross-linked N-telopeptide

Urine and serum cross-linked C-telopeptide

Urine total free deoxypyridinoline

If a calcium supplement is required, it should be taken in doses 600 mg at a time, as the calcium absorption fraction decreases at higher doses. Calcium supplements containing carbonate are best taken with food since they require acid for solubility. Calcium citrate supplements can be taken at any time

Several controlled clinical trials of calcium plus vitamin D have confirmed reductions in clinical fractures, including fractures of the hip (~20–30% risk reduction.

Vit D: the Institute of Medicine recommends daily intakes of 200 IU for adults <50>70 years.

Polycystic ovary syndrome - Williams endocrinology and NEJM review

Two natural androgens are testosterone, which is transported to target tissue by the circulation, and DHT, which is produced primarily by target tissues. Increased levels of these androgens can lead to hirsutism, which is excessive androgenic hair growth, or to virilization, a more severe form of androgen excess. Hirsutism is defined as the presence of terminal (coarse) hair in locations at which hair is not commonly found in women. It includes facial hair on the cheek, above the upper lip, and on the chin ( Fig. 16-26A and B ). The presence of midline chest hair is also significant ( Fig. 16-26C ). In addition, a male escutcheon, hair on the inner aspects of the thighs, and midline lower back hair entering the intergluteal area are hair growth patterns compatible with androgen excess. A moderate amount of hair on the forearms and lower legs by itself may not be abnormal, although it may be viewed by the patient as undesirable and may be mistaken for hirsutism. In contrast to hirsutism, virilization is a more severe form of androgen excess and implies significantly higher rates of testosterone production. Its manifestations include temporal balding, deepening of voice, decreased breast size, increased muscle mass, loss of female body contours, and clitoral enlargement. Normal length of clitoris is <1cm> in lenght and 0.7cm in diameter.

In this image, is possible to see a clitoromegaly (4cm lenght - 1.5cm diameter)

Testosterone in reproductive-age women is produced by two major mechanisms: (1) direct secretion by the ovary, accounting for roughly one third of testosterone production, and (2) conversion of the precursor androstenedione to testosterone in the peripheral (extragonadal) tissues, accounting for two thirds of testosterone production ( Fig. 16-28 ). ^{[216] [217]} These peripheral tissues include the skin and adipose tissue. Androstenedione, the direct precursor of testosterone, is produced in both the ovary and the adrenal. The C19 steroids DHEAS and DHEA of adrenal origin and DHEA of ovarian origin indirectly contribute to testosterone formation by first being converted to androstenedione that is subsequently converted to testosterone. Whereas testosterone is an androgen, DHEAS is a biologically inert steroid. Up to 20 mg of DHEAS are produced daily versus only 3 mg of androstenedione and 8 mg of DHEA per day. These C19 steroids of adrenal origin (DHEAS, DHEA) exert their effects after conversion to the potent androgen testosterone (see Fig. 16-28 ). Only androstenedione can be converted directly to testosterone. The conversion rate of circulating androstenedione to testosterone in extragonadal tissues is about 5% in both men and women. Conditions that decrease SHBG binding (e.g., androgen excess, obesity, acromegaly, hypothyroidism, and liver disease) also increase bioavailable testosterone, thus augmenting the effect of testosterone. The most useful initial test is a serum total testosterone level. An abnormal level in the presence of hirsutism or virilization may be associated with PCOS, hyperthecosis, nonclassic adrenal hyperplasia, or an androgen-secreting neoplasm. The majority of androgen-secreting tumors are of ovarian origin.

Polycystic Ovary Syndrome

PCOS is the most common form of chronic anovulation associated with androgen excess, perhaps occurring in 5% to 10% of reproductive-age women.^[146] The diagnosis of PCOS is made by excluding other hyperandrogenic disorders (e.g., nonclassic adrenal hyperplasia, androgen-secreting tumors, and hyperprolactinemia) in women with chronic anovulation and androgen excess

One of the most prominent features of PCOS is the history of ovulatory dysfunction (amenorrhea, oligomenorrhea, or other forms of irregular uterine bleeding) of pubertal onset. Thus, a clear history of cyclic predictable menses of menarchal onset makes the diagnosis of PCOS unlikely. Acquired insulin resistance associated with significant weight gain or an unknown cause, however, may occasionally induce the clinical picture of PCOS in a woman with a history of previously normal ovulatory function. Hirsutism may develop prepubertally or during adolescence, or it may be absent until the third decade of life. Seborrhea, acne, and alopecia are other common clinical signs of androgen excess. In extreme cases of ovarian hyperthecosis (a severe variant of PCOS), clitoromegaly may be observed. Nonetheless, rapid progression of androgenic symptoms and virilization are rare in ordinary PCOS. Some women may never have signs of androgen excess because of hereditary differences in target tissue sensitivity to androgens.^[151] Infertility related to the anovulation may be the only presenting symptom. During the physical examination, it is essential to search for and document signs of androgen excess (hirsutism or virilization or both), insulin resistance (acanthosis nigricans), and the presence of unopposed estrogen action (well-rugated vagina and stretchable clear cervical mucus) to support the diagnosis of PCOS.

this image shows hirsutism in: cheeks, upper lip and chin. An usual location of hirsutism, between the breasts.

Alternatively, another expert conference held in Rotterdam in 2003 defined PCOS, after the exclusion of related disorders, by two of the following three features: (1) oligo-ovulation or anovulation, (2) clinical and/or biochemical signs of hyperandrogenism, or (3) polycystic ovaries ( Fig. 16-31 ).

Rarely, serum testosterone levels higher than 2 ng/mL may be encountered in association with the most severe form of PCOS, ovarian hyperthecosis. Overall, it is much more common to observe high normal levels or borderline elevations of testosterone in women with PCOS. Prolactin and TSH should be obtained routinely to rule out mild androgen excess and anovulation that may be associated with hyperprolactinemia. The NIH-sponsored consensus conference on diagnostic criteria for PCOS in 1990 recommended that LH and the LH/FSH ratio are not required for the diagnosis of PCOS. By definition, nonclassic adrenal hyperplasia is not manifest as congenital virilization of external genitalia. a cross-section of all anovulatory women at any point in time reveals that approximately 75% have polycystic-appearing ovaries as determined by ultrasonography. Biochemical evidence of insulin resistance or glucose intolerance is also not necessary for the diagnosis of PCOS. Glucose intolerance should nonetheless be investigated. Therefore, plasma glucose levels should be measured after a 75-γ glucose load as a screen for glucose intolerance. Because endometrium is exposed to estradiol chronically in PCOS, these women respond to a challenge with a progestin (e.g., medroxyprogesterone acetate 10 mg/day orally for 10 days) by uterine bleeding within a few days after the last pill of progestin. The reasons for lack of uterine bleeding after a progestin challenge include pregnancy, insufficient prior estrogen exposure of the endometrium, or an anatomic defect. Women with PCOS have higher mean concentrations of LH but low or low-normal levels of FSH compared with levels found in normal women in the early follicular phase.^[254] The elevated LH levels are partly due to increased sensitivity of the pituitary to GnRH stimulation manifest by increases in LH pulse frequency and, in particular, LH pulse amplitude. In obese women with PCOS, LH levels are not increased.

Testosterone, androstenedione, and DHEA are secreted directly by the ovary, whereas DHEAS, elevated in about 50% of anovulatory women with PCOS, is almost exclusively an adrenal contribution. Pathologic mechanisms in polycystic ovary syndrome (PCOS). A deficient in vivo response of the ovarian follicle to physiologic quantities of follicle-stimulating hormone (FSH), possibly because of an impaired interaction between signaling pathways associated with FSH and insulin-like growth factors (IGFs) or insulin, may be an important defect in PCOS. This ovarian defect may be the key event responsible for anovulation in PCOS. Insulin resistance associated with increased circulating and tissue levels of insulin and bioavailable estradiol (E2), testosterone (T), and IGF-I gives rise to abnormal hormone production in a number of tissues. Oversecretion of luteinizing hormone (LH) and decreased output of FSH by the pituitary, decreased production of sex hormone–binding globulin (SHBG) and IGF-binding protein 1 (IGFBP-1) in the liver, increased adrenal secretion of dehydroepiandrosterone sulfate (DHEAS), and increased ovarian secretion of androstenedione (A) all contribute to the vicious circle that maintains anovulation and androgen excess in PCOS. Excessive amounts of E2 and T arise primarily from the conversion of A in peripheral and target tissues.

Overall, androstenedione of ovarian origin is the most strikingly elevated steroid in PCOS. Because such elevated production of androstenedione does occur in PCOS, extraovarian production of testosterone is biologically significant in this disease. In anovulatory women with PCOS, circulating levels of SHBG are reduced approximately 50%; this may be a hepatic response to increased circulating levels of testosterone and insulin. In turn, testosterone decreases serum SHBG levels, giving rise to a vicious feedback circle favoring low SHBG and high bioavailable testosterone levels.

Acanthosis nigricans is a gray-brown velvety discoloration and increased thickness of the skin, usually at the neck, groin, axillae, and under the breasts, and is a marker for insulin resistance

NEJM: Whereas luteinizing hormone regulates the

androgenic synthesis of theca cells, follicle-stimulating

hormone is responsible for regulating the

aromatase activity of granulosa cells, thereby determining

how much estrogen is synthesized from

androgenic precursors. When the concentration of

luteinizing hormone increases relative to that of

follicle-stimulating hormone, the ovaries preferentially

synthesize androgen. Since progestins

slow the GnRH pulse generator, low circulating

progestin levels in women with the polycystic ovary

syndrome may lead to an acceleration in the pulsatility

of GnRH,increased levels of luteinizing hormone,

and overproduction of ovarian androgen.

Insulin acts synergistically

with luteinizing hormone to enhance the

androgen production of theca cells. Insulin also inhibits

hepatic synthesis of sex hormone–binding

globulin, the key circulating protein that binds to

Testosterone

decreases lipoprotein lipase activity in abdominal

fat cells, and insulin resistance impairs the

ability of insulin to exert its antilipolytic effects.

The estrogenic

component of the oral contraceptive suppresses

luteinizing hormone and thus ovarian androgen

production. Estrogen also enhances hepatic

production of sex hormone–binding globulin (Fig.

2), thereby reducing the free, or unbound, fraction

of plasma testosterone available to occupy the androgen

receptor

Chronic complications of diabetes

The risk of chronic complications increases as a function of the duration of hyperglycemia; they usually become apparent in the second decade of hyperglycemia. Since type 2 DM often has a long asymptomatic period of hyperglycemia, many individuals with type 2 DM have complications at the time of diagnosis. For example, despite long-standing DM, some individuals never develop nephropathy or retinopathy. Many of these patients have glycemic control that is indistinguishable from those who develop microvascular complications, suggesting that there is a genetic susceptibility for developing particular complications

Mechanism of hyper glicemia

One theory is that increased intracellular glucose leads to the formation of advanced glycosylation end products (AGEs) via the nonenzymatic glycosylation of intra- and extracellular proteins. Nonenzymatic glycosylation results from the interaction of glucose with amino groups on proteins. AGEs have been shown to cross-link proteins (e.g., collagen, extracellular matrix proteins), accelerate atherosclerosis, promote glomerular dysfunction, reduce nitric oxide synthesis, induce endothelial dysfunction, and alter extracellular matrix composition and structure.

Intracellular glucose is predominantly metabolized by phosphorylation and subsequent glycolysis, but when increased, some glucose is converted to sorbitol by the enzyme aldose reductase. Increased sorbitol concentration alters redox potential, increases cellular osmolality, generates reactive oxygen species, and likely leads to other types of cellular dysfunction.

A third hypothesis proposes that hyperglycemia increases the formation of diacylglycerol leading to activation of protein kinase C (PKC). Among other actions, PKC alters the transcription of genes for fibronectin, type IV collagen, contractile proteins, and extracellular matrix proteins in endothelial cells and neurons

A fourth theory proposes that hyperglycemia increases the flux through the hexosamine pathway, which generates fructose-6-phosphate, a substrate for O-linked glycosylation and proteoglycan production. The hexosamine pathway may alter function by glycosylation of proteins such as endothelial nitric oxide synthase or by changes in gene expression of transforming growth factor (TGF-) or plasminogen activator inhibitor-1 (PAI-1).

Vascular endothelial growth factor A (VEGF-A) is increased locally in diabetic proliferative retinopathy and decreases after laser photocoagulation. TGF- is increased in diabetic nephropathy and stimulates basement membrane production of collagen and fibronectin by mesangial cells. A possible unifying mechanism is that hyperglycemia leads to increased production of reactive oxygen species or superoxide in the mitochondria; these compounds may activate all four of the pathways described above.

One of the major findings of the UKPDS was that strict blood pressure control significantly reduced both macro- and microvascular complications.

Retinopathy

The gravity of this problem is highlighted by the finding that individuals with DM are 25 times more likely to become legally blind than individuals without DM. Diabetic retinopathy is classified into two stages: nonproliferative and proliferative. Nonproliferative diabetic retinopathy usually appears late in the first decade or early in the second decade of the disease and is marked by retinal vascular microaneurysms, blot hemorrhages, and cotton wool spots (Fig. 338-9). Mild nonproliferative retinopathy progresses to more extensive disease, characterized by changes in venous vessel caliber, intraretinal microvascular abnormalities, and more numerous microaneurysms and hemorrhages. The pathophysiologic mechanisms invoked in nonproliferative retinopathy include loss of retinal pericytes, increased retinal vascular permeability, alterations in retinal blood flow, and abnormal retinal microvasculature, all of which lead to retinal ischemia. The appearance of neovascularization in response to retinal hypoxia is the hallmark of proliferative diabetic retinopathy (Fig. 338-9). These newly formed vessels appear near the optic nerve and/or macula and rupture easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal detachment. Fluorescein angiography is useful to detect macular edema, which is associated with a 25% chance of moderate visual loss over the next 3 years. Duration of DM and degree of glycemic control are the best predictors of the development of retinopathy; hypertension is also a risk factor. Laser photocoagulation is very successful in preserving vision. Proliferative retinopathy is usually treated with panretinal laser photocoagulation, whereas macular edema is treated with focal laser photocoagulation.

Nephropathy

Diabetic nephropathy is the leading cause of ESRD in the United States and a leading cause of DM-related morbidity and mortality. Both microalbuminuria and macroalbuminuria in individuals with DM are associated with increased risk of cardiovascular disease. Individuals with diabetic nephropathy commonly have diabetic retinopathy.

Like other microvascular complications, the pathogenesis of diabetic nephropathy is related to chronic hyperglycemia. Smoking accelerates the decline in renal function. Because only 20–40% of patients with diabetes develop diabetic nephropathy, additional susceptibility factors remain unidentified. One known risk factor is a family history of diabetic nephropathy.

Glomerular hyperperfusion and renal hypertrophy occur in the first years after the onset of DM and are associated with an increase of the glomerular filtration rate (GFR). During the first 5 years of DM, thickening of the glomerular basement membrane, glomerular hypertrophy, and mesangial volume expansion occur as the GFR returns to normal. After 5–10 years of type 1 DM, ~40% of individuals begin to excrete small amounts of albumin in the urine. Microalbuminuria is defined as 30–300 mg/d in a 24-h collection or 30–300 mg/mg creatinine in a spot collection (preferred method). Although the appearance of microalbuminuria in type 1 DM is an important risk factor for progression to overt proteinuria (>300 mg/d), only ~50% of individuals progress to macroalbuminuria over the next 10 years. In some individuals with type 1 diabetes and microalbuminuria of short duration, the microalbuminuria regresses. Once macroalbuminuria is present, there is a steady decline in GFR, and ~50% of individuals reach ESRD in 7–10 years. Once macroalbuminuria develops, blood pressure rises slightly and the pathologic changes are likely irreversible. Some individuals with type 1 or type 2 DM have a decline in GFR in the absence of micro- or macroalbuminuria and this is the basis for assessing the GFR on an annual basis using serum creatinine. Finally, it should be noted that albuminuria in type 2 DM may be secondary to factors unrelated to DM, such as hypertension, congestive heart failure (CHF), prostate disease, or infection.

Type IV renal tubular acidosis (hyporeninemic hypoaldosteronism) may occur in type 1 or 2 DM. These individuals develop a propensity to hyperkalemia, which may be exacerbated by medications [especially angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)]. Patients with DM are predisposed to radiocontrast-induced nephrotoxicity. Risk factors for radiocontrast-induced nephrotoxicity are preexisting nephropathy and volume depletion.

The recommended strategy for detecting microalbuminuria is outlined in Fig. 338-11 and includes annual measurement of the serum creatinine to estimate GFR.

Screening for microalbuminuria should be performed in patients with type 1 diabetes for more tan 5 years, in patients with type 2 diabetes, and during pregnancy

Non-diabetes-related conditions that might increase microalbuminuria are urinary tract infection, hematuria, heart failure, febrile illness, severe hyperglycemia, severe hypertension, and vigorous exercise

During the phase of declining renal function, insulin requirements may fall as the kidney is a site of insulin degradation. Furthermore, many glucose-lowering medications (sulfonylureas and metformin) are contraindicated in advanced renal insufficiency. pressure should be maintained at <130/80 style="background: yellow none repeat scroll 0% 0%; -moz-background-clip: -moz-initial; -moz-background-origin: -moz-initial; -moz-background-inline-policy: -moz-initial;">macroalbuminuria.

The ADA suggests modest restriction of protein intake in diabetic individuals with microalbuminuria (0.8 g/kg per day) or macroalbuminuria (<0.8>, which is the adult Recommended Daily Allowance, or ~10% of the daily caloric intake).

Neuropathy

Additional risk factors are BMI (the greater the BMI, the greater the risk of neuropathy) and smoking. The presence of cardiovascular disease, elevated triglycerides, and hypertension is also associated with diabetic peripheral neuropathy. The ADA recommends screening for distal symmetric neuropathy beginning with the initial diagnosis of diabetes and screening for autonomic neuropathy 5 years after diagnosis of type 1 DM and at the time of diagnosis of type 2 DM. All individuals with diabetes should then be screened annually for both forms of neuropathy.

Polyneuropathy/Mononeuropathy

The most common form of diabetic neuropathy is distal symmetric polyneuropathy. It most frequently presents with distal sensory loss, but up to 50% of patients do not have symptoms of neuropathy. Hyperesthesia, paresthesia, and dysesthesia also may occur. Any combination of these symptoms may develop as neuropathy progresses. Symptoms may include a sensation of numbness, tingling, sharpness, or burning that begins in the feet and spreads proximally. Neuropathic pain develops in some of these individuals, occasionally preceded by improvement in their glycemic control. Pain typically involves the lower extremities, is usually present at rest, and worsens at night. Both an acute (lasting <12>. As diabetic neuropathy progresses, the pain subsides and eventually disappears, but a sensory deficit in the lower extremities persists. Physical examination reveals sensory loss, loss of ankle reflexes, and abnormal position sense.

Diabetic polyradiculopathy is a syndrome characterized by severe disabling pain in the distribution of one or more nerve roots. It may be accompanied by motor weakness. Intercostal or truncal radiculopathy causes pain over the thorax or abdomen. Involvement of the lumbar plexus or femoral nerve may cause severe pain in the thigh or hip and may be associated with muscle weakness in the hip flexors or extensors (diabetic amyotrophy).

Mononeuropathy (dysfunction of isolated cranial or peripheral nerves) is less common than polyneuropathy in DM and presents with pain and motor weakness in the distribution of a single nerve. A vascular etiology has been suggested, but the pathogenesis is unknown. Involvement of the third cranial nerve is most common and is heralded by diplopia. Physical examination reveals ptosis and ophthalmoplegia with normal pupillary constriction to light. Sometimes other cranial nerves IV, VI, or VII (Bell's palsy) are affected. Peripheral mononeuropathies or simultaneous involvement of more than one nerve (mononeuropathy multiplex) may also occur.

Autonomic

Autonomic neuropathies affecting the cardiovascular system cause a resting tachycardia and orthostatic hypotension. Reports of sudden death have also been attributed to autonomic neuropathy. Gastroparesis and bladder-emptying abnormalities are often caused by the autonomic neuropathy seen in DM (discussed below). Hyperhidrosis of the upper extremities and anhidrosis of the lower extremities result from sympathetic nervous system dysfunction. Anhidrosis of the feet can promote dry skin with cracking, which increases the risk of foot ulcers. Autonomic neuropathy may reduce counterregulatory hormone release, leading to an inability to sense hypoglycemia appropriately (hypoglycemia unawareness).