Центрируйте для Здоровья и Образования Женщин

?> Центрируйте для Здоровья и Образования Женщин - Многократные Беременности

Многократные Беременности Бюллетень практики WHEC и клинические директивы управления для providers healthcare. Субсидия на образование обеспечило Здоровьем Женщины и центра образования (WHEC) Многократные беременности очаровывают и возражать обстановки. 1.05в 1.35%беременностей будем близнеццы и частость о двойниковать процесс различает широко в разные населени. Многократные рождения будут одни сейчас, задолжать в over- стимулирование об овуляция, это случается, когда овуляция стимулирование done в случае женщины бесплодие из-за ovulatory банкротство. Хотя dizygotic, двойникующие также, исчисляет различает широко моложе разные обстоятельства, monozygotic, двойникующие исчисляет будет, обычно, между 3.5до 4 за 1, 000 "необычно неизменными",. Частости кодонов, и так далее квадруплеты могут быть вычислены нанять гипотезу Hellin's примерно рядом. Это изложило что, когда частость о двойниковать будет n, это о кодоны будет n?, о квадруплеты n?, и так далее. Самое highest число на данный момент запротоколировало будет девять потомок. Печатайте о Близнеццах: Близнеццы, которые имеют характеристики, которые наживают им indisguishable эффективно "однояйцовые", в то время, как others, которые очень unlike рассмотрены "брасткие". Предшествующее всегда иметь одинаковый род, но, чем прежние могу быть разным родом. The terms identical and fraternal, although popular, are scientifically less useful and are best replaced by the terms monozygotic, and dizygotic, to indicate the mechanism of origin of the two types of twins. Monozygotic (однояйцовые) Близнеццы: Т.к. они проистекают от оплодотворения одних ovum, monozygotic двойникует будем генетически и очень однояйцовые, об одинаковом эротике, подобные в физическом возникновении. Физические разногласия посреди однояйцовые близнеццы нанесены рядом климатические факторы, anastomosis кораблей, resulting in разногласия в крови placental e.g.,поставляют от плаценты. Monozygotic, двойникующие, обычно, начинаться около конец о первой неделе и исход от деления о водоотталкивающей cell в два массе embryonic primordial. Впоследствии, два зародыша, каждые in его собственные amniotic sac, развивать внутри одни chorionic sac. Скорейшее деление embryonic клеток (2 в 3 дня) monozygotic двойникует, кто иметь два amnions, два chorions, и два плаценты, это может или могу быть не объединяы. О 30% о monozygotic двойникует исход от скорейшего деления. Прежнее деление embryonic клеток (9 в 15 дней) monozygotic близнеццами в одних amniotic sac и один sac из chorionic. Такие двойникует редко поставлены бодрые. Это было оценено среди monozygotic, которые частость monoamniotic двойникует двойникует будет о 4%. Dizygotic (брасткие) Близнеццы: Т.к. они проистекают от оплодотворения два ova до два еще сперматозоиды, dizygotic может двойниковать могу быть самые же или о та эротикой. Для одинаковой причины, они не будут похоже генетически, чем братья или сестры потерпеть в разы еще. Dizygotic twins always have two amnions and two chorions, but the chorions and placentas may be fused. Сочли Близнеццов: Если водоотталкивающий cell массовый, или embryonic диск, не делит полностью, various виды близнеццов могу сочедущими могу сформировать. Эти призваны согласно районы, которые скреплены, "thoracopagus" e.g.,указывает, это there будет начальные штуцер о thoracic районы. Это было оценено приблизительно, как только внутри, что monozygotic двойникует 40 каждых беременностей, двойникующие незаконченные и соче (сиамских) близнеццов исход. Внутри каком-либо пакует, близнеццы подключены в друг друг рядом кожа только или рядом cutaneous и еще ткани, e.g.,ливер. Какой-то сочли близнеццов успешно могу быть разлучены до хирургические технологи. Еще Многократные Рождения: Кодоны случаются и могут получить с (1) одни в беременностях о 8, 100, как только zygote и быть однояйцовыми; (2) два zygotes и состоять из однояйцовых близнеццов и единственный ребенок или; (3) три zygotes и быть или об одинаковом эротике эротик еще. Подобная комбинация случается в квадруплетах, пятерки, sextuplets и septuplets. Летальность и Болезненность: Многократные беременности остают кайфом - Рискует обстановкой, со летальностью публикующими perinatal исчисляет in развертывающими кантри, ранжирующие посреди 47 и 120 за 1, 000 рождения для близнеццов и посреди 93 и 203 за 1, 000 рождения для кодонов. Увеличенными опасность гибели в беременности twin's - higher, о пяти- створке опасность быть слегка higher за второго близнецца. Увеличенными опасность гибели в близнеццах продолжает в течение первого года жизни и этого не будет летальность до второго года для близнеццов, который исчисляет будем такие же как. Примерно 10% о доставк из из из из preterm будем twin gestations, и они отчитывать 25% о perinatal гибели в preterm доставк. Большое большинство гибелей в preterm многократные доставк случаются со gestations менее, чем 32 недели и рождения веса под 1500 gm. Связанность из увеличения из Intrauterine будет община в многократном gestation и также наживает напыщенный вклад high падению low- рождения - Вес и дистиллируют терпящим детенышей. Это также ассоциировано со существенной болезненностью. Большинство ребенок потерпеть о многократном gestation буду о фоска рождение утяжелять, менее, чем 2500 gm и будем в risk о существенные short term и лонга - Термин препятствует. Maternal Летальность и Болезненность: Они способствуют high падению физического дискомфорта, prolonged госпитализация, хирургическая доставка и social неудобство, associated со многократными беременностями. Некозырная общественность, которая часто просто рассматривает беременность так же вдвое, как интересующие и возуждающие, со вдвое ожидаемые счастливые исход, широко занижает кайф опасности многократных беременностей. Antenatal Опасность Посредничает в Многократных Gestations: antenatal рискует увеличением со кодонами, квадруплеты, ясно бескрайне и так далее. Одни задачи наплавили будем; Выкидыши: неизбежный недоносок будет по крайней мере вдвое как община в многократные беременности как в singleton беременность, и continuing беременность со resorption об одни или еще о зародышах могу быть даже одними. Врожденные аномалии из Уродств: будут примерно вдвое как община в twin ребенок как в singleton ребенок и четыре разы как община в кодоны, этому отчитывают майору уродств был 2.12%и минором уродств 4.13%. Вдвое близнеццы из monozygotic форсируют падение fetal уродства сверяющими со dizygotic близнеццы. Сочтенными близнеццы - редкое осложнение monozygotic двойниковать. Gravidarum: Hyperemesis excess тошнота и тошнить будет община со многократные беременность, могу быть ассоциированы со увеличивать гормональные уровни. Обработка такая же за singleton как. Беспомощность: примерно maternal громкость из в twin беременности крови будет 500 ml великие, чем в беременности из singleton и конечно fetal требования - пропорционально великие. Железо и folate дефицит anemias в, связи с этим будем одни. Гладьте пополнение о 60 в 80 mg и folic кислые пополнение о 1 mg за день порекомендованы в многократные беременности, и вместе с кайф- белок диета. Беременность Убедила Гипертонию: в многократных беременностях это - од и severe которые. Самые многие занятия предлагают, что это - в сравнении с singleton втройне еще. Polyhydramnios: does акутовые polyhydramnios случится, особенно близнеццы из monoamniotic. Это было доложено как случиться и в 5 до 8% о многократных беременностях, до падение из 28 недель был доложен как 1.7%все twin беременностей. Падение из Доставки: Preterm доставки из (до 37 недель) в twin gestations preterm приближается 50%. Это падение - на 12 разов higher, чем увидеть в беременности из и среднее длина gestation singleton противоположно уменьшения со number fetuses данными. Управление preterm трудится будет вполне похож на из беременности из singleton что. Связанность: пятые- о twin ребенок Увеличение Intrauterine показать клинический и объективный знак связанности из увеличения из intrauterine. Примерно 70% о ребенок терпеть о многократные gestations значительно увеличение ограничены. Примерно двойникуйте- Сдвойниковать Переливание: 15% о monochorionic двойникуйте, что беременности показывают клиническое доказательство близнеццом переливание синдром. В летальности из perinatal этих чехлов будет очень high в обоих близнеццах. Hemorrhage:, которая antepartum - пренебрегает увеличить в hemorrhage и падении previa; плаценты случайный hemorrhage и vasa previa - higher. Неврологический Вред: церебральный паралич, microcephaly, porencephaly и кратное encephalomalacia случается чаще в многократных беременностях, чем беременности из и singleton когда доставка чаще - preterm. У ребенок из Monochorionic есть значительно higher падение antenatal necrosis о церебральном белом деле, чем ребенок из или singleton dichorionic. Управление: Antepartum Nutritional Предупредительност: это порекомендовано, которые примерно тому maternal диетическому воздухоэаборнику в многократном gestation увеличивают daily рядом 300 kcal над это для беременности из singleton. Хотя выручка из для женщин со многократными gestations optimal веса была не определена, это было предложено, что женщины со близнеццами накапливают 35-45фунты. Ultrasonography:, которые это useful in оба предродовые диагностика и antepartum инспектирование. Со его использованием, небольшим, чем 10% о twin gestations будем undiagnosed впереди трудовые и доставка. Подробное обследование из о многократном gestation ультразвука должно быть произведено в течение второго триместра. Определение chorionicity будет самые точные в первые триместр; как беременность прогрессирует, это делает менее точным. До the third триместр, близнеццы следовать одинаковые увеличение изгибаться, это применять в singleton беременности. Обследование порядкового fetal увеличения должно включить оценивающим fetal вес зародыша и присвоить и по любому concordant увеличение из интервала. Routine Cervical Evaluation: either by clinical or ultrasonographic assessment has been investigated as an approach to predict preterm birth in the multiple gestations. Еженедельно числовой шейный экзамен для клинической аттестации о шейке был не ассоциирован со неблагоприятный maternal и fetal исход. Привык влагалищные Ultrasonography измерит шейную длину, ширину и просочить и осмотреть взаимосвязь этих измерений опасности рождения из preterm. Грядка Покоит: роль и величина грядки покоят дома или в больнице в предотвращении доставки из о многократном gestation preterm остает спорные. Госпитализация из Antepartum может быть toxemia беременности, что необходимоеый в многократных gestations для заведующих such as preterm осложнений трудится и осложненное fetal увеличение. Инспектирование: Antepartum routine использование и выгадываем о antepartum, что fetal инспектирование в незапутанном gestation из multifetal было не показано быть о выгоде. Когда связанность, из из осложненные fluid громкост, диссонанс, из из увеличения увеличения из из intrauterine беременность- убедили гипертония, fetal аномалии, monoamnionicity, или еще беременность осложнения случаться, испытание из и bio- physical давления из non- fetal инспектирования эпюра индицирован. Использование домой uterine активности наставляет был защищен до несколько предотвратить или суметь preterm трудиться в singleton или кратном gestations. Гибель об Одних Twin:, как только одинокий fetal выживать димайз будет выявлен, продиктую клиническому управлению gestational стареет о беременности и кондиции о зародыше. Когда гибель об одни зародыш случается до 34 недели о gestation, fetal движение считать и увеличили antepartum fetal инспектирование о выживать twin должны быть предприняты. Fetal компромисс или неземноеой fetal созревания из легкого предлагает надобность для доставки. Maternal consumptive coagulopathy со hypofibrinogenemia может иногда развить под эти обстоятельства. Доставка может быть приличествующей, если гибель one of близнецца случается после 34 недели gestation. Осложнение: Intrapartum Malpresentation, трос prolapse, связывать вовлечение (особенно в monoamnionic двойникует), в coordinate uterine акции, fetal тревожить и хирургическая интервенция будем все одни в течение труда в многократном gestation, чем в gestation из singleton. Запирать также о близнеццах посмотрно. Фазораспределение: Идеальный раз доставки для незапутанных беременностей, однако, неопределенный;, если избирательный доставка рассмотрена до 38 fetal недель gestation, зрелость из легкого должна быть оценена. Женщины со многократными беременностями должны идеально подвергать доставку до 40 недель gestation. Труд и Доставка: Когда познать gestations или женщина со думала кратное представляет в трудовые, конфирмация как можно скорее рядом ультразвук examination из fetal числа и подношений индицирован. Оба близнеццы должен быть проконтролированы постоянно в течение труда. Ultrasonography должны быть поставляемы определить сердечный курс о втором близнецце как его ориентирование, следующее доставку о первом близнецце чрезмерно. Приличествующий опытный pediatric и anesthesia штат должны быть уведомлены и поставляемые в доставке. Возможность для срочной cesarean доставки - и должна blood должны быть поставляемыми, т.к. необходимая вероятность рабочей интервенции, чрезмерно как hemorrhage, из postpartum увеличен. Проводите о Доставке: Delivery should be based on individual needs and may depend on the clinician's practice and experience. various twin подношения должно быть учтены. Twin A-Vertex with Twin B-Vertex: vaginal delivery is anticipated most of the time. Cesarean доставка должна быть только произведена для одинаковых индикаци прикладываемые в gestations из singleton. Не двойникует Вершину со Nonvertex: Twin B- cesarean доставка, не как, будет всегда необходимый. Влагалищная доставка близнецца B в подношении из nonvertex - reasonable опцион для neonate со оцененными, чем весом великим 1, 500 g. insufficient данные - защитить specific маршрут доставки (влагалищные или брюхоперые) из twin B чье рождение утяжеляет будет менее, чем 1, 500, хотя g, cesarean доставка произведена часто. Близнецец Nonvertex: широко, cesarean доставка - тот способ выбора, когда первый близнецец - nonvertex, such as breech или transverse подношение. Безопасность влагалищной доставки для этой группы не был документирован. Когда первый близнецец - и вторые есть вершина в подношении, возможность запертыми близнеццов breech существует. Интервал Посреди Доставк: Интервал посреди доставка каждого близнецца не будет in, определяющий переломный исход близнецца B. Surveillance of twin B with real time Ultrasonography and continuous monitoring of the fetal heart rate, however, are advised after the delivery of twin A. Rapid доставка может быть required из-за осложнения, placentae, such as abruption связывает выпадение, или уменьшение в fetal сердечном курсе. Если бы труд не возобновил in reasonable раз после доставка близнецца oxytocin увеличение со старательное fetal сердечное инспектирование из курса могу быть инициированы. Вершина из Once - в тазовом впуске, amniotomy могу быть произведены. Когда fetal кондиция диктует надобность ускорить доставку, внутренняя версию из и шерсть-обножка вычленение podalic могу быть подходящей альтернативой. Obstetricians должны селектировать доставку технику, со которыми они - самые удобные. Конспект In conclusion, multiple pregnancies require early detection and identification of number of pregnancies, early detection of the complications and their proper management. Преждевременные детеныши требуют prolonged и дорогостоящую заботу. Могу обучить здравоохранение кормильцами в пространстве терпящее образование и пригодность о можем свести летальность и болезненность. support группы - для родителей многократных рождений поставляемые в почти все пространство больницы, которые кайф- risk доставк Suggested Readings: Malone FD, D'Alton ME. Multiple gestation, In: Creasy, RK Resnik R. editors. Maternal-fetal medicine: principles and practice, 5th ed. Philadelphia (PA): Saunders; 2004: 513-536 ACOG Practice Bulletin. Multiple gestation: complicated twin, triplet, and high-order multifetal pregnancy. Number 56. October 2004 Simoes T, Amaral N, Lerman R et al. Prospective risk of intrauterine death of monochorionic-diamniotic twins. Am J Obstet Gynecol 2006;195:134-139 Lee YM, Cleary-Goldman J, Thaker HM et al. Antenatal sonographic prediction of twin chorionicity. Am J Obstet Gynecol 2006;195:863-867 Miura K, Nikawa N. Do monchorionic dizygotic twins increase after pregnancy by assisted reproductive technology? J Hum Genet 2005;50:1-6 Kahn B, Lumey LH, Zybert PA et al. Prospective risk of fetal death in singleton, twin, and triplet gestations: implications for practice. Obstet Gynecol 2003;102:685-692 Silver RM, Varner MW, Reddy U et al. Work-up of stillbirth: a review of the evidence. Am J Obstet Gynecol 2007;196:433-444 Lee YM, Wylie BJ, Simpson LL et al. Twin chorionicity and the risk of stillbirth. Obstet Gynecol 2008;111:301-308 >	Serum Calcium	Serum Phosphorus	Alkaline Phosphatase
Osteoporosis	Normal	Normal	Normal
Osteomalacia	Low	Low	Elevated
Hyperparathyroid	Elevated	Low	Elevated
Renal Failure; renal elevated osteodystrophy	Low	Elevated	Normal; (sometimes elevated)
Paget's disease	Normal	Normal	Very Elevated

Source: ACOG Practice Bulletin Number. Osteoporosis. Number 50, 2004

Bone Turnover Markers

Bone turnover markers are byproducts of bone resorption (deoxypyridinoline, N-telopeptides, and C-telopeptides from the breakdown of type I collagen) and bone formation (osteocalcin, bone-specific alkaline phosphatase, and procollagen type I N-terminal propeptide associated with bone matrix synthesis). They can be measured in urine or serum to determine a high bone turnover state of high bone turnover, which may indicate higher risk of fracture. High levels reflect a state of high bone turnover, which may indicate higher risk of fracture. Bone turnover markers have been used in clinical trials of osteoporosis therapies to demonstrate group response to treatment. Changes in bone turnover markers occur earlier than changes in BMD and can be used to ascertain the effect of treatment more promptly. Use of bone turnover markers in the management of individuals is more challenging because levels vary from day to day and throughout a single day. Bone turnover markers cannot be used to diagnose osteoporosis, and the usefulness of markers as an incentive for adherence has been questioned ⁽¹²⁾.

Prevention

A healthy life-style is important for those at risk for osteoporosis. Cessation of smoking eliminates the effects of nicotine on estrogen binding. Moderation in alcohol and caffeine intake will improve general health, and weight-bearing exercises provide mechanical stimulation for bone remodeling. Sedentary life-style is associated with reduced bone mass. The benefits of physical exercise include maintenance of bone mass and an increase in muscle strength and coordination. The risk of falling increases substantially with aging. Most falls that result in hip fractures occur indoors. The living environment should be monitored to reduce the risk of falling. Prevention of osteoporosis begins in childhood and adequate calcium intake is important. Many children and adolescents do not achieve the recommended daily intake of calcium. Insufficient calcium intake also can accelerate age-associated bone loss.

The two types of exercise necessary for bone health are weight-bearing and muscle-strengthening exercises. Weight-bearing exercises help build bone and keep bones strong. Strength training or resistance training helps to improve strength, balance, and flexibility. Perhaps its most important contribution is in preventing falls. Unfortunately, drawing evidence from research in this area is difficult for a variety of reasons. Until further research is conducted, knowledge about the impact of exercise on multiple aspects of osteoporosis is still insufficient.

Institute of Medicine Recommended Dietary Allowance for Calcium and Vitamin D

Age (years)	Calcium Recommended Dietary Allowance (mg/day)	Vitamin D Recommended Dietary Allowance (International units/day)
9-18	1,300	600
19-50	1,000	600
51-70	1,200	600
71 and older	1,200	800

Data from Institute of Medicine. Dietary reference intakes: calcium, vitamin D. Washington, DC: National Academics Press; 2011.

Treatment

Before initiating treatment, it is important to consider the possibility of secondary causes of osteoporosis. Fractures in a relatively young postmenopausal woman or a BMD lower than expected of age (e.g. a Z-score below normal for her age group) suggests the need to check for secondary causes of osteoporosis. An initial approach to evaluating for secondary causes of osteoporosis is suggested by American College of Obstetricians and Gynecologists (ACOG) are ⁽¹³⁾:

First Tier - complete blood count, metabolic profile, 24-hour urinary calcium level, 25-hydroxyvitamin D level, thyroid stimulating hormone (TSH) level;

Second Tier - celiac panel, serum protein electrophoresis

Treatments have been broadly classified as antiresorptive or anabolic, depending on the primary mechanism of action. There are many options for treating osteoporosis.

Bisphosphonates

This class of drugs reduces bone resorption by inhibiting osteoclasts; slows bone loss and increases bone mass. Bisphosphonate are analogues of inorganic pyrophosphate, and a number of these are currently under development. Vertebral fractures are reduced by 48% in the women treated with alendronate and risedronate ⁽¹⁴⁾,⁽¹⁵⁾. They are poorly absorbed from gastrointestinal tract and are recommended to be taken in the morning with 8 ounces of water, prior to any food or beverage. No food or beverage should be taken for the next 30 minutes to allow the alendronate to be absorbed. After taking alendronate or risedronate the woman should remain in an upright position, either sitting or standing to minimize the possibility of abdominal discomfort. The major side effects are abdominal discomfort, upper gastrointestinal bleeding, and musculoskeletal pain. One potential advantage of alendronate and risedronate are that they remain tightly bound to the surface of the bone for many years. It is not recommended for the patients with the renal failure or upper gastrointestinal problems. US Food and Drug Administration (FDA) has approved their use for the prevention of osteoporosis.

The four bisphosphonates approved in the United States, alendronate, risedronate, ibandronate, and zoledronate, have been extensively studied in large randomized controlled trial that have demonstrated anti-fracture benefit. All bisphosphonates significantly reduce vertebral fractures by 32-65% ⁽¹⁴⁾,⁽¹⁵⁾. Risedronate reduces non-vertebral fractures, and both alendronate and zoledronate significantly reduce hip fracture specifically. These drugs are classified as antiresorptive agents because the mechanism of action is inhibition of osteoclast resorption of bone. Inhibition of osteoclasts leads to a lesser decrease in bone formation by osteoblasts, but the net result is an increase in BMD and a decrease in bone turnover. Duration of effect after discontinuation may vary. Discontinuation of alendronate after 5 years of treatment resulted in maintenance of bone turnover markers below baseline for 5 years with BMD remained stable or decreased slowly ⁽¹⁶⁾. Discontinuing risedronate after 2 years of treatment resulted in significant loss of BMD during the first year ⁽¹⁷⁾.

Zoledronate is contraindicated in patients with acute renal failure or creatinine clearance of less than or equal to 35 mL/min. Patients should be screened for renal disease before zoledronate infusion because renal failure has occurred after infusion in patients with compromised renal function. Caution with regard to renal function should be exercised with other drugs in this class as noted in the product information sheets. Hypocalcemia should be corrected before the use of these drugs.

Government Approved Bisphosphonates for Postmenopausal Osteoporosis

Generic (brand name)	Dose and Route	Indication	Contraindication
Alendronate (Fosamax)	5 mg/day or 35 mg/week tablet or oral solution 10 mg/day or 70 mg/week tablet or oral solution	Prevention Treatment	Abnormalities of the esophagus; Inability to stand or sit upright for at least 30 minutes; Hypersensitivity to any component of this product; Hypocalcemia; Patients at increased risk of aspiration should not receive Fosamax oral solution
Alendronate + vitamin D3 (Fosamax Plus D, Fosavance)	70 mg + 2,800 IU/week; 70 mg + 5,600 IU/week	Treatment	Same as above
Risedronate (Actonel)	5 mg/day or 35 mg/week; or 75 mg in 2 consecutive day/month; or 150 mg/month	Prevention + Treatment	Same as above
Risedronate (Atelvia)	35 mg/week (delayed release)	Treatment	Same as above
Risedronate + calcium carbonate (Actonel with Calcium)	35 mg/week (day 1) + 1,250 mg Calcium for no-risedronate days (days 2-7 of 7-day treatment cycle)	Prevention + Treatment	Same as above
Ibandronate (Boniva)	150 mg/month; or 2.5 mg/day or 3 mg every 3 months IV (intravenous)	Prevention + Treatment Treatment	Same as above
Zoledronic acid (Reclast)	5 mg/2 year IV 5 mg/yearly IV	Prevention Treatment	Hypocalcemia; Creatinine clearance <35 mL/min and acute renal impairment; Hypersensitivity to Zoledronic acid any components of this product.

Adverse effects of bisphosphonates include musculoskeletal aches and pains, gastrointestinal irritation, and esophageal ulceration. Potential risks reported after marketing include osteonecrosis of the jaw, seizures, atypical fractures of the femoral shaft, and esophageal cancer. A precise understanding of the true risk of these events has been difficult to determine because of the lack of data on the incidence of these problems in the general population. Although rare cases of osteonecrosis of the jaw have been reported in patients using bisphosphonates for osteoporosis ⁽¹⁸⁾. It has been seen most commonly after dental extractions in those being treated with large intravenous doses of bisphosphonates in association with supportive cancer therapy ⁽¹⁹⁾. There is no requirement to discontinue bisphosphonates for dental procedures. However, there is likely to be no harm in discontinuing a bisphosphonate temporarily for a dental procedure, if the patient so desires, given the long duration of action of bisphosphonates

Denosumab

Denosumab (Prolia), an antiresorptive treatment, is a human monoclonal antibody to the receptor activator of nuclear factor-kB ligand. The receptor activator of nuclear factor-kB ligand binds to the receptor activator of nuclear factor-kB on the surface of osteoclasts and promotes proliferation and differentiation of these osteoclasts. The antibody blocks this interaction therein decreasing bone resorption and increasing BMD as a result ⁽²⁰⁾. Denosumab was approved in 2010 for treatment of postmenopausal women with osteoporosis who are at high risk of fracture. Studies revealed a vertebral and hip fracture reduction of 68% and 40%, respectively ⁽²⁰⁾. Denosumab (Prolia) is administered subcutaneously every 6 months. A higher rate of infections that required hospitalization was seen in the initial trials. However, concerns about suppression of the immune system leading to increased rates of cancer were not substantiated.

Partial Estrogen Agonists and Antagonists

Raloxifene (Evista) was the first drug in the class of partial estrogen agonists and antagonists (also known as selective estrogen receptor modulators) approved for the prevention and treatment of osteoporosis. It works as weak estrogen agonists in some systems, and estrogen antagonists in others. Raloxifene decreases the number and activity of osteoclasts and is approved for the prevention and treatment of postmenopausal osteoporosis. It decreases the incidence of vertebral fractures by 30% to 50% and increases BMD in the spine and femoral neck ⁽²¹⁾. Raloxifene is associated with a reduced risk of estrogen-dependent breast cancer, and may lower the risk of heart disease and stroke in women at high risk. However, the long-term effects of raloxifene on the vascular system are unknown, and increased risk of thromboembolic events similar to that reported with estrogens has been observed. As a result of its tendency to cause or exacerbate hot flashes, raloxifene is not recommended for newly menopausal women or for the treatment of vasomotor symptoms. However, it can reduce the risk of breast cancer in postmenopausal women at low risk of the disease, and is currently being evaluated for use in reducing the incidence of breast cancer in women at increased risk.

Calcitonin

Calcitonin (Miacalcin, Fortical) is a synthetic polypeptide based on salmon calcitonin, is available in a subcutaneous injectable form and as nasal spray. It inhibits bone resorption and is approved for the treatment of osteoporosis in women who are postmenopausal for at least 5 years. It increases vertebral bone mass and significantly reduces new vertebral fractures. It has been shown to reduce vertebral fractures and to reduce bone pain associated with vertebral fractures ⁽²²⁾. Objection to injectable now can be avoided by intranasal spray. Risks are: development of neutralizing antibodies-effect and absorption is variable. One spray in one nostril delivers the recommended dose of 200 IU of salmon calcitonin. Fracture reduction is less robust than with other agents and was not seen in early postmenopausal women. It should not be used until women are 5 years from menopause. Adverse effects include flushing and nausea with subcutaneous injection and local irritation with nasal spray.

Estrogen / Hormone Therapy (multiple brands)

It was one of first treatments for osteoporosis. It was widely used and showed effectiveness by increasing bone density at the spine and hip and by reducing hip, vertebral, and non-vertebral fractures. Estrogen / hormone therapy was also used to manage menopausal symptoms, and was widely used prior to the release of Women's Health Initiative (WHI) study findings in 2002. This trial found that estrogen / hormone therapy was effective at reducing hip fractures and preventing colon cancer, but that unexpectedly, women taking estrogen or estrogen plus progestin were found to have statistically significantly higher rates of cardiovascular disease, stroke, dementia, breast cancer, and other conditions that were studied. The investigators concluded that health risks associated with estrogen / hormone therapy outweighed the benefits ⁽²³⁾. As a result of these findings, estrogen's status was changed by the FDA. It is currently approved for the prevention of osteoporosis in women who are also experiencing menopausal symptoms. In cases where women do not have such symptoms, they should use another agent for the prevention of osteoporosis.

Contraindications are: undiagnosed abnormal genital bleeding; known, suspected, or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease; known or suspected estrogen-dependent neoplasia; active deep vein thrombosis, pulmonary embolism, or a history of these conditions; active or recent (within the past year) arterial thromboembolic disease (for example, stroke, myocardial infarction); liver dysfunction or disease; known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency); known hypersensitivity to any of the ingredients in these products; and known or suspected pregnancy.

Anabolic Agents for Osteoporosis
Teriparatide (Parathyroid hormone [PTH] 1-34, Forteo)

It is an anabolic, approved for the treatment of severe osteoporosis in postmenopausal women that showed very robust fracture reduction at vertebral and non-vertebral sites in clinical trials ⁽²⁴⁾. This drug has black-boxed warning because of the preclinical incidence of osteosarcoma in rats, although no increased osteosarcoma incidence has been reported in post-marketing surveillance of patients who received this agent. It is administered as a subcutaneous injection 20-microgram dose daily in conjunction with calcium and vitamin D for 24 months. After treatment period is completed, the patient may have to be maintained on another therapy, since the benefit of teriparatide wanes quite rapidly within 6 months to 1 year following discontinuation. Teriparatide has been studied in nursing home patients and was found to be safe and effective. However, there are few data suggesting it is actually being used, perhaps because of the need for a daily injection.

Future Osteoporosis Medications

Newer drugs for the treatment of osteoporosis have been evaluated in recent clinical trials. Odanacatib, an inhibitor of cathepsin K ( a proteinase believed to play a vital role in bone resorption and remodeling), decreased bone resorption, maintained bone formation, and increased BMD in a randomized, double-blinded, 2-year trial of postmenopausal women ⁽²⁵⁾. AMG785 is a monoclonal antibody targeted against sclerostin, an osteocyte-secreted protein that negatively regulates osteoblasts and inhibits bone formation. In a randomized, double-blind, placebo-controlled trial in healthy men and postmenopausal women AMG785 demonstrated dose-related increase in bone-formation markers and significant increases in BMD ⁽²⁵⁾.

Bone Density Screening Initiation

All major guidelines state that DXA screening should begin at age 65 years for women ⁽²⁶⁾. Most guidelines also agree that DXA screening can be used selectively for women younger than 65 years if they are postmenopausal and have other risk factors for fracture. Bone density should be screened in postmenopausal women younger than 65 years if any of the following risk factors are noted:

Medical history of a fragility fracture;

Body weight less than 127 lb.;

Medical causes of bone loss (medications or diseases);

Parental medical history of hip fracture;

Current smoker;

Alcoholism;

Rheumatoid arthritis.

After treatment initiation, one DXA scan 1 year or 2 years later can be used to assess the effect of treatment. If the BMD is improved or stable (no significant change), the DXA does not usually need to be repeated in the absence of new risk factors ⁽²⁷⁾. Testing generally should not be undertaken before 2 years after initiation of treatment because if often takes 18-24 months to document a clinically meaningful change. Although the use of depot medroxyprogesterone acetate (DMPA) is associated with loss of BMD, current evidence suggests that partial or full recovery of BMD occurs at the spine and at least partial recovery occurs at the hip after discontinuation of DMPA. Practitioners should not perform BMD monitoring solely in response to DMPA use because any observed short-term loss in BMD associated with DMPA use may be recovered and is unlikely to place an adolescent or adult woman at risk of fracture during use or in later years.

Treatment for Osteoporosis Recommendations

Lower bone density T-scores generally indicate more severe osteoporosis and higher risk of fracture. Every decrease of 1 standard deviation from age-adjusted bone density represents approximately a 10-12% change in BMD and an increase in the risk of fracture by a factor of approximately 2. Although few would withhold treatment from a woman with osteoporosis (T-score less than -2.5), whether to treat a woman with higher bone density scores has become a subject for debate. The National Osteoporosis Foundation (NOF) has chosen a T-score of -2 for women without risk factors and -1.5 for women with additional risk factors as the threshold for therapeutic treatment ⁽¹¹⁾. The Z-score may help in determining an alternative strategy, particularly with the Z-score is less than -1 and the patient would not have qualified for therapy solely on the criteria discussed above. Under these circumstances, a secondary cause for the bone loss should be sought. Monitoring a patient's response to treatment requires central bone densitometry. For women receiving osteoporosis therapy, bone mineral density BMD monitoring before 2 years of therapy are completed does not provide clinically useful information and may lead to erroneous assumption about the effect of therapy. Not observing an increase in BMD is not evidence of treatment failure. A decrease in vertebral bone mineral density greater than 4-5% indicates a need to evaluate the patient's compliance with therapy and dosing instructions and to search causes of bone loss.

Follow-up and Long-term management for at least 5 years: The most widely used bone medications are the bisphosphonates -- alendronate, risedronate, ibandronate, and zoledronate. Other FDA-approved bone medicines include estrogen or estrogen-progestin hormone therapy, raloxifene, parathyroid hormone, and calcitonin. After initiating a bone medicine, a DXA BMD can be measured in 1 to 2 years to assess changes in bone density. If the bone density is stable or increases, continue therapy. If compliance with treatment has been good and bone density was demonstrated to significantly decrease with treatment, consider a new regimen and reassess bone density in 1 to 2 years. An alternative approach is to measure fasting urinary cross-linked N-telopeptides of type I collagen (NTX) or serum type I collagen C-telopeptides (CTX) before and 3 to 6 months after starting antiresorptive treatment, such as a bisphosphonate. If the marker has decreased by 50% or more, treatment is likely to be successful and bone density can be assessed in 2 years. If the marker has not decreased by 50%, non-compliance or incorrect dosing, such as taking the bisphosphonate with food, is likely causes of a poor marker response ⁽¹²⁾.

All major guidelines state that treatment should be recommended for women who have a BMD T-score of less than or equal to -2.5. For women in the low bone mass category (T-score between -1 and -2.5), the fracture risk assessment tool (FRAX) calculator can be used to make an informed treatment decision. Women who are found to have a 10-year risk of major osteoporotic fracture greater than or equal to 20% or a risk of hip fracture greater than or equal to 3% using the FRAX calculator are candidates for medical pharmacologic therapy ⁽²⁸⁾. Women who have had a low-trauma fracture (especially of the vertebra or hip) also are candidates for treatment even in the absence of osteoporosis on the DXA report. Women with osteoporosis or who are at risk of osteoporosis should be counseled about lifestyle changes to reduce the risk of bone loss and osteoporotic factors. Recommendations include performing weight-bearing exercises and muscle-strengthening exercises to reduce the risk of fractures and falls, taking the appropriate amount to vitamin D and calcium, stopping smoking and avoiding second-hand smoke, reducing alcohol intake, and adopting fall-prevention strategies.

Treatment Selection: Bisphosphonates are generally considered first-line therapy, but raloxifene can be a good first choice in younger postmenopausal women for the previously described reasons. A woman using raloxifene can be transitioned to another therapy, such as bisphosphonate, in her 60s. Bisphosphonates can be selected on the basis of patient preference for a certain route of delivery or insurance coverage. Patients who have gastrointestinal problems or had gastrointestinal adverse effects with oral preparations may be better served with a parenteral bisphosphonate. For patients with adherence issues, an annual infusion of zoledronic acid may be preferred. Denosumab also is a good treatment option for the woman with a high risk of fracture. The subcutaneous injections every 6 months may appeal to some patients and not others. Combination therapy is not usually recommended. Although it may increase BMD to some degree, fracture data are not available. Risks, adverse effects, and cost with the use of two drugs may be higher than with one drug.

Follow-up with DXA Scan: If the initial BMD report indicates low bone mass, FRAX should be used to determine if the woman has a high risk of fracture. If she does, treatment should be recommended. If FRAX does not indicate a high risk of fracture, data from the Study of Osteoporotic Fractures suggest a screening interval of 1-5 years for a woman older than 65 years with a normal BMD or mild bone loss (T-score greater than or equal to -1.5), a 5-year screening interval for a T-score from -1.5 to -1.99, and a 1-year screening interval for a T-score between -2.0 and -2.49 ⁽²⁹⁾. The fracture risk assessment tool should continue to be used on an annual basis to monitor the important effect of age on fracture risk.

Fall Prevention Measures

Lighting - Provide accessible lighting for each part of the home use; use night-lights.

Floors - Remove throw rugs or secure them to the floor; remove all clutter from the floor; move cords and cables away from traffic path; use non-skid wax.

Storage - Store items at a height that does not require a step stool to reach.

Bathroom - Install safety grab bars in bath and shower; apply non-skid strips to bath and shower floor.

Indoors and Outdoor Stairs - Install handrails for the entire length of the stairs; provide adequate lighting; add non-skid treads or secure carpet indoors.

Compliance and Persistence with Osteoporosis Medications

Adherence has two components: compliance in taking the medication properly, and persistence in taking the medication over the long term. The consequences of poor adherence are highly detrimental in osteoporosis management; conversely, adherent patients have been shown to experience a 16% lower fracture rate than non-adherent patients ⁽³²⁾. With regard to dosing schedule, weekly and monthly bisphosphonate use has demonstrated significantly longer persistence than daily use, and more weekly and monthly users met predetermined criteria for good compliance than did daily users. Polypharmacy for multiple chronic conditions in older patients substantially challenges adherence to osteoporosis treatment regimens. Drug-related adverse events in this population may also exacerbate existing comorbidities, further decreasing adherence. It has been found that one year after initiating treatment, 45% of patients stop filling their osteoporosis prescriptions; older age and increasing numbers of comorbid conditions and medications unrelated to osteoporosis treatment all predicted lower adherence ⁽³³⁾.

Nine FDA-approved pharmaceutical therapies currently exist for osteoporosis, an important increase since 1995. However, regardless of the type or efficacy of the medication, it can only work if patient takes it. Unfortunately, many patients do not regard osteoporosis as a serious or chronic disease and do not take their medication as prescribed ⁽³⁰⁾. Compliance (the consistency and accuracy with which a medication is initially followed) and persistence (the length of time a regimen is continued) are the most challenging aspects of osteoporosis management, both for patients who must take the medication and for physicians who treat this disorder ⁽³¹⁾. Noncompliance to osteoporosis medication ultimately undermines the reason for taking medication and leads to the outcome of fracture. Indeed, a positive correlation exists between compliance to osteoporosis medication and lower fracture risk, as evidenced by a study of more than 11,000 postmenopausal women with osteoporosis. A 16% lower fracture rate occurred in adherent women who took at least 80% of the doses of their osteoporosis medications compared with non-compliant women ⁽³²⁾. One way in which patients do not comply with medication prescriptions is called secondary non-adherence. In this case, patients fill their prescriptions, take them home, and start to take them. Then something happens (e.g. side effects, cost, and forgetfulness) and the patients are no longer following their prescribed medication routine. Many studies have examined secondary non-adherence in osteoporosis and interventions have been developed to improve patient medication behavior, although many have been ineffective ⁽³⁴⁾.

What can be done to improve medication behaviors in osteoporosis? Greater communication between patients and healthcare providers can improve compliance and persistence, which can be accomplished through e-mails and phone calls, in addition to regular office visits. Consistent follow-up with the patient through visits, e-mails, and phone calls is essential for assessment of treatment tolerance and adherence. In a study that examined the effect of nurse monitoring on adherence to osteoporosis therapy in postmenopausal women, monitoring of patients increased adherence to therapy by 57% at 1 year ⁽³⁴⁾. Physicians who work with their patients to identify and resolve barriers that contribute to non-adherence, and who educate and empower patients in self-managing their medications, may help improve overall treatment adherence and facilitate positive treatment outcomes.

Summary

Osteoporosis is a serious disease with a prevalence that is expected to increase as the population ages. This disease deserves attention of both patients and physicians, especially since very effective means exist for identifying and assessing patients at risk for osteoporosis. Advances in imaging technology allow clinicians to diagnose osteoporosis before a clinically significant fracture occurs. Numerous therapies are available for the prevention and treatment of osteoporosis in postmenopausal women; however, variations exist in the overall efficacy of these product types, and in the range of skeletal sites at which beneficial effects are observed. Women with low bone density or established osteoporosis should be offered estrogen replacement therapy, alendronate, or calcitonin therapy. Application of these new tools and treatment by obstetrician-gynecologist may reduce the number of osteoporotic fractures experienced by our aging population. It is not only in the area of pharmacotherapies that changes are anticipated within the next few years. Greater emphasis will almost certainly be placed on identification of the determinants of osteoporotic fracture risk, to enable more effective targeting of preventive measures to those women at greatest risk. Treatment should be recommended for: women with a T-score of -2.5 or less; women who have had low-trauma fracture; and women who have a T-score from -1 to -2.5 and a FRAX score greater than or equal to 20% for risk of a major osteoporotic fracture (defined as forearm, hip, shoulder, or clinical spine fracture) or both in the next 10 years. FDA approved therapies should be used for medical treatment: raloxifene, bisphosphonates, PTH, Denosumab, and calcitonin.

What can be done to improve medication behaviors in osteoporosis? Greater communication between patients and healthcare providers can improve compliance and persistence, which can be accomplished through e-mails and phone calls, in addition to regular office visits. Consistent follow-up with the patient through visits, e-mails, and phone calls is essential for assessment of treatment tolerance and adherence. Physicians who work with their patients to identify and resolve barriers that contribute to non-adherence, and who educate and empower patients in self-managing their medications, may help improve overall treatment adherence and facilitate treatment outcomes. A number of safe and effective therapies, which can reduce fractures by approximately 50% at all sites, are available to treat osteoporosis. It is incumbent on physicians to identify at-risk individuals and implement appropriate therapy. Because medications adherence remains an important issue in osteoporosis, education and attention to patient preferences for medications may help prevent the fractures that lead to the negative outcomes of osteoporosis.

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