REVIEW URRENT C OPINION
Postmenopausal osteoporosis Dima L. Diab a and Nelson B. Watts b
Purpose of review The aim of this study is to provide a thorough updated review of the diagnosis and treatment of postmenopausal osteoporosis. Recent findings There have been several important findings in the field of postmenopausal osteoporosis over the past 1–2 years. Fewer morphometric vertebral fractures were found in women treated for 6 years with zoledronic acid compared with those who stopped treatment after 3 years. Longer duration of bisphosphonate therapy is associated with a higher risk of atypical femur fractures. Combination therapy with teriparatide and denosumab appears to increase bone mineral density to a greater extent than either therapy alone in postmenopausal women at high risk for fracture. There are several novel therapies under investigation for the treatment of osteoporosis, which are in various stages of development. Nonadherence to osteoporosis therapies continues to be a major problem in clinical practice. Summary There are numerous effective pharmacologic treatment options for postmenopausal osteoporosis. Bisphosphonate drug holidays continue to be an area of significant debate. Keywords diagnosis, fractures, postmenopausal osteoporosis, treatment
INTRODUCTION Osteoporosis is a generalized skeletal disorder characterized by compromised bone strength, which predisposes to an increased risk of fractures [1]. Osteoporosis has no clinical manifestations until there is a fracture. The Surgeon General’s report on bone health and osteoporosis published in 2004 suggests that this condition affects 8 million women and 2 million men in the USA, in addition to 34 million people with low bone mass [2]. These numbers are expected to steadily increase over time, with osteoporosis affecting an estimated 14 million people and low bone mass affecting an estimated 48 million people by the year 2020. The annual incidence of osteoporotic fractures is greater than 2 million, and this is expected to rise to more than 3 million by the year 2020 based on the data from the same report.
DIAGNOSIS Measurement of bone mineral density (BMD) by dual-energy x-ray absorptiometry of the spine, hip and/or forearm is the gold standard for establishing the diagnosis of osteoporosis, in which a T-score of 2.5 or lower is consistent with this condition (Table 1) [3 ]. A clinical diagnosis of osteoporosis
can be made in individuals who sustain a low trauma or fragility fracture regardless of the T-score. The 2013 National Osteoporosis Foundation (NOF) guidelines recommend BMD testing for all women 65 years of age and older, which is in agreement with the 2011 US Preventive Service Task Force recommendations for postmenopausal women [4]. [http:// www.nof.org/files/nof/public/content/resource/913/ files/580.pdf. Accessed August 1, 2013 (The NOF’s newly revised 2013 Clinician’s Guide to Prevention and Treatment of Osteoporosis is a very useful guide containing updated information and recommendations that serve as a reference point for clinical decision-making in the diagnosis and treatment of men and women at high risk for fracture.] Testing should be done sooner in women with clinical risk
a
Department of Internal Medicine, Division of Endocrinology/Metabolism and bMercy Health Osteoporosis and Bone Health Services, Cincinnati, Ohio, USA Correspondence to Dima L. Diab, MD, Department of Internal Medicine, Division of Endocrinology/Metabolism, Cincinnati VA Medical Center, University of Cincinnati Bone Health and Osteoporosis Center, 260 Stetson St, Suite 4200, Cincinnati, Ohio 45219, USA. Tel: +1 513 558 4444; fax: +1 513 558 8581; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2013, 20:501–509
&
DOI:10.1097/01.med.0000436194.10599.94
1752-296X ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-endocrinology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Parathyroids, bone and mineral metabolism &
KEY POINTS Osteoporosis is a common condition that can be diagnosed and treated before any fracture occurs. It is important to identify and address potential contributing factors by a careful history, physical examination, and basic laboratory testing. Several FDA-approved pharmacological treatments have been shown to significantly reduce the risk of fracture in postmenopausal women. Pharmacologic therapy must be individualized and paralleled with the treatment of potentially modifiable risk factors.
factors for fracture such as low body weight, history of prior fracture, family history of osteoporosis, smoking, excessive alcohol intake, or long-term use of high-risk medications such as glucocorticoids (http://www.nof.org/files/nof/public/content/ resource/913/files/580.pdf. Accessed August 1, 2013).
DIFFERENTIAL DIAGNOSIS AND WORK-UP Osteoporosis is classified as primary (related to estrogen deficiency and/or age), secondary (caused at least in part by other diseases or medications) and idiopathic (characterized by low bone density and fractures in young adults without known cause). There are numerous causes of secondary osteoporosis including endocrine and metabolic disorders, nutritional deficiencies, genetic disorders, and other miscellaneous conditions as well as medications (see Table 2) (https://www.aace.com/files/osteo-guidelines-2010.pdf. Accessed August 1, 2013) [5]. Potential contributing factors are found in about 30% of postmenopausal women with osteoporosis, and it is essential to identify and address these factors in order to appropriately manage these patients and avoid further bone loss despite pharmacologic
Table 1. WHO diagnostic classification of osteoporosis
intervention for osteoporosis [7,8 ]. Some studies suggest that patients with low Z-scores are more likely to have one or more underlying contributing factors [9], but others show that these factors are common in all patients with osteoporosis and that Z-score diagnostic thresholds have limited value in discriminating between primary and secondary osteoporosis [10,11 ]. The following diagnostic studies should be considered initially in postmenopausal women with osteoporosis: complete blood count, comprehensive metabolic panel, 25-hydroxyvitamin (OH) D level, and 24-h urinary calcium, sodium, and creatinine. Further testing may be performed in selected patients depending on the clinical picture and results of the initial work-up (http:// www.nof.org/files/nof/public/content/resource/913/ files/580.pdf. Accessed August 1, 2013) [8 ]. &
&
TREATMENT The treatment of osteoporosis involves a combination of counseling patients on risk factor reduction (nonpharmacologic measures) as well as discussing risks and benefits of the currently available pharmacologic therapies (pharmacologic management).
Nonpharmacologic measures Several interventions aimed at decreasing fracture risk should be recommended universally. These include an adequate intake of calcium and vitamin D, cessation of tobacco use, avoidance of excessive alcohol intake, participation in regular weight-bearing and muscle-strengthening exercise, and assessment of fall risk.
Adequate calcium and vitamin D intake Adequate intake of calcium and vitamin D is an important component in the prevention and treatment of osteoporosis. A recent study examined the health benefits and risks of calcium and vitamin D supplementation using data from the Women’s Health Initiative, with emphasis on fractures, cardiovascular disease, cancer, and total mortality [12 ]. This showed a substantial reduction in hip fracture risk [hazard ratio 0.65; 95% confidence interval (CI) 0.44–0.98] but no significant effect on other outcomes. The recommended total calcium intake for postmenopausal women is 1200 mg daily, with the preferred source being dietary [13,14]. Supplementation is recommended if this cannot be obtained through diet alone. &
T-scorea
Category Normal
1.0 and above
Low bone mass (osteopenia)
Between 1.0 and 2.5
Osteoporosis
2.5 and below &
Reproduced with permission from [3 ]. a The T-score compares an individual’s bone mineral density with the mean value for young normal individuals and expresses the difference as a standard deviation score.
502
www.co-endocrinology.com
Volume 20 Number 6 December 2013
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Postmenopausal osteoporosis Diab and Watts Table 2. Some causes of secondary osteoporosis Endocrine/metabolic diseases Hypogonadism; hypercalciuria; hyperthyroidism; hyperparathyroidism; Cushing’s syndrome; diabetes mellitus
Nutritional conditions
Drugs
Genetic disorders
Miscellaneous
Vitamin D deficiency; calcium deficiency; vitamin B12 deficiency; weight loss; malabsorption; gastric surgery; anorexia nervosa; chronic liver disease; alcoholism; malnutrition; prolonged total parenteral nutrition
Glucocorticoids; antiepilepsy drugs; excess thyroid; hormone; Depo-Provera; androgen deprivation therapy; aromatase inhibitors; heparin; thiazolidinediones; selective serotonin reuptake inhibitors; proton pump inhibitors; excess vitamin A; cyclosporine
Osteogenesis; imperfecta; homocystinuria; Ehlers-Danlos; syndrome; Marfan; syndrome; glycogen storage diseases; Gaucher’s disease; hypophosphatasia; porphyria; hemochromatosis
Rheumatoid arthritis; inflammatory bowel; disease; COPD; organ transplantation; immobilization; muscular dystrophy; multiple sclerosis; multiple myeloma; some cancers (leukemia and lymphomas); ESRD; mastocytosis; thalassemia; sickle cell disease; HIV
Reproduced with permission from [5]. Adapted with permission from [6]. COPD¼ chronic obstructive pulmonary disease ESRD¼ end-stage renal disease.
Vitamin D deficiency is common and supplementation is essential for the maintenance of bone and muscle strength. A recent pooled analysis of 11 double-blind, randomized, controlled trials of oral vitamin D supplementation in persons 65 years of age or older revealed that high-dose vitamin D supplementation [800 international units (IU) daily] was somewhat favorable in the prevention of hip fracture and any nonvertebral fracture [15 ]. Vitamin D replacement has also been shown to improve muscle strength, reduce body sway, and decrease fall risk in older individuals [16 ]. Vitamin D status is assessed by measurement of its major circulating metabolite, 25-OH D, with the minimum desirable 30 ng/mL [17,18 ]. Many patients require supplements of vitamin D, 2000 IU daily or more, to achieve this level. Vitamin D2 appears to be as effective as vitamin D3 in maintaining circulating concentrations of 25-OH D when given daily, but perhaps D2 is not as potent as D3 if given weekly or monthly [19,20 ]. &
&&
&&
&
Fall prevention Poor vision, poor hearing, poor balance and muscle weakness are critical determinants of fall risk and are significant independent predictors of the risk of hip fracture in elderly women [3 ]. The combined assessment of neuromuscular and visual impairment with BMD measurements improves the prediction of hip fractures [21]. Effective fall prevention interventions include home safety evaluation for high-risk or visually impaired patients, withdrawal of psychoactive medications, cataract surgery, exercise interventions that improve muscle strength and include balance training (such as Tai Chi), and vitamin D repletion in those with low vitamin D levels [22 ,23]. Using proper footwear and avoiding stairs if possible are also important measures in reducing fall risk. &
&
Pharmacologic management Based on the NOF guidelines (http://www.nof.org/ files/nof/public/content/resource/913/files/580.pdf. Accessed August 1, 2013), healthcare providers should consider treating postmenopausal women based on the following: T-score 2.5 or less at the lumbar spine, femoral neck, total hip, or one-third distal radius (after appropriate evaluation for potential contributing factors); a hip or vertebral (clinical or morphometric) fracture; low bone mass (T-score between 1.0 and 2.5); and a 10-year probability of a hip fracture 3% or more or a 10-year probability of a major osteoporosis-related fracture 20% or more based on the US-adapted WHO algorithm (i.e. using the FRAX Web-based tool) [3 ], although clinician’s judgment and/or patient preferences may indicate treatment for people with 10-year fracture probabilities below these levels. Clinical risk factors for fracture included in the WHO Fracture Risk Assessment Model (FRAX) are as follows: &
(1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11)
Current age; Sex; Low BMI (Kg/m2) A prior osteoporotic fracture (including morphometric vertebral fracture); Parental history of hip fracture; Oral glucocorticoids 5 mg/d or more of prednisone for 3 months or more (ever); Current smoking; Alcohol intake (3 or more drinks per day); Rheumatoid arthritis; Secondary osteoporosis; and Femoral neck BMD.
The current US Food and Drug Administration (FDA)-approved indications for bone-active agents in postmenopausal women are shown in Table 3. The efficacy of these agents has been established in a
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Parathyroids, bone and mineral metabolism Table 3. FDA-approved indications for bone-active agents for postmenopausal women Postmenopausal osteoporosis Drug
Prevention
Treatment
Estrogen Calcitonin (Miacalcin, Fortical) Raloxifene (Evista) Ibandronate (Boniva) Alendronate (Fosamax) Risedronate (Actonel) Risedronate (Atelvia) Zoledronate (Reclast) Denosumab (Prolia) Teriparatide (Forteo) &
Reproduced with permission from [3 ]. FDA, Food and Drug Administration.
popular choice for treatment of osteoporosis because of its relatively weak antifracture efficacy compared with other bone-active agents.
Raloxifene Raloxifene is a compound that can bind to estrogen receptors and cause estrogenic or antiestrogenic responses in different tissues. It is the only estrogen agonist/antagonist that is currently FDA-approved for the prevention and treatment of postmenopausal osteoporosis. In the Multiple Outcomes of Raloxifene Evaluation trial [26], the risk of vertebral fracture was reduced in both study groups receiving raloxifene [30% relative risk reduction or (RRR) for 60-mg/d group; 50% RRR for 120-mg/d group]. A recent retrospective cohort study showed that patients treated with alendronate and raloxifene had similar adjusted fracture rates in up to 8 years of adherent treatment [27 ]. Raloxifene also appears to lower the risk of breast cancer, although women receiving raloxifene had an increased risk of thromboembolism. A recent study showed that raloxifene, but not bisphosphonates, significantly suppressed circulating sclerostin concentration, an inhibitor of bone formation, suggesting that sclerostin may in part mediate the action of estrogen on bone metabolism [28 ]. &
number of large randomized pivotal clinical trials with fracture end-points and the current evidence for fracture reduction is shown in Table 4. Therapy needs to be individualized based on risk/benefit assessments, taking into account the presence of co-morbid medical conditions that are prevalent in older patients [3 ,24]. &
&
Calcitonin Calcitonin inhibits bone resorption by acting directly on osteoclasts. The efficacy of this agent was established in the Prevent Recurrence of Osteoporotic Fractures study in postmenopausal women with osteoporosis, which showed that 200 IU salmon calcitonin nasal spray per day decreased the risk of new vertebral fractures by 33–36% at the end of 5 years [25]. However, the discontinuation rate at the end of the study was high (59%). This is currently considered a less
Bisphosphonates Bisphosphonates reduce osteoclastic bone resorption by entering the osteoclast, causing loss of resorptive function and accelerating osteoclast apoptosis [29 ]. Alendronate was the first bisphosphonate approved by the FDA in 1995 for the treatment of osteoporosis, followed by risedronate in 2000, zoledronic acid in 2001, and ibandronate in 2005, and zoledronic acid in 2007. Approval of bisphosphonates in the USA was based on studies of 3–4 years’ duration, although &
Table 4. Evidence for fracture reduction for FDA-approved bone-active agents Drug
Vertebral fracture
Nonvertebral fracture
Hip fracture
Calcitonin (Miacalcin, Fortical)
No effect demonstrated
No effect demonstrated
Raloxifene (Evista)
No effect demonstrated
No effect demonstrated
Ibandronate (Boniva)
No effect demonstrated
No effect demonstrated
Alendronate (Fosamax)
a a
Risedronate (Actonel, Atelvia) Zoledronic acid (Reclast) Denosumab (Prolia) Teriparatide (Forteo)
No effect demonstrated &
Reproduced with permission from [3 ]. FDA, Food and Drug Administration. a Evidence for effect but not an FDA-approved indication.
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Postmenopausal osteoporosis Diab and Watts
some of these studies have been extended, with zoledronic acid, risedronate, and alendronate suggesting efficacy for up to 6, 7, and 10 years, respectively [30 ,31–33]. The extension of the alendronate Fracture Intervention Trial [Fracture Intervention Long-term eXtension or (FLEX)] enrolled subjects who had approximately 5 years of alendronate treatment in the Fracture Intervention Trial into a second 5-year study in which subjects were randomized to either continue alendronate or start placebo. At the end of the FLEX study, there were fewer clinical vertebral fractures in the long-term treated group that met statistical difference from the placebo group [2 vs. 5%, relative risk or (RR) 0.45, P ¼ 0.013] [32]. A posthoc analysis of the FLEX data indicated that nonvertebral fracture risk reduction was also observed in the subset of patients without prior vertebral compression fractures but only in those with T-scores entering FLEX of 2.5 or lower at the femoral neck hip [33]. In the 3-year extension of the zoledronate Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (PFT), subjects who received three doses of zoledronate in the placebo-controlled were assigned at random to one of two arms: a continuation group that received 6 years of zoledronic acid administration and a discontinuation group that received the initial 3 years of zoledronic acid then went to placebo [30 ]. At the end of 6 years, there were significantly fewer morphometric vertebral fractures in the group that continued treatment compared with the placebo group [14 vs. 30, odds ratio (OR) 0.51, 95% CI 0.26–0.95, P ¼ 0.035)], suggesting that patients at high fracture risk may benefit by continued treatment. In terms of long-term safety, concerns about two uncommon but possible time-related adverse events have emerged: osteonecrosis of the jaw (ONJ) and atypical femur fractures (AFFs). ONJ is defined as exposed necrotic bone in the maxillofacial region, not healing after 8 weeks in patients with no history of craniofacial radiation. It appears as areas of exposed yellow or white hard bone with smooth or ragged borders and can be associated with pain, swelling, paresthesias, suppuration, soft tissue ulceration, intra or extra-oral sinus tracks, and loosening of teeth. This can occur spontaneously, but is generally associated with invasive dental procedures such as tooth extraction. ONJ has been described in patients receiving chronic bisphosphonate therapy for treatment of osteoporosis but appears to be much more common in cancer patients receiving bisphosphonates in 10–12 times higher doses than those used to treat osteoporosis [34]. &&
&&
AFFs are thought to be stress fractures, which are frequently bilateral, are typically associated with minimal or no trauma, and are present with prodromal pain in the region of the fracture [35 ,36 ]. These fractures had been described in patients who have not received any treatment for osteoporosis. A recent case–control study found that longer use of bisphosphonates (5–9 years) was associated with a greater risk of atypical fractures (OR 117, 95% CI 34–402) compared with shorter use (
Postmenopausal osteoporosis Dima L. Diab a and Nelson B. Watts b
Purpose of review The aim of this study is to provide a thorough updated review of the diagnosis and treatment of postmenopausal osteoporosis. Recent findings There have been several important findings in the field of postmenopausal osteoporosis over the past 1–2 years. Fewer morphometric vertebral fractures were found in women treated for 6 years with zoledronic acid compared with those who stopped treatment after 3 years. Longer duration of bisphosphonate therapy is associated with a higher risk of atypical femur fractures. Combination therapy with teriparatide and denosumab appears to increase bone mineral density to a greater extent than either therapy alone in postmenopausal women at high risk for fracture. There are several novel therapies under investigation for the treatment of osteoporosis, which are in various stages of development. Nonadherence to osteoporosis therapies continues to be a major problem in clinical practice. Summary There are numerous effective pharmacologic treatment options for postmenopausal osteoporosis. Bisphosphonate drug holidays continue to be an area of significant debate. Keywords diagnosis, fractures, postmenopausal osteoporosis, treatment
INTRODUCTION Osteoporosis is a generalized skeletal disorder characterized by compromised bone strength, which predisposes to an increased risk of fractures [1]. Osteoporosis has no clinical manifestations until there is a fracture. The Surgeon General’s report on bone health and osteoporosis published in 2004 suggests that this condition affects 8 million women and 2 million men in the USA, in addition to 34 million people with low bone mass [2]. These numbers are expected to steadily increase over time, with osteoporosis affecting an estimated 14 million people and low bone mass affecting an estimated 48 million people by the year 2020. The annual incidence of osteoporotic fractures is greater than 2 million, and this is expected to rise to more than 3 million by the year 2020 based on the data from the same report.
DIAGNOSIS Measurement of bone mineral density (BMD) by dual-energy x-ray absorptiometry of the spine, hip and/or forearm is the gold standard for establishing the diagnosis of osteoporosis, in which a T-score of 2.5 or lower is consistent with this condition (Table 1) [3 ]. A clinical diagnosis of osteoporosis
can be made in individuals who sustain a low trauma or fragility fracture regardless of the T-score. The 2013 National Osteoporosis Foundation (NOF) guidelines recommend BMD testing for all women 65 years of age and older, which is in agreement with the 2011 US Preventive Service Task Force recommendations for postmenopausal women [4]. [http:// www.nof.org/files/nof/public/content/resource/913/ files/580.pdf. Accessed August 1, 2013 (The NOF’s newly revised 2013 Clinician’s Guide to Prevention and Treatment of Osteoporosis is a very useful guide containing updated information and recommendations that serve as a reference point for clinical decision-making in the diagnosis and treatment of men and women at high risk for fracture.] Testing should be done sooner in women with clinical risk
a
Department of Internal Medicine, Division of Endocrinology/Metabolism and bMercy Health Osteoporosis and Bone Health Services, Cincinnati, Ohio, USA Correspondence to Dima L. Diab, MD, Department of Internal Medicine, Division of Endocrinology/Metabolism, Cincinnati VA Medical Center, University of Cincinnati Bone Health and Osteoporosis Center, 260 Stetson St, Suite 4200, Cincinnati, Ohio 45219, USA. Tel: +1 513 558 4444; fax: +1 513 558 8581; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2013, 20:501–509
&
DOI:10.1097/01.med.0000436194.10599.94
1752-296X ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-endocrinology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Parathyroids, bone and mineral metabolism &
KEY POINTS Osteoporosis is a common condition that can be diagnosed and treated before any fracture occurs. It is important to identify and address potential contributing factors by a careful history, physical examination, and basic laboratory testing. Several FDA-approved pharmacological treatments have been shown to significantly reduce the risk of fracture in postmenopausal women. Pharmacologic therapy must be individualized and paralleled with the treatment of potentially modifiable risk factors.
factors for fracture such as low body weight, history of prior fracture, family history of osteoporosis, smoking, excessive alcohol intake, or long-term use of high-risk medications such as glucocorticoids (http://www.nof.org/files/nof/public/content/ resource/913/files/580.pdf. Accessed August 1, 2013).
DIFFERENTIAL DIAGNOSIS AND WORK-UP Osteoporosis is classified as primary (related to estrogen deficiency and/or age), secondary (caused at least in part by other diseases or medications) and idiopathic (characterized by low bone density and fractures in young adults without known cause). There are numerous causes of secondary osteoporosis including endocrine and metabolic disorders, nutritional deficiencies, genetic disorders, and other miscellaneous conditions as well as medications (see Table 2) (https://www.aace.com/files/osteo-guidelines-2010.pdf. Accessed August 1, 2013) [5]. Potential contributing factors are found in about 30% of postmenopausal women with osteoporosis, and it is essential to identify and address these factors in order to appropriately manage these patients and avoid further bone loss despite pharmacologic
Table 1. WHO diagnostic classification of osteoporosis
intervention for osteoporosis [7,8 ]. Some studies suggest that patients with low Z-scores are more likely to have one or more underlying contributing factors [9], but others show that these factors are common in all patients with osteoporosis and that Z-score diagnostic thresholds have limited value in discriminating between primary and secondary osteoporosis [10,11 ]. The following diagnostic studies should be considered initially in postmenopausal women with osteoporosis: complete blood count, comprehensive metabolic panel, 25-hydroxyvitamin (OH) D level, and 24-h urinary calcium, sodium, and creatinine. Further testing may be performed in selected patients depending on the clinical picture and results of the initial work-up (http:// www.nof.org/files/nof/public/content/resource/913/ files/580.pdf. Accessed August 1, 2013) [8 ]. &
&
TREATMENT The treatment of osteoporosis involves a combination of counseling patients on risk factor reduction (nonpharmacologic measures) as well as discussing risks and benefits of the currently available pharmacologic therapies (pharmacologic management).
Nonpharmacologic measures Several interventions aimed at decreasing fracture risk should be recommended universally. These include an adequate intake of calcium and vitamin D, cessation of tobacco use, avoidance of excessive alcohol intake, participation in regular weight-bearing and muscle-strengthening exercise, and assessment of fall risk.
Adequate calcium and vitamin D intake Adequate intake of calcium and vitamin D is an important component in the prevention and treatment of osteoporosis. A recent study examined the health benefits and risks of calcium and vitamin D supplementation using data from the Women’s Health Initiative, with emphasis on fractures, cardiovascular disease, cancer, and total mortality [12 ]. This showed a substantial reduction in hip fracture risk [hazard ratio 0.65; 95% confidence interval (CI) 0.44–0.98] but no significant effect on other outcomes. The recommended total calcium intake for postmenopausal women is 1200 mg daily, with the preferred source being dietary [13,14]. Supplementation is recommended if this cannot be obtained through diet alone. &
T-scorea
Category Normal
1.0 and above
Low bone mass (osteopenia)
Between 1.0 and 2.5
Osteoporosis
2.5 and below &
Reproduced with permission from [3 ]. a The T-score compares an individual’s bone mineral density with the mean value for young normal individuals and expresses the difference as a standard deviation score.
502
www.co-endocrinology.com
Volume 20 Number 6 December 2013
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Postmenopausal osteoporosis Diab and Watts Table 2. Some causes of secondary osteoporosis Endocrine/metabolic diseases Hypogonadism; hypercalciuria; hyperthyroidism; hyperparathyroidism; Cushing’s syndrome; diabetes mellitus
Nutritional conditions
Drugs
Genetic disorders
Miscellaneous
Vitamin D deficiency; calcium deficiency; vitamin B12 deficiency; weight loss; malabsorption; gastric surgery; anorexia nervosa; chronic liver disease; alcoholism; malnutrition; prolonged total parenteral nutrition
Glucocorticoids; antiepilepsy drugs; excess thyroid; hormone; Depo-Provera; androgen deprivation therapy; aromatase inhibitors; heparin; thiazolidinediones; selective serotonin reuptake inhibitors; proton pump inhibitors; excess vitamin A; cyclosporine
Osteogenesis; imperfecta; homocystinuria; Ehlers-Danlos; syndrome; Marfan; syndrome; glycogen storage diseases; Gaucher’s disease; hypophosphatasia; porphyria; hemochromatosis
Rheumatoid arthritis; inflammatory bowel; disease; COPD; organ transplantation; immobilization; muscular dystrophy; multiple sclerosis; multiple myeloma; some cancers (leukemia and lymphomas); ESRD; mastocytosis; thalassemia; sickle cell disease; HIV
Reproduced with permission from [5]. Adapted with permission from [6]. COPD¼ chronic obstructive pulmonary disease ESRD¼ end-stage renal disease.
Vitamin D deficiency is common and supplementation is essential for the maintenance of bone and muscle strength. A recent pooled analysis of 11 double-blind, randomized, controlled trials of oral vitamin D supplementation in persons 65 years of age or older revealed that high-dose vitamin D supplementation [800 international units (IU) daily] was somewhat favorable in the prevention of hip fracture and any nonvertebral fracture [15 ]. Vitamin D replacement has also been shown to improve muscle strength, reduce body sway, and decrease fall risk in older individuals [16 ]. Vitamin D status is assessed by measurement of its major circulating metabolite, 25-OH D, with the minimum desirable 30 ng/mL [17,18 ]. Many patients require supplements of vitamin D, 2000 IU daily or more, to achieve this level. Vitamin D2 appears to be as effective as vitamin D3 in maintaining circulating concentrations of 25-OH D when given daily, but perhaps D2 is not as potent as D3 if given weekly or monthly [19,20 ]. &
&&
&&
&
Fall prevention Poor vision, poor hearing, poor balance and muscle weakness are critical determinants of fall risk and are significant independent predictors of the risk of hip fracture in elderly women [3 ]. The combined assessment of neuromuscular and visual impairment with BMD measurements improves the prediction of hip fractures [21]. Effective fall prevention interventions include home safety evaluation for high-risk or visually impaired patients, withdrawal of psychoactive medications, cataract surgery, exercise interventions that improve muscle strength and include balance training (such as Tai Chi), and vitamin D repletion in those with low vitamin D levels [22 ,23]. Using proper footwear and avoiding stairs if possible are also important measures in reducing fall risk. &
&
Pharmacologic management Based on the NOF guidelines (http://www.nof.org/ files/nof/public/content/resource/913/files/580.pdf. Accessed August 1, 2013), healthcare providers should consider treating postmenopausal women based on the following: T-score 2.5 or less at the lumbar spine, femoral neck, total hip, or one-third distal radius (after appropriate evaluation for potential contributing factors); a hip or vertebral (clinical or morphometric) fracture; low bone mass (T-score between 1.0 and 2.5); and a 10-year probability of a hip fracture 3% or more or a 10-year probability of a major osteoporosis-related fracture 20% or more based on the US-adapted WHO algorithm (i.e. using the FRAX Web-based tool) [3 ], although clinician’s judgment and/or patient preferences may indicate treatment for people with 10-year fracture probabilities below these levels. Clinical risk factors for fracture included in the WHO Fracture Risk Assessment Model (FRAX) are as follows: &
(1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11)
Current age; Sex; Low BMI (Kg/m2) A prior osteoporotic fracture (including morphometric vertebral fracture); Parental history of hip fracture; Oral glucocorticoids 5 mg/d or more of prednisone for 3 months or more (ever); Current smoking; Alcohol intake (3 or more drinks per day); Rheumatoid arthritis; Secondary osteoporosis; and Femoral neck BMD.
The current US Food and Drug Administration (FDA)-approved indications for bone-active agents in postmenopausal women are shown in Table 3. The efficacy of these agents has been established in a
1752-296X ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-endocrinology.com
503
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Parathyroids, bone and mineral metabolism Table 3. FDA-approved indications for bone-active agents for postmenopausal women Postmenopausal osteoporosis Drug
Prevention
Treatment
Estrogen Calcitonin (Miacalcin, Fortical) Raloxifene (Evista) Ibandronate (Boniva) Alendronate (Fosamax) Risedronate (Actonel) Risedronate (Atelvia) Zoledronate (Reclast) Denosumab (Prolia) Teriparatide (Forteo) &
Reproduced with permission from [3 ]. FDA, Food and Drug Administration.
popular choice for treatment of osteoporosis because of its relatively weak antifracture efficacy compared with other bone-active agents.
Raloxifene Raloxifene is a compound that can bind to estrogen receptors and cause estrogenic or antiestrogenic responses in different tissues. It is the only estrogen agonist/antagonist that is currently FDA-approved for the prevention and treatment of postmenopausal osteoporosis. In the Multiple Outcomes of Raloxifene Evaluation trial [26], the risk of vertebral fracture was reduced in both study groups receiving raloxifene [30% relative risk reduction or (RRR) for 60-mg/d group; 50% RRR for 120-mg/d group]. A recent retrospective cohort study showed that patients treated with alendronate and raloxifene had similar adjusted fracture rates in up to 8 years of adherent treatment [27 ]. Raloxifene also appears to lower the risk of breast cancer, although women receiving raloxifene had an increased risk of thromboembolism. A recent study showed that raloxifene, but not bisphosphonates, significantly suppressed circulating sclerostin concentration, an inhibitor of bone formation, suggesting that sclerostin may in part mediate the action of estrogen on bone metabolism [28 ]. &
number of large randomized pivotal clinical trials with fracture end-points and the current evidence for fracture reduction is shown in Table 4. Therapy needs to be individualized based on risk/benefit assessments, taking into account the presence of co-morbid medical conditions that are prevalent in older patients [3 ,24]. &
&
Calcitonin Calcitonin inhibits bone resorption by acting directly on osteoclasts. The efficacy of this agent was established in the Prevent Recurrence of Osteoporotic Fractures study in postmenopausal women with osteoporosis, which showed that 200 IU salmon calcitonin nasal spray per day decreased the risk of new vertebral fractures by 33–36% at the end of 5 years [25]. However, the discontinuation rate at the end of the study was high (59%). This is currently considered a less
Bisphosphonates Bisphosphonates reduce osteoclastic bone resorption by entering the osteoclast, causing loss of resorptive function and accelerating osteoclast apoptosis [29 ]. Alendronate was the first bisphosphonate approved by the FDA in 1995 for the treatment of osteoporosis, followed by risedronate in 2000, zoledronic acid in 2001, and ibandronate in 2005, and zoledronic acid in 2007. Approval of bisphosphonates in the USA was based on studies of 3–4 years’ duration, although &
Table 4. Evidence for fracture reduction for FDA-approved bone-active agents Drug
Vertebral fracture
Nonvertebral fracture
Hip fracture
Calcitonin (Miacalcin, Fortical)
No effect demonstrated
No effect demonstrated
Raloxifene (Evista)
No effect demonstrated
No effect demonstrated
Ibandronate (Boniva)
No effect demonstrated
No effect demonstrated
Alendronate (Fosamax)
a a
Risedronate (Actonel, Atelvia) Zoledronic acid (Reclast) Denosumab (Prolia) Teriparatide (Forteo)
No effect demonstrated &
Reproduced with permission from [3 ]. FDA, Food and Drug Administration. a Evidence for effect but not an FDA-approved indication.
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Postmenopausal osteoporosis Diab and Watts
some of these studies have been extended, with zoledronic acid, risedronate, and alendronate suggesting efficacy for up to 6, 7, and 10 years, respectively [30 ,31–33]. The extension of the alendronate Fracture Intervention Trial [Fracture Intervention Long-term eXtension or (FLEX)] enrolled subjects who had approximately 5 years of alendronate treatment in the Fracture Intervention Trial into a second 5-year study in which subjects were randomized to either continue alendronate or start placebo. At the end of the FLEX study, there were fewer clinical vertebral fractures in the long-term treated group that met statistical difference from the placebo group [2 vs. 5%, relative risk or (RR) 0.45, P ¼ 0.013] [32]. A posthoc analysis of the FLEX data indicated that nonvertebral fracture risk reduction was also observed in the subset of patients without prior vertebral compression fractures but only in those with T-scores entering FLEX of 2.5 or lower at the femoral neck hip [33]. In the 3-year extension of the zoledronate Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (PFT), subjects who received three doses of zoledronate in the placebo-controlled were assigned at random to one of two arms: a continuation group that received 6 years of zoledronic acid administration and a discontinuation group that received the initial 3 years of zoledronic acid then went to placebo [30 ]. At the end of 6 years, there were significantly fewer morphometric vertebral fractures in the group that continued treatment compared with the placebo group [14 vs. 30, odds ratio (OR) 0.51, 95% CI 0.26–0.95, P ¼ 0.035)], suggesting that patients at high fracture risk may benefit by continued treatment. In terms of long-term safety, concerns about two uncommon but possible time-related adverse events have emerged: osteonecrosis of the jaw (ONJ) and atypical femur fractures (AFFs). ONJ is defined as exposed necrotic bone in the maxillofacial region, not healing after 8 weeks in patients with no history of craniofacial radiation. It appears as areas of exposed yellow or white hard bone with smooth or ragged borders and can be associated with pain, swelling, paresthesias, suppuration, soft tissue ulceration, intra or extra-oral sinus tracks, and loosening of teeth. This can occur spontaneously, but is generally associated with invasive dental procedures such as tooth extraction. ONJ has been described in patients receiving chronic bisphosphonate therapy for treatment of osteoporosis but appears to be much more common in cancer patients receiving bisphosphonates in 10–12 times higher doses than those used to treat osteoporosis [34]. &&
&&
AFFs are thought to be stress fractures, which are frequently bilateral, are typically associated with minimal or no trauma, and are present with prodromal pain in the region of the fracture [35 ,36 ]. These fractures had been described in patients who have not received any treatment for osteoporosis. A recent case–control study found that longer use of bisphosphonates (5–9 years) was associated with a greater risk of atypical fractures (OR 117, 95% CI 34–402) compared with shorter use (
