Addressing the Global Burden of Osteoporosis

Osteoporosis is a metabolic disease characterized by low bone mass and deterioration of bone tissue microarchitecture, leading to reduced mineral resistance and an increased risk of low-energy or fragility fractures.

Worldwide, osteoporosis affects an estimated 200 million women, and 1 in 3 women over 50 will experience fractures related to the disease, as will 1 in 5 men over 50. The most common related fractures are those of the vertebrae (spine), proximal femur (hip), and distal forearm (wrist).

Osteoporosis has many etiologies; The most common cause is bone loss related to estrogen deficiency, such as that which occurs after menopause. This article focuses primarily on postmenopausal osteoporosis and newer drug therapies, although the therapeutic interventions discussed here may also be included for male osteoporosis.

The goal is to provide guidance on appropriate screening, identification of secondary causes, and correct treatment of osteoporosis in postmenopausal women.

The skeletal system provides structural support for the body and storage of two essential minerals, calcium and phosphorus.

Individual bone mass reaches a peak between ages 25 and 30 and begins to decline around age 40.

The skeleton consists of a mineralized matrix with a highly active cellular fraction that includes osteocytes, osteoblasts and osteoclasts . Osteoblasts and osteoclasts play a critical role in bone remodeling, a dynamic process during which old bone is removed and new bone is added to the skeleton.

Osteocytes are believed to be the main cell that regulates remodeling. This process is affected by systemic hormones, including parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, calcitonin, growth hormone, glucocorticoids. , gonadal hormones, thyroid hormones and cytokines. Additionally, changes in mechanical force activate bone remodeling to improve skeletal strength and repair bone that has suffered microdamage.

The bone remodeling cycle is uncoupled with menopause and advancing age, resulting in more bone resorption than bone formation.

With the decrease in estrogen levels during menopause, the rate of bone remodeling increases 2 to 4 times. Increased bone resorption leads to a phase of accelerated bone loss and efflux of skeletal-derived calcium into the extracellular fluid. These changes lead to a negative total body calcium balance, further exacerbating skeletal losses.

Many other hormonal and systemic disorders can lead to accelerated bone loss regardless of age and estrogen status. These secondary causes of osteoporosis include vitamin D deficiency, hyperparathyroidism, hypercortisolism, hyperthyroidism, anorexia nervosa, rheumatoid arthritis, gastrointestinal diseases (e.g., celiac disease), plasma cell dyscrasias (e.g., multiple myeloma), chronic kidney disease and drugs (e.g., steroids). Excessive alcohol consumption and hypogonadism are secondary causes of bone loss in men.

> Osteoporosis detection

The decision to perform a bone density assessment should be based on the patient’s fracture risk profile and assessment of skeletal health. Regardless of clinical risk factors, women aged 65 years and older and men aged 70 years and older should undergo bone mineral density (BMD) testing.

Bone density assessment should be considered in younger postmenopausal women, women transitioning to menopause, and men aged 50 to 69 years with clinical risk factors for fracture. Additionally, people who have a fracture at age 50 or older and those with conditions that predispose to low bone mass or bone loss (rheumatoid arthritis) or who take medications (chronic glucocorticoids) should be considered for evaluation of fracture. Bone density.

> Measurement of bone mineral density

Measurement of the hip (femoral neck and total hip) and spine using dual-energy x-ray absorptiometry (DXA) is the preferred method for diagnosing osteoporosis, predicting future fracture risk, and monitoring patients. DXA measures bone mineral content (BMC) in grams and bone area (BOA) in square centimeters. The T score, a value used to diagnose osteoporosis, is calculated by subtracting the mean BMD of a reference population of young adults from the patient’s BMD and dividing it by the standard deviation (SD) of the young adult population.

BMD diagnoses of normal bone mass, osteopenia, and osteoporosis are based on the World Health Organization (WHO) diagnostic classification. In premenopausal women, the diagnosis of osteoporosis should not be made solely based on densitometric criteria. Of note, even if BMD is in the normal range, osteoporosis can be diagnosed based on the presence of a previous fragility fracture.

> Additional technologies to measure bone mass

Peripheral dual-energy X-ray absorptiometry, CT-based absorptiometry, quantitative computed tomography (QCT), peripheral QCT, and quantitative ultrasonographic densitometry can predict overall and site-specific fracture risk.

> Fracture risk assessment

All postmenopausal women and men aged 50 years and older should be evaluated for osteoporosis risk to determine the need for BMD testing.

Validated risk factors independent of BMD include older age, previous fracture, long-term glucocorticoid therapy, low body weight, family history of hip fracture, smoking, and excessive alcohol consumption.

> Initial evaluation

The initial evaluation for osteoporosis includes a detailed history to assess clinical risk factors for fracture and secondary causes of bone loss, a complete physical examination, and laboratory tests to assess general health and, specifically, mineral metabolism.

The medical history should focus on fracture risk factors (e.g., previous fractures, family history of osteoporosis or hip fracture, recent falls), height loss, medications associated with bone loss, smoking, alcohol use, and kidney stones.

Physical examination may reveal skeletal deformities due to unrecognized fractures (e.g., kyphosis or decreased rib-pelvis space) or identify possible secondary causes of skeletal fragility (e.g., blue sclera with osteogenesis imperfecta or bone tenderness with osteomalacia). .

• Initial laboratory evaluation includes serum creatinine, calcium, phosphorus, magnesium, 25-hydroxyvitamin D, and liver function tests.
   
• If clinically indicated, a complete blood count, PTH, thyroid-stimulating hormone, serum protein electrophoresis, and 24-hour urine calcium and cortisol should be measured.
   
• Increasingly used in the treatment of osteoporosis, markers of bone turnover can provide prognostic information about fracture risk and complement bone density measurements.
   
• Bone-specific alkaline phosphatase, osteocalcin (OC), and procollagen type I N-terminal propeptide (PINP) are specific markers of bone formation.

> Nutrition

Optimal bone health requires a combination of mechanical loading and adequate macronutrient and micronutrient intake.

The most important nutrients are calcium, vitamin D and protein . Calcium is important for the formation phase of bone remodeling.

Vitamin D generated from sunlight, food or supplements is converted in the liver to 25-hydroxy vitamin D which serves as a substrate for 1,25-dihydroxyvitamin D, a key regulator of active intestinal absorption of vitamin D. calcium. Optimal intake amounts for calcium and vitamin D remain controversial, but in general, 1,200 mg of calcium and 800 IU of vitamin D per day are recommended for most postmenopausal women and for men over 70 years of age.

Data on the effect of protein intake on bone density are conflicting. Some studies suggest that higher protein intake is associated with a lower risk of hip fractures and bone loss, while others indicate greater bone resorption and calcium excretion with high protein intake.

> Exercise

Although the beneficial effect of physical activity on bone density is small, it is associated with a lower risk of hip fractures in older women and a lower risk of falls by improving muscle strength, balance and mobility. People with osteoporosis (or seeking to prevent it) should exercise for at least 30 minutes 3 times a week.

> Fall Prevention

Since most osteoporosis-related fractures are due to falls, risk factors must be addressed. These include a personal history of falls, muscle weakness, gait instability, medications (e.g., narcotic pain relievers, anticonvulsants, benzodiazepines, and antidepressants), household hazards, and visual impairments.

> Approved Therapies

The pharmacological arsenal for the treatment of osteoporosis includes drugs that inhibit bone resorption: bisphosphonates, estrogens, selective estrogen receptor modulators (SERM), denosumab and calcitonin; and anabolic agents that stimulate new bone formation: teriparatide, abaloparatide, and romosozumab.

> Bisphosphonates

Bisphosphonates are the cornerstone of osteoporosis treatment and are chemically stable derivatives of inorganic pyrophosphate. With their high affinity for calcium crystals, these drugs selectively concentrate in the bone, decreasing bone resorption.

Bisphosphonates are preferentially incorporated into sites of active bone remodeling and inhibit bone resorption by rapidly inhibiting osteoclast activity. Those of the first generation that do not contain nitrogen (etidronate, clodronate and tiludronate) are now used infrequently due to their low potency and increased risk of osteomalacia.

Second- and third-generation bisphosphonates (alendronate, risedronate, ibadronate, pamidronate, and zoledronic acid) contain nitrogen and act primarily by inhibiting the enzyme farnesyl pyrophosphate (FPP) synthase in the mevalonate pathway (cholesterol biosynthetic pathway).

The most common adverse effects of bisphosphonates include gastrointestinal problems such as esophagitis and esophageal ulcers with oral preparations and myalgia and arthralgia with oral and intravenous bisphosphonates.

> Hormonal therapy for menopause: estrogen

The use of estrogen therapy is suggested in women younger than 60 years or less than 10 years post-menopause, who have vasomotor or climacteric symptoms associated with menopause, and those for whom bisphosphonates or denosumab are not appropriate. However, given the potential risks (e.g., myocardial infarction, stroke, invasive breast cancer, pulmonary embolism, and deep vein thrombophlebitis) associated with hormone therapy, especially when combined with a progestin, treatments should first be considered. without estrogen for the therapeutics and prevention of osteoporosis.

> Selective estrogen receptor modulators: raloxifene and bazedoxifene

MSREs bind with high affinity to the estrogen receptor and have agonist and antagonist properties depending on the target organ. Raloxifene (60 mg once daily) has estrogenic activity in bones, which prevents bone loss, improves BMD, and reduces the risk of fractures.

Bazedoxifene is only approved in the United States and Canada in combination with conjugated estrogens for the treatment of hot flashes or the prevention of osteoporosis in patients for whom other treatments are not appropriate.

> Denosumab

Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor kappa B ligand (RANKL). It reduces osteoclastogenesis, induces osteoclast apoptosis, decreases bone resorption, increases BMD and reduces the risk of fractures. Denosumab may be offered as an alternative initial treatment to postmenopausal women with osteoporosis at high risk of fractures.

> Calcitonin

Salmon calcitonin (intranasal or injectable) is approved to treat osteoporosis in women who are at least 5 years postmenopause. Studies show that calcitonin reduces the risk of vertebral but not non-vertebral fractures.

> Parathyroid hormone and related protein analogues: teriparatide and abaloparatide

Anabolic agents increase BMD by increasing bone formation when administered intermittently. There are now two approved peptides that are anabolic to bone: PTH (1–34) (teriparatide) and a PTH-related protein analog (abaloparatide).

Switching to an anabolic agent may be considered when a patient taking bisphosphonates continues to lose bone mass or suffers a fracture. Because the benefits of anabolic therapy are lost rapidly after discontinuation, most clinical guidelines recommend a course of teriparatide or abaloparatide followed by a bisphosphonate, raloxifene, denosumab, or menopausal hormone therapy.

Adverse effects of teriparatide include dizziness, leg pain, and cramps. Side effects of abaloparatide include nausea, postural hypotension, headache, and palpitations. Both agents can cause hypercalciuria and increase serum calcium, but persistent hypercalcemia is rare.

> Romosozumab

It is the newest anabolic agent approved for the treatment of osteoporosis and increases bone formation by reducing bone resorption.

The medication is administered as a monthly subcutaneous injection of 210 mg for 12 months. It should be considered a first-line therapy in patients with severe osteoporosis and multiple vertebral fractures or hip fracture. It can also be used in people in whom antiresorptive treatments have failed.

Romosozumab should not be offered to people at high risk of cardiovascular disease or stroke or those with a previous myocardial infarction or stroke in the past year. Additional adverse events observed included a small number of osteonecrosis of the jaw, atypical femoral fracture and injection site reactions.

Romosozumab should be followed by an antiresorptive agent to maintain BMD gains and prevent accelerated bone loss after completing the treatment course.

In addition to recommending adequate calcium and vitamin D intake, strength and weight-bearing exercise, smoking cessation, and limited alcohol consumption, drug therapy should be selected based on cost, safety profile, and effectiveness.

For patients with hip osteoporosis, drugs with proven efficacy at this site should be used, so ibadronate, raloxifene, and calcitonin should not be considered in this scenario. Due to their lower cost and greater clinical experience, bisphosphonates are often used as a first-line treatment for osteoporosis.

> Combination therapy

Combination therapy, usually a bisphosphonate with a non-bisphosphonate, is not recommended. May provide additional small increases in BMD compared to monotherapy; however, the effect on fracture rates is unknown. The additional cost and potential side effects, such as excessive suppression of bone turnover, must be considered against the potential benefits.

>  Monitoring response to treatment

Several studies have shown poor adherence to osteoporosis medications. One year after starting treatment, around 45% of patients do not request prescriptions again. Therefore, it is important to confirm whether patients are taking their medications and encourage adherence.

Sharing bone density results with patients modestly increases adherence to therapy. Various approaches have also been suggested to improve adherence, such as counseling programs and health care system interventions.

Repeat BMD assessment is recommended every 2 years, but it is recognized that more frequent testing may be warranted in certain clinical situations. A stable or increasing BMD is an acceptable response to therapy. Generally, a BMD loss greater than the least significant change (typically 5% at the lumbar spine, 4% at the total hip, and 5% at the femoral neck) over 2 years and a smaller than expected reduction in turnover markers bone loss in antiresorptive drugs is considered “failure” of therapy.

Osteoporosis is a global public health problem that is underdiagnosed and undertreated. Fragility fractures of the spine and hip can lead to chronic pain, depression, disability and death. Central DXA measurements are the gold standard for BMD assessment.

Secondary causes and risk factors for bone loss should be identified and treated. Pharmacological agents should be recommended along with a well-balanced diet, exercise, smoking cessation, and fall prevention in all patients at high risk of fracture.