osteoporosis

Dr. Nizar Abdulateef Assistant Professor & Consultant Rheumatologist

DISEASES OF BONEOSTEOPOROSIS

OSTEOPOROSIS

Definition
“Porous bones.” It is a condition where the skeleton becomes fragile and results in broken bones under normal use. “Silent” condition that happens slowly over years. The rate of bone loss (“resorption”) exceeds the rate of new bone formation (“acretion”).


WHO defined osteoporosis as: A disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk.


The prevalence of osteoporosis increases with age. In the USA, the estimated prevalence of osteopenia is 15 million in women and 3 million in men. The estimated prevalence of osteoporosis is 8 million in women and 2 million in men. Fractures related to osteoporosis affect 30% of women and 12% of men at some point in developed countries.

In UK, fractures are sustained by over 250 000 individuals annually. Most common sites for osteoporotic fractures are the forearm, spine, and hip. Hip fractures are associated with immediate mortality of 12% & continued mortality of 20%.

Pathogenesis

The underlying mechanism in all cases of osteoporosis is an imbalance between bone resorption and bone formation. In normal bone, there is constant matrix remodeling of bone; up to 10% of all bone mass undergoing remodeling at any point in time. Bone is resorbed by osteoclast cells (which derive from the bone marrow), after which new bone is deposited by osteoblast cells.


The 3 main mechanisms by which osteoporosis develops: Inadequate peak bone mass (the skeleton develops insufficient mass and strength during growth) Excessive bone resorption Inadequate formation of new bone during remodeling An interplay of these mechanisms underlies the development of fragile bone tissue.

Hormonal factors strongly determine the rate of bone resorption. Lack of estrogen (e.g. as a result of menopause) increases bone resorption as well as decreasing the deposition of new bone that normally takes place in weight-bearing bones. The α-form of the estrogen receptor appears to be the most important in regulating bone turnover.

In addition to estrogen, calcium metabolism plays a significant role in bone turnover. Deficiency of calcium and vitamin D leads to impaired bone deposition. In addition, the parathyroid glands react to low calcium levels by secreting parathyroid hormone (PTH), which increases bone resorption to ensure sufficient calcium in the blood.


The activation of osteoclasts is regulated by various molecular signals. RANKL (receptor activator for nuclear factor κB ligand) is one of best studied. This molecule is produced by osteoblasts and other cells (e.g. lymphocytes), and stimulates RANK (receptor activator of nuclear factor κB).Osteoprotegerin (OPG) binds RANKL before it has an opportunity to bind to RANK, and suppresses its ability to increase bone resorption. RANKL, RANK and OPG are closely related to tumor necrosis factor and its receptors.

Common osteoporotic fracture sites, the wrist, the hip and the spine, have a high trabecular bone to cortical bone ratio. These areas rely on trabecular bone for strength, and therefore the intense remodeling causes these areas to degenerate most when the remodeling is imbalanced. Around the ages of 30-35, cancellous or trabecular bone loss begins. Women may lose as much as 50%, while men lose about 30%.

Classification of Osteoporosis

Primary osteoporosis in the elderly can be classified as:• Type I (menopausal) osteoporosis: in persons aged 51-75, is 6X more common in women, and is associated with vertebral and Colles' (distal radius) fractures. • Type II (senescent) osteoporosis: in persons > 60, is 2X more common in women, and is associated with vertebral and hip fractures. Primary osteoporosis is result from decreasing levels of sex hormones that occur with age.Secondary osteoporosis may be due to many causes.

Risk factors for osteoporosis

Diseases & disorders associated with osteoporosis: Hypogonadal states (Turner syndrome, Klinefelter syndrome, anorexia nervosa, hyperprolactinemia) Endocrine disorders (Cushing's syndrome, hyperparathyroidism, thyrotoxicosis, DM, acromegaly and adrenal insufficiency) Pregnancy & lactation (reversible bone loss) Malnutrition & malabsorption. coeliac disease, Crohn's disease, lactose intolerance, surgery (after gastrectomy, intestinal bypass surgery or bowel resection) and severe liver disease (especially PBC)

Rheumatologic disorders (RA, AS, SLE & JIA) Renal insufficiency can lead to osteodystrophy. Hematologic disorders (multiple myeloma, lymphoma & leukemia, hemophilia, sickle-cell disease & thalassemia). Several inherited disorders (osteogenesis imperfecta, Marfan syndrome, hemochromatosis, glycogen storage diseases, homocystinuria & Gaucher's disease). Certain medications have been associated with an increase in osteoporosis.


Corticosteroid-induced osteoporosis
The risk increases when the dose of prednisolone exceeds 7.5 mg daily & is continued for > 3 months. Pathogenesis: Reduced bone formation due to direct inhibitory effect on osteoblast function Steroid-induced osteoblast & osteocyte apoptosis. Corticosteroids inhibit intestinal calcium absorption & cause renal leak of calcium, & this tends to reduce serum calcium leading to secondary hyperparathyroidism with increased osteoclastic bone resorption. Hypogonadism may occur with high-dose steroids.

Other medications: Barbiturates, phenytoin L-Thyroxine over-replacement Several drugs induce hypogonadism, for example aromatase inhibitors used in breast cancer Anticoagulants (long-term use of heparin and warfarin)

Osteoporosis in men

Osteoporosis is less common in men. Secondary cause can be identified in 50% of patients. Most common causes are hypogonadism, corticosteroid use and alcoholism. Testosterone deficiency results in an increase in bone turnover and uncoupling of bone resorption from bone formation.

Clinical features of osteoporosis

Progressive breaks in a person’s back causes a person to lose height. Spinal compression causes a gradual decrease in height due to forward bending of the upper spine (increased kyphosis). Loss of height can also result in a prominent abdomen even with no increase in weight.

Diagnosis of osteoporosis

The diagnosis of osteoporosis can be made by measuring the bone mineral density (BMD). The most popular method of measuring BMD is dual energy x-ray absorptiometry (DXA). Investigations to detect underlying causes (bone metastasis, multiple myeloma, Cushing's disease, etc.)

Conventional radiography For detecting complications of osteopenia, such as fractures For differential diagnosis of osteopenia For follow-up examinations in specific clinical settings (soft tissue calcifications, secondary hyperparathyroidism, or osteomalacia in renal osteodystrophy)

Radiography is relatively insensitive to detection of early disease & requires a substantial amount of bone loss (about 30%) to be apparent on x-ray images. The main radiographic features of generalized osteoporosis are cortical thinning and increased radioleucency. Frequent complications of osteoporosis are vertebral fractures for which spinal radiography can help considerably in diagnosis and follow-up.

Dual energy X-ray absorptiometry (DXA)It is considered the gold standard for the diagnosis of osteoporosis. Osteoporosis is diagnosed when the BMD is less than or equal to 2.5 SDs below that of a young adult reference population. This is translated as a T-score. WHO has established the following diagnostic guidelines: T-score -1.0 or greater is "normal“T-score between -1.0 and -2.5 is "low bone mass" (or "osteopenia")T-score -2.5 or above is osteoporosis


When there has been an osteoporotic fracture ("low-trauma fracture" or "fragility fracture"), defined as one that occurs as a result of a fall from a standing height, the term “severe osteoporosis” is used.For osteoporosis in men < 50 years of age and pre-menopausal women, Z-scores (comparison with age group rather than peak bone mass) rather than T-scores should be used.


Chemical biomarkers Useful tool in detecting bone degradation. The enzyme cathepsin K breaks down type-I collagen protein, an important constituent in bones. Prepared antibodies can recognize the resulting fragment, called a neoepitope, as a way to diagnose osteoporosis. Increased urinary excretion of C-telopeptides, a type-I collagen breakdown product, also serves as a biomarker for osteoporosis.

Other measuring tools Quantitative computed tomography differs from DXA in that it gives separate estimates of BMD for trabecular and cortical bone and reports precise volumetric mineral density in mg/cm3. Quantitative ultrasound has many advantages in assessing osteoporosis. The modality is small, no ionizing radiation is involved, measurements can be made quickly and easily, and the cost of the device is low compared with DXA and QCT devices. The calcaneus is the most common skeletal site for quantitative ultrasound assessment.

 Prevention of osteoporosis

Methods to prevent osteoporosis include changes of lifestyle. However, there are medications that can be used for prevention as well. As a different concept there are osteoporosis ortheses which help to prevent spine fractures and support the building up of muscles. Fall prevention can help prevent osteoporosis complications.

Lifestyle Smoking cessation and moderation of alcohol intake are commonly recommended in the prevention of osteoporosis. Achieving a higher peak bone mass through exercise and proper nutrition during adolescence is important for the prevention of osteoporosis. Jogging, walking, or stair climbing at 70-90% of maximum effort 3 times per week, along with 1,500 mg of calcium per day, increased bone density of the lumbar spine by 5% over nine months.

Nutrition Proper nutrition includes a diet sufficient in calcium and vitamin D. People at risk for osteoporosis (e.g. steroid use) are treated with vitamin D & calcium supplements & often with bisphosphonates. Vitamin D supplementation alone does not prevent fractures, & needs to be combined with calcium. Calcium supplements come in 2 forms: calcium carbonate and calcium citrate. Due to its lower cost, calcium carbonate is often the first choice, however it needs to be taken with food to maximize absorption. Calcium citrate is more expensive, but it is better absorbed. In addition, patients who are taking proton pump inhibitors or H2 blockers do not absorb calcium carbonate well; calcium citrate is the supplement of choice in this population.

In renal disease, more active forms of Vitamin D such as cholecalciferol or (1,25-dihydroxycholecalciferol or calcitriol which is the main biologically active form of vitamin D) is used, as the kidney cannot adequately generate calcitriol from calcidiol (25-hydroxycholecalciferol) which is the storage form of vitamin D.


Medication Bisphosphonate can be used in cases of very high risk. Other medicines prescribed for prevention of osteoporosis include raloxifene, a selective estrogen receptor modulator (SERM). Estrogen replacement therapy remains a good treatment for prevention of osteoporosis but, at this time, is not recommended unless there are other indications for its use as well. There is uncertainty and controversy about whether estrogen should be recommended in women in the first decade after the menopause. In hypogonadal men testosterone has been shown to give improvement in bone quantity and quality, but there are no studies of the effects on fractures or in men with a normal testosterone level.

Treatment of osteoporosis

There are several medications used to treat osteoporosis, depending on gender. Medications themselves can be classified as antiresorptive or bone anabolic agents. A major problem is gaining long-term adherence to therapy from patients with osteoporosis. Fifty percent of patients do not take their medications and most discontinue within 1 year.


Antiresorptive agents Bisphosphonates They are the main pharmacological measures for treatment. In confirmed osteoporosis, bisphosphonate drugs are the first-line treatment in women. The most often prescribed are sodium alendronate 10 mg a day or 70 mg once a week, risedronate 5 mg a day or 35 mg once a week and/or ibandronate once a month.

In patients who had suffered a low-impact hip fracture, annual infusion of 5 mg zoledronic acid reduced risk of any fracture by 35%, vertebral fracture risk from 3.8% to 1.7% and non-vertebral fracture risk from 10.7% to 7.6%. Oral bisphosphonates are relatively poorly absorbed, and must therefore be taken on an empty stomach, with no food or drink to follow for the next 30 minutes. They are associated with inflammation of the esophagus (esophagitis) and are therefore sometimes poorly tolerated.

Bone anabolic agentsTeriparatideTeriparatide (recombinant parathyroid hormone residues 1–34) has been shown to be effective in osteoporosis. It acts like PTH & stimulates osteoblasts, thus increasing their activity. It is used mostly for patients with established osteoporosis (who have already fractured), have particularly low BMD or several risk factors for fracture or cannot tolerate the oral bisphosphonates. It is given as a daily injection. Patients with previous radiation therapy, or Paget's disease, or young patients, should avoid this medication.

Other agents Strontium ranelate An alternative oral treatment. It has proven efficacy, especially in the prevention of vertebral fracture. Strontium ranelate was noted to stimulate the proliferation of osteoblasts, as well as inhibiting the proliferation of osteoclasts. Strontium ranelate is taken as a 2 g oral suspension daily, and is licenced for the treatment of osteoporosis to prevent vertebral and hip fracture.

Strontium ranelate has side effect benefits over the bisphosphonates, as it does not cause any form of upper GI side effect, which is the most common cause for medication withdrawal in osteoporosis. In studies a small increase in the risk of venous thromboembolism was noted. Strontium must not be taken with food or calcium-containing preparations as calcium competes with strontium during uptake. However, it is essential that calcium, magnesium, and vitamin D in therapeutic amounts must be taken daily, but not at the same time as strontium. Strontium should be taken on an empty stomach at night.

RANKL inhibitors Denosumab is a fully human monoclonal antibody that mimics the activity of osteoprotegerin. It binds to RANKL, thereby preventing RANKL from interacting with RANK and reducing its bone resorption. It was approved for use in the treatment of osteoporosis in 2010.

Nutrition Calcium Calcium is required to support bone growth, bone healing and maintain bone strength and is one aspect of treatment for osteoporosis. Recommendations for calcium intake is 1,200 mg per day. Calcium supplements can be used to increase dietary intake, and absorption is optimized through taking in several small (500 mg or less) doses throughout the day.

Quiz

Q1. Osteoporosis is a “silent” condition that happens slowly over years. TrueFalse

Q2. The prevalence of osteoporosis increases with age. True False

Q3. Modifiable risk factor (s) for osteoporosis include (s): Vitamin D deficiency Tobacco smoking Excess alcohol Malnutrition All of the above


Q4. Pathogenesis of CIO include (s): Reduced bone formation due to direct inhibitory effect on osteoblast function. Steroid-induced osteoblast & osteocyte apoptosis. Corticosteroids inhibit intestinal calcium absorption. All of the above

Q5. Antiresorptive agents used in treatment of osteoporosis include all of the following except: Bisphosphonates Raloxifene Calcitonin PTH Strontium ranelate