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Osteoporosis is the most common metabolic bone disease worldwide, and the associated fractures take an enormous toll on patients' lives as well as the healthcare system overall.

Despite significant advances in diagnostic technologies and treatments, a disturbing gap persists in patient care. "At-risk patients are often not screened to determine factors contributing to osteoporosis, and patients are not educated about fracture prevention," said Meryl Susan LeBoff, MD, director of the Skeletal Health and Osteoporosis Center and the Bone Density Unit at Brigham and Women's Hospital and Harvard Medical School in Boston.

"Most concerning, the majority of highest-risk women and men who have a fracture are not diagnosed and do not receive effective, FDA-approved therapies. And even those prescribed appropriate therapy are unlikely to take the medication as prescribed," she added.

In 2022, LeBoff and colleagues, on behalf of the Bone Health and Osteoporosis Foundation, published a consensus statement/ on prevention and treatment of osteoporosis.

Other practice guidelines for diagnosing and treating postmenopausal patients have been issued by the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE).

The North American Menopause Society also offers on managing osteoporosis in postmenopausal women.

Screening

Screening for osteoporosis should begin at age 65 for women, age 70 for men, and sooner in the presence of risk factors. Low-radiation axial dual-energy x-ray absorptiometry (DXA), the principal tool for assessing skeletal health, measures areal bone density -- the amount of bone mineral divided by the area of the bone scanned.

The results are reported as T-scores or Z-scores which are expressed in standard deviation (SD) units. Both scores are based on comparisons with values of people of the same sex and race/ethnicity and in the same country. The T-score compares a patient's bone density with the average value of a healthy young person, so a T-score of +1 represents a value of 1 SD above the young normal mean, whereas a value of 2.5 SDs below the young normal mean would equate to a T-score of −2.5.

The Z-score compares a patient's bone density with the average value of other people of the same age.

T-scores are used to define osteoporosis/osteopenia by bone density measurement. T-scores for normal, osteopenia -- i.e., decrease in bone mineral density below normal but not low enough to be considered osteoporotic -- and osteoporosis are indicated as follows:

• Normal bone density: –1 to +1

• Osteopenia: –1 to –2.5

• Osteoporosis: –2.5 or lower is categorized as osteoporosis

Each 1-point drop below 0 doubles the risk for fracture. "Maintain the diagnosis even if a subsequent T-score is above −2.5 in a patient diagnosed by adulthood fracture or previous T-score of –2.5," advised LeBoff, who is also director of the Bone Density Unit at Brigham and Women's. This means that the diagnosis of osteoporosis can be made in two different ways: (1) based on bone density assessment with T-score -2.5 or lower; or (2) based on the combination of osteopenia and the presence of a fracture.

The Z-score is used in patients younger than age 50 (and thus has limited value in postmenopausal women), and evaluates the number of standard deviations above or below the average bone density for the average person of the same age. The normal range for Z-score is –2.0 to +2.0.

Computed tomography (CT) imaging performed for other medical reasons has recently been suggested as an opportunistic to extract bone density information and detect low bone density and osteoporosis.

Magnetic resonance imaging (MRI) is another means of osteoporosis of the spine in at-risk persons. Many individuals with low back pain who have not had DXA undergo lumbosacral MRI.

"At present, MRI and CT are basically used in research settings," said Natalie E. Cusano, MD, MS, director of the Bone Metabolism Program at Lenox Hill Hospital in New York City, noting, however, that since DXA measures bone density but not bone quality, newer approaches will likely come into play.

One newer measure already in use, she said, is the trabecular bone score (TBS), an FDA-approved technique that uses special software to image grey-scale variation in the bone of the lumbar spine. "This imaging shows if there is a lot of heterogeneous-type versus homogenous-type bone," Cusano explained. "More heterogeneous bone is an independent indicator of low-quality bone and fracture risk."

Pharmacologic Therapies

There are many effective therapies for reducing the risk of fractures, the principal goal of treatment. These include anabolic agents that build bone, antiresorptive agents that decrease bone breakdown, and agents that do both. Patients at very high fracture risk may especially benefit from anabolic drugs.

All anti-fracture therapeutics treat but do not cure the disease. Bone deterioration resumes sooner or later when a medication is discontinued -- sooner for non-bisphosphonates and later for bisphosphonates. Elevated fracture risk may still be present.

FDA-approved options include estrogen agonists/antagonists, bisphosphonates, RANK ligand inhibitors, parathyroid hormone (PTH)–receptor agonists, and inhibitors of sclerostin, a regulatory protein in bone cells that controls skeletal breakdown and formation and increases the activity of osteoclasts. While most reduce the risk of fracture in the spine, not all reduce the risk of fractures at other skeletal sites.

Patients should be stratified by fracture risk, since this influences the initial choice of treatment, the AACE/ACE guidance stresses. Although most patients start treatment because of significant fracture risk, those at very high risk may require more advanced treatment to achieve an acceptable level of protection.

Among patients at very high risk are those with a fracture in the past 12 months, those with a fracture while on approved osteoporosis therapy or while on skeleton-harming drugs such as long-term glucocorticoids, those with multiple fractures, and those with a T-score below –3.0. Others in this risk group may have a history of injurious falls or a very high fracture probability by – that is, risk for any major osteoporosis fracture of >30%.

According to the consensus statement guidelines by LeBoff and co-authors, the benefits and risks of therapy should be assessed in the context of a drug's efficacy in reducing fracture risk; the onset, magnitude, and duration of effect; and the site of optimal fracture prevention.

The newer bone-building drugs actually improve bone quality, but other drugs will reduce the risk of breakage, which is the main goal, Cusano noted.

Bisphosphonates

Bisphosphonates, composed of two phosphonate groups, are the most widely prescribed drugs for both men and women at increased risk of fracture. Bisphosphonates slow bone resorption by promoting apoptosis of the osteoclasts.

This large class includes:

• Risedronate (Actonel)

• Alendronate (Fosamax)

• Ibandronate (Boniva)

• Zoledronic acid (Zometa)

• Pamidronate (Aredia)

• Etidronate (Didronel)

Possible side effects include nausea, dysphagia, throat irritation, dizziness, abdominal pain, and heartburn-like symptoms. Intravenous bisphosphonates avoid gastrointestinal upsets but can cause fever, headache, and muscle aches. Zoledronic acid may be linked to atrial fibrillation.

Calcitonin

This is a manufactured analog of the endogenous human hormone produced by the parafollicular cells in the thyroid, and can cut the risk of spine fractures by 25%. Used with calcium/vitamin D supplements, this well-tolerated drug helps control calcium levels and is given by daily injection or in a once-daily nasal spray. Because of an association with cancer in recent studies, however, use of this medication is limited.

Denosumab (Prolia)

This manufactured monoclonal antibody prevents RANKL-RANK interaction in bone, inhibiting osteoclast formation. It is given by injection once every 6 months. Compared with bisphosphonates, denosumab produces similar or better bone density results and reduces the chance of all types of fractures. Denosumab has serious side effects, however, including cracking in the mid-femur and osteonecrosis of the jaw, and there is a higher risk of vertebral fractures after cessation.

Estrogen/Testosterone

In women, starting estrogen therapy soon after menopause can help maintain bone density. A recent of data from the large-scale Women's Health Initiative confirmed that postmenopausal hormone therapy significantly reduced the risk of any clinical fracture, major osteoporotic fracture, and fracture of the hip in postmenopausal women regardless of FRAX score or history of falls.

But since this hormone may increase the risk of breast cancer and blood clots, it is generally reserved for midlife patients with menopausal symptoms.

In older men with declining testosterone levels, testosterone-replacement therapy may slow bone loss. However, testosterone is not approved for treatment of osteoporosis.

PTH receptor agonists

PTH functions to regulate the body's calcium level. Pioneering studies showed that PTH given intermittently acts as an anabolic, stimulating bone production rather than just slowing breakdown.

Newer PTH-mimicking agents include the bone-stimulating anabolics teriparatide (Forteo), a synthetic analog of PTH, and abaloparatide (Tymlos), a synthetic PTH-related peptide. Designed to treat patients at high risk for fracture, these agents are given subcutaneously for up to 2 years. Abaloparatide, for example, was found to reduce the risk of new vertebral fractures by about 86% and non-vertebral fractures by about 43% in postmenopausal women after 18 months of therapy.

PTH receptor agonists are used only for 2 years and can have side effects, including skin reactions at the injection site, bone pain, and hypercalcemia. These agents need to be followed by anti-resorptive drugs or the bone density gained will fairly rapidly be lost.

Raloxifene (Evista)

This once-daily pill slows bone loss and can significantly reduce fractures in the spine, although not at other sites. As a selective estrogen receptor modulator it acts as an estrogen agonist/antagonist, blocking the action of this hormone in some tissues and stimulating its impact on others such as bone. Raloxifene can also reduce breast cancer risk, but may cause hot flashes and blood clots, so it is not recommended for premenopausal women.

Romosozumab (Evenity)

This newest approved anabolic drug available for bone-building, a fully human antibody, may be suitable for patients who have already suffered an osteoporotic fracture and are at risk for another. As an inhibitor of sclerostin, romosozumab uniquely both stimulates new bone production and slows old bone resorption. It is given in monthly injections, is limited to 1 year of treatment, and can cause dental and jaw problems.

In one study, romosozumab lowered the risk of vertebral fractures by a benefit maintained over the second year of the trial when it was followed by 1 year of denosumab versus placebo followed by denosumab.

For the future, the main challenge for osteoporosis, Cusano said, is getting people screened and then treated appropriately. "There hasn't been enough focus on the diagnostic significance of low-trauma fractures. Even people treated for hip fracture don't always come away with a clear recommendation for follow-up for osteoporosis," she said.

A very of medications with anti-resorptive properties is an atypical break or crack in the middle of the femur. A second rare complication is delayed healing of the jawbone, or osteonecrosis, which can occur after an invasive dental procedure.

Read Part 1 of this series: New Insights Into the Complex Biology of Osteoporosis