These Other Medical Conditions and Treatments Can Also Increase Osteoporosis Risk

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Currently there is a knowledge gap about the detrimental impact of various other conditions and diseases on osteoporosis risk. “In general, primary care and subspecialists have a peripheral awareness of their prescribed treatments’ impact on bone health, but they may or may not be aware of the long-term effects,” said Susan B. Williams, MD, of the Cleveland Clinic. “The real awareness gap, however, lies in the fact that osteoporosis affects one in two women over age 50 and one in four men, with related fractures accounting for 432,000 hospital admissions a year in the U.S.”

Many disorders involve systemic inflammation treated with corticosteroid therapy, impaired vitamin D and calcium metabolism, and reduced uptake of essential nutrients in the intestines, all of which are inimical to bone. Clinicians should be aware of the need to assess vitamin D status, bone density, and fracture risk in patients in treatment for, or with a history of, a range of diseases that impact bone health.

Sex Hormone Status

“The most common medical condition related to bone loss and osteoporosis is estradiol deficiency in women most commonly due to menopause, followed by inflammatory conditions treated with glucocorticoids,” said David B. Karpf, MD, of Stanford Medicine in California. “Estradiol deficiency results in a two- to three-fold increase in the rate of bone turnover and a negative bone balance, as the increase in bone resorption exceeds the increase in bone formation. That leads to trabecular and cortical thinning, increased cortical porosity, and trabecular perforation.” These bone changes at the tissue level result in lower bone mass and increased risk of fracture.

Inflammatory Conditions, Diabetes, and Other Diseases

“Systemic inflammatory conditions such as rheumatoid arthritis, which is included as a clinical risk factor on the multifaceted FRAX [Fracture Risk Assessment Tool] calculator of 10-year fracture risk, roughly double the fracture risk, as do type 1 and type 2 diabetes. And the latter appear to do so independently of bone mineral density,” Karpf continued.

Other systemic inflammatory conditions — whether autoimmune or not — such as inflammatory bowel disease and ankylosing spondylitis probably carry a risk comparable to that of rheumatoid arthritis, he added.

The increased fracture risk in type 2 diabetes mellitus appears to be multifactorial and includes a greater chance of falling due to neuropathy, diabetes therapies, and decreased bone formation due to adiposity. “Making more adipocytes invariably means making fewer osteoblasts,” Karpf said.

Williams noted that insulin-sensitizers such as the thiazolidinediones used to treat type 2 diabetes can also diminish bone formation. These should be avoided in patients at increased fracture risk. Moreover, insulin and sulphonylureas open the door to hypoglycemia with subsequent falls and traumatic fractures.

“Long-term suppressive therapy with thyroxine for underactive thyroid is another risk factor, as is chronic hypercalciuria,” Karpf noted. “Many such patients should be prophylactically treated to decrease their risk of fractures while on these therapies.”

“Other drugs, such as those used to treat depression, and proton-pump inhibitors for stomach acid suppression, have been associated with higher fracture risk, although the possible causative mechanisms are not as clearly understood,” Williams said. Widely used anticoagulants such as heparin and warfarin have also been linked to fracture risk. In addition, some antiretroviral therapies used in HIV are associated with bone loss and osteoporosis.

Cancer

Other than bone cancer or cancer metastatic to the skeleton, the detrimental effect related to osteoporosis is primarily due to therapy, with the biggest risk from hormone suppressors such as aromatase inhibitors for breast cancer as well as orchiectomy or gonadotropin-releasing hormone suppressors in prostate cancer, Karpf noted. “The best example is aromatase inhibitors. By further decreasing estrogen levels in postmenopausal women, it increases the rate of bone turnover, resulting in more rapid loss of bone mass and impaired bone quality, and an apparently faster resolution of the effects of bisphosphonates.”

Williams added that although cancers can spread to the bones, “far more commonly it’s the chemotherapeutic agents used to treat cancer that can be toxic to bone and result in loss of bone quality and strength.”

Do most patients with the above conditions need to take medications to protect their bones regardless of their age and to have regular bone density and vitamin D checks?

“It would be appropriate to obtain a baseline dual-energy x-ray absorptiometry on any patient starting high-dose steroid therapy, a woman starting aromatase inhibitor therapy, or a man undergoing anti-testosterone therapy for prostate cancer,” Karpf said. “And to consider treating them for the duration of their hormone-lowering therapies with, for example, a bisphosphonate.”

Calculating Risk

What is the main takeaway message for physicians treating patients with any of the conditions associated with osteoporosis?

“Use the FRAX calculator to calculate 10-year risk of fractures, clicking on the rheumatoid arthritis box even if your patient has a different systemic inflammatory condition or diabetes,” Karpf said. This is one strategy to assist in adding in the additional risk, although this is not a proven method to do so.

It’s also important to understand that while the high-risk threshold for 10-year risk of major osteoporotic fracture (the numerator in the FRAX result) is indeed ≥20%, the high-risk threshold for 10-year risk of osteoporotic hip fracture (the denominator in the FRAX result) is not ≥3%, Karpf stressed. “This figure derives from two cost-effectiveness studies. Use an 8-10% 10-year risk for the threshold for hip fracture,” he said.

“And to understand that certain medications (most commonly glucocorticoids, aromatase inhibitors, testosterone-suppressive therapies in males, and chronic suppressive thyroxine treatment) can all increase the risk of fractures by substantially increasing the rate of bone turnover,” Karpf said.

Checklist of Exacerbators

Many predisposing conditions occur in young people and impair their attainment of peak bone density in early adulthood, thereby leaving them at later risk for osteoporosis. These include:

• Autoimmune and other inflammatory conditions: For example, type 1 diabetes, rheumatoid and psoriatic arthritis, lupus, multiple sclerosis, Grave’s disease, Crohn’s disease, and ulcerative colitis and associated steroid treatment.

• Inflammatory lung diseases such as asthma and emphysema also result in curtailed physical activity and reduced weight-bearing exercise. Even the use of strong topical corticosteroids for severe eczema can interfere with healthy bone remodeling and increase fracture risk.

• Digestive disorders: Celiac disease damages the lining of the gut, reducing the absorption of protein, calcium, and vitamin D. Nutrient malabsorption can be an issue in Crohn’s disease and ulcerative colitis. Bariatric surgery results in bone loss not only from the weight loss that ensues but also because of alterations in calcium and mineral metabolism.

• Type 1 and 2 diabetes mellitus: Long-term exposure to a diabetic environment leads to changes in bone metabolism and impaired bone micro-architecture through various mechanisms on molecular and structural levels. These changes predispose the bone to increased fracture risk and impaired osseous healing. Serum levels of osteocalcin, a marker of bone formation, are decreased in both type 1 and type 2 diabetes compared with healthy controls.

• Hyperthyroidism: The overproduction of thyroid hormone accelerates the breakdown of bone.

• Chronic kidney disease: Changes in mineral and metabolism as well as bone structure develop early in the course of chronic kidney disease. These include abnormalities of calcium, phosphorus, parathyroid hormone, and/or vitamin D, as well as abnormalities in bone turnover, mineralization, volume, linear growth, and strength. In addition, damaged kidneys result in a buildup of phosphorus that replaces calcium in the blood. In response, the parathyroid gland releases parathyroid hormone, which takes calcium out of the bones to correct the imbalance.

• Liver disease: Chronic liver disease is associated with a high risk of osteoporosis and hip fracture through mechanisms ranging from osteoclast-mediated bone resorption to bilirubin-related inhibition of osteoblast proliferation. A poorly functioning liver leads to vitamin D deficiency and reduced calcium levels in the body, which in turn prompt the body to make up the shortfall of calcium from bones. Again, corticosteroids for liver inflammation inhibit the osteoblasts and interfere with vitamin D metabolism and calcium absorption.

• Cancer surgery: Oophorectomy or orchiectomy results in sex hormone loss and increased risk.

• Seizure disorders: Taking high doses of anti-epileptic drugs over the long term may reduce the level of vitamin D in the blood and increase the risk of developing osteoporosis. Anti-epileptics accelerate vitamin D breakdown.

A Converse Effect?

As for a possible risk-heightening effect of osteoporosis on other conditions, previous research from China and Germany found that this skeletal condition may be a risk factor for dementia.

And a recent meta-analysis found that after adjusting for sex and other parameters, decreased bone mineral density was significantly associated with an increased incidence of atherosclerotic vascular abnormalities. The authors suggested that osteoporosis is an independent predictor of cardiovascular disease risk in both men and women.

Those findings are far from established, however, cautioned Karpf, and should not be used to raise anxiety and alarm people unnecessarily.

“When osteoporosis is severe, it can make ambulation difficult and even breathing difficult in those who develop severe kyphosis,” Williams said. “But for most individuals with osteoporosis, in the absence of fractures there are generally no additional risks of disease.”

Closing the Gap

Williams said she advises subspecialists in gastroenterology/hepatology, oncology, women’s health, organ transplant, and bariatric surgery to remain aware of the diseases, surgical procedures, and medications that raise risk and discuss them with an osteoporosis specialist: “They should build specific care paths into practice that will ensure every at-risk patient is assessed early in the diagnosis and treatment process,” she said.

Read previous installments in this series:

Part 1: New Insights Into the Complex Biology of Osteoporosis

Part 2: The Latest on Osteoporosis Treatment and Diagnosis

Part 3: Osteoporotic Fragility Fractures

Part 4: Case Study: First-Time Mom’s Severe Low Back Pain After Breastfeeding

Part 5: As Men Live Longer, Osteoporosis Looms Larger

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