This is a question that comes up often in a metabolic bone disease clinic, particularly when the patient has sustained more than one such fracture.

I don’t think there is a simple answer to this somewhat rhetorical question because stress fractures tend to occur in persons healthy enough to overload their skeletons. My thinking is that damage to trabecular bone micro-architecture occurs constantly during activities of daily living but the bone remodeling process is usually able to overcome this. As micro-cracks occur osteoblasts are recruited to heal them before they can propagate into true clinically apparent stress fractures. It is only if one keeps overloading the skeleton to a point where the accumulation of micro-cracks exceeds the ability to repair the damage that stress fractures happen.

All too often I see younger women who take on a vigorous exercise program (I have had a number of patients who somehow find time to put in two or more hours of exercise every day) and sustain a stress fracture within a few weeks or months of starting their program. Undaunted they allow themselves a week or so to “recover” before starting up again. However, this time they tend to protect the injured limb and simply overload the good one, increasing their risk of another such event. In that circumstance, a metabolic bone disease work-up is probably not indicated but a complete history particularly looking for any change in menstrual function is appropriate — ie, looking for the “female athlete triad.” I face an angry response almost every time I suggest that the patient tones down his or her load-bearing exercise program.

Sustained use of corticosteroids is clearly detrimental to skeletal health since they stimulate bone resorption and inhibit bone formation, limiting the body’s ability to repair micro-damage in a timely manner. Steroids also tend to impair muscle function such that the extent to which the patient can engage in vigorous exercise is reduced. However, the disruption of the normal bone remodeling cycle is likely to lead to fractures even when skeletal loading is reduced.

Osteoporosis therapies that inhibit bone resorption, particularly bisphosphonates with a long half-life in the skeleton, are also likely to diminish the ability of the skeleton to self-repair. The skeletal response is different to that of steroid exposure in that both resorption and formation are suppressed. There is usually a delay of three months or slightly longer between inhibition of resorption and inhibition of formation, and for some time, this leads to positive skeletal balance. There is mounting evidence that over time, in some patients, there is no longer any positive skeletal balance. To me, this should be a warning sign that it is time to give the skeleton a rest from therapy as I have discussed before. As long as bone mineral density is continuing to increase between successive DXA studies performed two years apart, the bisphosphonates should be continued.

Once you have demonstrated with successive DXA studies that there is no ongoing increase in bone mass, give serious consideration to temporarily discontinuing the therapy and give the remodeling cycle a chance to recover. Remember this is “off label” use of bisphosphonates so make certain you understand the rationale for interrupting therapy and have carefully explained that to the patient. Take the time to note that discussion carefully in the patient’s record. At the time when positive skeletal balance is no longer evident, your patient may still have a worryingly low bone density and be at increased risk for fracture. This is the time to remind the patient about safety and fall prevention as well as maintaining an adequate calcium, vitamin D and protein intake. If you and/or the patient are still concerned about fracture risk, consider initiating therapy with teriparatide. The insurance company may balk at first but not responding to bisphosphonates (which you have demonstrated with serial DXA) is an indication to use teriparatide in patients with increased risk of fracture.

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It is interesting how similar cases occasionally present in a series of pairs or triples. After not having seen hypothyroidism with persistently elevated thyroid-stimulating hormone levels while on high-dose levothyroxine therapy for several months, three cases came to see me in the same week. All had TSH >40 mIU/L despite being prescribed high-dose levothyroxine. The gentleman in my last post was not taking his levothyroxine daily because he could not afford to fill his prescription.

Later that same week, I saw a woman with mild dementia. She lives independently and has someone to help with cooking and cleaning. However, there is no one to assure that she takes her medications. Her TSH remains high because she cannot remember to take her levothyroxine and other medications every day.

Levothyroxine has an approximate seven-day half-life but the biologic effect may be longer. This means that it may be less important what exactly is taken on any particular day compared to what has been taken over the past week. Because of this, it is possible to give levothyroxine once or twice a week as directly observed therapy when necessary to ensure compliance.

There have only been a few case series with small numbers of patients reporting the safety and efficacy of once-weekly levothyroxine. Studies have shown that a single dose of as high as 3 mg of levothyroxine is well tolerated. Levels of free thyroxine are higher in the days immediately following the dose. However, as levels of T₄ decrease before the next dose, peripheral conversion to active triiodothyronine becomes more efficient. Such autoregulatory mechanisms maintain euthyroidism. Patients on once-weekly therapy tolerate it well and without evidence of cardiac symptoms or toxicity. Some authors suggest that a slightly larger dose than seven times the normal daily dose may be necessary.

In the patient described above, we will first arrange to have pill boxes filled by her pharmacist. If she continues to be unable to remember to take her levothyroxine, family members have volunteered to witness her taking her levothyroxine as directly observed therapy twice a week. I rarely have to resort to once- or twice-weekly directly observed therapy. However, I have used it a few times in the past with success when all else failed.

For more information:

• J Clin Endocrinol Metab. 1997;82:870-875.
• Postgrad Med J. 2007;83:e3.

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I saw an elderly man with thyroid-stimulating hormone levels that have remained in the 20 mIU/L to 40 mIU/L range, despite being prescribed 200 mcg or more of levothyroxine per day. The patient swore he was taking the levothyroxine every day as prescribed. His primary care physician was at a loss so he sent the patient to me.

This is a situation in which taking a thorough history is essential. Lack of response to levothyroxine therapy occurs due to variety of reasons. Medications such as bile acid sequestrants, sucralfate and others can interfere with absorption, as can taking medication with food, dietary fiber, soy or nutritional supplements containing iron. Gastrointestinal malabsorption, such as from celiac sprue or short bowel syndrome, can decrease absorption of levothyroxine. Increased clearance may occur from phenobarbital, phenytoin, carbamazepine and rifampicin. Weight gain or pregnancy can increase demand.

The most common reason for lack of response to levothyroxine, however, is non-compliance with therapy. Most often this is due to patients simply forgetting to take doses, such as an elderly individual with mild dementia. Pillboxes and other reminders can be very helpful in this situation.

In others, there is resistance to taking medication or pill of any kind. The dichotomy of hypothyroid patients who are sent to me is interesting. Many patients who have high-normal or slightly high TSH are asking for dose increase because of intolerable symptoms, which we oblige. There are a few, however, who refuse to take anything at all, even after I explain to them how much better they would feel. It amazes me that they would prefer to suffer with untreated hypothyroidism, even with a TSH of ≥40 mIU/L.

After tactfully asking this gentleman again if he was taking as prescribed, he confessed to skipping doses because he could not afford his prescription. We provided him with all the samples we had of his dose and will be retesting TSH in several weeks. Thyroid hormone replacement therapy is not costly compared to other prescription medications. However, it does not matter how inexpensive a medication is, if you cannot afford it then you cannot take it.

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