This is an extensive summary of current data on osteoporosis and my review of proceedings from NIH conference on 10/2018 on Preventing fractures in individuals with osteoporosis. This article is not for the impatient or weak hearted!
Many patients come to me because I am an integrative physician, hoping to escape pharmacologic therapies for osteoporosis. I do not have a magic bullet that significantly builds bone. Treatments that can potentially be of some help include lifestyle methods, nutrition, exercise, yoga, vibrational therapy, fixing hormone deficiencies, and ruling out secondary causes of bone loss. In particular daily exercise, adequate vitamin D3 with K, and a calcium-rich anti-inflammatory diet are essential to any approach to treating osteoporosis and osteopenia. While I have seen, in 23 years of clinical practice, that some patients stabilize bone loss without therapy, I have not observed significant increases of bone mass with \”natural approaches\” not involving hormones and I have only observed stabilization of bone mass with current anti-resorptive agents (which stabilize but do not build bone mass). I have only observed increased bone mass with anabolic agents or after fixing secondary causes of osteoporosis (thyrotoxicosis, hyperparathroids, hypercalciuria, nutritional malabsorption). Patients need to be compliant with lifestyle changes and therapies for any or all of these treatments to work.
What is osteoporosis and why don’t we manage this better?
Osteoporosis is a silent disease. It is diagnosed with bone mineral density test which documents that the individual has a bone density measurement that fall by 2 and ½ standard deviations or more below what is considered normal. Without testing, observable manifestations of osteoporosis include height loss, wrist fractures and vertebral fractures 10-15 years before presentation of hip fractures. Hip fractures are most problematic because they are associated with the greatest morbidity and mortality of this disease. There is a 20% likelihood of death within the year following a hip fracture.
While there has been great progress in the understanding and treatment of osteoporosis, there are profound challenges preventing adequate treatment of patients with osteoporosis. Many patients are not screened with bone mineral density tests, even after they have a hip fracture. Until recently, Medicare has not paid for preventive care of elder patients. There is low reimbursement or incentive for identifying, testing, and having a proactive approach to osteoporosis. Seven minute visits with doctors with patients with multiple problems are not conducive to opening the osteoporosis Pandora’s box. In addition, a low percentage of patient are offered therapy after hip fracture, (Solomon DH, JBMR 2014;29:1929). Many patients who are offered therapy decline it or stop using it out of disproportionate fears of side effects, felt to be caused by lay media misinterpretation of data. (Gina Kolata New York Times, June 2, 2016).
Severe side effects of bisphosphonates or denosumab are very rare (osteonecrosis of the jaw after dental extraction or procedure, and atypical fractures in the lateral sub-trochanteric area of the femoral neck (AFF)) and can occur after large doses are used in cancer therapy, or more than 5 years of low dose continuous drug therapy without thoughtful reassessment for continued need of drug or use of drug holiday. (Dell JBMR 2017, Black Endo Reviews 2018). Also certain ethnic groups may be more prone to side effects, such as the Asians, so drug selection and use of drug holidays if using a bisphosphonate is important for this ethnic group.
To put risks into a perspective that everyone can understand: the incidence of a major osteoporotic fracture in a high risk person (older, T score <2.5) is estimated at 3,100 people per 100,000 person-years, the incidence of osteonecrosis of the jaw is 1.03 per 100,000 person-years. The incidence of atypical fracture of the subtrochanteric region of the femur (AFF) after 2 years of bisphosphonate use is 2 per 100,000 person-years, and 78 after 8 years of continuous bisphosphonate use. Of note incidence of death by murder is 1.62 per 100,000 person-years (Brown JP. Canad, Fam Phys. 2014;60:324). Another variation on risk estimates of AFF after 5-8 years of bisphosphonate use is 6 per 10,000 person-years, and 129 per 100,000 person-years after more than 8 years.(Black and Adams ASBMR 9/2018.) Clearly risk increases with extended use of these drugs. Two groups have studied decrease risk of AFF after drug holidays. Risk decreases by 70-44% in the first year of discontinuing the bisphosphonate, 90-80% between 1-4 years, and 95-80% after 4 years of drug holiday. (Schilcher et al, Acta Ortho Scan, 2014, Adams ASBMR 9/2018 (Keisser-Permanente data).
Drugs that are used for osteoporosis include: estradiol (oral and transdermal) best used earlier in life at time of menopause and if no contraindications, Raloxiphene (evista), the bisphosphonates: alendronate (fosamax), residronate (actonel), ibandronate (Boniva), Zolendroic acid (Reclast), denosumab (Prolia), Anabolic agents: teriperatide (Forteo), and Abaloperatide (Tymlos), and mixed sclerostin AB ramosozumab (awaiting approval). All decrease vertebral fracture risk. Raloxiphene has been shown to decrease hip fracture risk.
Of the anabolic agents, Abaloperitide (tymlos) may be better than teraperatide (Forteo) on hip fracture risk. Bisphosphonates, raloxiphene or denisumab can be used after teriperitide or abaloperitide to stabilize bone gains after use of these agents. There is also data that Zolendroic acid decreased mortality after hip fracture.
I definitely consider bioidentical hormone replacement therapy (transdermal estradiol + /- micronized progesterone) as a preventative treatment in women with osteopenia who are still within 10 years of menopause onset and have no contraindications to HRT. This therapy is helpful and buys time before pharmacologic therapy is added.
Benefits of osteoporosis therapy: The following are the number of fractures prevented per 1000 osteoporotic women treated for 3 years based on analysis by Black and Rosen, NEJM 1/2016: Spine 75, non-vertebral 29 (hip 11), over all 100.
While all patients with low bone mineral density have a risk of fracture, the lower their bone mass, the higher the risk of fracture. At any low bone mineral density, risk is markedly amplified by age, frailty, and coexisting illnesses.
Who should be treated with pharmacologic therapy?
Patients with previous fractures. After a fracture, annualized risk of any subsequent fracture is 4.3% per year, and risk of hip fracture is 1.6% per year, during the subsequent 3-5 years.
Anyone with osteoporotic or hip fracture in the last year.
Patients with low bone densityT-score less than or equal to 2.5 and clinical risk factors (age, frailty [more than 3 falls per year], steroid use, thin and white or native American, remote history of fracture, and inflammatory conditions: Rheumatoid arthritis and diabetes).
Patients with osteopeniawhose FRAX analysis indicates 10 year risk of any osteoporotic fracture >20% or a hip fracture of >3%.
Who should not be treated with drugs approved for osteoporosis? If no risk factors and the bone mineral density T- score is more positive than minus 2.5, premenopausal women, and children.
What about Vertebral Fractures: Many patients do not know that they have had a vertebral fracture until they have a painful compressive wedge fracture. Bone experts like Dr. Felicia Cosman (OI, 2017) in NHAINES VFA Study have shown that a proactive spine imaging is required to find vertebral fractures. Five percent of women less than 60 years old have vertebral fractures, 11% in women 70-79, and 18% women over 80. Women with multiple vertebral fractures and very low bone mass are at highest risk. Being a woman and advancing age are strong factors associated with increased fracture risk.
What to do after a diagnosis of osteoporosis: After a patient has osteoporosis and fractures only conventional pharmacologic therapy has evidence-based data that show decreases in further risk of continuing to fracture. At this point the benefit of receiving therapy to treat osteoporosis and prevent further fracture is much higher that the potential risk of adverse effect. Treatment of osteoporosis-related is a life-long process.
Treating osteoporosis with drugs.
Once treatment is started it is a mutual long-term commitment. Bisphosphonate are usually paid for by insurance but are not the best option for high risk patients, or patients with disproportionate low spine bone mass relative to hip. Bisphosphonates cycles of 3-5 years are reasonable if there have been no fractures, and bisphosphonates are great game closers after anabolic therapy. Further anabolic therapy can be added to all anti-resorptives to further decrease risk of fracture.
Drug holidays from bisphosphonates
For patients who have osteoporosis and have been treated for 5 years, it is appropriate to take a drug holiday when using a bisphosphonate, like alendronate or Boniva. During this time data shows that bone mass remains stable (no bone loss over 3-5 years). The other benefit of a drug holiday is that the risk of other rare but potential complications of long term use of bisphosphonate (atypical femoral or subtrocanteric fracture and osteonecrosis of the jaw) rapidly decrease.
One thing to know before taking a drug holiday after five years of bisphosphante use is that a measurement of the bone mineral density at the hip should be made. There is a subset of patients that still have a low bone mineral density and have a persistently high risk of subsequent fracture. The lower the T-score is the higher the potential risk that the person is likely to fracture. For example, in individuals treated with Zolendroic acid (Reclast) for 3 years patients with T score less than or equal to -2.5 have a 9% risk of vertebral fracture in next 3 years whereas those with a T-score that is more positive have only a 3% risk of such fractures. For women treated with alendronate for 5 years, their subsequent 5 year risk for non-vertebral fracture (hip included) is still 29% if at the end of 5 year treatment hip their T-score is less than -2.5. Their risk of fracture is 20% if their T-score is between -2.5 to -2.0, and 10% if greater or more positive than -2.0. This is why some physicians might maintain osteoporosis therapy after 5 years, particularly for patients who have already experienced multiple fractures.
There are no drug holidays from anabolics (Teriperitide (24 months) or abaloperatide (18 months)), denosumab, or raloxiphene or estradiol. There is rapid bone loss after stopping any of these so one must use a bisphosphonate to hold on to the gains in bone mass or prevent rapid loss of gains.
For high risk patients the sequence and type of treatments matters
A problem with treatment of high risk patients is that when we use anti-resorptive agents it takes 3 years to see a protective effect and reduction of non-vertebral fracture if you receive Reclast (zolendronate: the typical dose used is 5mg intravenously once per year for 3 years) or Prolia (denosumab: the typical dose used is 60mg subcutaneous [SC] injection every 6 months for 3+… years). The expected risk reduction is only 20% (denosumab) and 25% (Reclast) (Black DM NEJM 2007;356:1809, Cummings SR, NEJM 2009;361:756) Thus for high risk patients, these types of treatments take a long time to show benefit.
In contrast, use of anabolic agents produces rapid vertebral and non-vertebral fracture risk reductions by 18-12 months: Forteo (teriperatide: the typical dose used is 20mcg SC daily) 65% and 53% reductions in fracture risk; Tymlos (abaloperitide: the typical dose used is 40mcg SC daily) 86% and 43% reductions in fracture risk, (romozozumab: the typical dose used is 210mg SC per month) 73% and 25% reductions in fracture risk (Neer R, NEJM 2001, Miller P. JAMA 2016, Cosman F NEJM 2016). Anabolic agents (teriperatide) are particularly effective when compared to bisphosphonate alendronate or residronate in preventing vertebral fracture in steroid induced osteoporosis (90%), and in acute painful vertebral fracture (50%), respectively. The same was found in the VERO trial in women with severe osteoporosis who already had vertebral fractures. Forteo effect was visible by 6 months, decreased relative risk of fracture by 48% at 12 months and 56%, when compared to residronate (bisphosphonate) (Kendle DL, Lancet;391:210, 2018). 60 % of these women had used other osteoporosis treatment, at some point in past 3 years. A similar finding is seen with romosozumab treatment for 12 months followed by alendronate 70 mg/day, 33% reduction in vertebral fracture at 12 months and 48% at 24 months compared to alendronate only treated group, and 38% reduction in hip fractures at 48 months. (Sagg KG, NEJM 377;1417,2017).
As mentioned above, for the effects of these anabolic agents to continue to be sustained one needs to add a bisphosphonate like alendronate or add Reloxifene to “close the game” (as they say in baseball).
Based on all this cumulative knowledge from these past trials and extended versions, I agree with the assessment that for individuals who have fractures with osteoporosis or osteopenia or who present with osteoporosis at very low bone mineral densities, like a T-score of -3 or less, the treatment sequence matters. For these high risk patients anabolic agents should be used first, followed by a bisphosphonate to sustain and maintain the gains.
More Advanced aspects of osteoporosis treatment
What to do for patients who continue to be high risk and or fracture while on bisphosphonates? (I am assuming, as any endocrinologist would, that secondary causes for osteoporosis have been addressed from the start). It turns out that switching the bisphosphonate for an anabolic agent may affect adversely patients who start with a very low hip bone density. Various studies show that the hip density declines in the first 12-18 months of treatment (1-3%) with teriperatide, before bone recovery is detected. (Cosman F, JBMR,2017). This effect does not happen if an anabolic agent like Forteo (teriperatide) is added to the bisphosphonate. Bone mass in fact increases in both vertebral and hip areas (Cosman F, JCEM 2009;94:3772-80.). Thus based on these data, most experts would add an anabolic agent to the bisphosphonate to avoid this resorptive effect. It is assumed that the benefit found with adding teriperatide will be echoed by adding abaloperitide or tymlos but studies specific to this question have not been done with tymlos.
What to do for patients who continue to be high risk and or fracture while on denozumab (prolia)?
Similarly, if a patient in on Denosumab (Prolia) and is then switched to anabolic teriperatide there is a drop in hip bone mineral density in first 12 months. If the patient is at risk for hip fracture or has a very low hip score, then add anabolic agent to denosumab.
When approved, you can also switch from denosomab to romosozumab as a single drug, and vice versa, but there must not be a break or placebo time because gains of 2 years are lost with one year of no treatment.
If the patient has not been on a bisphosphonate for 3 years or more or if the hip bone mineral density is in “good” shape (T score > -2.5 or 2.0/) then switching to anabolic agent alone is fine if new or painful fracture.
Other combinations
Another twist to this story is that the new drug being investigated, not yet approved in early 2019, (Romosozumab) indeed can be used alone to increase bone mass after a bisphosphonate, like alendronate, and it does not cause hip bone mineral density bone loss! (Langdahl B, Lancet 2017). This is actually very hopeful because most of us are concerned that after denosumab is started, we may not be able to stop, as there has recently been reports of occurrence of multiple vertebral fractures in individuals who stop denosumab after years of treatment.
The most effective combination to rapidly increase bone mineral density of the hip by 4% at 6 months of treatment and by 9% by 48 months is combining anabolic + denosumab for 2 years and continuing denosumab 2 years after. Although may get equivalent long term effect, but slower early increase in bone mass, if use teraperatide for 2 years followed by denosumab by 2 years. (Leder BZ Lancet 2015;386:1147-55).
How do I go about this in younger menopausal patients who have osteopenia or osteoporosis but are generally very fit and healthy?
If there are no contraindications, I generally use low dose transdermal estradiol hormone replacement therapy in my younger menopausal women to maintain their wellness and sexuality intact. This has the benefit to maintain their bone mass and prevent bone loss. Low doses are very effective. I never use oral estrogens to avoid concern of blood clot or stroke. I never use conjugated estrogens (premarin), though considered safe by conventional medicine, because it is more likely to be metabolized to estrone a more carcinogenic estrogen. Similarly, I never use “Progestins” (Provera [medroxyprogesterone], Augestin, norethindrone) because of their negative and carcinogenic effect on the breast. I always use natural progesterone in women with uteri, this is safer and protective for breast tissue.
Estradiol has not been recommended for primary treatment of osteoporosis because of the potential risks identified by the now faulty Women’s Health Initiative Study (WHI). In WHI older women (mean age 63) were given by mouth, non-bioidentical, conjugated estrogen (premarin) and non-bioidentical progestins 12 years after menopause. Initiating this therapy in older women led to a higher risk of stroke, pulmonaryemboli, invasive breast cancer, and probable dementia in comparison to placebo. As mentioned above non-biodentical progestins are dangerous. The findings seen with non bioidentical hormones have not been observed in women treated after menopause with bioidentical hormones. Please see a separate blog on this.
I also like Evista for younger women at risk of breast cancer to protect bones after menopause, but there is a risk of deep vein thrombosis (with all oral estrogens and selective estrogen modulators including osphena), so If I prescribe it I recommend an enteric baby aspirin with food. I also make sure that there is no thrombophilia. I delay “non-hormonal pharmacologic” treatment as long as possible in all patients unless they have fractured or are high risk.
A big issue is that we know that women rapidly loose bone in the first 4 years after menopause and we have not had an active way to prevent this without hormone replacement. So what can we do with someone who starts at a low bone mass and is not receiving hormone replacement therapy at menopause. A recent study this year in published in NEJM showed that Reclast every 18 months for 4 cycles stabilized bone mass in women with osteopenia, and prevented bone loss and future fractures, providing yet another choice for women who cannot or chose to not use bio-identical hormone replacement.
That was a mouthful of options and hope!
Be Well.